WO2009059989A1

WO2009059989A1 - Aqueous emulsions comprising a hydrophobic active ingredient

Info

Publication number: WO2009059989A1
Application number: PCT/EP2008/064979
Authority: WO
Inventors: Sonja Dick; Andreas Greiner; Joachim H. Wendorff
Original assignee: B. Braun Melsungen Ag
Priority date: 2007-11-06
Filing date: 2008-11-05
Publication date: 2009-05-14
Also published as: DE112008002914A5

Abstract

The invention relates to aqueous emulsions comprising a hydrophobic active ingredient, to methods for the production thereof, pharmaceutical compositions, such as therapeutic agents, diagnostic agents, and/or prophylactic agents, in particular anesthetic agents, which comprise the aqueous emulsions, to the use of the aqueous emulsions to produce medications, and to methods for the therapeutic and/or prophylactic treatment of the human or animal body and/or for diagnosis by administration of the aqueous emulsion.

Description

A hydrophobic drug containing aqueous emulsions

description

Field of the invention

The invention relates to a hydrophobic drug-containing aqueous emulsions, processes for their preparation, pharmaceutical compositions such as therapeutics, diagnostics and / or prophylactics, in particular anesthetics comprising the aqueous emulsion, the use of aqueous emulsions for the production of medicaments and methods for therapeutic and / or prophylactic treatment of the human or animal body and / or for diagnosis by administration of the aqueous emulsion according to the invention.

Background of the invention

Many pharmaceutical agents have a low solubility in water and therefore present difficulties in the preparation of medicaments containing these drugs. For new developments or new syntheses of active pharmaceutical ingredients, this problem is becoming increasingly important. An increasing number of substances has a solubility of less than 700 μg / ml and presents new challenges to galenics. Poorly soluble pharmaceutical agents very often do not reach a sufficiently high bioavailability after peroral administration. The reasons are to be sought in the too low saturation solubility and dissolution rate of the substances. Even intravenous administration is often out of the question because of the poor solubility of the active ingredients in water.

For many problem agents galenic measures do not lead to sufficient peroral bioavailability. A parenteral administration can not be done because either no suitable particle size can be achieved by the preparation of suspensions or the required solvent volume precipitates too large.

For many years, oil-in-water emulsions have been shown to be the drug carrier for the parenteral dosage form of poorly water-soluble but fat-soluble pharmaceutical agents. In oil-in-water emulsions, the oil core of the emulsions is used as an active ingredient vehicle. In particular, pharmaceutical active ingredients which are sparingly soluble in aqueous media can be incorporated in sufficient amounts in O / W emulsions with sufficient fat solubility. Due to the problem of solubility in the common oils, only a few products have so far been approved. Examples are intravenous therapy with Disoprivan ^®, diazepam Lipuro ^®, ^® and Lipotalon Etomidat- Lipuro ^®.

US-A-2004/0225022 describes aqueous pharmaceutical preparations in which propofol is emulsified. As surfactants, inter alia, lecithin or ethoxylated ethers or esters, as a solvent (vehicle) for propofol, for example, soybean oil is used. Preferred weight ratios of propofol to soybean oil are 1: 3 to 6 and 2: 3 to 6.

The oil-in-water emulsions used typically have a fat content of 10 to 20%, mainly consisting of long-chain and medium-chain triglycerides, 1 to 3% emulsifier (usually lecithin), 2 to 3% glycerol for isotonization and water as the outer phase for injections. By applying oil-in-water emulsions, a high caloric energy supply and substitution of essential fatty acids can be achieved. However, in parenteral nutrition, long and medium chain triglycerides are used as a readily available source of energy. This can lead to an increase in liver weight, especially with long-term dosing. Furthermore, parenteral administration of large amounts of lipid emulsions and / or the administration of lipid emulsions over a long period of time can lead to hyperlipidemia.

In addition, lipids are good breeding grounds for bacterial growth, which is particularly problematic in the production and storage of the drug can lead. Preservatives (bacteriostats) or substances that can inhibit the growth of germs in fat emulsions can simultaneously lead to intolerances. As such a preservative, which is slightly water-soluble, for example, benzyl alcohol is mentioned. In addition, some preservatives, such as sodium disulfite, cause reactions similar to an allergy in humans. Such reactions may be characterized by anaphylactic reactions and life-threatening or asthmatic flare-ups in humans susceptible to sulfites. It has also been demonstrated that sodium disulfite catalyzes the degradation of some drugs, such as propofol. On the other hand, the chelating property of preservatives, such as EDTA, results in an increased excretion of trace elements, such as zinc, copper and iron. Further, sterile filtration of the O / W emulsions with a commercially available sterile filter is not effective because the emulsions are thermodynamically too unstable and tend to break under the necessary shear force.

Also O / W emulsions are only partially stable to dilution or the addition of salts, glucose or other common excipients. To stabilize the emulsions therefore lecithins are used. The concentration of lecithin used in the 10 and 20% fat emulsions is usually about 1.2%. However, egg lecithin used as an emulsifier or soybean oil used as a solubilizer may induce anaphylactic or anaphylactoid reactions in humans allergic to egg lecithin and / or soybean oil.

In order to avoid the above-described disadvantages of oil-in-water emulsions, it has been attempted in the art to improve the solubility of poorly water-soluble pharmaceutical agents by the use of micelles as vehicles for these agents and their bioavailability using solubilizers / surfactants thereby increase.

For example, Cremophor ^® EL, a mixture of the reaction products of castor oil with ethylene oxide (molar ratio 1: 35), able to solubilize hydrophobic drugs in an aqueous environment. The critical Micelle concentration (CMC) of Cremophor ^® EL is 0.009 wt .-%. The size of the micelles from the main component of the Cremophor ^® EL, Polyoxyethylenglycerolricinoleat formed is below 100 nm. Investigations of paclitaxel, which was formulated with Cremophor ^® EL, have shown that the drug release through the micelle, however, slowed down. Furthermore, it turned out that Cremophor ^® EL can trigger allergic reactions, which is why it has lost much of its importance as a drug carrier.

