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    • 专利摘要:
    PHARMACEUTICAL EMULSION COMPOSITIONS WITH LOW OIL CONTENT THAT UNDERSTAND PROGESTOGEN The invention relates to a ready-to-use, sterile, ready-to-use oil-in-water emulsion composition for parenteral administration, comprising:. 0.015 to 0.5% by weight / volume of progesterone; . 0.5 to 10% by weight of oil, wherein the oil comprises at least 85% by weight / weight of triglycerides; . 0.0425 to 4.1% by weight / volume of phospholipid; . 80 to 99.4% by weight / volume of aqueous medium; wherein the composition has an osmolarity in the range 200-1000 mOsm / kg. The invention further relates to the use of the aforementioned composition in therapeutic or prophylactic treatment, the said treatment of which comprises the intravenous administration of the pharmaceutical emulsion.
    公开号:BR112012027279B1
    申请号:R112012027279-9
    申请日:2011-04-26
    公开日:2020-12-29
    发明作者:Laura Pickersgill；Eva-Maria Di Hoiser；Georg Achleitner
    申请人:Besins Healthcare Luxembourg Sarl；
    IPC主号:
    专利说明:

    FIELD OF THE INVENTION
    The invention relates to pharmaceutical compositions that comprise a progestogen, and to the therapeutic or prophylactic treatment of mammals that comprises the parenteral administration of a respective pharmaceutical composition. The compositions according to the invention are particularly suitable for the treatment of a traumatic injury to the central nervous system. BACKGROUND OF THE INVENTION
    Traumatic Brain Injury (TBI) is a non-degenerative, non-congenital aggression in the brain, of an external mechanical force, possibly leading to permanent or temporary deficiencies, cognitive, physical and psychosocial functions with a reduced or altered associated state of consciousness (Brown, AW, et.al, 2008, Arch. Phys. Med. Rehabil., 89 (Suppl 1), S3-8). TBI is the leading cause of death and disability in the world. It is estimated that more than 1.5 million Americans suffer a TBI each year, and the incidence of TBI in other industrialized countries is comparable to the USA (Traumatic Brain Injury: Methods for Clinical and Forensic Neuropsychiatric Assessment, p.2, Granacher, ed., CRC Press 2003). For example, in Europe, there are about 66,000 deaths per year, attributed to TBI (Socin, D.M., et al. (1995). JAMA 273 (22), 1778-1780). Some patients have a long-term or lifelong need to get help to perform activities of daily living as a result of TBI.
    Despite the enormity of the problem imposed by TBI, there are currently no drugs approved as effective in improving mortality, or in improving post-TBI outcomes. However, two recent clinical trials have demonstrated the success of treating TBI with the steroid hormone progesterone (Xiao et al, 2008, Crit Care, 12: R61; Wright et al Ann. Emerg. Med. 2007, 49: 391-402 ). Both studies demonstrated that progesterone is safe, and well tolerated in patients with TBI, and that the administration of progesterone to patients with TBI leads to decreased mortality.
    In addition, patent applications W02006 / 102644, WO2006102596 and W02008 / 039898, describe methods for the treatment of TBI by parenteral administration of progestogen.
    The most effective route of administration of progestogens such as progesterone is parenteral, or intravenous. However, the hydrophobic nature of the progesterone molecule, and, consequently, its poor solubility in water, presents formulation limitations. Aqueous solutions do not offer formulations capable of delivering effective therapeutic doses of progesterone to patients. However, progesterone is sufficiently lipophilic to allow therapeutically effective concentrations to be prepared in hydrophobic solvents, such as triglyceride-based solvents.
    Administration of hydrophobic drugs by intravenous oil-in-water infusion is known in the art. Examples include Taxol® and Abraxane®, which are nanoformulations of the chemotherapy drug paclitaxel, designed for intravenous administration, and Diprivan®, which is a lipid emulsion formulation of the propofol anesthetic marketed by APP pharmaceuticals, IL, USA. The intravenous administration of progesterone with an oil-in-water emulsion has also been described previously (Wright DW et al. Supra, Trotter et al, Journal of Clin. Endocrinol. & Metab. (1999) Vol.84, page 4531 ).
    The ProTECT study (Wright et al Ann. Emerg. Med. 2007, 49: 391-402) used a 2-component system, in which progesterone is first dissolved in an alcoholic solution (first component), and this alcoholic solution of progesterone is subsequently injected into the commercially available lipid emulsion, Intralipid® 20% (Fresenius Kabi, Sweden) (second component), and mixed manually (as by stirring), shortly before intravenous administration of alcoholic solution / emulsion mixture. There are several disadvantages to using this preparation method.
    First, the administration of alcoholic solutions to patients with TBI is not desirable. Second, during the presence of progesterone alcohol solubilizing aids, low shear manual mixing does not allow all progesterone to enter the oil phase. Consequently, these emulsions are capable of solubilizing only a limited amount of progesterone, and large amounts of lipids must therefore be administered in order to achieve the desired serum progesterone levels. However, the administration of large volumes of emulsion and / or large amounts of lipids to the patient can have serious consequences, such as the induction of hyperlipidemia or edema.
    The patient is, as a result, exposed to an undesirable lipid and / or liquid load, and is placed at risk for adverse reactions.
    In addition, undissolved progesterone is susceptible to crystallization and, subsequently, oxidation in aqueous phase, causing not only high levels of particles to accumulate in the composition, but also high levels of degradation products of the active ingredient. In reality, it has been shown that when an alcoholic progesterone solution is injected into a commercial lipid emulsion formulation (such as Intralipid® 20%), a fraction of the hormone is in the crystalline form, rather than staying solubilized in the emulsion. This non-solubilized progesterone has been reported to be adsorbed on the surface of infusion bags and feed ducts. The observation that not all progesterone enters the oil phase of the emulsions of these two components, leads to uncertainty regarding the concentration of progesterone reached in the final composition, and the bioavailability of the hormone.
    Finally, due to stability problems, the lipid-progesterone mixture of 2-component systems should be prepared just a few hours before administration (ie, the first component is added to the second component, and these are mixed within hours of use) , as the resulting mixture cannot be stored at room temperature. It is both time-consuming and inconvenient for doctors to prepare these mixtures on demand and is particularly satisfactory in the context of TBI therapy, where immediate treatment may be important for the patient's outcome.
    Alternative methods for manufacturing hormone-containing emulsions describe incorporating the hormone directly into the oil during the manufacture of the lipid emulsion.
    WO 96/10991 describes pharmaceutical compositions for transmucosal administration of estradiol in combination with a progestin.
    WO 01/28555 describes oil-in-water emulsion systems for the supply of polyfunctional active ingredients. Emulsions comprise, in addition to a
    active ingredient, polarity modifiers, capable of modifying the interaction between the polyfunctional active ingredient, and the oil phase, which serves as a bridge to reduce the effects of the polarity difference between the active ingredient and the oil.
    US 2007/0071777 describes a method for making a 20% lipid emulsion comprising progesterone, which serves as a stock solution which is used to prepare (by dilution) a 5% lipid emulsion, which is suitable for administration.
    CN101152186 describes the use of the surfactants Solutol S15 or poloxamer 188 in the preparation of injectable progesterone formulations. While the use of these surfactants achieves a high solubility of progesterone, the intravenous administration of high concentrations of these surfactants is associated with undesirable side effects, including moderate elevation in the release of histamine, hives and anaphylactic reactions (pruritus, erythema).
    Another method known in the art to 'increase the solubility of progesterone in lipid emulsions, is the use of organic solvents. Progesterone is highly soluble in benzoic acid or its derivatives. For example, JP 60-258110 describes the use of benzyl benzoate to increase the solubility of progesterone in a lipid emulsion. However, since benzyl alcohols and benzyl benzoate are generally toxic and known to cause allergies, their inclusion in compositions for parenteral administration is considered a serious danger.
    From this knowledge, the specialist of the technique is faced with several intrinsic problems of emulsions. For example, in most conditions, emulsions are thermodynamically unstable, since spontaneously agglomerated droplets lead to complete phase separation. The tendency towards phase separation and agglomeration presents problems with storage and handling, and increases the likelihood that the pharmaceutical emulsions initially prepared properly will remain in a less ideal, less effective and poorly characterized state by the final administration to a patient. . The presence of hydrophobic active agents in the emulsion, such as progesterone, further worsens these problems, since the drug itself destabilizes the emulsion. It therefore remains extremely difficult to formulate heat-sterilizable, storage-stable emulsions, capable of providing sufficiently high doses of therapeutically useful progesterone, and at the same time, safe for parenteral administration, and especially intravenously.
    None of the formulations known to date provide pharmaceutical compositions suitable for parenteral administration, which provide progestogen in a sufficiently high concentration, while exposing the patient to a minimal lipid and / or volume load. None of the formulations known to date provide pharmaceutical compositions suitable for parenteral administration, which demonstrate sufficient physical and / or chemical stability to allow heat sterilization and long-term storage of the emulsions.
    There is still a need for progesterone formulations that are sufficiently, chemically and physically stable that they can be sterilized in an autoclave and stored for extended periods of time, preferably at room temperature, before being used.
    In addition, there remains a need for low oil formulations that provide higher doses of progesterone by volume of lipids, so that therapeutically effective concentrations of progestogen can be administered to an individual, while exposing the patient at the lowest possible lipid load. OBJECTIVES OF THE INVENTION
    It is an object of the present invention to provide low oil content pharmaceutical emulsion compositions comprising progestogens, which are suitable for parenteral administration.
    It is an objective of the present invention to provide low oil content pharmaceutical emulsion compositions comprising progestogen, with an improved safety profile.
    It is still an object of the present invention to provide oil-in-water emulsions comprising progestogens that are sterilizable by heat.
    It is also an objective of the present invention to provide oil-in-water emulsions, which comprise progestogens with better storage stability, in such a way that they can be supplied in a ready-to-use form and stored for extended periods of time, before use.
    Another objective of the present invention is to provide improved pharmaceutical emulsion compositions, suitable for parenteral administration, capable of delivering high doses of progestogen per unit of oil administered.
    It is an additional object of the present invention to provide cost-effective compositions for safe, effective and convenient parenteral administration of progestogens to individuals. More specifically, it is an objective of the present invention to provide compositions for parenteral administration, which provide a greater availability of the progestogen contained therein (such as, for example, good pharmacokinetics and bioavailability, as may be reflected in serum hormone levels and / or plasma concentrations), whereas individuals' exposure to the compositions is administered at a lower lipid and / or volume load than the prior art compositions.
    It is a further object of the present invention to provide a method for the treatment of individuals with TBI.
    It is an object of the present invention to provide a method of making oil-in-water emulsions that comprise progestogen. SUMMARY OF THE INVENTION
    The present invention provides pharmaceutical compositions comprising progestins, such as progesterone, wherein said compositions are in the form of an emulsion comprising an aqueous phase, an oil and a surfactant. The compositions of the present invention, advantageously, have a low oil content, are ready for use, heat sterilizable, stable under storage, and safe for injection.
    The present invention also provides methods for the parenteral administration of the pharmaceutical compositions of the present invention. Such methods advantageously expose the individual to which they are administered, to a lower lipid level than the prior art compositions. The compositions of the present invention advantageously allow a greater concentration of progesterone to be supplied per unit of oil and / or volume by an individual in need thereof.
    The present invention is also directed to methods of treating conditions of the central nervous system and, especially, traumatic brain injury, with the compositions of the present invention, and with a method for the manufacture of the pharmaceutical compositions of the present invention. DETAILED DESCRIPTION OF THE INVENTION
    The present invention provides pharmaceutical compositions comprising progestogens, wherein said compositions are in the form of an emulsion comprising an aqueous phase, an oil phase, and one or more surfactants.
    One embodiment of the present invention provides a ready-to-use, sterile, ready-to-use, oil-in-water, emulsion composition for parenteral administration, comprising: • 0.015 to 0.5% by weight / volume of progesterone; • 0.5 to 10% by weight / volume of oil, where the oil comprises at least 85% by weight / weight of triglycerides; • 0.0425 to 4.1% by weight / volume, preferably 0.064 to 3.4% by weight / volume, of phospholipid; • 80 to 99.4% by weight / volume of aqueous medium; wherein the composition has an osmolality in the range of 200 to 1000 mOsm / kg. This particular embodiment of the present invention is referred to herein as the "progesterone modality".
