DE102009003980A1 - Formulation, useful for preventing propofol infusion syndrome, comprises propofol and a fatty emulsion with a triglyceride - Google Patents

Abstract

Formulation comprises propofol and a fatty emulsion with at least a triglyceride (I). Formulation comprises propofol and a fatty emulsion with at least a triglyceride of formula (R 1>-O-CH 2-CH(O-R 2>)-CH 2-O-R 3>) (I). R 1>-R 3>5-15C-alkanoyl, preferably n-heptanoyl.

Description

The The present invention relates to a propofol-containing formulation. In particular, the present invention relates to a formulation for the parenteral administration of propofol with reduced Risk of occurrence of Propofol Infusion Syndrome (PRIS). there With the above-mentioned formulation, new drugs are administered for administration Propofol both by infusion and by injection at reduced risk provided by PRIS.

propofol (2,6-Diisopropylphenol) is due to its favorable pharmacokinetic properties such as a short plasma half-life and a relatively small accumulation for many years as well controllable hypnotic and sedative used in medicine. It has little or no analgesic effect and is present especially for sedation in gastroscopy and colonoscopy, for example and maintenance of anesthesia as well as sedative used in intensive care medicine. It shows next to it the mentioned good controllability for the initiation an anesthesia more favorable features such as a reduced incidence of postoperative nausea compared to anesthetic gases and vomiting (PONV) and a comparatively comfortable fall asleep and wake up. It is also used for sedation or long-term sedation used in intensive care. Propofol is due to his very poor solubility in water with very good lipophilicity in fat emulsions parenterally, ie by infusion or by injection, the Patients administered.

However, parenteral administration of such propofol fat emulsions is by no means free of undesirable side effects and risks. For example, as an undesirable side effect of injection or infusion, vascular pain occurs. The prophylaxis of vascular pain includes the addition of a local anesthetic. EP 1 576 953 A1 for example, discloses a propofol-containing fat emulsion that is attached to a local anesthetic such as lidocaine to prevent vascular pain. EP 1 704 858 A1 describes a propofol-containing fat emulsion which additionally contains cyclodextrins and medium-chain fatty acid triglycerides, wherein the fatty acids have an even number of carbon atoms ("medium chain triglycerides (MCT)").

EP 1 875 901 A1 discloses a propofol-containing fat emulsion in which the emulsion particles have a well-defined size and the emulsion is additionally accompanied by an emulsifier.

Describe further US 5,731,555 and US 5,731,356 Propofol-containing emulsions with an edetate (EDTA) additive to prevent problems due to contamination of the emulsions by, for example, bacteria.

While It is common in the art, in the production fat emulsions on fats of naturally occurring fatty acids, that is, fatty acids with an even number of Carbon atoms are used in other areas The technique triglycerides of fatty acids with an odd number Amount of carbon atoms used. For example, triheptanoin (also: glycerol triheptanoate), the triglyceride of n-heptanoic acid, Use as official raw material in the EU for the marking of Risk Meat (since 12 September 2007) and beyond other applications found in the cosmetic industry. Of Furthermore, there are recent approaches, diseases of fatty acid metabolism by using odd-numbered To treat fatty acids in the corresponding emulsions.

US 6,740,679 describes n-heptanoic acid as an energy source for patients suffering from metabolic disorders, especially those of long-chain fatty acids. The use of said seven carbon fatty acid as a nutritional supplement for patients requiring an increase in energy production by fatty acid metabolism is also disclosed.

US 2008/0132571 A1 discloses preparations and methods for the treatment of catabolism effects in patients in which odd-numbered fatty acids and their glycerides are used to increase the intracellular ratio of AMP to ATP and to increase AMPK activity.

