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EP1708567A1 - Formulation d'agents actifs a plusieurs phases - Google Patents

Formulation d'agents actifs a plusieurs phases

Info

Publication number
EP1708567A1
EP1708567A1 EP04803882A EP04803882A EP1708567A1 EP 1708567 A1 EP1708567 A1 EP 1708567A1 EP 04803882 A EP04803882 A EP 04803882A EP 04803882 A EP04803882 A EP 04803882A EP 1708567 A1 EP1708567 A1 EP 1708567A1
Authority
EP
European Patent Office
Prior art keywords
phase
formulation
active ingredient
innermost
release
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04803882A
Other languages
German (de)
English (en)
Inventor
Daniel Rudhardt
Frank Ridder
Stefan Hofmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer Technology Services GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Technology Services GmbH filed Critical Bayer Technology Services GmbH
Publication of EP1708567A1 publication Critical patent/EP1708567A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/02—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings containing insect repellants
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
    • A01N25/04—Dispersions, emulsions, suspoemulsions, suspension concentrates or gels
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/26—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests in coated particulate form
    • A01N25/28—Microcapsules or nanocapsules
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N49/00—Biocides, pest repellants or attractants, or plant growth regulators, containing compounds containing the group, wherein m+n>=1, both X together may also mean —Y— or a direct carbon-to-carbon bond, and the carbon atoms marked with an asterisk are not part of any ring system other than that which may be formed by the atoms X, the carbon atoms in square brackets being part of any acyclic or cyclic structure, or the group, wherein A means a carbon atom or Y, n>=0, and not more than one of these carbon atoms being a member of the same ring system, e.g. juvenile insect hormones or mimics thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N51/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds having the sequences of atoms O—N—S, X—O—S, N—N—S, O—N—N or O-halogen, regardless of the number of bonds each atom has and with no atom of these sequences forming part of a heterocyclic ring
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N53/00—Biocides, pest repellants or attractants, or plant growth regulators containing cyclopropane carboxylic acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/06—Emulsions
    • A61K8/066—Multiple emulsions, e.g. water-in-oil-in-water
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/113—Multiple emulsions, e.g. oil-in-water-in-oil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5052—Proteins, e.g. albumin
    • A61K9/5057—Gelatin

