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
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
  • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
  • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
• • 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
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
  • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
  • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
  • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
  • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
• • 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
  • A61K31/12—Ketones
• • 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
  • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
  • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• • 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
• • 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
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
  • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
  • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches

Definitions

• the present invention relates to a dosage form for transdermal administration of at least one pharmaceutically active ingredient with a logP> 3, comprising dimethylethyleneurea as a penetration accelerator, the use of such a dosage form as a medicament and the use of dimethylethyleneurea as a penetration accelerator to increase the skin penetration of pharmaceutically active ingredients with a logP> 3.
• Dosage forms for transdermal administration of at least one pharmaceutically active agent have found widespread use in the last few years for the treatment of numerous diseases, since they are associated with advantages over other administration forms.
• the stomach, intestines and liver are spared by bypassing the gastrointestinal tract.
• the first-pass effect can be avoided and compliance increased, since the patient does not have to take tablets regularly.
• a disadvantage is that the skin, as an absorption organ, serves as a protective barrier from its evolutionary development and that therefore only a limited number of active substances to be applied transdermally are available which, due to their physico-chemical properties, are capable of permeation through the skin until they reach the systemic blood circulation.
• Permeability is the permeability of solids (also porous), especially thin partitions, for certain substances (gases, liquids, dissolved molecules, ions or atoms).
• the permeability of human or animal skin for small molecules, in particular for active pharmaceutical ingredients In technical terms, permeation is the process of wandering through or penetrating one substance through another. The term is often used in connection with the migration of cosmetic or pharmaceutical active ingredients into or through the skin.
• the classic measures include increasing the amount of permeation using chemical penetration accelerators.
• All penetration accelerators that can potentially be considered should be distinguished by the fact that they are non-toxic, non-irritating to the skin and non-allergenic. Above all, they should not produce any pharmacological effects of their own, either on the skin or in the organism. Penetration enhancers should be chemically and physically compatible with the drug substance concerned and other auxiliary substances in the dosage form.
• the ideal penetration accelerator should also be characterized by the fact that it also acts as a solvent for the drug in question if it does not dissolve in the intended transdermal vehicle, for example due to its physico-chemical properties.
• penetration accelerators can be divided into six classes without going into the individual modes of action at this point.
• Alcohols and polyols e.g. ethanol, propylene glycol, glycerol
• Fatty acids, terpenes and fatty acid derivatives e.g. oleic acid
• weakly surfactants that contain polar groups of suitable size e.g. anionic surfactants, such as sodium lauryl sulfate
• the object of the present invention was therefore to provide a dosage form for transdermal administration of at least one pharmaceutically active ingredient with a logP> 3, comprising at least one penetration accelerator, with which a satisfactory rate of permeation of the at least one pharmaceutically active ingredient into the patient's skin can be achieved can.
• the penetration accelerator should be chemically and physically compatible with the relevant active pharmaceutical ingredient and other auxiliary substances of the dosage form.
• the penetration accelerator should also be distinguished by the fact that it simultaneously acts as a solvent for the pharmaceutically active substance in question if it does not dissolve in the intended transdermal vehicle, for example due to its physico-chemical properties.
• a dosage form for transdermal administration of at least one pharmaceutically active agent comprising at least one pharmaceutically active agent with a logP> 3 and at least one penetration accelerator, which is characterized in that the at least one penetration accelerator comprises dimethylethylene urea.
• penetration accelerator penetration accelerator, penetration enhancer, permeation accelerator, permeation enhancer, penetration enhancer, permeation enhancer and enhancer can be used synonymously.
• DMEH Dimethylethyleneurea
• 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 the person skilled in the art, which 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.
• the logP value is the decadic logarithm of the n-octanol-water partition coefficient K ow .
• K ow is greater than one if a substance is more soluble in fat-like solvents such as n-octanol, less than one if it is more soluble in water. Accordingly, log P is positive for lipophilic and negative for hydrophilic substances.
• the form of the dosage form for transdermal administration of at least one pharmaceutically active agent is in principle not restricted.
• the dosage form according to the invention is preferably characterized in that it comprises a transdermal therapeutic system, a gel, a lotion, an ointment and / or a cream.
