EP4203916A1 - Perforation de la muqueuse - Google Patents

Perforation de la muqueuse

Info

Publication number
EP4203916A1
EP4203916A1 EP21772669.4A EP21772669A EP4203916A1 EP 4203916 A1 EP4203916 A1 EP 4203916A1 EP 21772669 A EP21772669 A EP 21772669A EP 4203916 A1 EP4203916 A1 EP 4203916A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutically active
microneedle system
mucosa
microneedle
active ingredient
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.)
Pending
Application number
EP21772669.4A
Other languages
German (de)
English (en)
Inventor
Dr. Andreas KOCH
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.)
LTS Lohmann Therapie Systeme AG
Original Assignee
LTS Lohmann Therapie Systeme AG
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 LTS Lohmann Therapie Systeme AG filed Critical LTS Lohmann Therapie Systeme AG
Publication of EP4203916A1 publication Critical patent/EP4203916A1/fr
Pending legal-status Critical Current

Links

Classifications

    • 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, needleless injectors
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • 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
    • 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
    • A61M2037/0046—Solid microneedles
    • 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
    • A61M2037/0061—Methods for using microneedles
    • 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
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/06—Head
    • A61M2210/0625—Mouth
    • 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
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • A61M5/3295—Multiple needle devices, e.g. a plurality of needles arranged coaxially or in parallel
    • A61M5/3298—Needles arranged in parallel

Definitions

  • the present invention relates to a kit comprising at least one microneedle system and at least one dosage form for the transmucosal administration of at least one pharmaceutically active substance, wherein the at least one dosage form for the transmucosal administration of at least one pharmaceutically active substance preferably comprises an oral thin film, this kit for use in the treatment of a patient, the use of a microneedle system for reducing the permeation barrier of a mucosa for at least one pharmaceutically active ingredient and a method for treating a patient, wherein first a microneedle system is applied to a site of a patient's mucosa and removed again, and then an oral Thin film, comprising at least one matrix polymer and at least one pharmaceutically active agent, on the site of the mucosa to which the microneedle system has been applied and removed again, au f is brought or wherein the microneedle system is applied to the mucosa simultaneously with a dosage form for transmucosal administration of at least one pharmaceutically active ingredient
  • Pharmaceutically active ingredients can be administered via the mucosa with appropriate dosage forms.
  • Oral thin films for example, are suitable for this purpose.
  • Oral thin films are thin films containing at least one pharmaceutically active ingredient that are applied directly to a mucosa (mucous membrane), preferably the oral mucosa, and preferably dissolve there.
  • a mucosa mucous membrane
  • These are, in particular, thin polymer-based films containing active substance which, when applied to a mucous membrane, in particular the oral mucosa, release the active substance directly into the latter.
  • This dosage form has the advantage that the active ingredient is largely absorbed through the oral mucosa, for example, and thus the "first-pass metabolism" that occurs with the conventional dosage form of an active ingredient in tablet form is avoided.
  • the active ingredient can be dissolved in the film, be emulsified or dispersed.
  • the active substance is absorbed particularly quickly there.
  • the absorption route via the oral mucosa is thus characterized by a relatively rapid passage of the active substance or permeation of the active substance.
  • an effective increase in blood pressure can be measured as pharmacological evidence after just two minutes.
  • OTFs are also preferred for indications that require a rapid onset of action, such as pain, nausea, dizziness, seizures, cardiac arrest, but also for the regulation of high blood pressure or blood sugar levels.
  • Suitable administration forms include, for example, textile carriers, for example made of cotton or cellulose, which are impregnated with a solution or suspension of the at least one pharmaceutically active ingredient.
  • Medical tamponades for example, such as those used in dentistry, are suitable here.
  • Clove oil or its main component eugenol, lavender oil or its main component linalool, methyl salicylate or ethanolic mixtures with glycerol and limonene are suitable as solvents.
  • Clove oils include clove blossom oil, clove leaf oil and clove stalk oil and are usually obtained by steam distillation from the various plant parts of the clove tree, Syzygium aromaticum (Myrtaceae).
  • Suitable amounts of active ingredient present in such textile carriers are, for example, 50 g per 100 g of textile carrier.