    Another embodiment of the present invention provides a sterile, pharmaceutical, oil-in-water emulsion composition for parenteral administration, comprising: • an oil; • an aqueous phase; • a progestogen, preferably progesterone; where progestogen: the weight / weight ratio of oil is greater than 1:32, and where the composition contains less than 2.5% by weight / volume of benzyl benzoate, and preferably contains less than 1.5% by weight / weight of polyethylene glycol 15-hydroxystearate. This second modality is referred to here as the "progestogen / oil modality". DEFINITIONS
    The term "oil" as used herein is easily interchangeable with the terms "lipid" and "fat", and refers to lipophilic high-boiling organic compounds that are liquid at body temperature (for example, about 37 ° C), and are pharmacologically acceptable in injectable formulations. The oils of the present invention comprise both glycerides and partial glycerides, residues of fatty acids and non-glycerides (such as cholesterol), as well as mixtures thereof. Phospholipids, unless otherwise stated, are not covered by the term "oil" as used herein.
    The term "oil-in-water emulsion", as used herein, refers to a colloidal dispersion system in which the liquid oil is dispersed in droplets (discontinuous phase) in an aqueous medium (continuous phase). -
    As used herein, the singular forms "o", "a", "um" and "uma" designate both the singular and the plural, unless expressly indicated to designate only the singular.
    As used herein, the phrase "therapeutically effective amount" means the dosage of the drug that provides the specific pharmacological response for which the drug is administered to an individual in need of such treatment. It is emphasized that the therapeutically effective amount or therapeutic level of a drug is not always effective in treating the conditions / diseases described herein, even if such dosage is considered to be a therapeutically effective amount by those skilled in the art. For convenience only, dosages, amount of drug administration, therapeutically effective amounts and exemplary therapeutic levels are provided below, with reference to adult human subjects. Those skilled in the art can adjust these amounts according to standard practices, as needed, to treat a specific individual and / or the condition / disease.
    The term "phospholipid" as used herein, refers to a glycerol ester with one or two fatty acids and a phosphate ion. In addition to glycerol-derived phospholipids, the term "phospholipid" as used herein also comprises sphingomyelin. The "aqueous medium", as used herein, refers to a liquid containing water.
    The term "low oil content" as used herein, refers to compositions that have a total lipid content by weight / vol. less than or equal to 10%.
    The term "high oil content" as used herein refers to compositions that have a total lipid content by weight / vol. more than 10%.
    Unless otherwise stated, whenever reference is made in this document to "percentage weight by volume" or "% weight / vol.", These terms describe the mass of the component in g per 100 mL of the composition in which it is contained .
    Unless otherwise stated, whenever reference is made in this document to "weight percent by weight" or "weight% by weight", these terms denote the mass of a component as a percentage of the mass of the composition, where the component is contained.
    Whenever "volume-weighted fat percentage> 5 μm", or "PFAT5" is referred to here, what is meant is that the weighted percentage by volume of dispersed fat has a diameter of more than 5 μm, measured according to the method described in USP, chapter <729>, Method II, using the Accusizer (780 Automatic Particle Sizer).
    Whenever "PCS" or (Photon Correlation Spectrometry) is referred to here, what is meant is that the PCS is measured according to the method described in USP, Chapter <729> Method, I, using the Zetasizer 1000 HSA (Malvern Instruments).
    Whenever "D [4.3]" (median diameter based on volume) or d (0.5) (average diameter based on volume) is referred to here, what is meant is that D [4.3], or d (0, 5) is measured according to the method described in USP <429> (particle size light diffraction measurement), using Mastersizer 2000 with the Hydro S dispersion unit (Malvern Instruments).
    Whenever "zeta potential" is referred to here, what is meant is that the electrokinetic potential in colloidal systems is as determined experimentally using Zetasizer 1000 HAS (Malvern Instruments).
    Whenever the term 'crystalline solid free'. ' is used here, it is understood that the emulsions of the present invention meet the standards for particle size and liquid injection counting (USP 788, Method 2 - Microscopic particle counting assay).
    The compositions according to the present invention are suitable for parenteral administration, especially intravenously. Consequently, the use of the emulsions of the present invention for parenteral administration is a second embodiment of the invention. The invention provides methods for treating a traumatic CNS injury, more particularly, a traumatic brain injury (TBI), by administering to a respective individual an emulsion comprising progestin in a therapeutically effective amount. The treatment of other central nervous system disorders and symptom relief is also contemplated, as will be discussed later.
    The invention further provides a process for preparing oil-in-water compositions that comprise progestogen.
    The emulsion compositions according to the present invention, advantageously, have a low oil content, in such a way that less lipids are supplied to the individual per unit volume, so that adverse side effects such as hyperlipidemia can be avoided. . The emulsion compositions according to the present invention can advantageously be sterilized by heat in an autoclave at 121 ° C for 15 min., Without compromising the physical or chemical integrity of the emulsions. Autoclaving sterilization is not only beneficial in terms of microbiological safety, but it is also more cost effective.
    The emulsion compositions according to the present invention are advantageously provided in a sterile, ready-to-use form, and have a shelf life of 1 or 2 years at room temperature.
    In one embodiment, the emulsion compositions of the present invention advantageously achieve improved solubility of the progestin in oil, while maintaining, or improving, the chemical and / or physical stability of the emulsions. In other embodiments, the emulsion compositions according to the present invention advantageously have a high proportion of progestin to oil, such that the desired levels of serum progestin can be achieved with the minimum of oil administered.
    In addition, the emulsion compositions of the present invention have benefits from the safety advantages over the prior art, in which, for example, a) the individual with TBI is exposed to less lipid per unit of progestin in administration, b ) the emulsions meet the standards for particle size and liquid injection counts, USP 788, method 2 and / or have a lower level of progestogen crystals, of the emulsion compositions c) have a low PFAT5 value, d) have the lower levels of chemical impurities, e) can be autoclaved using the gold standard method for microbiological safety, f) do not potentially comprise alcohol or organic solvents. toxic, and / or g), the compositions can be stored without compromising the physical stability of the emulsion.
    Administration of the compositions of the present invention advantageously provides a better consistency in the dosage of the patient, compared to the compositions of the prior art. This is achieved by optimizing the progestin to the oil, for the proportion of phospholipids in the emulsions, so that the progestin is completely solubilized in the oil phase and is, therefore, fully bioavailable.
    The administration of the pharmaceutical compositions of the present invention allows greater doses of progestogen to be administered, per unit volume and / or per unit of oil, in relation to the emulsions of the prior art, therefore, a higher level of serum progestogen can be obtained, and a lower level of plasma triglycerides can be obtained, as compared to the administration of prior art compositions. Composition Components Progestogen used in the "progestogen / oil modality"
    Compositions according to the above embodiment of the present invention comprise progestogen as an active pharmaceutical ingredient (API). As used here, "progestogen" includes both natural progesterone and synthetic progestogens. In general, progestogens have general Formula I, where Xi and X2 are independently selected from COCH3, OCOC5H11, OH, C = CH, OCOCH3, H, CH2C = N; where X3 is selected from H, CH3 or Cl; wherein X4 is selected from H, OH, or CH3; and where X5 is selected from CH3 or CH2CH3. Progestogens may contain ring structures with one or more double bonds, such as between carbons 3 and 4, 4 and 5, 5 and 6, 6 and 7, 5 and 10, 10 and 9, and / or 15 and 16. Formula I

    These progestogens include, for example, progesterone, and progesterone derivatives, such as 5-alpha-dihydroprogesterone, 6-dehydro-retroprogesterone (didrogesterone), hydroxyprogesterone caproate, levonorgestrel, norethindrone, norethindrone acetate, noretinodrelone, norgestrel, norgestrel, norgestrel, norgestrel, norgestrel, , and megestrol. The progesterone of the present invention also includes, but is not limited to changes that produce 17alpha-OH esters of progesterone, as well as modifications that introduce β-α-methyl, 6-methyl, 6-ene and 6-chloro substituents into progesterone, and / or 19-nor-progesterones. In addition, non-limiting examples of synthetic progestogens include norethindrone (Micronor®), norgestrel (Ovrette®), levonorgestrel (Norplant®, ethinyl estradiol çom; Alesse®, Nordette®), gestodene, medroxyprogesterone acetate (Provera®), promegestone, nomegestrol acetate, linestrenol, and dienogest.
    In one embodiment, the progestogen is selected from the group that; consists of progesterone, norethinodrel, norethindrone acetate, medroxyprogesterone, medroxyprogesterone 17-acetate, levonorgestrel, didrogesterone, hydroxyprogesterone caproate, norethindrone, gestodene, nomegestrol acetate, promegestone, dienogest, megmadolone and chlormadin, mixtures.
    In a preferred embodiment, the progestogen is selected from the group consisting of 5-alpha-dihydroprogestsrone, medroxyprogesterone, didrogesterone and progesterone, and / or mixtures thereof.
    In a highly preferred embodiment, the progestogen is progesterone. Progesterone
    The term "progesterone" as used herein refers to a member of the progestin family that has the following Formula II structure: Formula II

    Progesterone is also known as D4-pregnene-3,20-dione; delta-4-pregnene-3,20-dione, or pregn-4-ene-3,20-dione. In an even more preferred embodiment, the progesterone is micronized. Proquina (Mexico) is a supplier of micronized progesterone.
    Progestogen (including progesterone)
    The progestogen of the present invention can be in the form of a pharmaceutically acceptable salt.
    Compositions according to the "progestogen / oil modality" adequately comprise an amount of progestogen of at least 0.015% and not more than 0.5% by weight / vol.
    Preferably, the compositions according to both "progestogen / oil modality" and "progesterone modality" comprise a quantity of progestogen / progesterone of at least 0.03%, more preferably, at least 0.05%, still more preferably at least 0.1%, more preferably at least 0-16% by weight by total volume (weight / vol.).
    The compositions according to the present invention preferably comprise an amount of progestogen / progesterone that is less than or equal to 0.4%, more preferably less than or equal to 0.3%, even more preferably less than or equal to 0 , 25% in (weight / vol.).
    In a particularly preferred embodiment, the compositions according to the present invention comprise from 0.2% by weight by total volume of the progesterone, the micronized progesterone, preferably. Other pharmaceutically active ingredients
    The compositions according to the present invention can comprise one or more other therapeutic ingredients (APIs), such as other neurotrophic and / or neuroprotective agents. Such agents include, for example, compounds that reduce the excitotoxicity of glutamate, and improve neuronal regeneration. Such agents can be selected from, but are not limited to, the group comprising growth factors. By "growth factor" is meant an extracellular signaling molecule that stimulates a cell to grow or proliferate. In one embodiment, the compositions further comprise vitamin D as a second therapeutic agent, preferably in an amount sufficient to provide a dose of 200 to 1000 IU per day. For example, in certain embodiments, the compositions may comprise yitamin D, in a concentration of 0.1 IU / ml and 5 IU / ml, preferably from 0.5 IU / ml to 3 IU / ml.
    In other embodiments, the compositions of the present invention do not have any other active pharmaceutical ingredients. In a particularly preferred embodiment, the compositions of the present invention do not contain estradiol, more preferably, do not contain estrogen. Oily phase
    The compositions of the present invention are oil-in-water emulsions. The hydrophobic phase (or oil phase) of compositions according to the present invention is, or comprises an oil.
    Triglycerides are preferred oils. Preferably, the hydrophobic / oily phase comprises a triglyceride which has a melting point of less than 30 ° C, more preferably less than 20 ° C, and more preferably less than 10 ° C.
    Compositions according to the "progestogen / oil modality" suitably contain oil, which comprises at least 75% by weight / weight of triglycerides, more preferably at least 85% by weight / weight of triglycerides.
    In highly preferred embodiments, both in the "progestogen / oil modality" and in the "progesterone modality", the hydrophobic phase is an oil, comprising at least 90% by weight / weight of triglycerides, more preferably, at least 95% by weight / triglyceride weight. In a preferred embodiment, the oil phase is composed of "long chain triglycerides" (LCT) in an amount of at least 45% by weight / weight of the total oil, preferably at least 65% by weight / weight, more preferably at least 75% by weight / weight, more preferably at least 90% by weight / weight.
    In certain preferred embodiments, the oil of the emulsions of the present invention is, or comprises, a vegetable oil. The term "vegetable oil" refers to oil derived from the seeds of plants or nuts. Vegetable oils are usually "long chain triglycerides" (LCT), formed when three fatty acids (usually 14 to 22 carbons in length, with unsaturated bonds in varying numbers and locations, depending on the origin of the oil) form bonds of ester, with three hydroxyl groups in glycerol. In certain embodiments, highly purified vegetable oils (also called "super-refined") are used to ensure the safety and stability of oil-in-water emulsions. In certain embodiments, hydrogenated vegetable oils, which are produced by controlled hydrogenation of vegetable oil, can be used in the present invention.
