Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
  • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
• • 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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • 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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
  • A61K9/0021—Intradermal administration, e.g. through microneedle arrays or needleless injectors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
  • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
  • A61M2037/0023—Drug applicators using microneedles

Definitions

• Micronadelarray having an active ingredient in the form of salts having an active ingredient in the form of salts
• the invention relates to a microneedle array, in particular an applicator system, and its use for the intradermal administration of active ingredients in the form of salts, in particular drugs in the form of salts, said microneedle array for skin penetration to humans or animals is suitable and the microneedles consist of a formulation which contain at least one active ingredient in the form of a salt and at least one biodegradable polymer.
• Microneedle systems and devices using microneedle arrays for the painless intradermal (or transdermal) administration of drugs, particularly drugs, are well known in the art.
• the transdermal application of active substances in the form of salts is disclosed in Applicant's DE 102007041557 B4 for a patch or transdermal therapeutic system (TTS).
• the skin consists of several layers.
• the outermost skin layer, the stratum corneum has known barrier properties to prevent foreign substances from entering the body and exiting the body from the body.
• the stratum corneum which is a complex structure of compacted keratotic cell debris approximately 10-30 microns thick, forms a watertight membrane to protect the body. This natural impermeability of the stratum corneum prevents administration of most pharmaceuticals and other substances through the skin as part of an intradermal application.
• the administration of various substances therefore takes place, for example, by producing micropores or sections in the stratum corneum and supplying or applying a drug into or under the stratum corneum.
• numerous drugs e.g. also administered subcutaneously or intradermally or intracutaneously.
• the objective object of the invention is to provide a suitable dosage form for the intradermal administration of active ingredients in the form of salts.
• the invention relates to a device having the features of claim 1, namely a microneedle array for use in the intradermal application of a drug in the form of a salt comprising a plurality of microneedles on a carrier, wherein the microneedles consist of a formulation containing at least one active ingredient in Form of a salt and at least one biodegradable polymer.
• the penetrated microneedles are dissolved in situ and immediately resorb. This eliminates the need for the micro-needles to be hollow inside or have a channel, because the active ingredient in the form of salts is embedded in the skin embedded in a formulation. In the body, the formulation dissolves, and the active ingredient in the form of salts is released. Furthermore, it is a disadvantage of hollow microneedles that the cavities can become blocked by clotting blood during the wearing period.
• any suitable active ingredients are included in the form of salts which are suitable for intradermal administration.
• the active ingredient in the form of salts is preferably an active ingredient from the group of analgesics, such as. B. Narcotics.
• Preferred are morphine derivatives, heroin and buprenorphine, or fentanyl and its derivatives sufentanil and alfentanyl, but all in the form of their salts.
• the salts according to the invention are understood in particular to be fentanyl citrate or buprenorphine hydrochloride.
• Other known opioid salts such as oxycodone hydrochloride or morphine hydrochloride are also included.
• the salts be soluble in a pharmaceutically acceptable solvent such as ethanol.
• the term "soluble" means that 1 part of the salt dissolves in 10 to 30 parts of the solvent. The person skilled in the art is able to prepare corresponding salts for the active compounds.
• the microneedle array may comprise a plurality of microneedles for delivering a salt actives through the skin or into the skin of a patient, the microneedle array being applied to the skin of the patient.
• Each of the microneedles of the microneedle array preferably has an elongated shaft with two ends, one end of the shaft being the base of the microneedle with which the microneedle is attached to the planar support or with which the microneedle is integrated into the planar support.
• the base of the opposite end of the shaft is preferably designed tapered to allow the easiest possible penetration of the microneedle into the skin.
• the microneedle array of the invention is suitable for use in the intradermal application of an active ingredient in the form of a salt and comprises a plurality of microneedles on a carrier, the microneedles comprising or consisting of a formulation containing at least one active ingredient in the form of a salt and at least one contain biodegradable polymer.
• the biodegradable polymers may be particularly preferably
• water-soluble polymers preferably those polymers selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohols, cellulose, dextranes, alpha-hydroxy acids, such as lactic acid and / or glycolic acid, polylactides, polyglycolides, polylactide-co-glycolides, and copolymers thereof with polyethylene glycol, polyanhydrides, poly (ortho) ester,
• Polyurethanes polybutyric acids, polyvaleric acids, and polylactide-co-caprolactones.