It is also known in the art that poloxamers, i. H. Copolymers consisting of poly (ethylene oxide) and poly (propylene oxide) blocks and varying in their molecular weight, in the ratio of the polymer blocks and their surfactant properties, form micelles in aqueous solution in which the poly (ethylene oxide) blocks form the outer hydrophilic shell and the poly (propylene oxide) blocks form the hydrophobic core of the micelle. In poloxamer micelles, it is therefore known that hydrophobic drugs can be incorporated. Such poloxamer micelles have a small diameter in the range between 20 and 80 nm.

WO-A-2005/72343 describes aqueous pharmaceutical compositions containing a hydrophobic pharmaceutical agent and a poloxamer, preferably P188, as well as poly (ethylene glycol). The preferred weight ratio of active ingredient to poloxamer is given in the examples as 1: 6 to 1: 9, the preferred weight ratio of active ingredient to emulsifier in the aqueous pharmaceutical composition is 1:10 to 1:12.

WO-A-2004/10941 describes transparent aqueous compositions containing propofol and at least one excipient. As auxiliaries, poloxamers and / or PEG are preferably used. As preferred embodiments, weight ratios of propofol to polymer of 1: 12, 1: 11 and 1:10 are called.

In addition to poloxamer micelles, other polymer micelles are known which are suitable for the incorporation of hydrophobic active ingredients. EP-A-0 552 802 describes particles consisting of chemically fixed (cross-linked) copolymer micelles and a hydrophobic component. EP-A-0 520 888 describes nanoparticles in the form of micelles consisting of poly (lactide) / poly (ethylene glycol) copolymers and optionally a water-insoluble active ingredient.

US Pat. No. 6,322,805 describes the solubilization of hydrophobic, usually solid active substances by means of water-soluble micelles composed of amphiphilic block copolymers.

However, in micelles, the number ratio of solubilized molecules to surfactant molecules is low and rarely greater than 2, i. the inside of the micelles does not represent an independent oil phase that has the properties of the bulks, as opposed to emulsions. This is detectable by electron microscopy. An electron micrograph shows nanoparticles, such as micelles,

Emulsion drops and liposome, distinguishable. For the construction of micelles and the incorporation of hydrophobic drugs in it is a relatively large

PolymeπWirstoff ratio necessary, causing unnecessary burden on the body with the polymer.

The known in the prior art pharmaceutical compositions containing hydrophobic drugs thus have many disadvantages, such as

The need for a preservative and / or antimicrobial agents that

Risk of hyperlipidemia, the increase in weight with long-term dosing or high doses, the incompatibility of solubilizers, eg. B. soybean oil or

Cremophor ^® EL, as well as a large polymer (solubilizer): drug ratio and, as a result, a high risk of side effects.

Accordingly, the object of the invention was to provide an aqueous preparation containing at least one hydrophobic active ingredient which is free of lipids and has an improved active ingredient / polymer ratio compared with the prior art. Subject of the invention

The invention relates to the aqueous emulsion according to claim 1, the method according to claim 32 and claim 40, the pharmaceutical composition according to claim 37, the anesthetic according to claim 38 and the use of the emulsion according to the invention according to claim 39.

The reproduced in the dependent claims preferred embodiments of the invention is incorporated by reference.

Detailed description

The emulsion of the invention comprises water as the continuous phase, a hydrophobic pharmaceutical agent as a dispersed (discontinuous) phase, and at least one block copolymer wherein the hydrophobic pharmaceutical agent has a melting point of 25 ° C or less, the block copolymer is a poly (ethylene oxide). Block (hereinafter abbreviated to PEO) and at least one poly (lactide) block (abbreviated to PLA hereinafter) and the weight ratio of the hydrophobic drug to the block copolymer is 1: 1 to 10: 1.

Pharmaceutical agent

The hydrophobic pharmaceutical active substance used in the invention has a melting point of 25 ° C or less, such as 22 ° C or less, of 20 ⁰ C or less, or of 18 ° C or less, or a melting range up to 25 ° C to 22 ° C, up to 20 ⁰ C or up to 18 ° C.

The term "hydrophobic" in the context of the pharmaceutical agent means that at 20 ^° C., the solubility of the drug in water is 700 μg substance per ml water or less, such as 500 μg / ml or less or 350 μg / ml or less. In one embodiment of the invention, the hydrophobic active ingredient at 20 ⁰ C, a water solubility in the range of 20 ug / ml to 200 ug / ml.

The hydrophobic pharmaceutical active substance can be used in the field of human and / or veterinary medicine for therapy and / or prophylaxis.

Active ingredient according to this invention is a substance that produces a biological effect in a living organism. A biological effect is the totality of changes in a biological system caused by an active substance. Preferably, the biological effect is such that the active ingredient can be used for the prevention, alleviation, healing and / or detection of diseases. Thus, the active ingredient may be used as a pharmaceutically active ingredient in the manufacture of medicaments or, when used in the manufacture of medicaments, may become a pharmaceutically active ingredient of the medicaments.

In one embodiment of the invention, the hydrophobic drug is selected from the group consisting of propofol and its pharmaceutically acceptable salts or derivatives, propanidide, isoflurane, enflurane, sevoflurane, vitamin Ki (phytonadione, phylloquinone), clofibrate, ethyl ester of poppy seed iodinated fatty acids (e.g. available under the trade name Ethiodol ^®, Lipiodol ^®).

