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
• • 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
  • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene

Definitions

• Transdermal therapeutic system with reduced tendency to crystallize active substances.
• the present invention relates to a transdermal therapeutic system (TTS) in plaster form for the controlled delivery of active ingredients to human or animal skin, in which the recrystallization of the active ingredients is prevented or inhibited.
• TTS transdermal therapeutic system
• transdermal administration of active pharmaceutical ingredients is particularly useful if, after oral administration, a large proportion of the active ingredient is metabolized during the first passage through the mucous membranes of the gastrointestinal tract or is retained by the liver (first pass effect) and / or if the active substance has a low plasma half-life.
• transdermal administration presupposes that the dosage form used enables the active ingredient to be released as evenly as possible over a longer period of time.
• the highest possible active ingredient release rates (flux rates) should be able to be achieved through the skin in order to build up and maintain a sufficiently high plasma level so that the desired therapeutic effect occurs.
• the area of the active substance-containing patch, via which the active substance is released to the skin must be increased accordingly in order nevertheless to enable the administration of therapeutically effective doses.
• the enlargement of the delivery area is a disadvantage because there is a risk with large-area systems that complete skin contact is not achieved and the drug delivery is thus disrupted. Patients also prefer small patches.
• the rate of drug delivery depends on the one hand on the permeability properties of the skin for the active ingredients concerned and on the other hand on the concentration of the active ingredient in the matrix of the transdermal therapeutic system.
• the permeability properties of the skin can be improved by permeation enhancers; substances suitable for this are known in principle to the person skilled in the art.
• DE-OS 195 00 662 describes a transdermal therapeutic system with an estradiol-containing active substance reservoir based on ethyl cellulose with a high proportion of rosin esters as a tackifying resin, together with up to 20% by weight lauric acid, which recrystallize the active substance and thus Counteracting reduction in its release rate.
• estradiol for example silicon dioxide (US Pat. No. 5,676,968) or anhydrous glycerol (WO 96/05814).
• the addition of such substances is often associated with disadvantages, e.g. For example, the mechanical properties (cohesion) of the patch may be impaired, or problems may arise in the manufacture of these patches.
• the object of the present invention was therefore to provide a transdermal therapeutic system which has a simple structure and is inexpensive to produce, and which is capable of delivering active pharmaceutical ingredients to the skin at high delivery rates, with skin permeation rates being achieved are said to be well above the pereaction rates achievable by known systems, but are in any case sufficient for therapeutic purposes or for contraception, without the surface area of the plasters becoming unacceptably large.
• transdermal therapeutic systems in plaster form, which have the structure described in the preamble of claim 1, allow very high skin permeation rates for active substances if the active substance-containing reservoir contains at least one film-forming agent and at least one crystallization of the main components / which contains active ingredient (s) preventing or suppressing polymer. Further advantageous embodiments of the transdermal therapeutic systems according to the invention are described in the subclaims.
• transdermal therapeutic system which contained the active ingredients estradiol and norethindro- nanoate
• skin permeation rates were achieved which exceeded those of the reference product Evorel Conti by a multiple.
• Values were determined for both the estradiol permeation and the norethindrone acetate permeation, each corresponding to four times the value achieved with the reference product Evorel Conti. This increase in skin permeation makes it possible to provide skin patches containing active ingredients with a very small area.
• a substance is preferably used which is selected from the group comprising derivatives of cellulose, polymethyl methacrylates and polyacrylates.
• cellulose derivatives In particular, ethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose are particularly preferred. Combinations of different film formers can also be used.
• the proportion of the film-forming agent (s) is preferably 10 to 50% by weight, based on the active substance-containing reservoir.
• the TTS according to the invention contain at least one polymer which prevents the crystallization of the active substance (s); the proportion of this polymer or these polymers is 10 to 50% by weight, based on the active substance-containing reservoir.
• An ethylene-vinyl acetate-vinylpyrrolidone copolymer is particularly preferably used as the crystallization-inhibiting polymer.
• the systems according to the invention are distinguished by a certain water absorption capacity; the reservoir containing the active substance can preferably absorb or contain at least 15% by weight of water, particularly preferably at least 20% by weight.
• the active substance concentration, based on the active substance-containing reservoir, is dependent on the active substance used in each case and is preferably in the range from 0.5 to 20% by weight, based on the active substance-containing reservoir.
• the active substance-containing reservoir can have a content of at least one enhancer, whereby an enhancer is understood to be a substance which improves the skin permeation of the active substances to be administered.
• the enhancer (s) are added at a concentration of 0.5 to 50% by weight, based on the reservoir containing the active ingredient.