• such polymers are also water-soluble, which dissolve in water or ethanol or alcohol-water mixtures at room temperature up to 50% or in the boiling heat, that is at about 78 ° C, up to 80%.
• the microneedles may have a shaft with a round cross-section or a non-round cross-section, for example with a triangular, quadrangular or a polygonal cross-section.
• the shaft may have one or more passages that extend from the needle base to the needle tip or approximately to the needle tip.
• the microneedles can be designed as (reverse) hook, wherein a or more of these microneedles has one or more such hooks.
• the microneedles can be helically designed and rotatably arranged, thereby facilitating the penetration into the skin when applying a rotating movement and effecting an anchoring in the skin (DE 103 53 629 A1), in particular at the desired penetration depth in the epidermis.
• the diameter of a microneedle is usually between 1 pm and 1000 mhi, preferably between 10 pm and 100 pm.
• the diameter of a passage is usually between 3 pm and 80 pm and is suitable for the passage of preferably liquid substances, solutions and material preparations.
• the length of a microneedle is usually between 5 pm and 6,000 pm, in particular between 100 pm and 700 pm.
• the microneedles are attached with their base to a flat carrier or integrated into a flat carrier.
• the microneedles are preferably arranged substantially perpendicular to the surface of the carrier standing.
• the microneedles can be arranged regularly or irregularly.
• An array of multiple microneedles may comprise microneedles having different cross-sectional shapes, different sized diameters and / or different lengths.
• the assembly may also comprise solid microneedles, as well as having semi-solid composites.
• the density of the microneedles on a support can be 5 to 5,000 pieces / cm 2 , especially 5 to 1,000 pieces / cm 2 .
• the microneedle array may comprise a planar carrier, wherein the carrier has a substantially disc-shaped, plate-shaped or foil-like basic shape.
• the carrier may have a round, oval, triangular, square or polygonal base.
• the carrier may be made of different materials, for example, a metal, a ceramic, a semiconductor, an organic material, a polymer or a composite.
• materials which are suitable for the preparation of the carrier it is possible to cite preferably films or sheet-like materials, for example microporous membranes, preferably of polyethylene (PE) or polypropylene (PP), or diffusion membranes, preferably of ethylene-vinyl acetate copolymer (EVA ) or polyurethane (PUR).
• PE polyethylene
• PP polypropylene
• EVA ethylene-vinyl acetate copolymer
• PUR polyurethane
• Suitable materials for the production of Carriers may be selected from the group comprising polyesters such as polyethylene terephthalates (PET), polycarbonates (PC), polyether ketones (PAEK), polyethylene naphthalate (PEN), polybutylene terephthalate (PBT), polyurethanes (PU), polystyrenes (PS), polyamides (PA), Polyoxymethylene (POM), polyolefins such as polyethylene (PE) and polypropylene (PP), polytetrafluoroethylene (PTFE), polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polylactate (PLA), polymethyl methacrylate (PMMA) and cellulosic based plastics such as cellulose hydrate or Cellulose acetate includes.
• Suitable materials for the preparation of the support may also be selected from the group of metals comprising aluminum, iron, copper, gold, silver, platinum, alloys of the aforementioned metals and other pharmaceutically acceptable metal foils or metal
• the carrier is made of a flexible material, such as a plastic.
• a wearer of a flexible material can better conform to the skin surface and its curvature than a wearer of a non-flexible material. This achieves better contact of the microneedle array with the skin, thereby improving the reliability of the microneedle array.
• the microneedle array is a planar or planar microneedle array.
• applicator systems can be used to apply a microneedle array under pressure to the skin and result in a sudden load on the skin.
• the microneedle system comprising a microneedle array is configured with an applicator.
• Such applicators advantageously permit the activation of a pressure mechanism to penetrate the microneedle array into the skin or stratum corneum (see, for example, WO02008091602A2, WO2016162449A1).
• the applicator system comprising a microneedle array can be configured with conventional functional objects which allow fixation on the skin, as well as allow easy handling for pressure exertion on the skin and in particular can contain at least one fixative.