Propofol (2,6-diisopropylphenol) is a highly effective lipophilic narcotic which is dissolved in the commercial preparations in a lipid emulsion. Propofol acts as a hypnotic, but has no analgesic (ie analgesic) effect. It is used to induce and maintain general anesthesia and to sedate ventilated patients as part of intensive care treatment and for sedation, such as gastric (gastroscopy) or colonoscopy (colonoscopy) alone or with an analgesic. As a special positive properties of propofol apply the relatively pleasant falling asleep and waking up of the patient, mainly because of its rapid anesthesia and short duration of action. When using Propofol, nausea and vomiting (PONV) are less common than with anesthetic gases. The hypnotic effect of propofol occurs after ingestion in the bloodstream due to rapid adjustment of drug balance between blood and brain usually after 10 to 50 seconds.

Propofol is a colorless to slightly yellowish oily liquid at room temperature with a melting point of 18 ° C. The only ionizable functionality is the

Hydroxyl group which has a pK _a value of about 11. The remaining essential parts of the molecule, consisting of a benzene ring and isopropyl

Side-chain groups are highly hydrophobic, followed by the low

Solubility in water (about 150 μg / ml at 25 ° C) and good solubility in organic solvents.

Block copolymer

The block copolymer used according to the invention comprises at least one poly (ethylene oxide) block and at least one poly (lactide) block.

Poly (lactide) and its copolymers are the biodegradable polymers most extensively studied for the manufacture of depot dosage forms. They are also used as absorbable surgical sutures and provide the matrix of on the market drug-containing implants (z. B. Zoladex ^®) and microparticles (z. B. Enantone Depot ^®) represents.

Polyesters of L-lactic acid, racemate D, L-lactic acid and copolymers of L-lactide with D-lactide or with D, L-lactide are degraded by the body. Suitable PLA are composed of monomers of D-lactic acid or L-lactic acid or of D-lactic acid and L-lactic acid monomers. In addition to polymers of D, L-lactic acid, copolymers of D, L-lactic acid with glycolic acid are used for the block copolymer used according to the invention.

Poly (ethylene oxide) (PEO) is well known for its hydrophilicity, water solubility, nontoxicity and excellent biocompatibility.

In a specific embodiment of the invention, the block copolymer is a diblock copolymer PEO-PLA, a triblock copolymer PEO-PLA-PEO, a triblock copolymer Copolymer PLA-PEO-PLA or a tetrablock copolymer PEO-PLA-PEO-PLA, preferably a diblock copolymer PEO-PLA or a triblock copolymer PEO-PLA-PEO. Particularly preferred is the use of diblock copolymer PEO-PLA.

The block copolymer according to the invention can be prepared in a manner known to the person skilled in the art. For the preparation of a triblock copolymer, polyethylene oxide may be reacted with an appropriate amount of lactide (for example D, L-lactide, L-lactide or D-lactide) in the presence of a suitable catalyst, for example a catalytic tin compound such as stannous oxide or tin ( II) octoate, be reacted at a temperature in the range of 120 ⁰ C to 180 ⁰ C. To prepare a diblock copolymer, poly (ethylene glycol) methyl ester can be reacted under the same conditions with an appropriate amount of lactide (for example, D, L-lactide, L-lactide, or D-lactide).

Since PEO with a relatively high molecular weight (over 10,000 g / mol) is not suitable for filtration through the human kidney, smaller PEO sections should be chosen for the block copolymers. In a further embodiment of the invention, the poly (ethylene oxide) block in the abovementioned block copolymers has an average molecular weight (Mw) of from 1000 g / mol to 7000 g / mol, preferably from 2500 g / mol to 6000 g / mol preferably from 4500 g / mol to 5500 g / mol.

In a particular embodiment of the invention, the poly (lactide) block in the abovementioned block copolymers has an average molecular weight (Mw) of from 800 g / mol to 8000 g / mol, preferably from 2000 g / mol to 7000 g / mol or 4000 g / mol to 7000 g / mol, more preferably from 5500 g / mol to 6500 g / mol.

In one embodiment of the invention, the block copolymer has an average molecular weight (Mw) of from 3000 g / mol to 20 000 g / mol, preferably from 4000 g / mol to 15000 g / mol, more preferably from 5500 g / mol to 10000 g / mol on.

Unless otherwise specified in the context of the present invention, a molecular weight of 1000 corresponds to a mass of 1 kDa. In a particular embodiment of the invention, the diblock copolymer has a PEO: PLA molar ratio ranging from 1: 0.05 to 1: 1.3, alternatively from 1: 0.1 to 1: 1.2, preferably from 1: 0 , 2 to 1: 1.0 or from 1: 0.25 to 1: 0.75 and also preferably from 1: 0.35 to 1: 0.65 or from 1: 0.45 to 1: 0.55 , In another embodiment, the diblock copolymer has a molar ratio PEO: PLA in the range of 1: 0.01 to 1: 0.30 and / or in the range of 1: 0.50 to 1: 1.3.

In an alternative embodiment of the invention, the triblock copolymer has a PEO: PLA molar ratio in the range of from 3: 1 to 25: 1, preferably from 4: 1 to 20: 1, preferably from 5: 1 to 15: 1, more preferably from 7 : 1 to 10: 1 up.

A block copolymer to be used according to the invention may be prepared by any suitable method known to those skilled in the art. For example, US-B-6322805 in its Preparation Examples 1 to 4 describes the preparation of triblock copolymers having a PEO: PLA molar ratio of 1: 0.31, 1: 0.37, 1: 0.49 and 1: 0.61 and in its Preparation Examples 5 to 8, the preparation of diblock copolymers having a molar ratio PEO: PLA of 1: 0.15, 1: 0.31, 1: 0.46 and 1: 0.55. US Pat. No. 6,322,205 starts from a commercially available bifunctional polyethylene oxide for the preparation of the triblock copolymers or from a commercially available monofunctional polyethylene oxide for the preparation of the diblock copolymers, in which, until the desired molecular weight of the polylactide chain is obtained in the presence of a catalyst , Stannous octoate, lactide units are grafted.

emulsion

Emulsions are disperse systems consisting of two immiscible liquid or liquid crystalline phases. One liquid forms the inner, ie the dispersed (discontinuous) phase, the other the outer, that is the continuous phase. Depending on the dispersion medium, ie the outer phase, a distinction is made between different emulsion types. In the emulsions according to the invention, water forms the continuous phase, while the hydrophobic active ingredient forms the disperse phase in which water in turn can be dispersed. The weight ratio of the hydrophobic drug to the block copolymer in the emulsion of the present invention is 1: 1 to 10: 1. In a preferred embodiment of the invention, the weight ratio of the drug to the block copolymer is 1.5: 1 to 5: 1.

