MXPA06007031A - Multiphase active ingredient formulation - Google Patents

Abstract

The invention relates to a formulation having a plurality of phases containing active ingredients. Said formulation is characterised in that:it contains a first, innermost, finely distributed phase (I) consisting of active ingredients or an active ingredient solution, preferably some of the phase particles being surrounded by a barrier sheath (M);the formulation has a second, intermediate phase (II) that serves as a dispersant for the first, inner phase (I) and can also be dissolved in the active ingredient;and the formulation has a third, outer phase (III) that serves as a dispersant for the second intermediate phase and can, in turn, be dissolved in the active ingredient and/or can be in the form of solid particles that can, in turn, be surrounded by a barrier sheath. In this way, a plurality of biological active ingredients can be produced in the different phases in different concentrations and with a respectively controlled release rate in a single formulation. According to the invention, a mechanical stabilisation is achieved by solidifying the intermediate phase (II), enabling the formulation to be stable for a longer period of time even once it has been applied to a surface. Furthermore, by selecting a suitable solvent for the outer phase, the formulations limit the release of the active ingredient from the innermost phase, and the capsules are not emptied and can thus be stored for a longer period of time.

Description

FORMULATION OF ACTIVE INGREDIENTS OF MULTIPLE PHASES Field of the Invention The invention relates to a formulation containing active ingredients with a plurality of phases containing active ingredients. Background of the Invention A large number of active ingredients are liquid or are in the form of a substance dissolved in a liquid. A way was sought to control the release over time of this active ingredient in a selected manner after it has been applied to a surface that is in contact with a gaseous space. In particular, a way was sought to delay the release of the active ingredient, to control the rate of release of the active ingredient, to provide chemically or biologically incompatible active ingredients, in a formulation and / or to prepare a capsule formulation in stable form. to storage. A formulation with these properties would allow use, for example, in the skin or on the surface of leaves. Conventional formulations of liquids, such as solutions, emulsions or double emulsions, generally release the active ingredient very rapidly after REF: 173796 from the application of a thin film to a surface. Double emulsions and emulsions are destroyed by the evaporation dispersion medium and capillary forces which then arise, and release kinetics since in the case of simple solutions it is determined solely by the vapor pressure of the solution of active ingredients. Formulations that are based on mechanically stable capsules and have been prepared in a conventional manner, for example, by interfacial polymerization or lyophilization, are generally stable so that they remain intact even in the dry state and can release the active ingredient either by very slow diffusion through the wall of the capsule or only if the capsule has been mechanically destroyed. In addition, capsules containing active ingredients are often dispersed before use in a liquid phase, (e.g., in the crop protection field) or suspended in a considerable excess of a liquid phase during the preparation. Months, sometimes years often pass until they are used. In the field of pharmacy, durability is often required from three to five years. Due to the primarily desired semi-permeability of the capsule walls, the active ingredient diffuses accordingly until the dispersant becomes saturated in the outer phase, meaning that in certain cases only a small amount of active ingredient remains in the capsules and However, a concentration in the external phase which produces undesired side effects (for example, toxicity) was reached, or the effective or optimum concentration for the initial effect is exceeded. In addition, in some cases, there is a need to provide two or more active ingredients to achieve a broad spectrum of activity against biological pests / parasites in a formulation that normally can not be formulated at the concentration required in a presentation as a result, for example, of different solubilities in the toxicologically acceptable solvents or as the result, for example, of chemical incompatibility. A frequently used way of developing formulations with delayed or controlled release behavior is the use of microcapsules. These can be prepared in conventional manner in various ways and can consist of either capsules with liquid or solid contents. These processes are interfacial polymerization, precipitation reactions, complete and simple coacervation, and complex emulsification (double and microemulsions). These processes are known in general and are described in numerous publications (see, for example T.