  • the mucosa represents a very hydrophilic permeation barrier (it consists of more than 90% water)
  • the active ingredients to be applied there should be at least readily water-soluble and thus generally more hydrophilic than lipophilic. This can be achieved, for example, by administering pharmaceutically acceptable salts of drugs.
  • the readily water-soluble hydrochlorides of the opioid bases fentanyl and buprenorphine, which are used instead of the bases themselves, in particular for the treatment of breakthrough pain, should be mentioned here.
  • the invention was therefore based on the object of providing a way of briefly and reversibly reducing the permeation barrier of the mucosa in order to ensure advantageous absorption of pharmaceutically active substances, in particular of lipophilic pharmaceutically active substances, in particular with a logP greater than 3 or pharmaceutically active substances with a molecular weight > 300 g/mol.
  • kits comprising at least one microneedle system and at least one dosage form for transmucosal administration of at least one pharmaceutically active substance, in particular an oral thin film comprising at least one matrix polymer and at least one pharmaceutically active substance.
  • microneedles has the advantage that the permeation barrier of the mucosa is temporarily and reversibly reduced and thus an advantageous absorption of pharmaceutically active substances, in particular of lipophilic pharmaceutically active substances, preferably with a logP greater than 3 or pharmaceutically active substances with a molecular weight > 300 g/mol.
  • microneedles is understood to mean needles, preferably made of a hard material, with a length of 5 to 1000 ⁇ m.
  • the length to diameter ratio is preferably from 5:1 to 1000:1.
  • the kit according to the invention is preferably characterized in that the at least one administration form for transmucosal administration comprises an oral thin film, the oral thin film comprising a matrix polymer and at least one pharmaceutically active substance.
  • the oral thin film may be single-layered or multi-layered.
  • the kit according to the invention is preferably characterized in that the at least one matrix polymer comprises a water-soluble and/or water-swellable polymer.
  • Water-soluble and/or water-swellable polymers include chemically very different, natural or synthetic polymers whose common feature is their solubility or swellability in water or aqueous media.
  • the kit according to the invention is preferably characterized in that the at least one matrix polymer is selected from the group consisting of starch and starch derivatives, dextrans, cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acids, polyacrylates , polyvinylpyrrolidones, polyvinyl alcohols, poly(lactide-co-glycoid), hyaluronic acid, polyethylene oxide polymers, polyacrylamides, polyethylene glycols, gelatin, collagen, alginates, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and natural gums , where this group is not final.
  • hyaluronic acid particularly preferred are hyaluronic acid, cellulose derivatives, alginates and/or poly(lactide-co-glycoid) since they are polymers of biological origin and should therefore be pharmaceutically acceptable.
  • the at least one pharmaceutically active substance contained in the oral thin film according to the invention is not subject to any restriction.
  • the kit according to the invention is preferably characterized in that the at least one pharmaceutically active substance comprises a pharmaceutically active substance with a logP>3 and/or with a molecular weight of greater than 300 g/mol.
  • the kit according to the invention is also preferably characterized in that the at least one pharmaceutically active substance has a logP > 2, preferably greater than 2.2 or 2.4 or 2.6 or 2.8 or 3.0 or 3.2 or 3, 4 or 3.6 or 3.8 or 4 or 4.2 or 4.4 or 4.6 or 4.8 or 5 or 6 or 7.
  • the n-octanol-water partition coefficient K ow (also notations such as octanol/water partition coefficient are common and correct) is a dimensionless partition coefficient known to those skilled in the art, which is the ratio of the concentrations of a chemical in a two-phase system of n-octanol and water and is therefore a measure of the hydrophobicity or hydrophilicity of a substance.
  • the logP value is the common logarithm of the n-octanol-water partition coefficient K ow .
  • Kow is greater than one when a substance is more soluble in fat-like solvents such as n-octanol and less than one when it is more soluble in water.
  • log P is positive for lipophilic substances and negative for hydrophilic substances.
  • the at least one pharmaceutically active ingredient preferably has a molecular weight of more than 300 g/mol or more than 1000 g/mol, preferably more than 1500 g/mol or more than 2000 g/mol, in particular more than 2500 g/mol or more than 3000 g/mol or more than 3500 g/mol or more than 4000 g/mol or more than 4500 g/mol or more than 5000 g/mol.
