Method for producing an oil-in-water emulsion

Abstract

The present invention relates to a method for the efficient production of an oil-in-water emulsion preferably for parenteral administration, characterized in that most of the aqueous phase is added only after the energy-intensive homogenization of the pre-emulsion, i.e. an emulsion with a low water content is first produced and subsequently the emulsion is "diluted".

Description

Field of the Invention

[0001] The present invention relates to the production of oil-in-water emulsions, emulsions produced according to the method of the present invention, and their use as pharmaceuticals or for providing parenteral nutrition. Background Art

[0002] An emulsion is a dispersion system of two immiscible liquids. In an emulsion, a distinction is made between the internal or dispersed phase (divided into discrete droplets) and the external phase (dispersant).

[0003] Such systems are unstable without additional additives, but can be stabilized, for example, by adding an emulsifier. Emulsifiers belong to the group of surface-active substances. They attach to the phase boundary, promote the formation of droplets (which form the internal phase in the external phase), and counteract phase separation.

[0004] In an oil-in-water emulsion, the oil droplets are dispersed in the aqueous phase.

[0005] The production of oil-in-water emulsions serves various purposes, for example as a basis for emulsions for parenteral nutrition or as an emulsion containing a pharmaceutical (such as propofol).

[0006] Oil-in-water emulsions for parenteral administration must also have an osmolarity as similar as possible to that of blood (at least when administered in larger volumes), i.e., an isosmotic agent must be added to the emulsion.

[0007] The disadvantage of these oil-in-water emulsions is that their production (especially in terms of the quality required for parenteral administration) is complex and has a very high rejection rate.

[0008] Pharmaceutical oil-in-water emulsions for parenteral use are produced as a standard two-stage method, in which a pre-emulsion is first produced from an aqueous phase (containing an isosmotic agent), an emulsifier, and an oil phase, in which the diameter of the oil droplets is in the micrometer range. The pre-emulsion can be produced, for example, with the aid of a rotor-stator disperser.

[0009] Then, for example, an emulsion is obtained from the pre-emulsion by a multi-stage high-pressure homogenization method. In this method, the oil droplets are minimized so that such an emulsion also meets the requirements of a formulation for parenteral administration (especially in terms of the droplet size distribution).

[0010] In the case of an oil-in-water emulsion for parenteral administration, for physiological reasons (due to the anatomy and size of blood vessels), the average diameter of the oil droplets must not exceed 0.5 μm.

[0011] Furthermore, in the case of an emulsion for parenteral administration, the PFAT5 value (the percentage ratio of oil droplets with a diameter greater than 5 μm in the oil phase of an oil-in-water emulsion) must be below 0.05% (see USP 729).

[0012] However, situations often occur where this limit value is exceeded. In fact, PFAT5 values higher than 0.05% are found in approximately 20% to 30% of the emulsions produced. These batches have to be destroyed, which causes huge economic losses.

[0013] In addition, the methods currently implemented as standards are very time-consuming and energy-intensive.

[0014] Therefore, the object of the present invention is to provide a time-saving and energy-saving method for producing an oil-in-water emulsion, which allows an emulsion that meets the high requirements of a composition for parenteral administration to be obtained reliably and reproducibly. Summary of the Invention

[0015] This object is unexpectedly achieved by the following: in the method for producing an oil-in-water emulsion according to the present invention, most of the aqueous phase is added only after the energy-intensive homogenization of the pre-emulsion, that is, an emulsion with a lower water content is first produced and then the emulsion is diluted.

[0016] Therefore, the present invention relates to a method for producing an oil-in-water emulsion, the oil-in-water emulsion comprising an aqueous phase and an oil phase of 1% to 40%, preferably 5% to 30%, most preferably 10% to 30% relative to the total weight of the emulsion, wherein the method comprises the following steps:

[0017] a) Providing an oil phase, the oil phase comprising one or more oils and optionally at least one pharmaceutically acceptable antioxidant and / or at least one pharmaceutically acceptable co-emulsifier,

[0018] b) Providing an aqueous phase 1, the aqueous phase 1 comprising water and optionally at least one pharmaceutically acceptable co-emulsifier and / or at least one substance for setting the pH value and / or at least one pharmaceutically acceptable preservative and / or at least one pharmaceutically acceptable isotonic agent, wherein the isotonic agent is present at a concentration of at most 18%, preferably 15%, particularly preferably at most 14.3% relative to the total weight of the aqueous phase 1,

[0019] c) Producing a pre-emulsion by mixing the oil phase provided in step a) with the aqueous phase 1 provided in step b),

[0020] d) Producing a first emulsion by homogenizing the pre-emulsion provided in step c),

[0021] e) Providing an aqueous phase 2, the aqueous phase 2 comprising water and optionally at least one pharmaceutically acceptable isotonic agent and / or at least one substance for setting the pH value and / or at least one pharmaceutically acceptable preservative,

[0022] f) The emulsion is produced by mixing the first emulsion provided in step d) with the aqueous phase 2 provided in step e), and

[0023] g) The emulsion obtained in step f) is sterilized,

[0024] wherein the emulsion is filled into a suitable container before or after sterilization,

[0025] wherein at least one pharmaceutically acceptable emulsifier is added in step a) and / or step b), and

[0026] wherein the aqueous phase 1 provided in step b) provides no more than 70%, preferably no more than 50%, particularly preferably no more than 30% and most preferably no more than 20% of the total amount of water contained in the emulsion.

[0027] The present invention also relates to an oil-in-water emulsion obtained according to this method and its use as a drug or for providing parenteral nutrition.

[0028] Furthermore, the present invention relates to the first emulsion obtained in step d). Detailed Description

[0029] In the case of known methods for producing an oil-in-water emulsion, first a pre-emulsion is produced by intensive mixing of the entire aqueous phase and the entire oil phase in the presence of at least one emulsifier (previously added to the oil phase or the aqueous phase according to its chemical nature), at least one isotonic agent (if applicable) and (if applicable) at least one preservative, (if applicable) at least one agent for setting the pH value and / or other water-soluble substances being previously added to the aqueous phase, and at least one antioxidant and (if applicable) other lipophilic components being previously added to the oil phase.

[0030] This pre-emulsion is transferred to an emulsion by homogenization, for example by means of a high-pressure homogenizer, an inverse jet disperser or using ultrasound, in which the average size of the oil droplets is significantly reduced compared to the pre-emulsion.

[0031] These processes are time-consuming and energy-intensive and in some cases require large-scale equipment.

[0032] It has now unexpectedly been found that when producing the pre-emulsion and obtaining the emulsion, the aqueous phase portion can be omitted and added only after emulsification without negatively affecting the quality of the emulsion, provided that the concentration of the isotonic agent in the aqueous phase 1 during the emulsification process does not exceed 18%, preferably 15%, particularly preferably 14.3% relative to the total weight of the aqueous phase 1.

[0033] A method for producing an oil-in-water emulsion (the oil-in-water emulsion comprising an aqueous phase and an oil phase of 1% to 40%, preferably 5% to 30%, most preferably 10% to 30% based on the total weight of the emulsion) according to the present invention comprises the following steps:

[0034] a) providing an oil phase, the oil phase comprising one or more oils and optionally at least one pharmaceutically acceptable antioxidant and / or at least one pharmaceutically acceptable co-emulsifier,

[0035] b) providing an aqueous phase 1, the aqueous phase 1 comprising water, optionally at least one pharmaceutically acceptable co-emulsifier and / or at least one pH-setting substance and / or at least one pharmaceutically acceptable preservative and / or at least one pharmaceutically acceptable isotonic agent, wherein the isotonic agent is present at a concentration of at most 18%, preferably 15%, particularly preferably at most 14.3% based on the total weight of the aqueous phase 1,

[0036] c) producing a pre-emulsion by mixing the oil phase provided in step a) with the aqueous phase 1 provided in step b),

[0037] d) producing a first emulsion by homogenizing the pre-emulsion provided in step c),

[0038] e) providing an aqueous phase 2, the aqueous phase 2 comprising water, optionally at least one pharmaceutically acceptable isotonic agent and / or at least one pH-setting substance and / or at least one pharmaceutically acceptable preservative,

[0039] f) producing the emulsion by mixing the first emulsion provided in step d) with the aqueous phase 2 provided in step e), and

[0040] g) sterilizing the emulsion obtained in step f),

[0041] wherein the emulsion is filled into a suitable container before or after sterilization,

[0042] wherein at least one pharmaceutically acceptable emulsifier is added in step a) and / or step b), and

[0043] wherein the aqueous phase 1 provided in step b) provides no more than 70%, preferably no more than 50%, particularly preferably no more than 30% and most preferably no more than 20% of the total amount of water contained in the emulsion.