• a transdermal therapeutic system (also called transdermal patch) is understood to mean a system to be applied to the skin, preferably a patch, with a fixed application area, which can deliver a pharmaceutically active agent to the body of a patient in a controlled manner, preferably in terms of time and quantity.
• Such systems generally have a backing layer as the backing layer, which protects the plaster and its contents from the outside and is optionally printed with information.
• a backing layer as the backing layer, which protects the plaster and its contents from the outside and is optionally printed with information.
• On the skin side it is preferably provided with a release liner, which covers the sticky side of the system. The release liner is removed before the system is glued on and is often siliconized for easier removal.
• matrix plasters matrix plasters
• membrane systems also called reservoir or depot systems or reservoir or depot plasters
• the active ingredient is contained in a matrix consisting of one or more layers, which lies directly on the skin with the help of an adhesive layer.
• the Matrix is also the adhesive layer. The rate of diffusion of the active ingredient out of the matrix determines the rate of resorption.
• the active ingredient in membrane systems, there is a reservoir of the active ingredient under a carrier film, the active ingredient being released from the reservoir into the skin in a controlled manner through a porous membrane.
• the active substance is preferably present in the reservoir as a solution or suspension.
• a carrier material such as, for example, a flow, which has been soaked with this solution and / or suspension, can preferably serve as a reservoir.
• transdermal therapeutic system for the patient are a safe, reliable, exact and painless dosage of active pharmaceutical ingredients and the simpler therapy for children, elderly and patients in need of care. Furthermore, transdermal therapeutic systems are ideal for patients with swallowing difficulties and with extended intervals between intake, especially in the case of multi-day patches.
• transdermal therapeutic system on the manufacturer side are the possible formulation of pharmaceutically active ingredients with only low oral bioavailability, a controlled, even supply of pharmaceutically active ingredients without active ingredient peaks, good control of the drug dosage by varying the area, no loss of active ingredient by avoidance first-pass metabolism in the liver and no breakdown of the active ingredient in the gastrointestinal tract.
• Gels usually include gelled liquids. They are preferably produced with suitable swelling agents (gel formers). These include, for example, celluloses, starches, carbomers, gelatine, xanthan, bentonite, agar and / or pectin.
• suitable swelling agents include, for example, celluloses, starches, carbomers, gelatine, xanthan, bentonite, agar and / or pectin.
• Gels can be clear or opaque.
• Gels are used, among other things, for the local or systemic administration of active ingredients and for moist wound treatment.
• a lotion is an externally applied liquid, aqueous or aqueous alcoholic preparation with suspended or emulsified pharmaceutically active ingredients and possibly auxiliaries.
• Lotions are usually more liquid than creams or ointments and are therefore easier to apply to large areas of the skin.
• a lotion is an externally applied oil-in-water emulsion or water-in-oil emulsion. It is very light and does not smear.
• Lotions are used, among other things, for the local or systemic administration of active ingredients and for moist wound treatment.
• An ointment preferably a suspension ointment, is a semi-solid preparation for external use.
• Ointments preferably consist of a single-phase base, in which solid or liquid substances can be dispersed.
• Ointments can also contain emulsifiers and water.
• fatty oils, fats, waxes, petroleum products such as petrolatum and paraffins, triglycerides and / or macrogols (PEG) can be used.
• Ointments are used, among other things, for the local or systemic administration of active ingredients and for moist wound treatment.
• a cream is a semi-solid preparation, usually for use on the skin.
• a cream is preferably a multiphase preparation which consists of a lipophilic and an aqueous phase and contains at least one pharmaceutically active ingredient.
• a cream is used, among other things, for the local or systemic administration of active ingredients and for moist wound treatment.
• the dosage form according to the invention in the form of a gel, a lotion, an ointment and / or a cream is preferably characterized in that the at least one penetration accelerator is dimethylethyleneurea in an amount of 10 to 30% by weight, preferably 12 to 25% by weight , particularly preferably from 15 to 18% by weight, based on the total weight.
• the dosage form according to the invention is preferably characterized in that the at least one pharmaceutically active agent has a logP> 3, preferably greater than 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 dosage form according to the invention is preferably characterized in that the at least one pharmaceutically active agent with a logP> 3 has a water solubility of less than 0.01 mg / ml (at 20 ° C.).