A significantly more serious problem than vascular pain in the administration of propofol-containing fat emulsions is the occurrence of the "propofol infusion syndrome (PRIS)". This is a syndrome (described only recently). Cremer et al., Long-term propofol infusion and cardiac failure in adult head-injured patients, Lancet 2001, 357, 117-118 ) rarely occurs under sedation by propofol, but is then accompanied by a lethality of up to 85%. PRIS occurs in both children and adults and is accompanied by one or more of the following clinical features: metabolic acidosis, rhabdomyolysis, arrhythmia, cardiac and / or renal failure, hyperkalemia, hyperlipidemia and hepatomegaly. In addition, an association between propofol infusions of doses> 4 mg · kg ^-1 · h ^-1 at more than 20 h duration and the occurrence of PRIS is seen ( Kam, D. Cardone, Anesthesia 2007, 62, 690-701 ). The exact causes of the occurrence of PRIS are currently unknown. Thus, it has not been established whether propofol itself, a metabolite or the combination with endogenous or therapeutically administered catecholamines and / or glucocorticoids are responsible for the serious disorder. Furthermore, the literature discusses theories related to mitochondrial toxicity, mitochondrial defects, impaired tissue-level oxygen exchange, and carbohydrate deficiency (probably also due to the rarity and difficulty of diagnosing the syndrome) ( K. Ahlen et al., European Journal of Anaesthesiology 2006, 23, 990-998 ).

As well the treatment options of PRIS are currently limited. These include the immediate termination of the propofol supply, the Switching to alternative hypnotics, an acidosis correction, cardiovascular stabilization, under certain circumstances, pacemaker stimulation, hemofiltration Dialysis and adequate calorie intake in the form of Carbohydrates.

It There is thus a need for a method or preparation with whose propofol help patients are parenterally administered can and greatly reduces the risk of occurrence of PRIS is.

In front In this context, it was an object of the present invention to provide a Provide formulation with the help of Propofol safely per Injection or infusion given at reduced risk of PRIS can be.

Surprisingly it has been found that by using triglycerides with fatty acid residues, having an odd number of carbon atoms in propofol carrier emulsions the occurrence of PRIS in parenteral administration should be avoided could.

wobei unabhängig von einander mindestens einer der Reste R¹, R² oder R³ ein Alkanoyl-Rest mit einer ungeraden Zahl von 5 bis 15 Kohlenstoffatomen ist.An object of the present invention is accordingly a formulation comprising propofol and a fat emulsion with at least one triglyceride (A) of the formula (I),

wherein independently of one another at least one of the radicals R ¹ , R ² or R ^{3 is} an alkanoyl radical having an odd number of 5 to 15 carbon atoms.

The Triglyceride (A) to be used according to the invention Fat emulsion consists of glycerol, which is esterified with fatty acids at least one of which is an odd number of carbon atoms having 5 to 15 carbon atoms.

According to the present invention have the odd-numbered Alkanoyle one Chain length of 5 to 15 carbon atoms. Preferred is it is the Alkanoyle, by one or more of the following Fatty acids selected from the group consisting from pentanoic acid (C5: 0, n-valeric acid), heptanoic acid (C7: 0, enanthic acid), nonanoic acid (C9: 0, Pelargonic acid), undecanoic acid (C11: 0, undecyclic acid), Tridecanoic acid (C13: 0, tridecylic acid) and pentadecanoic acid (C15: 0, pentadecylic acid) are derived.

It is preferred that independently of one another at least one of the radicals R ¹ , R ² or R ³ in the triglyceride (A) has a chain length of 5 to 9 carbon atoms.

It is particularly preferred that independently of each other at least one of R ¹ , R ² or R ³ in the triglyceride (A) n-heptanoyl, ie a triglyceride consisting of an esterified glycerol, wherein at least one, preferably at least two hydroxyl groups Heptanoic acid are esterified.

Especially is the triglyceride (A) triheptanoin, a glycerin in which the three hydroxy groups are esterified with n-heptanoic acid.