Definitions

  • the invention relates to an active ingredient-containing formulation with several active ingredient-containing phases.
  • a large number of active substances are liquids or are present as a substance dissolved in liquid.
  • a way was sought to specifically control the time course of the release of such an active substance after it was applied to a surface which is in contact with a gas space.
  • a search was made for a way to delay the release of the active ingredient, to control the release rate of the active ingredient, to provide chemically or biologically incompatible active ingredients in a formulation and / or to produce a capsule formulation that can be stored.
  • a formulation with these characteristics would be used e.g. allow on the skin or on the surface of leaves.
  • active ingredient-containing capsules are often dispersed in the liquid phase before use (for example in the field of crop protection) or are suspended in a clear excess of a liquid phase during manufacture. Months, sometimes years, then often pass before use. In the field of pharmacy, shelf life of three to five years is often required. Because of the mostly desired semi-permeability of the capsule walls, the active ingredient diffuses into the outer phase until the dispersant is saturated, so that under certain circumstances only a little active ingredient remains in the capsules and / or a concentration is reached in the outer phase that is already undesirable Side effects generated (eg toxicity) or the effective concentration optimal for the initial effect is exceeded.
  • Side effects generated eg toxicity
  • microcapsules can be manufactured conventionally in different ways and can consist of capsules with liquid or solid contents. These processes are interfacial polymerization, interfacial precipitation reactions, complex and simple coacervation, as well as complex emulsification (double and micro-emulsions).
  • a relatively new process for the encapsulation of solid or liquid dispersion particles is the layer-by-layer growth of an envelope membrane, which is produced by alternately applying cationic and anionic polyelectrolytes, possibly with the inclusion of charged nanoparticles, on the particle surfaces (cf. GB Sukhorukov et al. Colloids and Surfaces A, 137, 253-266 (1998); patent WO 9947252, WO 9947253).
  • the polyanions and cations present in solution are precipitated directly onto the surfaces by shifting the pH and / or salt content (cf. 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 methods is that after removing the dispersing agent, e.g. after application to a surface, the coated emulsion droplets are often not stable, but melt away quickly.
  • the object of the invention is to develop a new process which makes it possible to provide a formulation with the desired properties mentioned above, that is to say after the formulation has been applied to a surface, the active ingredient in a defined concentration in the outer phase (dispersing agent) in order to achieve a desired initial effect offers a controlled release rate from the capsule to set a delayed, long-lasting effect and ensures the shelf life of such a capsule suspension.
  • the above object was achieved by a formulation consisting of several phases, in which the active substance can be present in different concentrations in each phase.
  • the release from the different phases takes place at different speeds, so that tion of the respective amounts of wi and the type of solvent / dispersant used, the kinetics and the total amount of active ingredient released can be varied.
  • the invention relates to an active ingredient-containing formulation with a plurality of active ingredient-containing phases, which is characterized in that the formulation has a first innermost finely divided phase (I) which consists of active ingredient or active ingredient solution, of which some phase particles are preferably surrounded by a barrier sheath (M) , and that the formulation has a second, middle phase (II), which serves as a dispersant for the first, inner phase (I) and can also be dissolved in the active ingredient, and that the formulation has a third outer phase (III), which serves as a dispersing agent for the second middle phase and in turn can be dissolved and / or present in solid particle form in the active ingredient, which in turn can be surrounded by a barrier sheath.
  • This principle is shown schematically in FIG. 1.
  • phases (I) and (II) are not dispersed in one another and subsequently in the outer phase (III) as described, but instead form a 3-phase layer system in the sense that the middle phase (II) is the inner one Phase (I) is covered and phase (II) itself is covered by phase (III).
  • This variant of the invention can be particularly advantageous if the active substance diffuses from the innermost phase rapidly and slow release can only be achieved by minimizing the phase interfaces.
  • the invention furthermore relates to the fact that, in the manner described, several biologically active substances can be produced in the various phases in different concentrations and with a controlled release rate in a single formulation.
  • a formulation is preferred which is characterized in that the barrier sheath is a microcapsule in the various phases.
  • the barrier sheath is a microcapsule in the various phases.
