IL111356A - Colloidally dispersible active compound formulations comprising a copolymer of vinylpyrrolidone and/or vinylcaprolactam - Google Patents

Description

'τκιί *ΙΉΙΠ i*mi m^ya mi inn ¾n> m ^inmio i /i iiT?t>i Colloidal ly dispersible active compound formulations comprising a capolymer of vinyl pyrrol idone and/or vinylcaprolactam BAYER AKTIENGESELLSCHAFT C. 94982 The present invention relates to the use of copolymers based on vinylpyrrolidone for formulation of active compounds which are sparingly soluble in water and, where appropriate, sparingly soluble in apolar solvents .

The bioavailability and therefore the action of an active compound is determined to a large degree by its solubility. As a rule, an active compound can display its physiological action only in dissolved form. Difficulties therefore often occur with sparingly soluble active compounds in providing active compositions for administration or application.

Attempts are made to increase the bioavailability of sparingly soluble active compounds and therefore to reduce the dose needed by various formulation options which improve either the water-solubility of the active compound or the rate of solution.

In US-4 412 986, the solubility of the active substance is thus increased considerably by preparation of amorphous active compound coprecipitates with water-compatible polymers, such as polyvinylpyrrolidone (PVP) , because after dissolving of the coprecipitate, the active compound is present in supersaturated form for a relatively long period of time. PVP, possibly in combination with other excipients, such as, for Le A 29 890 - 1 - example, surfactants, is widely used for formulation of aqueous active compound formulations which are stable to crystallization. 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 thus describe the provision of PVP-containing phenytoin or clemastine fumarate, piroxicam, danazole, pranoprofen or tranilast solutions.

As an alternative, the preparation of colloidal dispersions by means of precipitation from organic active compound solutions is described. Colloidal aqueous dispersions, also called hydrosols, the particle size of which is < 0.1 μ can in principle be produced by precipitation. Thus, for example, M. List, in his inaugural dissertation published in 1987 at the University of Basle under the title "Hydrosols, an intravenous drug form for the preparation of injections and infusions of active compounds which are sparingly soluble in water", and DE 3 742 473 describe the preparation of colloidal dispersions which can be administered intravenously. The dispersions are prepared by mixing a solution of an active compound which is sparingly soluble in water in a water-miscible organic solvent with an aqueous phase, it being possible for both the organic and the aqueous phase to contain stabilizers or other additives. US 4 826 689 describes the preparation of monodisperse colloidal dispersions by controlled addition of an aqueous stabilizer solution to a solution of the active compound in an organic phase which is pure or contains Le A 29 890 - 2 - a cosolvent, if appropriate, the quality of the dispersion being determined to a large degree by the preparation conditions, such as batch volume, temperature and stirring and metering speed. According to DD 293 727 A, colloidal dispersions of the active compound 2 -hydroxy-5-methyl-laurophenone can be prepared by means of the use of PVP as a stabilizer.

However, ' the formulation principles mentioned, which correspond to the prior art, have some disadvantages. Although coprecipitates give a supersaturated solution of the active compound after being dissolved in water, the degree of supersaturation is relatively low in most cases. Furthermore, the supersaturated solutions crystallize out again in the course of time, which has an adverse effect on the bioavailability of the active compound. Application of the active compound is also made difficult. Thus, for example, several filters and nozzles are present in spray units which are usually used for application of aqueous formulations of plant protection compositions. All these filters and also the nozzles can easily be blocked to a greater or lesser degree by active compound which has crystallized out during application of aqueous spray liquors based on solid active compounds.

A critical factor of the preparation of colloidal dispersions of active compounds having a marked tendency to crystallize by precipitation from organic solution is the conversion of the particles present in Le A 29 890 amorphous form directly after the precipitation into the thermodynamically more stable crystalline phase. In US 4 826 689, the active compound is stabilized in this amorphous, meta-stable state for some time by control of the precipitation conditions. However, this patent specification refers to the need to separate off the precipitation product from the dispersion medium and subsequently dry it in order to avoid recrystallization of the amorphous active compound particles. To prepare a hydrosol which is stable with respect to the particle size, the solvent must be removed after the precipitation. The inaugural dissertation by P. Gassmann published in 1990 at the University of Basle with the title "Preparation and stabilization of hydrosols for intravenous administration" shows that in the case of preparation of hydrosols from active compounds of one and the same substance class, the stability greatly depends on the structural and physicochemical features of the individual substances . Experiments with the dihydropyridines darodipine and isradipine thus showed that hydrosols of isradipine are up to 20 times more stable than comparable hydrosols of isradipine.