  • the kit according to the invention is preferably characterized in that the at least one pharmaceutically active ingredient has a water solubility of less than 1.0 mg/ml, preferably less than 0.5 mg/ml or 0.1 mg/ml or 0.05 mg/ml or 0.001 mg/ml (at 20°C).
  • the at least one pharmaceutically active ingredient in the kit according to the invention is preferably from the group consisting of hypnotics, sedatives, antieleptics, waking amines, psychoneurotropics, neuroleptics, neuromuscle blockers, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, Antitussives, expectorants, analgesics, thyroid hormones, sex hormones, glucocorticoid hormones, antidiabetics, antitumor agents, antibiotics, chemotherapeutics, narcotics, anti-Parkinson agents, anti-Alzheimer agents and/or triptans, this group not being final.
  • the at least one pharmaceutically active ingredient preferably comprises riociugat, tetrahydrocannabinol, cannabidinol, dronabinol, thyroid hormones and/or insulin, since these drugs have so far eluded a successful parenteral route of administration.
  • the at least one pharmaceutically active agent preferably comprises an agent from the group of emergency medications.
  • emergency medications are preferably selected from the group comprising adrenaline, amiodarone, antidiuretic hormone, apomorphine, atropine, butylscopolaminium bromide, clonazepam, dantrolene, dexamethasone, diazepam, entolimod, etomidate, flumazenil, furosemide, glucagon, glucocorticoids, glucose, haloperidol, heparin, ketamine, Levosalbutamol, lidocaine, lorazepam, metoprolol, midazolam, morphine, naloxone, nitroglycerin, obidoxime chloride, orciprenaline, organic nitrates, propofol, salbutamol, terbutaline, theophylline, tocolytic, trimedoxime bromide and/or ura
  • the amount of active ingredient in the oral thin film depends on its kind and is usually 0.01 to 70% by weight, preferably 0.1 to 50% by weight, particularly preferably 1 to 40% by weight based on that Total weight of the oral thin film.
  • the oral thin film also contains at least one excipient selected from the group consisting of colorants, flavorings, sweeteners, taste-masking agents, surfactants, enhancers, pH regulators, preservatives, antioxidants and/or emollients.
  • excipients are preferably contained in the oral thin film each in an amount of 0.001 to 20% by weight.
  • the basis weight of the oral thin film is preferably about 40 to 300 g/m 2 , more preferably about 100 to 250 g/m 2 .
  • a microneedle system also referred to as a microneedle array, preferably comprises a system comprising a multiplicity of microneedles on a carrier.
  • the needles which preferably have a length of 5 ⁇ m to 1000 ⁇ m, can be made of different materials, such as ceramics, steel, polymers or SiCh.
  • the kit according to the invention is preferably characterized in that the microneedle system is a microneedle system based on glass, SiCh, steel, ceramics, starch and starch derivatives, dextrans, cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, Polyacrylic acids, polyacrylates, polyvinylpyrrolidones, polyvinyl alcohols, poly(lactide-co-glycoid), hyaluronic acid, polyethylene oxide polymers, polyacrylamides, polyethylene glycols, gelatin, collagen, alginates, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and natural gums, this group
  • Microneedle systems based on hyaluronic acid, cellulose derivatives, alginates and/or poly(lactide-co-glycoid) are particularly preferred, since they are polymers of biological origin and should therefore be pharmaceutically compatible (except for specific allergic reactions to these substances).
  • Suitable microneedle systems are known to those skilled in the art and are described, for example, in US7658728, US7785301 or US8414548, the content of which is hereby incorporated in its entirety. Suitable microneedle systems are available, for example, under the trade name "AdminPatch” from the company “nanobioSciences” (CA, USA).
  • the kit according to the invention is preferably characterized in that the microneedle system has microneedles with a length of 100 ⁇ m to 600 ⁇ m, preferably 250 ⁇ m to 350 ⁇ m, particularly preferably about 300 ⁇ m.
  • the kit according to the invention is also preferably characterized in that the microneedle system has 30 to 400, preferably 200 to 250 microneedles per cm 2 . In another embodiment, the kit according to the invention is preferably characterized in that the microneedle system has 39 microneedles per cm 2 .