  • both a capsule with a solid polymer wall and a capsule are closed under microcapsule.
  • the microcapsule of the barrier casing is particularly preferably based on a polymer.
  • the outer third phase (III) is an oil phase with limited solubility for the active ingredient (s), preferably made of silicone oil or native oils, for example Castor oil - or perfluorinated organic compounds.
  • This outer phase can also contain dispersing agents (surfactants) or thickeners (e.g. aerosils, polymers).
  • the second, middle phase (II) is based on a thickened phase containing polymer or solid particles, e.g. a gelatin solution
  • the second middle phase (II) consists of a polymer solution or particle dispersion which can be gelled thermoreversibly, ie liquid at the temperatures of manufacture and / or application and semi-solid at the temperatures during storage and / or use is firm.
  • the active ingredient (s) preferably have a low solubility in this middle phase.
  • the innermost phase (I) consists of the pure or a solution of an active ingredient.
  • This phase can be present as an emulsion droplet stabilized with surfactants or as a solid or semi-solid dispersion particle.
  • the inner phase can also consist of a microcapsule containing the liquid, solid or semi-solid active ingredient.
  • the capsule wall of the microcapsule (M) can be produced, for example, by complex coacervation and constitutes a first barrier for the active ingredient.
  • the thickened, semi-solid matrix phase simultaneously provides the necessary mechanical stability, which allows the formulation to be applied as a film without the matrix phase being immediately destroyed.
  • these multiple capsules are in turn dispersed in the outer phase (III), which can consist of a defined solution of the active ingredient (s) or a phase which has only a very low saturation solubility for the active ingredient (s) or no solubility at all.
  • the active ingredient (s) can also be dispersed in the form of emulsion droplets.
  • the particle sizes of the innermost phase (I) can be varied by the amount of substances used and the type of dispersion. They are typically on the order of 1-10 ⁇ m.
  • the size of the particles from the emulsified intermediate phase (II) and inner phase (I) is typically in the order of 10-500 ⁇ m.
  • the active substance (s) is / are in different phases and the release of the active substance (s) is determined by the kinetics of the diffusion in the phases and by the phase boundaries as well as by the physical limit solubility / s of the active ingredient (s) determined in the phases. Because the amounts used the active ingredient can be varied in the different phases, the desired release profile can be set in a targeted manner.
  • Another object of the invention is the use of the formulation according to the invention for the gradual delayed release of active substances.
  • the active ingredient (s) can thus be released from the following phases:
  • Active ingredient is present in molecular form or as droplets in the solid or semi-solid matrix (II), which also ensures mechanical stability when applied as a film and whose saturation solubility determines the diffusion profile of the active ingredient.
  • the active ingredient is present as a microcapsule (I) in the solid or semi-solid matrix (II) and must therefore penetrate another barrier shell.
  • Another advantage of the multiple capsule system is the possibility of producing formulations which contain more than one active substance by introducing different active substances into the different phases, the necessary release profile of which can then be set separately.
  • chemically or physically incompatible active ingredients can be formulated together.
  • concentration of free active substance in the outer phase (III) can be determined by choosing suitable solvents and mixtures, in the sense that a suitable saturation solubility is set in the outer phase.
  • the multiple capsule system can also be used to release active substances into a liquid environment.
  • Formulations based on the described invention can preferably be used in the field of dermal formulations in humans and animals and in the field of crop protection.
  • auxiliaries and solvents are preferably used that are toxicologically safe and are approved by the responsible authorities / or are in principle classified as registrable.
  • These solvents are e.g. , but not exclusively:
  • medium chain triglycerides e.g. Miglyol 810, 812
  • native oils e.g. castor oil, sesame oil, peanut oil
  • partially hydrolyzed fats or low-ethoxylated reaction products of such partially hydrolyzed fats e.g. Labrafil, Gelucire
  • hydrophobic esters of native fatty acids e.g. isopropyl myristate
  • higher polarity hydrophobic solvents e.g. triethyl citrate, triacetin
  • semi-solid or solid matrix-forming systems in which the active ingredient is integrated in a molecularly disperse manner and which are liquid during manufacture and solid during storage and / or application e.g. fats, shellac, polyethylene glycols PEG 1000, 1500, 3000
  • compositions in which the active ingredient (s) and the solvents of the inner and outer phase are insoluble or only to a very limited extent and which in turn can act as solvents for the thickening additives (polymers, hydrotalcites).
  • solvents are, for example, but not exclusively:
  • hydrophilic solvents of suitable polarity (dielectric constant) (e.g. propylene glycol, ethanol, ethanediol, glycerin, low-chain polyethylene glycols PEG 200, 300, 400)
  • suitable polarity e.g. propylene glycol, ethanol, ethanediol, glycerin, low-chain polyethylene glycols PEG 200, 300, 400
  • the middle phase can still contain surfactants, for example, but not exclusively: ionic surfactants (dodecyl sulfate sodium salt (SDS), cationic surfactants (cetyl trimethyl ammonium chloride) or natural or synthetically produced polyelectrolytes (gelatin, Polystyrene sulfonate) or polymeric nonionic dispersants (polyvinyl alcohol-polyvinyl acetate copolymers, for example movioles)
  • ionic surfactants dodecyl sulfate sodium salt (SDS)
  • cationic surfactants cetyl trimethyl ammonium chloride
  • natural or synthetically produced polyelectrolytes gelatin, Polystyrene sulfonate
  • polymeric nonionic dispersants polyvinyl alcohol-polyvinyl acetate copolymers, for example movioles
  • solvents are, for example, but not exclusively:
  • medium chain triglycerides e.g. Miglyol 810, 812
  • native oils e.g. castor oil, sesame oil, peanut oil
  • partially hydrolyzed fats or low-ethoxylated reaction products of such partially hydrolyzed fats e.g. Labrafil, Gelucire
  • hydrophobic esters of native fatty acids e.g. isopropyl myristate
  • higher polarity hydrophobic solvents e.g. triethyl citrate, triacetin
  • Silicone oils or perfluorinated solvents which have a low solubility for the hydrophilic middle phase as well as for the oils of the inner phase and for the active substances, e.g. Dimethylpolysiloxanes of different chain lengths. (e.g. Dow Corning Q7-9120 Silicon Fluid Series 20, 100, 350, 1000), cSt, higher cyclic dimethyloligosiloxanes (e.g.
  • dodecamethylcyclohexasiloxane perfluorinated alkanes or perfluorinated polyethylene oxides; preferably those silicone oils or organic oils which have a low viscosity, high vapor pressure and good spreading behavior, so that after application to skin or plants they ensure rapid distribution of the matrix phase particles and then volatilize without residue, e.g. to avoid greasy residues, e.g. cyclic polysiloxanes octamethylcyclotetrasiloxane D4, decamethylcyclopentasiloxane D5, short-chain linear oligodimethylsiloxanes (e.g.
  • polyethylene oxide-polypropylene oxide-polyethylene oxide copolymers e.g. Pluronics, poloxamers
  • ethoxylated carboxylic acid esters or alkyl ethers e.g. Cremophore
  • polyethylene oxide-modified polydimethylsiloxanes
  • Cationic and anionic polyelectrolytes can preferably be used to initially stabilize the inner phase in the middle matrix phase and to produce the first diffusion-controlling membrane wall (M), for example, but not exclusively: polystyrene sulfonate (PSS), polyallylamine hydrochloride (PAH), Polydiallyl-dimethylammonium chloride, gelatin, carboxymethyl cellulose,
  • PSS polystyrene sulfonate
  • PAH polyallylamine hydrochloride
  • Polydiallyl-dimethylammonium chloride gelatin
  • carboxymethyl cellulose carboxymethyl cellulose
  • Polymers that have thermoreversible thickening properties in the respective solvent can be used which show a thermally induced phase transition between liquid and liquid crystal / semi-solid between the production conditions and storage conditions.
  • hydrophilic phase (II) there are, for example, but not exclusively, to be mentioned: polymers and polyelectrolytes derived from natural substances (eg hydrocolloids: gelatin, xanthan, pectins, carrageenan, carboxymethyl cellulose), surfactant-forming LC phases (eg polyethylene oxide) Polypropylene oxide-polyethylene oxide copolymers Pluronics / poloxamers, polylactide-co-glycolide block copolymers with polyethylene glycol), synthetically produced polymers (eg partially hydrolyzed polyvinyl acetates of a suitable degree of hydrolysis: Mowiol 3-83, 10-74, poly-N-isoproypylacrylamide such as NIPAAM polymers and simply thickening agents Polyvinyl alcohol, polyacrylic acid and their polyacrylic ester copolymers, carboxymethyl cellulose,
  • Hydroxy propyl methyl cellulose hydroxy ethyl cellulose, inorganic minerals (e.g. hectorite, silica).
  • those polymers and feedstocks can be used which are soluble or dispersible in the solvents used which have a suitable dielectric constant, e.g. but not exclusively: polyacrylamides,
  • Polyacrylic acid esters, N-isopropylacrylamide, polyvinyl acetates and vinyl acetate-vinyl alcohol copolymers of low degree of hydrolysis eg Polyviol 45/450
  • feedstocks that act as a solid matrix phase for the active substance can act, e.g. feedstocks derived from natural products (shellac, beeswax) or higher molecular weight polyethylene oxides (e.g. PEG 1000, 1500, 3000)
  • the same feedstocks can be used for the outer phase (III), which are selected according to the criteria for the inner phase (I), but this will usually be dispensed with if the formulations are capable of spreading surface is a decisive criterion after application.
  • Active ingredients with high potential for skin irritation e.g. pyrethroids flumethrin, permetlirine, cyfluthrins), insecticidal systemic active ingredients (e.g. imidacloprid), volatile agents, i.e. e.g. repellant substances (e.g. N, N-diethyl-m-toluamide DEET, 1- piperidinecarboxylic acid 2- (2-hydroxyethyl) -l-methylpropyl ester KBR 3023) or attractants / pheromones, (e.g. 8,10-E, E- Dodecadienol, Codlemone), caring agents (e.g. vitamins), anti-inflammatory agents (cortisone) or fungicidal agents (e.g. clotrimazole).