• the water solubility of the at least one pharmaceutically active ingredient is preferably less than 0.005 mg / ml, particularly preferably less than 0.001 mg / ml (at 20 ° C.).
• the at least one pharmaceutically active agent preferably has a molecular weight of more than 300 g / mol, preferably more than 350 g / mol or more than 400 g / mol, in particular more than 450 g / mol.
• the dosage form according to the invention is preferably characterized in that the at least one pharmaceutically active agent from the group consisting of hypnotics, sedatives, antieleptics, wake-up amines, psychoneurotropics, neuroleptics, neuro-muscle blockers, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, hypotensics, diuretics , Vasopressors, antitussives, expectorants, analgesics, thyroid hormones, sex hormones, glucocorticoid hormones, antidiabetics, Antitumor agents, antibiotics, chemotherapeutics, narcotics, anti-Parkinson agents, anti-Alzheimer's agents and / or triptans is selected.
• the at least one pharmaceutically active agent from the group consisting of hypnotics, sedatives, antieleptics, wake-up amines, psychoneurotropic
• the at least one pharmaceutically active agent is particularly preferably selected from the group consisting of sedatives. Examples are olanzepine, curcumin and felodipine.
• the at least one pharmaceutically active agent is particularly preferably not selected from the group comprising cannabinoids such as cannabidiol and / or cannbidivarol.
• the dosage form according to the invention is preferably characterized in that the dosage form represents a transdermal therapeutic system, the transdermal therapeutic system having a backing layer and a matrix layer containing the at least one pharmaceutically active agent with a logP> 3.
• the penetration accelerator dimethylethylene urea is preferably contained in the matrix layer.
• the backing layer is preferably impermeable to the at least one pharmaceutically active agent.
• the type of consideration is not limited.
• the consideration can include plastic or metal foils but also knitted fabrics, knitted fabrics or nonwovens.
• PET polyethylene terephthalate
• the transdermal therapeutic system according to the invention preferably has a removable protective layer on the side of the matrix layer that is not the consideration.
• the same materials can be used for the removable protective layer as for the backing layer, provided that they have been given a suitable surface treatment, such as e.g. B. siliconization, are removable.
• the transdermal therapeutic system according to the invention is preferably characterized in that the at least one penetration accelerator is dimethylethyleneurea in an amount of 10 to 30% by weight, preferably 12 to 25% by weight, particularly preferably 15 to 18% by weight or of 18% by weight to 25% by weight, based on the active substance-containing matrix layer, is present in the matrix layer.
• the transdermal therapeutic system according to the invention is preferably characterized in that the ratio of the penetration accelerator dimethylethyleneurea to the at least one pharmaceutically active agent is 1: 1 or> 1: 1. Particularly suitable are ratios of the penetration accelerator dimethylethylene urea to the at least one pharmaceutically active agent of 1.5: 1.
• the transdermal therapeutic system according to the invention is preferably characterized in that the matrix layer comprises at least one polymer selected from the group consisting of polyacrylates and / or polymethacrylates, natural and / or synthetic rubbers, polysiloxanes, styrene-butadiene block copolymers, isobutylene and / or ethylene-vinyl acetate copolymers.
• the transdermal therapeutic system according to the invention is preferably characterized in that the matrix layer comprises at least one polymer selected from the group consisting of silicone-based pressure-sensitive adhesives or silicone pressure-sensitive adhesives, in particular amine-resistant silicone pressure-sensitive adhesives.
• the silicone pressure-sensitive adhesives which can be used according to the invention are preferably pressure-sensitive adhesives based on silicone polymers, such as a dimethiconol / trimethylsiloxysilicate cross-polymer and / or a trimethylsilyl-treated dimethiconol / trimethylsiloxysilicate cross-polymer, which preferably contains at least 30% by weight, in particular 35 to 95% by weight, particularly preferably 40 to 90% by weight or 40 to 60% by weight or 45 to 55% by weight Silicone polymer (s), based on the silicate, contain.
