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
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • 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
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/428—Thiazoles condensed with carbocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • 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
• • 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
  • A61K9/7061—Polyacrylates

Definitions

• the invention relates to a transdermal delivery system (TDS) for the administration of at least one dopamine agonist through the skin.
• TDS transdermal delivery system
• Dopamine is a biogenic amine and an important messenger substance (neurotransmitter) in the nervous system that, among other things, controls the motor system in the central nervous system. Persistent dopamine deficiency can lead to depression, drive disorders, loss of motivation and movement disorders. In extreme cases, dopamine deficiency in the brain leads to Parkinson's syndrome (Parkinson's disease), which u. a. in symptoms such as gross trembling and / or head wobbling, increased muscle tension, mask-like frozen facial expression and vegetative side effects. The symptoms are caused by the death of nerve cells in the substantia nigra, which in turn causes a deficiency of the messenger substance dopamine in the brain. At present, it is also assumed that the RLS (Restless Leg
• the missing dopamine may be replaced by its prodrug levodopa, which is metabolized to dopamine after passing the blood-brain barrier, or by agonists.
• the agonists stimulate the dopamine receptors and thus have an effect analogous to dopamine.
• the dopamine receptors five different forms are known today: the receptors Di to D5. Agonists with a selectivity for the D2 receptor family, such. Pramipexole, ropinirole, piribedil, rotigotine and Apomorphine, have thereby gained special importance for the treatment of Parkinson's disease.
• the dopamine agonists are mostly used in the form of tablets for the treatment of disorders caused by dopamine deficiency, whereby transdermal administration systems for administering a dopamine agonist are also known in the prior art.
• transdermal therapeutic system for the administration of pramipexole has been described, which is capable of delivering the active ingredient over a longer period of 4 to 7 days.
• the patent application EP 0 428 038 describes the treatment of paroxinsonism and schizophrenia with the dopamine agonist pramipexole using a transdermal administration system. Furthermore, a skin patch with the active ingredient rotigotine for monotherapy in Parkinson's disease of the pharmaceutical company Schwarz under the name Neupro® in the trade.
• Transdermal delivery systems are for administering drugs through the skin of a patient in their bloodstream.
• TDS typically include a reservoir for the drug, a drug-impermeable backing, and a protective film that is removed prior to application of the system.
• the transdermal administration of drugs has a number of advantages over conventional dosage forms such as tablets. The effectiveness of the administration is not impaired by food intake, nor is it subject to the first-pass effect of the liver and it makes it possible to maintain a demand-based active ingredient blood level even over longer periods of time.
• the release of the active ingredient from the TDS can only be controlled to a limited extent, since in particular the skin-permeable small and / or lipophilic drugs are released very quickly from the TDS. This results in a very high initial delivery and their concentration decreases relatively quickly, especially in the skin-near layer of the TDS, so that the active ingredients do not permeate through the skin at the desired constant release rate and consequently not as constant a blood level as possible over a longer period Period of time such as 72 hours can be achieved.
• transdermal delivery system from which skin-accessible low molecular weight dopamine agonists can be released over a longer period of time such as 72 hours at a more uniform release rate.
• Embodiments of transdermal administration systems with a substantially constant release of active substance have an active substance-containing matrix arranged between a backing layer and a peelable protective film,
• active ingredient-containing matrix comprises:
• a polymer matrix comprising:
• the proportion of COOH groups in the polymer matrix is selected from the range of 0.5 to 15 mol%, preferably 3 to 1 1 mol% and most preferably 5 to 9 mol%, and
• Another advantage of using a polymer matrix of an acrylate / vinyl acetate copolymer with the simultaneous presence of functional COOH groups is to provide a stable physical system in which the active ingredient contained even after prolonged storage such. B. 6 weeks at room temperature (25 ° C) o- even higher temperatures such as 40 ° C shows no recrystallization.
• the matrix of the TDS comprises the polymer matrix (1) and the at least one active substance (2) and optionally further additives (3).
• the polymer matrix containing the active ingredient is based on a hydroxyl group-containing acrylate / vinyl acetate copolymer (Ia) and also contains carboxy groups (Ib) in a proportion of 0.5 to 15 mol%, preferably 3 to 11 mol%, and completely particularly preferably 5 to 9 mol%.
• hydroxy group-containing acrylate / vinyl acetate copolymer (Ia) constitutes the major part by weight of the polymer matrix and (lb) (i) the hydroxyl group.