Kondo, Journal of Oleo Science 50, 1 (2001); T. Kondo, Journal of Oleo Science 50, 81 (2001) or C. Thies, Encycl. Poly. Sci. Eng. 9, 724 (1987)). A relatively new method of encapsulating solid or liquid dispersion particles is the layer-by-layer growth of a layer membrane that is produced by alternating deposition of cationic and anionic polyelectrolytes, where it is appropriate with incorporation of charged nanoparticles (compare: GB Su horukov et al., Colloids and Surfaces A, 137, 253-266 (1998); WO 9947252, WO 9947253). In an alternative variant of the described process, it is possible, in a coacervation process, to carry out the precipitation of polyelectrolytes at the interfaces of the pre-emulsified liquid droplets or solid particles also by the one-step process. In this regard, the polyanions and polycations, which are present together in solution, are precipitated directly on the surfaces when displacing the pH and / or salt content (compare WO 2002009864 Encapsulation of liquid template particles using amphiphilic polyelectrolytes, DE 10050382, WO 2002031092 Method for the inclusion of perfume oil in washing and cleaning agents or cosmetics). The disadvantage of the described process is that, following removal of the dispersant, for example, after application to a surface, the coated emulsion drops are often not stable, but rapidly melt. Description of the Invention The object of the invention is to develop a new process that makes it possible to provide a formulation with the desired properties mentioned above, ie, after application of the formulation to a surface, it delivers the active ingredient in a concentration defined in the outer phase (dispersant) to achieve a desired initial effect, allows a controlled rate of release from the capsule to establish a lasting and delayed effect, and ensures stability in the storage of this capsule suspension. The above object was achieved by a formulation consisting of a plurality of phases in which the active ingredient may be present in each phase at a different concentration. The release from the various phases proceeds at different rates, meaning that, by varying the amounts of the active ingredient used in each case and the type of solvent / dispersant used, it is possible to vary the kinetics and amount of the active ingredient released completely. The invention provides a formulation containing active ingredient with a plurality of phases containing active ingredients which is characterized in that the formulation has a finely divided inner first phase (I) consisting of the active ingredient or solution of active ingredient, of which Preferably some particles of the phase are surrounded with a barrier layer (M), and that the formulation has a second intermediate phase (II) that serves as a dispersant for the first interior phase (I) and in which the active ingredient it can also be dissolved, and that the formulation has a third external phase (III) that serves as a dispersant for the second intermediate part and in which the active ingredient can be present in its dissolved form and / or in the form of particles solid, which may again be surrounded by a barrier layer. This principle is shown schematically in Figure 1. In a special case of the invention, phases (I) and (II) do not disperse as it describes within the other and subsequently in the outer phase (III), but rather they form a three-phase layer system in the sense that the intermediate phase (II) covers the inner phase (I), and the phase (II) itself is covered in turn by the phase (III).

This variant of the invention can be particularly advantageous if the diffusion of the active ingredient from the innermost phase takes place more rapidly and only slow release can be achieved by minimizing the phase interfaces. The solidification of the intermediate phase (II) is also described in order to mechanically stabilize the dispersion of the inner phase (I) after application to a surface, and in this way obtain delayed release of the active ingredient in the inner phase (I ) and / or the intermediate phase (II). The invention further provides that, in the manner described, it is possible to prepare a plurality of biologically effective active ingredients in the different phases by varying the concentrations and with a release rate that is controlled in each case in an individual formulation. Preference is given to a formulation characterized in that the barrier layer in the various phases is a microcapsule. In the text below, microcapsule is understood to mean either a capsule with a solid polymer wall, or a capsule whose wall consists of a relatively thin polymer layer, or membrane that can be produced, for example, by coacervation. The microcapsule of the barrier layer is particularly preferably based on a polymer. In a preferred formulation, the third outer phase (III) is an oil phase with limited solubility for the active ingredient or active ingredients, preferably silicone oil or natural oils, eg, castor oil, or perfluorinated organic compounds. . This outside f may additionally comprise dispersion aids (surfactants) or thickeners (e.g., Aerosils, polymers). In a further preferred formulation, the second intermediate phase (II) is based on a thickened phase containing single or polymer particles, for example, a gelatin formulation. In a particularly preferred additional formulation, the second intermediate phase (II) consists of a polymer solution or particle dispersion that can be gelled in a thermoreversible manner, that is, it is liquid at the temperatures of separation and / or application , and semi-solid or solid at temperatures during storage and / or use. In addition, the active ingredient / active ingredients preferably exhibit low solubility in this intermediate phase. The innermost phase (I) consists of the pure active ingredient or an active ingredient solution. This phase can be present as a drop of emulsion stabilized with surfactants, or a solid or semi-solid dispersion particle. The inner phase may also consist of a microcapsule comprising the liquid, solid or semi-solid active ingredient. The capsule wall of the microcapsule (M) can be prepared, for example, by complete coacervation and represents a first barrier to the active ingredient. These droplets, dispersion particles or microcapsules of phase (I) are introduced into the second liquid, thickened or semi-solid phase of matrix (II), which represents the second barrier. The matrix base, semisolid, thickened at the same time produces required mechanical stability, which allows the application of the formulation in the form of a film without immediate destruction of the matrix phase. Finally, the microcapsules are again dispersed in the outer phase (III) which may consist of a defined solution of the active ingredient and / or the active ingredients or of a phase having only a very low saturation solubility or no solubility at all for the active ingredient / active ingredients. In this outer phase saturated with active ingredient, the active ingredient / active ingredients can also be further presented in dispersed form in the form of emulsion droplets. The particle sizes of the innermost phase (I) can be varied through the amount of substances used in the type of dispersion. They are typically in the order of magnitude of 1-10 μm. The particle size of the emulsified intermediate phase (II) and the inner phase (I) is typically in the order of magnitude of 10-500 μm. In this multi-phase system, the active ingredient / active ingredients are thus presented in different phases and the release of the active ingredient / active ingredients is determined by the kinetics of the diffusion in the phases and by the limits of the phases, and by the solubilities limit. , physical of the active ingredient / active ingredients in the phases. Since the amounts of the active ingredient used in the various phases are variable, the desired release profile can be adjusted in a selected manner. The disadvantage of conventional capsule formulations, the emptying of the capsules by continuous release in the outer phase during storage is likewise overcome in this way. The invention further provides the use of the formulation according to the invention for delayed release of the active ingredients. Release behavior of multi-phase systems In summary, the active ingredient / active ingredients in this way can be released from the following phases: a) rapid release to ensure immediate effect (effect of annihilation): from the external phase ( III) which consists of the pure active ingredient, a solution of the active ingredient or an emulsion. b) delayed release: the active ingredient is present as a molecular solution or as drops in a solid or semi-solid matrix (II), which additionally ensures mechanical stability when applied in the form of a film and whose saturation solubility determines the profile of diffusion of the active ingredient. c) decelerated release: the active ingredient is in the form of the microcapsule (I) in the solid or semi-solid matrix (II) and therefore an additional barrier layer must also penetrate. An additional advantage of the multi-capsule system is the possibility of also preparing formulations comprising more than one active substance by introducing several active ingredients into the various phases, the required release profile of which then can be adjusted separately in each case . In the case of a very different dissolution behavior in the individual phases, the physically or chemically incompatible active ingredients can also be formulated together in this way.