  • the present invention also relates to the kit according to the invention as described above for use in treating a patient.
  • the present invention also relates to the use of a microneedle system, as described above, for reducing or lowering the permeation barrier of a mucosa for at least one pharmaceutically active substance.
  • a mucosa includes, in particular, the human oral mucosa.
  • the at least one pharmaceutically active ingredient according to this use is to be understood as defined above.
  • the present invention further relates to a method for treating a patient, comprising the steps of a) applying a microneedle system to a site of a patient's mucosa, b) removing the microneedle system and c) applying an oral thin film comprising at least one matrix polymer and at least one pharmaceutically active Active substance on the part of the mucosa to which the microneedle system was applied in step a) and removed again in step b).
  • the mucosa preferably includes the human oral mucosa.
  • microneedle system and the at least one pharmaceutically active substance are to be understood as defined above.
  • the microneedle system is preferably pressed onto the patient's mucosa with a pressure of 1 to 5N, preferably about 3N.
  • the pressing time is preferably 2 to 20 seconds, particularly preferably 5 to 15 seconds and in particular about 10 seconds.
  • the microneedle system is then removed and the oral thin film is applied to the same site, preferably within 5 to 15 seconds, preferably within 5 seconds.
  • the present invention also relates to a method for treating a patient, comprising the steps of a) application of a microneedle system to a site of a patient's mucosa, b) simultaneous application of a dosage form for transmucosal administration of at least one pharmaceutically active agent to the side of the microneedle system which does not contact the mucosa.
  • the mucosa preferably includes the human oral mucosa.
  • microneedle system and the at least one pharmaceutically active substance are to be understood as defined above.
  • the microneedle system is preferably pressed onto the patient's mucosa with a pressure of 1 to 5N, preferably about 3N.
  • the administration form for the transmucosal administration of at least one pharmaceutically active substance can be, for example, a textile carrier, such as a tamponade used in dentistry, which is impregnated with a solution or suspension of the at least one pharmaceutically active substance.
  • the present invention also relates to a biodegradable microneedle system comprising at least one pharmaceutically active ingredient and at least one biodegradable polymer.
  • microneedles is understood to mean needles, preferably made of a hard material, with a length of 5 to 1000 ⁇ m. The length to diameter ratio is preferably from 5:1 to 1000:1.
  • microneedle system After the microneedle system has been administered, it dissolves in the patient's mouth, releasing the pharmaceutically active ingredient it contains.
  • the biodegradable microneedle system according to the invention is further preferably characterized in that the microneedle system has microneedles with a length of 100 ⁇ m to 500 ⁇ m, preferably 250 ⁇ m to 350 ⁇ m and/or 50 to 400, preferably 200 to 250 microneedles per cm 2 .
  • the biodegradable microneedle system according to the invention is further preferably characterized in that the at least one biodegradable polymer is a polymer based on sugar, hyaluronic acid or polyvinylpyrrolidone.
  • the at least one pharmaceutically active substance contained in the biodegradable microneedle system according to the invention is not subject to any restriction.
  • the biodegradable microneedle system according to the invention is preferably characterized in that the at least one pharmaceutically active substance comprises a pharmaceutically active substance with a logP>3 and/or with a molecular weight of greater than 300 g/mol.
  • the biodegradable microneedle system according to the invention is also preferably characterized in that the at least one pharmaceutically active ingredient has a logP > 2, preferably greater than 2.2 or 2.4 or 2.6 or 2.8 or 3.0 or 3.2 or 3 ,4 or 3.6 or 3.8 or 4 or 4.2 or 4.4 or 4.6 or 4.8 or 5 or 6 or 7.
  • the n-octanol-water partition coefficient K ow (also spellings such as octanol/water partition coefficient are common and correct) is a dimensionless partition coefficient known to those skilled in the art that indicates the ratio of the concentrations of a chemical in a two-phase system of n-octanol and water and thus a measure of the hydrophobicity or hydrophilicity of a substance is.
  • the logP value is the common logarithm of the n-octanol-water partition coefficient K ow .
  • Kow is greater than one when a substance is more soluble in fat-like solvents such as n-octanol and less than one when it is more soluble in water.
