SK127094A3 - Colloid desperseable preparations of effective matters - Google Patents

Abstract

The present application relates to the use of copolymers based on vinylpyrrolidone in the formulation of active substances which have low solubility in water, and where appropriate, low solubility in apolar solvents.

Description

Technical field

The invention relates to the use of vinylpyrrolidone-based copolymers in the formulation of sparingly water-soluble and optionally apolar solvents of sparingly soluble active substances.

BACKGROUND OF THE INVENTION

The bioavailability and thus the effect of the active substance is strongly determined by its solubility. As a rule, the active substance can only exert its physiological effects in dissolved form. For this reason, hardly soluble active substances often have difficulty in producing the active agents for application or in yield.

By various formulation choices which either improve the water solubility of the active substance or the rate of dissolution, it seeks to increase the bioavailability of sparingly soluble substances and thereby reduce the required dose.

According to U.S. Pat. No. 4,412,986, the production of amorphous coprecipitates of active ingredients with water-compatible polymers such as polyvinylpyrrolidone (PVP) substantially increases the solubility of the active ingredient, since the active ingredient is present in a supersaturated form for a long time after dissolution of the coprecipitate. Polyvinylpyrrolidone, optionally in combination with other excipients, such as surfactants, is often used in the formulation of aqueous crystalline-stable active ingredient formulations. Thus, EP 212 853 A2, JP 04 018 015, JP 04 018 022, JP 04 149 132, JP 03 287 535 and JP 02 264 716 disclose the preparation of polyvinylpyrrolidone-containing solutions of Phenotoin, Clemastine-Fumarate, Piroxicam, Danazol, Pranoprofen and Tranilast.

As an alternative, the preparation of colloidal dispersions by precipitation from organic solutions of the active substances is described. In principle, colloidal aqueous dispersions, also called hydrosols, having a particle size of <0.1 μ can be produced by precipitation. Thus, for example, M. List describes in his inaugural dissertation 1987 at the University of Basel under the name Hydrosols, an intravenous dosage form for the production of injections and infusions of sparingly water-soluble active substances and DE 3 742 473 for the production of colloidal, intravenously applicable dispersions. The preparation is carried out by mixing a solution of the water-insoluble active ingredient in a water-miscible organic solvent with an aqueous base, wherein both the organic and aqueous phases may contain stabilizers or other additives.

US 4,826,689 describes the production of monodisperse colloidal dispersions by the metered addition of an aqueous stabilizer solution to a solution of the active ingredient in a pure or optionally cosolvent-containing organic phase, with production conditions such as batch volumes, mixing and dosing temperatures strongly affecting dispersion quality.

According to DD 293 727 A, the active compounds 2-hydroxy-5-methyl-laurophenone stabilizer can be prepared.

colloidal dispersions using PVP as

However, the aforementioned prior art formulation principles are burdened with some disadvantages. Although the co-precipitates give supersaturated solutions of the active ingredients after dissolution in water, the degree of supersaturation is in most cases relatively low. In addition, the supersaturated solutions recrystallize over time, which has a negative effect on the bioavailability of the active ingredient. Thus, for example, various filters and nozzles are present in the spray devices which are commonly used to apply aqueous preparations of plant protection agents. All these filters, as well as the nozzles, can be more or less easily clogged by the crystallized active ingredients when applying aqueous solids spray slurries.

In the production of colloidal dispersions from active ingredients with a strong tendency to crystallize by precipitation from an organic solution, the critical conversion directly after the precipitation of amorphous particles present into the thermodynamically stable crystalline phase is critical.

In U.S. Pat. No. 4,826,689, by controlling the precipitation conditions, the active ingredient stabilizes for some time in this amorphous, metastable state. In this patent, however, it is pointed out that it is necessary to separate the product of precipitation from the dispersion medium and the subsequent drying in order to avoid recrystallization of the amorphous particles of the active substance. In order to produce a hydrosol stable in particle size, the solvent must be removed after precipitation.