The synthesis of the triglyceride (A) is familiar to the person skilled in the art. The required ungeradzahli fatty acids (pentane, heptane, nonane, undecane, tridecane and pentadecanoic) are commercially available, for. Likewise, there are numerous commercial sources of supply of different variants of the triglyceride (A) as such: For example, triheptanoin from Condea Chemie GmbH (Witten, Germany) can be obtained as special oil 107. Trinonanoin, Triundecanoin or Tripentadecanoin are z. B. by Chemos GmbH (Regenstauf, Germany) available.

The triglyceride (A) may, in addition to the essential fatty acid radicals according to the invention having an odd number of carbon atoms between 5 and 15, also have further even-numbered fatty acid radicals. Here, in the formulation according to the invention, fat emulsions are preferred which have the triglyceride (A) in which at least one fatty acid residue derives from omega-3 and / or omega-6 fatty acids. Omega-3 and omega-6 fatty acids are biologically important building blocks / nutrients that the human organism itself can not fully produce and that act as precursors to prostaglandins, eicosanoids and structural components of cell membranes. The source of omega-6 fatty acids are various oils of vegetable origin, including soybean oil and safflower diuretic oil, the use of which is prior art for the preparation of intravenous fat emulsions. Also of prior art is the processing of oils of marine origin ("fish oil") as a source of omega-3 fatty acids in intravenous fat emulsions ( EP-A-0298293 ), with highly purified fish oil concentrates are preferred, the extraction of which is made from cold-water fish such as salmon, herring, sardines or mackerel. Their content of omega-3 fatty acids is preferably 40% or above.

Further preferred is triglyceride (A) in which at least one fatty acid residue is selected from the group consisting of medium-chain Fatty acids (eg caprylic acid C8: 0, capric acid C10: 0, lauric acid C12: 0), long-chain saturated Fatty acids (eg myristic C 14: 0, palmitic acid C16: 0, stearic acid C18: 0), monounsaturated Fatty acids (palmitoleic acid C16: 1, oleic acid C18: 1), polyunsaturated fatty acids from omega-3 and omega-6 type, e.g. B. eicosapentaenoic acid (EPA, C20: 5 omega-3), docosahexaenoic acid (DHA, C22: 6 omega-3), Linoleic acid (LA, C18: 2 omega-6) or gamma-linolenic acid (GLA, C18: 3 omega-6). In a further preferred embodiment According to the present invention, the triglyceride (A) is a randomized one structured lipid with a random distribution of Alkanoyl radicals with odd carbon number and the alkanoyl radicals with even carbon number in positions sn-1, sn-2 and sn-3 of the triglyceride molecule (A). Alternative and special Preferably, the triglyceride (A) is a chemically defined one structured lipid, that is, it is a chemical defined distribution of the alkanoyl radicals with odd number of carbon atoms in positions sn-1 and sn-3 and the even alkanoyl radicals Carbon number at position sn-2 of the triglyceride molecule in front.

For the case that the invention to be used Fat emulsions wholly or partially chemically defined or randomized contain structured lipids, are preferably vegetable oils as a source of omega-6 fatty acids or fish oil as a source of omega-3 fatty acids for manufacture the structured lipids. Randomized structured triglycerides are available for example by chemical transesterification a mixture of a desired plant and / or Fish oil with a triglyceride of odd-numbered fatty acids with a chain length of 5 to 15. In the case of chemically defined Structured lipids are transesterified enzymatically starting from the same basic materials.

In Another preferred embodiment of the present invention Invention includes the formulation of the invention a fat emulsion containing at least one additional triglyceride (B) other than (A).

Prefers The triglyceride (B) includes triglycerides marine or vegetable Origin. Because the recovery of pure omega-3 or omega-6 fatty acids from fish oil or vegetable oils or the chemical Synthesis of these fatty acids on the one hand consuming and costly while on the other hand the said oils are marine or vegetable origin high in the corresponding Having fatty acids, it is according to the present Invention not required, omega-3 or omega-6 fatty acids or omega-3 or omega-6 fatty acids containing triglycerides to isolate from these oils, but the oils can be used as such for the preparation of the invention Fat emulsions are used.

