Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/15—Depsipeptides; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents

Definitions

• the present invention relates to orally administrable agents containing cyclic and open chain depsipeptides
• the present invention relates to orally administrable endoparasiticidal compositions which contain cyclic and open-chain depsipeptides, consisting of amino acids and hydroxycarboxylic acids, as building blocks and 6 to 30 ring or chain atoms
• depsipeptides used in the agents according to the invention are sparingly water-soluble. Orally administrable solutions can only be prepared with the aid of suitable colourants
• the active ingredient solution In order to ensure good bioavailability of the active ingredients, it is desirable to administer the active ingredient solution in a gelatin capsule.
• the solution must neither attack the gelatin capsule, nor must the solvent slowly come out of the
• the present invention relates to
• Depsipeptides alone or in a mixture with other active ingredients characterized in that these active ingredients consist of a solvent mixture Propylene glycol
• Soft gelatin capsule is included.
• Emulsifier 1 to 10% Emulsifier 1 to 10%.
• Active ingredient 0.1 to 20% - propylene glycol 5 to 20%
• Emulsifier 1 to 8% Emulsifier 1 to 8%.
• the present invention furthermore relates to the preparation of endoparasiticidal agents which can be administered orally and which contain cyclic depsipeptides consisting of amino acids and hydroxycarboxylic acids as ring building blocks and 6 to 30 ring atoms.
• Preferred cyclic depsipeptides are those with 18 to 24 ring atoms.
• Depsipeptides with 18 ring atoms include compounds of the general formula (I):
• R 1 , R 3 and R 5 independently of one another for hydrogen straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, mercaptoalkyl, alkylthioalkyl,
• R 2 , R A and R 6 independently of one another are hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl,
• R 1, R 3 and R 5 independently of one another represent straight-chain or branched C j -C 8 - alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, see -
• (Fmoc) amino-C, -C 6 -alkyl in particular 9-fluorenyl-methoxycarbonyl- (Fmoc) amino-propyl, 9-fluorenylmethoxycarbonyl (Fmoc) amino-butyl, C 2 -C 8 - Alkenyl, in particular vinyl, allyl, butenyl, C 3 -C 7 -cycloalkyl, in particular cyclopentyl, cyclohexyl, cycloheptyl, C 3 -C 7 -cycloalkyl-C, -C 4 -alkyl, in particular cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl -C, -C 4 -alkyl, in particular phenylmethyl, which may be replaced by radicals from the halogen, in particular fluorine, chlorine, bromine or iodine
• R 2 , R 4 and R 6 independently of one another for straight-chain or branched C, -C 8 -alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, see-butyl, tert-butyl, pentyl, isopentyl, see-pentyl , Hexyl, isohexyl, see -
• R 1 , R 3 and R 5 independently of one another for straight-chain or branched C, -C 8 -alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, see-butyl, pentyl, isopentyl, see-pentyl, hexyl, isohexyl , see -hexyl, heptyl,
• R 2 , R 4 and R 6 independently of one another for straight-chain or branched C, -C 8 alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, see-pentyl , Hexyl, isohexyl, sec -
• R 1 , R 3 and R 5 independently of one another for straight-chain or branched C ] -C 8 -alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, see-butyl, pentyl, isopentyl, see-pentyl, hexyl, isohexyl , See -hexyl, heptyl, isoheptyl, see -heptyl, octyl, isooctyl, see -Octyl C, -C 8 alkenyl, msbeson- special allyl, C 3 -C 7 cycloalkyl-C, -C 4 alkyl, in particular Cyclohexylmethyl,
• R 2 , R 4 and R 6 independently of one another for straight-chain or branched C, -C 8 -alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, see-butyl, pentyl, isopentyl, see-pentyl, hexyl, isohexyl , See -hexyl, heptyl, isoheptyl, see -heptyl, octyl, isooctyl, see -Octyl, C 2 -C 8 alkenyl, in particular vinyl, allyl, C 3 -C 7 cycloalkyl-C r C 4 -alkyl , in particular Cyclo ⁇ hexylmethyl, phenyl-C j -C 4 -alkyl, in particular phenylmethyl which if appropriate by one or more identical or different may be substituted an ⁇ above
• radicals R 1 to R 6 have the following meaning
• R 1 , R 2 , R 3 , R 4 independently of one another are hydrogen, C, -C 10 alkyl or aryl, in particular phenyl, which are optionally substituted by hydroxy, C, -C 10 alkoxy or halogen
• R 1 , R 2 , R 3 , R 4 independently of one another are hydrogen, C, -C 10 alkyl or aryl, in particular phenyl, which are optionally substituted by hydroxy, C, -C 10 alkoxy or halogen
• A represents an amino protective group which can be removed selectively from the active ester protective group, such as benzyl or benzyloxycarbonyl, and
• R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the meaning given above,
• R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the meaning given above, cyclized in the presence of a coupling reagent, in the presence of a basic reaction auxiliary and in the presence of a diluent
• the carboxy-activated derivatives of the open-chain hexadepsipeptides required as starting materials for carrying out process a are generally defined by the formula (II).