From the inaugural dissertation work of P. Gapmann of r. 1990 at the University of Basel entitled Production and stabilization of hydrosols for intravenous application shows that in the production of hydrosols from one and the same class of substances stability is strongly dependent on the structural and physical chemical characteristics of the individual substances. Thus, in the experiments with the dihydropyridines Darodipine and Isradipine, it has been shown that the hydrosols of Isradipine are up to 20 times more stable than the comparative hydrosols.

It is clear from the state of the art that the preparation of sparingly soluble preparations which are characterized by good performance and good application properties, based on the available formulation principles and using formulation auxiliaries, is difficult to achieve. However, the preparation of conditionally enhanced efficacy makes it possible to reduce the required dose of the active substance, which again leads to a reduction in side effects and environmental damage.

SUMMARY OF THE INVENTION

It is an object of the present invention to use hydrophobic comonomers containing vinylpyrrolidone and / or vinylcaprolactam copolymers in poorly soluble active ingredient formulations.

The formulations form homogeneous solutions or colloidal dispersions in aqueous media, which exhibit substantially improved stability, improved application properties and increased efficacy compared to the present aqueous active ingredient formulations.

In essence, the compositions according to the invention contain, in addition to the active ingredient (A), a vinyl ester copolymer of vinylpyrrolidone and / or vinylcaprolactam (B), a surfactant (C) and optionally additives (D) and / or solvents (E).

The copolymers (B) according to the present invention are random copolymers of at least one vinylpyrrolidone and / or vinylcaprolactam and hydrophobic vinyl monomers. Examples of such vinyl monomers include the higher cyclic vinyl lactams, the core alkylated vinyl caprolactam, vinyl ester, vinyl ether, maleic acid and monoesters or maleic esters with linear or branched chain are random copolymers of vinylpyrrolidone and vinyl ester of the vinylpyrrolidone, styrene ester, styrene ester. Especially CH-CH;

CH _n

I c — o I o

-CH -

CH;

wherein x is in the range of 0 to 16 m, preferably in the range of 0 to 6, and wherein they are greater than 1, preferably greater than 10, and the weight percent of vinyl ester in the total polymer is 5 to 90%, preferably in the range 10 to 80%; 30 to 80%.

For example, copolymers of vinylpyrrolidone and vinyl acetate (x = 0) are commercially available under the trade name Luviskol VA ^R by BASF and under the trade name Agrimer VA ^R by ISP.

These vinylpyrrolidone-based copolymers are poorly soluble or insoluble in water alone. Therefore, it is all the more surprising that these copolymers can be used in the production of aqueous dispersions and solutions of active ingredients, while at the same time achieving significantly better stability than known formulations which contain, for example, pure water-soluble polyvinylpyrrolidone or surfactants as stabilizer.

For the purposes of the present invention, surfactants (C) are nonionic, cationic and anionic emulsifiers, such as fatty acid and polyoxyethylene esters, fatty alcohol ethers and polyoxyethylene ethers, alkyl aryl polyglycol ethers, alkyl sulfonates, alkyl sulfates, alkyl aryl sulfonates and arylsulfonates. Examples of such surfactants are given in the excipient lexicon (Fiedler, H. P. Lexicon der Hilfstoffe für Pharmazie, Kosmetik und angrenzende Gebiete, Edition Cantor Aulendorf (1981)). They can be used singly or in admixture. Particularly suitable surfactants are, for the purposes of the present invention, ionic surfactants such as sodium dodecyl sulfate, sodium dioctylsulfosuccinate and monoethanolamine dodecylbenzenesulfonic acid salt.

The additives (D) in the formulations of the present invention are, as regards the plant protection active ingredient formulations, cold stabilizers which improve the low temperature storage properties of the formulations and adhesion enhancers which have a positive effect on the adhesion of the water spray slurry. produced from these preparations on plants. Examples of cold stabilizers include urea, glycerol and propylene glycol. Suitable adhesion promoters are preferably carboxymethylcellulose, natural and synthetic polymers such as acacia, polyvinyl alcohol and polyvinyl acetate, as well as natural phospholipids, for example, cephalins and lecithins, and also synthetic phospholipids.