  • repellant substances e.g. N, N-diethyl-m-toluamide DEET, 1- piperidinecarboxylic acid 2- (2-hydroxyethyl) -
  • the manufacture of the multiphase system described here can generally be described by the following steps:
  • Known standard dispersion and emulsification processes can be used to emulsify or disperse the innermost phase (I) (e.g. stirrers, ultrasound sources, Ultra-Turrax, membrane emulsion). Ionic or nonionic surfactants or polymers are used to stabilize the innermost phase (I).
  • the continuous phase can already represent the intermediate or matrix phase (II) or only in a later step e.g. obtain the final composition of the intermediate phase (II) by adding soluble polymers.
  • Encapsulation of the emulsified or dispersed innermost phase (I) All or part of the innermost phase (I) is encapsulated by one of the known encapsulation processes such as interfacial polymerization, interfacial precipitation reactions, complex or simple coacervation or polyelectrolyte precipitation.
  • An alternative way is to encapsulate the innermost phase (I) outside the continuous phase before step 1 by a known method, such as spray drying.
  • the emulsion or suspension thus obtained is then emulsified in a further dispersion step in the outer phase (III).
  • Common dispersion or emulsification processes and nonionic or ionic surfactants or polymeric stabilizers are used again.
  • the intermediate phase is solidified during or after step 3.
  • the consolidation can e.g. by changing the temperature, pH or ionic strength in the intermediate phase (II) and the outer phase (III).
  • a simple modification of this manufacturing process can be used to produce a multi-phase formulation which is not in the form of a complex emulsion but is in the form of a simple layer system comprising several phases.
  • the melirfacil capsules consisting of phase (I) and (II) can be distributed quickly. It is also often desired that this outer carrier phase evaporates quickly after application.
  • the property mentioned under (a) ensures that the multiple capsules remain stable on the surface and release the active substance (s) in a controlled manner.
  • Fig. 1 is a diagram of the structure of the active ingredient formulation according to the invention
  • 3 a is a microscopic picture of the primary capsule
  • 3b is a microscopic picture of the multiple capsule
  • Fig. ' 3c is a microscopic picture of the formulation of Fig. 3a after application to a surface
  • 3d shows a microscopic picture of the formulation according to FIG. 3b after application to a surface
  • Fig. 4 shows the diagram of the structure of a further variant of the active substance formulation
  • Fig. 5 a is a diagram of the release of flumethrin as a function of time
  • 5b is a microscopic picture of a flumethrin formulation 5c shows a microscopic picture of the flumethrin formulation according to FIG. 5b after aging
  • KBR 3023 is a liquid active ingredient that is only slightly soluble in water and is only sparingly soluble in silicone oils.
  • the outer phase consists of a KBR / silicone oil mixture (III).
  • the middle matrix phase consists of an aqueous gelatin solution (II), which is liquid during production, since the temperature was above the gel temperature. After cooling to room temperature, this matrix is semi-solid or solid.
  • KBR 3023 droplets form the inner phase (I) and are present in the gelatin matrix as microcapsules with a polymeric shell which has been produced by complex coacervation of PSS and PAH (M).
  • Step 1
  • the silicone oil phase consists of a linear silicone oil DC 5 (Dow Corning, 0.3 g liquid KBR + 0.2 g emulsifier 5225 C + 1.5 g oil). Dispersion with UT followed by rapid cooling through an ice bath. Stirring time of approx. 15 min.
  • FIG. 3a The primary capsules formed after step 2 are shown in FIG. 3a.
  • FIG. 3b shows the multiple capsule with a solidified intermediate phase.
  • the saturation of the outer (III) and the intermediate phase (II) with KBR 3023 prevents the diffusion of KBR 3023 from the inner phase (I) during storage of the formulation.
  • KBR droplets without shell can alternatively or additionally be dispersed both in the gelatin matrix (II) and in the outer phase (III).
  • KBR droplets without a shell can also be emulsified in the outer phase.
  • this formulation was' skar used in the formulation of a dermal drug formulation for tick and flea control in veterinary medicine.
  • the formulation is shown schematically in FIG. 4.
  • the active ingredient (flumethrin) is dissolved in an oily phase (I), this is emulsified in an aqueous gelatin solution above the gel temperature (II) and this emulsion itself is dispersed in an outer silicone oil phase (III). After cooling below the gel point, the gelatin matrix solidifies.
  • the silicone oil phase is chosen so that the physical limit solubility in the outer phase corresponds exactly to the concentration that is favorable for an immediate effect of the active ingredient after application.
  • the active ingredient flumethrin is thus enriched in the outer phase until this optimal concentration is reached.
  • the release from the innermost phase is delayed by the gelatin matrix, since the skin temperature is below the softening point of the gelatin gel.