By the use of fish oil, but especially of soybean or safflower pistachio, will automatically become long-chain Saturated fatty acids provided as theirs above-mentioned representatives of myristic, palmitic and stearic acid, likewise the monounsaturated oleic acid, the both in marine oils and - in particularly high Concentration - contained in olive oil.

Medium-chain fatty acids or triglycerides are contained in semi-synthetic MCT oil (miglyol oil) and although more than 90% (based on the total fatty acid content) as caprylic and capric acid. In this form they are particularly suitable to be used as triglyceride (B) in the fat emulsion to be used according to the invention.

In a preferred embodiment, the inventive Formulation an emulsion, in addition to triglyceride (A) at least another triglyceride (B) comprising at least one fatty acid residue, the is selected from the group consisting of medium-chain Fatty acids (eg caprylic acid C8: 0, capric acid C10: 0, lauric acid C12: 0), long-chain saturated Fatty acids (eg myristic C 14: 0, palmitic acid C16: 0, stearic acid C18: 0), monounsaturated Fatty acids (palmitoleic acid C16: 1, oleic acid C18: 1), polyunsaturated fatty acids from omega-3 and omega-6 type, e.g. B. eicosapentaenoic acid (EPA, C20: 5 omega-3), docosahexaenoic acid (DHA, C22: 6 omega-3), Linoleic acid (LA, C18: 2 omega-6), gamma-linolenic acid (GLA, C18: 3 omega-6).

In Another preferred embodiment of the present invention Invention is the amount of triglyceride (A) 40 to 80 Wt .-%, more preferably 50 to 70 wt .-%, based on the total weight all triglycerides in the emulsion.

The Fat emulsion of the formulation according to the invention Contains next to the triglyceride (A) and optionally other Triglycerides / lipids advantageously water for injections as well as other auxiliaries and additives, as in the prior art in the preparation of intravenous fat emulsions, z. As emulsifiers, co-emulsifiers, stabilizers and suitable Substances for stopping isotonicity.

When Emulsifiers become physiologically well-tolerated emulsifiers used, such. B. phospholipids animal or vegetable Origin. Preference is given to purified lecithins, such. Soybean lecithin or Egg lecithin or partial fractions derived therefrom. The phospholipid content in the invention to be used Emulsion is preferably 0.4 to 2.0 wt .-%, preferably 0.6% to 1.5% wt .-%, each based on the total weight of Emulsion.

Farther Co-emulsifiers can be used, for. As the alkali salts of long-chain fatty acids (such as sodium stearate, sodium oleate etc.) or - as sole co-emulsifiers or in combination with others - cholesterol or cholesterol esters (eg Cholesterol acetate). When alkali salts of long-chain fatty acids as Co-emulsifiers find their concentration as well as in the case of the use of cholesterol or cholesterol esters alone or in combination with other co-emulsifiers 0.01% by weight in each case to 0.1 wt .-%, preferably 0.02 to 0.04 wt .-%, each based on the total weight of the emulsion.

The Fat emulsion of the formulation according to the invention can, especially if they are polyunsaturated fatty acids like omega-3 or omega-6 fatty acids, with Antioxidants enriched, which prevents the formation of unwanted Protect peroxides. As antioxidants come first of all Vitamin E (alpha, beta or gamma tocopherol) and vitamin C (e.g. As ascorbyl palmitate), wherein the vitamins E and C or their isomers or derivatives are present either alone or in combination can. Depending on the content of long-chain, special polyunsaturated fats in the inventive Preparation is their weight percentage between 0.002 and 0.03% (alpha-tocopherol) or 0.001 and 0.015% (ascorbyl palmitate), in each case based on the total weight of the invention used Emulsion.

In a special embodiment contains the fat emulsion, the invention in the inventive Formulation is also L-carnitine in one Amount of preferably 0.01 to 0.1 wt .-%, each based on the total weight of the emulsion.

In In another embodiment, the inventive Formulation also the vitamins biotin and / or cobalamin contain: Their concentrations are 1-10 mg biotin or 0.1-1 mg cobalamin per 100 g lipid portion of the formulation.