Solvents (E) which can be used are all polar solvents which are usually usable for this purpose and do not polar organic solvents. In polyethylene glycol with a variety such as methyl isobutyl ketone is dimethylformamide, cyclic acids and isopropyl alcohol, consideration is given to propylene glycol, molecular weight, ketones, and cyclohexanone, amides such as compounds such as N-methylpyrrolidone, N-methylcaprolactam and butyrolactone; solvents such as dimethylsulfoxide, aromatic hydrocarbons such as xylene, esters such as propyl glycol monoethyl ether acetate, dibutyl adipate, hexyl acetate, heptyl acetate, tri-n-butyl citrate and di-n-butyl ester, phthalic ester glycol ethers such as propylene glycol methyl ether alcohols such as ethyl alcohol, n-propyl alcohol, n-butyl alcohol, isoamyl alcohol, isobutyl alcohol, benzyl alcohol, n-amyl alcohol, tetrahydrofuryl alcohol and 1-methoxy-2-propyl alcohol. Particularly preferred are N-methylpyrrolidone, dimethylformamide, dimethylsulfoxide, propylene glycol, polyethylene glycol, ethyl alcohol and isopropyl alcohol.

In principle, the preparations according to the invention can be used for all active substances. Preferably, however, the formulations are suitable for the active ingredients (A) having a water solubility of <0.5 g / 100 ml, especially <0.1 g / 100 ml and in particular <0.01 g / 100 ml at room temperature.

Examples of such active substances are known dihydropyridines, such as nimodipine, nifedipine, nizoldipine, darodipine, isradipine, felodipine or / fungicides:

2-ani1ino-4-mety1-6-cyclopropyl-pyrimidine,

2 ', ^{6'-dibromo-2-methyl-4'-trifluoromethoxy-4-trifluoromethyl-1-1,3tizol} 5-carboxanilide;

2,6-dichloro-N- (4-trifluoromethylbenzyl) benzimide;

(E) -2-methoxyimino-N-methyl-2- (2-phenoxyphenyl) acetamide;

8-hydroxychino.línsulfát;

Methyl (E) -2- {2- [6- (2-cyanophenoxy) -pyrimidin-4-yloxy] phenyl) -3metoxyakrylát;

Methyl (E) -methoximino [alpha- (o-tolyloxy) -o-toly1] acetate;

2-Phenylphenol (OPP), Aldimorph, Ampropylphos, Anilazine, Azaconazole, Vanalaxyl, Benodanil, Benomyl, Binapacryl, Biphenyl, Bitertanol, Blasticidin-S, Bromuconazole, Bupirimate, Buthiobate, Captafol, Captan, Quinometin, Cardendazin, Carendazin, Carendazin Chloroneb, Chloropicrin, Chlorothalonil, Clozolinate, Cufraneb, Cymoxanil, Cyproconazole, Cyprofuram, Dichlorophen,

Diclobutrazole, Diclofluanid, Diclomezin, Dicloran, Diethofencarb, Difenoconazole, Dimethiriinol, Dimethornorph, Diniconazal, Dinocap, Diphenylamine, Dipyrithion, Ditalimfos, Dithianon, Dodine,

Drazoxolone, Edifenphos, Epoxyconazole, Ethirimol, Etridiazole, Fenarimol, Fenbuconazole, Fenfuram, Fenitropane, Fenpiclonil, Fenpropidine, Fenpropimorph, Fentinacetate, Fentinhydroxyd, Flbam, Flimonone, Fluimonone, Fluimonone, Fluimonone, Fluimonone, Fluimonone, Fluimonone, Fosetyl-Aluminum, Ftalide, Fuberidazole, Furalaxyl, Furmecyclox, Guazatine, Hexachlorobenzol, Hexaconazole, I-Lymexazole, Imazalil, Iprobenfos

mancopper.

Imibenconazole, Iminoctadine,

Isoprothiolan, Kasugamycin,

Mepanipyrim, Mepronil, Metalixyl, Metconazole, Methfuroxam, Metriam, Metsulfovax (IBP), Iprodion,

Macozeb, Maneb, Methasulfocarb, Myclobutanil,

Nickel-dimethyldithiocarbamat, Nitrothal-isopropyl, Ofurance, Oxadixyl, Oxamocarb, Oxycarboxin, Pencycuron, Phosdiphen, Pimaricin,

Penconazole, Polyoxin,

probenazole.