[0044] The present invention also relates to an oil-in-water emulsion produced according to this method and its use as a drug or for providing parenteral nutrition.

[0045] The invention also relates to the emulsion which can be packaged, stored and transported before further processing of the emulsion obtained in step d) of the method according to the invention in steps e), f) and g).

[0046] The invention also relates to the emulsion obtained in step d), which is used for further processing in steps e), f) and g) of the method according to the invention.

[0047] The method according to the invention is advantageous in several respects:

[0048] Firstly, due to the reduction in the volume of the aqueous phase, the capacity of the homogenization tool is saved, which results in a shorter homogenization time and thus a significant improvement in yield / efficiency. (Thus, for example, a high-pressure homogenizer requires approximately one hour to homogenize 1000 kg of a pre-emulsion.)

[0049] Secondly, since a smaller mass has to be processed in an energy-intensive working step, time and energy are saved. In addition to the increased efficiency during homogenization mentioned above, the heating of the aqueous phase in particular is more efficient in terms of energy and time due to its reduced mass.

[0050] Thirdly, there is also significant potential for savings in terms of the vessel and space dimensions within the production facility.

[0051] The method also unexpectedly provides an emulsion of better quality. An improvement can particularly be found in the droplet size distribution.

[0052] Therefore, the droplet size distribution of the emulsion produced by the method according to the invention is more reproducible and narrower.

[0053] In addition, the PFAT5 value of the emulsion produced by the method according to the invention is significantly lower.

[0054] The emulsion produced by the method according to the invention preferably has a PFAT5 value of less than 0.05%, particularly preferably less than 0.04%, more preferably less than 0.03% and most preferably less than 0.02%.

[0055] The emulsion produced by the method according to the invention preferably has an average PFAT5 value of less than 0.035%, particularly preferably less than 0.030%, and very particularly preferably less than 0.025%. Quite particularly preferably, the emulsion produced by the method according to the invention is more preferably less than 0.020%, even more preferably less than 0.015% and most preferably less than 0.010%. A sample volume of at least 10 has to be used to determine this average value.

[0056] In the case of production according to known standard methods, it is generally found in practice that the PFAT5 value is higher than 0.05%. Unexpectedly, the method according to the present invention reduces the PFAT5 value to well below 0.05%, and the average PFAT5 value is well below 0.035%. The present invention also relates to a system for producing an oil-in-water emulsion, wherein the oil-in-water emulsion comprises an aqueous phase and an oil phase of 1% to 40% t, preferably 5% to 30%, most preferably 10% to 30% relative to the total weight of the emulsion, and the system comprises

[0057] a) a first vessel and a first device for mixing and / or dispersing, preferably stirring, the components in the first vessel, the first vessel being for providing an oil phase comprising: one or more oils and optionally at least one pharmaceutically acceptable antioxidant and / or at least one pharmaceutically acceptable co-emulsifier,

[0058] b) a second vessel and a second device for mixing and / or dispersing, preferably stirring, the components in the second vessel, the second vessel being for providing an aqueous phase 1 comprising: water, optionally at least one pharmaceutically acceptable co-emulsifier and / or at least one substance for setting the pH value and / or at least one pharmaceutically acceptable preservative and / or at least one pharmaceutically acceptable isotonic agent, wherein the isotonic agent is present at a concentration of at most 18% t, preferably at most 15%, relative to the total weight of the aqueous phase 1,

[0059] c) a tank for receiving the components from the first vessel via a first sterile filter and the components from the second vessel via a second sterile filter, wherein the tank has a third device for mixing and / or dispersing for producing a pre-emulsion by mixing the oil phase from the first vessel and the aqueous phase 1 from the second vessel,

[0060] d) a homogenizer, preferably a high-pressure homogenizer, for producing a first emulsion by homogenizing the pre-emulsion,

[0061] e) a storage tank and (if applicable) a third device for mixing, preferably stirring, the components in the storage tank, the storage tank being for providing an aqueous phase 2 comprising: water and optionally at least one pharmaceutically acceptable isotonic agent and / or at least one substance for setting the pH value and / or at least one pharmaceutically acceptable preservative,

[0062] f) a device for transferring the emulsion to the storage tank for producing an emulsion by mixing the first emulsion from the homogenizer with the aqueous phase 2 from the storage tank, and

[0063] g) a device for sterilizing the emulsion,

[0064] h) A device for filling the emulsion into a suitable container before or after sterilization,

[0065] wherein at least one pharmaceutically acceptable emulsifier is added in the first vessel and / or the second vessel, and

[0066] wherein the aqueous phase 1 provided in the second vessel provides no more than 70%, preferably no more than 50%, particularly preferably no more than 30% and most preferably no more than 20% of the total amount of water contained in the emulsion.

[0067] According to the present invention, the tank c) can be the same as the vessel a) or the vessel b) in the system for producing an oil-in-water emulsion.

[0068] Use of the oil-in-water emulsion produced according to the present invention

[0069] The oil-in-water emulsion produced by the method according to the present invention is preferably administered parenterally, particularly preferably intravenously, and is used as a drug or provides parenteral nutrition.

[0070] Component

[0071] Wherein the concentration of the component is given as a percentage, and the percentage information relates to the mass ratio (mass / mass). Therefore, the meaning of "10% oil phase relative to the total weight of the emulsion" is the same as "10 g oil phase / 100 g emulsion".

[0072] Oil

[0073] The oil-in-water emulsion produced by the method according to the present invention contains an oil phase of 1% to 40%, preferably 5% to 30%, most preferably 10% to 30% (for example, 10%, 20% or 30%) relative to the total weight of the emulsion.

[0074] The oil phase can contain many different oils. For example, it contains one or more oils selected from the following: animal oils (such as fish oil, fish oil extract or krill oil), oils produced by microorganisms, algal oil, fungal oil, synthetic or partially synthetic oils, and vegetable oils (such as soybean oil, sunflower oil, coconut oil, olive oil, rapeseed oil, peanut oil, palm oil, sesame oil, safflower oil, almond oil, linseed oil or cottonseed oil).

[0075] Preferably, the oil phase contains soybean oil, sunflower oil, coconut oil, medium-chain triglycerides (MCT), olive oil, rapeseed oil, fish oil, fish oil extract, krill oil or a mixture thereof.

[0076] Particularly preferably, the oil phase contains soybean oil, MCT, olive oil, fish oil or a mixture thereof, such as a mixture of soybean oil and MCT or a mixture of fish oil, soybean oil, olive oil and MCT.

[0077] In a particularly preferred embodiment, the oil phase comprises 25% to 35%, preferably 30%, of soybean oil, 25% to 35%, preferably 30%, of MCT, 20% to 30%, preferably 25%, of olive oil, and 10% to 20%, preferably 15%, of fish oil, relative to the total weight of the oil phase.

[0078] According to the European Pharmacopoeia 6.0, in the context of the present invention, "fish oil" is understood as "purified fish oil" and "purified fish oil rich in n-3 fatty acids". It contains at least 9% of docosahexaenoic acid (DHA) and at least 13% of eicosapentaenoic acid (EPA) as triglycerides, relative to the total weight of the fish oil.