The molar ratio of active ingredient: block copolymer is preferably in the range from 400: 1 to 50: 1, more preferably in the range from 300: 1 to 70: 1.

In one embodiment of the invention, the content of the block copolymer in the emulsion is from 0.1 to 1.0% by weight, preferably from 0.2 to 0.85% by weight, preferably from 0.3 to 0, 7 wt .-%, also preferably from 0.4 to 0.55 wt .-%, based on the total weight of the emulsion.

In one embodiment of the invention, the content of active ingredient is one of the emulsion from 0.5 to 10.0 wt .-%, preferably from 1.0 to 8.0 wt .-%, preferably from 1.5 to 6.5 wt %, also preferably from 2.0 to 4.0% by weight, based on the total weight of the emulsion.

The emulsion according to the invention preferably has a narrow particle size distribution. For parenteral dosage forms, it is important to keep the microparticulate content low. Large particles are considered to be responsible for many side effects when administering infusions. Therefore, it is generally argued that particles larger than 5 μm in particle diameter should be avoided, since otherwise the capillaries (5-7 μm in diameter) could not easily pass through and therefore the risk of embolism (partial or complete occlusion of a Blood vessel). Theoretically, the risk of injected particles having a diameter greater than that of red blood cells is the occurrence of pulmonary embolism. On the other hand, fat-like particles with a particle diameter of greater than 7.5 microns can adapt to the shape of the capillaries and pass through the pulmonary vessels without difficulty. From this point of view, individual particles with a particle diameter of greater than 5 microns are tolerable, especially when it comes to moldable particles such. B. drug drops is. The USP XXII (United States Pharmacopeia) allows even a few particles with a particle diameter of up to 25 microns. However, in order to achieve a high bioavailability and a high stability of the emulsions, particle sizes of less than 2 μm, in some cases significantly less than 1 μm are required in many cases.

In one embodiment of the invention, the average droplet size (average diameter of the droplets) of the dispersed phase is 2 μm or less, for example, the average droplet size is 1 μm or less and is preferably in the range of 75 nm to 500 nm, more preferably in the range of 75 The mean droplet size is measured by photon correlation spectroscopy (PCS, USP 30, General Chapter 729), also called dynamic light scattering.

The emulsion according to the invention is preferably stable. The term "stable" in connection with the emulsion according to the invention means that when stored at 25 ° C. for at least one year, preferably at least two years, no coalescence of the dispersed drops of the active substance occurs, which leads to drops having an average drop size of more than 1 micron leads.

In a further embodiment of the invention, the mean droplet number of the dispersed phase of the emulsion according to the invention in the range of 1.5 ¹ IO ¹¹ to 6.0 ¹ IO ¹² per ml of emulsion, preferably in the range of 5 ¹ IO ¹¹ to 1.2 ¹ IO ¹² per ml of emulsion. The mean number of drops per ml of emulsion can be calculated by means of the density of the active substance and the mean drop volume.

In a further preferred embodiment of the invention, the emulsion has an osmolality in the range from 250 to 400 mOsmol / kg, preferably in the range from 280 to 350 mOsmol / kg.

The emulsion of the invention preferably has a pH in the physiologically acceptable range, in particular a pH in the range of 6.5 to 8, preferably in the range of 7.0 to 7.5. In a particular embodiment of the invention, the emulsion may further comprise adjuvants and / or adjuvants selected from the group consisting of glycerol, at least one pharmaceutically acceptable salt and preservative.

The concentration of glycerol in the emulsion according to the invention is preferably from 1 to 5% by weight, more preferably about 2.5% by weight, based on the total weight of the emulsion.

In a further embodiment of the invention, the emulsion according to the invention contains as pharmaceutically acceptable salt sodium chloride, preferably in a concentration of about 0.9% by weight, based on the total weight of the emulsion (physiological saline).

In a further embodiment of the invention, the emulsion according to the invention, if necessary, contains as the pharmaceutically acceptable salt sodium hydroxide for adjusting (raising) the pH of the emulsion.

The emulsion of the invention may further contain a preservative. The preservative is preferably selected from the group consisting of EDTA, disodium edetate, sodium disulfite, cysteine and its salts, benzyl alcohol and mixtures thereof. Most preferably, the emulsion according to the invention contains no preservative.

The emulsions according to the invention are preferably parenterally administrable, preferably injectable or infusible or both, particularly preferably intravenous, intramuscular and / or subcutaneously injectable or infusible or both. Special embodiments

anesthetics:

In a specific embodiment, the emulsion according to the invention comprises a narcotic selected from the group consisting of propofol, propanidide, isoflurane, enflurane and sevoflurane.

In a preferred embodiment, the emulsion according to the invention comprises propofol.

In a further embodiment, the emulsion according to the invention comprises propanidide.

In an alternative embodiment, the emulsion according to the invention comprises isoflurane.

In a further embodiment, the emulsion according to the invention comprises enflurane.

In another embodiment, the emulsion according to the invention comprises sevoflurane.

The emulsion of the invention containing a narcotic as described above is as defined above. In the following, preferred embodiments are described.

In the case where the narcotic is propofol, the content of propofol is preferably from 0.5 to 2.0% by weight, preferably from 1.0 to 2.0% by weight, based on the total weight of the emulsion.