  • log P is positive for lipophilic substances and negative for hydrophilic substances.
  • the at least one pharmaceutically active ingredient preferably has a molecular weight of more than 300 g/mol or more than 1000 g/mol, preferably more than 1500 g/mol or more than 2000 g/mol, in particular more than 2500 g/mol or more than 3000 g/mol or more than 3500 g/mol or more than 4000 g/mol or more than 4500 g/mol or more than 5000 g/mol.
  • the biodegradable microneedle system according to the invention is preferably characterized in that the at least one pharmaceutically active substance has a water solubility of less than 1.0 mg/ml, preferably less than 0.5 mg/ml or 0.1 mg/ml or 0.05 mg/ml. ml or 0.001 mg/ml (at 20°C).
  • the at least one pharmaceutically active ingredient is preferably not present in the biodegradable microneedle system in the form of a salt.
  • the at least one pharmaceutically active ingredient in the biodegradable microneedle system according to the invention is preferably from the group consisting of hypnotics, sedatives, antieleptics, waking amines, psychoneurotropics, neuroleptics, neuromuscle blockers, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, Vasopressors, antitussives, expectorants, analgesics, thyroid hormones, sex hormones, glucocorticoid hormones, antidiabetics, antitumor agents, antibiotics, chemotherapeutics, narcotics, anti-Parkinson agents, anti-Alzheimer agents and/or triptans, this group not being final.
  • the at least one pharmaceutically active agent preferably comprises riociugat, tetrahydrocannabinol, cannabidinol, dronabinol, thyroid hormones, apomorphine hydrochloride, adrenaline hydrogen tartrate and/or insulin, since these agents have hitherto eluded a successful parenteral route of administration.
  • the at least one pharmaceutically active agent preferably comprises an agent from the group of emergency medications.
  • emergency medications are preferably selected from the group comprising adrenaline, amiodarone, antidiuretic hormone, apomorphine, atropine, butylscopolaminium bromide, clonazepam, dantrolene, dexamethasone, diazepam, entolimod, etomidate, flumazenil, furosemide, glucagon, glucocorticoids, glucose, haloperidol, heparin, ketamine, Levosalbutamol, lidocaine, lorazepam, metoprolol, midazolam, morphine, naloxone, nitroglycerin, obidoxime chloride, orciprenaline, organic nitrates, propofol, salbutamol, terbutaline, theophylline, tocolytic, trimedoxime bromide and/or ura
  • the amount of active substance in the biodegradable microneedle system according to the invention depends on its type and is usually 0.01 to 70% by weight, preferably 0.1 to 50% by weight, particularly preferably 1 to 40% by weight, based on the total weight of the oral thin film.
  • the biodegradable microneedle system according to the invention also contains at least one auxiliary selected from the group consisting of dyes, flavorings, sweeteners, taste-masking agents, surfactants, enhancers, pH regulators, preservatives, antioxidants and/or plasticizers.
  • excipients are preferably contained in the oral thin film each in an amount of 0.001 to 20% by weight.
  • Eugenol is preferably present as an enhancer in the biodegradable microneedle system according to the invention.
  • the present invention further relates to a biodegradable microneedle system as described above for use as a medicament.
  • the present invention also relates to a biodegradable microneedle system as described above for use as a medicament for application to the oral mucosa of a mammal, in particular for application to the human oral mucosa.
  • FIG. 3 Comparison of in vitro permeation profiles of a saturated
  • FIG. 4 Comparison of in vitro permeation profiles of a saturated
  • the active substance flux after pretreatment with a microneedle system is higher by a factor of 2.0 compared to administration without pretreatment.
  • FIG. 5 Comparison of in vitro permeation profiles of a self-dissolving microneedle system applied directly into the mucosa and loaded with sumatriptan succinate on the in vitro mucosa model according to example 5.
  • the comparative example was the same system but applied inversely, ie with the needle side up and not invading the mucosa.
  • To the in vivo contact pressure in the oral cavity To simulate, the microneedle systems were weighed down from above with lead balls as weights, both in the comparison and in the example of the invention.
  • the active substance flux with the microneedle system applied into the mucosa is higher by a factor of 2.0 compared to the system without penetrating it.