    Examples of vegetable oils include, but are not limited to, almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut oil, corn oil, seed oil cotton, olive oil, peanut oil, palm oil, palm kernel oil, canola oil, safflower oil, soybean oil, sunflower oil and sesame oil. Hydrogenated and / or partially hydrogenated forms of these oils can also be used. Preferred oils are safflower oil, sesame oil, corn oil, olive oil and / or soy. The most preferred oils are safflower and / or soybean oil.
    Compositions in which the oily phase is soybean oil are most highly preferred. In particularly preferred embodiments, soybean oil can have a palmitic acid content between 9 and 13%, a stearic acid content between 2.5% and 5%, an oleic acid content, between 17% and 30%, a linoleic acid content between 48% and 58%, and a linolenic acid content between 5% and 11%.
    In a preferred embodiment, the emulsion compositions comprise no more than 3% by weight / weight, more preferably less than 2% by weight / weight and more preferably still less than 1% by weight / weight of structured triglycerides. A "structured triglyceride", as used herein, is a triglyceride comprising triglycerides, or mixtures of triglycerides, with at least one fatty acid group having a carbon chain length of 6-12 carbon atoms, and at least one group of fatty acid with a carbon chain length of more than 12 carbon units.
    In another embodiment, the emulsion compositions comprise triglycerides structured in an amount expressed as% by weight / weight of the total oil phase, of not more than 30%, preferably not more than 20%, more preferably not more than 10 %, more preferably not more than 5%.
    In certain embodiments, the oil of the oil-in-water emulsion compositions described herein can additionally, or alternatively, comprise medium chain triglycerides. "Medium chain triglycerides ^" (MCTs) are another class of triglyceride oil that can be of natural or synthetic origin. MCTs are formed from fatty acids of 6 to 10 carbons in length. MCTs are used extensively in emulsion for injection as a source of calories. Said oil is commercially available as, for example, Miglyol 812 (Sasol GmbH Germany), or CRODAMOL GTCC-PN (Croda Inc., New Jersey). Other low melting medium chain oils can also be used in the present invention. In certain embodiments, combinations of vegetable oil and MCT oil are used in the present invention. In preferred embodiments, the oil contained in the compositions of the present invention comprises less than, or equal to 35% by (weight / weight) of. medium chain triglycerides (MCT), preferably less than, or equal to 25% by (weight / weight) of MCT, more preferably less than, or equal to 10% by (weight / weight) of MCT, more preferably, less than, or equal to 5% by weight (weight / weight) of MCT.
    In another embodiment, the oil phase comprises animal fat. The term "animal fat" refers to oil derived from an animal source. Animal fat also comprises triglycerides, but the lengths of these, and the unsaturated bonds present in them, in the three fatty acid chains vary, compared to vegetable oils.
    Animal fats from sources that are solid at room temperature can be processed to become liquid, if desired. Other types of animal fats that are inherently liquid at room temperature include marine oils, such as fish oils. Fish oil triglycerides generally have fatty acids containing 12 to 22 carbon atoms. Examples of exemplary fish oils include, for example, highly purified fish oil concentrates.
    In certain embodiments, the oil phase is a mixture of one or more of an LCT oil and / or an MCT oil and / or an oil of marine origin. Although MCTs are supposed to allow better solubilization of the active ingredients compared to less polar LCTs, the presence of MCTs predominantly in injectable emulsions is associated with adverse metabolic effects, and can therefore present problems of safety and stability. In addition, MCT hydrolysis products, such as caprylic acid esters, are known to have harmful neurological side effects. In preferred embodiments, the compositions of the present invention therefore comprise not more than 3% by weight / weight of MCT, preferably not more than 2% by weight / weight of MCT, more preferably not more than 1% weight / weight of MCT. In preferred embodiments, the emulsions of the present invention do not contain MCT oils.
    In one embodiment, the emulsion contains no more than 0.9% by weight / weight, preferably no more than 0.8% by weight / weight, more preferably, no more than 0.5% by weight / weight of a polarity modifier selected from the group consisting of monoglycerides, diglycerides, acetylated monoglycerides, acetylated diglycerides and / or mixtures thereof. In another embodiment, the emulsion does not contain more than 0.9% by weight / weight, preferably not more than 0.8% by weight / weight, more preferably not more than 0.5% by weight / weight of monoglyceride.
    Expressed differently, the emulsion preferably contains no more than 30%, more preferably not more than 20%, even more preferably, not more than 10%, and more preferably, not more than 5% by weight of phospholipid, of a polarity modifier selected from the group consisting of monoglycerides, diglycerides, acetylated monoglycerides, acetylated diglycerides and / or mixtures thereof. It is believed that the use of a polarity modifier in a significant concentration in relation to the phospholipid content of the emulsions, has an adverse effect on the stabilizing properties of phospholipid.
    In another embodiment, the compositions comprise a polarity modifier selected from the group consisting of monoglycerides, diglycerides, acetylated monoglycerides, acetylated diglycerides and / or mixtures thereof, in an amount expressed as% by weight / weight of the total oil phase , less than 20%, preferably less than 10%, more preferably less than 5%, more preferably less than 2%.
    In another embodiment, the oil phase consists of less than, or equal to 10% by weight / weight of the total oil of monoglycerides and / or acetylated monoglycerides.
    The total oil content (weight / vol.) Of the compositions according to the "progestogen / oil modality" of the present invention is at least 0.5%, and not more than 10% (weight / vol.).
    The total oil content of the compositions according to both "progesterone modality" and "progestogen / oil modality" is preferably at least 1%, more preferably at least 2%, even more preferably at least 4%, more preferably at least 5% by weight (vol.). The total oil component of the emulsion of the present invention is preferably less than or equal to 9% in (weight / vol.), Even more preferably less than or equal to 8% (weight / vol.), And more preferably less than or equal to 7% in (pes / vol.). In a highly preferred embodiment, the compositions of the present invention comprise 6% by weight / vol. of oil, preferably soybean oil. Preferred soy oils can contain a linoleic acid content greater than 48%, and an oleic acid content greater than 17%. An example of a soybean oil that contains these properties is the refined soybean oil from Fresenius Kabi (Sweden).
    In certain embodiments, a substantial proportion of the progestogen is comprised in the oil droplets of the oil-in-water emulsion. In certain modalities in excess of 80% of the progestogen, it is dissolved and; remains inside the oil droplets. In certain embodiments more than 85%, 90%, 92%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% of the progestogen is dissolved in the oil phase. Aqueous medium
    The oil-in-water emulsions of the present invention further comprise an aqueous medium. "Aqueous medium" or "aqueous phase" refers to a liquid containing water. In preferred embodiments, the aqueous medium is water and / or an aqueous buffer solution. The compositions according to the "progestogen / oil modality" of the present invention suitably comprise 80 to 99.4% by weight / vol., Preferably the compositions according to both the "progestogen / oil modality" and the "progesterone modality" comprises 90 to 97% by weight / vol. aqueous medium.
    The compositions according to the present invention also optionally comprise 0 to 4 mM of a physiologically compatible buffering agent. Phospholipid
    The compositions of the present invention further comprise one or more emulsifying / surfactant agents, including phospholipids. The emulsifiers used in the present invention are preferably of natural origin. Emulsifiers of natural origin include soy lecithin, egg lecithin, sunflower oil lecithin, sphingosine, gangliosides, and phytosphingosine, and combinations thereof. Hydrogenated lecithin, that is, the controlled hydrogenation product of lecithin, can also be used in the present invention. The compositions according to the "progestogen / oil modality" of the present invention suitably comprise 0.0425% to 4.1% by weight / vol., Preferably 0.0644% to 3.4% by weight / vol. of phospholipids.
    Examples of phospholipids useful in the present invention include, but are not limited to, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid and mixtures thereof. These typically have 4 to 22 carbon atoms, and more generally 10 to 18 carbon atoms, and varying degrees of saturation. The phospholipid component of the oil-in-water emulsion can be a single phospholipid, or one; mixture of several phospholipids. The phospholipids used can be natural or synthetic, but they must be acceptable for parenteral administration, especially intravenous administration.
    A non-exhaustive list of suitable phospholipids is recorded below:
    Phosphatidic acids, 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), 1,2-Distearoyl-sn-glycero-3-phosphatidic acid, sodium salt (DSPA, Na); phosphocholines, including 1,2-Dilauroyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimiristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1, 2-Distearoil-sn-glycero-3-phosphocholine (DSPC); phosphoethanolamines, including, 1,2-dilauroyl-sn-glycero-3 - phosphoethanolamine (DLPE), 1,2-dimiristoyl-sn-glycero-3 phosphoethanolamine (DMPE), 1,2-Dipalmitoyl-sn-glycero-3- phosphoethanolamine (DPPE), 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE); phosphoglycerols, including 1,2-Dilauroyl-sn-glycero-3-phosphoglycerol sodium salt (DLPG, Na), 1,2-dimiristoyl-sn-glycero-3-phosphoglycerol, sodium salt (DMPG, Na), 1, 2-dimiristoyl-sn-glycero-3-phospho-sn-1-glycerol, ammonia salt (DMP-sn-1G, NH4), 1,2-Dipalmitoyl-sn-glycero-3-phosphoglycerol, sodium salt, ( DPPG, Na), 1,2-Distearoil-sn-glycero-3-phosphoglycerol, sodium salt (DSPG, Na), 1,2-Distearoil-sn-glycero-3-phospho-sn-1-glycerol, salt sodium (DSP-sn-lG, Na); phosphoserines, including 1,2-Dipalmitoyl-sn-glycero-3-phospho-L-serine, sodium salt (DPPS, Na); mixed chain phospholipids, including 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocolin (POPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol, sodium salt (POPG, Na), l-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol, ammonia salt (POPG, NH4); lysophospholipids, including l-palmitoyl-2-smooth-sn-glycero-3-phosphocholine (P-smooth-PC), l-stearoyl-2-smooth-sn-glycero-3-phosphocholine (S-smooth-PC); pegylated phospholipids, including N- (carbonyl-methoxypolyethylene glycol 2000) -MPEG-2000-DPPE, sodium salt, N- (carbonyl-methoxy polyethylene glycol 5000) MPEG-5000-DSPE, sodium salt, N- (carbonyl-methoxy polyethyleneglycol 5000) MPEG -5000-DPPE, sodium salt, N- (carbonyl methoxypolyethylene glycol 750) -MPEG -750-DSPE, sodium salt, N- (carbonyl methoxypolyethylene glycol 2000), MPEG-2000-DSPE, sodium salt.
    In a preferred embodiment, the amount of phospholipids in the compositions according to the present invention, by weight, based on the total volume of the composition (weight / vol.), Is at least 0.064%, preferably at least 0.085%, more preferably at least 0.25%, even more preferably at least 0.3%, even more preferably at least 0.35%, more preferably at least 0.5%.
    In another preferred embodiment, the amount of phospholipid in the compositions according to the present invention, by weight, based on the total volume of the composition (weight / vol.), Is less than or equal to 3.4%, preferably less than or equal to at 3.3%, more preferably less than or equal to 2.6%, even more preferably less than or equal to 2.3%, even more preferably less than or equal to '2.2%, more preferably less than or equal to 2, 1%.
    The highly preferred compositions comprise phospholipid in an amount (weight / vol.), Within the range of 0.7% to 2.0%, preferably within the range of 1.0% to 1.3%, more preferably 1 , 02%. Compositions comprising phospholipids within these limits show excellent physical and pH stability during storage.
    In a highly preferred embodiment, the phospholipid component comprises a mixture of phospholipids, such as phosphatidylcholine in 79%, phosphatidylethanolamine in 18%, sphingomyelin in 2%, and lysophosphatidylcholine in 1%.
    In a preferred embodiment, the source of the phospholipid emulsifying agent of the present invention is preferably egg lecithin. According to the "United States Pharmacopoeia" (USP), lecithin is an unregistered nomenclature that describes a complex mixture of acetone-insoluble phospholipids, which mainly consists of; phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol combined with various amounts of other substances such as triglycerides, fatty acids, and carbohydrates.
    Soy lecithin and egg lecithin (including hydrogenated versions of these compounds) have a long history of safety in biological systems, also have combined emulsification and solubilization properties, and tend to be metabolized in vivo to harmless substances, more quickly than than most synthetic surfactants. Commercially available soy phospholipids / lecithin are the products of Centrophase and Centrolex (Central Soya), Phospholipon (Phospholipid GmbH, Germany), Lipoid (Lipoid GmbH, Germany), EPIKURON (Degussa), and PL90 (Fresenius Kabi, Sweden). In a highly preferred embodiment, the source of phospholipid is egg lecithin.