• a and R 1 to R 6 preferably represent those radicals which have already been associated with the description of the substances of the formula (I) according to the invention have been mentioned as preferred for these substituents
• the carboxy-activated fourth pentafluorophenyl esters of the formula (II-a) used as starting materials can be obtained by processes known from the literature (see L Kisfaludy et al J Org Chem 35 (1970), S 3563, L Kisfaludy et al J Org Chem 44 (1979), S 654-655)
• the cyclization of the compounds of formula (II) is preferably carried out in the presence of a suitable hydrogenation catalyst and in the presence of a basic reaction auxiliary using diluents
• Suitable catalysts for carrying out process a are all customary hydrogenation catalysts. Preference is given to using noble metal catalysts, such as platinum, platinum oxide, palladium or ruthenium, if appropriate on a suitable support such as carbon or silicon dioxide All suitable acid binders such as amines, in particular tertiary amines, and alkali and alkaline earth bonds can be used as basic reaction auxiliaries.
• Examples include the hydroxides, oxides and carbonates of lithium, sodium, potassium, magnesium, calcium and barium, as well as further basic compounds such as triethylamine, trimethylamine, tribenzylamine,
• Trihexylamine N, N-dimethyl-aniline, N, N-dimethyl-toluidine, N, N-dimethyl-p-aminopyridine, N-methyl-pyrrolidine, N-methyl-piperidine, N-methyl-imidazole, N-methyl pyrrole, N-methyl-morpholine, N-methyl-hexamethyleneimine, pyridine, 4-
• Pyrrolidino-pyridine 4-dimethylamino-pyridine, quinoline, ⁇ -picoline, ß-picoline,
• DBU Diazabicycloundecene
• Heteroaromatics such as pyridine, N-methylimidazole or 4-pyrrolidino-pyridine, are preferably used.
• halogenated hydrocarbons in particular chlorinated hydrocarbons, such as tetrachlorethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichloroethylene, pentachloroethane, difluorobenzene, chlorobenzene, 1,2-dichloroethane, 1,2-dichloroethane benzene, chlorotoluene, trichlorobenzene; Alcohols such as methanol, ethanol, isopropanol,
• Butanol Ethers such as ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, di-n-butyl ether, di-isobutyl ether, diisoamyl ether, diisopropyl ether, anisole, phenetol, cyclohexylmethyl ether, diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, dichlorodiethyl ether; Nitro hydrocarbons such as nitromethane, nitroethane, nitrobenzene, chloronitrobenzene, o-nitrotoluene; Nitriles such as acetonitrile, butyronitrile,
• ethers such as dioxane, and mixtures of alcohols and ethers
• Process a is carried out by adding compounds of the formula (Ila) in a diluent in the presence of a basic reaction auxiliary and a suitable hydrogenation catalyst in the presence of hydrogen
• the reaction time is about 4 to 20 hours.
• the reaction is carried out at temperatures between +20 ° C and +200 ° C, preferably between +70 ° C and + 155 ° C.
• the process is preferably carried out under an inert gas atmosphere and at the pressure which sets itself when heated to the required reaction temperature under the reaction conditions
• Amounts of a suitable hydrogenation catalyst for example palladium / carbon, dropwise in excess dioxane with continuous passage of hydrogen at 95 ° C.