In a preferred embodiment contains the formulation according to the invention 0.1-5% by weight, preferably 0.25 to 3 wt .-%, more preferably 0.5 to 2 wt .-% propofol, based on the total weight of the formulation.

In a further preferred embodiment, the formulation according to the invention additionally contains EDTA (ethylenediamine tetra-acetate) in a concentration of 0.001-0.01% by weight or, more preferably, of 0.0025-0.0075% by weight of EDTA. Alternatively or additionally, the formulation according to the invention tion other or other physiologically acceptable and the state of the art corresponding bacteriostats such. As benzyl alcohol, methyl benzoate or alkali salts of medium-chain fatty acids.

In an additionally preferred embodiment the formulation according to the invention finally another local anesthetic of the type of lidocaine or procaine. The local anesthetic can be dissolved or emulsified form in the formulation of the invention be included or together with the invention Formulation as a kit.

One Another subject of the invention is a medicament comprising the inventive formulation.

A preferred embodiment provides a drug Prophylaxis of PRIS.

there are preferred embodiments of the present invention Medicines for parenteral administration, wherein the parenteral Administration includes both infusion and injection.

The Isotonization of the fat emulsion is preferably carried out with the aid of Polyols such as glycerol, xylitol or sorbitol, in an amount of preferably 2 to 3 wt .-% in each case based on the total weight the emulsion, are used. As a preferred isotonizing agent serves glycerol.

• ¹⁾ Für den Anteil der mittelkettigen Triglyceride (Caprylsäure/Caprinsäure Triglyceride) wurde eine handelsübliche Mischung (Miglyol 812, Sasol Germany GmbH, Witten, Deutschland) verwendet.
• ²⁾ Als strukturiertes Lipid wurde das Triglycerid (A), bestehend aus Glycerin, welches mit Heptansäure in den Positionen sn-1 und sn-3 und Eicosapentaensäure ((EPA), C2O:5 Omega- 3) in der Position sn-2 des Triglycerids verestert ist, eingesetzt.

For the production of the formulation according to the invention as well as the fat emulsion to be used according to the invention as well as of the medicament according to the invention, the lipophilic components 1-10 (if required depending on the preparation example) listed in the table below are roughly mixed and dispersed with the aid of an Ultra-Turrax homogenizer. Thereafter, the hydrophilic components are added 11-14, with sodium oleate or stearate and NaOH used as aqueous solutions and the pH of the batch mixture with the aid of the latter components are adjusted to a value of 8.0- 9.0. The actual homogenization of the batch is then carried out in a high-pressure homogenizer at pressures of about 400 kg / cm ² . The finished emulsion is filled into suitable glass or plastic containers and heat sterilized according to the usual procedures for parenteralia. This results in a sterile, pyrogen-free and stable fat emulsion having an average droplet size of less than 0.5 microns and has a shelf life of at least 24 months at room temperature. Examples example 1 Example 2 Example 3 Example 4 Example 5 Example 6 1 propofol 100 g 200 g 200 g 200 g 200 g 100 g 2 triheptanoin 800 g 800 g 1400 g 1000 g 600 g - 3 Medium-chain triglycerides ¹⁾ - - - 400 g - - 4 soy 200 g - - 300 g - - 5 Safflordistelöl - - 300 g - 200 g - 6 Fischölkonzentr. - 200 g 300 g 300 g 200 g - 7 Structure. Lipid ²⁾ - - - - - 1000 8th phospholipids 80 g 80 g 120 g 120 g 80 g 80 g 9 α-tocopherol 200 mg 500 mg 1500 mg 1500 mg 1000 mg 50 mg 10 Ascorbyl palmitate 500 mg 200 mg 600 mg 300 mg 400 mg 200 mg 11 Sodium oleate 3.0g 3.0g 3.0g 3.0g 3.0g 3.0g 12 glycerol 25 25 22.5 22.5 25 25 13 NaOH ad pH 8-9 ad pH 8-9 ad pH 8-9 ad pH 8-9 ad pH 8-9 ad pH 8-9 14 Water for injections ad 10 liters ad 10 liters ad 10 liters ad 10 liters ad 10 liters ad 10 liters