    In certain embodiments, the total amount of emulsifier, including phospholipids, in the compositions of the present invention is within a range of 0.05% to 4.8% by weight, based on the total volume of the composition (weight / vol.)
    In preferred embodiments, the amount of lecithin (weight / vol.) According to the present invention is less than, or equal to 4.2%, preferably less, or equal to 3.4%, more preferably less, or equal at 2.9%, even more preferably less than, or equal to 2.6%, even more preferably less than, or equal to 2.5%, more preferably less, or equal to 2.0%.
    In certain embodiments, the total amount of lecithin, especially egg lecithin, (weight / vol.) Is greater than or equal to 0.08%, with greater preference greater than or equal to 0.1%, even more preferably greater than or equal to 0.15%, more preferably greater than or equal to 0.2%, even more preferably greater than or equal to 0.3%, even more preferably greater than or equal to 0.35%, more preferably greater than or equal to 0.6%.
    The most highly preferred compositions include egg lecithin in an amount (by weight / vol.) Within the range of 0.8% to 2.3%, preferably 0.9% to 1.5%, more preferably 1.0 % to 1.3%, even more preferably 1.2%.
    In one embodiment, egg lecithin comprises from 60 to 80% by weight / weight, preferably 67% by weight / weight of phosphatidylcholine; from 10 to 20% by weight / weight, preferably 15% by weight / weight of phosphatidylethanolamine; 3% by weight / weight, preferably 2% by weight / weight of sphingomyelin; and 3% by weight / weight, preferably 1% by weight / weight of lysophosphatidylcholine. "PL90 egg lecithin" (Fresenius Kabi AB) is an example of an egg lecithin that has a phospholipid content.
    In one embodiment, the compositions of the present invention comprise more than 1.5% by weight / weight, preferably not more than 1.2% by weight / weight, more preferably not more than 0.8% by weight / weight, and more preferably not more than 0.4% by weight / weight of polyethylene glycol 15-hydroxystearate. In another embodiment, the compositions of the present invention comprise more than 1.5% by weight / weight, preferably not more than 1.2% by weight / weight, more preferably not more than 0.8% by weight / weight, more preferably not more than 0.4% by weight / weight of polyethylene glycol ester and / or polyethylene-propylene glycol. Co-surfactant
    The compositions according to the present invention optionally comprise a co-surfactant. Not limited to theory, it is thought that co-surfactants stabilize lipid droplets during the formation of the emulsion, thus influencing the droplet size of the emulsion and the stability of the final emulsion composition. Co-surfactants suitable for use in the compositions of the present invention are those that prevent the flocculation and / or coalescence of the lipid emulsion. Examples of co-surfactants include, but are not limited to, cholesterol, oleic acid, oleate, TweenδO (PEG-sorbitan monooleate), HCO-60, Solutol H15 (polyoxyethylene-660-hydroxystearate), PEG-400 (polyethylene glycol ),
    Pluronic F68 (BASF), Cremophor EL (polyoxyethylene-35-ricinoleate), or the bile acid salt, 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 their mixtures, preferably from C1-6 C20r fatty acids salts thereof, and / or mixtures thereof, preferably from Cys fatty acids, salts thereof, and / or mixtures thereof. In highly preferred embodiments, the fatty acid is monounsaturated.
    In some embodiments, the co-surfactant may be present in the compositions of the present invention, in an amount in (weight / vol.) Greater than or equal to 0.005%, preferably greater than or equal to 0.01%, more preferably greater than or equal to 0.02%. In other embodiments, the co-surfactant may be present in the compositions of the present invention in an amount in (weight / vol.) Less than or equal to 4%, preferably less than or equal to 1%, more preferably less than or equal to 0 , 04%. In a preferred 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 alkaline salts thereof. Oleate and / or oleic acid, and sodium oleate, in particular, are highly preferred co-surfactants.
    In certain embodiments, where the co-surfactant is oleate and / or oleic acid, the co-surfactant is present in an amount in (weight / vol.) Equal to or greater than 0.005%, preferably equal to or greater than 0.01 %, even more preferably, equal to or greater than 0.02%. In certain embodiments, where the co-surfactant is oleate and / or oleic acid, the co-surfactant is present in an amount (weight / vol.) Less than or equal to 0.5%, preferably less than or equal to 0, 2%, more preferably less than or equal to 0.1%, more preferably less than or equal to 0.05%.
    In a highly preferred embodiment, the co-surfactant is sodium oleate, and is present in an amount of 0.03% by weight / vol.
    The compositions of the present invention are preferably suitable for parenteral infusion, preferably, intravenous infusion, over extended periods of time. A typical duration of administration can be, for example, 3 to 7 days. In preferred embodiments, the concentration of certain co-surfactants should therefore be kept to a minimum, to avoid side effects such as irritation, inhibition of cytochrome P450, etc. In preferred embodiments Pluronic F68 (poly (ethylene glycol) - 13-poly (propylene glycol co-propylene glycol) is present in an amount of less than 0.7% (weight / weight), preferably less than 0.5% (weight / In another preferred embodiment, Solutol-HS (Macrogol-15-hydroxystearate) is present in an amount of less than 1.2% (weight / weight), preferably less than 1% (weight / weight). Osmotic agent
    Compositions according to the "progestogen / oil modality" of the present invention suitably comprise an osmotic agent and / or a tonicity modulator. Preferably, the latter compositions have an osmolality in the range of 200-1000 mOsm / kg. According to a preferred embodiment, both "progestogen / oil" and "progesterone", the compositions according to the present invention are isotonic and iso-osmotic. The compositions of the present invention advantageously have an osmolality of 220-600 mOsm / kg, more preferably 230-360 mOsm / kg.
    Suitable osmotic agents and / or tonicity modulators include potassium chloride or. sodium, trehalose, sucrose, sorbitol, glycerol, glucose ,. xylitol, mannitol, polyethylene glycol, propylene glycol, albumin, amino acids and mixtures thereof. In certain embodiments, an osmolality of 270-330 mOsm / kg, preferably 280- 300 mOsm / kg, is achieved with an agent that also increases osmotic pressure, such as glycerol, dextrose, lactose, sorbitol or sucrose.
    In a preferred embodiment, the osmotic agent is a physiologically acceptable polyol, such as glycerol, sorbitol or xylitol. In a preferred embodiment, the osmotic agent is glycerol.
    The osmotic agent and / or tonicity regulator of the compositions of the present invention is generally used in a concentration that has no adverse biological effects. The final product is preferably isotonic, in order to allow the emulsion to be infused, either through a central venous catheter or a peripheral one.
    In preferred embodiments, where glycerol is the osmotic agent, it is present in a concentration in (weight / vol.) Greater than 1%, preferably greater than 2%, more preferably greater than 2.3%. In other preferred embodiments, glycerol is present in a concentration in (weight / vol.) Of less than 5%, preferably less than 3%, more preferably less than 2.7%. In a highly preferred embodiment, the emulsions of the present invention comprise 2.5% glycerol. PH regulating agent
    The compositions according to the present invention have a pH within the range of pH 6.0 to pH 9.0, preferably pH 6.5 to pH 8.5, more preferably pH 7.0 to pH 8.0. The pH of the compositions can be adjusted by methods known in the art, for example, by using an appropriate base, which neutralizes the negative charge on the fatty acids, and by using an appropriate buffer, or a combination of these . A wide variety of bases and buffers are suitable for use with the emulsions of the present invention. One skilled in the art will appreciate that adding the buffer to the emulsion will affect not only the final pH, but also the ionic strength of the emulsion. High ionic strength buffers can have a negative impact on the emulsion's zeta potential and are therefore undesirable. In a preferred embodiment, the pH is adjusted to the desired value, by adding IN sodium hydroxide. Optional additives
    The compositions according to the present invention optionally comprise one or more pharmaceutically acceptable additives, such as acidifying, alkalizing agents, binders, chelators, complexing agents, solubilizing agents, antiseptics, preservatives (including antimicrobial and antioxidant agents), suspending agents , stabilizing agents, wetting agents, viscosity modifying agents, solvents, cryoprotectants, thinners, lubricants, or other biocompatible materials. In certain embodiments, such additives assist in stabilizing colloidal dispersion or in transforming the formulations of the present invention into biocompatibles.
    In one embodiment, the compositions of the present invention do not comprise vitamin E. In another embodiment, the compositions of the present invention do not comprise vitamin C. In another embodiment, the compositions of the present invention do not comprise hexa sodium phytate. In a preferred embodiment, the compositions of the present invention are free of, or substantially free from alcohol. In another embodiment, the compositions of the present invention are free of, or substantially, free of ethanol. In another modality,. the compositions of the present invention, additionally, or alternatively do not contain organic solvents.
    Preferably, the compositions according to the "progesterone modality" of the present invention contain less than 2.5% by weight / vol. benzyl benzoate.
    Both compositions according to the "progesterone modality" and compositions according to the "progestogen / oil modality" preferably comprise less than 1% by weight / vol. benzyl benzoate. Even more preferably, said compositions comprise less than 1% by weight / vol. benzyl alcohols and / or their derivatives.
    In preferred embodiments, the compositions of the present invention do not contain benzyl benzoate, and in highly preferred embodiments they do not contain benzyl alcohols and / or their derivatives. In a preferred embodiment, the compositions of the present invention do not contain cyclodextrin. Proportions of Emulsion Components
    Although exemplary amounts of different components that can be included in the compositions of the present invention are presented above, other aspects of the invention relate to proportions of specific components, as will be discussed below. Progestogen: Oil proportion
    As noted above, the compositions of the present invention advantageously have a low oil content, such that a minimum of lipid is provided to the individual per unit volume of the administered composition, so that adverse side effects, such as hyperlipidemia, can avoided. In addition, in some embodiments, the compositions achieve improved progesterone solubility in oil, while maintaining, or improving, the chemical and / or physical stability of the emulsions, such that higher doses of progesterone can be delivered to a individual per unit of oil.
    Compositions according to the "progesterone modality" typically contain progesterone and oil, in a ratio of progesterone to the total oil component in (weight / weight) of at least 1:35, more preferably, of at least 1:33, even more preferably, at least 1:32.
    According to particularly preferred embodiments of the "Progestogen / oil modality" and "progesterone modality", the ratio of progestogen to the total oil component in (weight / weight) is at least 1:31. Typically, the latter ratio is not more than 1:22, more preferably, not more than 1:23, more preferably not more than 1:24, more preferably not more than 1:25, more preferably not more than 1:26, more preferably it is not more than 1:27, even more preferably, it is not more than 1: 28 and, more preferably, it is not more than 1: 29. In one embodiment, the ratio of progestogen to the component of oil is between 1:32 and 1:25 in (weight / weight), even more preferably from 1:31 to 1:29 in (weight / weight).
    In preferred embodiments, the compositions of the present invention comprise progestogen, preferably progesterone, in an amount expressed as% by weight / weight of the oil, greater than 1%, preferably greater than 1.5%, more preferably greater than or equal to 2%, especially greater than or equal to 2.2%. In even more preferred embodiments, the progestogen is present in an amount greater than 2.5%, even more preferably greater than 3%, more preferably greater than 3.2% by weight / weight of the oil. Phospholipid: Oil proportion
    It has been found that excessive amounts of phospholipid in oil-in-water compositions can lead to an increase in phospholipid degradation products after autoclaving and / or storage, causing a drop in pH, which in turn has a negative impact about: the stability of the emulsion. In addition, the excess of phospholipid can lead to an increase in the number of "large" micelles free of fat in the compositions, and, consequently, to an undesirable increase in the PFAT5 value. On the other hand, compositions with a very low level of phospholipids do not show sufficient stability of emulsion droplets to withstand sterilization by autoclaving and storage. The compositions of the present invention have an optimized level of oil and phospholipids, such that an optimal particle size distribution and superior physical stability are achieved, while a pH within the desired range is maintained during heat sterilization and storage.
    In one embodiment, the compositions of the present invention comprise phospholipid in an amount expressed as% by weight / weight of the oil, greater than or equal to 6.8%, preferably greater than or equal to 8.4%, more preferably greater than or equal to 12%, even more preferably greater than or equal to 14%, more preferably greater than or equal to 15%.
    In one embodiment, the compositions of the present invention comprise phospholipid in an amount expressed as% by weight / weight of the oil, less than or equal to 43%, preferably less than or equal to 42.5%, more preferably less than or equal to 26 %, even more preferably less than or equal to 25%, more preferably less than or equal to 22%.
    In a highly preferred embodiment, phospholipid is present in an amount within the range of 16 to 18% in (weight / weight) of the oil.