In the case where the narcotic is propanidide, the content of propanidide is preferably from 0.5 to 10.0% by weight, preferably from 4.0 to 6.0% by weight, for example 5.0% by weight. %, based on the total weight of the emulsion. In the case where the narcotic is selected from the group consisting of isoflurane, enflurane and sevoflurane, the content of the narcotic is preferably from 0.5 to 10.0% by weight, preferably from 1.0 to 8.0% by weight. %, preferably from 1.5 to 6.5 wt .-%, also preferably from 2.0 to 4.0 wt .-%, based on the total weight of the emulsion.

The emulsion according to the invention containing a narcotic as hydrophobic active ingredient may further contain at least one block copolymer in the ratio propofol to block copolymer of 1: 1 to 10: 1, wherein the block copolymer is a diblock copolymer PEO-PLA or a triblock Copolymer PEO-PLA-PEO.

The poly (ethylene oxide) block preferably has an average molecular weight (Mw) of 1000 g / mol to 7000 g / mol, preferably 2500 g / mol to 6000 g / mol, particularly preferably from 4500 g / mol to 5500 g / mol ,

The poly (lactide) block preferably has an average molecular weight (Mw) of from 800 g / mol to 8000 g / mol, preferably from 2000 g / mol to 4200 g / mol.

The block copolymer preferably has an average molecular weight (Mw) of from 3,000 g / mol to 20,000 g / mol, preferably from 4,000 g / mol to 15,000 g / mol, more preferably from 5,500 g / mol to 10,000 g / mol.

The diblock copolymer preferably has a molar ratio PEO: PLA in the range from 1: 0.05 to 1: 1.3, alternatively up to 1: 0.62 or 1: 0.49, preferably from 1: 0.08 to 1: 1.0 alternatively to 1: 0.31 or to 1: 0.23.

The triblock copolymer preferably has a PEO: PLA molar ratio ranging from 3: 1 to 25: 1, preferably from 4: 1 to 20: 1, preferably from 5: 1 to 15: 1, more preferably from 7: 1 to 10: 1 on.

The content of the block copolymer in the narcotic-containing emulsion is preferably from 0.1 to 1.0% by weight, preferably from 0.2 to 0.85% by weight. preferably from 0.3 to 0.7 wt .-%, also preferably from 0.4 to 0.55 wt .-%, based on the total weight of the emulsion.

In an embodiment wherein the diblock copolymer has a molar ratio of PEO: PLA in the range of 1: 0.05 to 1: 0.15, the content of the block copolymer in the narcotic-containing emulsion is in the range of 0.4 to 1.2 wt .-%, based on the total weight of the emulsion. At a molar ratio of PEO: PLA in the range of 1: 0.15 to 1: 0.28, the content of the block copolymer is preferably from 0.1 to 0.6% by weight, for example, 0.2 to 0.45% by weight .-%, based on the total weight of the emulsion. At a molar ratio of PEO: PLA in the range of 1: 0.25 to 1: 0.5, for example, 1: 0.28 to 1: 0.35, the content of the block copolymer is preferably from 0.2 to 0.4 Wt .-%, based on the total weight of the emulsion. At a molar ratio PEO: PLA in the range of 1: 0.45 to 1: 0.8, for example 1: 0.5 to 1: 0.65, the content of the block copolymer is preferably from 0.05 to 0.5 Wt .-%, for example 0.1 to 0.3 wt .-% or 0.15 to 0.25 wt .-%, based on the total weight of the emulsion.

The mean droplet size of the dispersed phase is preferably 2 μm or less, for example 1 μm or less, preferably measured by photon correlation spectroscopy, and is preferably in the range of 75 nm to 500 nm, most preferably in the range of 75 nm to 300 nm.

The mean droplet number of the dispersed phase per ml of the emulsion of the invention is in the range of 1.5 ¹ IO ¹¹ to 6.0 ¹ IO ¹² per ml of emulsion, preferably in the range of 5 ¹ IO ¹¹ to 1.2 ¹ IO ¹² per ml of emulsion , The mean number of drops per ml of emulsion can be calculated from the density of the narcotic and the mean drop volume.

The emulsion preferably has an osmolality in the range from 250 to 400 mOsmol / kg, preferably in the range from 280 to 350 mOsmol / kg. The emulsion of the invention has a pH in the physiologically acceptable range, in particular in the range of 6.5 to 8, preferably in the range of 7.0 to 7.5.

The emulsion may further contain the above-mentioned additives and / or auxiliaries.

production method

The emulsion according to the invention can in principle be prepared by any method known in the art. An exemplary process for preparing the emulsion according to the invention comprises homogenizing a mixture which comprises water, the hydrophobic active substance, the at least one block copolymer and optionally additives and / or auxiliaries.

In a specific embodiment, the method according to the invention comprises the following steps:

(i) mixing the active ingredient with the block copolymer; (ii) adding water, optionally containing additives and / or adjuvants, to the mixture obtained under (i); and (iii) homogenization of the mixture obtained under (ii).

In a specific embodiment of the invention, the homogenization is carried out by means of a homogenizer, preferably at a pressure in the range of 300 bar to 1000 bar, such as piston-gap high-pressure homogenizer, or by means of a microfluidizer, preferably at a pressure in the range of 300 bar to 1000 bar , in particular 400 bar to 600 bar, for example about 500 bar.

Suitable homogenizers are, for example, the Lab 2000 and the APV Micron LAB 40 (available from APV Systems, D-Unna). A suitable microfluidizer is, for example, Model 110-Y from Microfluidics. In one embodiment of the invention, the mixture is homogenized for a period of 2 to 10 minutes, preferably 4 to 7 minutes, at a rate in the range of 15,000 rpm to 30,000 rpm, preferably from 19,000 rpm to 24,000 Stirred rpm, preferably by means of Ultra Turrax (available from IKA ^® -Werke GmbH & CO. KG, Staufen, Germany).