Propiconazole, Propineb,

Prochloraz, Pyrazophos

Procymidone, Pyrifenox,

Nuarimol, Pefurazoat, Piperalin,

Propamocarb, Pyrimethanil,

Pyroquilone, Quintozen (PCNB), Tebuconazole, Tecloftalam, Tecnazen,

Tetraconazole, Thiabendazole, Thicycophene, Thiophanate-methyl, Thiram, Tolclophos-methyl, Tolylfluanid, Triadimefon, Triadimenol, Triazoxide, Trichlamide, Tricycloazole, Tridemorph, Triflumizole, Triforin, Triticonazole, Validamycin A, Vinclozolin, Zinclozolin, Zinc.

Insecticides, acaricides, nematicides:

Abamectin, Acephat, Acrinathrin, Alanycarb, Aldicarb, Alphamethrin, Amitraz, Avermectin, AZ 60541, Azadirachtin, Azinphos A, Azinposh M, Azocyclotin, 4-bromo-2- (4-chlorophenyl) -1 (ethoxymethyl) -5- (trifluoromethyl) ) -lH-pyrrole-3-carbonitrile,

Bendiocarb, Benfuracarb, Bensultap, Betacyluthrin, Bifenthrin, BPMC, Brofenprox, Bromophos A, Buencarb, Buprofezin, Butocarboxin, Butyl-pyridaben, Cadusos, Carbaryl, Carbofuran, Carbophenothion, Carbosulphan, Cartboluletho, Cartbull, Loreto

Chlorethoxyphos, Chlorfenvinphos, Chlorfluazuron, Chlorormephos, N - [(6-chloro-3-pyridinyl) methyl] -N'-methyl-ethanimidamide,

Chlorpyrifos, Chlorpyrifos M, Cis-Resmethirin, Clocyrthrin, Clofentezin, Cyanophos, Cycloprothrin, Calutlutin, Cyhalothrin, Cyhexatin, Cypermethrin, Cyromazine, Deltamethrin,

Demeton S, Demeton-S-methyl, Diafenthiuron,

Dichlofenthion, Dichlorvos, Dicliphos, Dicrotohphos, Diethion, Diflubenzuron, Dimethoat, Dimethylvinphos, Dioxathion,

Disulfotone, Edifenphos, Einamectin, Esfenvalerate, Ethiofencarb, Ethion, Ethofenprox, Ethoprophos, Etrimphos,

Fenazaquin, Fenbutatinoixd, Fenitrothion,

Fenothiocarb, Fenoxycarb, Fenpropathrin, Fenpyrad, Fenpyroximat, Fenthion, Fenvalerate, Fiprnil, Fluazinam, Fluazuron, Flucycloxuron, Flucythrinat, Flufenoxuron,

Fluvalinate, Fonophos, Formothion, Fosthizat

IICH, Heptenophos, Hexaflumuron

Iprobenphos, Isazophos, Isofenphos,

Demeton M, Diazinon

Fenaraiphos, Fenobucarb,

Flufenprox, Fubfenprox, Hexythiazox, Isoprocarb,

turathiocarb.

imidacloprid,

Isoxathion, Ivemectin, Lamda-cyhalothrin, Lufenuron, Malathion, Mecarbam, Mervinphos, Mesulfenphos, Metaldehyde, Methacrifo, Methamidophos, Methidiathion, Methiocarb, Methomyl, Methocarb, Milbemectin, O, N, N, N M, Oxydeprofos,

Parathion A, Parathion M, Permethrin, Phentoat, Phorat, Phosalon, Phosmet, Phosphamdon, Phoxim, Pirimicarb, Pirimiphos M, Pirimiphos A Pyradaphenthion, Pyresmethrin, Pyrethrum, Pyridaben, Pyrimidifen, Pyriproxifen, Quinalphos, Salithion, Sebufos, Silafluoren, Sulfotep, Sulproos, Tebufenozide, Tebufenpyrad, Tebupirimphos, Teflubenzino, Temphobarbosin, Teflutloros Thionazine, Thuringiensin, Tralomethrin, Triarathen, Triazophos, Triazuron, Trichlorfon, Triflumoron, Trimethacarb, Vamidothion, XMC, Xalylcarb.

