WO1997021428A1 - Cortisone spray for topical administration - Google Patents

Cortisone spray for topical administration Download PDF

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Publication number
WO1997021428A1
WO1997021428A1 PCT/CH1996/000434 CH9600434W WO9721428A1 WO 1997021428 A1 WO1997021428 A1 WO 1997021428A1 CH 9600434 W CH9600434 W CH 9600434W WO 9721428 A1 WO9721428 A1 WO 9721428A1
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Prior art keywords
pharmaceutical composition
dermal
combination
component
active ingredient
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PCT/CH1996/000434
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German (de)
French (fr)
Inventor
Hans Georg Weder
Marc Antoine Weder
Original Assignee
Vesifact Ag
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Priority to AU76899/96A priority Critical patent/AU7689996A/en
Priority to EP96939798A priority patent/EP0866689A1/en
Publication of WO1997021428A1 publication Critical patent/WO1997021428A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams

Definitions

  • the present invention relates to a pharmaceutical composition for the dermal application of hydrocortisone or a derivative thereof, a process for the preparation of this pharmaceutical composition and its use in therapy
  • the body's own glucocorticoid hormone hydrocortisone (cortisol), Merck Index Elevenlh Edition (1989), No. 47J0, page 4711, chemical name: 11, 17, 21-trihydroxypregn-4- en-3,20-dione, is used dermally as an anti-inflammatory agent for treatment of inflammatory skin diseases, e.g. Eczema, psoriasis, dermatitis, contact allergies, etc. administered The Index Nominum 1992/93, Swiss Pharmaceutical Society, Medpharm, Be ent ß c Publ. D-Stuttgari, lists 81 dermal preparations with registered trademarks for the active ingredient hydrocortisone. There are also numerous of the derivatives, especially the 21 acetate
  • the present invention is therefore based on the object of producing a dermal preparation for the active ingredient hydrocortisone with improved effectiveness at low dosage.
  • the present invention is therefore based on the object in the narrower sense, to produce an improved dermal preparation for the active ingredient hydrocortisone, which is suitable for over-the-counter dispensing as a so-called OTC preparation (over-the-counter preparation) as part of the so-called self-medication
  • the solution to the problem is based on the consideration that by increasing the solubility of the active ingredient hydrocortisone in the formulation base, an improvement in activity should be achieved with a consistently low concentration.
  • Hydrocortisone itself is poorly soluble in water, which is an essential component in dermal formulations.
  • Merck Index, loc. eit. indicates a water solubility of 0.28 mg / ml (25 ° C)
  • the active ingredient is more soluble in ethanol 15 mg / ml (25 ° C)
  • the addition of large amounts of ethanol to improve the solubility of the active ingredient is for dermal preparations unfavorable, since ethanol also acts as a solvent for other components of the formulation and requires the skin to dry out.
  • a lipophilic formulation base consisting of a partial fatty acid ester of polyoxyethylene sorbitan, a phospholipid and a neutralol is suitable for producing a particularly homogeneous, finely dispersed, nanodispersion of the active ingredient hydrocortisone
  • the subject of the present invention is a pharmaceutical composition for the dermal application of a corticoid, which contains the following components: a) the active ingredient 1 l, 17,21-trihydroxypregn-4-en-3,20-dione (hydrocortisone) or a derivative thereof, optionally in combination with a wound treatment agent, b) at least one partial fatty acid ester of polyoxyethylene sorbitan or a combination thereof; c) at least one essentially pure phospholipid of the formula:
  • R C ⁇ o- 2 o-acyl, R 2 hydrogen or C ⁇ o- 2 o-acyl, R 3 hydrogen, 2-trimethylamino-1-ethyl, 2-amino-1-ethyl, C M - alkyl, C ⁇ - 5 alkyl substituted by Carboxy, C 2 .5-alkyl substituted by hydroxy, C 2 . 5- alkyl substituted by carboxy and hydroxy or C ⁇ -s-alkyl substituted by carboxy and amino, which mean inositol or the glyceryl group, or salts of these compounds; d) a triglyceride of the formula:
  • Ri, R 2 and R 3 Cg. 24 is acyl; e) water as carrier liquid in the purity required for dermal application; and optionally f) excipients suitable for dermal dosage forms.