An additional ntage of the multi-capsule system is to establish the concentration of the free active ingredient in the outer phase (III) by choosing suitable solvents and solvent mixtures, in the sense that an appropriate saturation solubility is established in the outer phase. In principle, the multiple capsule system can also be used to release active ingredients in a liquid environment. Feeding Materials Formulations based on the described invention can be used preferentially in the field of dermal formulations in humans and animals, and also in the field of crop protection. Consequently, preference is given to using auxiliary and solvent products that are toxicologically safe and are authorized / classified in principle as authoritative by the competent authorities. I) Solvents Inner phase (I): The active solid or liquid or solutions of these active ingredients in pharmaceutical and environmentally acceptable, non-toxic oils with low polarity (dielectric constant) or solutions in solid matrix phases. These solvents are, for example, enunciatively and without limitation: medium chain triglycerides (for example Migliol 810, 812); natural oils (for example, castor oil, sesame oil, peanut oil), partially hydrolyzed fats or reaction products of these partially hydrolyzed fats with low degrees of ethoxylation (for example Labrafil, Gelucire); hydrophobic esters of native fatty acids (e.g., isopropyl myristate); hydrophobic solvents of higher polarity (for example, triethyl citrate, triacetin); solid or semi-solid matrix forming systems in which the active ingredient is incorporated in a molecularly dispersed form and which are liquid during the preparation of solids during storage and / or application (eg fats, shellac, polyethylene glycols PEG 1000, 1500, 3000). Matrix phase (II): Relatively hydrophilic, non-toxic, pharmaceutically or environmentally acceptable systems, in which the active ingredient / active ingredients and the solvents of the interior and exterior phases are insoluble or soluble, only to a very limited extent and which can act in turn as solvents for thickener additives (polymers, hydrotalcites). These solvents are, for example, without limitation: water, mixtures of water with other hydrophilic solvents, hydrophilic solvents of suitable polarity (dielectric constant) (for example, propylene glycol, ethanol, ethanediol, glycerol, polyethylene glycols of low PEG chain length) 200, 300, 400). The intermediate phase may also comprise surfactants for the initial stabilization of the interior phase during the preparation, for example, but not limited to: ionic surfactants (sodium dodecyl sulfonate (SDS)), cationic surfactants (cetyltrimethylammonium chloride) or natural or synthetically produced polyelectrolytes (gelatin, polystyrene sulfonate) or polymeric non-ionic dispersants (Polyvinyl alcohol-polyvinyl acetate copolymers, for example, Moviols). External dispersion phase (III): Liquid or solid active ingredients or solutions of these active ingredients in non-toxic, pharmaceutically and environmentally acceptable oils with low polarity (dielectric constants). These solvents are, for example, without limitation: medium chain triglycerides (for example, Migiyol 810, 812) natural oils (for example, castor oil, sesame oil, peanut oil), partially hydrogenated fats or reaction products of these partially hydrogenated fats with low degrees of ethoxylation (for example Labrafil, Gelucire); hydrophobic esters of native fatty acids (e.g., isopropyl myristate); hydrophobic solvents of higher polarity (eg, triethyl citrate, triacetin); - silicone oils or perfluorinated solvents having a low dilution capacity for the hydrophilic intermediate phase and also for the oils of the interior phase and for the active ingredients, for example dimethyl-polysiloxanes of variable chain length (for example, Dow Corning Q7-9120 Silicon Fluid Series 20, 100, 350, 1000), cSt, higher cyclic dimethyloligosiloxanes (eg, dodecamethylcyclohexasiloxane), perfluorinated alkanes or perfluorinated polyethylene oxides; Preferably those silicone agents or organic oils having a low viscosity, high vapor pressure and good spreading behavior such that, after use in skin or plants, ensure rapid distribution of the particles of the matrix phase and then volatilize without leaving a residue so as to avoid greasy residues, for example, cyclic polysiloxanes, octamethylcyclotetrasiloxane D4, decamethylcyclopentasiloxane D5, linear short chain oligodimethylsiloxanes (for example DOW Corning Q7-9180 Silicon Fluid Series 0.65 cSt hexamethyldisiloxane, 1 cSt octamethyltrisiloxane, 5 cSt). The outer phase may also additionally comprise surfactants and dispersants to stabilize the matrix phase, for example, but not exclusively: copolymers of polyethylene oxide-polypropylene oxide-polyethylene oxide (for example, Pluronics, poloxamers), ethoxylated carboxylic esters or alkyl ethers (for example, Cremophors), polydimethylsiloxanes modified with polyethylene oxide (for example, DOW Corning DC 5225C, DC 3225C, Emulsifier ). 11) Polymeric and thickener feed materials: For the initial stabilization of the inner phase in the intermediate matrix phase and to produce the first diffusion control membrane wall (M), the cationic and anionic polyelectrolytes can be preferentially, for example, without limitation: polystyrene sulfonate (PSS), polyallylamine hydrochloride (PAH), polydiallyldimethylammonium chloride, gelatin, carboxymethylcellulose, xanthan.