herbicides:

anilides such as Diflufenican and Propanil; acrylic carboxylic acids such as dichloropicolinic acid, Dicamba and Picoloram; aryloxyalkanoic acids such as Fluroxypyr and Triclopyr, aryloxy-phenoxy-alkanoic esters such as Diclofop-methylFenoxaprop-ethyl, Fluazifot-butyl, Haloxyfop-methyl and Quizalofopethyl; azinones such as Chloridazone and Norflurazone; carbamates such as Chlorpropham, Desmedipham, Phenmedipham and Propham; chloroacetanilides such as Alachlor, Acetochlor, Butachlor, Metazachlor, Metolachlor, Pretilachlor and Propachlor; dinitroanilines such as Oryzalin, Pendimethalin and Trifluralin; diphenyl ethers such as Acifluorfen, Bifenox, Fluoroglycofen, Forroesafen, Halosafen, Lactofen and Oxyfluorfen; ureas such as Clortoluron, Diuron, Fluometuron, Isoproturon, Linuron and Methabenzthiazuron; hydroxylamines such as Alloxydim, Clethodim, Cycloxydim, Stoxydim and Tralkoxydim; imidazolinones such as Imazethypyr, Imazamethabenz, Imazapyr and Imazaquin; nitriles such as Bromoxynil, Dichlobenil and Ioxinyl; oxyacetamides such as Mefenacet; sulphonylureas, such as Amidosulforon,

Bensulforon-methyl, Chlorimuron-ethyl, Chlorsulfuron, Cinosulfuron,

Metsulfuron-methyl, Pyrazosulfuron-ethyl,

nicosulfuron,

Thifensulfuron-methyl,

Primisulfuron, Triasulfuron and Tribenuron-methyl; thiolcarbamates such as butylate, Cycloate, Diallate, LTCTC, Esprocarb, Molinate, Prosulfocarb, Thiobencarb and Triallate; triazines such as Atrazine, Cyanazine, Simazine, Simetryne, Terbutryne and Terbutylazine; triazinones such as Hexazinone, Metamitron and Metribuzins and others such as Aminotriazole, Benfuresate, Bentazone, Cinmethylin, Clomazone, Clopyralid, Difenzoquat, Dithiopyr, Ethofumesate, Flurochloridone, Glufosinate, Isoxosinate, Isoxosinate, Glyphosyteate, Glyphosinate, Glyphosyteate tridiphane.

The active compounds may be present in the preparations individually or in combination with other soluble or insoluble active compounds.

The formulations of the present invention are prepared by simple mixing with optional heating.

The compositions of the present invention may be used as such in the form of concentrates or in the form of plant protection products or medicaments for oral, parenteral and transdermal administration. In plant protection, they can be used both for leaf, soil and trunk applications and for seed treatment.

By dispersing the preparations according to the invention into the aqueous phase, depending on the type of the polymers (B) and the surfactant (C) used, homogeneous solutions or colloidal dispersions are formed which are characterized by high stability. These aqueous systems are formulations. The concentration of the active ingredient in the aqueous dosage form is in the range of 0.0001 to 3% by weight, preferably in the range of 0.001 to 2% by weight. To produce such aqueous solutions or dispersions, the composition of the present invention is mixed with the desired amount of the aqueous phase, optionally mixing and / or pumping. The use of special dispersing devices such as shear homogenizers is not necessary here.

The ratio of active ingredient (A) to polymer (B) can vary within wide limits and is readily detectable by preliminary experiments. In general, the weight ratio of active ingredient to polymer, depending on the active ingredient, is in the range of 1: 0.2 to 1: 10, preferably in the range of 1: 0.2 to 1: 3. The amount of additional additives in the formulation according to the invention wide range. However, it should be adjusted so that the composition, after simple mixing with water, forms a homogeneous solution or colloidal dispersion with particles in the range of 0.01 to 0.4 µm, preferably in the range of 0.03 to 0.2 µηι.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate the invention.