[0079] The term "fish oil extract" refers to a mixture having a high content of EPA and DHA, which is obtained, for example, by supercritical fluid extraction of fish oil and subsequent purification (e.g., chromatography). Alternatively, the oil can be extracted as described in US6750048. Further extraction and / or purification methods are described in WO2001 / 076715 and WO2001 / 076385. The fish oil extract contains EPA and DHA in esterified form (e.g., in the form of triglycerides or ethyl esters).

[0080] The term "medium-chain triglyceride" refers to triglycerides of fatty acids having a chain length of 6 to 12 carbon atoms (e.g., caprylic acid, capric acid, lauric acid, and myristic acid).

[0081] Water

[0082] Since the oil-in-water emulsion produced by the method according to the present invention is preferably administered parenterally, the water used to provide aqueous phase 1 and aqueous phase 2 is preferably water for injection (WFI).

[0083] Emulsifying agent

[0084] The method according to the present invention includes adding at least one emulsifier. The term "emulsifier" refers to an amphiphilic substance that stabilizes an emulsion by reducing the interfacial tension between the oil phase and the water phase.

[0085] The emulsifier can be any pharmaceutically acceptable emulsifier suitable for producing an oil-in-water emulsion. Suitable emulsifiers are lecithin, chemically modified lecithin (such as hydrated and / or ethoxylated lecithin), phospholipids, sphingolipids, sterols (such as cholesterol and its derivatives and basic and alkaline earth salts, stigmasterol), bile acids and their salts (such as sodium cholate, sodium glycocholate, sodium taurocholate), block polymers and block copolymers (such as poloxamers such as Pluronic F-68, F-127, and poloxamines such as Totronic 1304), polyglycerol ethers, polyglycerol esters, esters of sugars with fatty acids and / or fatty alcohols (such as sucrose monostearate, glyceryl monooleate) and ethoxylated sorbitan fatty acid esters (such as, Tween 20, 40, 60, 80).

[0086] They are used at a concentration of 0.1% to 5%, preferably 0.6% to 3%, relative to the total weight of the emulsion.

[0087] Preferably, the emulsifier is lecithin, which can be of animal (such as from krill or egg yolk) or plant (such as soy lecithin) origin. The most preferred emulsifier according to the present invention is egg lecithin.

[0088] Egg lecithin is preferably used at a concentration of 0.3% to 2.5%, preferably 0.6% to 1.5%, relative to the total weight of the emulsion.

[0089] Co-emulsifying agent

[0090] The method according to the present invention may include adding at least one co-emulsifier. The term "co-emulsifier" refers to an amphiphilic substance that stabilizes the emulsion by reducing the interfacial tension between the oil phase and the water phase and accumulates at the phase interface together with the emulsifier. Different from emulsifiers, a co-emulsifier alone is not necessarily suitable for forming self-associating structures, such as micelles. Co-emulsifiers are generally used at a lower concentration than emulsifiers.

[0091] Suitable co-emulsifiers are, for example, saturated and unsaturated fatty acids and their salts.

[0092] They are used at a concentration of 0.005% to 1% relative to the total weight of the emulsion.

[0093] The co-emulsifier is preferably unsaturated, preferably a long-chain monounsaturated fatty acid or its basic salt, most preferably oleic acid or sodium oleate. The amount of the co-emulsifier used is preferably between 0.01% and 1%, particularly preferably between 0.02% and 0.5%, relative to the total weight of the emulsion.

[0094] Cosolvent

[0095] The method according to the invention may include adding at least one co-solvent. The term "co-solvent" refers to a molecule that can improve the stability of the emulsion produced by the method according to the invention. They reduce the dielectric constant of water and make its environment more hydrophobic. Additionally, co-solvents increase the amount of emulsifier dispersed in the aqueous phase. The availability of free emulsifier supports the dissolution of hydrophobic molecules.

[0096] Suitable co-solvents are, for example, ethanol, propylene glycol (1,2 - propylene glycol), polyethylene glycol (PEG) with a molecular weight of 100 - 20,000 g / mol, and polypropylene glycol (PPG) with a molecular weight of 180 to 7000 g / mol.

[0097] They are used at a concentration of 0.1% to 2.0%, preferably 0.70% to 1.40%, particularly preferably 0.80% to 1.30%, and most preferably 0.90% to 1.20% relative to the total weight of the emulsion.

[0098] Preferably, they are added in step e) of the method according to the invention.

[0099] The co-solvent is preferably PEG, particularly preferably PEG 200 or PEG 400.

[0100] The amount of PEG used is preferably between 0.7% and 1.4%, particularly preferably between 0.9% and 1.2% relative to the total weight of the emulsion.

[0101] Isotonic agent

[0102] The method according to the invention may include adding at least one pharmaceutically acceptable isotonic agent.

[0103] Suitable isotonic agents are salts (such as sodium chloride), polyols (such as mannitol or glycerol), and sugars (such as lactose or glucose).

[0104] They are used at a concentration of 0.1% to 10%, preferably 0.5% to 5%, particularly preferably 0.7% to 3% relative to the total weight of the emulsion.

[0105] The isotonic agent is preferably a polyol, particularly preferably glycerol.

[0106] Preferably, glycerol is used in an amount of 1% to 5%, particularly preferably 1% to 3%, and most preferably 2% to 2.5% relative to the total weight of the emulsion.

[0107] The osmolarity of the emulsion produced by the method according to the invention is preferably between 305 and 420 mOsmol / kg, measured using a vapor pressure osmometer model 5520 (Vapro TM ) according to USP 785.

[0108] Antioxidant

[0109] The method according to the invention may include adding at least one antioxidant. The antioxidant may be any pharmaceutically acceptable substance having antioxidant effects. Examples of suitable antioxidants are sodium metabisulfite, sodium bisulfite, sodium sulfite, sodium thiosulfite, thioglycerol, thiosorbitol, mercaptoacetic acid, cysteine (preferably as cysteine hydrochloride), n-acetylcysteine, citric acid, α-tocopherol, β-tocopherol, γ-tocopherol, hydrophilic derivatives of vitamin E, lipophilic derivatives of vitamin E (such as vitamin E acetate), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tertiary butylhydroquinone (TBHQ), monothioglycerol, propyl gallate, histidine, coenzyme Q10, tocotrienols, carotenoids, quinones, bioflavonoids, polyphenols, ascorbic acid (vitamin C) and ascorbic acid derivatives (such as ascorbyl palmitate, isoascorbic acid) and uric acid.

[0110] The antioxidant is used at a concentration of 0.001% to 0.5%, preferably 0.01% to 0.3%, relative to the total weight of the emulsion.

[0111] The antioxidant is preferably selected from α-tocopherol, β-tocopherol, γ-tocopherol and mixtures thereof.

[0112] The antioxidant is most preferably α-tocopherol.

[0113] α-Tocopherol is used at a concentration of 0.01% to 0.3%, particularly preferably 0.05% to 0.2%, relative to the total weight of the emulsion.

[0114] Substance for setting pH value

[0115] The method according to the invention may include adding at least one substance for setting the pH value.

[0116] The substance for setting the pH value may be any pharmaceutically suitable acid or base.

[0117] Suitable acids are citric acid, lactic acid, phosphoric acid and hydrochloric acid (HCl).

[0118] The acid is preferably dilute hydrochloric acid, particularly preferably 0.1 M or 1 M hydrochloric acid.

[0119] Suitable bases are alkaline bases and alkaline earth bases.

[0120] The base is preferably sodium hydroxide and is used in the form of an aqueous solution (caustic soda).

[0121] The substance for setting the pH value is most preferably 0.1 M or 1 M caustic soda.

[0122] Preservative

[0123] The method according to the invention may include adding at least one pharmaceutically acceptable preservative.