• an applicator system is one such system which includes a device which causes the microneedle array to be administered to the skin in the form of a salt and intradermally applied in the form of a salt.
• the applicator system may comprise a triggering device which is controlled electrically or mechanically.
• the applicator system may include a plunger which applies or applies the microneedle array to the skin so that the microneedles penetrate into the skin.
• the triggering device may comprise, for example, a pump, a syringe or a spring, so that a piston stroke can take place with sufficient energy.
• the piston may be of any shape and nature and is intended to be accomplished in the first place by providing the microneedle array from a first position to a second position for delivery of the active ingredients to the skin.
• the applicator system may further include a push button or thread.
• the microneedle array may contain fixing means, which are preferably fixed by means of a pressure-sensitive adhesive strip or plaster on the skin of a patient or volunteers, also called needle plasters.
• pressure-sensitive adhesives are highly viscous substances that stick to the skin after a short light pressure, so-called pressure-sensitive adhesives (PSA). They have high cohesive and adhesive forces.
• PSA pressure-sensitive adhesives based on poly (meth) acrylates based on polyisobutylenes or based on silicones can be used.
• the fixing means may consist of a band, elastic band, rubber or belt. Such fixatives can be used to secure attachment to the body.
• the invention also relates to an applicator system according to the invention comprising a microneedle array or a microneedle array for intradermal application, which has fixing agents for the skin.
• intradermal application (synonym:" intracutaneous application ) describes according to the invention the administration of any active ingredients via the microneedle array into the skin and requires puncturing or penetration of the microneedles into the skin.
• the invention also relates to a method for intradermal administration, wherein a microneedle array having a plurality of microneedles is applied to a carrier, in particular by means of an applicator, wherein the microneedles consist of a formulation containing at least one active ingredient in the form of a salt and at least one biological degradable polymer included.
• the invention relates to the use of a microneedle array having a plurality of microneedles on a carrier, in particular a corresponding applicator system, wherein the microneedles consist of a formulation containing at least one active ingredient in the form of a salt and at least one biodegradable polymer, for intradermal administration.
• fentanyl citrate is equivalent to the daily introductory dose of transdermal pain therapy.
• the PET film is placed with the side facing away from the needles on a pressure-sensitive adhesive-coated fabric, that the adhesive tissue projects beyond the needle patch.
• needle patches and adhesive tissue are covered with a deep-drawn foil made of siliconized HDPE foil 175 pm to protect the polymic needles.
• the thermoformed film is peeled off.
• the needle plaster is glued on a pain patient and through the fixed the needle segment on all sides superior adhesive layer.
• the needles of fentanyl citrate and Resomer R 202 are thereby pushed through the cornea. Resomer R 202 disintegrates and thereby releases fentanyl citrate into the subcutaneous tissue, from which it enters the bloodstream with a delay.
• fentanyl citrate 5 g are in 95 g of polyvinyl alcohol above the glass transition temperature of the mixture of both components by melt extrusion in a suitable for each 3D printer homogeneous strand "so-called. extruded filament "extruded and then wound on a roll.
• this drug polymer strand is melted and brought in the form of needles. It creates needles with a height of 0.5 to 1.0 mm.
• the room temperature and humidity is kept as low as possible to make the curing process as quickly as possible and to prevent water absorption of the hygroscopic polymer.
• the film is placed with the side facing away from the needles on a pressure-sensitive adhesive-coated film that the adhesive film projects as a "patch" the needle patch.
• a pressure-sensitive adhesive-coated film that the adhesive film projects as a "patch" the needle patch.
• needle patches and adhesive tissue are covered with a deep-drawn foil made of siliconized HDPE foil 175 pm to protect the polymic needles.
• the thermoformed film is peeled off.
• the needle plaster is glued to a pain patient and fixed by the needle segment on all sides superior adhesive layer.
• the needles of fentanyl citrate and polyvinyl alcohol are thereby pushed through the cornea. Polyvinyl alcohol dissolves and thereby releases fentanyl citrate below the stratum corneum, from where it enters the bloodstream.