To stabilize the phases and to adjust the diffusion rate of the active ingredients through the phase phase limits, preference is given to using those polymers and inorganic particles that are dispersible or soluble in the phases with adequate dielectric constant. The solubility of the polymers is understood to mean that the solvent of the particular phase, in particular of the middle matrix phase (II), represents a thermodynamically good solvent in the sense of the Flory-Huggins theory (? < 0.5) for the polymer, and this has in this way a gel-forming effect. Particular preference is given here to those polymers having thermoreversively thickening properties in the particular solvent. Alternatively, these polymers or surface active auxiliaries can be used, which exhibit a thermally induced liquid / liquid crystalline / semi-solid phase transition between the preparation conditions and the storage conditions. For the more hydrophilic phase (II), it can be mentioned in this way, for example, but not exclusively: polymers and polyelectrolytes derived from natural substances (for example, hydrocolloids, gelatin, xanthan, peptinas, carragahen, carboxymethylcellulose) , active surface-active substances that form LC phases (for example, polyethylene oxide-polypropylene oxide-polyethylene oxide copolymers, pluronics / poloxamers, block copolymers of polylactide-co-glycolide with polyethylene glycol), synthetically prepared polymers (eg, polyvinyl acetates - partially hydrolyzed of suitable degree of hydrolysis; Mowiol 3-83, 10-74, poly-N-isopropylacrylamide NIPAAM, and simply thickener polymers, such as polyvinyl alcohol, polyacrylic acid and polyacrylic ester copolymers of the same, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, inorganic minerals (for example, hector It is possible for the intermediate phase (I) to use these polymers and feedstocks which are soluble or dispersible in the used solvents of suitable dielectric constant, for example, without limitation: polyacrylamides, polyacrylate esters, N-isopropylacrylamide, polyvinyl acetate and copolymers of vinylo-polyvinyl alcohol of low degree of hydrolysis (for example Polyviol 45/450),) ethylcelluloses, methylcelluloses, inorganic thickeners (silica, aerosil), or those feeding materials which can be act by themselves as a solid matrix phase for the active ingredient, eg, feed materials obtained from natural products (shellac, beeswax) or higher molecular weight polyethylene oxides (e.g., PEG 1000, 1500 , 3000). For the outer phase (III) it is in principle possible to use the same stabilization feedstocks that were chosen according to the criteria for the inner phase (I), but are generally distributed when the spreading capacity of these formulations in the surface after the application is a decisive criterion. III) Active ingredients In the multi-phase systems according to the invention it is possible to incorporate a plurality of encapsulated active ingredients with variable properties and release profiles separately from one another. The non-exclusive examples are: Active ingredients with a high potential for irritation to the skin (for example, pyrethroids, flumethrin, permethrin, cyfluthrin), insecticidal systemic active ingredients (for example, imidacloprid), easily volatilizable agents, ie for example repellents (for example, N, N-diethyl-m-toluamide DEET, 2- (2 -hydroxyethyl) -1-methylpropyl-1-piperidinecarboxylate KBR 3023) or attractants / pheromones (eg, 8, 10-E, E-dodecadienol, codlemone), active care ingredients (eg vitamins), anti-inflammatory active ingredients (cortisone) or fungicidal active ingredients (for example, clotrimazole). Production of the multi-phase systems The preparation of the multi-phase system described herein can be described in general by the following steps: 1) Emulsifier or dispersion of the innermost phase (I) in a continuous phase. Known processes can be used. of normal emulsification and dispersion to emulsify or disperse the innermost phase (I) (for example, stirrers, ultrasound source, Ultrathorax, membrane emulsion). Ionic or non-ionic surfactants, or polymers, are used to stabilize the innermost phase (I). The continuous phase can represent the intermediate phase or matrix phase (II) and only achieves the final composition of the intermediate phase (II) in a final step, for example, by adding soluble polymers. 2) Encapsulation of the innermost phase (I) dispersed or emulsified All or some of the innermost phase (I) is encapsulated by one of the known encapsulation methods, such as interfacial polymerization, interfacial precipitation reactions, complex coacervation or simple or precipitation with polyelectrolytes. An alternative way is the encapsulation of the innermost phase (I) out of the continuous phase before step 1 by a known method, such as for example lyophilization. 3) Emulsification of the emulsion, dispersion or dispersion of microcapsule resulting in an external phase (III). The resulting emulsion or suspension is then emulsified in a further dispersion step in the outer phase (III). The usual dispersion or emulsification methods and the non-ionic or ionic surfactants or polymeric stabilizers are again used for this. 4) Solidification of the intermediate phase (II) during or after the second emulsification step (step 3) In the last step, the intermediate phase solidifies during or after step 3. The solidification can be induced, for example, by changing the temperature, pH or ionic concentration in the intermediate phase (II) and the external phase (III). Through the simple modification of this preparation process it is possible to prepare a multi-phase formulation which is not in the form of a complex emulsion, but in the form of a simple layer system of a plurality of phases.