    In another embodiment, the compositions of the present invention comprise lecithin, preferably egg lecithin, in an amount expressed as% by weight / weight of the oil, greater than or equal to 8%, preferably greater than or equal to 10%, plus preferably greater than or equal to 13%, even more preferably greater than or equal to 15%, more preferably greater than or equal to 18%.
    In one embodiment, the compositions of the present invention comprise lecithin, preferably egg lecithin, in an amount expressed as% by weight / weight of the oil, less than or equal to 50%, preferably less than or equal to 48%, plus preferably less than or equal to 40%, even more preferably less than or equal to 33%, more preferably less than or equal to 31%.
    In a highly preferred embodiment, egg lecithin is present in an amount within the range of 19 to 21% by (weight / weight) of the oil. Co-surfactant: Oil proportion
    In certain embodiments of the present invention, the compositions comprise a co-surfactant, preferably oleate or oleic acid. In one embodiment, the surfactant is present in an amount expressed in% by weight / weight of the oil, greater than 0.02%. Preferably, the concentration of co-surfactant contained in the composition, in an amount expressed as% by weight / weight of the oil, is greater than or equal to 0.08%, preferably greater than or equal to 0.1%, still more preferably it is greater than or equal to 0.3%. In another preferred embodiment, the concentration of surfactant contained in the composition, in an amount expressed as% by weight / weight of the oil, is less than or equal to 2%, preferably less than or equal to 0.9%, even more preferably it is less than or equal to 0.7%.
    In a highly preferred embodiment, the co-surfactant is oleate or oleic acid, and is present in an amount of 0.5% of the oil in (weight / weight). . Co-surfactant: Phospholipid ratio
    In one embodiment of the present invention, the compositions comprise phospholipids and a co-surfactant, preferably oleate. In this modality, the co-surfactant and phospholipids are present, preferably, in a proportion of co-surfactant for phospholipids in (weight / weight), greater than or equal to 1:85, preferably greater than or equal to 1:82, more preferably greater than or equal to 1:68, even more preferably greater than or equal to 1:51, more preferably greater than or equal to 2:85. In this modality, the co-surfactant and phospholipids are present, preferably, in a proportion of co-surfactant for phospholipids in (weight / weight) less than or equal to 1:12, preferably less than or equal to 1:17, more preferably less than or equal to 1:20, even more preferably less than or equal to 1:26, more preferably less than or equal to 1:34.
    In a preferred embodiment in which the co-surfactant is oleate, the ratio of co-surfactant to phospholipid in (weight / weight) is within the range of 1:51 to 1:30, preferably 1:51 to 1: 34.
    In another embodiment of the present invention, the compositions comprise lecithin and a co-surfactant, preferably oleate. In this embodiment, the co-surfactant and lecithin are preferably present in a ratio of co-surfactant to lecithin in (weight / weight) greater than or equal to 1: 100, preferably greater than or equal to 1:80, more preferably greater than or equal to 1:70, even more preferably greater than or equal to 1:60, more preferably greater than or equal to 1:50. In this embodiment, the co-surfactant and lecithin are preferably present in a proportion in (weight / weight) less than or equal to 1:15, preferably less than or equal to 1:20, more preferably less than or equal to 3:70 , even more preferably less than or equal to 1:30, more preferably less than or equal to 1:40.
    In a preferred embodiment where the co-surfactant is oleate, and lecithin is egg lecithin, the ratio of co-surfactant to lecithin (weight / weight) is within the range of 1:60 to 1:30, from preferably 1:60 to 1:35.
    Progestogen: Phospholipid ratio
    In one embodiment, the progestogen is present in an amount of less than 58% by weight / weight of phospholipid, preferably less than 29% by weight / weight of phospholipid. Preferably, in another embodiment, in the compositions according to the present invention, the progestogen is progesterone, and the progesterone is present in an amount expressed as% by weight / weight of phospholipid, greater than 7.8%, preferably greater than 9.8%, more preferably greater than 13%, even more preferably greater than 15%.
    Preferably, in another embodiment, in the compositions according to the present invention the progestogen is progesterone, and :. progesterone is present in an amount, expressed in% by weight / weight of phospholipid, of less than 47%, preferably less than 39%, more preferably less than 26%, even more preferably less than 20%.
    In one embodiment of the compositions according to the present invention, the progestogen is progesterone, and the phospholipid is supplied by lecithin, progesterone and lecithin are present in a (weight / weight) ratio of 1: 15 to 2: 5, preferably from 1:12 to 1: 3, more preferably from 1: 9 to .2: 9, even more preferably from 2: 15 to 1: 6. In a preferred embodiment, the ratio of lecithin to progesterone in (weight / weight) is less than 1: 2, preferably less than 1: 4. Progestogen: Proportion of co-surfactant
    In one embodiment, the co-surfactant is present in the compositions according to the present invention, in an amount greater than 2.5% by weight of the progestogen, preferably greater than 5% by weight of the progestogen. Packing
    The compositions of the present invention are preferably ready for use. The term "ready for use", as used herein, means that no further manipulation, such as dilution or mixing together of various components, is necessary.
    The compositions of the present invention can be supplied in sealed packages. The packaging must be compatible for use with formulations of lipids and progestogens. Examples of materials not suitable for packaging lipid formulations include PVC and DEHP. Suitable packaging that is compatible with lipid formulations includes, but is not limited to, glass bottles and polypropylene based bags. Conventional glass is a preferred packaging for the compositions of the present invention. In a preferred embodiment, the compositions are packaged in a sealed container. The container can be wrapped to provide protection from the physical environment. In one embodiment, the composition is packaged in a sealed container with a volume of 250 ml. In one embodiment, the composition is packaged in a sealed container under a headspace of inert gas.
    In other embodiments, the compositions are packaged in inert containers. In one embodiment, inert containers are slightly occluded. In another embodiment, the container comprises a double layered wall, and in preferred embodiments, the area between the two layers is filled with an inert gas, in order to prevent oxidation.
    For prolonged storage, the packaging material must avoid diffusion of oxygen from the ambient air, for the compositions of the present invention, in order to avoid the formation of oxygen degradants within the compositions.
    In another embodiment, the composition is packaged in a unit dose. A unit dose provides sufficient composition, either for administering a bolus dose of progestogen to an individual, or for administering the composition during the first hour, preferably within the first 2 hours, more preferably, within the first 4 hours of treatment. The unit dose allows quick and convenient administration of the composition in emergency situations, for example, by paramedics in the ambulance, or by rescuers / doctors at the site of an injury / event occurrence. Non-limiting examples of forms of. unit dose are injectable preparations, pre-filled syringes, glass vials, and / or in sealed bags.
    In other embodiments, the composition is packaged within a device similar to the insulin pump device, which is used to deliver continuous infusion therapy, or in a cartridge designed for use with the respective device. Examples of insulin pumps are those marketed by MiniMed and Disetronic. Such pumps may comprise, for example, a cannula, a pump reservoir or cartridge, in which the composition is stored, which can be operated by battery, and means that allow the user to control the exact quantity of the asset to be supplied, such as for example, a computer chip. Highly preferred mode
    In a highly preferred embodiment of the composition according to the present invention, the compositions comprise from 0.15 to 0.25% by weight / vol. progesterone; from 5.0 to 7.0% by weight / vol. of Oil; from 1.0 to 1.4% by weight / vol. egg lecithin; from 80 to 98.9% by weight / vol. of water, and have a pH of 6.0-9.0. Compositions according to this highly preferred embodiment represent an agreement between the administration of the most desirable amount of progestin per unit volume of liquid, the distribution of the most desirable amount of progestin per unit of oil, physical stability and the safety of the emulsion administration . Emulsion properties
    The compositions according to the present invention have a milky white appearance, and are presented as visually homogeneous emulsions. PFAT5 value
    The "United States Pharmacopeia" (USP) sets the limit for the distribution of globule size in injectable lipid emulsions (USP 729 - Pharm. Forum. 2005; 3: 1448-1453). The limit for fat globules with a diameter> 5 μm in injectable emulsions, expressed as the weight percentage of volume weighted> 5 μm, is not more than 0.05%, or PFAT5 is not more than 0.05%. Compositions that have a PFAT5 value greater than 0.05% are not considered safe for intravenous administration. The PFAT5 value of an emulsion can be influenced by several factors, including the total oil content of the emulsion, the choice of co-surfactant, the proportion of co-surfactant to oil, and the stability of the drops of the coalescence emulsion and / or flocculation.
    The compositions according to the present invention have a PFAT5 value less than or equal to 0.05%, preferably less than or equal to 0.04%, even more preferably less than or equal to 0.02%, more preferably less than or equal to 0.01%.
    In one embodiment, 100% of the emulsion droplets of the compositions of the present invention are less than or equal to 5 μm in diameter, and 98% of the droplets, preferably 99% of the droplets, are less than or equal to 1.5 μm in diameter. The particle size distribution of drops larger than 1 μm in diameter is determined by the Coulter counter (Coulter Multisizer III). PCS
    In one embodiment, droplets smaller than or equal to 1 μm in diameter, have a maximum z average of 350 nm, and / or a poly-dispersion value of no more than. 0.25. In a preferred embodiment, droplets less than or equal to 1 μm in diameter, have a maximum z average of 250 nm, and / or a polydispersion value of no more than 0.20. In an even more preferred embodiment, droplets less than or equal to 1 μm in diameter, have a maximum z average of 220 nm, and / or a polydispersion value of no more than 0.15. Median droplet size
    The size of the emulsion droplets is the key parameter that determines the kinetics of the destabilization of the emulsion, since the size of the drops directly influences the rate of phenomena such as coalescence, skimming, flocculation, Ostwald Maturation and, finally, separation phase. The size of the emulsion droplets is therefore an indication of emulsion stability. Several parameters influence the size of the emulsion droplets, including, for example, the type of oil, the type of surfactant, and the co-surfactant, the presence of active ingredients, the amount of oil, and the proportions of oil for surfactant and of oil for co-surfactant.
    In one embodiment, the droplet particles of the emulsion of the compositions according to the present invention, have a median diameter based on volume, or D [4.3], of 300 nm, preferably 230 nm, more preferably 200 nm, still more preferably 185nm, and even more preferably 180nm.
    In a highly preferred embodiment, the compositions according to the present invention maintain a median diameter based on volume, or D [4.3], of 300 nm, preferably 230 nm, more preferably 200 nm, even more preferably ^ 185nm, and more preferably 180nm, after one, preferably two, even more preferably, three autoclave cycles at 121 ° C for 15 minutes, and / or, after storage at 60 ° C for 3 weeks, preferably 4 weeks. Average droplet size
    In one embodiment, the emulsion droplet particles of the compositions according to the present invention have an average diameter based on volume, or d (0.5), of 300 nm, preferably ^ 250 nm, more preferably 200 nm, even more preferably 185nm, and more preferably 180nm.
    In a highly preferred embodiment, the compositions according to the present invention maintain an average diameter based on volume, or d (0.5), of £ 300 nm, preferably 250 nm, more preferably 200 nm, even more preferably 185 nm , and most preferably 180nm, after one, preferably two, and even more preferably three autoclave cycles at 121 ° C for 15 minutes, and / or, after storage at 60 ° C for 3 weeks, preferably 4 weeks. Span
    The "Span" Mastersizer value is a measure of the width, or spread of the particle size distribution curve, which is calculated by the formula d (v, 0.9) - d (v, 0, l)) / d (v, 0.5) by the Mastersizer unit. In a specific embodiment, the compositions of the present invention have a "Span" of 2400, such as 2100. Zeta potential
    The zeta potential is related to the stability of the emulsion. Emulsions with a high zeta potential are electrically stabilized, while those with a low zeta potential tend to coagulate or flocculate. The zeta potential of emulsions is influenced, for example, by the choice and amount of surfactant and co-surfactant, the pH of the emulsions, as well as the ionic strength of the aqueous solution.
    In one embodiment, the compositions of the present invention have a zeta potential in the range of -30 mV to -70 mV, preferably from -40 mV to -65 mV, preferably - 51 mV to -60 mV. In addition, the zeta potential of the emulsion compositions of the present invention can be -30 mV, -35 mV, -40 mV, -45 mV, -50 mV, -55mV, -60 mV, -65 mV or -70 mV, or superior. Particular Matter
    In certain embodiments, the compositions are free of crystalline solid at room temperature (for example, at one or more temperatures selected from temperatures from 4 ° C, from 2 ° C to 8 ° C or from 20 ° C to 25 ° C). The preparation contains 0 to 12 particles per ml, equal to, or greater than, 10 μm and 0-2 particles per ml, equal to, or greater than, 25 μm. Emulsion stability Physical stability
    The compositions according to the present invention are surprisingly heat sterilizable. "Heat sterilizable", as used herein, means that the compositions maintain their physical stability, that is, they do not separate in phases or show signs of flocculation and / or coalescence of the droplets, after treatment in an autoclave at 121 ° C for 15 minutes.