EXAMPLE 1 A copolymer of 30 parts by weight of Nimodipine, 5 parts by weight of vinylpyrrolidone and 70% by weight of parts by weight is dispersed in 225% by weight of vinyl acetate and 0.225 of sodium dodecyl sulfate is dissolved in 19 ethyl alcohol (96%). This concentrate by weight of water. For dispersion, the aqueous phase is introduced and the concentrate is added simultaneously with stirring. Although both the active substance and the polymer used in the pure form are insoluble in water, a clear solution is formed which does not become cloudy after a long time.

As a measure of the crystallization tendencies of the active ingredient in the aqueous dispersion, the dissolved active ingredient content is determined after a defined period of standing of 24 hours at room temperature. The procedure is as follows: 24 hours after production, a sample is taken from the batch and, after removal of the fractions of crystallized active substance, the dispersion is optionally filtered through a 0.45 µm filter. A defined amount of the filtrate is dissolved in ethyl alcohol and the active substance content is determined spectrophotometrically. By comparing the experimentally determined content of the active substance with the theoretical content, the proportion of dissolved and / or colloidal occurring active substance can be determined.

The filterable drug content was 24 mg / ml after 24 hours.

Comparative Example 1

A concentrate containing the active ingredient was prepared according to Example 1, but the copolymer was replaced with an equal weight fraction of pure water-soluble polyvinylpyrrolidone (Luviskol K 30 from BASF). Immediately after manufacture, the aqueous phase caused by the strong crystallization of the active substance, for one hour the crystallizing active substance forms a strong sediment on the bottom and the supernatant liquid is clear and practically colorless, which suggests that the active substance has been quantitatively crystallized. The content of filterable drug 24 hours after manufacture is 0%.

it will cloud what is already one

Example 2 parts by weight of Nimodipine, 4 parts by weight of a copolymer of 20% by weight of vinylpyrrolidone and 80% by weight of vinyl acetate and 0.225 parts by weight of sodium dodecyl sulfate are dissolved in 15 parts by weight of ethyl alcohol (96%). This concentrate is dispersed in 225 parts by weight of water. For dispersion, the aqueous phase is introduced and the concentrate is added simultaneously with stirring. A colloidal opalescent dispersion is formed which does not visually change after standing for 24 hours. After 24 hours, the filterable drug content was 87% of the initial concentration of 4 mg / ml.

EXAMPLES 3-8 parts by weight of Nimodipine, 5 parts by weight of copolymer made from vinylpyrrolidone and vinyl acetate in the amounts shown in Table 1 below, and 0.0113 parts of sodium dodecyl sulfate are dissolved in 19 parts of ethyl alcohol (96%). This concentrate is dispersed in 225 parts by weight of water according to Example 1. Depending on the ratio of monomers in the polymer used, homogeneous solutions or colloidal opalescent dispersions are formed which do not change their appearance after 24 hours or also crystallize virtually quantitatively. The contents of the filterable active ingredient were determined after standing for 24 hours according to Example 1. It has been shown that, with an increasing proportion of vinyl acetate, crystallization inhibiting the effect of the copolymer increases. However, pure vinyl acetate is unsuitable for the preparation of the compositions of the present invention. The results are shown in Table 1 below.

Table 1

Pr. The ratio of monomers in the polymer (% by weight) the appearance of the aqueous mixture after manufacture 24 hours Contents of active substance after 24 hours. 3 vinylpyrrolidone 100 limpid crystals with sheer 3 vinyl acetate 0 Kvapil. 4 vinylpyrrolidone 60 limpid crystals with clear 9 vinyl acetate 40 Kvapil. 5 vinylpyrrolidone 50 limpid crystals with 29 vinyl acetate 50 opal. Kvapil. 6 vinylpyrrolidone 30 opalescence . Opalescence. 82 vinyl acetate 70 7 vinylpyrrolidone 20 opalescence . Opalescence. 88 vinyl acetate 80 8 vinylpyrrolidone 0 coarsely coarsely 0 vinyl acetate 100 Partik. Partik.

Comparative Example 2

The dispersion of this comparative example is prepared essentially according to Example 1 of DE 37 42 473, but Darodipine is replaced by Nimodipine from the dihydropyridine class.