  • This pharmaceutical composition is characterized by favorable phase properties of the solubilized active ingredient. With opalescence and transparency in the backlight, it can only be seen from an extremely low milky haze that the suspension still shows physical differences from the ideal state of a real molecular solution. Electron microscopic images show that a population of more than 98% of the active ingredient is in a Gaussian distribution as a dispersion of particles (nanoparticles) with a particle size smaller than approx. 50 nm (nanodispersion).
  • a preferred embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a) the active ingredient hydrocortisone or the 21 acetate, optionally in combination with dexpanthenol, b) the combination consisting of polysorbate 20, 80 and 60, c) purified lecithin from soybeans, d) a triglyceride the group of neutral oils, and e) water as carrier liquid in the purity required for dermal application, and optionally f) auxiliaries suitable for dermal dosage forms
  • the active ingredient hydrocortisone - component a) - is contained in the pharmaceutical composition defined above in the dosage permissible for dermal application.
  • the active ingredient hydrocortisone - component a) - is contained in the pharmaceutical composition defined above in the dosage permissible for dermal application.
  • the commercial formulations according to the Red List or Medicinal Compendium of Switzerland, Documed Basel, Switzerland there is one dose in non-prescription dermal preparations from about 0.1 to 0.5% (converted to free hydrocortisone)
  • a derivative of hydrocortisone is in particular 21-acetate, 21-acetate-17-propionate (aceponate), 21-bendazac, 17 ⁇ -butyrate, 17 ⁇ -butyrate-21-propionate, 21-cipionate (cyclopentane propionate), 21-dinatium phosphate , 21-hydrogen succinate, 21 -sodium succ ⁇ nate, 21 - tebutate (tert-butyl acetate), 17-valerate or the xanthate
  • the active ingredient hydrocortisone or one of the derivatives mentioned can be contained in the pharmaceutical composition in combination with a known wound treatment agent or epithelizing agent, for example dexpanthenol
  • Component b) - partial fatty acid ester of polyoxyethylene sorbitan preferably consists of an essentially pure or a mixture of different esters of sorbitan, in which the structure of the fatty acid groups and the length of the polyoxyethylene chains vary.
  • the sorbitan is preferably etherified by three hydrophilic polyoxyethylene chains and esterified by a hydrophobic fatty acid group But the sorbitan can only be done by one or two hydrophilic polyoxyethylene chains must be etherified and correspondingly esterified by three or two hydrophobic fatty acid groups.
  • the sorbitan basic body is substituted by at least one to a maximum of three hydrophilic polyoxyethylene groups and accordingly by a maximum of three and at least one hydrophobic fatty acid group
  • the polyoxyethylene chain is straight-chain and preferably has 4-10, in particular 4-8, ethylene oxide units.
  • the ester groups on the sorbitan base are derived from a saturated or unsaturated, straight-chain carboxylic acid and an even number of 8-20 carbon atoms.
  • the ester group derived from this carboxylic acid is preferably straight-chain with 12, 14, 16 and 18 carbon atoms, for example n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl
  • the ester group derived from an unsaturated carboxylic acid with an even number of 8-20 C atoms is preferably straight-chain with 12, 14, 16 and 18 C atoms, for example Oleoyl.
  • the esters of sorbitan mentioned fulfill the information given in the British Pharmacopoeia (special monograph) or Ph. Helv. VII.
