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
  • A61Q17/005—Antimicrobial preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B42/00—Surgical gloves; Finger-stalls specially adapted for surgery; Devices for handling or treatment thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B42/00—Surgical gloves; Finger-stalls specially adapted for surgery; Devices for handling or treatment thereof
  • A61B42/10—Surgical gloves
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
• • 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
• • 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
  • A61K8/11—Encapsulated compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/41—Amines
  • A61K8/416—Quaternary ammonium compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/43—Guanidines
• • 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
  • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L31/16—Biologically active materials, e.g. therapeutic substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q3/00—Manicure or pedicure preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
  • A61K2800/41—Particular ingredients further characterized by their size
  • A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
  • A61K2800/52—Stabilizers
  • A61K2800/524—Preservatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
  • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
  • A61L2300/206—Biguanides, e.g. chlorohexidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
  • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
  • A61L2300/208—Quaternary ammonium compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
  • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
  • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
  • A61L2300/622—Microcapsules

Definitions

• the present invention relates to microcapsules containing water-soluble amphiphilic substances such as antiseptics, to their preparation process and to their applications.
• microcapsules are particles of spherical shape, the size of which ranges between 1 and 1250 ⁇ m, made up of a support material containing the encapsulated substance. Depending on the structure of the support material, there are two types of microcapsules:
• microcapsules also called microspheres in which the support material is a continuous network, in which the substance to be encapsulated is dispersed.
• microcapsule includes only reservoir type microcapsules.
• Many substances can be encapsulated: they can be chemicals such as drugs or pesticides, or macromolecules such as enzymes, and also living cells.
• microcapsules are used in many fields such as pharmacy, bio-industry, cosmetics, food industry, pulp industry, etc ...
• EP 52 510 which describes microcapsules prepared by a phase separation technique using a coacervation, such as mineral oils or vegetable oils.
• microcapsules prepared by this method as well as by other similar methods have the disadvantage of forming agglutinates (inter-adhesion of particles), during the preparation of said microcapsules.
• aqueous phase added to the organic phase, mixing the two phases with stirring and / or in the presence of an emulsifying agent and then evaporating the solvent, generally with stirring and at room temperature, to obtain the microcapsules desired.
• Application EP 145 240 more particularly describes microcapsules produced by preparing a W / O emulsion (primary emulsion) comprising an aqueous internal layer containing a hydrophilic substance and a substance known as drug retention (natural or synthetic mucilage or compounds of molecular weights and more particularly gelatin) and an oily layer containing a polymer, preferably a polylactic acid or a copolymer of lactic acid and glycolic acid or their mixtures, in a water-immiscible solvent such as dichloromethane , then by thickening or solidifying said aqueous internal layer so as to obtain a viscosity greater than 5,000 centipoise, then by preparing a secondary W / O / W emulsion, in the presence of a conveying surfactant finally, by subjecting the emulsion thus obtained to evaporation of the solvent.
• a W / O emulsion primary emulsion
• microcapsules with a diameter of between 0.5 and 400 ⁇ m.
• These microcapsules of the prior art have the major drawback of not being suitable for the encapsulation of amphiphilic substances and of being more particularly intended to provide preparations for controlled release of the active principle located in the internal aqueous layer.
• the problem which the Applicant has posed does not relate to the production of microcapsules for internal use and controlled release but is essentially relating to microcapsules more particularly suitable for external use, and which allow the release of an antiseptic located in the central nucleus with aqueous phase, only during the crushing of said microcapsules.
• Another method used to encapsulate liquid substances is microencapsulation by interfacial polycondensation.
• microcapsules have a certain rigidity and are therefore not suitable for certain applications for which it is preferable that the active principle is released only during the crushing of the microparticles, and this, by the exercise of a certain pressure on the object containing said particles, for example when a glove for medical use is inadvertently pierced by a needle.
• the Applicant has sought to develop more flexible microcapsules, of greater maneuverability and usable in numerous applications, in which they allow the release of the active principle, and in particular of an ammonium quaternary, only by crushing.
• the present invention relates to microcapsules comprising at least one active principle, characterized in that they contain a hydrophilic internal core comprising at least one amphiphilic, water-soluble and gellable active principle, having a viscosity greater than 5 centipoise, coated in a wall selected from the group which includes walls based on a copolymer of ethylene and vinyl acetate (EVA), walls based on a copolymer of vinylidene chloride and vinyl chloride and walls based on polycarbonate.
• EVA ethylene and vinyl acetate
• the amphiphilic, water-soluble and gellable substance is dimethyldidecylammonium, at a concentration of between 5 and 50% (w / w), preferably between 20 and 35%.