[0124] Suitable preservatives are p-hydroxybenzoic acid and derivatives and salts thereof, sorbic acid and derivatives and salts thereof, benzyl alcohol, chlorobutanol, thimerosal, chlorhexidine and its salts, phenylmercury salts, chlorocresol, ethylenediaminetetraacetic acid and its salts, and phenoxyethanol.

[0125] They are used at a concentration of from 0.001% to 2.0% relative to the total weight of the emulsion.

[0126] The preservative is preferably ethylenediaminetetraacetic acid (EDTA) or its salt, and is used at a concentration of from 0.05% to 0.8%, preferably from 0.1% to 0.7%, relative to the total weight of the emulsion.

[0127] Container

[0128] The emulsion produced by the method according to the invention is filled into a suitable container before or after sterilization.

[0129] Suitable containers are bottles, syringes, ampoules, vials, cans or bags. They may be composed of any suitable material (such as glass, metal, composite material or plastic), and if applicable, coated with plastic or silicone, for example.

[0130] Suitable containers are preferably glass or plastic bottles, glass or plastic syringes, glass or plastic vials or plastic bags.

[0131] The emulsion obtained in step d) of the method according to the invention may also be filled into a suitable container before further processing.

[0132] Suitable containers include, for example, sterile intermediate bulk containers of steel, stainless steel or plastic.

[0133] Step a)

[0134] Providing the oil phase includes mixing different oils (if a mixture of oils is used), and optionally adding at least one emulsifier and / or at least one co-emulsifier and / or at least one antioxidant.

[0135] Providing the oil phase may also include adding at least one drug, preferably a lipophilic drug, which is dissolved, suspended or dispersed, preferably dissolved, in the oil phase.

[0136] Lipophilic drugs can be, for example, clevidipine, docetaxel, paclitaxel, dexamethasone, diazepam, cyclosporine, etomidate, flurbiprofen, bupivacaine, amphotericin B or propofol.

[0137] In a preferred embodiment, propofol is added to the oil phase.

[0138] Providing the oil phase may also include adding at least one vitamin or a vitamin derivative preferably dissolved in the oil phase, preferably a lipophilic vitamin or a lipophilic vitamin derivative. Lipophilic vitamins are vitamins A, D, E and K. Lipophilic derivatives are, for example, ascorbyl palmitate.

[0139] The oil phase is preferably provided by stirring and heating.

[0140] The oil phase is preferably heated to 40°C to 90°C, preferably 50°C to 80°C.

[0141] If an emulsifier is added to the oil phase, it is preferably heated to a temperature between 70°C and 80°C to facilitate / accelerate the dissolution / dispersion of the emulsifier and / or co-emulsifier.

[0142] If an emulsifier is added to aqueous phase 1, the oil phase is preferably heated to a temperature between 50°C and 60°C such that, in step c), the oil phase has the same temperature as aqueous phase 1.

[0143] Step b)

[0144] The aqueous phase 1 provided in step b) provides no more than 70%, preferably no more than 50%, particularly preferably no more than 30% and most preferably no more than 20% of the total amount of water contained in the emulsion.

[0145] Aqueous phase 1 preferably provides no less than 1%, 2% or 3% of the total amount of water contained in the emulsion.

[0146] Providing aqueous phase 1 may include mixing water with at least one emulsifier and / or at least one co-emulsifier and / or at least one preservative.

[0147] It may also include preferably setting the pH value to a value between 6.0 and 10.0, particularly between 7.0 and 9.0, particularly preferably between 8.0 and 9.0.

[0148] Additionally, providing aqueous phase 1 may include adding at least one pharmaceutically acceptable isotonic agent. The concentration of the isotonic agent should not exceed 18%, preferably 15%, particularly preferably 14.3% relative to the total weight of aqueous phase 1.

[0149] The provided aqueous phase 1 may further include adding at least one drug, preferably a water-soluble drug, that is dissolved, suspended, or dispersed, preferably dissolved, in the aqueous phase 1.

[0150] The provided aqueous phase 1 may further include adding at least one vitamin, preferably at least one water-soluble vitamin, that is dissolved, suspended, or dispersed, preferably dissolved, in the aqueous phase 1. Water-soluble vitamins are vitamin B1, B2, B6, B12, folic acid, biotin, and vitamin C.

[0151] The aqueous phase 1 is preferably provided by stirring and heating. The stirring tool can be an internal or external high-shear mixer (e.g., a rotor-stator system from companies IKA or Ystral).

[0152] The aqueous phase 1 is preferably heated to 40°C to 90°C, particularly preferably 50°C to 80°C.

[0153] If an emulsifier is added to the oil phase, the aqueous phase 1 is preferably heated to a temperature between 70°C and 80°C such that in step c), the aqueous phase 1 has the same temperature as the oil phase.

[0154] If an emulsifier is added to the aqueous phase 1, the aqueous phase 1 is preferably heated to a temperature between 50°C and 60°C to facilitate / accelerate the dissolution / dispersion of the emulsifier and / or co-emulsifier.

[0155] Step c)

[0156] A pre-emulsion is provided by mixing the oil phase provided in step a) with the aqueous phase 1 provided in step b). The mixing is preferably carried out by stirring. The stirring tool can be an internal or external high-shear mixer (e.g., a rotor-stator system from companies IKA or Ystral).

[0157] The emulsion can be heated by inputting shear energy during emulsion formation. The temperature is preferably maintained (e.g., via a heat exchanger) between 50°C and 65°C.

[0158] Step d)

[0159] According to the present invention, an emulsion is produced in step d) by high-pressure homogenization, sonication, or by means of an inverse jet disperser. Preferably, the emulsion is produced by high-pressure homogenization.

[0160] The homogenization is preferably carried out at a temperature of 40°C to 70°C, particularly preferably 40°C to 60°C, and most preferably 50°C to 60°C.

[0161] The high-pressure homogenization can be carried out with all conventional high-pressure homogenizers (e.g., using a device of the Ariete type from company GEA).

[0162] High-pressure homogenization is preferably carried out in a two-stage high-pressure homogenizer (preferably at 350 to 600 bar in stage 1 and at 0 to 150 bar in stage 2) for a plurality of preferably 4 to 6 cycles.

[0163] Step e)

[0164] Providing the aqueous phase 2 may include mixing water with at least one pharmaceutically acceptable isotonic agent and / or at least one substance for setting the pH value and / or at least one pharmaceutically acceptable preservative and / or at least one cosolvent.

[0165] It may also include preferably setting the pH value to a value between 6.0 and 10.0, particularly between 7.0 and 9.0, and most preferably between 8.0 and 9.0.

[0166] At least one drug or vitamin, preferably a water-soluble drug or water-soluble vitamin, may also be added to the aqueous phase 2. The drug and / or vitamin is dissolved, suspended or dispersed, preferably dissolved, in the aqueous phase 2. Water-soluble vitamins are vitamin B1, B2, B6, B12, folic acid, biotin and vitamin C.

[0167] The aqueous phase 1 is preferably provided by stirring. The stirring tool may be an internal or external high-shear mixer (e.g., a rotor-stator system from companies IKA or Ystral).

[0168] The aqueous phase 2 is preferably temperature-controlled to 5°C to 25°C, particularly preferably 10°C to 20°C, and most preferably 10°C to 15°C.

[0169] Step f)

[0170] An emulsion is produced in step f) by mixing the emulsion obtained in step d) with the aqueous phase 2 provided in step e), preferably by adding the emulsion to the aqueous phase 2 (which is preferably stored in a suitable tank / vessel).

[0171] An emulsion is preferably produced by stirring with an internal propeller stirrer.

[0172] The emulsion is preferably inflated with nitrogen such that the oxygen content of the emulsion is preferably less than 0.5 mg / l.

[0173] Step g)

[0174] The emulsion can be sterilized using all suitable methods (e.g., by radiation, autoclaving or inflation).