  • the product descriptions published by the named manufacturers with the information on data sheets for the relevant product apply, in particular specifications such as shape, color, HLB value, viscosity, rising melting point and solubility
  • Suitable partial fatty acid esters of polyoxyethylene sorbitan are commercially available under the word symbol Tween * 81 from ICI and have the chemical names polyoxyethylene (20 or 4) sorbitan monolaurate (TWEEN 20 and 21), polyoxyethylene (20) sorbitan monopalmitate or monostearate ( TWEEN 40 and 60), polyoxyethylene (4 or 20) sorbitan monostearate or tristearate (TWEEN 61 and 65), polyoxyethylene (20 or 5) sorbitan mono oleate (TWEEN 80 or 81) or polyoxyethylene (20) -sorbitan trioleate (TWEEN 85) known
  • a combination consisting of TWEEN 20, TWEEN 80 and TWEEN 60 or polysorbate 20, 80 and 60 is used as component b)
  • Component b) is contained in the pharmaceutical composition in a proportion (based on the total weight of the formulation) of approximately 1.0% to 5.0%, preferably 1.0% to 3.0% Component c) - Phospholipid of the formula I
  • the nomenclature of the phosphohpides (I) and the numbering of the C atoms is carried out using the "Nomenclature of Lipids" from the IUPAC-IUB Commission on in Eur J ofBiochem 79, 1 1-21 (1977) Biochemical Nomenclature (CBN) given recommendations (sn-nomenclature, stereospecific numbe ⁇ ng)
  • R 1 and R 2 with the meanings C ] 0-2 o-acyl are preferably straight-chain C 10 .
  • Straight-chain C 10-20 alkanoyl R 1 and R 2 with an even number of C atoms are, for example, n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl
  • Straight-chain C ⁇ o- 2 o-alkenoyl R 1 and R 2 with a double bond and an even number of carbon atoms are, for example, 6-cis or 6-trans, 9-cis or 9-trans-dodecenoyl, tetradecenoyl, hexadecenoyl , Octadecenoyl or icosenoyl, in particular 9-cis-octa-decenoyl (oleoyl), further 9,12-cis-octadecadienoyl or 9, 12,15-cis-octadecatrienoyl
  • a phospholipid (I) in which R 3 denotes 2-trimethylamino-1-ethyl is designated with the trivial name lecithin and a phospholipid (I) in which R 3 denotes 2-amino-1-ethyl with the trivial name cephalin are suitable, for example naturally occurring cephalin or lecithin, for example cephalin or lecithin from soybeans or chicken eggs with different or identical acyl groups R 1 and R 2 , or mixtures thereof
  • the phospholipid (I) can also be of synthetic origin.
  • synthetic phospholipid is used to define phosphohpides which have a uniform composition with respect to R 1 and R 2 .
  • Such synthetic phosphohpides are preferably the lecithins and cephalins defined above, whose acyl groups R 1 and R 2 have a defined structure and are derived from a defined fatty acid with a purity higher than about 95%.
  • R 1 and R 2 can be the same or different and unsaturated or saturated
  • Rj is preferably saturated, for example n-hexadecanoyl, and R 2 is unsaturated, for example 9-c ⁇ s- octadecenoyl (oleoyl)
  • phospholipid (I) defines phosphohpides which have no uniform composition with respect to Rj and R 2 .
  • Pholipids are also lecithins and kephalins, the acyl groups R 1 and R 2 of which are structurally indefinable and derived from naturally occurring fatty acid mixtures
  • the requirement "essentially pure" phospholipid (I) defines a degree of purity of more than 90% (by weight), preferably more than 95%, of the phospholipid (I), which can be determined using suitable determination methods, for example paper chromatography, with thin-layer chromatography HPLC or enzymatic. Color test, is detectable
  • R 3 is C M alkyl, for example methyl or ethyl. The meaning methyl is preferred
  • R 3 with the meanings C ⁇ _ 5 alkyl substituted by carboxy, C 2 . 5 - Alkyl substituted by hydroxy or C 2 .5-alkyl substituted by carboxy or hydroxy are for example 2-hydroxyethyl, 2,3-dihydroxy-n-propyl, carboxymethyl, 1- or 2-carboxyethyl, dicarboxymethyl, 2-carboxy -2-hydroxyethyl or 3-carboxy-2,3-dihydroxy-n-propyl
  • R 3 with the meaning C 2 - 5 alkyl substituted by carboxy and amino is for example 3-Am ⁇ no-3-carboxy-n-propyl or 2-amino-2-carboxy-n-propyl, preferably 2-Am ⁇ no-2- carboxyethy!
