EP1703892A2 - Uv light-stable semi-solid transdermal systems comprising a photosensitive active agent and an uv-absorbing component - Google Patents

Uv light-stable semi-solid transdermal systems comprising a photosensitive active agent and an uv-absorbing component

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Publication number
EP1703892A2
EP1703892A2 EP04803546A EP04803546A EP1703892A2 EP 1703892 A2 EP1703892 A2 EP 1703892A2 EP 04803546 A EP04803546 A EP 04803546A EP 04803546 A EP04803546 A EP 04803546A EP 1703892 A2 EP1703892 A2 EP 1703892A2
Authority
EP
European Patent Office
Prior art keywords
semi
solid
dosage form
form according
transdermal dosage
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.)
Withdrawn
Application number
EP04803546A
Other languages
German (de)
French (fr)
Inventor
Hans-Peter Podhaisky
Stefan Bracht
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.)
Bayer Pharma AG
Original Assignee
Schering AG
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Filing date
Publication date
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Application filed by Schering AG filed Critical Schering AG
Priority to EP04803546A priority Critical patent/EP1703892A2/en
Publication of EP1703892A2 publication Critical patent/EP1703892A2/en
Withdrawn legal-status Critical Current

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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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • 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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/34—Gestagens

Definitions

  • UV-stable, liquid or semi-solid transdermal dosage form with photosensitive agent (description)
  • This invention relates to semi-solid and liquid pharmaceutical dosage forms for transdermal application with a UV-sensitive photosensitive pharmaceutical agent and at least one UV-absorbing excipient (UV absorber).
  • the invention relates in particular to transdermal gels whose gel base is composed of water, alcohol, at least one gel-forming polymer and optionally further ingredients.
  • Such gels are also referred to as hydroalcoholic gels.
  • transdermal application of pharmaceutically active substances has various advantages over oral administration of the drug, such as, for example, no first pass metabolization of the active ingredient by circumvention of the gastrointestinal tract, uniform release of the active ingredient several hours, due to the Depotfunktion the skin thereby maintaining a constant plasma level.
  • transdermal therapeutic systems have so far been able to prevail essentially two different dosage forms.
  • Semi-solid transdermal dosage forms, and especially gels have also been established in recent years.
  • An essential advantage of this form over the transdermal patches is the better skin compatibility of the non-occlusive drug form. Further advantages are seen in an individual dosability and in the fact that the user is visibly stigmatized as a sick person or otherwise worthy of treatment.
  • Various pharmaceutical active substances which are suitable for transdermal administration for example nifedipine, nicotine, arylpropionic acid and benzophenone derivatives, gestodene, levonorgestrel, estradiol and other hormones suitable for transdermal administration) are photosensitive. Photosensitive substances absorb radiation within the wavelength spectrum of sunlight, especially within the ultraviolet range (UV, 280-400 nm).
  • Exposure to light of pharmaceutical preparations containing light-sensitive active substances can lead to a photochemical degradation of the active ingredients and, in extreme cases, to a loss of effect of the preparation.
  • the degradation products may be the cause of phototoxic or photoallergic reactions of the skin.
  • ketoprofen gels, as well as other arylpropionic acid and benzophenone derivatives under the influence of sunlight lead to an increased occurrence of phototoxic and partial photoallergic skin reactions due to photosensitizing properties of this class of substances.
  • suitable protective measures must be taken for transdermal formulations containing photosensitive agents.
  • UVB light (280-320) penetrates the entire epidermis to the basal stratum.
  • the longer-wave UVA light 320-400 nm penetrates into the connective tissue.
  • Transdermal gels are usually applied over a very large area (100-200 cm 2 and more), and complete drug delivery from the outermost layer of the skin (stratum corneum) to systemic circulation takes up to 24 hours.
  • stratum corneum the main penetration barrier, acts as a drug reservoir that stores large portions of the drug for several hours.
  • WO-A1-03 / 082960 describes the preparation of a gel which may contain pharmaceutically active substances.
  • WO-A1-01/60399 discloses a gel containing diclofenac and the patent WO-A2-02 / 051421 describes a gel composition with at least one androgenic steroid for the treatment and / or prophylaxis of hypogonadism. All patents do not refer to the sensitive problem of photosensitivity and light protection in semisolid transdermal dosage forms. The object of the invention is therefore to provide a semi-solid transdermal
  • the object is achieved by a semi-solid or liquid dosage form containing a UV-sensitive pharmaceutical active ingredient and at least one UV absorber without pharmacological activity in the concentrations used, this being dissolved or dispersed in the dosage form.
  • the semi-solid dosage form may be a hydroalcoholic gel.
  • application forms, such as creams, solutions and suspensions prove to be beneficial. Surprisingly, with a suitable choice of the UV
  • UV absorber a spatial separation between pharmaceutical active ingredient and UV absorber can be achieved under the conditions of use: While the transdermal agent necessarily belongs to the group of skin-permeating pharmaceutical active ingredients, the UV absorber is selected according to the invention from the group of as little skin penetrating or permeating substances. After the active substance and the absorber are initially mixed with one another in the starting form of the drug forms transdermal gel or transdermal solution according to the invention, a spatial separation of the two components occurs during diffusion into and through the skin. The poorly penetrating UV absorber remains in the outer layers of the skin and thus lies spatially between the deeper penetrating active ingredient and the UV radiation acting from outside the body.
  • the distribution coefficient (s) [log P] of the UV absorber (s) is preferably greater than 3.0 or less than 1.0, more preferably greater than 5.0 or less than 0.0.
  • UV absorbers are preferred which can penetrate or permeate the skin only to a small extent, since they are either too lipophilic or too hydrophilic.
  • the molar mass of / the UV absorber / s is preferably be greater than 250 gmol '1. It is particularly preferred / are UV absorbers having a molecular weight greater than 500 g / mol. UV-absorber with a molecular weight above
  • the UV absorber (s) may be present in a proportion of 1-10%, preferably 2-5%. If the semi-solid dosage form according to the invention contains volatile constituents such as, for example, ethanol, methanol, isopropanol or DMSO, the proportion relates to the sum of the non-volatile vehicle constituents or, in other words, to the formulation remaining on the skin after the removal of all volatile constituents. It was possible to determine UV-absorbing substance (s) whose absorption maximum lies within the wave range which is responsible for the photochemical decomposition of the active substance to be protected.
  • volatile constituents such as, for example, ethanol, methanol, isopropanol or DMSO
  • the UV-absorbing substance (s) can be selected from the group consisting of p-aminobenzoic acid and aminobenzoic acid derivatives, preferably 2-ethylhexyl 4-dimethylaminobenzoate, and cinnamic acid and Derivatives, preferably 4-methoxycinnamic acid isoamyl residues, and also 3-benzylidenebornan-2-one and benzylidenebornan-2-one derivatives, preferably
  • UVA_Bereich 4- bis (polyethoxyl) aminobenzoate polyethoxyethylester, 2,2 'dihydroxy-4,4'-dimethoxybenzophenon- 5, 5'-di-sodium sulfonate, 4-methoxycinnamic acid 2-ethylhexyl ester,
  • the dosage form according to the invention may contain as pharmaceutical active ingredient at least one hormone.
  • the pharmaceutical active substance / gestagen preferably gestodene or levonorgestrel or estrogen, preferably ethinylestradiol or a combination of estrogen and progestogen, preferably gestodene and ethinylestradiol, as well as androgens, preferably testosterone , Methyltestosterone or methylnortestosterone (MENT) as well as 7 ⁇ -methyl-1 1 ß-fluoro-1 9-nortestosterone (eF-MENT).