In a more specific embodiment, the inventive method as a further step comprises the step of sterilization of the emulsion, preferably by heating the emulsion to a temperature in the range of 90 ⁰ C to 140 ⁰ C, preferably from 115 ° C to 130 ⁰ C, preferably for a Duration in the range of 7 minutes to 25 minutes, preferably from 12 minutes to 18 minutes.

Medicines / Pharmaceutical Composition / Therapy / Prophylaxis / Diaqnostics

Another object of the present invention relates to a pharmaceutical composition comprising the emulsion according to the invention. The pharmaceutical composition is preferably selected from the group consisting of a therapeutic, a diagnostic and a prophylactic.

A particular object of the present invention relates to an anesthetic comprising the above-described emulsion according to the invention, for example containing an active substance of the group consisting of propofol, propanidide, isoflurane, enflurane, sevoflurane or mixtures thereof, and preferably containing propofol.

Another object of the present invention relates to a diagnostic agent (contrast agent) comprising the above-described inventive emulsion, for example containing ethyl esters of iodinated fatty acids from poppy seed oil.

Another object of the present invention relates to a lipid-lowering medicament comprising the above-described inventive emulsion, for example containing clofibrate. Another object of the present invention relates to a vitamin preparation comprising the above-described inventive emulsion, for example containing vitamin Ki.

The emulsion according to the invention can be used for the preparation of a medicament for human or veterinary medicine. In particular, the emulsion of the invention containing one selected from the group consisting of propofol, propanidide, isoflurane, enflurane, sevoflurane or mixtures thereof, and preferably propofol, may be used to prepare an anesthetic. Alternatively, the ethyl ester of the iodinated fatty acids of poppy oil-containing emulsion of the present invention may be used for the preparation of a diagnostic agent (contrast agent). Furthermore, the vitamin Ki-containing emulsion according to the invention can be used for the preparation of a vitamin preparation. In addition, the clofibrate-containing emulsion of the present invention can be used for the preparation of a lipid-lowering drug.

The emulsion according to the invention can furthermore be used for the prophylaxis and / or therapy and / or diagnosis in human or veterinary medicine, in particular as anesthetic, diagnostic agent, lipid-lowering medicament and vitamin preparation.

Another object of the present invention relates to a method for therapeutic and / or prophylactic and / or diagnostic treatment of the human or animal body by administering the emulsion of the invention defined above, containing the hydrophobic drug, preferably by parenteral administration, preferably by injection or infusion, especially preferably by intravenous, intramuscular and / or subcutaneous injection or infusion.

The invention is further illustrated by the following examples, but is not limited thereto. Examples

The procedures described below were in commercial, on the

Field of the invention carried out in common devices. The preparation of the emulsions and nanosuspensions on a small scale was carried out at a pressure of 500 bar using a Microfluidizers Model 110-Y of the company

Microfluidics for a period of 20 min. Propofol was used as active ingredient in one

Concentration of 1.0 wt .-%, based on the total weight of the emulsion used. The pH of the emulsions was adjusted to 7.0-7.5 with 1 N NaOH.

The quality of the propofol and glycerol used corresponds to the quality according to known monographs.

In Tables 1 to 5, the mean droplet size is in each case indicated, which was calculated from the droplet size distribution measured by means of photon correlation spectroscopy.

Production Example

To prepare a block copolymer of the invention, DL-lactide and poly (ethylene glycol) methyl ester (PEGME) were mixed in a 50 ml nitrogen flask with tin (II) octoate as a catalyst under an argon atmosphere. With constant stirring, the mixture was heated at 130 ⁰ C for 4 h. The resulting block copolymer was taken up in 30 ml of chloroform and precipitated in 500 ml of diethyl ether. After 12 h, the precipitate was filtered off and dried at 40 ⁰ C at 15 mbar. The resulting block copolymer was dissolved in 200 ml of tetrahydrofuran (THF) and separated from the tin precipitate by centrifugation followed by filtration. After filtration, the THF solution was concentrated to about 60 ml. The block copolymer was again precipitated in 600 ml of diethyl ether and dried at 15 mbar for 12 h at 40 ⁰ C. The molecular weights (Mw) of the blocks and of the block copolymers obtained and the PEO: PLA ratios of the resulting block copolymers are shown in Table A. Table A

example 1

1 g of propofol, 2.5 g of glycerol and 0.15 g of a diblock copolymer having a PEO: PLA ratio of 1: 0.22, 1: 0.31, 1: 0.49 or 1: 0.61 mixed with 96.35 g of deionized water, stirred for 5 minutes with an Ultra Turrax 21000 U / min and then homogenized with a Microfluidizer at 500 bar. The results are shown in Table 1.

Table 1

Example 2

Propoxyl, 2.5 g glycerol and 0.3 g of a diblock copolymer having a PEO: PLA ratio of 1: 0.22, 1: 0.31, 1: 0.49 or 1: 0.61 with 96.2 g mixed deionized water for 5 min with an Ultra Turrax 21000 rev / min and then homogenized with a Microfluidizer at 500 bar. The results are shown in Table 2.

Table 2

Example 3

1 g of propofol, 2.5 g of glycerol and 0.1 g of a diblock copolymer having a PEO: PLA ratio of 1: 0.31, 1: 0.49 or 1: 0.61 were deionized with 96.4 g Water mixed, stirred for 5 min with an Ultra Turrax 21000 U / min and then homogenized with a Microfluidizer at 500 bar. The results are shown in Table 3.

Table 3

Example 4

One gram of propofol, 2.5 grams of glycerin and 0.5 grams of a diblock copolymer having a PEO: PLA ratio of 1: 0.22 were mixed with 96.0 grams of deionized water for 5 minutes with an 21,000-liter Ultra Turrax Stirred and then homogenized with a Microfluidizer at 500 bar. The results are shown in Table 4.