    The compositions according to the present invention are surprisingly stable for storage. "Stable storage", as used herein, means that the compositions maintain their physical stability, that is, they do not separate in phases or show signs of flocculation and / or coalescence of the droplets, after three, preferably after four weeks of storage at 60 ° C.
    In a highly preferred embodiment, the compositions according to the present invention have a PFAT5 value of less than 0.05%, preferably less than or equal to 0.03%, even more preferably less than or equal to 0.02%, more preferably less than or equal to 0.01%, after autoclaving at 121 ° C for 15 minutes, and / or after three, preferably after four weeks of storage at 60 ° C.
    The compositions of the present invention typically do not show any signs of discoloration after sterilization by autoclaving at 121 ° C for 15 minutes, and / or storage at 60 ° C for three, preferably for four weeks.
    In another highly preferred embodiment, the droplets of the composition emulsion according to the present invention, show an increase in the average diameter based on the volume, or d (0.5) which is not more than 2%, preferably not more than 1 , 5%, even more preferably not more than 1%, after autoclaving at 121 ° C for 15 minutes, and / or after three, preferably after four weeks of storage at 60 ° C.
    In another embodiment, the droplets of the emulsion of compositions according to the present invention show an increase in average diameter based on volume, or D [4.3], which is not greater than 2.5%, preferably not greater than 2%, even more preferably not more than 1.5%, after autoclaving at 121 ° C for 15 minutes, and / or after three, preferably after four weeks of storage at 60 ° C. Chemical stability
    In one embodiment, the progestogen content of compositions according to the present invention is not reduced by more than 10% by weight of progestogen, preferably it is not more than 5% by weight of progestogen, even more preferably, it is not more than 2% by weight of progestogen, after one, preferably two, even more preferably, three autoclave cycles at 121 ° C for 15 minutes, and / or after three, preferably after four weeks of storage at 60 ° Ç.
    In another embodiment, the amount of progestogen-derived degradation / oxidation products in the compositions of the present invention is not more than 1% by weight of progestogen, preferably 0.7% by weight of progestogen, for any individual chemical species, and the total sum of degradation / oxidation products derived from progestogen does not exceed 3% by weight of progestogen, after one, preferably two, even more preferably, three autoclave cycles at 121 ° C for 15 minutes, and / or after preferably three weeks of storage at 60 ° C.
    In a particularly preferred embodiment, where the progestogen is progesterone, the individual levels of 6-ketoprogesterone, 6-hydroxyprogesterone, and 20-hydroxyprogesterone (α- and β-), or δ-6-progesterone is not more than 1%, preferably not more than 0.7% by weight of progesterone, and the total sum of progesterone degradation products is not more than 3% by weight of progesterone, after one, preferably two, even more preferably, three autoclaving cycles at 121 ° C for 15 minutes, and / or after three, preferably after four weeks of storage at 60 ° C.
    Progestogens and degradation / oxidation products derived from progestogens can be quantified by HPLC.
    Emulsion components themselves are also subject to chemical instability. For example, phospholipids are broken down into non-esterified fatty acids (NEFA) during storage. This is especially problematic during thermal stress, such as autoclaving and / or prolonged storage.
    An accumulation of NEFA negatively affects the pH of the emulsion and the zeta potential. For these reasons, NEFA levels should be limited in compositions of the present invention.
    Preferably, the levels of non-esterified fatty acids (NEFA) of pre or post autoclaving and / or storage compositions after three, or after four weeks at 60 ° C is 12mEq / L, preferably less than £ 8mEq / L. Sterility
    In a preferred embodiment, the compositions according to the present invention are sterile. As used herein, "sterile" refers to compositions that pass the USP Capitulo <71> sterility test. Preferred embodiments are compositions that meet the requirements of the USP Chapter 8 "bacterial endotoxin test" and preferably meet the requirements of the USP Chapter 15 "pyrogen test". Process Another aspect of the present invention relates to a method of making an oil-in-water emulsion composition, as defined above, which comprises the steps of: a) combining phospholipids, water, and optionally, an agent osmotic to produce an aqueous composition; b) combination of progestin and oil to produce an oily composition; and c) combining the aqueous composition and the oil composition followed by homogenization to form a homogeneous oil-in-water emulsion. According to a particularly preferred embodiment, the aqueous composition is homogenized so as to produce a homogeneous suspension, before said aqueous composition is combined with the oil composition. In another advantageous embodiment, progestogen is added to the oil at a temperature of at least 40 ° C to facilitate dilution of the progestogen. Preferably, the oil composition is filtered before being combined with the aqueous composition. A particularly preferred embodiment of the manufacturing method comprises the steps of: A) dissolving an osmotic agent in an aqueous medium, and stirring; B) adding the surfactant, preferably egg lecithin, and stirring; C) optionally, the addition of a surfactant and a pH regulating agent, and mixing; D) dissolution of progestin in oil to form an oily phase; E) filtration of the oil phase, ■ followed by the addition of the filtered oil phase to the aqueous phase, and mixing; F) homogenization to form a homogeneous emulsion; G) optional addition of water; H) optional addition of Na.OH IN sufficient to adjust the pH from 8.0 to 8.8; I) optional addition of sufficient aqueous medium to reach the final volume.
    In a particularly preferred embodiment, homogenization is carried out greater than or equal to 350 bars, preferably greater than, or equal to 370 bar.
    In particularly preferred embodiments, the methods of making the emulsions of the present invention involve the steps of dissolving egg lecithin in an aqueous medium (instead of oil), adding the oily phase to the aqueous phase (instead of vice versa), homogenization greater than or equal to 350 bars. It is believed that these steps result in emulsions with advantageous properties, in terms of particle size and emulsion stability.
    In another preferred embodiment, the emulsion is packaged in sealed containers, and preferably sterilized by heating to at least 121 ° C (for example, 121 ° C to 123 ° C) for a minimum of 15 minutes waiting. The autoclave program is preferably a rotating cycle.
    The following provides a detailed example of a manufacturing method. The person skilled in the art will readily understand that various modifications and variations can be made, and yet fall within the scope of the invention. Pre-emulsion preparation
    A clean container (container A) is filled to approximately 15% of the total volume, with the aqueous medium. The temperature of the aqueous medium is adjusted to about 55 ° C to 60 ° C, and the aqueous medium is degassed with nitrogen until its residual oxygen content is 0.1 mg / L. The aqueous medium is maintained under a nitrogen atmosphere, with a residual oxygen content of 0.1 mg / L, throughout the duration of the emulsion manufacturing process. An osmotic agent is added to the aqueous medium and stirred with a magnetic stirrer for approximately 3 to 5 minutes, at about 50 Hz. Lecithin is added to the aqueous mixture. The co-surfactant and a pH regulator are optionally added, and the mixture is stirred with a high shear mixer (for example, Ultra Turrax) at about 50 Hz, until a homogeneous suspension, with no surfactant on the surface of the aqueous phase , be obtained.
    Oil phase: Oil is added to a second container (container B), and the temperature is adjusted to about 60 ° C. Progestogen is then dissolved in the heated oil, by stirring with a magnetic stirrer at about 50 Hz for about 10 min. +/- 5min.
    The oil phase of container B is filtered through a 0.2 μm filter, and slowly transferred to the aqueous phase in container A. The pre-emulsion is obtained by constant stirring at about 50 Hz for about 15 minutes, with a high shear mixer (eg Ultra Turrax) until a visually homogeneous pre-emulsion is obtained. Preparation of the Emulsion
    The pre-emulsion then goes through about 4 homogenization cycles. Each homogenization cycle comprises a first stage in which the pre-emulsion is subjected to approximately 400 +/- 30 bars of pressure, at a temperature of about 50 to 80 ° C (after heat exchange), and a second stage where the pre-emulsion is subjected to approximately 100 +/- 30 bars of pressure, at a temperature of about 55 to 80 ° C (after heat exchange).
    The emulsion is filtered through a 10μm filter in a clean storage tank, containing enough aqueous medium to give an emulsion volume equal to approximately 90% of the final volume. The aqueous medium is degassed with nitrogen until the residual oxygen reaches 0.1 mg / L, and is kept under a nitrogen layer. The emulsion is cooled to about 25 to 30 ° C. A pH regulator is optionally added to achieve a pH of 8.0 to 8.8. An additional aqueous medium can be added to bring the emulsion to the final concentration. Fill
    The emulsion is transferred to a filling machine, where it is placed for packaging and sealing, such as in glass bottles. The filling device is washed and stored under a nitrogen atmosphere. The nitrogen stream is blown into the package before filling, and during the filling process, in such a way that the oxygen content in the package remains 0.1 mg / l. In a preferred embodiment, about 255 +/- 1.5 ml of emulsion is added to each packaging unit. The filled packages are then evacuated. In a preferred embodiment, the packages go through 4 air evacuation cycles, each cycle consisting of 0.5 seconds of air evacuation, followed by 0.5 seconds of nitrogen gasification, and a final vacuum value of 0.60 bar (0.40 bar absolute) is reached. The packages are preferably capped with a rubber cap (for example, Stelmi RG6720 halobutyl stoppers).
    The packaged emulsion is sterilized by autoclaving for a maximum of approximately 16 hours of waiting time (ie, within about 16 hours of post-filling). The autoclaving process involves heating to about 121 ° C (about 121 ° C to about 123 ° C) for a minimum of about 15 minutes of waiting time. The autoclave program is preferably a rotating cycle. The autoclaving process can be performed one to three times. After sterilization, the vials are visually checked for signs of fat-free droplets. The emulsion is stored at about 15 ° C to about 25 ° C. Treatment Method
    The pharmaceutical emulsions of the present invention can be administered parenterally, preferably intravenously or intraarterially, to individuals, for therapeutic or prophylactic use. In a preferred embodiment, the individual is a mammal, more preferably a human.
    The formulations have neuroprotective and / or neuroregenerative properties. The formulations are useful in the treatment or prevention of disorders or conditions of the nervous system. Exemplary disorders and conditions include, but are not limited to, conditions of the central nervous system (CNS) or, spinal cord injury, traumatic brain injury, mild head trauma, including concussion characterized by a temporary loss of brain function, pediatric brain injury, disorders degenerative CNS, such as Parkinson's disease, dementia, including Alzheimer's disease, demyelinating conditions such as chronic and multiple sclerosis, peripheral diabetic neuropathology.
    Other exemplary disorders and conditions include ischemic neurological conditions, such as ischemic CNS injuries, stroke, including ischemic stroke, hemorrhagic stroke and transient ischemic attacks, and cognitive impairments attributed to cardiopulmonary bypass during heart surgery, for example , the post-perfusion syndrome. Other examples include aphasia, sleep disorders and anxiety disorders, such as post-traumatic stress disorder.
    The formulations are also useful in providing relief from the symptoms associated with the diseases listed above, such as restoring cognitive function, restructuring sleep patterns, normalizing mood disorders, etc. The formulations of the present invention are also useful in the treatment of disorders, post-traumatic stress disorder.
    In one embodiment, the present invention relates to methods for treating a mammal with a traumatic CNS injury, more particularly, a traumatic brain injury (TBI). The methods comprise treating a TBI in a mammalian individual, by administering to the subject in need, a pharmaceutical composition according to the present invention, such that the therapeutically effective concentration of progestogen is provided. In a preferred embodiment, the mammalian individual is a human being. The method of the present invention comprises the parenteral administration of the pharmaceutical compositions comprising progestogen, of the present invention, to an individual who has a traumatic CNS injury, more particularly, a TBI. According to the method of the present invention, the pharmaceutical composition is used to promote a positive therapeutic response with respect to traumatic CNS injury.
    TBI is physical damage to brain tissue that temporarily or permanently impairs brain function. The diagnosis is clinically presumed and can be confirmed by imaging (mainly CT). Clinical manifestations vary widely in terms of severity and consequences. Lesions are generally classified as open or closed. Open lesions involve penetration of the scalp and skull. Closed injuries usually occur when the head is hit, when it hits an object, or is shaken violently, causing the brain to accelerate and decelerate rapidly. Thus, the compositions of the present invention can be used to treat a TBI, including, uncut trauma (i.e., closed wounds), as well as penetrating trauma. By "treatment" is meant any improvement in the individual who has an injury .; traumatic CNS, including both an improvement in morphological recovery (ie, increased tissue viability) and / or behavior recovery. The improvement can be characterized as an increase in the rate and / or size of the behavioral and anatomical recovery after traumatic CNS injury. Consequently, a "positive therapeutic response" includes both a complete and a partial response. Various methods for determining whether a complete or partial therapeutic response has occurred are discussed in detail in patent applications W02006 / 102644, W02006 / 102596, and W02008 / 039898.