  • the 1st permeation value after 10 minutes for the example according to the invention is higher by a factor of about 4 compared to the comparative example.
  • FIG. 6 Comparison of in vitro permeation profiles of a self-dissolving microneedle system applied directly into the mucosa and loaded with adrenaline hydrogen tartrate on the in vitro mucosa model according to example 6.
  • the comparative example was the same system but applied inversely, ie with the needle side up and not invading the mucosa.
  • the microneedle systems were weighed down from above with lead balls as weights, both in the comparison and in the example according to the invention.
  • the active substance flux with the microneedle system applied into the mucosa is four times higher than with the system without penetrating it.
  • FIG. 7 Comparison of in vitro permeation profiles of a self-dissolving microneedle system applied directly into the mucosa and loaded with salbutamol sulfate on the in vitro mucosa mode according to example 7.
  • the comparative example was the same system but applied inversely, ie with the needle side up and not invading the mucosa.
  • the microneedle systems were weighed down from above with lead balls as weights, both in the comparison and in the example according to the invention.
  • the active substance flux with the microneedle system applied into the mucosa is higher by a factor of 2 compared to the system without penetrating it.
  • FIG. 8 Comparison of in vitro permeation profiles of a self-dissolving microneedle system applied directly into the mucosa and loaded with apomorphine hydrochloride on the in vitro mucosa model according to example 8.
  • the comparison example was the same system but applied inversely, ie with the needle side up and not invading the mucosa.
  • To the in vivo contact pressure in the oral cavity To simulate, the microneedle systems were weighed down from above with lead balls as weights, both in the comparison and in the example of the invention.
  • the active substance flux with the microneedle system applied into the mucosa is higher by a factor of 3 compared to the system without penetrating it.
  • FIG. 9 Comparison of in vitro permeation profiles of a self-dissolving microneedle system applied directly into the mucosa and loaded with sumatriptan base on the in vitro mucosa model according to example 9.
  • the comparative example was the same system but applied inversely, ie with the needle side up and not invading the mucosa.
  • the microneedle systems were weighed down from above with lead balls as weights, both in the comparison and in the example according to the invention. An active ingredient flux could not be measured in the comparative example. In contrast, a high active substance flux could be observed in the microneedle system applied to the mucosa.
  • FIG. 10 Comparison of in vitro permeation profiles of an oral thin film containing ulipristal acetate on the in vitro mucosa model according to example 10. A flux of active substance could only be observed after pretreatment with a microneedle system. Without pretreatment, no permeated active substance could be detected.
  • the donor and acceptor media used were each selected with regard to the solubility of the example active substances
  • the donor solutions used were applied directly to the mucosa surface using pipettes.
  • the amount of donor solutions for example active substances 1, 2 and 3 was 150 ⁇ l in each case.
  • the contact pressure was 3 N by thumb pressure, controlled using a table scale.
  • the pressing time was 10 see.
  • Example 4 the donor solution was injected (900 ⁇ l) onto or into the dental tamponade used (length and diameter each 1 cm).
  • the microneedle system was fixed to the underside of the tamponade and applied together perpendicularly through the head of the Franz cells to the mucosa surface and fixed in a fixed position with a suitable plug and with moderate pressure.
  • Example 5-9 drug-loaded biodegradable microneedle systems were evaluated using Franz diffusion cells as described above.
  • Example 10 an oral thin film containing an active ingredient was applied to the mucosa surface that had been pretreated analogously to Examples 1 to 3 with the “AdminPatchTM” microneedle system (needle length 600 ⁇ m).
  • a saturated solution of riociguat in clove oil (Primavera® bio clove bud, Oy-Mittelberg, Germany) was used as the donor solution.
  • Dermatosed skin from the esophagus of a pig with a layer thickness of 400 ⁇ m was used as a skin model.
  • a saturated solution of human insulin in natural human saliva was used as the donor solution. Dermatosed skin from the esophagus of a pig with a layer thickness of 400 ⁇ m was used as a skin model.
  • Phosphate buffer pH 5.5
  • Tween® 20 an organic solubilizer for maintaining “sink” conditions
  • a saturated solution of tetrahydrocannabinol in clove oil (Primavera® bio Nelkenknospe, Oy-Mittelberg, Germany) was used as the donor solution.