• the proportion of the COOH groups contained in the polymer matrix as a whole is in the range of 0.5 to 15 mol%, preferably 3 to 1 mol%, and most preferably 5 to 9 mol%, based on The molecular weight of the polymer matrix, regardless of whether the polymer matrix of a polymer mixture (lb) (i) or a copolymer (lb) (ii) is formed.
• the term acrylate / vinyl acetate copolymer is to be understood as meaning that at least one ester of acrylic acid or methacrylic acid, or (meth) acrylate, and vinyl acetate are present in the copolymer as monomers, while other comonomers may also be present.
• the hydroxy groups are introduced into the copolymer either by using hydroxyalkyl esters of acrylic acid or methacrylic acid as acrylate monomers in the copolymer, or by containing hydroxyalkyl esters of acrylic acid or methacrylic acid as further comonomers.
• the hydroxyl group-containing acrylate / vinyl acetate copolymer comprises at least the following two comonomers: (a) at least one hydroxyalkyl (meth) acrylate copolymerizable with vinyl acetate and (b) vinyl acetate.
• the hydroxy group-containing acrylate / vinyl acetate copolymer may also be composed of at least three different monomers, (a) at least one hydroxyl-containing monomer copolymerizable with (meth) acrylates and vinyl acetate, (b) the vinyl acetate and (c) at least one alkyl (meth) acrylate in which the alkyl group 1 may contain up to 12 carbon atoms, ie an ester of acrylic acid or methacrylic acid with a C 12 alcohol.
• the hydroxyl-containing monomer copolymerizable with (meth) acrylates and vinyl acetate is preferably a hydroxyalkyl (meth) acrylate.
• Preferred hydroxyl-containing comonomers (a) are the hydroxyalkyl (meth) acrylates whose hydroxyalkyl group comprises an OH group and 2 to 12 carbon atoms, in particular 2 to 6 carbon atoms, particularly preferably 2 to 4 carbon atoms. Hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxybutyl acrylate, hydroxyethyl methacrylate, hydroxypropyl methacrylate and hydroxybutyl methacrylate are very particularly preferred.
• the alkyl (meth) acrylates (c) preferably have an alkyl group having 1 to 12 carbon atoms, and more preferably 1 to 8 carbon atoms.
• the alkyl (meth) acrylates are, for example, methyl acrylate, ethyl acrylate, isopropyl acrylate, butyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, glycidyl acrylate and the corresponding methacrylates
• the acrylate / vinyl acetate copolymer may also be crosslinked with conventional crosslinking agents such as aluminum acetylacetonate or polybutyl titanate.
• Hydroxy-containing acrylate / vinyl acetate copolymers which may be crosslinked, are available, for example, from Henkel under the names Duro-Tak® 87-2287, Duro-Tak® 87-2516, Duro-Tak® 87-2525, Duro-Tak ® 87-4287 or Duro-Tak® 87-208A commercially available.
• Duro-Tak® 87-2287 Duro-Tak® 87-2516
• Duro-Tak® 87-2525 Duro-Tak ® 87-4287
• Duro-Tak® 87-208A commercially available.
• the hydroxyl group-containing acrylate / vinyl acetate copolymer is in admixture with a homo- or copolymer containing an acid monomer having a functionalized COOH group such as acrylic acid or methacrylic acid.
• the carboxyl group-containing polymer is selected such that the proportion of COOH groups in the polymer matrix ranges from 0.5 to 15 mol%, preferably from 3 to 1 mol%, and most preferably from 5 to 9 mol% -% lies.
• the polymer matrix may be formed from a mixture of a hydroxy group-containing acrylate / vinyl acetate copolymer and a carboxy group-containing acrylate / vinyl acetate copolymer.
• the proportion of the carboxyl group-containing acrylate / vinyl acetate copolymer in the mixture is preferably in the range from 5 to 35% by weight and in particular in the range from 10 to 30% by weight.
• it is a carboxy group-containing acrylate / vinyl acetate copolymer, i. H. a copolymer composed of at least three different monomers, (a) at least one carboxy-containing monomer copolymerizable with (meth) acrylates and vinyl acetate, such as the said monomers acrylic acid or methacrylic acid, (b) the vinyl acetate and (c) at least one Alkyl (meth) acrylate in which the alkyl group may contain 1 to 12 carbon atoms, d. H. an ester of acrylic acid or methacrylic acid with a C 12 alcohol. These copolymers may optionally be crosslinked.