    By "therapeutically effective amount" is meant a concentration of progestogen that is sufficient to cause a therapeutic effect.
    Thus, the concentration of a progestogen in a unit dose administered in accordance with the present invention is effective in the treatment or prevention of a neuronal injury, which follows traumatic injury to the central nervous system and therefore causes a neuroprotective effect. Neurodegeneration is the progressive loss of neurons in the central nervous system. As used here, the term "neuroprotection" is the capture and / or reversal of neurodegeneration progression after a traumatic CNS injury. The therapeutically effective amount will depend on many factors, including, for example, the specific activity of the progestogen, the severity and pattern of the traumatic injury, the resulting neuronal injury, the patient's responsiveness, the patient's weight, along with other variability intrapersonal, the mode and / or method of administration, and the progestogen formulation used.
    The emulsion compositions comprising progestogen of the present invention can be administered using any acceptable method known in the art, including intravenous (IV), intramuscular (IM) or subcutaneous (SC) injection. In specific embodiments of the invention, the pharmaceutical composition comprising progestogen is administered by IV injection. When administered intravenously, the pharmaceutical composition comprising progestogen can be administered by infusion over a period of 1 to 144 hours. In some modalities, progestogen infusion occurs over a period of 24 to 72 hours, over a period of 48 to 96 hours, or over a period of 24 to 144 hours. In a preferred embodiment, the progestogen infusion occurs over a period of 96 to 120 hours.
    In one embodiment of the present invention, the composition is administered by parenteral administration, preferably intravenously, in a total dose of 0.1 ng to 100 g per kg of body weight, from 10 ng to 50 g per kg of body weight, from 100 ng to 1 g per kg of body weight, from 1 μg to 100 mg per kg of body weight, from 1 mg to 90 mg per kg of body weight, from 2 mg to 80 mg per kg of body weight, and from 3 mg to 70 mg per kg of body weight. Alternatively, the amount of progestogen administered to achieve an effective therapeutic dose is 0.1 ng, 1 ng, 10 ng, 100 ng, 1 μg, 10 μg, 100 μg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg , 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 500 mg per kg of body weight, or more. In a preferred embodiment, progestogen is administered intravenously, in a total dose between 50 mg and 90 mg per kg of body weight.
    Progestogen can be administered once or several times a day. The duration of treatment can be once a day, for a period of 1, 2, 3, 4, 5, 6, 7 days or more. The daily dose can be administered either by a single dose in the form of an individual dosage unit, or by several smaller dosage units, or by multiple administration of dosages subdivided at certain intervals. Subsequent dosage units can be administered at any time, after the initial administration, in such a way that the therapeutic effect is achieved. For example, additional dosage units can be administered to protect the individual from the secondary edema wave that can occur during the first post-injury days. In a preferred embodiment, the dosage unit is administered no more than 8 hours after the injury.
    In specific embodiments of the invention, progestogen is administered in a constant dosage regimen. By "constant dosing regimen" is meant that the progestogen is administered in a total hourly constant infusion dose of progestogen throughout the course of treatment. In other embodiments of the invention, the therapy is administered in a "two-level dosing regimen". By "two-level dosing regimen" is meant that the composition is administered over two periods of dosing time. In one embodiment, the total hourly dose of progestin, administered .. during the first period of time of the two-level dosing regimen, is a higher dose of total progestin infusion per hour than that given during the second time period of the two-level dosing regimen. In a specific embodiment, a continuous dose of 0.71mg / kg / hr administered intravenously, during the first period of time of the progestogen two-level dosing regimen, and a dose of 0.5mg / kg / hr is administered during the second period of time, on the two-level progestogen dosing regimen. In a highly specific modality, the first period of time of the dosing regimen of the two levels has a duration of 1 hour, and the second period of time has a total duration of 120 hours.
    The present method of treatment normally reaches a final serum level of progestogen in the individual from 100 ng / ml to 1000 ng / ml, 1100 ng / ml to 1450 ng / ml, 100 ng / ml to 250 ng / ml, 200 ng / ml at 350 ng / ml, 300 ng / ml at 450 ng / ml, 350 ng / ml at 450 ng / ml, 400 ng / ml at 550 ng / ml, 500 ng / ml at 650 ng / ml, 600 ng / ml at 750 ng / ml, 700 ng / ml at 850 ng / ml, 800 ng / ml at 950 ng / ml, 900 ng / ml at 1050 ng / ml, 1000 ng / ml at 1150 ng / ml, 1100 ng / ml at 1250 ng / ml, 1200 ng / ml at 1350 ng / ml, 1300 ng / ml at 1500 ng / ml. In specific modalities, the serum progestogen level comprises 100 ng / ml, 250 ng / ml, 300 ng / ml, 350 ng / ml, 360 ng / ml, 370 ng / ml, 380 ng / ml, 390 ng / ml, 400 ng / ml, 410 ng / ml, 420 ng / ml, 430 ng / ml, 440 ng / ml, 450 ng / ml, 500 ng / ml, 750 ng / ml, 900 ng / ml, 1200 ng / ml, 1400 ng / ml or 1600 ng / ml. The serum concentration of the progestogen can be determined by calculating the area under the curve (AUC) over time after IV administration of the reference composition to an individual, as described in W02006 / 102596.,
    In other embodiments of the present invention, at least one additional neuroprotective agent can be combined with the progestogen (either as part of the same composition, or as a separate composition) to improve neuroprotection after a traumatic CNS injury. Such agents include, for example, vitamin D, and / or compounds that reduce the excitotoxicity of glutamate and improve neuronal regeneration. Such agents can be selected from, but are not limited to, the group comprising growth factors. By "growth factor" is meant an extracellular signaling molecule that stimulates a cell to grow or proliferate. When progestogen is administered in conjunction with other pharmaceutically active agents, (that is, other neuroprotective agents) lower concentrations of progestogen may be therapeutically effective.
    With this invention now generally described, it will be better understood by reference to certain specific examples which are included here for purposes of illustration only, and are not intended to be limiting of the present invention, unless specified. EXAMPLES Example 1 - Preferred Mode.
    The formulation of Example 1 is a 6% oil emulsion composition, comprising 0.2% progesterone and 1.2% egg lecithin. Phospholipid is present in an amount of 17% of the oil in (weight / weight), and the oil to progesterone ratio is 1:30 in (weight / weight). Table I

    The emulsion from Table I was manufactured as follows. Components, mixtures and the final emulsion were kept under nitrogen gas, and at a temperature of 55 ° C to 60 ° C, unless otherwise specified. 180L of water for injection (w.f.i.) was added to a first container, heated to 58 ° C, while being mixed at 50Hz and degassed with nitrogen until the residual oxygen concentration of 0.1 mg / L was obtained. 9.98 kg of glycerol (anhydrous glycerin, Axelis, Austria) were added to the water and mixed for 5 minutes at 50 Hz. 23, 97 kg of soy oil (Fresenius Kabi, Sweden) were added to a second container, stirred at 50 Hz and heated to 58 ° C. 0.81 kg of progesterone (micronized progesterone (by Proquina, Mexico) was added to the heated soy oil under constant stirring. 4.77 kg of egg lecithin (PL90, Fresenius Kabi, Sweden), were added to the water mixture and heated glycerol, followed by 0.12 kg of oleic acid (Merck KGaA) and 470 ml of 1M NaOH (Merck KGaA). The contents of the first container were stirred with Ultra Torrax (UT) at 50Hz until a homogeneous suspension was obtained (approximately 15 minutes).
    When the oil phase in the second vessel reached a temperature of 56 ° C and the progesterone was completely dissolved, the mixture was stirred for an additional 15 minutes. The oil phase was filtered through a 0.2 µm filter, and slowly transferred to the first container (over a period of about 18 minutes). Two 5L volumes of water for injection, heated to 58 ° C were used to wash the second container, before adding it to the first container. An additional 110 mL of 1M NaOH was used to bring the pH to pH 8.0. The pre-emulsion was stirred with UT at 50Hz for 15 minutes, and a visually homogeneous pre-emulsion was achieved.
    The pre-emulsion was then subjected to 4 homogenization cycles, each cycle lasting about 70 min., And each, consisting of two homogenization steps. The first cycle consisted of a first stage at 418 bars, and a second stage at 108 bars. The second consisted of a first stage at 407 bars, and a second stage at 103 bars. The third cycle consisted of a first stage at 411 bars, and a second stage at 102 bars. The final cycle consisted of a first stage at 410 bars, and a second stage at 101 bars. The temperature of the pre-emulsion was between 50 ° C and 67 ° C, including throughout. 150 L of water for injection was added to a storage tank, heated to 27.9 ° C and degassed with nitrogen gas to achieve a residual oxygen concentration of 0.1 mg / L. The emulsion was filtered through a 10μm filter in the storage tank containing water for injection. The emulsion was cooled to 27 ° C, sampled, and sufficient water (23L) was added to bring the emulsion to the final concentration. The final emulsion was degassed with a residual oxygen content of 0.1 mg / L, and stored under nitrogen gas at 27 ° C for 11 hours before filling the emulsion in vials. The emulsion was filled in glass bottles, and sealed, generating packaged unit doses of about 250 ml. The amount of oxygen in the emulsion was maintained at a level of 0.1 mg / L throughout the filling process, by gasifying the vials with nitrogen before filling, and the gasification of the emulsion and the vials during filling.
    The bottles were sterilized in an autoclave with a rotation cycle, at 121 ° C for a retention time of 15 min. (basket with sample rotation at 4 rpm).
    The data in the table below shows the physical and chemical characteristics of the emulsion of example 1 before sterilization, after sterilization by autoclaving at 121 ° C for 1.5 minutes, and after storing the sterile emulsion at 60 ° C for 3 weeks, and for 4 weeks.


    The emulsions of Example 1 have a particle size distribution representative of stable and safe to administer compositions. Accusizer values show that the PFAT5 value is well within the limit of <0.05%. Mastersizer data shows that the emulsions have low mean particle size values (d (0.5)) and low mean particle size values (D [4.3]), which are representative of stable emulsions.
    In addition, the particle size values do not show any increase. significant after heat sterilization or storage at 60 ° C for 3 or 4 weeks. The emulsion compositions of Example 1 also exhibit NEFA, LPC and pH values within specification after sterilization and storage.
    Comparative Example 2 - Oil-in-Water Emulsions containing Progesterone
    The formulation in Table II is an emulsion composition of 20% of the oil, in which the phospholipid is present in an amount of 6% of the oil in (weight / weight), and the progesterone is present in an amount of 3% of the oil in (weight / weight). The 20% emulsion formulation in Table II was further diluted with saline or water to produce 5% oil emulsions, comprising 0.26% phospholipids and 0.15% progesterone. Emulsions at 5% produced with saline are not homogeneous (that is, separated in phase), and emulsions at 5% produced with water have very low osmolality. The formulations of Example 2, therefore, are outside the scope of the claims of the present invention. Table II
    A. The 20% oil emulsion formulation from Table II (Example 2A) was produced using the following method. 400 g of soy oil was heated in a container at about 70 ° C. 12 g of progesterone was added to the soybean oil, and the mixture was stirred with a magnetic stirrer. 400 ml of water was placed in a separate container and heated to about 70 ° C. 50 g of glycerol was added to the aqueous phase and dissolved by a high shear mixture. 24g of egg lecithin was added to the glycerol solution under high shear mixture. The oil phase was slowly added to the water phase under a constant high shear mixture. 0.6 g of sodium oleate was added, and the solution was also mixed. The resulting pre-emulsion was subjected to 4 cycles of homogenization at 400 bar (Minilab homogenizer). The emulsion was allowed to cool to 25 ° C, the final volume was adjusted to 100% (2L), and the emulsion was stirred. The emulsion was filtered through a 5 μm filter, and filled into 50 ml glass bottles. The vials were autoclaved at 121 ° C for a retention time of 15 min. B. The 5% oil emulsion of Example 2B was prepared by diluting 500 ml of the non-autoclaved emulsion of Example 2A with 1500 ml of 0.9% NaCl. After dilution with 0.9% NaCI, the 10 phase separate emulsions. C. The emulsion of Example 2C was prepared by diluting 500 ml of the non-autoclaved emulsion of Example 2A with 1500 ml of water for injection. The emulsion was filtered through a 5 μm filter. The emulsion was placed in 50 ml glass bottles. The vials were autoclaved at 121 ° C for a retention time of 15 minutes, and stored for 3 weeks at 60 ° C.