• ¹⁾ For the proportion of medium-chain triglycerides (caprylic acid / capric acid triglycerides) was a commercial Liche mixture (Miglyol 812, Sasol Germany GmbH, Witten, Germany) used.
• ²⁾ As a structured lipid, the triglyceride (A), consisting of glycerol, containing heptanoic acid in positions sn-1 and sn-3 and eicosapentaenoic acid ((EPA), C2O: 5 omega-3) in position sn-2 of the Triglycerides esterified is used.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• EP 1576953 A1 [0003]
• EP 1704858 A1 [0003]
• EP 1875901 A1 [0004]
• US 5731555 [0005]
• US 5731356 [0005]
• - US 6740679 [0007]
• US 2008/0132571 A1 [0008]
• - EP 0298293 A [0021]

Cited non-patent literature

• - Cremer et al., Long-term propofol infusion and cardiac failure in adult head-injured patients, Lancet 2001, 357, 117-118 [0009]
• - Kam, D. Cardone, Anesthesia 2007, 62, 690-701 [0009]
• K. Ahlen et al., European Journal of Anesthesiology 2006, 23, 990-998 [0009]

Claims (17)

A formulation comprising propofol and a fat emulsion with at least one triglyceride (A) of the formula (I),

wherein independently of one another at least one of the radicals R ¹ , R ² or R ^{3 is} an alkanoyl radical having an odd number of 5 to 15 carbon atoms. A formulation according to claim 1, characterized in that the fat emulsion at least one additional Triglyceride (B), which is different from (A) and which at least has a fatty acid residue selected from the group consisting of medium-chain fatty acids, comprising caprylic acid, capric acid or lauric acid; long-chain saturated fatty acids, comprising Myristic acid, palmitic acid or stearic acid; monounsaturated fatty acids comprising palmitoleic acid or oleic acid; and polyunsaturated Fatty acids of the omega-3 and omega-6 type, comprising eicosapentaenoic acid, Docosahexaenoic acid, linoleic acid and gamma-linolenic acid. A formulation according to claim 1 or 2, characterized in that the triglyceride (A) as randomized or chemically defined structured triglyceride. A formulation according to any one of claims 1 to 3, characterized in that independently of one another at least one of the radicals R ¹ , R ² or R ³ in the triglyceride (A) has a chain length of 5 to 9 carbon atoms. A formulation according to any one of claims 1 to 4, characterized in that independently of one another at least one of the radicals R ¹ , R ² or R ³ in the triglyceride (A) is n-heptanoyl. Formulation according to any of claims 1 to 5, characterized in that the Triglyceride (A) is triheptanoin. Formulation according to any of claims 1 to 6, characterized in that the Amount of triglyceride (A) 40 to 80 wt .-%, based on the total weight all triglycerides in the emulsion. Formulation according to any of claims 1 to 7, characterized in that the Amount of triglyceride (A) 50 to 70 wt .-%, based on the total weight all triglycerides in the emulsion. Formulation according to any of claims 1 to 8, characterized in that the Amount of Propofol 0.1 to 5 wt .-%, based on the total weight the formulation is. Formulation according to any of claims 1 to 9, characterized in that the Amount of Propofol 0.25 to 3 wt .-%, based on the total weight the formulation is. Formulation according to any of claims 1 to 10, characterized in that the Amount of propofol 0.5 to 2 wt .-%, based on the total weight the formulation is. Formulation according to any of claims 1 to 11, characterized in that the Formulation additionally contains EDTA. A pharmaceutical composition comprising the formulation after any the previous claims. Medicament according to claim 13 for the prophylaxis of PRIS. Medicament according to claim 13 or 14 for parenteral administration. Medicament according to claim 14 for administration by infusion. Medicament according to claim 14 for administration by injection.