• the catalysts generally contain 0.5 to 2.5 mol, preferably 1.0 to 2.0 mol, of solution 4-pyrrolidinoxyridin and 0.5 to 10%, preferably 2 to 5% alcohol (based on the solvent)
• N-benzyloxycarbonyl- also N-benzyl- and N-tert-butoxycarbonyl-substituted pentafluorophenyl esters of the formula (Ila) can be used, the latter can be according to U Schmidt (cf. BU Schmidt et al, Synthesis (1991) S 294-300 [ Cyclize didemnin A, B and C]) in a two-phase system
• U Schmidt cf. BU Schmidt et al, Synthesis (1991) S 294-300 [ Cyclize didemnin A, B and C]
• the reaction mixture is cooled, the entire reaction mixture is concentrated in vacuo, extracted with an organic solvent and worked up in a manner known per se.
• the products obtained can be purified in the usual way by recrystallization, vacuum distillation or column chromatography.
• Formula (II) provides a general definition of the open-chain hexadepsipeptides required as starting materials for carrying out process b.
• R 1 to R 6 preferably represent those radicals which have already been mentioned as preferred for these substituents in connection with the description of the substances of the formula (I) according to the invention.
• Uronium reagents such as 2- (1 H-benzotriazol-1-yl) - 1, 1, 3, 3 -tetramethyluronium tetrafluoroborate (TBTU)
• phosphonium reagents such as bis (2-oxo-3-oxazolidinyl) phosphonium acid chloride (BOP-Cl), benzotriazole-1-yl-oxy-tris (dimethylamino-phosphonium) hexafluorophosphate (BOP) and phosphonic acid ester reagents is preferred ⁇ cien, such as diethyl cyanophosphonate (DEPC) or diphenylphosphoryl azide (DPPA)
• DEPC diethyl cyanophosphonate
• DPPA diphenylphosphoryl azide
• the basic reaction auxiliaries for carrying out process b are the tertiary amines mentioned in process a, in particular trialkylamines such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine
• halogenated hydrocarbons mentioned in process a are used as diluents for carrying out process b.
• Process b is carried out by combining compounds of the formula (II) in the presence of one of the stated coupling reagents and in the presence of a basic reaction auxiliary in a diluent and stirring under high dilution conditions.
• the reaction time is 4 to 72 hours.
• the reaction takes place at temperatures between -5 ° C and +100 ° C, preferably between -5 ° C and +50 ° C, particularly preferably at 0 ° C to room temperature. It is operated under normal pressure.
• D-lactic acid of formula (II) generally 1.0 to 3.0 moles, preferably 1.0 to 1.5 moles of coupling reagent.
• reaction solution is washed in a slightly alkaline manner, the organic phase is separated off, dried and concentrated in vacuo.
• the products obtained can be recrystallized in the customary manner.
• the open-chain depsipeptides used as starting compounds can be prepared by processes known per se, for example the one described by H -G Lerchen and H Kunz (Tetrahedron Lett 26 (43) (1985) S 5257-5260; 28 (17) (1987) ) S 1873-1876) using the esterification method according to B F. Gisin (Helv Chim Acta 56 (1973) S 1476)
• the cyclic depsipeptides with 24 ring atoms include compounds of the general formula (Ia)
• R , d , R 2d , R l la and R 12a independently of one another are C ⁇ g -alkyl, C, .8 -haloalkyl, C 3.6 -cycloalkyl, aralkyl, aryl,
• R 3a , R 5a , R 7a , R 9a independently of one another represent hydrogen or straight-chain or branched C j .g-alkyl, which is optionally by hydroxy, C, _ 4 - O o
• Guanidino, -SH or C M -alkylthio may be substituted and furthermore aryl or aralkyl which may be substituted by halogen, hydroxy, C M -alkyl, C, _ 4 -alkoxy,
• R 4d , R 6a , R 8a , R 10a independently of one another for hydrogen, straight-chain C, .5 -alkyl, C 2.6 -alkenyl, C 3 . 7- Cycloalkyl, which may optionally be substituted by hydroxy, C j ⁇ alkoxy, carboxy, carboxamide, imidazolyl, indolyl, guanidino, SH or C j _ 4 - alkylthio, and for aryl or aralkyl which by halogen, hydroxy, C j .4 alkyl, C j .4 alkoxy may be substituted
• phenylethyl which may optionally be substituted by the radicals indicated for phenyl
• R 3a to R 10a have the meaning given above.