  • Dermatosed skin from the esophagus of a pig with a layer thickness of 400 ⁇ m was used as a skin model.
  • CBD cannabidiol
  • Phosphate buffer pH 5.5
  • Tween® 20 an organic solubilizer for maintaining “sink” conditions
  • a saturated solution of tetrahydrocannabinol in clove oil (Primavera® bio Nelkenknospe, Oy-Mittelberg, Germany) was used as the donor solution. Dermatosed skin from the esophagus of a pig with a layer thickness of 400 ⁇ m was used as a skin model.
  • Phosphate buffer pH 7.4 without further additives was used as the acceptor medium; As a water-soluble salt, sumatriptan succinate is very soluble in this acceptor.
  • the donor system was a polyvinylpyrrolidone-based microneedle system loaded with sumatripan succinate, which dissolves on contact with water and temperatures > 32 °C.
  • sumatriptan succinate, polyvinylpyrrolidone, polysorbate 80 and glycerol were dissolved in water in proportions of 5:20:1:1:73 (each in % by weight).
  • the final solution was poured into silicone needle-negative matrices, the surface of which was vapor-deposited with a thin layer of platinum.
  • the negative matrices were then dried overnight at room temperature. After the drying process, the dried microneedle systems were carefully pressed out of the matrices and stored away from moisture until further use.
  • the active ingredient content was 4.25 mg sumatriptan succinate per 0.785 cm 2 system or 5.41 mg/cm 2 .
  • Dermatosed skin from the esophagus of a pig with a layer thickness of 400 ⁇ m was used as a skin model.
  • microneedle system remained in the mucosa throughout the permeation period, with the cell head also being filled with lead balls to reduce the in vivo contact pressure (e.g. between the lower jaw and the oral mucosa) in the to simulate the oral cavity.
  • a separating film based on siliconized PET polyethylene terephthalate was placed in between to protect the self-dissolving microneedle system from the lead bullets.
  • Phosphate buffer pH 6.0 containing 0.1% by weight of L-ascorbic acid was used as the acceptor medium; Adrenaline hydrogen tartrate is very soluble in this acceptor.
  • the biodegradable microneedle system was produced and used analogously to example 5, with adrenaline hydrogen tartrate being used as the pharmaceutically active ingredient.
  • Phosphate buffer pH 7.4 without further additives was used as the acceptor medium; Salbutamol sulfate is very soluble in this acceptor.
  • biodegradable microneedle system was produced and used analogously to example 5, with salbutamol sulfate being used as the pharmaceutically active ingredient.
  • Phosphate buffer pH 6.8 containing 0.1% by weight of L-ascorbic acid was used as the acceptor medium; Apomorphine hydrochloride is very soluble in this acceptor.
  • biodegradable microneedle system was produced and used analogously to example 5, with apomorphine hydrochloride being used as the pharmaceutically active ingredient.
  • Phosphate buffer pH 6.0
  • Tween 20 was used as the acceptor medium; Sumatriptan base is very soluble in this acceptor.
  • the biodegradable microneedle system was produced and used analogously to example 5, with sumatriptan base being used as the pharmaceutically active ingredient.
  • the preparation of the oral thin film was as follows:
  • the oral thin film had the following composition (in percent by mass):
  • Phosphate buffer pH 7.4 with 2% by weight Tween 20 was used as the acceptor medium; Ulipristal acetate is very soluble in this acceptor.
  • the surface of the mucosa was treated with the microneedle system "AdminPatchTM” (needle length 600 pm) from the company “nanobioSciences” (CA, USA) made of steel with a contact pressure of 3 N by thumb pressure, controlled using a table scale for 10 seconds.
  • administerTM needle length 600 pm
  • CA nanobioSciences
  • the oral thin film was applied, preferably with the simultaneous addition of 100 ⁇ l of Glandosane® to loosen the oral thin film.
  • Oral thin films should always be dissolved as quasi-solids.
  • the means for dissolving should preferably simulate the naturally produced saliva which causes the dissolving or at least dissolving of the oral thin film in vivo.
  • Glandosane® was used for reasons of better solubility.