• fentanyl citrate 5 g are heated in 95 g of polyvinyl alcohol to a temperature above the melting temperature of the mixture and brought by injection molding process, the melt in the form of needles. It creates needles with a height of 0.5 to 1.0 mm.
• the room temperature and humidity is kept as low as possible to make the curing process as quickly as possible and to prevent water absorption of the hygroscopic polymer.
• the film is placed with the side facing away from the needles on a pressure-sensitive adhesive-coated film that the adhesive film projects as a "patch" the needle patch. Needle patches and adhesive tissue are used for storage a thermoforming foil made of siliconized HDPE film 175 mih covered to protect the polymic needles.
• thermoformed film is peeled off.
• the needle plaster is glued to a pain patient and fixed by the needle segment on all sides superior adhesive layer.
• the needles of fentanyl citrate and polyvinyl alcohol are thereby pushed through the cornea.
• Polyvinyl alcohol dissolves and thereby releases fentanyl citrate below the stratum corneum, from where it enters the bloodstream.
• 7.5 g of buprenorphine HCF are heated in 92.5 g of polyvinyl alcohol to a temperature above the melting temperature of the mixture, extruded by twin-screw extruder and printed the resulting strand by 3D printing in the form of needles on a drug-impermeable film so that needles with a height of 0 , 5- 1.0 mm arise.
• the room temperature and humidity is kept as low as possible to make the curing process as quickly as possible and to prevent water absorption of the hygroscopic polymer.
• the film is placed with the side facing away from the needles on a pressure-sensitive adhesive-coated film that the adhesive film projects as a "patch" the needle patch.
• thermoformed film is peeled off.
• the needle plaster is glued to a pain patient and fixed by the needle segment on all sides superior adhesive layer.
• the needles of buprenorphine HCF and polyvinyl alcohol are thereby pushed through the cornea. Polyvinyl alcohol dissolves and thereby releases buprenorphine HCF below the stratum corneum, from where it enters the bloodstream.
• buprenorphine HCF 5 g are dissolved in 25 g of a 30% ethanolic solution of polyvinylpyrrolidone K30 and in a matrix containing Negativwerianangen for a needle array of eg 64 needles with a catches of about 0.8 mm and a width of about 0, 2mm with a needle distance of approx. 0.3 mm. Above it is a recess for an array plate with a height of about 0.2 mm and an area of 1 cm 2 . After the agent has dried out, becomes a drug-free base plate consisting of a 30% methanolic solution of PVPVA64 dosed over the needles to create a slightly flexible plate that simultaneously connects the needles as a unit.
• the film is placed with the side facing away from the needles on a pressure-sensitive adhesive-coated film that the adhesive film projects as a "patch" the needle patch.
• a pressure-sensitive adhesive-coated film that the adhesive film projects as a "patch" the needle patch.
• needle patches and adhesive tissue are covered with a thermoforming foil made of siliconized HDPE foil 175 mhi to protect the polymic needles.
• the thermoformed film is peeled off.
• the needle plaster is glued to a pain patient and fixed by the needle segment on all sides superior adhesive layer.
• the needles of buprenorphine HCF and polyvinylpyrrolidone are thereby pushed through the cornea.
• PVP K30 dissolves and releases buprenorphine HCF below the stratum corneum, from where it enters the bloodstream.

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• Health & Medical Sciences (AREA)
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• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
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• Veterinary Medicine (AREA)
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• Inorganic Chemistry (AREA)
• Engineering & Computer Science (AREA)
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• Emergency Medicine (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
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• Heart & Thoracic Surgery (AREA)
• Chemical Kinetics & Catalysis (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 2018
  • 2018-12-14 ES ES18833180T patent/ES2908820T3/es active Active
  • 2018-12-14 JP JP2020532587A patent/JP7837672B2/ja active Active
  • 2018-12-14 CN CN201880080460.6A patent/CN111542309A/zh active Pending
  • 2018-12-14 CA CA3085633A patent/CA3085633A1/en active Pending
  • 2018-12-14 US US16/771,586 patent/US12397142B2/en active Active
  • 2018-12-14 EP EP18833180.5A patent/EP3723725B1/de active Active
  • 2018-12-14 WO PCT/EP2018/085083 patent/WO2019115815A1/de not_active Ceased
• 2024
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