  • the gel formers of the semi-solid dosage form are preferably selected from the group consisting of celluloses, preferably hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, methylhydroxyethylcellulose,
  • Polymethacrylates polyacrylate-polyalkylacrylate crosspolymer, acryloyldimethyltaurate / vinylpyrrolidone copolymer polyvinyl alcohol,
  • Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID) in the form of gels used to treat puffiness and inflammation of the soft tissues (eg tendons, tendon sheaths, ligaments and joint capsules), especially in the shoulder and elbow area; Sports and accident injuries such as bruises, sprains, strains is used. Under the influence of sunlight, the occurrence of phototoxic and photoallergic skin reactions for such gels is described. The active substance ketoprofen is protected from light-induced decomposition by the addition of UV absorber Uvinul DS 49. Ketoprofen 2.5%
  • Uvinul DS 49 has a molecular weight of about 478.4 g / mol and a calculated LogP value of -1.9.
  • the gel base is made from Carbopol, TEA and water according to well known pharmaceutical regulations. Thereafter, Uvinul DS 49 and EDTA are incorporated into this basis. Isopropanol, propylene glycol and ketoprofen are mixed and then incorporated into the gel base.
  • Example 2 Gestoden restroom preparations can be used for hormone replacement therapy. Under UV light it can lead to a decomposition of the active substance and concomitantly to an active loss. Gestoden 1%
  • Uvinul MC 80 has a molecular weight of about 290 g / mol and a calculated Log P value of 5.37. Gestoden and Uvinul MC 80 are dissolved in ethanol. Subsequently, diethylene glycol monoethyl ether, isopropyl myristate and water are added and mixed well. Thereafter, the gel is formed by portionwise incorporation of hydroxypropyl cellulose and allowed to q uellen sufficiently in accordance with pharmaceutical regulations.
  • Ethinyl estradiol-containing preparations can be used for hormone replacement therapy. Under the influence of UV light, it can lead to the decomposition of ethinylestradiol and a concomitant loss of efficacy. Ethinyl estradiol 0.2%
  • Water ad 1 00% Tinosorb S has a molecular weight of 627.80 g / mol and a distribution coefficient Log-P of 9.
  • Ethinylestradiol and Tinosorb S are dissolved in ethanol. Subsequently, diethylene glycol monoethyl ether, isopropyl myristate and water are added and mixed well. Thereafter, the gel is formed by portionwise incorporation of hydroxypropyl cellulose and allowed to swell sufficiently according to pharmaceutical regulations.
  • Example 4
  • a combination of the hormones ethinyl estradiol and gestodene can be used for contraception. Under the influence of UV light, it can lead to a degradation of the active ingredients and thus to a loss of activity.
  • Triethanolamine (TEA) 1% ethinyl estradiol, gestodene and Tinosorb S are in the ethanolic
  • the gel base is made from Carbopol, TEA and water according to well known pharmaceutical regulations. Propylene glycol and diethylene glycol monoethyl ether are mixed and then the ethanolic phase incorporated into the gel.
  • Example 5 The active ingredient 7 ⁇ -methyl-1 ⁇ -fluoro-1,9-nortestosterone (eF-MENT) can be used for hormone replacement therapy in hypogonadal men.
  • eF-MENT 7 ⁇ -methyl-1 ⁇ -fluoro-1,9-nortestosterone
  • Tris (hydroxymethyl) aminomethane ad pH 5.8 eF-MENT and Tinosorb S were first dissolved in 96% ethanol.
  • Pemulen TR-1 and HPC were swollen in this ethanolic solution. Propylene carbonate was added and mixed with stirring. Subsequently, isopropyl myristate was added and it became mixed again. The whole mixture was passed through a funnel into a mixer / homogenizer system and stirred briefly. The mixture was then homogenized for 1 minute at 2000-3500 rpm (eg with a rotor-stator homogenizer). Glycerin 86%, and the total amount of purified water was added as a streak-free mixture in several steps (sucked), and the gel q again significantly after. It was stirred (about 5 minutes) until a clear dissolution of the gel was visible.
  • cyclomethicone was incorporated with stirring into the mixture.
  • a 10% strength aqueous tromethamine solution was added for neutralization with stirring in 3 substeps.
  • homogenization was continued for 2 minutes at 2700 rpm.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Reproductive Health (AREA)
  • Gynecology & Obstetrics (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Cosmetics (AREA)

Abstract

The invention relates to semi-solid and liquid pharmaceutical administration forms for transdermal application, comprising a pharmaceutical active ingredient that is photosensitive in the UV spectrum and at least one UV absorbent adjuvant (UV absorber), the latter being dissolved or dispersed in the administration form. Preferably, the inventive administration form is a transdermal gel, whose gel base is composed of water, alcohol, at least one gel-forming polymer and optionally additional ingredients. Gels of this type are also referred to as hydroalcoholic gels. The invention provides an administration form comprising a photosensitive active ingredient, which permits the application system to be highly stable without the disadvantages that are present during the application of conventional semi-solid transdermal application forms. Thus the harmful accompanying effects, such as e.g. the absorption of light protection substances by the body, which can potentially result from intentional light protection measures, are kept to an absolute minimum.

Description

UV-stabile, flüssige oder halbfeste transdermale Darreichungsform mit lichtempfindlichen Wirkstoff (Beschreibu ng) UV-stable, liquid or semi-solid transdermal dosage form with photosensitive agent (description)
Technisches Gebiet Die Erfindung betrifft halbfeste und flüssige pharmazeutische Darreichungsformen zur transdermalen Anwendung mit einem im UV-Bereich lichtempfindlichen pharmazeutischen Wirkstoff und mindestens einem UV- Licht absorbierenden Hilfsstoff (UV Absorber).Technical Field This invention relates to semi-solid and liquid pharmaceutical dosage forms for transdermal application with a UV-sensitive photosensitive pharmaceutical agent and at least one UV-absorbing excipient (UV absorber).
Unter den halbfesten und flüssigen transdermalen Darreichungsformen betrifft die Erfindung insbesondere transdermale Gele, deren Gelgrundlage aus Wasser, Alkohol, mindestens einem gelbildenden Polymer und ggf. weiteren Inhaltsstoffen zusammengesetzt ist. Solche Gele werden auch als hydroalkoholische Gele bezeichnet.Among the semi-solid and liquid transdermal administration forms, the invention relates in particular to transdermal gels whose gel base is composed of water, alcohol, at least one gel-forming polymer and optionally further ingredients. Such gels are also referred to as hydroalcoholic gels.