  • the outer phase also contains another dispersed active ingredient (imidacloprid) to ensure comprehensive insecticidal activity.
  • the spreading power of the silicone oil phase supports the rapid distribution of the dispersed particles of the matrix phase and the second active ingredient on the skin.
  • the use of a silicone oil with low vapor pressure also ensures that this phase evaporates quickly after spreading and thus leaves no greasy impression. This example is shown schematically in the figure.
  • TCA taurocholic acid
  • PHB methyl parahydroxybenzoate
  • gelatin 0.063 g of taurocholic acid (TCA), 0.0945 g of methyl parahydroxybenzoate (PHB) and 0.7245 g of gelatin are weighed in successively to 0.725 g of water. It is stirred at a temperature above the gel temperature with a magnetic stirrer until the gelatin has dissolved.
  • the approx. 60-80 ° C warm inner oil phase (I) is added dropwise to the warm gelatin phase (II).
  • the speed of the UT must be increased gradually so that maximum dispersion always takes place.
  • the temperature is checked.
  • the temperature is kept at approx. 50 - 60 ° C by means of a water bath. Addition time approx. 4 min, stirring time approx. 6 min.
  • the warm primary emulsion is then added to the approx. 50 ° C warm oil phase while stirring with the UT.
  • the temperature is kept at approx. 45 - 50 ° C by means of a water bath. Addition time approx. 4 min, stirring time approx. 2 min. Then the water bath is replaced with ice / NaCl. With this cooling to RT, stirring is continued.
  • FIG. 5 a shows the release of flumethrin into the outer phase (III) as a function of time. It can be seen that by varying the gelatin concentration in the intermediate phase (II) the release rate and amount can be varied significantly. The release rate and amount can also be varied by changing the temperature.
  • FIG. 5b shows a microscopic picture of the formulation.
  • the particles can be seen which consist of the intermediate phase (II) and the flumethrin droplets (I) emulsified therein.
  • FIG. 5c shows a formulation stored at 40 ° C. for 30 days in fluorescent light. The light areas consist of flumethrin (I) and you can see that the active ingredient does not move from the inner phase (I) and the intermediate phase (II) to the outer phase (III) even after storage is diffused. Otherwise the continuous outer phase (III) would appear bright in this image.
  • FIG. 6 a third example is the development of an Attract & Kill formulation with a particularly long-lasting constant release of the attractant for fruit growing.
  • This example is shown schematically in Figure 6.
  • An attractant (pheromone Codlemone, Ia) was melted in a suitable concentration into a highly viscous to solid matrix (beeswax, higher molecular weight polyethylene glycols, shellac) (I).
  • This formulation represents one of the special cases described, in the sense that phases (II) - a silicone oil phase - and (III) - a castor oil phase - were filled together as a 2-phase system via a highly viscous to solid depot phase (I).
  • the silicone oil phase (II) contained further attractant (Ia) for immediate release.
  • Castor oil as 3rd phase (III) serves to control the release rate and at the same time acts as a solvent for a 2nd active ingredient (cyfluthrin, purple). Additional control can be done by controlling the size of the interface between phases (I) and (11/111) by controlling the diffusion. To further reduce the release rate, phase II can also be dispensed with entirely.
  • the formulation can be applied to the plants either as a drop with a suitable applicator or poured into a molding vessel. In this case, the outer phase is also enriched with a thickener (Aerosil) to prevent the formulation from flowing immediately.
  • the diffusion kinetics of the attractant from the inner phase ensures a constant concentration profile in the formulation, so that a release from the outer phase into the air can be maintained in the necessary concentration for more than 100 days.
  • the volume ratios of phases (II) and (III) were varied.
  • the preparation of the reservoir (step 1) and the completion of the formulations are identical in all cases.
  • Step 1 (reservoir): liquefy 0.285 g beeswax, add 15 mg Codlemone. Dispersion with a magnetic stirrer. This warm mixture is dropped into, for example, a crimp cap N20 and allowed to solidify.
  • Step 2 (phase 2): a) Add 1.22 mg pheromone Codlemone to 1.27 g silicone oil (Fluka DC 200 1020 mPas). Dispersion with magnetic stirrer. b) Mix 0.77 g silicone oil (Fluka DC 200 1020 mPas) with 1.22 mg pheromone Codlemone. Dispersion with magnetic stirrer c) no silicone oil phase
  • Step 3 (phase 3): a) Warm up 0.548 g of castor oil (27%), while adding 80 mg of cyfluthrin. Stir in the heat until a clear solution has formed. b) Heat 1.04 g of castor oil (52%), while adding 80 mg of cyfluthrin. Stir in the heat until a clear solution has formed. c) Heat 1.82 g of castor oil (91%), while adding 80 mg of cyfluthrin. Stir in the heat until a clear solution has formed. 1.22 mg of Codlemone are added to the solution.
  • the warm phase 3 was dispersed in phase 2. After homogenization, 98 mg of Aerosil 150 are added. The solid is added in portions with stirring. The crimp cap filled with the reservoir is now filled with the pasty phase homogeneously and without air trapping.