[0175] Sterilization is preferably carried out by autoclaving. Autoclaving is preferably carried out at a pressure of 2 bar and a temperature of 116°C to 123°C for 8 to 21 minutes.

[0176] Before autoclaving, it is preferred to fill the emulsion into one of the above suitable containers.

[0177] Embodiment

[0178] 1. A method for producing an oil-in-water emulsion, the oil-in-water emulsion comprising an aqueous phase and an oil phase of 1% to 40%, preferably 5% to 30%, most preferably 10% to 30% based on the total weight of the emulsion, wherein the method comprises the following steps:

[0179] a) Providing an oil phase, the oil phase comprising one or more oils and optionally at least one pharmaceutically acceptable antioxidant and / or at least one pharmaceutically acceptable co-emulsifier,

[0180] b) Providing an aqueous phase 1, the aqueous phase 1 comprising water, optionally at least one pharmaceutically acceptable co-emulsifier and / or at least one pH-setting substance and / or at least one pharmaceutically acceptable preservative and / or at least one pharmaceutically acceptable isotonic agent,

[0181] wherein the isotonic agent is present at a concentration of at most 18%, preferably 15%, particularly preferably at most 14.3% based on the total weight of the aqueous phase 1,

[0182] c) Producing a pre-emulsion by mixing the oil phase provided in step a) with the aqueous phase 1 provided in step b),

[0183] d) Producing a first emulsion by homogenizing the pre-emulsion provided in step c),

[0184] e) Providing an aqueous phase 2, the aqueous phase 2 comprising water, optionally at least one pharmaceutically acceptable isotonic agent and / or at least one pH-setting substance and / or at least one pharmaceutically acceptable preservative,

[0185] f) Producing the emulsion by mixing the first emulsion provided in step d) with the aqueous phase 2 provided in step e), and

[0186] g) Sterilizing the emulsion obtained in step f),

[0187] wherein the emulsion is filled into a suitable container before or after sterilization,

[0188] wherein at least one pharmaceutically acceptable emulsifier is added in step a) and / or step b), and

[0189] wherein the aqueous phase 1 provided in step b) provides no more than 70%, preferably no more than 50%, particularly preferably no more than 30% and most preferably no more than 20% of the total amount of water contained in the emulsion.

[0190] 2. The method according to embodiment 1, wherein the emulsion is provided for parenteral administration, and the water used to provide the aqueous phase in steps b) and e) is preferably water for injection (WFI).

[0191] 3. The method according to embodiment 1 or 2, wherein the pharmaceutically acceptable emulsifier is added at a concentration of 0.1% to 5% relative to the total weight of the emulsion.

[0192] 4. The method according to any one of the foregoing embodiments, wherein the pharmaceutically acceptable emulsifier is lecithin.

[0193] 5. The method according to embodiment 4, wherein the lecithin is added in step a).

[0194] 6. The method according to embodiment 4, wherein the lecithin is added in step b).

[0195] 7. The method according to any one of the foregoing embodiments, wherein the pharmaceutically acceptable co-emulsifier is sodium oleate and is added in step b).

[0196] 8. The method according to any one of embodiments 1 to 6, wherein the pharmaceutically acceptable co-emulsifier is oleic acid and is added in step a).

[0197] 9. The method according to any one of the foregoing embodiments, wherein the oil-in-water emulsion comprises a pharmaceutically acceptable isotonic agent.

[0198] 10. The method according to any one of the foregoing embodiments, wherein the pharmaceutically acceptable isotonic agent is a polyol, preferably glycerol.

[0199] 11. The method according to any one of the foregoing embodiments, wherein the pharmaceutically acceptable isotonic agent is added in step b).

[0200] 12. The method according to any one of the foregoing embodiments, wherein the pharmaceutically acceptable isotonic agent is added in steps b) and e).

[0201] 13. The method according to any one of the foregoing embodiments, wherein the isotonic agent is added only in step e).

[0202] 14. The method according to any one of the foregoing embodiments, wherein the oil phase comprises one or more oils selected from the group consisting of animal oils, oils produced by microorganisms, algal oils, fungal oils, synthetic or partially synthetic oils, and vegetable oils.

[0203] 15. A method according to one of the foregoing embodiments, wherein the emulsion comprises an oil phase of 10% or 20% relative to the total weight of the emulsion.

[0204] 16. A method according to one of the foregoing embodiments, wherein the oil phase comprises at least one vegetable oil and / or at least one animal oil.

[0205] 17. A method according to one of the foregoing embodiments, wherein the oil phase comprises soybean oil, medium-chain triglycerides, olive oil, structured lipids, fish oil, fish oil extract, krill oil, or a mixture thereof.

[0206] 18. A method according to one of the foregoing embodiments, wherein the oil phase comprises soybean oil, medium-chain triglycerides, olive oil, fish oil, fish oil extract, or a mixture thereof.

[0207] 19. A method according to one of the foregoing embodiments, wherein the oil phase comprises soybean oil, medium-chain triglycerides, olive oil, and fish oil.

[0208] 20. A method according to one of the foregoing embodiments, wherein the oil phase comprises 25% to 35%, preferably 30%, of soybean oil, 25% to 35%, preferably 30%, of medium-chain triglycerides, 20% to 30%, preferably 25%, of olive oil, and 10% to 20%, preferably 15%, of fish oil, relative to the total weight of the oil phase.

[0209] 21. A method according to one of the foregoing embodiments, wherein in step b) and / or step e), the pH value is set to a value between 6.0 and 10.0, preferably between 7.0 and 9.0, particularly preferably between 8.0 and 9.0, using NaOH.

[0210] 22. A method according to one of the foregoing embodiments, wherein the average diameter of the oil droplets in the first emulsion after homogenization in step d) and in the emulsion obtained in step f) and sterilized in step g) is between 100 and 500 nm, preferably between 150 and 450 nm.

[0211] 23. A method according to one of the foregoing embodiments, wherein the PFAT5 value of the first emulsion after homogenization in step d) and of the emulsion obtained in step f) and before and after sterilization in step g) is less than 0.05%, preferably less than 0.04%, particularly preferably less than 0.03%, and most preferably less than 0.02%.

[0212] 24. A method according to one of the foregoing embodiments, wherein the average PFAT5 value of the first emulsion after homogenization in step d) and of the emulsion obtained in step f) before and after sterilization in step g) is less than 0.035%, preferably less than 0.030%, particularly preferably less than 0.025%, more preferably less than 0.020%, even more preferably less than 0.015% and most preferably less than 0.010%.

[0213] 25. A method according to one of the foregoing embodiments, wherein at least one drug and / or at least one vitamin is added in step a) and / or step b) and / or step e) and / or step f), wherein the drug and / or the vitamin added in step a) is preferably lipophilic, and the drug and / or the vitamin added in step b) and / or e) is preferably water-soluble.

[0214] 26. A method according to one of the foregoing embodiments, wherein, in step a), a drug is added to the oil phase, preferably a lipophilic drug, particularly preferably a lipophilic drug selected from: clevidipine, docetaxel, paclitaxel, dexamethasone, diazepam, cyclosporine, etomidate, flurbiprofen, bupivacaine, amphotericin B or propofol, most preferably propofol.

[0215] 27. A method according to one of the foregoing embodiments, wherein the homogenization in step d) is carried out for 4 to 6 cycles in a two-stage high-pressure homogenizer, and wherein the homogenization is carried out in stage 1 at 350 to 600 bar and in stage 2 at 0 to 150 bar.

[0216] 28. A method according to one of the foregoing embodiments, wherein the oil phase provided in step a) and the aqueous phase 1 provided in step b) are temperature-adjusted to 40°C to 90°C, preferably temperature-adjusted to 50°C to 80°C, and then the pre-emulsion is produced in step c).

[0217] 29. A method according to embodiment 28, wherein the oil phase provided in step a) and the aqueous phase 1 provided in step b) are temperature-adjusted to 70°C to 80°C, and then the pre-emulsion is produced in step c).