1 g of ethyl cellulose N7 (DOW Chemical) and 0.4 g of Nimodipine are dissolved in 40 parts of ethyl alcohol (96%). This solution is poured rapidly into 200 ml of distilled water at 20 ° C with vigorous stirring. Ethanol was evaporated in a rotary evaporator at 50 ° C under reduced pressure for 5 minutes. According to Example 1, the active substance content is determined after filtration through a 0.45 μτη filter after 24 hours. The active substance content is 21% of the theoretical maximum content.

To prepare the test solution, dilute the test preparation with water to the desired concentration. The spray slurries of the following formulations suitable for use are all transsudent. When the polymer is discharged or blended with pure polyvinylpyrrolidone in the compositions of the present invention, coarse dispersions, turbid and unstable spray slurries are formed.

Example 9

The active compound [2-methyl-1 [[[1- (4-methylphenyl) ethyl] amino] carbonyl] propyl] carbamic acid 1-methylethyl ester is processed as the organic concentrate of the present invention using the quantities indicated. in the following Table 2. After dilution of the concentrate with water, a light-transmissive, crystalline-resistant, colloidal dispersion is obtained. And sedimentation, when the Luviskol VA polymer is omitted or replaced by a pure polyvinylpyrrolidone such as Luvisol K 30 ^R , after dilution of the concentrate with water, a cloudy, coarse particle dispersion is obtained which settles within a few minutes. For comparison of biological activity, a standard preparation of the active ingredient concentrate is prepared in the form of a suspension, as shown in Table 2 below.

Table 2

The composition of the invention Standard preparation 25% wettable powder 15% of active substance 25% of active substance 5% emulsifier 1 16% emulsifier 2 3% emulsifier 2 5% emulsifier 3 5% of Luviskol VA 64 5% Ultrasil VN 3 1% anhydrous citric acid residue: n-methylpyrrolidone residue: Sillitin Z

Emulsifier 1:

Emulsifier 2: Emulsifier 3: Ultrasil VN 3: Sillitin Z: Luviskol VA 64 dodecylbenzenesulfonic acid monoethanolamine salt of nonylphenol-10-glycol ether alkylaryl polyglycol ether highly dispersed amorphous silica ground silicon dioxide acetic acid copolymer / vinyl acetate copolymer 60).

Evaluation of biological effect

To test the efficacy of the active ingredient in the compositions of the present invention, young tomato plants are sprayed with aqueous formulations of compositions at various concentrations up to droplet wetness. For comparison, other tomato plants are separately treated with aqueous formulations of a standard formulation at a comparable active ingredient concentration. After spraying has dried, all plants are inoculated with an aqueous suspension of Phytophera infestans. The plants are placed in an incubation chamber at 20 ° C and 100% relative humidity. Evaluation of the infestation of plants in dependence on the concentration of the active substance is carried out 3 days after inoculation.

In this test, the effect of the preparation according to the invention is achieved at a concentration of active substance which is by a factor of 2 lower than that of the standard preparation.

Example 10

The active substance 4-chloro-N-3'-bis (4-chlorophenyl) -4'5'-dihydro (1,4'-bi-1H-pyrazole) -1'-carboxamide is treated as an organic concentrate according to the present invention in Use of components, the amount of which is given in Table 3 below. After dilution of the concentrate with water, a light-transmissive colloidal dispersion is obtained which is resistant to crystallization and sedimentation. When the Luviskol VA ^R polymer is omitted or replaced by a pure polyvinylpyrrolidone such as Luvisol K 30 ^R , a cloudy, coarse particle dispersion is obtained after dilution of the concentrate with water, which settles within a few minutes. To compare the biological activity, a standard preparation of the active ingredient concentrate is prepared in the form of a suspension, as shown in Table 3 below.