• silicone polymers such as a dimethiconol / trimethylsiloxysilicate cross-polymer and / or a trimethylsilyl-treated dimethiconol / trimethylsiloxysilicate cross-polymer, which preferably contains at least 30% by weight, in particular 35 to 95% by weight, particularly preferably 40 to 90% by weight or 40 to 60% by weight or 45 to 55% by weight Silicone poly
• the silicone pressure-sensitive adhesives that can be used according to the invention are pressure-sensitive adhesives that are produced on the basis of silicone polymers, such as dimethiconol / trimethylsiloxysilicate crosspolymers and / or a trimethylsilyl-treated dimethiconol / trimethylsiloxysilicate crosspolymers, which are preferably 40% by weight silicone polymers and contain 60% by weight of silicate.
• silicone polymers such as dimethiconol / trimethylsiloxysilicate crosspolymers and / or a trimethylsilyl-treated dimethiconol / trimethylsiloxysilicate crosspolymers, which are preferably 40% by weight silicone polymers and contain 60% by weight of silicate.
• Such an adhesive can be referred to as “medium tack adhesives”.
• the silicone pressure-sensitive adhesives that can be used according to the invention are pressure-sensitive adhesives that are produced on the basis of silicone polymers, such as dimethiconol / trimethylsiloxysilicate cross-polymers and / or a trimethylsilyl-treated dimethiconol / trimethylsiloxysilicate cross-polymer, which is preferably 45 wt % Silicone polymer and 55% by weight silicate.
• silicone polymers such as dimethiconol / trimethylsiloxysilicate cross-polymers and / or a trimethylsilyl-treated dimethiconol / trimethylsiloxysilicate cross-polymer, which is preferably 45 wt % Silicone polymer and 55% by weight silicate.
• Such an adhesive can be referred to as a "high-tack adhesive”.
• silicone pressure-sensitive adhesives can also be used, for example a 1: 1 (by weight) ratio of a “medium tack adhesive” and a “high tack adhesive” as described above.
• All silicone pressure-sensitive adhesives as described above preferably contain n-heptane as a solvent.
• the silicone pressure-sensitive adhesives described above are preferably present in an amount of from 50 to 80% by weight, preferably from about 60 to 75% by weight, solids content in the respective solvent, preferably in n-heptane.
• the silicone pressure sensitive adhesives have a peel adhesion of about 700 g / cm for the high tack adhesive and / or 900 g / cm for the medium tack adhesive, as defined above.
• the silicone pressure sensitive adhesives have a shear value of about 14 kg / 6.3 cm 3 for the high tack adhesive and about 17 kg / 6.3 cm 3 for the medium tack adhesives, as defined above.
• the silicone pressure sensitive adhesives have a viscosity at 0.01 rad / s and 30 ° C (P) of about 5 ⁇ 10 6 P for the adhesive with high tack and about 1 ⁇ 10 8 P for the adhesives with medium tack, as defined above.
• Silicone pressure-sensitive adhesives and in particular silicone hot-melt pressure-sensitive adhesives, which are suitable for use in the context of the present invention and as described above, are known to the person skilled in the art and are commercially available.
• Suitable silicone pressure sensitive adhesives for use in the present invention include, for example, the hot melt pressure sensitive adhesives BIO-PSA 7-4201 and / or BIO-PSA 4301 from Dow Corning.
• BIO-PSA 7-4201 is a "medium tack adhesive”
• BIO-PSA 7-4301 is a "high tack adhesive” as defined above.
• BIO-PSA 7-4301 which is a "high tack adhesive" as defined above, is particularly preferred.
• These are preferably pressure-sensitive adhesive polymers. This has the advantage that no additional adhesive layer has to be applied to the matrix in order to fix the transdermal therapeutic system on the patient's skin.
• the transdermal therapeutic system is preferably fixed on the patient's skin by a further adhesive layer.
• the transdermal therapeutic system according to the invention is preferably characterized in that the at least one polymer in an amount of 40 to 98% by weight, preferably 50 to 80% by weight, particularly preferably 60 to 75% by weight, based on the active ingredient-containing matrix layer is present in the matrix layer, the matrix layer preferably being understood as a single-layer matrix, ie the TTS according to the invention is not a multilayer system.
• the dosage form according to the invention is preferably a transdermal therapeutic system designed as a membrane system, the at least one pharmaceutically active agent being present in the matrix layer in a reservoir, from which the at least one pharmaceutically active agent is released in a controlled manner through a porous control membrane covering the reservoir can be.
• matrix layer also includes the term reservoir.