Der UV-Absorber liegt in dem Gel gelöst oder dispergiert vor. Stand der Technik Es ist aus der Patent- und Fachliteratur bekannt, dass eine transdermale Applikation von pharmazeutisch wirksamen Substanzen verschiedene Vorteile gegenüber einer oralen Zufuhr des Arzneistoffes aufweist, wie beispielsweise keine first pass Metabolisierung des Wirkstoffes durch Umgehung des Gastroi ntestinaltraktes, gleichmäßige Freisetzung des Wirkstoffes über mehrere Stunden , bedingt durch die Depotfunktion der Haut dadurch die Aufrechterhaltung eines gleichbleibenden Plasmaspiegels. Bei den bekannten transdermalen therapeutischen Systemen haben sich bisher im Wesentlichen zwei verschiedene Arzneiformen durchsetzen können. Es existiert eine große Anzahl von therapeutischen Pflastern, die den Wirkstoff in einer Matrix gelöst oder suspendiert enthalten. In den letzten Jahren haben sich darüber hinaus halbfeste transdermale Darreichungsformen und hier vor allem Gele, etabliert. Ein wesentlicher Vorteil dieser Form gegenüber den transdermalen Pflastern besteht in der besseren Hautverträglichkeit der nichtokklusiven Arzneiform . Weitere Vorzüge werden in einer individuellen Dosierbarkeit und darin gesehen, dass der Anwender nicht sichtbar als kranke oder anderweitig behandlungswürdige Person stigmatisiert wird. Verschiedene pharmazeutische Wirkstoffe, die sich zur transdermalen Applikation eignen (z. B. Nifedipin, Nicotin, Arylpropionsäure- und Benzophenonderivate, Gestoden, Levonorgestrel, Estradiol und andere zur transdermalen Applikation geeignete Hormone), sind lichtempfindlich. Lichtempfindliche Substanzen absorbieren Strahlung innerhalb des Wellenlängenspektrums des Sonnenlichtes, vor allem innerhalb des ultravioletten Bereiches (UV, 280-400 nm). Durch Lichtexposition von pharmazeutischen Zubereitungen mit lichtempfindlichen Wirkstoffen kann es zu einem photochemischen Abbau der Wirkstoffe und damit im Extremfall zu einem Wirkverlust der Zubereitung kommen. Darüber hinaus können die Abbauprodukte Ursache für phototoxische oder photoallergische Reaktionen der Haut sein . Beispielsweise ist bekannt, daß Ketoprofen-Gele wie auch andere Arylpropionsäure- und Benzophenonderivate unter dem Einfluss von Sonnenlicht zu einem gehäuften Auftreten von phototoxischen und teilweisen photoallergischen Hautreaktionen führen, die auf photosensibilisierende Eigenschaften dieser Substanzklasse zurückzuführen sind. Um derartige Zersetzungsvorgänge zu verhindern, müssen für transdermale Zubereitungen mit lichtempfindlichen Wirkstoffen geeignete Schutzmaßnahmen getroffen werden. Auf dem Gebiet der transdermalen Pflaster besteht wegen des geschichteten Aufbaus mit typischerweise mindestens einer wirkstoffhaltigen Klebschicht und einer rückseitigen Kunststofffolie (Backing Layer) die Möglichkeit, den UV-Absorber vom Wirkstoff räumlich getrennt unterzubringen. Erfinderische Lösungen für diese Situation werden beispielsweise in EP1449526 vorgeschlagen. Bei geschichtet aufgebauten Pflastern besteht insbesondere die Möglichkeit, den UV-Absorber in einer Schicht vorzusehen, die der wirkstoffhaltigen Schicht räumlich vorgelagert ist, in dem Sinne, dass die schädlichen Lichtstrahlen zuerst die UV-Absorber- Schicht durchdringen müssen, bevor sie die wirkstoffhaltige Schicht erreichen. So kann der Wirkstoff besondere gut vor UV-Licht geschützt werden. Auf andere transdermale Arzneiformen wie Lösungen und halbfeste Zubereitungen ist diese Prinzip jedoch nicht übertragbar, da dort solche eindeutigen Möglichkeiten der räumlichen Trennung von Wirkstoff und UV- Absorber innerhalb der Darreichungsfrom nicht gegeben sind. Bei den bisher bekannten transdermalen Gelen findet der Lichtschutz nur insoweit Beachtung, dass die Zubereitungen in lichtundurchlässigen Verpackungen, meist aluminisierte Siegelrandbeutel / Sachets, konfektioniert sind. Diese Methode des Lichtschutzes von halbfesten TTS während der Lagerung allein kann aber unzureichend sein. Sie setzt voraus, dass der lichtempfindliche Wirkstoff nach dem Auftragen der Zubereitung auf die Haut nicht mehr dem Sonnenlicht ausgesetzt ist. Der Schutz vor Sonnenlicht kann z. B. durch das Tragen von Kleidung über der Applikationsstelle erfolgen. Dies stellt jedoch für den Anwender insbesondere in klimatisch warmen Gegenden oder während klimatisch warmer Perioden des Jahres im Zusammenhang mit geringer Bekleidung eine unerwünschte Beschränkung der Anwendungsorte am Körper dar. Es ist bekannt, dass der UV-Anteil des Sonnenlichtes in die Haut eindringt. So durchdringt UVB-Licht (280-320) die gesamte Epidermis bis zum Stratum basale. Das längerwellige UVA-Licht (320-400 nm) dringt bis in das Bindegewebe vor. Transdermale Gele werden in der Regel sehr großflächig angewandt (1 00-200 cm2 und mehr), und der vollständige Wirkstofftransport von der äußersten Schicht der Haut (Stratum corneum) bis in die systemische Zirkulation nimmt bis zu 24 Stunden in Anspruch. Vor allem das Stratum corneum als Hauptpenetrationsbarriere fungiert als ein Wirkstoffreservoir, das große Teile des Arzneistoffes für mehrere Stunden speichert. In diesen Bereich kann das komplette Spektrum des UV-Lichtes vordringen und so photochemische Zersetzungsreaktionen verursachen. Unter diesen Gesichtspunkten stellt sich die Problematik der Lichtempfindlichkeit während der Anwendung bei transdermalen Gelen noch stärker dar als bei transdermalen Pflastern. Bei den letzteren ist die exponierte Applikationsfläche in der Regel viel kleiner sowie weiterhin mindestens eine außen liegende Rückschicht aus einer Kunststofffolie vorgesehen, die in der Regel immer einen minimalen UV-Schutz bietet. Aus der Patentliteratur sind halbfeste TTS (Gele) mit pharmazeutischen, auch lichtempfindlichen Wirkstoffen bekannt.The UV absorber is dissolved or dispersed in the gel. PRIOR ART It is known from the patent and technical literature that transdermal application of pharmaceutically active substances has various advantages over oral administration of the drug, such as, for example, no first pass metabolization of the active ingredient by circumvention of the gastrointestinal tract, uniform release of the active ingredient several hours, due to the Depotfunktion the skin thereby maintaining a constant plasma level. In the known transdermal therapeutic systems have so far been able to prevail essentially two different dosage forms. There are a large number of therapeutic patches containing the active ingredient dissolved or suspended in a matrix. Semi-solid transdermal dosage forms, and especially gels, have also been established in recent years. An essential advantage of this form over the transdermal patches is the better skin compatibility of the non-occlusive drug form. Further advantages are seen in an individual dosability and in the fact that the user is visibly stigmatized as a sick person or otherwise worthy of treatment. Various pharmaceutical active substances which are suitable for transdermal administration (for example nifedipine, nicotine, arylpropionic acid and benzophenone derivatives, gestodene, levonorgestrel, estradiol and other hormones suitable for transdermal administration) are photosensitive. Photosensitive substances absorb radiation within the wavelength spectrum of sunlight, especially within the ultraviolet range (UV, 280-400 nm). Exposure to light of pharmaceutical preparations containing light-sensitive active substances can lead to a photochemical degradation of the active ingredients and, in extreme cases, to a loss of effect of the preparation. In addition, the degradation products may be the cause of phototoxic or photoallergic reactions of the skin. For example, it is known that ketoprofen gels, as well as other arylpropionic acid and benzophenone derivatives, under the influence of sunlight lead to an increased occurrence of phototoxic and partial photoallergic skin reactions due to photosensitizing properties of this class of substances. In order to prevent such decomposition processes, suitable protective measures must be taken for transdermal formulations containing photosensitive agents. In the field of transdermal patches is because of the layered structure with typically at least one active ingredient-containing adhesive layer and a backside plastic film (backing layer) the possibility to accommodate the UV absorber spatially separated from the drug. Inventive solutions to this situation are suggested, for example, in EP1449526. In the case of layered patches, it is possible in particular to provide the UV absorber in a layer which is spatially upstream of the active substance-containing layer, in the sense that the harmful light rays must first penetrate the UV absorber layer before they reach the active substance-containing layer , Thus, the active ingredient can be well protected from ultraviolet light. However, this principle is not transferable to other transdermal drug forms such as solutions and semi-solid preparations, since such clear possibilities of spatial separation of active ingredient and UV absorber within the Darreichungsfrom are not given. In the transdermal gels known hitherto, the protection of light is only taken into account to the extent that the preparations are opaque Packaging, usually aluminized sealed pouches / sachets, are made up. However, this method of photoprotection of semi-solid TTS during storage alone may be insufficient. It presupposes that the photosensitive agent is no longer exposed to sunlight after application of the preparation to the skin. The protection from sunlight can z. B. by wearing clothes over the application site. However, this represents an undesirable restriction of the application sites on the body for the user, especially in climatically warm areas or during climatically warm periods of the year in connection with low clothing. It is known that the UV component of sunlight penetrates into the skin. Thus, UVB light (280-320) penetrates the entire epidermis to the basal stratum. The longer-wave UVA light (320-400 nm) penetrates into the connective tissue. Transdermal gels are usually applied over a very large area (100-200 cm 2 and more), and complete drug delivery from the outermost layer of the skin (stratum corneum) to systemic circulation takes up to 24 hours. In particular, the stratum corneum, the main penetration barrier, acts as a drug reservoir that stores large portions of the drug for several hours. In this area, the full spectrum of UV light can penetrate and cause photochemical decomposition reactions. From these points of view, the problem of photosensitivity during use in transdermal gels is even more pronounced than in transdermal patches. In the case of the latter, the exposed application area is generally much smaller, and furthermore at least one outer back layer made of a plastic film is provided, which generally always provides minimal UV protection. From the patent literature semi-solid TTS (gels) with pharmaceutical, also photosensitive agents are known.