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  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
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  • Epidemiology (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Toxicology (AREA)
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  • Dermatology (AREA)
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  • Insects & Arthropods (AREA)
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Abstract

L'invention concerne une formulation contenant des agents actifs à plusieurs phases contenant des agents actifs. Ladite invention se caractérise en ce que cette formulation présente une première phase (I) finement dispersée et la plus à l'intérieur, constituée d'un agent actif ou d'une solution d'agents actifs, certaines particules de phase étant, de préférence, entourées d'une enveloppe barrière (M) ; cette formulation présente une deuxième phase intermédiaire (II), servant d'agent dispersant pour la première phase intérieure (I) et pouvant être également dissoute dans l'agent actif, et ladite formulation présente une troisième phase extérieure (III), servant d'agent dispersant pour la deuxième phase intermédiaire et pouvant être, à son tour, dissoute dans l'agent actif et/ou se présenter sous forme de particules solides, qui peuvent être, à leur tour, entourées d'une enveloppe barrière. Selon ladite invention, plusieurs agents biologiquement actifs peuvent être produits de cette manière dans les différentes phases en différentes concentrations et avec une vitesse de libération respectivement contrôlée dans une formulation unique. Cette invention concerne également l'obtention d'une stabilisation mécanique par durcissement de la phase intermédiaire (II), qui permet de conférer à cette formulation une stabilité à plus long terme, même une fois appliquée sur une surface. Selon ladite invention, ces formulations limitent la libération de l'agent actif à partir de la phase la plus à l'intérieur par la sélection d'un solvant approprié pour la phase extérieure ; les capsules ne sont pas vidées et peuvent ainsi supporter un stockage à long terme.
EP04803882A 2003-12-19 2004-12-15 Formulation d'agents actifs a plusieurs phases Withdrawn EP1708567A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10359792A DE10359792A1 (de) 2003-12-19 2003-12-19 Mehrphasige Wirkstoffformulierung
PCT/EP2004/014261 WO2005063016A1 (fr) 2003-12-19 2004-12-15 Formulation d'agents actifs a plusieurs phases