Table 4

Example 5

1 g of propofol, 2.5 g of glycerol and 0.59 g or 1.0 g of a diblock copolymer having a PEO: PLA ratio of 1: 0.09 were mixed with 95.91 g and 95.5 g of deionized water, respectively mixed. Stirred for 5 min with an Ultra Turrax 21000 U / min and then homogenized with a Microfluidizer at 500 bar. The results are shown in Table 5.

Table 5

Claims

claims

An emulsion comprising water as the continuous phase, a hydrophobic pharmaceutical agent as the dispersed phase and at least one block copolymer, characterized in that the hydrophobic pharmaceutical

Active ingredient has a melting point of 25 ° C or less, the block copolymer comprises at least one poly (ethylene oxide) block (PEO) and at least one poly (lactide) block (PLA) and the weight ratio of the hydrophobic drug to the block copolymer 1 : 1 to 10: 1.

2. Emulsion according to claim 1, characterized in that the weight ratio of the hydrophobic active substance to the block copolymer is 1.5: 1 to 5: 1.

3. Emulsion according to one of claims 1 to 2, characterized in that the block copolymer is selected from the group consisting of diblock copolymer PEO-PLA, triblock copolymer PEO-PLA-PEO, triblock copolymer PLA-PEO-PLA and tetrablock copolymer PEO-PLA-PEO-PLA, preferably from the group consisting of diblock copolymer PEO-PLA and triblock copolymer PEO-PLA-PEO.

4. Emulsion according to one or more of claims 1 to 3, characterized in that the poly (ethylene oxide) block of the block copolymer has an average molecular weight (Mw) of 1000 g / mol to 7000 g / mol, preferably 2500 g / mol to 6000 g / mol, more preferably 4500 g / mol to 5500 g / mol.

5. Emulsion according to one or more of claims 1 to 4, characterized in that the poly (lactide) block of the block copolymer has an average molecular weight (Mw) of 800 g / mol to 8000 g / mol, preferably

2000 g / mol or 4000 g / mol to 7000 g / mol, more preferably 5500 g / mol to 6500 g / mol.

6. Emulsion according to one or more of claims 1 to 5, characterized in that the block copolymer has an average molecular weight (Mw) of 3000 g / mol to 20,000 g / mol, preferably 4000 g / mol to 15,000 g / mol, more preferably 5500 g / mol to 10000 g / mol.

Emulsion according to one or more of Claims 1 to 6, characterized in that the diblock copolymer PEO-PLA has a molar ratio of PEO: PLA in the range from 1: 0.05 to 1: 1.3, alternatively 1: 0 , 1 to 1: 1.2, preferably from 1: 0.2 to 1: 1.0 or from 1: 0.25 to 1: 0.75 and also preferably from 1: 0.35 to 1: 0.65 or from 1: 0.45 to 1: 0.55.

Emulsion according to one or more of Claims 1 to 7, characterized in that the triblock copolymer PEO-PLA-PEO has a molar ratio of PEO: PLA in the range from 3: 1 to 25: 1, preferably from 4: 1 to 20 : 1, preferably from 5: 1 to 15: 1, more preferably from 7: 1 to 10: 1.

9. Emulsion according to one or more of claims 1 to 8, characterized in that it has a content of block copolymer of 0.1 to 1.0 wt .-%, preferably from 0.2 to 0.85 wt .-% , preferably from 0.3 to 0.7 wt .-%, also preferably from 0.4 to 0.55 wt .-%, based on the

Total weight of the emulsion having.

10. Emulsion according to one or more of claims 1 to 9, characterized in that it has a content of active ingredient of 0.5 to 10.0 wt .-%, preferably from 1.0 to 8.0 wt .-%, preferably from 1.5 to 6.5 wt .-%, also preferably from 2.0 to 4.0 wt .-%, based on the total weight of the emulsion having.

Emulsion according to one or more of Claims 1 to 10, characterized in that the mean droplet size of the dispersed phase, measured by photon correlation spectroscopy, is 2 μm or less, or 1 μm or smaller, and preferably from 75 nm to 500 nm, preferably 75 nm to 300 nm.

12. Emulsion according to one or more of claims 1 to 11, characterized in that it has an osmolality in the range of 250 to 400 mOsmol / kg, preferably in the range of 280 to 350 mOsmol / kg.

13. Emulsion according to one or more of claims 1 to 12, characterized in that it has a pH in the physiologically acceptable range, preferably in the range of 6.5 to 8 or in the range of 7.0 to 7.5.

14. Emulsion according to one or more of claims 1 to 13, characterized in that it further comprises additives and / or adjuvants selected from the group consisting of preservatives, glycerol and pharmaceutically acceptable salts, especially sodium chloride and sodium hydroxide.

Emulsion according to one or more of claims 1 to 14, characterized in that the hydrophobic active ingredient is selected from the group consisting of propofol, propanidide, isoflurane, enflurane, sevoflurane, vitamin Ki, clofibrate and ethyl esters of iodinated fatty acids from poppy seed oil.

16. An emulsion according to claim 1, comprising:

Propofol as hydrophobic agent and at least one block copolymer in propofol to block copolymer weight ratio of 1: 1 to 10: 1, wherein the block copolymer is a diblock copolymer PEO-PLA or a triblock copolymer PEO-PLA-PEO.

17. Emulsion according to claim 16, characterized in that it has a propofol content of from 0.5 to 2.0% by weight, preferably from 1.0 to 2.0% by weight, based on the total weight of the emulsion, having.

18. An emulsion according to claim 1, comprising:

Propanidide as a hydrophobic drug and at least one block copolymer in the weight ratio propanidide to block copolymer of 1: 1 to 10: 1, wherein the block copolymer is a diblock copolymer PEO-PLA or a triblock copolymer PEO-PLA-PEO.