• dimethyldidecylammonium is understood to mean both the basic product and its salts (halides, dihalides, organic salts, for example).
• Quaternary ammoniums are in fact of particular interest in local applications, such as bactericides, fungicides and virucides. For example, the action of dimethyldidecylammonium on the HIV virus has been demonstrated.
• the microcapsules in accordance with the invention contain amphiphilic and water-soluble substances, in particular quaternary ammoniums, whereas such substances usually favor oil / water emulsions and destabilize emulsions of water / oil type and are sufficiently flexible so that the active ingredient (s) are not released only under pressure crushing.
• the amphiphilic, water-soluble and gellable active principle is associated with at least one other substance, compatible with said active principle.
• said substance is an antiseptic chosen from the group of bisguanidines.
• the second substance is in particular a chlorhexidine salt and more particularly chlorhexidine digluconate.
• the hydrophilic internal core is either based on pure water, or based on a mixture of water and a hydrophilic polymer, or based on a hydroalcoholic mixture, including a hydrophilic polymer and a polyol.
• the hydrophilic polymer is in particular a polyvinyl alcohol and the polyol is in particular glycerol or ethylene glycol.
• the wall comprises a copolymer of ethylene and vinyl acetate
• the percentage of vinyl acetate in said copolymer is between 30 and 46%.
• the percentage of vinyl acetate is 40%.
• the present invention also relates to a process for preparing microcapsules by a solvent evaporation method, which comprises a step of preparing a water in oil emulsion (W / O), a hydrophilic, aqueous phase or hydroalcoholic containing at least one substance to be encapsulated in an oily phase containing a suitable polymer in solution in a suitable solvent and a second stage of formation of microcapsules by evaporation of solvent, which process is characterized in that:
• A- the production of the W / O emulsion comprises: (a) a step during which the hydrophilic, aqueous or hydroalcoholic phase containing at least one amphiphilic, water-soluble and gellable substance to be encapsulated, at a concentration such as said aqueous phase or hydroalcoholic has a viscosity greater than 5 centipoise, -which substance is possibly associated with at least one other substance compatible with said gelling substance, - is emulsified in an oily phase containing a copolymer chosen from the group consisting of ethylene / vinyl acetate, copolymers of vinylidene chloride and vinyl chloride (PVDC / PVC) and polycarbonate polymers, dissolved in a water immiscible and volatile solvent [primary water in oil emulsion (W / O)] ;
• Evaporation of the solvent can in particular be carried out by suitable stirring of the medium.
• the amphiphilic, water-soluble and gellable substance is dimethyldidecylammonium.
• said dimethyldidecylammonium is present at a concentration of between 5 and 50% (w / w), preferably between 20 and 35%.
• the second substance is in particular a chlorhexidine salt such as the hydrochloride diacetate or the chlorhexidine digluconate.
• hydrophilic phase of step (a) when the hydrophilic phase of step (a) is an aqueous phase, the latter comprises water, optionally combined with a hydrophilic polymer; when the hydrophilic phase of step (a) is a hydroalcoholic phase, the latter consists of a polyol immiscible with the solvent of the copolymer of the wall of said microcapsules, optionally combined with a hydrophilic polymer.
• copolymers are advantageously dissolved in a halogenated and volatile solvent, chosen for example, without limitation, from dichloromethane and a suitable mixture of dichloromethane / acetone.
• said lubricating agent is advantageously talc (second aqueous phase), at a concentration of the order of 1.3 to 5% by weight in water.
• step (c) is carried out either at room temperature, or by heating to a temperature between 40 ° C and 70 ° C.
• the process according to the invention makes it possible to obtain, without adding an emulsifying agent and in particular a surfactant, flexible microcapsules, containing at least one amphiphilic substance, water-soluble and gellable, of homogeneous dimensions, sufficiently elastic so as not to be crushed and to release the active principle which they contain only after the exertion of a significant pressure, and not during a simple manipulation.
• microcapsules are particularly well suited for external use, and can be incorporated, without limitation, into papers, textiles (woven and non-woven), including dressing objects (dressings, compresses) and operating drapes. , sponges and materials based on polymers, in particular elastomers (gloves for medical or surgical use, condoms etc.), to nail brushes (surgical brushes, for example), to disinfecting powders, etc. .
• EXAMPLE 1 Preparation of microcapsules in accordance with the invention containing a single active principle and the inner core of which is aqueous.