It can be seen from the prior art that provision of formulations of sparingly soluble active compounds, which are distinguished by a good activity and good application properties, on the basis of the formulation principles available, and formulation auxiliaries used in this context can be achieved only with difficulty. However, a formulation-related increase in activity Le A 29 890 - 4 - allows the dose of active compound needed to be reduced, which in turn leads to fewer side effects and less pollution of the environment.

The invention relates to the use in formulations of sparingly water-soluble active compounds of vinylpyr-rolidone and/or vinylcaprolactam copolymers which contain hydrophobic comonomers .

In aqueous media, the formulations form homogeneous solutions or colloidal dispersions which are distin-guished by a significantly increased stability, better application properties and an increased activity compared with the usual aqueous active compound formulations .

The formulations according to the invention essentially comprise, in addition to the active compound (A) , a vinylpyrrolidone and/or vinylcaprolactam vinyl ester copolymer (B) , a surfactant (C) and if appropriate additives (D) and/or a solvent (E) .

Copolymers (B) in the context of the invention are random copolymers of at least one vinylpyrrolidone and/or vinylcaprolactam and hydrophobic vinyl monomers . Examples of these vinyl monomers are higher cyclic vinyl-lactams , nuclear-alkylated vinylpyrrolidone, vinylcaprolactam, vinyl esters, vinyl ethers, styrene, maleic anhydride and mono- or diesters of maleic acid with linear or branched alcohols. Random copolymers of Le A 29 890 - 5 - vinylpyrrolidone and vinyl esters of the integral formula in which x is between 0 and 16, preferably between 0 and 6, and n and m are greater than 1, preferably greater than 10, and the weight content of the vinyl ester in the total polymer is 5-90%, preferably between 10 and 80%, and particularly preferably between 30 and 80%, are particularly preferred.

Copolymers of vinylpyrrolidone and vinyl acetate (x = 0) are obtainable, for example, under the trade name Luviskol VA® from BASF and under the trade name Agrimer VA® from ISP.

Le A 29 890 - 6 - These copolymers based on vinylpyrrolidone are themselves only poorly soluble or even insoluble in water. It is therefore all the more surprising that these copolymers can be used for preparation of aqueous active compound dispersions and solutions and thereby produce a considerably better stability than known standard formulations which comprise, for example, a pure water-soluble polyvinylpyrrolidone or only surfactants as the stabilizer.

Possible surfactants (C) in the context of the invention are nonionic, cationic and anionic emulsifiers, such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkylaryl polyglycol ethers, alkylsulfonates , alkyl sulfates, alkylarylsulfonates and aryl sulfates. Examples of such surfactants are listed in the dictionary of auxiliaries (Fiedler, H.P. "Lexikon der Hilfsstoffe fiir Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Auxiliaries for Pharmacy, Cosmetics and related fields]", edition, Cantor Aulendorf (1981)). They can be employed individually or also as a mixture. Particularly suitable surfactants in the context of the invention are ionic surfactants, such as Na dodedcyl sulfate and Na dioctylsulfosuccinate and dodecy-lbenzenesulfonic acid monoethanolamine salt.

Additives (D) in the formulations according to the invention, where these are formulations for plant protection active compounds, are low temperature Le A 29 890 - 7 - stabilizers which improve the storage properties of the formulation at a low temperature, and adhesion promoters which have a positive effect on the adhesion of the aqueous spray liquor prepared from the formulations to the plant . Examples of low temperature stabilizers are urea, glycerol and propylene glycol. Possible adhesion promoters are, preferably, carboxymethylcellulose, naturally occurring and synthetic polymers, such as gum arabic, polyvinyl alcohol, polyvinyl acetate and naturally occurring phospholipids, such as cephalins and lecithins, and also synthetic phospholipids.