• control membrane comprises a polymer film
• the polymer on which the polymer film is based is selected from polyethylene, polypropylene, polyurethane, silicone and / or copolymers of ethylene and vinyl acetate.
• the transdermal therapeutic system according to the invention is preferably characterized in that the matrix layer comprises further auxiliaries selected from the group consisting of plasticizers, crystallization inhibitors, stabilizers, antioxidants and / or neutralizers.
• Each of these auxiliaries can be present in the matrix layer in an amount of 0.1 to 10% by weight, based on the weight of the matrix layer.
• the transdermal therapeutic system according to the invention is preferably characterized in that the at least one pharmaceutically active agent is present in the matrix layer in an amount of 0.1 to 50% by weight, based on the weight of the matrix layer.
• the transdermal therapeutic system according to the invention is preferably characterized in that the transdermal therapeutic system has a loading with the at least one pharmaceutically active agent of greater than 6 mg / cm 2 .
• the transdermal therapeutic system according to the invention is preferably characterized in that the transdermal therapeutic system has a load with the at least one pharmaceutically active agent of 6 mg / cm 2 to 8.5 mg / cm 2 or from 7.5 to 8.5 mg / cm 2 .
• the area here preferably relates to the area of the matrix layer or of the reservoir.
• the penetration accelerator dimethylethylene urea can be used alone or in combination with other penetration accelerators.
• Other suitable penetration accelerators include fatty acids and / or fatty acid esters, such as pentanoic acid, hexanoic acid, octanoic acid, nonanoic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, isoverlinic acid, neoheptonic acid, oleic acid, neoheptonic acid, palmitic acid, isostearic acid , Petroselinic acid, elaidic acid, oleic acid, arachidonic acid, gadoleic acid, erucic acid, ethyl acetate, methyl propylate, butyl acetate, methyl valerate, diethyl sebacitate, methyl laurate, ethyl oleate, is
• the dosage form according to the invention is preferably characterized in that no penetration accelerators from the class of pyrrolidones, in particular N-methyl-2-pyrrolidone, sulfoxides, in particular dimethyl sulfoxide (DMSO), formamides, in particular dimethylformamide (DMF), and / or l-dodecylazacycloheptane -2-one or laurocapran (azone) and / or derivatives are present in the dosage form.
• pyrrolidones in particular N-methyl-2-pyrrolidone
• sulfoxides in particular dimethyl sulfoxide (DMSO)
• formamides in particular dimethylformamide (DMF)
• DMF dimethylformamide
• azone laurocapran
• the dosage form according to the invention is particularly preferably characterized in that only dimethylethylene urea is contained in the dosage form as a penetration accelerator.
• the present invention also relates to a dosage form as described above for use as a medicament.
• the present invention also relates to the use of dimethylethylene urea as a penetration accelerator for increasing the skin penetration of pharmaceutically active ingredients with a logP> 3, preferably greater than 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. Description of the characters:
• FIG. 1 Comparison of in vitro permeation profiles of progesterone in different transdermal enhancer systems.
• FIG. 2 Comparison of in vitro permeation profiles of felodipine in different transdermal enhancer systems.
• FIG. 3 Comparison of in vitro permeation profiles of curcumin in different transdermal enhancer systems.
• FIG. 4 Comparison of in vitro permeation profiles of olanzapine in different transdermal enhancer systems.
• Carrier film e.g. made of polyethylene terephthalate
• one layer adhesive matrix polymer contains the active ingredient, enhancer and polymer excipient.
• FIG. 6 Schematic representation of a transdermal application system for saturated active ingredient enhancer solutions with occlusion effect, as it is preferably used for Examples 1 to 3 for the administration of progesterone, felodipine and curcumin.
• Backing layer e.g. PET film coated with silicone bio PSA # 4302 (Dow Corning).
• Self-adhesive adhesive ring eye
• polyethylene foam and synthetic rubber as an adhesive for fixing the backing layer
• Textile and needled fleece preferably with a weight of up to 150 g / m 2 , with regard to absorption behavior suitable for the absorption of the active ingredient preparation (solution, gel, ointment), for example made of polyester or viscose, such as Paramoll® N260 / 150 (Lohmann , Neuwied (Germany)) or TWE-Vlies 120 from (TWE, Dierdorf (Germany)).
• the application area is, for example, 1.165 cm 2 .