Die WO-A1 -03/082960 beschreibt die Hestellung eines Gels, welches pharmazeutische Wirkstoffe enthalten kann. In der WO-A1 -01 /60399 wird ein Diclofenac enthaltendes Gel aufgezeigt und die Patentschrift WO-A2- 02/051421 beschreibt eine Gelzusammensetzung mit mindestens einem androgenen Steroid zur Behandlung und/oder Prophylaxe von Hypogonadismus. Alle Patentschriften nehmen keinen Bezug auf die sensible Problematik der Lichtempfindlichkeit und des Lichtschutzes bei halbfesten transdermalen Darreichungsformen. Darstellu ng der Erfindu ng Aufgabe der Erfindung ist es deshalb, eine halbfeste transdermaleWO-A1-03 / 082960 describes the preparation of a gel which may contain pharmaceutically active substances. WO-A1-01/60399 discloses a gel containing diclofenac and the patent WO-A2-02 / 051421 describes a gel composition with at least one androgenic steroid for the treatment and / or prophylaxis of hypogonadism. All patents do not refer to the sensitive problem of photosensitivity and light protection in semisolid transdermal dosage forms. The object of the invention is therefore to provide a semi-solid transdermal
Darreichungsform mit einem lichtempfindlichen pharmazeutischen Wirkstoff bereitzustellen , wobei das Applikationssystem eine hohe Stabilität ohne die bei Anwend ung der konventionellen halbfesten transdermalenTo provide dosage form with a photosensitive pharmaceutical agent, wherein the application system has a high stability without the application of the conventional semi-solid transdermal
Applikationsformen bekannten Nachteile realisiert. Dabei sollten die aus dem beabsichtigten Lichtschutz für den Anwender möglicherweise resultierende schädliche Begleitwirkungen, wie z. B. Aufnahme von Lichtschutzstoffen in den Körper, so gering wie möglich gehalten werden. Erfindungsgemäß wird die Aufgabe durch eine halbfeste oder flüssige Darreichungsform mit einem Gehalt an einem UV-lichtempfindlichen pharmazeutischen Wirkstoff und mindestens einem UV-Absorber ohne pharmakologische Wirksamkeit in den eingesetzten Konzentrationen gelöst, wobei dieser in der Darreichungsform gelöst oder dispergiert vorliegt. Erfindungsgemäß kann die halbfeste Darreichungsform ein hydroalkoholisches Gel sein. Auch Applikationsformen, wie Cremes, Lösungen und Suspensionen erweisen sich als vorteilhaft. Überraschenderweise kann bei einer geeigneten Auswahl des UV-Application forms known disadvantages realized. In this case, the possibly resulting from the intended sunscreen for the user harmful harmful effects, such. B. Inclusion of light stabilizers in the body, are kept as low as possible. According to the invention the object is achieved by a semi-solid or liquid dosage form containing a UV-sensitive pharmaceutical active ingredient and at least one UV absorber without pharmacological activity in the concentrations used, this being dissolved or dispersed in the dosage form. According to the invention, the semi-solid dosage form may be a hydroalcoholic gel. Also, application forms, such as creams, solutions and suspensions prove to be beneficial. Surprisingly, with a suitable choice of the UV
Absorbers eine räumliche Trennung zwischen pharmazeutischem Wirkstoff und UV-Absorber unter den Anwendungsbedingungen erreicht werden: Während der transdermale Wirkstoff notwendigerweise zu der Gruppe gut hautpermeierender pharmazeutischer Wirkstoffe gehört, wird der UV-Absorber erfindungsgemäß aus der Gruppe möglichst wenig hautpenetrierender bzw. permeierender Stoffe ausgewählt. Nachdem in den erfindungsgemäßen Arzneiformen transdermales Gel oder transdermale Lösung im Ausgangszustand der Wirkstoff und der Absorber zunächst miteinander vermischt vorliegen, kommt es bei der Diffusion in und durch die Haut zu einer räumlichen Trennung beider Komponenten. Der schlecht penetrierende UV-Absorber bleibt in den äußeren Hautschichten zurück und liegt so räumlich zwischen dem tiefer eindringenden Wirkstoff und der von außerhalb des Körpers einwirkenden UV-Strahlung . Für die Auswahl eines geeigneten UV-Absorbers werden erfindungsgemäß der Logarithmus des Verteilungskoeffizienten zwischen 1 - Octanol und Wasser (Log P oct/H2o im folgenden Log P bezeichnet) sowie das Molekulargewicht, herangezogen. Der Verteilungskoeffizient/en [log P] des/der UV-Absorber/s ist vorzugsweise größer als 3,0 oder kleiner als 1 ,0, besonders bevorzugt größer als 5,0 oder kleiner als 0,0. Damit werden UV-Absorber bevorzugt, die die Haut nur in geringem Maße penetrieren oder permeieren können, da sie entweder zu lipophil oder zu hydrophil sind . Die molare Masse des/der UV-Absorber/s ist vorzugsweise größer als 250 gmol"1 sein. Besonders bevorzugt ist/sind UV-Absorber mit einer molaren Masse größer 500 g/mol. UV-Absorber mit einem Molekulargewicht oberhalbAbsorbers a spatial separation between pharmaceutical active ingredient and UV absorber can be achieved under the conditions of use: While the transdermal agent necessarily belongs to the group of skin-permeating pharmaceutical active ingredients, the UV absorber is selected according to the invention from the group of as little skin penetrating or permeating substances. After the active substance and the absorber are initially mixed with one another in the starting form of the drug forms transdermal gel or transdermal solution according to the invention, a spatial separation of the two components occurs during diffusion into and through the skin. The poorly penetrating UV absorber remains in the outer layers of the skin and thus lies spatially between the deeper penetrating active ingredient and the UV radiation acting from outside the body. For the selection of a suitable UV absorber according to the invention, the logarithm of the distribution coefficient between 1 - octanol and water (Log P oct / H2 o in the following log P referred to) and the molecular weight, used. The distribution coefficient (s) [log P] of the UV absorber (s) is preferably greater than 3.0 or less than 1.0, more preferably greater than 5.0 or less than 0.0. Thus, UV absorbers are preferred which can penetrate or permeate the skin only to a small extent, since they are either too lipophilic or too hydrophilic. The molar mass of / the UV absorber / s is preferably be greater than 250 gmol '1. It is particularly preferred / are UV absorbers having a molecular weight greater than 500 g / mol. UV-absorber with a molecular weight above