The advantages of the invention described herein are summarized as follows: a) The solidification of the intermediate phase of a double emulsion directly after or during the second emulsification step. As a result of this, the particles of the double emulsion achieve greater mechanical stability and remain intact for a longer time during or after the drying operation than, for example, double non-solidified emulsions. b) By choosing a solvent that spreads well on a surface (eg, plant cuticle or human or animal skin) for the outer phase which additionally has a defined limit solubility for the active ingredient / active ingredients to ensure a initial effect, the multiple capsule consisting of the phase (I) and (II) can be distributed quickly. In addition, it is often desired that this external carrier phase volatilizes rapidly after application. The property mentioned under (a) ensures that - the capsules,. , multiple on the surface also then remain stable and release the active ingredient / active ingredients in a delayed and controlled manner. c) The combination of double emulsion and microcapsules, which leads to a system with a plurality of barriers for the active ingredient. This allows the distribution of the active ingredient substance in different phases with variable barrier properties and in this way the control of the release. d) The selected adjustment of the solubility of the active ingredient in the interior, intermediate and exterior phase through the choice of suitable materials, as a result of which the diffusion of the active ingredient through the various phases and of this way the release profile. e) Overcoming the storage problem: capsules through which the active ingredient can penetrate in principle do not empty even after storage for a year since the active ingredient only has limited solubility, or is not soluble at all, in the outer phase. The invention is illustrated in more detail below, for example, with reference to the figures. These show: Figure 1 a scheme for accumulation of the active ingredient formulation according to the invention Figure 2 a scheme for an alternative accumulation of the active ingredient formulation Figure 3a a micrograph of the primary capsule Figure 3b a micrograph of the multiple capsule Figure 3c a micrograph of the formulation according to Figure 3a after application to a surface Figure 3d a micrograph of the formulation according to figure 3b after application to a surface Figure 4 scheme for accumulation of a further variant of the active ingredient formulation Figure 5a a diagram for the release of flumethrin as a function of time Figure 5b a micrograph of a flumethrin formulation Figure 5c a micrograph of the flumethrin formulation according to to Figure 5b after aging. Figure 6 schematically shows the embodiment of example 3. Figure 6a shows a series of measurements in which the mixing ratios between the castor oil and the silicone oil were continuously changed.