• the enhancer (s) is / are preferably selected from the group containing the following substances: lauric acid diethanolamide (e.g. Comperlan LD), oleic acid diethanolamide (e.g. Comperlan OD), coconut fatty acid diethanolamide (e.g. Comperlan COD), D-alpha-tocopherol (e.g. Copherol), hexyl laurate (e.g. Cetiol A), 2-octyldodecanol (e.g. eutanol) and Dexpanthenol.
• lauric acid diethanolamide e.g. Comperlan LD
• emulsifiers or plasticizers are added to the active substance-containing reservoir in a concentration of up to 10% by weight, preferably from 0.1 to 5% by weight.
• emulsifiers or plasticizers are known in principle to the person skilled in the art.
• tackifying resins can also be added to the drug reservoir.
• the active substance-containing reservoir is made up of two or more layers.
• the individual layers can contain different active substances or active substance concentrations, or have a different polymer composition, or otherwise differ in their composition.
• a sheet-like structure can be introduced between individual layers of the active substance-containing reservoir, which can be, for example, a membrane, a film, a textile fabric, a textile material or a nonwoven material.
• the TTS according to the invention is provided with an additional pressure-sensitive adhesive layer and / or a pressure-sensitive edge; this is particularly useful if the stickiness of the matrix containing the active ingredient does not appear to be sufficient.
• the TTS according to the invention are characterized by a small layer thickness; the layer thickness of the active substance-containing reservoir is preferably 0.02 mm to 0.5 mm, particularly preferably 0.03 to 0.2 mm.
• the structure of the TTS according to the invention comprises an active substance-impermeable backing layer and also an active substance-impermeable, removable protective layer.
• Particularly suitable as a backing layer are polyesters, which are notable for their particular strength, but moreover almost any other compatible plastics, such as. B. polyvinyl chloride, ethylene vinyl acetate, vinyl acetate, polyethylene, polypropylene, cellulose derivatives or combinations of different films, and many others.
• the backing layer can be provided with an additional layer, e.g. B. by vapor deposition with metals or other diffusion-blocking additives such as silicon dioxide, aluminum oxide or similar substances which are known to the person skilled in the art.
• removable protective layer as for the back layer, provided that they can be treated with a suitable surface treatment, such as. B. siliconization, is removable.
• a suitable surface treatment such as. B. siliconization
• other removable protective layers such as paper treated with polytetrafluoroethylene, cellophane, polyvinyl chloride, or the like, can also be used.
• the TTS according to the invention enable comparatively high active substance release rates and are therefore particularly suitable for the transdermal administration of active substances, in particular for the prophylaxis and therapy of diseases in humans or in veterinary medicine.
• the following examples describe TTS having a composition according to claim 1 and the skin permeation rates achieved therewith.
• the adhesive solution obtained in this way is coated on the backing layer (Ho taphan RN 23, Mitsubishi), so that after drying an active ingredient-containing reservoir with a weight per unit area of 80-90 g / m 2 results.
• This layer is covered with the removable protective layer (Hostaphan RN 100, vapor-coated with aluminum on one side and siliconized on both sides).
• Examples 2 and 3 were also prepared in the manner described above, the composition of which, like the composition of Example 1, can be seen from Table 1.
• Ethylcell. Ethyl cellulose Examples 4, 5 and 6
• Example 4 The hormone content in Examples 4 to 6 corresponds to that in Examples 1 to 3 (Oes / NeA combination; 2.5% by weight Oes and 5.0% by weight NeA; see Table 1).
• Durotak 387-2287 acrylate / methacrylate vinyl acetate
• [ ⁇ g / cm 2 -h] in Examples 2 and 3 can be increased by 3.6 or 3.9 times and the norethindrone acetate flux by 3.2 or 3.9 times. This means that the TTS area, which is 16 cm 2 in the Evorel Conti, can be reduced to approximately 4 cm 2 in the TTS according to the invention.
• transdermal therapeutic systems according to the invention are completely free from recrystallization phenomena, while Evorel Conti tends to crystallize the active ingredient.
• Examples 1 and 2 and the commercial product Evorel Conti measured the water absorption capacity as follows.
• the TTS were weighed and hung in a thin layer chromatography chamber in a saturated water vapor atmosphere for one week. After removal, the water content of the TTS was determined by coulometric titration according to Karl Fischer. The results are shown in Table 4.
• the increased water absorption of the TTS according to the present invention leads to an increase in the solubility of the active substance (s) in the active substance-containing reservoir and thus an unexpectedly increased active substance release.

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• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Dermatology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Applications Claiming Priority (3)

Publications (1)

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• 2000
  • 2000-05-25 DE DE10025971A patent/DE10025971B4/de not_active Expired - Fee Related
• 2001
  • 2001-05-12 US US10/296,378 patent/US20030175330A1/en not_active Abandoned
  • 2001-05-12 JP JP2001585732A patent/JP2003534271A/ja active Pending
  • 2001-05-12 KR KR1020027015860A patent/KR20030001556A/ko not_active Application Discontinuation
  • 2001-05-12 CA CA002410336A patent/CA2410336A1/en not_active Abandoned
  • 2001-05-12 WO PCT/EP2001/005438 patent/WO2001089487A1/de not_active Application Discontinuation
  • 2001-05-12 EP EP01943353A patent/EP1283705A1/de not_active Withdrawn
  • 2001-05-12 AU AU2001265949A patent/AU2001265949A1/en not_active Abandoned
  • 2001-05-23 AR ARP010102443A patent/AR028611A1/es unknown

Non-Patent Citations (1)

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