• a carboxy group-containing copolymer which consists of acrylic acid or methacrylic acid (or short (meth) acrylic acid) and vinyl acetate is formed and may optionally be crosslinked.
• Carboxy group-containing copolymers are also available from Henkel under the names Duro-Tak® 87-2051, Duro-Tak® 87-2052, Duro-Tak® 87-2054, Duro-Tak® 87-2677, Duro-Tak® 87 -2 194, Duro-Tak® 87-2 196 and Duro-Tak® 87-2825 are commercially available.
• the carboxy groups are incorporated into the acrylate / vinyl acetate copolymer in the form of an acid comonomer having a COOH functional group.
• the acrylate / vinyl acetate copolymer contains, in addition to the above-mentioned at least 2 comonomers: (a) hydroxy group-containing monomer copolymerizable with vinyl acetate and (b) vinyl acetate or at least 3 comonomers: (a) hydroxy group-containing vinyl acetate copolymerizable monomer, (b) vinyl acetate and (c) alkyl (meth) acrylate furthermore at least one further carboxy group-containing comonomer copolymerizable with the other comonomers.
• the comonomer containing carboxy groups is selected so that the proportion of COOH groups in the polymer matrix is in the range of 0.5 to 15 mol%, preferably 3 to 11 mol%, and most preferably 5 to 9 mol -% lies.
• a commercially available mixture of an acrylate / vinyl acetate adhesive with functional OH and COOH groups under the name Duro-Tak® 87-2979 from Henkel is also available.
• the dopamine agonists contained in the TDS have a relatively low molecular weight of less than 350 g / mol, and preferably less than 320 g / mol, i. H. they can permeate well through the skin.
• the dopamine agonists and in particular the abovementioned active compounds in the form of physiologically acceptable salts.
• the salts are formed starting from the active substance present in free form as base with physiologically acceptable acids, such as inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid) or organic acids (eg acetic acid, lactic acid, succinic acid, ⁇ p - Feiklare, maleic acid, methanesulfonic acid or p-toluenesulfonic acid).
• physiologically acceptable acids such as inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid) or organic acids (eg acetic acid, lactic acid, succinic acid, ⁇ p - Feiklare, maleic acid, methanesulfonic acid or p-toluenesulfonic acid).
• the stated molar mass of 350 g / mol refers to the active ingredient in free
• these are agonists with a selectivity for the D2 receptor family.
• the dopamine agonists are selected from the following compounds:
• Pramipexole or (S) -4,5,6,7-tetrahydro-N6-propylbenzothiazole-2,6-diamine; MW (molecular weight [g / mol]) 2 1 1, 33;
• Ropinirole or 4- [2- (dipropylamino) ethyl] -1,3-dihydro-2H-indol-2-one; MW 260.38;
• Lisuride or 3- (9,10-didehydro-6-methyl-8a-ergolinyl) -1,1-diethylurea; MW 338.45;
• the dopamine agonist is the pramipexole (C10H17N3S) having a molecular weight of 2 1 1, 33 g / mol, its dihydrochloride (C10H17N3S ⁇ 2HC1) having a molecular weight of 284.26 g / mol and / or its dihydrochloride monohydrate (C 10H17N3S ⁇ 2HC1 ⁇ H2O) with a molecular weight of 302, 30 g / mol.
• pramipexole is used in the form of the free base.
• the proportion of the dopamine agonist in the matrix is preferably in the range from 1 to 9% by weight, based on the total weight of the constituents of the matrix, preferably in the range from 3 to 8
• Wt .-% in particular in the range of 4 to 7 wt .-%.
• the polyvinylpyrrolidone (PVP) is further included as a crystallization retardant in the matrix. It has been found that the physical stability of the TDS can be improved if pramipexole, PVP is incorporated into the matrix in order to prevent crystallization of the active ingredient and especially of the active ingredient.
• the amount of PVP is preferably 2 to 15 wt .-%, in particular 4 to 15 wt .-% and more preferably 5 to 12 wt .-%, based on the total weight of the components contained in the matrix.
• further customary additives may be present in the matrix, such as permeation enhancers, tackifiers, plasticizers, solvents and the like.
• the matrix is particularly preferably composed of the hydroxyl-containing and carboxy-containing polymer matrix based on acrylate / vinyl acetate, the at least one dopamine agonist and polyvinylpyrrolidone and unavoidable impurities and residues caused by the preparation process, such as, for example, solvent residues in small proportions of less than 1% by weight. -% and even below 0.5 wt .-%.