Eg Employs 1 As an example, this principle was applied to the formulation of KBR 3023. This example is shown schematically in Figure 2. KBR 3023 is a liquid active ingredient that is only slightly soluble in water and is also soluble in silicone oil only to a limited extent. In the example formulation, the outer phase consists of a mixture of KBR / silicone oil (III). The intermediate matrix phase consists of a solution (II) of aqueous gelatin which is liquid during the preparation since the operating temperature was above the gel temperature.

After cooling to room temperature, this matrix is solid or semi-solid. Drops of KBR 3023 form the inner phase (I) and are in the form of microcapsules with a polymeric layer that was prepared by coacervation complemented by PSS and PAH (M), in the gelatin matrix. The following preparation procedure is an example of this formulation: Step 1: Dissolve 0.038 g of sodium dodecyl sulfate (SDS) in 5 g of water (saturated with KBR 3023), Addition of 2.5 g of KBR 3023. Dispersion using Ultrathorax (UT).

Step 2: Addition of 5 g of aqueous solution of PSS saturated with KBR (concentration: 2.06 g / 100 g). With the Ultrathorax running, dropwise addition of 5 g of aqueous PAH solution saturated with KBR (concentration 0.96 g / 100 g). Step 3: Careful mixing of 0.5 g of hot gelatin solution at 25% concentration with 0.5 g of primary emulsion. The mixture is added to 2 g of hot silicone oil phase. The silicone oil phase consists of a linear silicone oil DC5 (Dow Corning, 0.3 g of liquid KBR + 0.2 g of emulsifier 5225 C + 1.5 g of oil). Dispersion with UT with subsequent rapid cooling by an ice bath. After stirring, time of approximately 15 minutes. Figure 3a shows the primary capsules produced by step 2. Figure 3b shows the multiple capsule with the solidified intermediate phase. If the emulsions of Figure 3a are applied to a surface, then the primary particles are destroyed after a few minutes and the KBR 3023 is in the form of a free film (Figure 3c). However, if the emulsion of Figure 3b is applied as a film, then the multiple capsules are still stable even after 24 h (Figure 3d). This demonstrates one of the decisive advantages of the invention described herein. In addition, the saturation of the outer phase (III) and of the intermediate phase (II) with KBR 3023 prevents the diffusion of KBR 3023 from the inner phase (I) during the storage of the formulation. By simply modifying the above formulation, KBR drops without a layer can be alternatively or additionally expressed both in the gelatin (II) matrix and in the outer (III) phase. Likewise, KBR drops without a layer can be emulsified alternatively or additionally in the outer phase. Example 2 As a further example, this formulation principle was applied to the formulation of a dermal formulation of active ingredient to control ticks and fleas in veterinary medicine. The formulation is shown schematically in Figure 4. Here, the active ingredient (flumethrin) is dissolved in an oily phase (I), which is emulsified in an aqueous gelatin solution above the temperature of gel (II), and this emulsion is dispersed by itself in the outer phase (III) silicone oil. After cooling to below the gel point, the gelatin matrix solidifies. The silicone oil phase is chosen such that the physical limit solubility in the outer phase corresponds exactly to the concentration which is favorable for the active ingredient to be effective directly after the application. During storage after preparation, the active ingredient flumethrin accumulates in this way in the outer phase until this optimum concentration is reached. During the course of time, the release from the innermost phase is delayed by the gelatin matrix since the temperature of the skin is below the softening point of the gelatin gel. The outer phase also additionally comprises an additional dispersed active ingredient (imidacloprid) in order to ensure a thorough insecticidal action. As a result of its spreadability, the silicone oil phase aids in the rapid distribution of the dispersed particles of the matrix phase and of the second active ingredient in the skin. The use of a silicone oil with a low vapor pressure further ensures that this phase evaporates quickly after spreading and thus does not leave behind a greasy impression. This example is shown schematically in Figure 4. The following preparation procedure is an example of this formulation: Preparation of the various phases: Interior phase (I): 1.89 g of flumethrin and 0.108 g of Lipoid S100 are weighed in 0.702 g of Migiyol and dissolved at elevated temperature. Intermediate phase (II): 0.063 g of TCA, 0.0945 g of PHB and 0.7245 g of gelatin are weighed one after the other in 0.725 g of water. The >; The mixture is stirred at a temperature above the gel temperature using a magnetic stirrer until the gelatin has dissolved. Outer phase of oil (III): 0.8925 g of sodium stearate and 6 g of NTN (imidacloprid) are added to 44,108 g of silicone oil (Fluka