Solvents (E) which can be used are all the polar and non-polar organic solvents which can usually be employed for such purposes . Possible solvents are propylene glycol, polyethylene glycol of various molecular weights, ketones, such as methyl isobutyl ketone and cyclohexanone, and furthermore amides, such as dimethylformamide, and moreover cyclic compounds, such as N-methyl-pyrrolidone, N-methylcaprolactam and butyrolactone, and also strongly polar solvents, such as dimethyl sulfoxide, and furthermore aromatic hydrocarbons, such as xylene, and in addition esters, such as propylglycol monomethyl ether-acetate, dibutyl adipate, hexyl acetate, heptyl acetate, tri-n-butyl citrate and di-n-butyl phthalate, glycol ethers, such as propylene glycol methyl ether, and furthermore alcohols, such as ethanol, n- and i-propanol, n- and i-butanol, n- and i-amyl alcohol, benzyl alcohol, Le A 29 890 - 8 - tetrahydrofuryl alcohol and l-me hoxy-2-propanol . Particularly preferred solvents are n-methylpyrrolidone, dimethylformamide, dimethylsulfoxide, propylene glycol, polyethylene glycol, ethanol and i-propanol.

In principle, formulations according to the invention can be applied to all drugs. However, they are particularly suited for active compounds (A) which have a water solubility at room temperature of <0.5 g/100 ml, specifically <0.1 g/100 ml and in particular <0.01 g/100 ml. Examples of such active compounds are dihydropyridines, such as, for example, nimodipine, nifedipine, nitrendipine, nisoldipine, darodipine, isradipine, and felodipine.

Other examples of active compounds are pesticides like: Fungicides : 2-Anilino-4-methyl-6-cyclopropyl-pyrimidin; 2' ,6'-Di-bromo-2-methyl-4 ' - trifluoromethoxy-41 -trifluoro-methyl-1, 3-thizole-5-carboxanilid; 2 , 6 -Dichloro-N- (4-tri-fluoromethylbenzyl) benzamid; (E) -2-Methoxyimino-N-meth-yl-2- (2-phenoxyphenyl) -acetamid; 8 -Hydroxychinolin-sulfat; Methyl- (E) -2- {2- [6- (2-cyanophenoxy) -pyrimidin-4-yloxy] -phenyl) - 3 -methoxyacrylat ; Methyl- (E) -methoximino [alpha- (o-tolyloxy) -o-tolyl] acetat 2-Phenylphenol (OPP) , Aldimorph, Ampropylfos, Anilazin, Azaconazol, Benalaxyl, Benodanil, Benomyl, Binapacryl, Biphenyl, Bitertanol, Blasticidin-S , Bromuconazole , Le A 29 890 - 9 - Buthiobate, Captafol, Captan, Carbendazim, Carboxin, Chinome thionat (Quinomethionat ) , Chloroneb, Chloropicrin, Chlorothalonil , Chlozolinat, Cufraneb, Cymoxanil, Cyproconazole, Cyprofuram, Dichlorophen, Diclobutrazol , Diclofluanid, Diclomezin, Dicloran, Die thof encarb , Difenoconazol , Dime thirimol , Dimethomorph, Diniconazol, Dinocap, Diphenylamin, Dipyrithion, Ditalimfos, Dithianon, Dodine, Drazoxolon, Edifenphos, Epoxyconazole, Ethirimol, Etridiazol, Fenarimol, Fenbuconazole, Fenfuram, Fenitropan, Fenpiclonil , Fenpropidin, Fenpropimorph, Fentinacetat , Fentinhydroxyd, Ferbam, Ferimzone, Fluazinam, Fludioxonil, Fluoromide, Fluquinconazole, Flusilazole, Flusulfamide, Flutolanil, Flutriafol, Folpet, Fosetyl-Aluminium, Fthalide, Fuberidazol, Furalaxyl, Furmecyclox, Guazantine, Hexachlorobenzol , Hexaconazol, Hymexazol, Imazalil, Imibenconazol , Iminoctadin, Iprobenfos, (IBP), Iprodion, Isoprothiolan, Kasugamycin, Mancopper, Mancozeb, Maneb, Mepanipyrim, Mepronil, Metalaxyl, Metconazol, Methasulfocarb, Methfuroxam, etiram, etsulfovax, Myclobutanil , Nickel -dimethyldithiocarbamat , Nitrothal - isopropyl , Nuarimol, Ofurace, Oxadixyl, Oxamocarb, Oxycarboxin, Pefurazoat, Penconazol, Pencycuron, Phosdiphen, Pimaricin, Piperalin, Polyoxin, Probenazol, Prochloraz, Procymidon, Propamocarb, Propiconazole, Propineb, Pyrazophos, Pyrifenox, Pyrimethanil , Pyroguilon, Quintozen (PCNB) , Tebuconazol, Tecloftalam, Tecnazen, Tetraconazol , Thiabendazol , Thicyofen, Thiophanat-methyl, Thiram, Tolclophos-methyl , Tolylfluanid, Le A 29 890 - 10 - Triadimefon, Triadimenol, Triazoxid, Trichlamid, Tricyclazol, Tridemorph, Triflumizol ( Triforin, Triticonazol , Validamycin A, Vinclozolin, Zineb, Ziram.