500 g/mol besitzen nur ein geringes Penetrations- und Permeationsvermögen für die Haut. In der erfindungsgemäßen transdermalen Darreichungsform kann /können der/die/ UV-Absorber in einem Anteil von 1 -1 0% enthalten sein , vorzugsweise 2-5% . Sofern die erfindungsgemäße halbfeste Darreichungsform leichtflüchtige Bestandteile wie beispielsweise Ethanol, Methanol, Isopropanol oder DMSO enthält, bezieht sich der Mengenanteil auf die Summe der nicht-leichtflüchtigen Vehikelbestandteile oder anders ausgedrückt auf die nach dem Abgang aller flüchtigen Bestandteile auf der Haut verbleibende Formulierung . Es konnten UV-absorbierenden Substanz(en) ermittelt werden, deren Absorptionsmaximum innerhalb des Wellenbereiches liegt, der für die photochemische Zersetzung des zu schützenden Wirkstoffes verantwortlich ist. Sofern ein Schutz über einen breiteren UV-Spektralbereich bzw. darin liegende Absorptionsmaxima des Wirkstoffes notwendig ist, erweist es sich als vorteilhaft, zwei UV-absorbierende Substanzen mit unterschiedlichen Absorptionsmaxima zu kombinieren . Weiterhin kann/können bei den erfindungsgemäßen halbfesten Darreichungsformen die im UV-Bereich absorbierende/n Substanz/en aus der Gruppe ausgewählt sein, die p-Aminobenzoesäure und Aminobenzoesäurederivate, vorzugsweise 4-Dimethylamino- benzoesäure-2-ethyl-hexylester, sowie Zimtsäure und ihre Derivate, vorzugsweise 4-Methoxyzimtsäureisoamyleste sowie 3-Benzyliden- bornan-2-on und Benzylidenbornan- 2-on-Derivate, vorzugsweise 3-500 g / mol have only a low penetration and permeability for the skin. In the transdermal dosage form according to the invention, the UV absorber (s) may be present in a proportion of 1-10%, preferably 2-5%. If the semi-solid dosage form according to the invention contains volatile constituents such as, for example, ethanol, methanol, isopropanol or DMSO, the proportion relates to the sum of the non-volatile vehicle constituents or, in other words, to the formulation remaining on the skin after the removal of all volatile constituents. It was possible to determine UV-absorbing substance (s) whose absorption maximum lies within the wave range which is responsible for the photochemical decomposition of the active substance to be protected. If protection over a broader UV spectral range or absorption maxima of the active substance lying therein is necessary, it is advantageous to combine two UV-absorbing substances with different absorption maxima. Furthermore, in the semi-solid dosage forms according to the invention, the UV-absorbing substance (s) can be selected from the group consisting of p-aminobenzoic acid and aminobenzoic acid derivatives, preferably 2-ethylhexyl 4-dimethylaminobenzoate, and cinnamic acid and Derivatives, preferably 4-methoxycinnamic acid isoamyl residues, and also 3-benzylidenebornan-2-one and benzylidenebornan-2-one derivatives, preferably
(4')Methylbenzyliden-bornan- 2-on , 3-(4-Sulfo)benzylidenbornan-2-on, sowie Salicylsäurederivate, vorzugsweise 4-lsopropylbenzylsalicylat, Salicylsäure- 2-ethylhexylester, 3,3,5-Trimethyl-cyclohexylsalicylat, sowie 3-l midazol-4-yl- acrylsäure und ihre Ester, 2-Phenylenbenzimidazol-5-Sulfonsäure, Methylen- bis-benzotriazolyl-tetramethylbutylphenol , 2-Cyan-3,3-diphenylacrylsäure, Butylmethoxy-dibenzoyl-methan , sowie Benzophenone oder Benzophenon- Derivate, vorzugsweise Benzophenon-3, Benzophenon-4, umfasst. Als besonders geeignet im Sinne der vorliegenden Erfindung haben sich nachfolgende, im UV-Bereich, dabei schwerpunktmäßig im UVA_Bereich absorbierende, Substanzen herausgestellt: 4- Bis(polyethoxyl)aminobenzoesäure-polyethoxyethylester, 2,2 '-Dihydroxy- 4,4'-dimethoxybenzophenon-5, 5 '-di-Natriumsulfonat, 4-Methoxyzimtsäure-2- ethylhexylester,(4 ') methylbenzylidene-bornan-2-one, 3- (4-sulfo) benzylideneburnan-2-one, and salicylic acid derivatives, preferably 4-isopropylbenzyl salicylate, salicylic acid 2-ethylhexyl ester, 3,3,5-trimethyl cyclohexyl salicylate, and 3-l midazol-4-yl-acrylic acid and their esters, 2-phenylene benzimidazole-5-sulfonic acid, methylene-bis-benzotriazolyl-tetramethylbutylphenol, 2-cyano-3 , 3-diphenylacrylic acid, butylmethoxy-dibenzoyl-methane, and benzophenones or benzophenone derivatives, preferably benzophenone-3, benzophenone-4. Particularly suitable have the purposes of the present invention, following, found substances in the UV region, with a special focus in the absorbent UVA_Bereich: 4- bis (polyethoxyl) aminobenzoate polyethoxyethylester, 2,2 'dihydroxy-4,4'-dimethoxybenzophenon- 5, 5'-di-sodium sulfonate, 4-methoxycinnamic acid 2-ethylhexyl ester,
3-(4'-Trimethylammonium)benzylidenbornan-2-on-Methylsulfat, 2,4,6-Trianilin-p-(carbo-2'-ethyl-hexyl- 1 '-oxy)-1 ,3,5-triazin , Dioctyl Butamido Triazin, Bis-Ethylhexyloxyphenol Methoxyphenyltriazin , Terephthaloyliden- dicampher-sulfonsäure, Polymer von N-[2(und4)-(2-oxoborn-3- ylidenmethyl)benzyl]acrylamid , Drometriazol trisiloxan und 2,2'-(1 ,4- Phenylen)bis(1 H-benzimidazol-4,6-disulfonsäure, Mononatriumsalz). Die Handelsnamen von besonders bevorzugten UV-Absorbern für den UVA- Bereich sind Tinuvin® 326 und Tinosorb® S sowie Mexoryl® XL . Im Falle von Substanzen, die chemisch sauer reagieren wie Carbonsäuren oder Sulfonsäuren können auch deren pharmazeutisch akzeptable Salze wie vorzugsweise und ohne Anspruch auf Vollständigkeit K- , Na- und Triethanolamin(=TEA)-Salze zum Einsatz kommen. Ferner kann die erfindungsgemäße Darreichungsform als pharmazeutischen Wirkstoff mindestens ein Hormon enthalten. Weiterhin kann/können beim erfindungsgemäßen halbfesten TTS der/die pharmazeutische/n Wirkstoff/e Gestagen/e, vorzugsweise Gestoden oder Levonorgestrel oder Estrogen/e, vorzugsweise Ethinylestradiol oder eine Kombination von Estrogen und Gestagen, vorzugsweise Gestoden und Ethinylestradiol sowie weiterhin Androgene, vorzugsweise Testosteron, Methyltestosteron oder Methylnortestosteron (MENT) sowie 7α-Methyl-1 1 ß- fluor-1 9-nortestosteron (eF-MENT) sein. Die Gelbildner der halbfesten Darreichungsform werden bevorzugt aus der Gruppe ausgewählt, die Cellulosen, vorzugsweise Hydroxyethylcellulose, Hydroxypropylcellulose, Methylcellulose, Methyl hydroxyethylcellulose,3- (4'-trimethylammonium) benzylidenebbornan-2-one methylsulfate, 2,4,6-trianilin-p- (carbo-2'-ethyl-hexyl-1'-oxy) -1, 3,5-triazine, Dioctyl butamido triazine, bis-ethylhexyloxyphenol, methoxyphenyl triazine, terephthaloylidene dicamphorsulfonic acid, polymer of N- [2 (and 4) - (2-oxoborn-3-ylidenemethyl) benzyl] acrylamide, dromazolizole trisiloxane and 2,2 '- (1,4 - Phenylene) to (1 H-benzimidazole-4,6-disulfonic acid, monosodium salt). The trade names of particularly preferred UV absorbers for UVA region are Tinuvin ® 326 and Tinosorb ® S and Mexoryl ® XL. In the case of substances which react chemically acidic such as carboxylic acids or sulfonic acids and their pharmaceutically acceptable salts such as preferably and without claim to completeness K, Na and triethanolamine (= TEA) salts are used. Furthermore, the dosage form according to the invention may contain as pharmaceutical active ingredient at least one hormone. Furthermore, in the case of the semisolid TTS according to the invention, the pharmaceutical active substance / gestagen (s), preferably gestodene or levonorgestrel or estrogen, preferably ethinylestradiol or a combination of estrogen and progestogen, preferably gestodene and ethinylestradiol, as well as androgens, preferably testosterone , Methyltestosterone or methylnortestosterone (MENT) as well as 7α-methyl-1 1 ß-fluoro-1 9-nortestosterone (eF-MENT). The gel formers of the semi-solid dosage form are preferably selected from the group consisting of celluloses, preferably hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, methylhydroxyethylcellulose,