• R la , R 2a , R lla and R 12a independently of one another represent methyl, ethyl, propyl, isopropyl or n-, s-, t-butyl,
• R 3a , R 5a , R 7a , R 9a for hydrogen, straight-chain or branched C, .8 alkyl, in particular methyl, ethyl, propyl, i-propyl, n-, s-, t-butyl, which if necessary by C " Alko ⁇ y 'in particular methoxy, ethoxy, imidazolyl, indolyl or C,. 4 - alkylthio, in particular methylthio, ethylthio may be substituted, furthermore represent phenyl, benzyl or phenethyl, which may optionally be substituted by halogen, in particular chlorine.
• R 4a , R 6a , R 8a , R l üa independently of one another for hydrogen, methyl, ethyl, n-
• Ethoxy, imidazolyl, indolyl, methylthio, ethylthio may be substituted and, for isopropyl, s-butyl, may furthermore represent optionally halogen-substituted phenyl, benzyl or phenylethyl.
• the compounds of the formula (Ia) can be prepared by open-chain octadepsipeptides of the formula (IIc)
• Suitable coupling reagents are all compounds which are suitable for forming an amide bond (see, for example, Houben-Weyl, Methods of Organic
• reagents and methods are preferably suitable, active ester method with pentafluorophenol (Pfp), N-hydroxysuccinimide, 1-hydroxybenzot ⁇ azole, coupling with carbodimides, such as dicyclohexylcarbodiimide or N '- (3-
• phosphonium reagents such as benzotriazol-1-yl-oxy-t ⁇ s (d ⁇ methylam ⁇ nophosphon ⁇ um) -hexafluorophosphate (BOP), B ⁇ s (2-ox ( oxa- zohd ⁇ n
• the reaction takes place at temperatures of 0-150 ° C., preferably at 20 to
• Suitable diluents are all inert organic solvents. These include in particular aliphatic and aromatic, optionally halogenated hydrocarbons, such as pentane, hexane, heptane, cyclohexane, petroleum ether, gasoline, ligroin, benzene, toluene, methylene chloride, ethylene chloride, chloroform,
• the compounds of the formulas (IIc) and the coupling reagents are used in a ratio of 1 1 to 1 1.5 to one another. An approximately equimolar ratio is preferred.
• the agents according to the invention are suitable for combating pathogenic endoparasites which occur in humans and in animal husbandry and animal breeding in useful, breeding, zoo, laboratory, experimental and hobby animals. They are against all or individual developmental stages the pests and against resistant and normally sensitive species effective By combating the pathogenic endoparasites disease, death and reduced performance (e.g. in the production of meat, milk, wool, skin, eggs, honey, etc.) are reduced, so that the use of Active ingredients a more economical and simple animal husbandry is possible.
• the pathogenic endoparasites include cestodes, trematodes, nematodes and acantocephals in particular
• Cyclophyllidea for example Mesocestoides spp, Anoplocephala spp, Paranoplocephala spp, Moniezia spp., Thysanosomsa spp, Thysaniezia spp, Avitellina spp, Stilesia spp., Cittotaenia spp., Andyra spp, Bertiella spp, Echinatcus spp, Echinia spp., Taenia spp spp, Davainea spp, Raillietina spp, Hymenolepis spp, Echinolepis spp, Echinocotyle spp, Diorchis spp, Dipylidium spp, Joyeuxiella spp, Diplopyhdium spp
• Piagiorchis spp Prosthogonimus spp, Dicrocoehum spp, Eurytrema spp, Troglotrema spp, Paragonimus spp, Colly ⁇ clum spp, Nanophyetus spp, Opisthorchis spp, Clonorchis spp Metorchis spp, Heterophyes spp, Metagonimus spp
• Oesophagostomum spp Chabertia spp, Stephanurus spp, Ancylostoma spp, Uncina ⁇ a spp, Bunostomum spp,
• Globocephalus spp Syngamus spp, Cyathostoma spp, Metastrongylus spp,
• AAnngeiioossttrroonngevylluuss spp Aelurostrongylus spp, Filaroides spp, Parafilaroides spp, T ⁇ chostrongylus spp, Haemonchus spp, Ostertagia spp, Marshallagia spp, Coope ⁇ a spp, Nematodirus spp, Hyostrongyluspullsup, Spp, Hyostrongylusp
• Oxyu ⁇ da for example Oxyu ⁇ s spp, Enterobius spp, Passalurus spp, Syphacia spp, Aspiculu ⁇ s spp, Heterakis spp