Insecticides / Acaricides / Nematicides: Abamectin, Abamectin, Acephat, Acrinathrin, Alanycarb, Aldicarb, Alphamethrin, Amitraz, Avermectin, AZ 60541, Azadirachtin, Azinphos A, Azinphos , Azocyclitin, Bacillus thuringiensis, 4-Bromo-2- (4-chlorphenyl) -1- ( ethoxyme thyl ) -5- ( t r if luorome thyl ) - lH-pyrrole - 3 -carbonitrile, Bendiocarb, Benfuracarb, Bensultap, Betacyluthrin, Bifenthrin, BPMC, Brofenprox, Bromophos A, Bufencarb, Buprofezin, Butocarboxin, Butylpyridaben, Cadusafos, Carbaryl, Carbofuran, Carbophenothion, Carbosulfan, Cartap, Chloethocarb, Chlorethoxyfos , Chloretoxyfos , Chlorfenvinphos , Chlorfluazuron, Chlormephos , N- [ (6-Chloro-3-pyridinyl) -methyl] -N' -cyano-N-methylethanimidamide, Chlorpyrifos , Chlorpyrifos M, Cis-Resmethrin, Clocythrin, Clofentezin, Cyanophos, Cycloprothrin, Cyfluthrin, Cyhalothrin, Cyhexatin, Cypermethrin, Cyromazin, Deltamethrin, Demeton M, Demeton S, Demeton-S-methyl , Diafenthiuron, Diazinon, Dichlofenthion, Dichlorvos, Dicliphos, Dicrotyphos, Diethion, Difluobenzuron, Dimethoat, Dimethyl inphos , Dioxathion, Disulfoton, Edifenphos, Emamectin, Esfenvalerat , Ethiofencarb, Ethion, Ethofenprox, Ethoprophos, Etofenprox, Etrimphos, Fenamiphos, Fenazaquin, Fenbutatinoxid, Fenitrothion, Fenobucarb, Fenothiocarb, Fenoxycarb, Le A 29 890 - 11 - Fenpropathrin, Fenpyrad, Fenpyroximat , Fenthion Fenvalerate, Fipronil, Fluazinam, Fluazuron Flucycloxuron, Flueythrinat , Flufenoxuron, Flufenprox Fluvalinate, Fonophos, Formothion, Fosthiazat Fubfenprox, Furathiocar , HCH, Heptenophos Hexaflumuron, Hexythiazox, Imidacloprid, Iprobenfos Isazophos, Isofenphos, Isoprocarb, Isoxathion Ivemectin, Lamda-cyhalothrin, Lufenuron, Malathion Mecarbam, Mervinphos, Mesulfenphos , Metaldehyd ethacrifos, Methamidophos , Methidathion, ethiocarb ethomyl, Metolcarb, Milbemectin, Monocrotophos Moxidectin, Naled, NC 184, Nitenpyram, Omethoat Oxamyl, Oxydemethon , Oxydeprofos, Parathion A Parathion , Permethrin, Phenthoat, Phorat, Phosalon Phosmet, Phosphamdon, Phoxim, Pirimicarb, Pirimiphos Pirimiphos A, Profenofos, Profenophos, Promecarb Propaphos, Propoxur, Prothiofos, Prothiophos, Prothoat Pymetrozin, Pyrachlophos, Pyraclofos, Pyraclophos Pyradaphenthion, Pyresmethrin, Pyrethrum, Pyridaben Pyrimidifen, Pyriproxifen, Quinalphos, Salithion Sebufos, Silafluofen, Sulfotep, Sulprofos Tebuf enoz ide , Tebuf enpyrad , Teburimimpho s Teflubenzuron, Tefluthrin, Temephos, Terbam, Terbufos Tetrachlorvinphos, Thiafenox, Thiodicarb, Thiofanox Thiomethon, Thionazin, Thuringiensin, Tralomethrin Triarathen, Triazophos, Triazuron, Trichlorfon Triflumuron, Trimethacarb, Vamidothion, XMC, Xylylcarb Zetamethrin .