    Emulsion compositions at 20% (2A) have a PFAT5 value that exceeds the limits established by USP, chapter <729>. In addition, the 20% compositions have D [4.3], and d (0.5) values higher than the compositions of the present invention, and these values increase after autoclaving, indicating physical instability.
    The dilution of 20% oil emulsions of Example 2A with 0.9% NaCl, induced the resulting emulsions (2B) to phase separation. Dilution of the 20% oil emulsions of Example 2A with water to obtain the 5% (2C) oil emulsions generated homogeneous white emulsions, with a very low osmolality. Analysis of the physicochemical properties of 2C emulsions revealed that they have a PFAT5 value that far exceeds the maximum value defined by USP, chapter <729>. In addition, the median particle size, and the average particle size values are greater than the equivalent values observed for the emulsions according to the present invention, and increase after autoclaving, indicating poor physical stability.
    Comparative Example 3 - Oil-in-Water Emulsions containing Progesterone and Estradiol
    The formulation in Table III is a 20% oil emulsion composition, in which phospholipid is present in an amount of 6% of the oil in (weight / weight), and the progesterone is present in an amount of 3% of the oil in (weight / weight). The formulation additionally contains 0.066% Estradiol hemihydrate. The 20% emulsion formulation from Table III was diluted with saline or water to produce 5% oil emulsions, comprising 0.26% phospholipids, and 0.15% progesterone. The formulations of example 3 are outside the scope of the claims of the present invention. Table III
    A. The emulsion of Example 3A was manufactured using the following method. 400 g of soybean oil was heated in a container at 70 ° C. 12 g of progesterone and 1.32 g of estradiol hemihydrate were added to the soybean oil. The mixtures were stirred with a magnetic stirrer. 400 ml of water was placed in a separate container and heated to 70 ° C. 50g of glycerol was added to the aqueous phase and dissolved by a high shear mixture. 24g egg lecithin was added to the glycerol solution with a high shear mixture. The oily phase was slowly added to the aqueous phase under a constant high shear mixture. 0.6 g of sodium oleate was added, and the solution was also mixed. The resulting preemulsion was subjected to 4. 400 bar homogenization cycles (Minilab homogenizer),. The emulsion was allowed to cool to 25 ° C, the final volume was adjusted to 100% (2L), and the emulsion was stirred. The emulsion was filtered through a 5 μm filter. The emulsion was placed in 50 ml glass bottles. The vials were sterilized in an autoclave at 121 ° C for a retention time of 15 min. B. The emulsion of Example 3B was made by diluting 500 ml of the non-autoclaved emulsion of Example 2A, with 1500 ml of 0.9% NaCl, and stirred. After dilution with 0.9% NaCI, separate phase emulsions.
    C. The emu) Ls of Example 3C was made by diluting 500 ml of the non-autoclaved emulsion of Example 5 3A, with 1500 ml of water for injection, and stirred. The emulsion was filtered through a 5 μm filter. The emulsion was placed in 50 ml glass bottles. Some vials were sterilized in an autoclave at 121 ° C for a retention time of 15 min., And then stored for 3 or 10 4 weeks at 60 ° C.
    The 20% emulsion compositions have a PFAT5 value that exceeds the limits set by USP chapter <729>. In addition, the 20% compositions have D [4.3], and d (0.5) values greater than the compositions of the present invention, and these values increase after autoclaving, indicating physical instability.
    The 20% dilution of oil emulsions of Example 3A, with 0.9% NaCl, resulted in the resulting emulsions (3B) with separate phases.
    The dilution of the oil emulsions in 20% of Example 3A with water, to generate oil emulsions in 5% (3C) generated homogeneous white emulsions, with very low osmolality.
    The analysis of the physicochemical properties of 3C emulsions revealed that they have a PFAT5 value that far exceeds the maximum value defined by USP, chapter <729>. In addition, the mean and median values of particle size are greater than the equivalent values observed for the emulsions according to the present invention. Example 4 - Effect of Phospholipid
    The following example demonstrates the effect of varying the phospholipid content of emulsion compositions on the properties of emulsions. The 6% oil emulsions from Table IV were prepared by the method described below. The emulsions contained 0.2% progesterone, and either 1.8%, 1.5%, 0.9%, or 0.6% lecithin. Table IV
    The emulsions of Example 4 of AD were prepared using the following method. 600 g of soy oil (Fresenius Kabi, Sweden) was added to a container, and heated to 58 ° C.
    The oil was kept under an atmosphere of nitrogen gas while 20g of progesterone (progesterone micronized by Proquina, Mexico) was added to the soybean oil, and dissolved by mixing with a magnetic stirrer. Water for injection was placed in a second container and heated to 58 ° C. 250g of glycerol (anhydrous glycerol, Axelis, Austria) was added to the aqueous phase and dissolved by a high shear mixture. The indicated amount of egg lecithin (PL90 by Fresenius Kabi, Sweden), and 3 g of sodium oleate (Merck KGaA) were added to the aqueous phase.
    The oil phase was added slowly to the aqueous phase under a constant high shear mixture. 9 ml of NaOH was added to the mixture and stirred by a high shear mixture.
    The pre-emulsion underwent four homogenization cycles, each cycle comprising 2 stages. The first stage consists of 400 +/- 30 bars, and the second stage consists of 100 +/- 30 bar. The emulsion was cooled to 20 ° C, enough water for injection was added to generate the final volume of the emulsion at 100%, and the emulsion was stirred by a high shear mixture. Whenever necessary, sufficient amount of NaOH (1 M) was added to adjust the pH of the emulsion (for example, emulsion A: 3 ml of NaOH). The emulsion was filtered through a 10μm filter, and placed in 50 ml glass bottles. The bottles were sterilized in a rotation cycle for 15 min. at 121 ° C. Sterilization was repeated twice. The vials were subsequently stored for 3 or 4 weeks at 60 ° C.





    The A-D compositions formed homogeneous white emulsions with particle size parameters that represent safety, to administer heat and storage stable emulsions; PFAT5 values are well within the acceptable range (^ 0.05%). With the decrease in the lecithin content, a clear tendency to increase the "span", the values D [4,; 3], and d (0.5) are observed, and it is indicative of the reduction of the physical stability of the emulsions. t
    In particular, a greater increase in particle size (D [4.3], d (0.5)) is seen more in 0.6% lecithin emulsions (formulation 4D) than in high emulsion formulations of lecithin. 15 Example 5 - Co-surfactant effect
    The following example demonstrates how the absence of the co-surfactant content of the emulsion compositions affects the properties of the emulsions. The 6% oil emulsions from Table V were prepared by the method described below. Table V

    The emulsion of Example 5 was prepared by the following method. 60g of soy oil (Fresenius Kabi, Sweden) was added to a container, and heated to 72 ° C. The oil was kept under an atmosphere of nitrogen gas, while 2 g of progesterone (progesterone micronized by Proquina, Mexico) was added to the soybean oil and dissolved by mixing with a magnetic stirrer. Water for injection was placed in a second container and heated to 65 ° C. 25g of glycerol (anhydrous glycerol, Axelis, Austria) was added to the aqueous phase and dissolved by a high shear mixture. 12g of egg lecithin (PL90 by Fresenius Kabi, Sweden) was added to the aqueous phase. The oily phase was / slowly added to the aqueous phase under constant high shear mixture. The pre-emulsion was subjected to five homogenization cycles, at 600 bars. The emulsion was cooled to 20 ° C, enough water for injection was added to generate the final volume of the emulsion at 100%, and the emulsion was stirred by a high shear mixture. 500 μl of NaOH was added to the mixture to adjust the pH of the emulsion. The emulsion was filtered through a 10 μm filter, and placed in 50 ml glass bottles. The bottles were sterilized in a rotation cycle, for 15 minutes at 121 ° C. Sterilization was repeated twice so that the samples were subjected to stability tests.
    5 Co-surfactant-free emulsion compositions produced viable emulsions. The parameters of particle size D [4.3], d (0.5), Span and PFAT5 values were slightly elevated in relation to the emulsions containing the co-surfactant (Example 1).
    权利要求:
    Claims (16)
    [0001]
    1. Pharmaceutical oil-in-water emulsion composition, ready for use, and sterile for parenteral administration characterized by comprising: • 0.015 to 0.5% by weight / volume, preferably 0.05 to 0.4% by weight / volume progesterone; • 0.5 to 10% by weight / volume of oil, where the oil comprises at least 85% by weight / weight of triglyceride; • 0.0425 to 4.1% by weight / volume, preferably 0.064 to 3.4% by weight / volume of phospholipid; • 80-99.4% by weight / volume of aqueous medium; where the composition has an osmolarity in the range of 200-1000 mOsm / kg and where the emulsion contains no more than 1.2% by weight / weight of polyethylene glycol 15-hydroxystearate.
    [0002]
    Composition according to claim 1, characterized in that the progesterone is present in an amount greater than 1% by weight / weight of oil, preferably greater than 1.5% by weight / weight of oil.
    [0003]
    Composition according to any one of the preceding claims, characterized in that the phospholipid is present in the range of 6.8-43% by weight / weight of oil, preferably 8.4-42.5% by weight / weight of oil, more preferably 12-26% by weight / weight of oil, even more preferably 14-25% by weight / weight of oil.
    [0004]
    Composition according to any one of the preceding claims, characterized in that the composition contains 0.005-4% by weight / volume of a co-surfactant.
    [0005]
    5. Composition according to claim 4, characterized in that the co-surfactant is selected from the group consisting of C12-C22 fatty acids, their salts and / or mixtures, preferably from C16-C20 fatty acids, their salts and / or mixtures, more preferably, from C18 fatty acids, their salts and / or mixtures.
    [0006]
    6. Composition according to claim 5, characterized in that the co-surfactant is selected from oleate, oleic acid and their combinations, and is present in the range of 0.005-0.5% by weight / volume.
    [0007]
    Composition according to any one of the preceding claims, characterized in that the composition contains an osmotic agent, preferably glycerol.
    [0008]
    Composition according to any one of the preceding claims, characterized in that the oil is composed of at least 90% by weight / weight, preferably at least 95% by weight / weight, of triglycerides.
    [0009]
    Composition according to any one of the preceding claims, characterized in that the composition is suitable for intravenous administration.
    [0010]
    Composition according to any one of the preceding claims, characterized in that the composition is packaged in a sealed container under an upper space of inert gas.
    [0011]
    Composition according to any one of the preceding claims, characterized in that it comprises: • 0.15-0.25% by weight / volume of progesterone; • 5-7% by weight / volume of oil; • 1.0-1.4% by weight / volume of egg lecithin; • 80-98.9% by weight / volume of water; wherein the composition has a pH of 6.0-9.0.
    [0012]
    Composition according to any one of the preceding claims, characterized in that the composition has a PFAT5 value <0.05%.
    [0013]
    Composition according to any one of the preceding claims, characterized in that the droplet particles of the dispersed oil phase have an average diameter based on volume of <300nm, preferably <250nm, more preferably <200nm, even more preferably <185nm, more preferably <180nm.
    [0014]
    Composition according to any one of the preceding claims, characterized in that it is for use in the therapeutic or prophylactic treatment of a mammal, the treatment comprising the parenteral, preferably intravenous, administration of the pharmaceutical emulsion to the mammal.
    [0015]
    15. Method of manufacturing a composition as defined in any of claims 1 to 14, the method characterized by comprising the steps of: a. combining water, phospholipid, and optionally an osmotic agent to produce an aqueous composition; B. combining progesterone and oil to produce an oily composition; ç. combine the aqueous composition and the oil composition, followed by homogenization to form a homogeneous oil-in-water emulsion.
    [0016]
    16. Method according to claim 15, characterized by the combination of step c) being achieved by adding the oil composition to the aqueous composition, followed by homogenization of more than or equal to 350 bar.
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    法律状态:
    2018-05-29| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2018-07-03| B25G| Requested change of headquarter approved|Owner name: BESINS HEALTHCARE LUXEMBOURG SARL (LU) |
    2019-02-26| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2019-10-01| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2020-05-05| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2020-10-20| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-12-29| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 26/04/2011, OBSERVADAS AS CONDICOES LEGAIS. |
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    US32796810P| true| 2010-04-26|2010-04-26|
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    US201061424402P| true| 2010-12-17|2010-12-17|
    EP10195760.3|2010-12-17|
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    US61/424,402|2010-12-17|
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    US61/424,407|2010-12-17|
    PCT/EP2011/056548|WO2011134944A2|2010-04-26|2011-04-26|Low-oil pharmaceutical emulsion compositions comprising progestogen|
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