Publications (1)

Publication Number Publication Date
EP1708567A1 true EP1708567A1 (fr) 2006-10-11

Family

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EP04803882A Withdrawn EP1708567A1 (fr) 2003-12-19 2004-12-15 Formulation d'agents actifs a plusieurs phases

Country Status (9)

Country Link
US (1) US20070104795A1 (fr)
EP (1) EP1708567A1 (fr)
JP (1) JP2007514686A (fr)
AU (1) AU2004308077A1 (fr)
BR (1) BRPI0417204A (fr)
CA (1) CA2550351A1 (fr)
DE (1) DE10359792A1 (fr)
NO (1) NO20063192L (fr)
WO (1) WO2005063016A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102005030017A1 (de) * 2005-06-27 2007-01-04 Beiersdorf Ag Emulsion mit Repellentien
GB0526416D0 (en) * 2005-12-23 2006-02-08 Syngenta Ltd Formulation
US9186640B2 (en) * 2007-08-28 2015-11-17 Pepsico, Inc. Delivery and controlled release of encapsulated lipophilic nutrients
EP2550863A1 (fr) * 2011-07-27 2013-01-30 Bayer Intellectual Property GmbH Particules contenant une matière active à base de polyacrylate

Family Cites Families (7)

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Publication number Priority date Publication date Assignee Title
GB568009A (en) * 1942-11-24 1945-03-14 Harry Hurst Improvements in or relating to toxicological preparations
GB929403A (en) * 1958-12-22 1963-06-19 Upjohn Co Encapsulated emulsions and processes for their preparation
WO1983003061A1 (fr) * 1982-03-04 1983-09-15 Battelle Development Corp Microcapsules doubles
GB9410092D0 (en) * 1994-05-19 1994-07-06 Kelco Int Ltd Emulsion, method and use
CA2320900C (fr) * 1998-03-19 2009-10-27 Bristol-Myers Squibb Company Systeme d'apport a liberation lente biphasique destine a des medicaments a solubilite elevee et procede associe
DE19947147A1 (de) * 1999-10-01 2001-04-05 Bayer Ag Mikrokapseln
EP1499303A4 (fr) * 2002-04-10 2007-07-25 Fred H Miller Systeme capsulaire a plusieurs compartiments et plusieurs phases

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2005063016A1 *

Also Published As

Publication number Publication date
JP2007514686A (ja) 2007-06-07
BRPI0417204A (pt) 2007-02-06
US20070104795A1 (en) 2007-05-10
WO2005063016A1 (fr) 2005-07-14
NO20063192L (no) 2006-09-14
AU2004308077A1 (en) 2005-07-14
DE10359792A1 (de) 2005-07-21
CA2550351A1 (fr) 2005-07-14

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