• the basis weight of the polymer matrix is selected in particular from the range from 40 to 120 g / m 2 and preferably from 50 to 100 g / m 2 .
• backing films usually so-called backing films made of a polymer are used, which are among the polyolefins, olefin
• Copolymers polyesters, copolyesters, polyamides, copolyamides and polyurethanes.
• polyesters and, in particular, polyethylene terephthalates and polycarbonates may be mentioned.
• polyethylenes polypropylenes or polybutylenes, polyethylene oxides, polyurethanes, polystyrenes, polyamides, polyimides, polyvinyl acetates, polyvinyl chlorides, polyvinylidene chlorides, copolymers such as acrylonitrile-butadiene-styrene terpolymers or ethylene-vinyl acetate Copolymers.
• the backing layer is impermeable to the active ingredient.
• TDS with a covering layer called Overtape, which is used for reliable large-area attachment of the TDS on the skin. It may also be impermeable to the drug and prevent uncontrolled leakage of drug.
• the removable protective film of the TDS protects the matrix from soiling.
• Suitable materials for the peelable protective film are, for example, polyester, polypropylene, polyvinyl chloride, aluminum and paper, wherein at least one side of the protective film or carrier film has a silicone coating, polyethylene coating, fluorosilicone coating or polytetrafluoroethylene coating.
• FIG. 1a shows the course of the cumulative permeated amount of pramipexole over 72 hours for four different TDS proteins. Shows formulations that differ in their COOH content in the polymer matrix, and
• Examples 1 to 3 Comparative Example 1 4 different TDSs (Examples 1 to 3 and Comparative Example 1) with pramipexole were prepared, which differ in the polymer matrix used.
• a polymer matrix is used which consists of a mixture of a hydroxyl-containing polyacrylate / vinyl acetate (Duro-Tak® 87-2516) and a carboxy group-containing polyacrylate / vinyl acetate (Duro-Tak® 87-2051) in is formed in different proportions.
• the comparative example uses a hydroxyl group-containing polyacrylate / vinyl acetate (Duro-Tak® 87-2516), i. H. There are no carboxy groups in the polymer matrix.
• Table 1 The exact compositions are given in Table 1 below, the percentage proportions given are based on percent by weight, based on the total weight of the constituents contained in the matrix: TABLE 1
• Example 1 76.5% DT 87-2516 8.5% DT 87-2051 5% 10%
• Example 1 For the preparation of the TDS, the pramipexole is dissolved in each case in ethanol, then the polyvinylpyrrolidone is added in portions. The mixture is stirred until everything is dissolved, and then added with stirring the dissolved in ethyl acetate and heptane or ethyl acetate matrix polymers.
• the homogeneous coating composition is applied as a thin film to a siliconized film, whereupon the solvents contained are removed as far as possible by heating.
• the dried matrix is laminated with a protective film of a polyethylene terephthalate film. Finally, patches of suitable size are punched out of the formed laminate and used for in vitro studies on the permeation rate of pramipexole from the four different TDS formulations.
• Example 1 The physical stability of the formulation according to Example 1 was tested by storing appropriate patches for 6 weeks at a temperature of 5 ° C, 25 ° C and a relative humidity of 60% and 40 ° C and a relative humidity of 75% and the occurrence of Crystals were examined visually under the microscope with 20x magnification. The addition of PVP to the polymer matrix prevented the recrystallization of the active ingredient under all conditions of temperature and humidity. Examples 4 and 5
• the effect of a permeation enhancer contained in the polymer matrix on drug release from the system was tested.
• the following two TDSs were prepared according to the method described above, which differ in the system by the presence of the permeation improver lauryl lactate, the stated percentages being by weight based on the total weight of the constituents contained in the matrix:
• the cumulative release rate of pramipexole was determined in vitro as described above.
• the permeation enhancer lauryl lactate contained in the TDS of Example 5 the cumulative permeated drug curve is sigmoidal as compared to the system of Example 4, ie the release of the pramipexole from the formulation of Example 4 which does not contain a permeation enhancer is above one longer period like 3 days even more evenly.
• the addition of a permeation enhancer to the matrix should therefore be avoided.

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• 2012
  • 2012-04-03 DE DE201210205493 patent/DE102012205493A1/de not_active Ceased
• 2013
  • 2013-04-02 WO PCT/EP2013/056947 patent/WO2013150032A1/fr not_active Ceased
  • 2013-04-02 EP EP13714270.9A patent/EP2833875A1/fr not_active Withdrawn

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