• Ascaridia From the order of the Ascaridia, for example Asca ⁇ s spp, Toxascans spp, Toxocara spp Parasca ⁇ s spp, Anisakis spp, Ascaridia spp From the order of the Spiru ⁇ da, for example Gnathostoma spp, Physaloptera spp, Thelazia spp, Gongylonema spp, Habronema spp, Parabronema spp, Draschia spp, Dracunculus spp
• Filariida for example Stephanofilaria spp, Parafilana spp, Setaria spp, Loa spp, Dirofila ⁇ a spp, Litomosoides spp, Brugia spp, Wuchereria spp,
• the livestock and breeding animals include mammals such as cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer,
• Fur animals such as mink, chinchilla, washable, birds such as chickens, geese, turkeys, ducks, ostriches, sweet and saltwater fish such as trout, carp, eels, reptiles, insects such as honeybees and silkworms
• Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats
• the pets include dogs and cats
• the application can be prophylactic as well as therapeutic
• Suitable vegetable or synthetic fatty acid esters of polyhydric alcohols are fatty acid triglycerides, preferably medium-length fatty acid triglycerides, particularly neutral oils, such as neutral vegetable oils, and in particular fractionated coconut oils, as are known, for example, under the trade name Miglyol and are commercially available, for which purpose again Lexicon of auxiliaries, 3rd edition, pages 808 to 809, (1989) by Fiedler. This includes, for example, Miglyol 810. This is a fractionated coconut oil, the triglycerides of caprylic acid and
• Capric acid contains and has a molecular weight of about 520. It has a fatty acid composition with C 6 at most 2%, C g about 65 to 75%, C 10 about 25 to 35% and C 12 at most 2%, has an acid number of about 0, 1, has a saponification number of approximately 340 to 360 and a maximum iodine number of 1 Miglyol 812 This is a fractional one Coconut oil, which contains triglycerides of caprylic acid and capric acid and has a molecular weight of about 520.
• It has a fatty acid composition with C 6 at most 3%, C 8 about 50 to 65%, C 10 about 30 to 45% and C 12 at most 5%, has an acid number of approximately 0.1, has a saponification number of approximately 330 to 345 and has a maximum iodine number of 1 Miglyol 818
• Captex 355 ⁇ T ⁇ glyce ⁇ d of caprylic acid and capric acid This triglyceride has a fatty acid content of caproic acid of about 2%, of caprylic acid of about 55% and of capric acid of about 42%. It has an acid number of at most 0.1, has a saponification number of at most about 325 to 340 and has a maximum iodine number of 0.5
• Triglycerides of caprylic acid and capric acid are suitable, such as the products known under the trade name My ⁇ tol and commercially available, for which reference is made, for example, to Lexicon of Auxiliaries, 3rd Edition, page 834 (1989) by Fiedler.
• the associated product Myritol 813 has a maximum acid number 1, has a saponification number of about 340 to 350 and has an iodine number of about 0.5
• monoglycerides diglycerides and mono / di-glycerides, in particular esterification products of caprylic acid or capric acid with glycerol.
• Preferred products in this class are, for example, the products which contain or consist essentially or practically of monoglycerides and diglycerides of caprylic acid / capric acid and such products are commercially available under the trade name Imwitor, for which reference is made to Fiedler's Lexikon der Hilfsscher, 3 edition, page 645 (1989).
• a particularly suitable product from this class for use in the compositions according to the invention is the product Imwitor 742, in which it is an esterification product from a mixture of about 60 parts by weight (ppw) caprylic acid and about 40 parts by weight (ppw) capric acid with glycerin.