Le A 29 890 - 12 - Herbicides : Anilides like Diflufenican, Propanil; Arylcarboxylic acids like Dichlorpicoline acid, Dicamba, Picloram,-Aryloxyalcanoic acids like 2,4 D, 2,4 DB, 2,4 DP, Fluroxypyr, MCPA, MCPP, Triclopyr; Aryloxy-phenoxy-alcanoic acid esters like Diclofop Methyl, Fenoxaprop-ethyl, Fluazifop-butyl, Haloxyfop methyl, Quizalofop ethyl; Azinones like Chloridazon, Norflurazon; Carbamates like Chlorpropham, Desmedipham, Phenmedipham, Propham; Chloracetanilides like Alachlor, Acetochlor, Butachlor, Metazachlor, Metolachlor, Pretilachlor , Propachlor; Dinitroanilines like Oryzalin, Pendimethalin, Trifluralin,- Diphenylethers like Acifluorfen, Bifenox, Fluoroglycofen, Fomesafen, Halosafen, Lactofen, Oxyfluorfen; Ureas like Chlortoluron, Diuron, Fluometuron, Isoproturon, Linuron, Methabenzthiazuron,- Hydroxylamines like Alloxydim, Clethodim, Cycloxydim, Sethoxydim, Tralkoxydim; Imidazolines like Imazethapyr, Imazamethabenz , Imazapyr, Imazaquin; Nitriles like Bromoxynil, Dichlobenil, Ioxynil; Oxyacetamides like Mefenacet; Sulfonylureas like Amidosulfuron, Bensulfuron-Methyl , Chlorimuron ethyl, Chlorsulfuron, Cinosulfuron, Metsulfuron-methyl , Nicosulfuron, Primisulfuron, Pyrazosulfuronethyl , Thifensulfuron-methyl, Triasulfuron, Tribenuron-methyl; Thiolcarbamates like Butylate, Cycloate, Diallate, EPCT, Esprocarb, Molinate, Prosulfocarb, Thiobencarb, Triallate; Triazines like Atrazin, Cyanazin, Simazin, Le A 29 890 - 13 - Simetryne, Terbutryne, Terbutylazin; Triazinone like Hexazinon, Metamitron, Metribuzin; others like Aminotriazol , Benfuresate, Bentazone, Cinmethylin, Clomazone, Clopyralid, Difenzoquat, Dithiopyr, Ethofumesate , Fluorochl oridone , Glufosinate, Glyphosate, Isoxaben, Pyridate, Quinchlorac, Quinmerac, Sulphosate, Tridiphane .

The formulation can comprise the active compounds individually or in combination with other soluble or insoluble active compounds .

The formulations according to the invention are prepared by simple mixing, if appropriate with heating.

The formulations according to the invention can be used as such in the form of concentrates or in the form of plant protection compositions or medicaments for oral, parenteral and transdermal use. In plant protection, they can be used for both leaf, soil and stem application and in seed treatment.

By dispersing the formulations according to the invention into an aqueous phase, homogeneous solutions or colloidal dispersions which are distinguished by a high stability are formed, depending on the nature of polymer (B) employed and surfactant (C) used. These aqueous systems are the application form of the formulations. The active compound concentration in the aqueous application form is between 0.0001 and 3% by Le A 29 890 - 14 - weight, preferably between 0.001 and 2% by weight. To prepare such an aqueous solution or dispersion, the formulation according to the invention is mixed with the particular desired amount of aqueous phase, if appropriate with stirring and/or pumping. It is not necessary here to use special dispersing units, such as shear homogenizers .

The ratio of active compound (A) to polymer (B) can be varied within a wide range and can easily be determined by preliminary experiments. In general, the weight ratio of active compound to polymer is between 1:0.2 and 1:10, preferably between 1:0.2 and 1:3, depending on the active compound. The amounts of further additives in the formulation according to the invention can be varied within a relatively wide range. However, they are adjusted such that, after simple mixing with water, the formulation forms a homogeneous solution or a colloidal dispersion having particles in the size range of 0.01-0.4 μτα, preferably in the size range of 0.03-0.2 μτη.