DC 200 20 mPas). By means of the UT (20 500 rpm), the suspension is homogenized and heated simultaneously at about 40-60 ° C. Preparation of the formulation: The internal phase (I) of oil at approximately 60-80 ° C hot is added dropwise to the heated gelatin phase (II). Here, the speed of the UT must be increased in stages such that maximum dispersion always takes place. The temperature is controlled at the same time. The temperature is maintained at approximately 50-60 ° C by means of a water bath. The addition time is about 4 minutes, after a stirring time of about 6 minutes. Then, with stirring using the UT, the hot primary emulsion is added to the outer oil phase at about 50 ° C. The temperature is maintained at about 45-50 ° C by means of a water bath. The addition time of about 4 minutes, time after stirring about 2 minutes. The water bath is then replaced with ice / NaCl. The mixture is further stirred during this cooling at room temperature. Figure 5a shows the release of flumethrin as a function of time. It can be seen that by varying the concentration of gelatin in the intermediate phase (II), it is possible to vary considerably the speed and amount of release. Similarly, by changing the temperature it is possible to vary the release rate and the quantity. Figure 5b shows a micrograph of the formulation. Particles consisting of the intermediate phase (II) and drops (I) of flumethrin emulsified therein are evident. Figure 5c shows a formulation stored for 30 days at 40 ° C in fluorescent light. The pale areas consist of flumethrin (I) and it can be seen that the active ingredient, even after storage, has not diffused from the inner phase (I) and the intermediate phase (II) to the outer phase (III). Otherwise, the outer phase contains (III) will also appear clear in this photograph. In order to make the most visible multiple capsules, a formulation without NTN was used in the outer phase (III) for these photographs. Example 3 Finally, as a third example, the development of an attack and annihilation formulation with a particularly long-lasting constant release of the attractant for fruit cultivation can be specified. This example is shown schematically in Figure 6. Here, an attractant (pheromone codlemone, la) was fused at a suitable concentration in a highly viscous to solid matrix (beeswax, relatively high molecular weight polyethylene glycols, shellac) ( I). This formulation represents one of the special cases described in the sense that phases (II), a phase of silicone oil, and (III), a phase of castor oil, have been charged together as a two-phase system on a phase () from highly viscous to solid deposit. Here, the phase (II) of silicone oil comprises in turn additional attractant (la) for immediate release. Castor oil as the third phase (III) serves to control the rate of release and at the same time functions as a solvent for a second active ingredient (cyfluthrin, Illa). Additional control can take place by the size of the interface between phases (I) and (11) / (III) through the control of diffusion. To further reduce the rate of release, it is also possible to completely dispense with phase II. The formulation can be applied to the plants either by using a suitable applicator such as drops or pouring into a molded container. In this case, the outer phase is also enriched with a thickener (Aerosil) in order to prevent the formulation from slipping immediately. The kinetics of diffusion of the attractant from the lower phase ensures a constant concentration profile in the formulation, meaning that the release from the outer phase to the air at the required concentration can be maintained for more than 100 days. Three examples are given below in which the volume relationships of phases (II) and (III) have varied. The preparation of the tank (step 1), such as the preparation of the formulations, are identical in all cases. Preparation of the various phases: Step 1 (Deposit): Liquify 0.2 85 g of beeswax, addition of 15 mg of codlemone. Dispersion with magnetic stirrer. This hot mixture is added dropwise to, for example, a curled lid N20 and allowed to solidify. Step 2 (Phase 2): a) Add 1.22 mg of the pheromone-codlemone to 1.27 g of silicone oil (Fluka CD 200 1020 mPas). Dispersion with magnetic stirrer. c) add 1.22 mg of the pheromone codlemone to 0.77 g of silicone oil (fluka DC 200 1020 mPas). Dispersion with magnetic stirrer. c) no silicone oil phase. Step 3 (phase 3): a) Heat 0.548 g of castor oil (27%), with additional agitation 80 mg of cyfluthrin. At high temperature, stir until a clear solution has formed. b) Heat 1.04 castor oil (52%), with additional agitation to 80 mg cyfluthrin. At high temperature, stir until a clear solution has formed. c) Heat 1.82 g of castor oil (91%), with additional agitation 80 mg of cyfluthrin. At high temperature, stir until a clear solution is formed. 1.22 mg of codlemone are added to the solution. Preparation of the formulations: The heated phase 3 is dispersed in phase 2.