• Imwitor 742 is usually a yellowish crystalline mass that is liquid at around 26 ° C. It has an acid number of a maximum of 2 has an iodine number of maxima l 1, has a saponification number of about 235 to 275, contains about
• 40 to 50% monoglycerides has a free glycerol content of maximum 2%, has a melting point of approximately 24 to 26 ° C, contains non-saponifiable constituents of maximum 0.3% and has a maximum peroxide number of 1
• Sorbitan fatty acid esters of various known types such as are commercially available under the trade name Span, for example, and these include, for example, sorbitan monolauryl esters, sorbitan monopalmitylesters, sorbitan monostearyl esters, sorbitan ternaryl esters, sorbitan monooleylesters and sorbitan monoleole esters, and this is described, for example, on 3 Lexikon auxiliaries , Pages 1139 to 1 140 (1989) by Fiedler
• Pentaerythne fatty acid and polyalkylene glycol ethers such as pentaerythne dioleate, pentaerythene distearate, pentaerythene monourate, pentaerythene polyglycol ether and pentaerythrene monostearate and also pentaerythritol mono-stearate, and also pentaerythritol fatty acid ester, which is referred to in Lexicon of auxiliaries from 1989 to 923, 924, 324, 324
• Monoglycerides such as glycemonic monooleate, glycemonic monopalmitate and glycemic monostearate, as are known, for example, under the trade names Myvatex, Myvaplex and Myverol and are commercially available, for which Lexicon of auxiliaries, 3 edition, page 836 (1989) by Fiedler is referenced and acetylated, for example, monoacetylated and diacetylated monoglycerides, as they are known, for example, under the trade name Myvacet and are commercially available, for which reference is made to Lexicon of auxiliaries, 3rd edition, page 835 (1989) by Fiedler
• Mono- and difatty acid esters of propylene glycol such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol ostearate, propylene glycol laurate, propyl englykol ⁇ cinoleate, propylene glycol stearate and the like, for which purpose on lexicon of the auxiliaries13 ff
• Fiedler is particularly preferred Propyl englykolcaprylsaure- cap ⁇ nsaurediester, which is known under the trade name Miglyol 840 and is commercially available, for which reference is made to Lexicon of auxiliaries, 3 edition, page 809 (1989) by Fiedler Miglyol 840 has a fatty acid content of C 6 a maximum of about 3 percent, C 8 about 65 to 80 percent, C 10 about 15 to 30 percent and C 12 a maximum of 3 percent, and has an acid number of 0.1 or less, a saponification number of about 320 to 340 and an iodine number of a maximum of 1
• Other suitable products in this class are Capmul MCT ⁇ , Captex 300 (1) , Captex 800 ° ⁇ , Neobee M5 (2) and Mazo! 1400 (3) Imw ⁇ tor (4)
• Imwitor 742 is particularly preferred as glycerol fatty acid ester.
• the agents according to the invention furthermore contain a pharmaceutically acceptable emulsifier.
• Nonionic hydrophilic surfactants and nonionic lipophilic surfactants are preferred.
• suitable hydrophilic surfactants that can be used as surface-active components are reaction products of natural or hydrogenated vegetable oils and ethylene glycol, namely polyoxyethylene glycol, natural or hydrogenated vegetable oils, such as polyoxyethylene glycol natural or hydrogenated
• Castor oils Such products can be obtained in a known manner, for example by reacting a natural or hydrogenated Rmzinusols or fractions thereof with ethylene oxide with a molar ratio of, for example, about I 35 to about 1 60 and with optional removal of the free polyethylene glycol components from the product, as described in DE -B 1 182 388 and
• DE-B 1 518 819 is particularly suitable are the various surfactants which are available under the Cremophor name.
• Cremophor RH40 with a saponification number of about 50 to 60, an acid number of less than 1, are particularly suitable iodine number of less than 1, a water content (according to Fischer) of less than 2%, one
• Polyoxyethylene sorbitan fatty acid esters for example the mono- and trilauryl esters, mono- and tripalmyl esters, mono- and tristearyl esters and mono- and trioleyl esters, as are known under the trade name Tween and are available commercially, for which purpose on Lexicon of auxiliaries, 3 edition, pages 1300 to 1304 (1989) by Fiedler, for example the following products.
• Tween 20 polyoxyethylene (20) sorb ⁇ tanmonolaurat
• Tween 40 polyoxyethylene (20) sorb ⁇ tanmonopalm ⁇ tat
• Tween 60 polyoxyethylene (20) sorb ⁇ tanmonostearat
• Tween 80 polyoxyethylene (20) sorbitan monooleate
• Tween 65 polyoxyethylene (20) sorb ⁇ tant ⁇ stearate
• Tween 85 polyoxyethylene (20) sorbitan trioleate
• Tween 21 polyoxyethylene (4) sorbitan monolaurate
• Tween 61 polyoxyethylene (4) sorbitan monostearate
• Tween 81 polyoxyethylene (5) sorb ⁇ tanmonooleat
• Particularly preferred products from this class for use in the compositions according to the invention are the products Tween 40 and Tween 80 mentioned above
• Polyoxyethylene fatty acid esters for example the known types of polyoxyethylene stearic acid esters, which are commercially available under the trade name Myrj, for which purpose on Lexicon of auxiliaries, 3 edition, page 834 (1 989) of F ed ed er he ngwi e sen wi rd, and also thief known polyoxyethylene fatty acid esters, which are commercially available under the trade name Cetiol
• HE Fiedler's Lexicon of Auxiliaries, 3rd Edition, page 284 (1989), and this is a particularly preferred product from this class for use in the compositions according to the invention
• Product Myrj 52 which has a refractive index n ⁇ 0 of about 1.1, has a melting point of about 40 to 44 ° C, has an HLB value of about 16.9, has an acid number of about 0 to 1 and has a saponification number of about 25 to 35
• Copolymers of polyoxyethylene and poly oxy propy len as they are known, for example, under the trade names Pluronic and Emkalyx and are commercially available, for which reference is made to Fiedler's Lexikon der Hilfsstoffe, 3 edition, pages 956 to 958 (1989).