The following examples serve to illustrate the invention.

Example 1 1 part by weight of nimodipine, 5 parts by weight of a copolymer of 30% by weight of vinylpyrrolidone and 70% by weight of vinyl acetate and 0.225 part by weight of Le A 29 890 - 15 - sodium dodecyl sulfate are dissolved in 19 parts by weight of ethanol (96%) . This concentrate is dispersed into 225 parts by weight of water. For the dispersion, the aqueous phase is taken as the initial phase and the concentrate is added rapidly, while stirring. Although both the active compound and the polymer employed are water-insoluble in the pure form, a clear solution is formed, which does not become cloudy even after standing for a relatively long time.

The content of dissolved active compound is determined after a defined period of standing of 24 hours at room temperature as a measure of the tendency of the active compound to crystallize in the aqueous dispersion. The procedure for this is as follows: 24 hours after preparation of the dispersion, a sample of the batch is taken and is filtered through a 0.45 μπι filter (Millipore brand) to remove any crystallized active compound contents (= non-filterable active compound) . A defined amount of filtrate is dissolved in ethanol and the active compound content is determined by spectrophotometry. The proportion of active compound present in dissolved and/or colloidal form can be determined by relating the experimentally determined active compound content to the theoretical content.

The content of filterable active compound after 24 hours is 82% of the concentration employed of 4 mg/ml .

Le A 29 890 - 16 - Comparison Example 1 A concentrate containing active compound is prepared according to Example 1, but the copolymer is replaced by equal amounts by weight of a pure water-soluble poly-vinylpyrrolidone (Luviskol K 30 from BASF) .

Immediately after the preparation, the aqueous phase becomes very cloudy because of crystallization of the active compound. After only one hour, the crystallized active compound forms a thick sediment and the supernatant is clear and practically colorless, from which quantitative crystallization of the active compound can be concluded. The content of filterable active compound 24 hours after preparation is 0%.

Example 2 1 part 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 part by weight of sodium dodecyl sulfate are dissolved in 15 parts by weight of ethanol (96%) . This concentrate is dispersed into 225 parts by weight of water. For the dispersion, the aqueous phase is taken as the initial phase and the concentrate is added rapidly, while stirring. A colloidal opalescent dispersion is formed, which does not change visually even after standing for a period of 24 hours. The content of filterable active compound after 24 hours was 87% of the concentration employed of 4 mg/ml.

Le A 29 890 17 - Examples 3 bo 7 1 part by weight of nimodipine, 5 parts by weight of a copolymer prepared from the amounts by weight of vinyl -pyrrolidone and vinyl acetate shown in Table 1 and 0.0113 part by weight of sodium dodecyl sulfate are dissolved in 19 parts by weight of ethanol (96%) . This concentrate is dispersed into 225 parts by weight of water in accordance with Example 1. Homogeneous solutions or colloidal opalescent dispersions which do not change in their appearance after 24 hours or crystallize out practically quantitatively are formed, depending on the monomer ratio in the polymer employed. The content of filterable active compound shown in the table was determined in accordance with Example 1 after a standing time of 24 hours. It is found that as the content of vinyl acetate increases, the crystallization-inhibiting action of the copolymer increases. However, pure vinyl acetate is not suitable for preparation of the formulations according to the invention .

Comparison Example 2 The dispersion of Comparison Example 2 was prepared essentially in accordance with Example 1 of DE 37 42 473 Al , but the darodipine was replaced by nimodipine as the active compound from the substance class of dihydropyridines : Le A 29 890 - 18 - 1 g of ethylcellulose N7 (DOW Chemical) and 0.4 g of nimodipine are dissolved in 40 ml of ethanol 96%. This solution is poured rapidly into 200 ml of distilled water at 20°C, while stirring vigorously. Ethanol is evaporated off in a rotary evaporator at 50 °C under reduced pressure for 5 minutes . The active compound content is determined 24 hours after filtration through a 0.45 μτα filter in accordance with Example 1. The active compound content is 21% of the theoretical maximum content.