[0218] 30. A method according to embodiment 28, wherein the oil phase provided in step a) and the aqueous phase 1 provided in step b) are temperature-adjusted to 55°C to 65°C, and then the pre-emulsion is produced in step c).

[0219] 31. A method according to one of the foregoing embodiments, wherein the aqueous phase 2 in step e) is temperature-controlled to 5°C to 25°C, preferably temperature-controlled to 10°C to 20°C, and particularly preferably temperature-controlled to 10°C to 15°C.

[0220] 32. A method according to one of the foregoing embodiments, wherein the emulsion is filled into a suitable container and then sterilized, and wherein the sterilization is preferably carried out by autoclaving.

[0221] 33. A method according to one of the foregoing embodiments, wherein the suitable container is a glass bottle, a plastic or glass syringe, or a plastic bag.

[0222] 34. An oil-in-water emulsion comprising an aqueous phase and an oil phase of 1% to 40%, preferably 5% to 30%, and most preferably 10% to 30% based on the total weight of the emulsion obtainable by a method according to one of embodiments 1 to 32.

[0223] 35. The oil-in-water emulsion according to embodiment 34, used as a medicament.

[0224] 36. The oil-in-water emulsion according to embodiment 34 or 35, for providing parenteral nutrition.

[0225] 37. An oil-in-water emulsion obtained in step d) of a method according to one of embodiments 1 to 30.

[0226] 38. Use of the oil-in-water emulsion according to embodiment 37 for further processing in steps e), f) and g) of a method according to one of embodiments 1 to 33.

[0227] 39. A system for producing an oil-in-water emulsion comprising an aqueous phase and an oil phase of 1% to 40%, preferably 5% to 30%, and most preferably 10% to 30% based on the total weight of the emulsion, the system comprising

[0228] a) a first vessel and a first device for mixing and / or dispersing, preferably stirring, the components in the first vessel, the first vessel for providing an oil phase comprising: one or more oils preferably selected from animal oils, oils produced by microorganisms, algal oils, fungal oils, synthetic or partially synthetic oils, and vegetable oils, and optionally at least one pharmaceutically acceptable antioxidant and / or at least one pharmaceutically acceptable co-emulsifier.

[0229] b) A second vessel and a second device for mixing and / or dispersing, preferably stirring, the components in the second vessel, the second vessel being for providing an aqueous phase 1 comprising the following components: water, optionally at least one pharmaceutically acceptable co-emulsifier and / or at least one substance for setting the pH value and / or at least one pharmaceutically acceptable preservative and / or at least one pharmaceutically acceptable isotonic agent, wherein the isotonic agent is present at a concentration of at most 18%, preferably at most 15%, relative to the total weight of the aqueous phase 1.

[0230] c) A tank for receiving the components from the first vessel via a first sterile filter and the components from the second vessel via a second sterile filter, wherein the tank has a third device for mixing and / or dispersing for producing a pre-emulsion by mixing the oil phase from the first vessel and the aqueous phase 1 from the second vessel.

[0231] d) A homogenizer, preferably a high-pressure homogenizer, for producing a first emulsion by homogenizing the pre-emulsion.

[0232] e) A storage tank and (if applicable) a third device for mixing, preferably stirring, the components in the storage tank, the storage tank being for providing an aqueous phase 2 comprising the following components: water, optionally at least one pharmaceutically acceptable isotonic agent and / or at least one substance for setting the pH value and / or at least one pharmaceutically acceptable preservative.

[0233] f) A device for transferring the emulsion to the storage tank for producing an emulsion by mixing the first emulsion from the homogenizer and the aqueous phase 2 from the storage tank, and

[0234] g) A device for sterilizing the emulsion.

[0235] h) A device for filling the emulsion into a suitable container before or after sterilization, wherein at least one pharmaceutically acceptable emulsifier is added in the first vessel and / or the second vessel, and wherein the aqueous phase 1 provided in the second vessel provides no more than 70%, preferably no more than 50%, particularly preferably no more than 30% and most preferably no more than 20% of the total amount of water contained in the emulsion.

[0236] Examples

[0237] Example 1

[0238] In a series of tests, it was determined how much the aqueous phase 1 could be reduced to in terms of the phase volume ratio (the amount of the internal phase (herein the oil phase) relative to the total amount of the aqueous phase 1 and the oil phase) and what effect the concentration of the isotonic agent (here glycerol) had.

[0239] The method carried out in Test I corresponds to a known standard method.

[0240]

[0241] Table 1

[0242] The oil (a mixture of soybean oil, MCT, olive oil and fish oil according to Example 2 or 3) has been tempered to 55 °C to 60 °C, an antioxidant (α-tocopherol) has been added and stirred for an additional 15 minutes.

[0243] In parallel, the amount of water for injection (WFI) indicated in Table 1, the amount of glycerol indicated in the table and the amount of caustic soda required to set the pH value to 8.5 to 8.75 were each weighed in another vessel, tempered to 55 °C to 65 °C, and the emulsifier (egg lecithin) and co-emulsifier (sodium oleate) were successively added and dispersed in the WFI (aqueous phase 1).

[0244] The heated oil phase was incorporated into the aqueous phase 1 via a sterile filter and mixed for an additional 30 minutes.

[0245] The remaining WFI and glycerol (aqueous phase 2) were stored in a tank in the amounts indicated in Table 1 and tempered to 5 °C to 15 °C.

[0246] The pre-emulsion was homogenized under high pressure (4 cycles at 400 / 100 bar) using an MF-110F microfluidizer from the company Microfluidics and added to a storage tank with WFI or a polyol / WFI mixture.

[0247] Surprisingly, it was found that the aqueous phase 1 could be reduced to a phase volume ratio of at least up to 0.67 (Test IV). In the homogenization step, emulsion formation failed with a glycerol concentration of 20% in the aqueous phase 1.

[0248] In the emulsification step, emulsion formation was successful with a glycerol concentration of up to 14.3% in the aqueous phase 1 (Test IV). Therefore, the polyol concentration in the emulsification step should be less than 18%, preferably less than 15%, relative to the total weight of the aqueous phase 1.

[0249] Example 2

[0250] Using the raw materials indicated in Table 2, 157 batches of emulsion were produced according to the conventional production method (A) and 156 batches were produced according to the method of the present invention (B).

[0251] Method A)

[0252] Combine soybean oil, MCT oil, olive oil, and fish oil and temper to 55°C to 60°C; then add an antioxidant (α-tocopherol) and stir for an additional 15 minutes.

[0253] In parallel, weigh 240 kg of WFI and the amount of caustic soda required to set the pH value to 8.5 to 8.75 in another vessel, temper to 55°C to 65°C, and successively add glycerol, egg lecithin, and sodium oleate and disperse them in the WFI (aqueous phase 1).

[0254] Incorporate the heated oil phase into aqueous phase 1 via a sterile filter and mix for an additional 30 minutes.

[0255] Homogenize the primary emulsion using a Rannie 12.51H high-pressure homogenizer from company APV (4 cycles at 400 / 100 bar). Then, reset the pH value to a value between 8.5 and 8.75 and also set the water content.

[0256]

[0257]

[0258] Table 2

[0259] Method B)

[0260] Combine soybean oil, MCT oil, olive oil, and fish oil and temper to 55°C to 60°C; then add an antioxidant and stir for an additional 15 minutes.

[0261] In parallel, weigh 148.50 kg of WFI and the amount of caustic soda required to set the pH value to 8.5 to 8.75 in another vessel, temper to 55°C to 65°C, and successively add glycerol, egg lecithin, and sodium oleate and disperse them in the WFI (aqueous phase 1).

[0262] Incorporate the heated oil phase into aqueous phase 1 via a sterile filter and mix for an additional 30 minutes.

[0263] Store the remaining WFI in a tank and temper to 5°C to 15°C.