After the homogenization, 98 mg of Aerosil are added 150. The solid is added in portions with stirring. The heavy lid is filled with the reservoir then filled completely with the pasty phase in a homogeneous manner and without trapped air. The release rates achieved in the gas phase depend on the mixing ratio of the silicone phase (II) and the phase (III) of castor oil. Through variation, the kinetics can be adapted to the desired conditions and / or requirements. Figure 6a shows a measurement series in which the mixing ratios between the castor oil and the silicone oil were continuously changed. It is noted that in relation to this date, the best method known by the applicant to carry out the present invention is that which is clear from the present description of the invention.

Claims (9)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Formulation containing active ingredient with a plurality of phases containing active ingredient characterized in that the formulation has a first, inner, finely divided phase, consisting of the active ingredient or solution of active ingredients, of which some particles are preferably preferred. of the phase are surrounded by a barrier layer, and in that the formulation has a second intermediate phase which serves as a dispersant for the first interior phase and in which the active ingredient can be dissolved as well, and in which the formulation has a third phase exterior that serves as a dispersant for the second intermediate phase and in which the active ingredient can be present in turn in dissolved form and / or in the form of solid particles, which can again be surrounded, with a barrier layer.

2. Formulation according to claim 1, characterized in that the intermediate phase when applied to the formulation of a surface acts as a mechanical stabilization of the innermost phase and thus offers a longer service life of the dispersion of the innermost phase.

3. Formulation according to claim 1 or 2, characterized in that a plurality of biologically effective active ingredients in the various phases are combined at varying concentrations and with a release rate that is controlled in each case in an individual formulation.

Formulation according to one of claims 1 to 3, characterized in that the formulation limits the release of the active ingredient from the innermost phase by choosing a suitable solvent for the outer phase.

Formulation according to one of claims 1 to 4, characterized in that the barrier layer in the various phases is a microcapsule.

6. Formulation according to claim 5, characterized in that the microcapsule of the barrier layer is based on a polymer.

Formulation according to one of claims 1 to 6, characterized in that the third external phase is an oil phase, preferably silicone oil or castor oil.

8. Formulation according to one of claims 1 to 7, characterized in that the second interior phase is based on gelatin.

9. Use of the formulation according to one of claims 1 to 8 for controlled delayed release of the active ingredients. SUMMARY OF THE INVENTION The invention relates to a formulation having a plurality of phases containing active ingredients. This formulation is characterized in that: it contains a first phase (I), finely distributed, more internal, consisting of active ingredients or a solution of active ingredient, preferably some of the particles of the phase that are surrounded by a cover ( M) barrier; the formulation has a second intermediate phase (II) which serves as a dispersant for the first inner phase (I) and the active ingredient can also be dissolved; and the formulation has an external third phase (III) that serves as a dispersant for the second intermediate phase and can be dissolved, in turn, in the active ingredient and / or can be in the form of solid particles which in turn can be surrounded by a barrier cover. In this way, a plurality of biological active ingredients can be produced in the different phases in different concentrations and with a respectively controlled release rate in an individual formulation. According to the invention, a mechanical stabilization is achieved by solidifying the intermediate phase (II), allowing the formulation to be stable for a longer period of time once it has been applied to a surface. In addition, by selecting a suitable solvent for the outer phase, the formulations limit the release of the active ingredient from the innermost phase, and the capsules that are not emptied and thus can be stored for a longer period of time.