• Self-adhesive polyurethane film as a control membrane and to fix the system on the skin, e.g. Suprasorb® (Lohmann & Rauscher, Neuwied (Germany)).
• Diffusion membrane here preferably native human skin.
• TTS as a single-layer matrix system with a self-adhesive polymer matrix based on a silicone adhesive of the Bio-PSA TM 7-4301 type (Dow Corning Corp., Midland, MI, USA), as is preferred for the administration of olanzapine according to the example 5 is used.
• Carrier film e.g. made of polyethylene terephthalate.
• one layer adhesive matrix polymer contains the active ingredient, enhancer and polymer excipient.
• Skin model human skin, dermatomized 500 pm, (female belly, date of birth 1968).
• DMEH penetration acceleration of DMEH is clearly superior to that of the comparison compounds.
• the effect of DMEH is greater by a factor of about 10 (dimethyl isosorbide) or 4 (dipropylene glycol).
• Active ingredient curcumin (test active ingredient; logP 3.62)
• Skin model human skin, dermatomized 500 pm, (female belly, date of birth 1979).
• Loading saturated solution of curcumin in DMEH, donor amount 150 pl as a direct application on the epidermal skin surface (corresponds to a Loading concentration of 12.75 mg / cm 2 , which is very high compared to that of dimethyl isosorbide with only 1.29 mg / cm 2).
• the penetration acceleration of DMEH is clearly superior to that of the comparison compound.
• the effect of DMEH is about a factor of 5 greater than the effect of dimethyl isosorbide.
• Skin model human skin, not dermatomized, full skin, (female belly, date of birth 1967).
• active ingredient loading 10% by weight in the transdermal therapeutic system corresponds to 6 mg / cm 2 (with a wet pull-out line thickness of 3000 ⁇ m). This is very high compared to the transdermal therapeutic system with Eutanol G as a penetration accelerator with a load of only 0.26 mg / cm 2.
• Transdermal therapeutic system as a single-layer matrix system with a self-adhesive polymer matrix based on the acrylate type Durotak TM 2054 (Henkel, Düsseldorf) and the non-adhesive polymer type Eudragit TM E100 (Rohm, Darmstadt) in a ratio of 4: 1 as an adjuvant with 18% by weight DMEH as a penetration accelerator.
• the cumulative permeated amount of curcumin at the predetermined changeover times is shown in FIG.
• the penetration acceleration of DMEH is clearly superior to that of the comparison compound. Based on the 72h value or the flux rate in steady state, the effect of DMEH is about a factor of 3.6 greater than the effect of Eutanol G.
• Skin model human skin, not dermatomized, full skin, (female belly, date of birth 1967).
• active ingredient loading 10% by weight in the transdermal therapeutic system corresponds to 6.47 mg / cm 2 (with a wet pull-out line thickness of 3000 ⁇ m). This is very high compared to the transdermal therapeutic system with Eutanol G as a penetration accelerator with a load of only 0.26 mg / cm 2.
• Transdermal therapeutic system as a single-layer matrix system with a self-adhesive polymer matrix based on the silicone type BIO-PSA TM 7-4301 (from Dow Corning Corp., Midland, MI, USA) with 18% by weight of DMEH as Penetration accelerator (see Figure 8).
• the cumulative permeated amount of olanzepine at the predetermined changeover times is shown in FIG. 7.
• Skin model human skin, not dermatomized, full skin, (female belly, date of birth 1985).
• active ingredient loading 20% by weight in the transdermal therapeutic system corresponds to 8.5 mg / cm 2 with a wet pull-out line thickness of 1200 ⁇ m. This loading is very high compared to the transdermal therapeutic system with Eutanol G as a penetration accelerator with a loading of only 0.26 mg / cm 2.
• Transdermal therapeutic system as a single-layer matrix system with a self-adhesive polymer matrix based on the silicone type BIO-PSA TM 7-4301 (from Dow Corning Corp., Midland, MI, USA) with 30% by weight of DMEH as Penetration accelerator (see Figure 8).
• the cumulative permeated amount of olanzepine at the predetermined changeover times is shown in FIG. 7.
• the penetration acceleration of DMEH is clearly superior to that of the comparison compound.
• the effect of DMEH is about a factor of 6 greater than the effect of Eutanol G.

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