  • Glandosane® artificial saliva is a spray for Use in the oral cavity for dry mouth and for oral care in the intensive care unit.

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Abstract

L'invention concerne un kit qui comprend au moins un système de microaiguille et au moins une forme d'administration pour une administration par voie transmucosale d'au moins un ingrédient pharmaceutiquement actif qui comprend de préférence un film mince oral, à utiliser dans le traitement d'un patient, l'utilisation d'un système de microaiguille pour réduire la barrière de perméation d'une muqueuse pour au moins un ingrédient pharmaceutiquement actif, et une méthode pour traiter un patient ; un premier système de microaiguille étant appliqué sur une région d'une muqueuse d'un patient puis étant retirée, un film mince oral qui comprend au moins un polymère matriciel et au moins un ingrédient pharmaceutiquement actif étant ensuite appliqué sur la région de la muqueuse où le système de microaiguille a préalablement été appliqué puis retiré, ou le système de microaiguille étant appliqué sur la muqueuse simultanément avec une forme d'administration pour une administration transmucosale d'au moins un ingrédient pharmaceutiquement actif. L'invention concerne également un système de microaiguille biodégradable qui comprend au moins un ingrédient pharmaceutiquement actif et au moins un polymère biodégradable.
EP21772669.4A 2020-08-28 2021-08-25 Perforation de la muqueuse Pending EP4203916A1 (fr)

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DE102020122557.1A DE102020122557A1 (de) 2020-08-28 2020-08-28 Mucosa-Perforierung
PCT/DE2021/100715 WO2022042799A1 (fr) 2020-08-28 2021-08-25 Perforation de la muqueuse

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KR (1) KR20230058452A (fr)
CN (1) CN116056738A (fr)
AU (1) AU2021334058A1 (fr)
BR (1) BR112023003399A2 (fr)
CA (1) CA3192247A1 (fr)
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US7658728B2 (en) 2006-01-10 2010-02-09 Yuzhakov Vadim V Microneedle array, patch, and applicator for transdermal drug delivery
JP5049268B2 (ja) * 2006-04-07 2012-10-17 久光製薬株式会社 マイクロニードルデバイスおよびマイクロニードル付き経皮薬物投与装置
US7785301B2 (en) 2006-11-28 2010-08-31 Vadim V Yuzhakov Tissue conforming microneedle array and patch for transdermal drug delivery or biological fluid collection
EP2271301A4 (fr) 2008-03-27 2014-07-02 Agigma Inc Procédés et compositions pour la délivrance d agents
US20110150946A1 (en) * 2008-08-22 2011-06-23 Al-Ghananeem Abeer M Transdermal Delivery of Apomorphine Using Microneedles
KR101033514B1 (ko) * 2009-06-02 2011-05-09 (주)마이티시스템 유연한 미세바늘 패치 시스템 및 그 제작방법
US20160128947A1 (en) 2012-10-22 2016-05-12 Stc. Unm Bioadhesive films for local and/or systemic delivery
JP2017514646A (ja) * 2015-04-03 2017-06-08 ソーチョウ ユニバーシティー 膨潤型シルクフィブロインマイクロニードル薬物送達システム及びその製造方法
US20190022022A1 (en) 2016-05-05 2019-01-24 Aquestive Therapeutics, Inc. Pharmaceutical compositions with enhanced permeation
CN209316551U (zh) * 2018-05-24 2019-08-30 优微（珠海）生物科技有限公司 一种可溶性微针贴片
CN108837299B (zh) * 2018-07-18 2020-08-07 武汉大学 一种智能调节血糖的微针贴片及其制备方法
DE102019100483A1 (de) * 2019-01-10 2020-07-16 Lts Lohmann Therapie-Systeme Ag Oraler Dünnfilm

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BR112023003399A2 (pt) 2023-04-11
DE102020122557A1 (de) 2022-03-03
WO2022042799A1 (fr) 2022-03-03
CA3192247A1 (fr) 2022-03-03
US20240024647A1 (en) 2024-01-25
JP2023546646A (ja) 2023-11-07
KR20230058452A (ko) 2023-05-03
MX2023002424A (es) 2023-03-22
AU2021334058A1 (en) 2023-05-11

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