Le A 29 890 - 19 - Table 1 Le A 29 890 - 20 - Example 9 The active ingredient (a.i.) [2-Methyl-l-[[[l-(4-methylphenyl)ethyl]amino]carb-onyl]propyl]carbaminic aci d-l -methylethyl ester was formu l ated as an organi c concentrate according to the invention using ingredients in amounts as indicated in the table below. By dilution of the concentrate with water, a translucent aqueous colloidal dispersion was obtained which was stable against crystallisation and sedimentation. If the polymer Luviskoi VA® 64 was left out or was replaced by a pure polyvinylpyrrolidone like Luvisol K 30®, dilution of the concentrate with water resulted in cloudy dispersions, containing coarse particles, which tended to form sediments within minutes. For comparison of the biological efficacy, a standard suspension concentrate formulation of the active ingredient was prepared according to the same table.

Le A 29 890 - 21 - Emulsifier 1 dodecylbenzenesulfonic acid monoethanolamine salt Emulsifier 2 nonylphenol 10-glycol ether Emulsifier 3 alkylaryl polyglycol ether Ultrasil VN 3Λ highly disperse amorphous silicon dioxide Sillitin Z Λ ground silica Luviskol VA 64 vinylpyrrolidone/vinyl acetate (60/40) copolymer assessment of the biological efficacy To test for activity of the drug in the formulation according to the invention, young tomato plants were sprayed dripping wet with aqueous preparations of this formulation having different concentrations. For comparison, a separate set of young tomato plants was treated with aqueous preparations of a standard formulation, in comparable concentrations with respect to the active ingredient. After drying of the spray coating, all plants were inoculated with aqueous spore suspensions of the fungi Phytophtera infestans. The plants were placed in an incubation cabin at 100% relative humidity at 20°C. Assessment of the plant infest as a function of the concentration of the active ingredient was carried out 3 days after inoculation.

In this test, the formulation according to the invention showed an onset of action at active ingredient concentrations which were smaller by a factor of two compared to the standard formulation.

Le A 29 890 - 22 - Example 10 The active ingredient (a.i.) 4-Chlor-NJ3'-bis(4-chlorphenyl)-4')5'-dihydro-fl,4'-bi-lH-pyrazol)-l-carboxamid was formulated as an organic concentrate according to the invention using ingredients in amounts as indicated in the table below. By dilution of the concentrate with water, a translucent aqueous colloidal dispersion was obtained which was stable against crystallisation and sedimentation. If the polymer Luviskol VA® 64 was left out or was replaced by a pure polyvinylpyrrolidone like Luvisol K 30®, dilution of the concentrate with water resulted in cloudy dispersions, containing coarse particles, which tended to form sediments within minutes. For comparison of the biological efficacy, a standard suspension concentrate formulation of the active ingredient was prepared according to the same table.

Le A 2 9 890 - 23 - Formulation according to the Standard formulation 1 : SC 200 invention: Solvent: 54.0% of Solvent: 20.0% of BP N-methyl- Enerthene 2367 pyrrolidone 10.0% of propanediol Emulsifier: 13.0% of Emulsifier: 5.0% of Emulsifier 1 Emulsifier PS 29 0.5% of Renex 36 Polymer: 13.4% of Thickener: 0.1 of Kalzan S Luviskol VA 64 Microbicide: 0.1% of Preventol D2 a.i. content: 20.0% a.i. content: 19% Remainder: demineralized water assessment of the biological efficacy a) Phaedon cochloeariae To test the activity of the drug in the formulation according to the invention against Phaedon chloeariae, cabbage (Brassica oleracea) leaves were dipped in aqueous preparations of this formulation having different concentrations. For comparison, a separate set of leaves was treated with aqueous preparations of the standard formulation, in comparable concentrations with respect to active ingredient. After treatment, the leaves were infested with mustard beetle (Phaedon chloeariae) larvae. After 7 days, the mortality of the larvae was Le A 29 890 - 24 - assessed. As a criterion of relative biological efficacy of the formulation of the invention in comparison to the standard formulation, the ratio of the concentrations where 50% mortality (LD 50) occurred was determined according to the following equation: relative efficacy = LD 50 (formulation of invention) / LD 50 (standard formulation). In this test, the relative efficacy of the formulation according to the invention exceeded a factor of 8. b) Plutella xylostella To test the activity of the drug in the formulation according to the invention against Plutella xylostella, cabbage (Brassica oleracea) leaves were dipped in aqueous preparations of this formulation having different concentrations. For comparison, a separate set of leaves was treated with aqueous preparations of the standard formulation, in comparable concentrations with respect to active ingredient. After treatment, the leaves were infested with caterpillars of the cabbage moth (Plutella xylostella). After 7 days, the mortality of the caterpillars was assessed according to the procedure outlined in Example 10 a.