[0264] Homogenize the pre-emulsion using a Rannie 12.51H high-pressure homogenizer from company APV (4 cycles at 400 / 100 bar) and add it to a storage tank with a glycerol / WFI mixture. Then, set the pH value and water content.

[0265] Determine the PFAT5 value for each batch.

[0266] The following average values and standard deviations are obtained:

[0267] Average PFAT5 (Method A, n = 157): 0.035 ± 0.021

[0268] Average PFAT5 (Method B, n = 156): 0.006 ± 0.004

[0269] Thus, the method according to the invention significantly reduces the average PFAT5 value (see also Figure 1 ).

[0270] None of the batches produced according to the method of the invention need to be destroyed because they have a PFAT5 value of more than 0.05%. In particular, none of the batches produced according to the method of the invention have a PFAT5 value greater than 0.017%.

[0271] Average droplet diameter (D 50 ) is not different. However, Method B according to the invention results in a smaller deviation of the average droplet diameter.

[0272] The following droplet sizes (indicating the mean and standard deviation) have been measured:

[0273] D 50 (Method A): 351 nm ± 18 nm

[0274] D 50 (Method B): 353 nm ± 6 nm

[0275] Example 3

[0276]

[0277]

[0278] Table 3

[0279] Soybean oil, MCT oil, olive oil and fish oil were combined and tempered to 55 °C to 60 °C; then an antioxidant was added and it was stirred for an additional 15 minutes.

[0280] In parallel, 115 kg of WFI and the amount of caustic soda required to set a pH value of 8.5 to 8.75 were weighed in another vessel, tempered to 55 °C to 65 °C, and egg lecithin and sodium oleate were successively added and dispersed in the WFI (aqueous phase 1).

[0281] The heated oil phase was incorporated into aqueous phase 1 via a sterile filter and mixed for an additional 30 minutes.

[0282] Glycerol and the remaining WFI (aqueous phase 2) were stored in a tank and tempered to 5 °C to 15 °C.

[0283] The pre-emulsion was homogenized under high pressure (4 cycles at 400 / 100 bar) using a Rannie 12.51H high-pressure homogenizer from company APV, and added to a storage tank with a glycerol / WFI mixture.

[0284] Then, the pH value and water content were set.

[0285] Just after production, the average droplet diameter was 360 nm (D 50 ), the PFAT5 value was 0.006%, and the content of non-esterified fatty acids (NEFA) was 2.0 mEq / L.

[0286] Example 4

[0287]

[0288]

[0289] Table 4

[0290] Soybean oil, MCT oil, oleic acid, and propofol were combined, tempered to 55 °C to 65 °C and stirred for 15 minutes.

[0291] In parallel, 99 kg of WFI and the amount of caustic soda required to set the pH value to 8.0 to 8.75 were weighed in another vessel, tempered to 55 °C to 65 °C, and egg lecithin was added and dispersed in the WFI (aqueous phase 1).

[0292] The heated oil phase was incorporated into the aqueous phase 1 via a sterile filter and mixed for an additional 30 minutes.

[0293] Glycerol and the remaining WFI (aqueous phase 2) were stored in a tank and tempered to 5 °C to 15 °C.

[0294] The pre-emulsion was homogenized under high pressure (4 cycles at 400 / 100 bar) using an MF-110F microfluidizer from company Microfluidics, and added to a storage tank with a glycerol / WFI mixture.

[0295] Then, the pH value (to 8.2) and water content were set. The average droplet diameter was 236 nm (D 50 ).

[0296] Example 5

[0297] Raw material Amount (kg) Water for injection (WFI) 76.00 EDTA 0.06 Glycerol 22.50 Sodium oleate 0.30 Egg lecithin 12.00 NaOH 1M Appropriate amount Soybean oil 100.00 Propofol 10.00 WFI Add to 1000 Nitrogen Appropriate amount

[0298] Table 5

[0299] Adjust the temperature of the soybean oil to 73 °C to 77 °C. Add the egg lecithin in batches and stir for an additional 15 minutes until all the egg lecithin is dissolved.

[0300] In parallel, weigh 76 kg of WFI and the amount of caustic soda required to set the pH value to 8.5 to 9.5 in another vessel, and adjust the temperature to 73 °C to 77 °C. Then add EDTA and sodium oleate and dissolve (aqueous phase 1).

[0301] Incorporate the heated oil phase into the aqueous phase 1 via a sterile filter and mix for an additional 30 minutes.

[0302] Store the glycerol and the remaining WFI (aqueous phase 2) in a tank and adjust the temperature to 5 °C to 15 °C.

[0303] Homogenize the pre-emulsion under high pressure using an MF-110F microfluidizer from the company Microfluidics (6 cycles at 490 / 0 bar), and add it to the storage tank with the glycerol / WFI mixture.

[0304] Then, set the water content and the pH value.

[0305] The average droplet diameter is 267 nm (D 50 ).

[0306] Example 6

[0307]

[0308] Table 6

[0309] Adjust the temperature of the soybean oil to 73 °C to 77 °C. Add the egg lecithin in batches and stir for an additional 15 minutes until all the egg lecithin is dissolved.

[0310] In parallel, Weigh 140 kg of WFI, 0.30 kg of sodium oleate and the amount of caustic soda required to set the pH value to 8.5 to 9.5 in another vessel, and adjust the temperature to 73 °C to 77 °C (aqueous phase 1).

[0311] Incorporate the heated oil phase into the aqueous phase 1 via a sterile filter and mix for an additional 30 minutes.

[0312] Store the glycerol and the remaining WFI (aqueous phase 2) in a tank and adjust the temperature to 5 °C to 15 °C.

[0313] Homogenize the pre-emulsion under high pressure using an MF-110F microfluidizer from the company Microfluidics (6 cycles at 560 / 120 bar), and add it to the storage tank with the glycerol / WFI mixture.

[0314] Then, the water content and pH value are set.

[0315] The average droplet diameter is 393 nm (D 50 ).

[0316] Description of the figure

[0317] Figure 1 Shows the average value (and standard deviation) of the PFAT5 values (measured according to USP 729, method 2) of the emulsion batches obtained according to Example 2. In this case, the grey bars represent the average PFAT5 values of the batches produced according to Method A, while the black bars represent the average PFAT5 values of the batches produced according to Method B of the present invention.

Claims

1. A method for producing an oil-in-water emulsion, the oil-in-water emulsion comprising an aqueous phase and an oil phase of 1% to 40% relative to the total weight of the emulsion, wherein the method comprises the following steps a) providing an oil phase comprising one or more oils selected from animal oils, microbially produced oils, medium-chain triglycerides, structured lipids, and vegetable oils, and a pharmaceutically acceptable antioxidant and / or at least one pharmaceutically acceptable co-emulsifier, b) providing an aqueous phase 1 comprising water and at least one pharmaceutically acceptable co-emulsifier and / or at least one pH-setting substance and / or at least one pharmaceutically acceptable preservative and / or at least one pharmaceutically acceptable isotonic agent, wherein the isotonic agent is present at a concentration of at most 18% relative to the total weight of the aqueous phase 1, c) producing a pre-emulsion by mixing the oil phase provided in step a) with the aqueous phase 1 provided in step b), d) producing a first emulsion by homogenizing the pre-emulsion provided in step c), e) providing an aqueous phase 2 comprising water and at least one pharmaceutically acceptable isotonic agent and / or at least one pH-setting substance and / or at least one pharmaceutically acceptable preservative, f) producing the emulsion by mixing the first emulsion provided in step d) with the aqueous phase 2 provided in step e), and g) sterilizing the emulsion obtained in step f), wherein the emulsion is filled into a suitable container before or after sterilization, wherein at least one pharmaceutically acceptable emulsifier is added in step a) and / or step b), and wherein the water in the aqueous phase 1 provided in step b) is present at no more than 30% relative to the total weight of the water in the emulsion, wherein the emulsion is provided for parenteral administration.