Methylhydroxypropylcellulose, Na-Carboxyl methylcellulose, Chitosan-EDTA, Hochdisperses Siliziumdioxid, Gefälltes Siliziumdioxid, Bentonit, Stärken vorzugsweise, Maisstärke, Reisstärke, Kartoffelstärke, Weizenstärke, Carboxymethylamylopektin-Na, Tragant, Alginate, Polyacrylate,Methylhydroxypropylcellulose, Na-carboxymethylcellulose, chitosan-EDTA, fumed silica, precipitated silica, bentonite, starches preferably corn starch, rice starch, potato starch, wheat starch, carboxymethylamylopectin sodium, tragacanth, alginates, polyacrylates,
Polymethacrylate, Polyacrylat-Polyalkylacrylat-Crosspolymer, Acryloyldimethyltaurat/Vinylpyrrolidon Copolymer Polyvinylalkohol,Polymethacrylates, polyacrylate-polyalkylacrylate crosspolymer, acryloyldimethyltaurate / vinylpyrrolidone copolymer polyvinyl alcohol,
Polyvinylpyrrolidon, umfasst. Die Erfindung wird durch nachfolgende Beispiele näher erläutert. Beispiel 1 Ketoprofen ist ein nichtsteroidales Antiphlogistikum (NSAI D), das in der Form von Gels zur Behandlung von Schwellungen und Entzündungen der gelenknahen Weichteile (z. B. Sehnen, Sehnenscheiden, Bänder und Gelenkkapseln), insbesondere im Bereich der Schulter und des Ellenbogens; Sport- und Unfallverletzungen wie Prellungen, Verstauchungen, Zerrungen zum Einsatz kommt. Unter Einfluß von Sonnenlicht ist das Auftreten von phototoxischen und photoallergischen Hautreaktionen für derartige Gele beschrieben. Der Wirkstoff Ketoprofen wird durch den Zusatz des UV- Absorbers Uvinul DS 49 vor der lichtinduzierten Zersetzung geschützt. Ketoprofen 2,5 %Polyvinyl pyrrolidone. The invention is explained in more detail by the following examples. Example 1 Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID) in the form of gels used to treat puffiness and inflammation of the soft tissues (eg tendons, tendon sheaths, ligaments and joint capsules), especially in the shoulder and elbow area; Sports and accident injuries such as bruises, sprains, strains is used. Under the influence of sunlight, the occurrence of phototoxic and photoallergic skin reactions for such gels is described. The active substance ketoprofen is protected from light-induced decomposition by the addition of UV absorber Uvinul DS 49. Ketoprofen 2.5%
Carbopol 940 1 % Uvinul DS 49 2 %Carbopol 940 1% Uvinul DS 49 2%
(2,2'-Dihydroxy-4,4 '-dimethoxybenzophenon-5,5'-di-Natriumsulfonat) Triethanolamin (TEA) 1 %(2,2'-dihydroxy-4,4 '-dimethoxybenzophenon-5,5' -di-sodium sulfonate), triethanolamine (TEA) 1%
Isopropanol 20%Isopropanol 20%
Propylenglycol 20% EDTA 0, 1 %Propylene glycol 20% EDTA 0, 1%
Wasser ad 1 00%Water ad 1 00%
Uvinul DS 49 hat ein Molekulargewicht von ca. 478,4 g/mol sowie einen rechnerischen LogP-Wert von -1 .9. Die Gelgrundlage wird aus Carbopol, TEA und Wasser nach den allgemein bekannten pharmazeutischen Vorschriften hergestellt. Danach wird Uvinul DS 49 und EDTA in diese Grundlage eingearbeitet. Isopropanol, Propylenglycol und Ketoprofen werden vermengt und anschließend in die Gelgrundlage eingearbeitet. Beispiel 2 Gestodenhaltige-Präparate können zur Hormonersatztherapie verwendet werden. Unter UV-Licht kann es zu einer Zersetzung des Wirkstoffes und damit einhergehend zu einem Wirkverlust kommen. Gestoden 1 %Uvinul DS 49 has a molecular weight of about 478.4 g / mol and a calculated LogP value of -1.9. The gel base is made from Carbopol, TEA and water according to well known pharmaceutical regulations. Thereafter, Uvinul DS 49 and EDTA are incorporated into this basis. Isopropanol, propylene glycol and ketoprofen are mixed and then incorporated into the gel base. Example 2 Gestodenhaltige preparations can be used for hormone replacement therapy. Under UV light it can lead to a decomposition of the active substance and concomitantly to an active loss. Gestoden 1%
Uvinul MC 80 2%Uvinul MC 80 2%
(4-Methoxyzimtsäure 2-ethylhexyl ester) Diethylenglycolmonoethylether 10%(4-Methoxycinnamic acid 2-ethylhexyl ester) Diethylene glycol monoethyl ether 10%
Isopropylmyristat 1 0%Isopropyl myristate 1 0%
Ethanol 70%Ethanol 70%
Hydroxypropylcellulose 1 ,5Hydroxypropylcellulose 1, 5
Wasser ad 1 00% Uvinul MC 80 hat ein Molekulargewicht von ca. 290 g/mol sowie einen rechnerischen Log P-Wert von 5.37. Gestoden und Uvinul MC 80 werden in Ethanol gelöst. Anschließend werden Diethylenglycolmonoethylether, Isopropylmyristat und Wasser zugegeben und gut vermengt. Danach wird durch portionsweise Einarbeitung von Hydroypropylcellulose das Gel geformt und entsprechend der pharmazeutischen Vorschriften ausreichend q uellen gelassen.Water ad 1 00% Uvinul MC 80 has a molecular weight of about 290 g / mol and a calculated Log P value of 5.37. Gestoden and Uvinul MC 80 are dissolved in ethanol. Subsequently, diethylene glycol monoethyl ether, isopropyl myristate and water are added and mixed well. Thereafter, the gel is formed by portionwise incorporation of hydroxypropyl cellulose and allowed to q uellen sufficiently in accordance with pharmaceutical regulations.
Beispiel 3 Ethinylestradiol-haltige Präparate können zur Hormonersatztherapie verwendet werden. Unter Einfluß von UV-Licht kann es zur Zersetzung von Ethinylestradiol und einem damit einhergehenden Wirkungsverlust kommen. Ethinylestradiol 0,2%Example 3 Ethinyl estradiol-containing preparations can be used for hormone replacement therapy. Under the influence of UV light, it can lead to the decomposition of ethinylestradiol and a concomitant loss of efficacy. Ethinyl estradiol 0.2%
Tinosorb S 2%Tinosorb S 2%
(Bis-Ethylhexyloxyphenyl Methoxyphenyltriazin) Diethylenglycolmonoethylether 10%(Bis-ethylhexyloxyphenyl methoxyphenyltriazine) diethylene glycol monoethyl ether 10%
Isopropylmyristat 1 0%Isopropyl myristate 1 0%
Ethanol 70%Ethanol 70%
Hydroxypropylcellulose 1 ,5%Hydroxypropylcellulose 1, 5%
Wasser ad 1 00% Tinosorb S hat ein Molekulargewicht von 627,80 g/mol sowie einen Verteilungskoeffizienten Log-P von 9.Water ad 1 00% Tinosorb S has a molecular weight of 627.80 g / mol and a distribution coefficient Log-P of 9.