In this test, the relative efficacy of the formulation according to the invention was 30. c) Sporoptera frugiperda To test the activity of the drug in the formulation according to the invention against Sporoptera frugiperda, cabbage (Brassica oleracea) leaves were dipped in aqueous preparations of this formulation having different concentrations. For Le A 29 890 - 25 - comparison, a separate set of leaves was treated with aqueous preparations of a standard formulation, in comparable concentrations with respect to active ingredient. After treatment, the leaves were infested with caterpillars of the eulet moth (Poroptera frugiperda). After 7 days, the mortality of the caterpillars was assessed according to the procedure outlined in Example 10 a.

In this test, the relative efficacy of the formulation according to the invention was 20. d) Heliotis viriscens To test the activity of the drug in the formulation according to the invention against Heliotis viriscens, cabbage (Brassica oleracea) leaves were dipped in aqueous preparations of this formulation having different concentrations. For comparison, a separate set of leaves was treated with aqueous preparations of a standard formulation, in comparable concentrations with respect to active ingredient. After treatment, the leaves were infested with tobacco budworm (Heliotis viriscens). After 7 days, the mortality of the budworm was assessed according to the procedure outlined in Example 10 a.

In this test, the relative efficacy of the formulation according to the invention was 7.5.

Le A 29 890 - 26 -

Claims (9)

1 1 1356/2 - 27 - C L A I M S;

1. A colloidally dispersibie liquid composition comprising A) a sparingly soluble active compound, B) a random copolymer of (i) at least one of vinylpyrrolidone and vinylcaprolactum and (ii) at least one hydrophobic comonomer which reduces to water-solubility of the copolymer compared to a homopolymerv of (i), (ii) being present in 5 to 90% by weight of the copolymer, and C) at least one surfactant, the composition being dispersibie in water to form a colloidal dispersion of higher stability and higher bioavailability than a like composition from which (B) is absent.

2. A composition according to claim 1 , wherein (i) comprises vinylpyrrolidone and (ii) comprises vinyl acetate.

3. A composition according to claim 1 , further comprising at least one of D) an additive, and E) a diluent. 111356/2 - 28 -

4. A composition according to claim 1 , wherein A comprises at least one member selected from the group consisting of a dihydropyridine, azole, nitromethylene, arylpyrazoline, valinamide carbamate, benzothiophenecarboxamide and benzoylurea.

5. A composition according to claim 1 , wherein A comprises a pharmaceutically active compound.

6. A composition according to claim 1 , wherein A comprises a plant protection compound.

7. In the treatment of plants or of animals or humans with a sparingly soluble bioactive compound, the improvement wherein such compound is employed as a composition according to claim 1.

8. In the treatment of plants or of animals or humans with a sparingly soluble bioactive compound, the improvement wherein such compound is employed as a composition according to claim 4.

9. A composition according to claim 1 , comprising A) a sparingly water-soluble normally solid active compound, B) a random copolymer of (i) at least one of vinylpyrrolidone and vinylcaprolactam and (ii) about 40 to 90% by weight of a vinyl ester of an alkanecarboxylic acid of the formula - 29 - 111356/1 CH3 I (CH2)x I c=o I . o I H wherein X is from 0 to 16; at least 10 mer units of each of.(i) and (ii) being in the copolymer, and C) a surfactant. A composition according to claim 9} wherein A) is a pharmaceutically active compound, and B) (ii) is vinyl acetate. A composition according to claim 10, comprising A) nimodipine, B) a random copolymer of vinylpyrrolidone and about 40 to 90% by weight or vinyl acetate, and C) a surfactant. 111356/1 - so ¬ il. A process for preparing a dispersible liquid composition which is colloidally dispersible in water comprising dissolving in a solvent therefore A) an active compound which is sparingly soluble in water, B) a random copolymer of \) at least one of vinylpyrrolidone and vinylcapro!actom and (ii) at least one hydrophobic comonomer which reduces the water^solubility of the copolymer compared to a homopolymer of (i), (ii) being present in 5-90% by weight of the copolymer, and C) at least one surfactant, said components A), B) and C) being dissolved together prior to addition to water, the composition being dispersible in water to form a colloidal dispersion of higher stability and higher bioavailability than a like composition form which B) is absent.— For the Applicants.