19. An emulsion according to claim 18, characterized in that it has a content of propanidide of 0.5 to 10.0 wt .-%, preferably from 4.0 to

6.0 wt .-%, for example, 5.0 wt .-%, based on the total weight of the emulsion having.

20. An emulsion according to claim 1, comprising: isoflurane, enflurane or sevoflurane as the hydrophobic active ingredient and at least one block copolymer in the weight ratio of hydrophobic drug to block copolymer of 1: 1 to 10: 1, wherein the block copolymer is a diblock copolymer PEO PLA or a triblock copolymer PEO-PLA-PEO.

21. An emulsion according to claim 20, characterized in that it has an active ingredient content of 0.5 to 10.0 wt .-%, preferably 1.0 to 8.0 wt .-%, preferably from 1.5 to 6, 5 wt .-%, also preferably from 2.0 to 4.0 wt .-%, based on the total weight of the emulsion having.

Emulsion according to one or more of Claims 16 to 21, characterized in that the block copolymer comprises a poly (ethylene oxide) block having an average molecular weight (Mw) of from 1000 g / mol to 7000 g / mol, preferably 2500 g / mol to 6000 g / mol, more preferably from 4500 g / mol to 5500 g / mol.

Emulsion according to one or more of Claims 16 to 22, characterized in that the block copolymer comprises a poly (lactide) block having an average molecular weight (Mw) of 800 g / mol to 8000 g / mol, preferably 2000 g / mol to 4200 g / mol.

Emulsion according to one or more of Claims 16 to 23, characterized in that the block copolymer has an average molecular weight (Mw) of from 3000 g / mol to 20 000 g / mol, preferably from 4000 g / mol to 15000 g / mol, particularly preferably from 5500 g / mol to 10000 g / mol.

25. Emulsion according to one or more of claims 16 to 24, characterized in that the diblock copolymer has a molar ratio PEO: PLA in the range of 1: 0.05 to 1: 1.3, alternatively to 1: 0.62 or 1 0.49, preferably from 1: 0.08 to 1: 1.0 alternatively to 1: 0.31 or to 1: 0.23.

Emulsion according to one or more of Claims 16 to 25, characterized in that the triblock copolymer has a molar ratio PEO: PLA in the range from 3: 1 to 25: 1, preferably from 4: 1 to 20: 1, preferably from 5 : 1 to 15: 1, more preferably from 7: 1 to 10: 1.

27. Emulsion according to one or more of claims 16 to 26, characterized in that the emulsion has a content of block copolymer of 0.1 to 1.0 wt .-%, preferably from 0.2 to 0.85 wt. %, preferably from 0.3 to 0.7 wt .-%, also preferably from 0.4 to 0.55 wt .-%, based on the total weight of the emulsion having.

Emulsion according to one or more of claims 16 to 27, characterized in that the average droplet size of the dispersed phase is 2 μm or smaller or 1 μm or smaller, and preferably from 75 nm to 500 nm, preferably from 75 nm to 300 nm ,

29. Emulsion according to one or more of claims 16 to 28, characterized in that it has an osmolality in the range of 250 to 400 mOsmol / kg, preferably in the range of 280 to 350 mOsmol / kg.

30. Emulsion according to one or more of claims 16 to 29, characterized in that it has a pH in the physiologically acceptable range, preferably in the range of 6.5 to 8 or in the range of 7.0 to 7.5.

31. An emulsion according to any one of claims 16 to 30, characterized in that it further comprises additives and / or adjuvants selected from the group consisting of preservatives, glycerol and pharmaceutically acceptable salts, especially sodium chloride and / or sodium hydroxide.

32. A process for the preparation of the emulsion defined in any one of the preceding claims, comprising homogenizing a mixture comprising water, the hydrophobic active substance, the at least one block copolymer and optionally additives and / or auxiliaries.

33. The method according to claim 32, characterized in that it comprises the following steps:

(i) mixing the hydrophobic drug with the block copolymer;

(ii) adding water, optionally containing additives and / or adjuvants, to the mixture obtained under (i); and (iii) homogenization of the mixture obtained under (ii).

34. The method according to one or more of claims 32 to 33, characterized in that the homogenization by means of a homogenizer or by means of a microfluidizer, preferably in each case at a pressure in the range of 300 bar to 1000 bar.

35. The method according to one or more of claims 32 to 34, characterized in that the mixture before homogenizing for a period of 2 to 10 minutes, preferably from 4 to 7 minutes, at a speed in the range of 15000 U / min to 30,000 Rpm, preferably from 19000 rev / min to 24000 rev / min is stirred.

36. The method according to one or more of claims 32 to 35, characterized in that it comprises the step of sterilizing the emulsion as a further step, preferably by heating the emulsion to a temperature in the range of 90 ⁰ C to 140 ⁰ C, preferably from 115 ° C to 130 ⁰ C, preferably for a duration in the range of 7 min to 25 min, preferably from 12 min to 18 min.

37. A pharmaceutical composition comprising the emulsion defined in one or more of claims 1 to 31.

An anesthetic comprising the emulsion defined in one or more of claims 16 to 31.

39. Use of the emulsion defined in one or more of claims 1 to 31 for the prophylaxis and / or therapy and / or diagnosis in human or veterinary medicine, in particular as anesthetic, diagnostic, lipid-lowering drug and vitamin preparation.

40. A method for the therapeutic and / or prophylactic treatment of the human or animal body and / or for diagnosis by administering the emulsion defined in one or more of claims 1 to 31, preferably by parenteral administration, preferably by

Injection or infusion, more preferably by intravenous, intramuscular and / or subcutaneous injection or infusion.

41. The emulsion as claimed in one or more of claims 1 to 31, comprising an active substance selected from the group consisting of propofol,

Propanidide, isoflurane, enflurane and sevoflurane, preferably propofol, for use as anesthetic.