Ethinylestradiol und Tinosorb S werden in Ethanol gelöst. Anschließend werden Diethylenglycolmonoethylether, Isopropylmyristat und Wasser zugegeben und gut vermengt. Danach wird durch portionsweise Einarbeitung von Hydroypropylcellulose das Gel geformt und entsprechend der pharmazeutischen Vorschriften ausreichend quellen gelassen. Beispiel 4Ethinylestradiol and Tinosorb S are dissolved in ethanol. Subsequently, diethylene glycol monoethyl ether, isopropyl myristate and water are added and mixed well. Thereafter, the gel is formed by portionwise incorporation of hydroxypropyl cellulose and allowed to swell sufficiently according to pharmaceutical regulations. Example 4
Eine Kombination der Hormone Ethinylestradiol und Gestoden kann zur Kontrazeption verwendet werden. Unter Einfluß von UV-Licht kann es zu einem Abbau der Wirkstoffe und damit zu einem Wirkverlust kommen. Ethinylestradiol 0,4%A combination of the hormones ethinyl estradiol and gestodene can be used for contraception. Under the influence of UV light, it can lead to a degradation of the active ingredients and thus to a loss of activity. Ethinyl estradiol 0.4%
Gestoden 1 %Gestoden 1%
Tinosorb S 2%Tinosorb S 2%
(Bis-Ethylhexyloxyphenyl Methoxyphenyltriazin) Diethylenglycolmonoethylether 10%(Bis-ethylhexyloxyphenyl methoxyphenyltriazine) diethylene glycol monoethyl ether 10%
Propylenglycol 5%Propylene glycol 5%
Carbopol 940 1 %Carbopol 940 1%
Ethanol 50%Ethanol 50%
Triethanolamin (TEA) 1 % Ethinylestradiol , Gestoden und Tinosorb S werden in der ethanolischenTriethanolamine (TEA) 1% ethinyl estradiol, gestodene and Tinosorb S are in the ethanolic
Phase gelöst. Die Gelgrundlage wird aus Carbopol, TEA und Wasser nach den allgemein bekannten pharmazeutischen Vorschriften hergestellt. Propylenglycol und Diethylenglycol-monoethylether werden vermengt und anschließen die ethanolische Phase in das Gel eingearbeitet. Beispiel 5 Der Wirkstoff 7α-Methyl-1 1 ß-fluor-1 9-nortestosteron (eF-MENT) kann zur Hormonersatztherapie bei hypogonadalen Männern eingesetzt werden. Propylencarbonat 10,0%Phase solved. The gel base is made from Carbopol, TEA and water according to well known pharmaceutical regulations. Propylene glycol and diethylene glycol monoethyl ether are mixed and then the ethanolic phase incorporated into the gel. Example 5 The active ingredient 7α-methyl-1β-fluoro-1,9-nortestosterone (eF-MENT) can be used for hormone replacement therapy in hypogonadal men. Propylene carbonate 10.0%
Ethanol 54,0% Gereinigtes Wasser -29,0%Ethanol 54.0% Purified water -29.0%
Ef-MENT 0,8%Ef-MENT 0.8%
Tinosorb S 1 ,0%Tinosorb S 1, 0%
Acrylat/C1 0-30 Alkylacrylat 0,8%Acrylate / C1 0-30 alkyl acrylate 0.8%
Crosspolymer (Permulen TR-1 ) Methylcellulose (Tylopur MH 1000) 0,5%Crosspolymer (Permulen TR-1) Methylcellulose (Tylopur MH 1000) 0.5%
Glycerin 86% 1 ,0%Glycerin 86% 1, 0%
Cyclomethicon 1 ,5%Cyclomethicone 1, 5%
Isopropylmyristat 0,5%Isopropyl myristate 0.5%
Tris-(hydroxymethyl)aminomethan ad pH 5,8 eF-MENT und Tinosorb S wurden zunächst in Ethanol 96% gelöst.Tris (hydroxymethyl) aminomethane ad pH 5.8 eF-MENT and Tinosorb S were first dissolved in 96% ethanol.
Pemulen TR-1 und HPC (Klucel HF) wurden in dieser ethanolischen Lösung aufgequollen. Es wurde Propylencarbonat zugegeben und unter Rühren gemischt. Anschließend wurde Isopropylmyristat zugegeben, und es wurde erneut gemischt. Das Gesamtgemisch wurde über einen Trichter in ein Mischer/Homogenisator-System und mit kurz gerührt. Danach wurde für 1 Minute mit 2000-3500 rpm homogenisiert (z. B. mit einem Rotor-Stator- Homogenisator). Glycerin 86%, und die Gesamtmenge des gereinigten Wassers wurde als schlierenfreies Gemisch in mehreren Teilschritten zugegeben (eingesogen), und das Gel q uoll nochmals deutlich nach. Es wurde solange gerührt (ca. 5 Minuten), bis eine deutliche Auflärung des Gels sichtbar wurde. Anschließend wurde Cyclomethicon unter Rühren in das Gemisch eingearbeitet. Anschließend wurde unter Rühren in 3 Teilschritten eine 10%ige wässrige Tromethamin-Lösung zur Neutralisation zugegeben. Am Ende der Einarbeitung wurde nochmals 2 Minuten mit 2700 rpm homogenisiert. Pemulen TR-1 and HPC (Klucel HF) were swollen in this ethanolic solution. Propylene carbonate was added and mixed with stirring. Subsequently, isopropyl myristate was added and it became mixed again. The whole mixture was passed through a funnel into a mixer / homogenizer system and stirred briefly. The mixture was then homogenized for 1 minute at 2000-3500 rpm (eg with a rotor-stator homogenizer). Glycerin 86%, and the total amount of purified water was added as a streak-free mixture in several steps (sucked), and the gel q again significantly after. It was stirred (about 5 minutes) until a clear dissolution of the gel was visible. Subsequently, cyclomethicone was incorporated with stirring into the mixture. Subsequently, a 10% strength aqueous tromethamine solution was added for neutralization with stirring in 3 substeps. At the end of the incorporation, homogenization was continued for 2 minutes at 2700 rpm.

Claims

Ansprüche claims
1 . Halbfeste oder flüssige transdermale Darreich ungsform mit einem Gehalt an einem UV-lichtempfindlichen pharmazeutischen Wirkstoff dadurch gekennzeichnet, dass mindestens ein UV-Absorber ohne pharmakologische Wirksamkeit in den eingesetzten Konzentrationen enthalten ist und dieser in der Darreichungsform gelöst oder dispergiert vorliegt.1 . Semi-solid or liquid transdermal dosage form containing a UV-sensitive pharmaceutical active ingredient, characterized in that at least one UV absorber is present without pharmacological activity in the concentrations used and this is dissolved or dispersed in the dosage form.
2. Halbfeste oder flüssige transdermale Darreichungsform nach Anspruch 1 , dadurch gekennzeichnet, dass die Darreichungsform ein hydroalkoholisches2. Semi-solid or liquid transdermal dosage form according to claim 1, characterized in that the dosage form is a hydroalcoholic
Gel ist.Gel is.
3. Halbfeste oder flüssige transdermale Darreichungsform nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass der/d ie Verteilungskoeffizient/en [log P] des/der UV-Absorber/s) entweder größer als 3,0 oder kleiner als 1 ,0 ist/sind, vorzugsweise größer als 5,0 oder kleiner als 0, 0.3. Semi-solid or liquid transdermal dosage form according to claim 1 or 2, characterized in that the / the distribution coefficient (s) [log P] of the UV absorber (s) is either greater than 3.0 or less than 1.0 are /, preferably greater than 5.0 or less than 0, 0.
4. Halbfeste oder flüssige transdermale Darreichungsform nach mindestens einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass die molare Masse des/der UV-Absorber/s größer als 250 gmol"1 ist/sind, vorzugsweise größer als 500 gmol"1 '.4. Semi-solid or liquid transdermal dosage form according to at least one of the preceding claims, characterized in that the molar mass of the / UV absorber / s greater than 250 gmol "1 is / are, preferably greater than 500 gmol " 1 '.