• the encapsulated antiseptic is dimethyldidecylammonium chloride ("BARDAC 22" ® LONZA FRANCE); it is a quaternary ammonium salt, which therefore has all the properties of this chemical class:
• fungi fungi, and viruses (retroviruses, especially HIV),
• the commercial aqueous solution is 60%. In the present example, this solution is diluted to half.
• the viscosity of the "Bardac 22" ® solution is measured using a capillary viscometer at 20 ° C (Ubbelohde tube). Viscosities with 28, 36 and 47 centipoise values at 20 ° C are obtained for 20%, 30% and 40% solutions.
• the wall of the microcapsules consists of EVA (ethylene / vinyl acetate copolymer) containing
• the water used during the tests is purified and deionized. This quality is essential for the dissolution of the antiseptic since it is incompatible with divalent cations.
• Dichloromethane or methylene chloride is a volatile chlorinated solvent, the boiling point of which is 40 ° C.
• ALKON aqueous suspension of 40% zinc stearate
• microcapsules When the microcapsules are formed, it is filtered, for example, on a Buchner funnel with a vacuum flask.
• microcapsules are thus collected on filter paper.
• EXAMPLE 2 Another preparation of microcapsules in accordance with the invention containing a single active principle.
• FIG. 1 shows the appearance of the microcapsules obtained, observed under the microscope and which are well differentiated from one another.
• the unstable W / O primary emulsion is vigorously shaken and introduced into 800 g of pure water with stirring (first external phase).
• the secondary emulsion is formed instantly.
• microcapsules When the microcapsules are formed, we filter, for example, on a B ⁇ chner funnel with a vacuum flask.
• microcapsules are recovered on the filter paper.
• EXAMPLE 4 Another preparation of microcapsules with hydroalcoholic content.
• Glycerol (or ethylene glycol) 66.0%.
• the internal hydroalcoholic phase then contains 15% Bardac ® (w / w) and 2.5% polyvinyl alcohol (w / w).
• EXAMPLE 5 Preparation of microcapsules (aqueous internal phase) in accordance with the invention containing two active ingredients.
• the aqueous phase is prepared, which comprises a mixture of "Bardac” ® and chlorhexidine digluconate ("Hibitane” ® , for example).
• the "Bardac” ® 60% and the “Hibitane” ® 20% are half diluted in water and then mixed; the mixing can possibly be done before dilution.
• Example 6 Another preparation of microcapsules (internal hydroalcoholic phase) in accordance with the invention containing two active ingredients.
• Glycerol (or ethylene glycol) 57.5%.
• This internal aqueous-alcoholic phase then contains 12.6% of Bardac ® (w / w), 2.4% of Hibitane® (w / w) and 2.5% polyvinyl alcohol (w / w).
• the surfactants tested are:
• PVA polyvinyl alcohol
• PVA 4/125 Insoluble in most organic solvents PVA 4/125 is soluble in water. Its solutions are colloidal, and their viscosity increases with concentration, until a gel forms. They play a stabilizing role in dispersions of polymer or colloidal metals. Their evaporation makes it possible to bind particles of active principles by solid bridges of PVA during the manufacture of the tablets (wet granulation).
• HLB Hydrophilic Hydrophilic Balance
• the tested products have an HLB> 10:
• Tables III, IV and V show the role of the order of introduction of the constituents (1st and 2nd phase) and the role of temperature.
• the assay method consists in measuring the surface tension of the aqueous solution containing "Bardac” ® and in determining the concentration of the surfactant by reference to a previously established calibration curve.
• the measurement is carried out with dynamic contact angle measurement equipment, CAHN DCA 312 ® , with input system and data processing software suitable for determining the surface tension.
• a parallelepiped glass slide (without soiling by passage through a flame), suspended vertically on the weighing pan is soaked in the solution to be analyzed; tracking the blade extraction force at the programmed speed allows the surface tension to be calculated.
• FIG. 2 illustrates the results obtained and comprises on the abscissa the concentration (c) of "Bardac 22" ® in mg / 1 and on the ordinate the surface tension in dynes / cm (Ts).
• the latex film On a pill box containing demineralized water, the latex film is deposited, which is pierced with a series of needles so as to drive the solution contained in the microcapsules towards demineralized water.

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• 1991
  • 1991-08-02 FR FR9109864A patent/FR2679777B1/fr not_active Expired - Fee Related
• 1992
  • 1992-07-31 WO PCT/FR1992/000759 patent/WO1993002668A1/fr not_active Application Discontinuation
  • 1992-07-31 JP JP5503338A patent/JPH06509503A/ja active Pending
  • 1992-07-31 EP EP92918055A patent/EP0597036A1/de not_active Withdrawn

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