Table 3

Formulation Standard Formulation 1 of the Invention SC 200 Solvent: 54.0% N-Methyl Solvent: 20.0% BP Pyrolidone Enerthen 2367

10.0% propanediol emulsifier: 13.0% emulsifier I emulsifier: 5% PS 29 emulsifier 0.5% Renex 36 polymer: 13.0% Luviskol

VA 64 Diluent: 0.1% Kalzan S Active ingredient content: 20.0% Microbicide: 0.1% Preventol D2 Active ingredient content: 19% Residue: Desalinated water .17

Evaluation of biological activity

(a) Phaedon cochleariae

To test the efficacy of the active ingredient in the formulation of the present invention against Phaedon cochleariae, the cabbage leaves are dipped in the aqueous formulation formulation with various other cabbage leaves separately of the standard active ingredient formulation. After this concentration. For comparison, Phaedon cochleariae larvae are placed on the leaves with an aqueous formulation with comparable processing concentrations. After 7 days, the larval mortality value is evaluated. As a measure of the relative biological activity of the formulation of the present invention compared to a standard formulation, the concentration ratio at 50% mortality is determined according to the following equation:

relative efficiency = LD 50 (formulation according to the invention) / LD 50 (standard formulation).

In this test, the formulation according to the invention showed more than eight times higher efficacy.

(b) Plutella xylostella

To test the efficacy of the active ingredient in the formulation of the present invention against Plutella xylostella, the cabbage leaves are dipped in the aqueous formulation formulation at various concentrations. For comparison, other cabbage leaves are separately treated with an aqueous formulation of a standard formulation with comparable active compound concentrations. After this treatment, Plutella xylostella caterpillars are placed on the leaves. After 7 days, the mortality value is evaluated as described in Example 10a). In this test, the composition of the invention showed a relative efficacy of 30.

(c) Sporoptera frugiperda

To test the efficacy of the active ingredient in the formulation of the present invention against Sporoptera frugiperda, cabbage leaves are dipped in the aqueous formulation formulation at various concentrations. For comparison, other cabbage leaves are separately treated with an aqueous formulation of a standard formulation with comparable active compound concentrations. After this treatment, the caterpillars of Sporoptera frugiperda are placed on the leaves. After 7 days, the mortality rate of the caterpillars was evaluated as described in Example 10a). In this test, the composition of the invention showed relative efficacy. 20th

¹¹ (d) Heliotis viriscens í

μ,

To test the efficacy of the active ingredient in the formulation of the present invention against Heliotis viriscens, the cabbage leaves are dipped in the aqueous formulation formulation at various concentrations. For comparison, other cabbage leaves are separately treated with an aqueous formulation of a standard formulation with comparable active compound concentrations. After this treatment, the caterpillars of Heliotis viriscens are placed on the leaves. After 7 days, the mortality rate of the caterpillars was evaluated as described in Example 10a). In this test, the formulation of the invention showed a relative efficacy of 7.5.

/ y / / z-%

Claims (8)

PATENT CALLS Colloidal dispersible liquid active ingredient formulations comprising, as component A, a sparingly soluble active ingredient, as component B, a copolymer of vinylpyrrolidone and / or vinylcaprolactam and at least one hydrophobic comonomer which reduces the water solubility of the polymer, as component C one or more surfactants; other additives and / or diluents miscible with components A and B or D, such as components D and E. Dispersible liquid formulations according to claim 1, comprising as component B a random copolymer of vinylpyrrolidone and vinyl ester of the formula CX ₀ N ^υ CH-CH; CK I (C ^h 2) x c = o I o -CH - CH; d. I in which X is from 0 to 16 and n and m are greater than 1. Composition according to claim 1, characterized in that the proportion by weight of the hydrophobic comonomer in the polymer is 5 to 90%. Compositions according to claim 1, characterized in that component A is an active ingredient selected from the group consisting of dihydropyridines, azoles, nitromethylene, arylpyrazolines, valinamide carbamates, benzothiophenecarboxamides and / or benzoylurea. Use of the active ingredient preparations according to claim 1 in the form of concentrates or after dilution with water as medicaments or plant protection products. Aqueous plant protection compositions comprising an active ingredient preparation according to claim 1. Aqueous medicament comprising an active ingredient preparation according to claim 1. Process for the preparation of aqueous preparations of sparingly soluble active substances, characterized in that the active substance (A) is mixed with a copolymer (B) of vinylpyrrolidone and a hydrophobic comonomer and with a surfactant (C) in water.