5. Halbfeste oder flüssige transdermale Darreichungsform nach einem oder mehreren der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass der/ die UV-Absorber in einem Anteil von 1 - 1 0% enthalten ist , vorzugsweise 2-5%, bezogen auf die Summe der Masse der nicht-leichtflüchtigen Vehikelbestandteile.5. Semi-solid or liquid transdermal dosage form according to one or more of the preceding claims, characterized in that the / the UV absorber is contained in a proportion of 1 - 1 0%, preferably 2-5%, based on the sum of the mass nonvolatile vehicle components.
6. Halbfeste oder flüssige transdermale Darreichungsform nach mindestens einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass die im UV-Bereich absorbierende/n Substanz/en aus der Gruppe ausgewählt ist/sind, die p-Aminobenzoesäure und Aminobenzoesäurederivate,6. Semi-solid or liquid transdermal dosage form according to at least one of the preceding claims, characterized in that the ultraviolet-absorbing substance (s) is / are selected from the group consisting of p-aminobenzoic acid and aminobenzoic acid derivatives,
3-Benzylidenbornan-2-on und Benzylidenbornan- 2-on-Derivate, vorzugsweise 3-(4')Methylbenzyliden-bornan- 2-on, 3-(4-Sulfo)benzylidenbornan-2-on, 3-(4'- Trimethylammonium)-benzylidenbornan-2-on-Methylsulfat, Polymer von N- [2(und4)-(2-oxoborn-3-ylidenmethyl)benzyl]acrylamid, sowie Salicylsäurederivate umfasst.3-Benzylidenbornan-2-one and benzylidenebornan-2-one derivatives, preferably 3- (4 ') methylbenzylidene-bornan-2-one, 3- (4-sulfo) benzylideneburnan-2-one, 3- (4'-methylbenzylidene-bornan-2-one Trimethylammonium) -benzylidenbornan-2-one methylsulfate, polymer of N- [2 (and 4) - (2-oxoborn-3-ylidenemethyl) benzyl] acrylamide, and salicylic acid derivatives.
7. Halbfeste oder flüssige transdermale Darreichungsform nach mindestens einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass mindestens eine im wesentlichen im UVA- Bereich absorbierende Substanz enthalten ist, aus der Gruppe, die 2,4,6-Trianilin-p-(carbo-2'-ethyl-hexyl- 1 '-oxy)-1 ,3,5-triazin, Dioctyl Butamido Triazin, Bis-Ethylhexyloxyphenol Methoxyphenyltriazin, 3-lmidazol-4-yl-acrylsäure, 2- Phenylenbenzimidazol-5-sulfonsäure und ihre K-, Na- und Triethanolamin(=TEA)-Salze, 2,2'-(1 ,4-Phenylen)bis(1 H- benzimidazol-4, 6-disulfonsäure, Mononatriumsalz), Methylen bis- benzotriazolyl-tetramethylbutylphenol, Drometriazol trisiloxan, 2- Cyan-3, 3-diphenylacrylsäure, Terephthaloyliden-dicampher- sulfonsäure, Butylmethoxy-dibenzoyl-methan, sowie Benzophenone oder Benzophenon-Derivate, vorzugsweise Benzophenon-3, Benzophenon-4, 2,2'-Dihydroxy-4,4'- dimethoxybenzophenon-5,5 '-di-Natriumsulfonat umfasst. 7. Semi-solid or liquid transdermal dosage form according to at least one of the preceding claims, characterized in that at least one substantially UVA absorbing substance is included from the group consisting of 2,4,6-trianiline p- (carbo-2'-ethyl-hexyl-1'-oxy) -1, 3,5-triazine, dioctyl butamido triazine, bis-ethylhexyloxyphenol methoxyphenyl triazine, 3-imidazol-4-yl-acrylic acid, 2-phenylene benzimidazole-5-sulfonic acid and their K, Na and triethanolamine (= TEA) salts, 2, 2 '- (1,4-phenylene) bis (1H-benzimidazole-4,6-disulfonic acid, monosodium salt), methylenebisbenzotriazolyl-tetramethylbutylphenol, drometriazole trisiloxane, 2-cyano-3,3-diphenylacrylic acid, terephthaloylidene-dicampheric acid sulfonic acid, Butylmethoxy dibenzoyl-methane, and benzophenone or benzophenone derivatives, preferably benzophenone-3, benzophenone-4, 2,2 '-dihydroxy-4,4' - comprises dimethoxybenzophenone-5,5 '-di-sodium sulfonate.
8. Halbfeste oder flüssige transdermale Darreichungsform nach mindestens einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass als lichtempfindlicher pharmazeutischer Wirkstoff mindestens ein Hormon enthalten ist . 8. Semi-solid or liquid transdermal dosage form according to at least one of the preceding claims, characterized in that at least one hormone is contained as the photosensitive pharmaceutical active ingredient.
9. Halbfeste oder flüssige transdermale Darreichungsform nach mindestens einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass der pharmazeutische Wirkstoff ein Gestagen, vorzugsweise Gestoden oder Levonorgestrel ist.9. Semi-solid or liquid transdermal dosage form according to at least one of the preceding claims, characterized in that the pharmaceutical active substance is a gestagen, preferably gestodene or levonorgestrel.
10. Halbfeste oder flüssige transdermale Darreichungsform nach mindestens einem der Ansprüche 1 bis 8, dadurch gekennzeichnet, dass der pharmazeutische Wirkstoff ein Estrogen, vorzugsweise Ethinylestradiol ist.10. Semi-solid or liquid transdermal dosage form according to at least one of claims 1 to 8, characterized in that the pharmaceutical active substance is an estrogen, preferably ethinylestradiol.
1 1. Halbfeste oder flüssige transdermale Darreichungsform nach den Ansprüchen 9 und 1 0, dadurch gekennzeichnet, dass zwei Wirkstoffe in einer Kombination von Gestagen und Estrogen, vorzugsweise Gestoden und Ethinylestradiol ist.1 1. Semi-solid or liquid transdermal dosage form according to claims 9 and 1 0, characterized in that two active ingredients in a combination of progestogen and estrogen, preferably gestodene and ethinyl estradiol.
12. Halbfeste oder flüssige transdermale Darreichungsform nach mindestens einem der Ansprüche 1 bis 8, dadurch gekennzeichnet, dass der pharmazeutische Wirkstoff ein Androgen, vorzugsweise Testosteron, Methyltestosteron, Methylnortestosteron (MENT) oder 7α-Methyl-1 1 ß-fluor-19-nortestosteron (ef-MENT) ist. 12. Semi-solid or liquid transdermal dosage form according to at least one of claims 1 to 8, characterized in that the pharmaceutical active substance is an androgen, preferably testosterone, methyltestosterone, methylnortestosterone (MENT) or 7α-methyl-1 1β-fluoro-19-nortestosterone ( ef-MENT).
13. Halbfeste oder flüssige transdermale Darreichungsform nach mindestens einem der vorhergehenden Ansprüche , dadurch gekennzeichnet, dass das System farblos und transparent ist. 13. Semi-solid or liquid transdermal dosage form according to at least one of the preceding claims, characterized in that the system is colorless and transparent.
EP04803546A 2003-12-10 2004-12-06 Uv light-stable semi-solid transdermal systems comprising a photosensitive active agent and an uv-absorbing component Withdrawn EP1703892A2 (en)

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EP03028353A EP1541136A1 (en) 2003-12-10 2003-12-10 UV light-stable semi-solid transdermal systems comprising a photosensitive active agent and an UV-absorbing component
PCT/EP2004/013839 WO2005055975A2 (en) 2003-12-10 2004-12-06 Uv-stable semi-solid transdermal systems comprising a photosensitive active ingredient and a uv absorber
EP04803546A EP1703892A2 (en) 2003-12-10 2004-12-06 Uv light-stable semi-solid transdermal systems comprising a photosensitive active agent and an uv-absorbing component

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EP1541136A1 (en) 2005-06-15
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WO2005055975A2 (en) 2005-06-23
BRPI0416979A (en) 2007-02-21
JP2007534643A (en) 2007-11-29
WO2005055975A3 (en) 2009-03-12
MXPA06006534A (en) 2006-08-01
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