2. The method according to claim 1, wherein the oil-in-water emulsion comprises an aqueous phase and an oil phase of 5% to 30% relative to the total weight of the emulsion.

3. The method according to claim 1, wherein the oil-in-water emulsion comprises an aqueous phase and an oil phase of 10% to 30% relative to the total weight of the emulsion.

4. The method according to claim 1, wherein the microbially produced oil comprises algal oil and / or fungal oil.

5. The method according to claim 1, wherein the aqueous phase 1 provided in step b) provides no more than 20% of the total amount of water contained in the emulsion.

6. The method according to claim 1, wherein the water used to provide the aqueous phase 1 and the aqueous phase 2 in steps b) and e) is water for injection (WFI).

7. The method according to claim 1, wherein the pharmaceutically acceptable emulsifier is added at a concentration of 0.1% to 5% relative to the total weight of the emulsion.

8. The method according to claim 1, wherein the pharmaceutically acceptable emulsifier is lecithin.

9. The method according to claim 1, wherein the pharmaceutically acceptable co-emulsifier is sodium oleate and is added in step b).

10. The method according to claim 1, wherein the pharmaceutically acceptable co-emulsifier is oleic acid and is added in step a).

11. The method according to claim 1, wherein the oil-in-water emulsion comprises a pharmaceutically acceptable isotonic agent.

12. The method according to claim 1, wherein the pharmaceutically acceptable isotonic agent is a polyol.

13. The method according to claim 1, wherein the pharmaceutically acceptable isotonic agent is glycerol.

14. The method according to claim 1, wherein the pharmaceutically acceptable isotonic agent is added in step b).

15. The method according to claim 1, wherein the pharmaceutically acceptable isotonic agent is present in step b) at a concentration of at most 15% relative to the total weight of the aqueous phase 1.

16. The method according to claim 1, wherein the pharmaceutically acceptable isotonic agent is present in step b) at a concentration of at most 14.3% relative to the total weight of the aqueous phase 1.

17. The method according to claim 1, wherein the isotonic agent is added only in step e).

18. The method according to claim 1, wherein the emulsion comprises an oil phase of 10% or 20% relative to the total weight of the emulsion.

19. The method according to claim 1, wherein the oil phase comprises vegetable oil and / or animal oil.

20. The method according to claim 1, wherein the oil phase comprises soybean oil, olive oil, fish oil, fish oil extract, krill oil, or a mixture thereof.

21. The method according to claim 1, wherein the oil phase comprises soybean oil, medium-chain triglycerides, olive oil, fish oil, fish oil extract, or a mixture thereof.

22. The method according to claim 1, wherein the oil phase comprises soybean oil, medium-chain triglycerides, olive oil, and fish oil.

23. The method according to claim 1, wherein the oil phase comprises 25% to 35% of soybean oil, 25% to 35% of MCT, 20% to 30% of olive oil, and 10% to 20% of fish oil, based on the total weight of the oil phase.

24. The method according to claim 1, wherein the oil phase comprises 30% of soybean oil, 30% of MCT, 25% of olive oil, and 15% of fish oil, based on the total weight of the oil phase.

25. The method according to claim 1, wherein the pH value is set to a value between 6.0 and 10.0 with NaOH in step b) and / or step e).

26. The method according to claim 1, wherein the pH value is set to between 7.0 and 9.0 with NaOH in step b) and / or step e).

27. The method according to claim 1, wherein the pH value is set to between 8.0 and 9.0 with NaOH in step b) and / or step e).

28. The method according to claim 1, wherein the average diameter of the oil droplets in the emulsion obtained in step d) and in the emulsion obtained in step f) and sterilized in step g) is between 100 and 500 nm.

29. The method according to claim 1, wherein the average diameter of the oil droplets in the emulsion obtained in step d) and in the emulsion obtained in step f) and sterilized in step g) is between 150 and 450 nm.

30. The method according to claim 1, wherein the PFAT5 value of the emulsion obtained in step d) and of the emulsion obtained in step f) and before and after sterilization in step g) is less than 0.05%.

31. The method according to claim 1, wherein the PFAT5 value of the emulsion obtained in step d) and of the emulsion obtained in step f) and before and after sterilization in step g) is less than 0.04%.

32. The method according to claim 1, wherein the PFAT5 value of the emulsion obtained in step d) and of the emulsion obtained in step f) and before and after sterilization in step g) is less than 0.03%.

33. The method according to claim 1, wherein the PFAT5 value of the emulsion obtained in step d) and of the emulsion obtained in step f) and before and after sterilization in step g) is less than 0.02%.

34. The method according to claim 1, wherein the average PFAT5 value of the emulsion obtained in step d), and the emulsion obtained in step f) before and after sterilization in step g) is less than 0.035%.

35. The method according to claim 1, wherein the average PFAT5 value of the emulsion obtained in step d), and the emulsion obtained in step f) before and after sterilization in step g) is less than 0.030%.

36. The method according to claim 1, wherein the average PFAT5 value of the emulsion obtained in step d), and the emulsion obtained in step f) before and after sterilization in step g) is less than 0.025%.

37. The method according to claim 1, wherein the average PFAT5 value of the emulsion obtained in step d), and the emulsion obtained in step f) before and after sterilization in step g) is less than 0.020%.

38. The method according to claim 1, wherein the average PFAT5 value of the emulsion obtained in step d), and the emulsion obtained in step f) before and after sterilization in step g) is less than 0.015%.

39. The method according to claim 1, wherein the average PFAT5 value of the emulsion obtained in step d), and the emulsion obtained in step f) before and after sterilization in step g) is less than 0.010%.

40. The method according to claim 1, wherein one or more drugs and / or one or more vitamins are added in step a) and / or step b) and / or step e) and / or step f).

41. The method according to claim 1, wherein the drug propofol is added to the oil phase in step a).

42. The method according to claim 1, wherein the homogenization in step d) is carried out for 4 to 6 cycles in a two-stage high-pressure homogenizer, and wherein the homogenization is carried out in stage 1 at 350 to 600 bar and in stage 2 at 0 to 150 bar.

43. The method according to claim 1, wherein the oil phase provided in step a) and the aqueous phase 1 provided in step b) are temperature-adjusted to 40°C to 90°C, and then the pre-emulsion is produced in step c).

44. The method according to claim 1, wherein the oil phase provided in step a) and the aqueous phase 1 provided in step b) are temperature-adjusted to 50°C to 80°C, and then the pre-emulsion is produced in step c).

45. The method according to claim 1, wherein the aqueous phase 2 provided in step e) is temperature-controlled to 5 °C to 25 °C.

46. The method according to claim 1, wherein the aqueous phase 2 provided in step e) is temperature-controlled to 5 °C to 20 °C.

47. The method according to claim 1, wherein the aqueous phase 2 provided in step e) is temperature-controlled to 10 °C to 15 °C.

48. The method according to claim 1, wherein the emulsion is filled into a suitable container and then sterilized.

49. The method according to claim 1, wherein the emulsion is filled into a glass bottle, a plastic syringe or a plastic bag and then sterilized.

50. The method according to claim 1, wherein the sterilization is carried out by autoclaving.

51. An oil-in-water emulsion obtained by the method according to any one of claims 1 to 50, the oil-in-water emulsion comprising an aqueous phase and an oil phase of 1% to 40% relative to the total weight of the emulsion.

52. An oil-in-water emulsion obtained by the method according to any one of claims 1 to 50, the oil-in-water emulsion comprising an aqueous phase and an oil phase of 5% to 30% relative to the total weight of the emulsion.

53. An oil-in-water emulsion obtained by the method according to any one of claims 1 to 50, the oil-in-water emulsion comprising an aqueous phase and an oil phase of 10% to 30% relative to the total weight of the emulsion.

54. The oil-in-water emulsion according to any one of claims 51 to 53, which is used as a medicine or for providing parenteral nutrition.

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