• Pluronic F68 is a particularly preferred product which class for use in the compositions according to the invention.
• Block copolymers of polyoxyethylene and polyoxypropylene such as are known and commercially available, for example, under the trade name Poloxamer, for which reference is made to Fiedler's Lexikon der Hilfsscher, 3 Edition, page 959 (1989).
• Poloxamer for which reference is made to Fiedler's Lexikon der Hilfsscher, 3 Edition, page 959 (1989).
• a particularly suitable product in this class for the The product in the compositions according to the invention is poloxamer
• Lecithins which are suitable for use in the compositions according to the invention include, in particular, soybean lecithins
• transesterification products of natural vegetable glycols and polyalkylene polyols.
• Such transesterification products are known in the prior art and can be prepared, for example, using the processes generally described in US Pat. No. 3,288,824. They include transesterification products various natural, for example non-hydrogenated, vegetable oils such as corn oil, kernel oil, almond oil, peanut oil, olive oil and palmol as well as mixtures thereof with polyethylene glycols, in particular with polyethylene glycols, which have an average molecular weight of 200 to 800.
• Preferred products are obtained by transesterification of 2 moles of a natural vegetable oil with 1 Mol of polyethylene glycol, which has an average molecular weight of 200 to 800, for example.
• Various forms of this class of transesterification products are known and are commercially available under the trade name Labrafil, for which reference is made to Fiedler's Lexikon der Hilfsstoffe, 3 Edition, page 707 (1989) as Components
• Labrafil M 1944 CS which is a transesterification product of kernol and polyethylene glycol, which has an acid number of about 2, a saponification number of about 145 to 175 and an iodine number of about 60 to 90
• Labrafil M 2130 CS which is a transesterification product of C 12 -C ] 8 -glycine and polyethylene glycol, which has a melting point of about 35 to 40 ° C, has an acid number of less than 2, has a saponification number of about 185
• thickeners such as bentonites, colloidal silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and metacrylates
• the active compounds can also be present in the agents according to the invention in a mixture with synergists or with other active compounds which act against pathogenic endoparasites.
• Such active compounds are, for example, L-2,3,5,6-tetrahydro-6-phenyl-imidazothiazole and benzimidazole carbamates like Febrantel also pyrantel, traziquantel ivermectin
• Ready-to-use preparations contain the active ingredients in concentrations of 10 ppm - 20 percent by weight, preferably 0.1-20 percent by weight
• Emulsifier, oil and propylene glycol are mixed with gentle warming (40 ° C) and the active ingredients are added with stirring. A clear solution is created which is filled into soft gelatin capsules

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• 1995
  • 1995-12-02 DE DE19545044A patent/DE19545044A1/de not_active Withdrawn
• 1996
  • 1996-11-20 WO PCT/EP1996/005100 patent/WO1997020547A1/de not_active Application Discontinuation
  • 1996-11-20 EP EP96939850A patent/EP0866690A1/de not_active Withdrawn
  • 1996-11-20 AU AU76936/96A patent/AU7693696A/en not_active Abandoned
  • 1996-11-20 HU HU0000262A patent/HUP0000262A3/hu unknown
  • 1996-11-20 JP JP9520917A patent/JP2000502064A/ja active Pending
  • 1996-11-20 CN CN96199748A patent/CN1207673A/zh active Pending
  • 1996-11-20 BR BR9611678A patent/BR9611678A/pt not_active Application Discontinuation

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