  • Phosphohpides (I) with these groups can be in salt form, for example as the sodium or potassium salt
  • Phosphohpides (1) in which Ri denotes the inositol or glyceryl group, are known under the names phosphatidylinositol and phosphatidylglycerol
  • 9-cis-dodecenoyl (lauroleoyl), 9-cis-tetradecenoyl (myristoleoyl), 9-cis-hexadecenoyl (palmitoleoyl), 6-cis-octadecenoyl (petroseloyl), 6-trans-octadecenoyl (petroselecoyoyl), 9 (Oleoyl), 9-trans-octadecenoyl (Elaidoyl), 9,12-cis-octadecadienoyl (Linoleoyl), 9,12, 15-cis-octadecatrienoyl (Linolenoyl), l l-cis-octadecenoyl (Vaccenoyl), 9-cis Icosenoyl (gadoleoyl), 5,8, 11,14-cis-eicosatetra
  • Component c) is added in a preferred concentration of about 0.05 to 1.0% by weight, preferably 0.05 to 0.1% by weight, based on the total weight of the formulation.
  • purified is used Lecithin from soybeans of the quality LIPOID S 100
  • R 1, R 2 and R 3 are straight-chain Cs- 24- acyl with an even number of C atoms, in particular n-octanoyl, n-dodecanoyl, n-tetradecanoyl, n -Hexadecanoyl, n-octadecanoyl, 9-cis-dodecenoyl, 9-cis-tetradecenoyl, 9-cis-hexadecenoyl, 9-cis-octadecenoyl or 9-cis- icosenoyl.
  • Ri, R 2 and R 3 can be identical or different
  • the individual groups R 1 , R 2 and R 3 are themselves structurally uniformly defined. This is characteristic of synthetic or semisynthetic triglycerides, R 1, R 2 and R-, but can also consist of different acyl groups of different structure. This is for triglycerides of natural origin characteristic
  • a triglyceride of the formula II is a semisynthetic or synthetic, essentially pure triglyceride or a pharmaceutically usable triglyceride of natural origin.
  • a triglyceride of natural origin is preferred, eg peanut, sesame, sunflower, olive, corn germ, soybean, castor -, Cottonseed, rapeseed, safflower, grape seed, fish or coconut oil
  • a triglyceride defined by the term neutralol with different acyl groups of different structure is used, for example a triglyceride of the fractionated coconut fatty acids C 8 -Cio of the Migiyol ® type, for example MIGLYOL 812
  • the triglyceride (II) is contained in the pharmaceutical composition defined above in a preferred concentration range of approximately 0.1 to 2.0% by weight, preferably 0.1 to 1.0% by weight, based on the total weight of the formulation Component e) - water as carrier liquid in the purity required for dermal application - is germ and pyrogen free according to the regulations of the national pharmacopoeia
  • auxiliaries suitable for dermal formulations - is contained as an optional component.
  • auxiliaries are contained in creams, ointments, gels, lotions, pastes, foams, tinctures or lotions
  • ethanol in particular in small amounts of approx. 0.1 to 5%, isopropanol, furthermore preservatives, for example benzalkonium chloride, phenoxyethanol, furthermore benzoic acid or its salts, 4-hydroxy-benzoic acid ester (PHB ester), phenols, eg tert -Butyl-4-methoxy- or di-tert-butyl-4-methylphenol, benzyl alcohol, 4-chloro- or 2,4-dichlorobenzyl alcohol, 2-phenylethanol, chlorhexidine diacetate or digluconate, thiabendazole, cetyltriammonium bromide, cetylpyridinium bromidium bromide, phenododecarboxylic acid, phenodinodinodromide , Antioxidants, e.g.
  • the present invention also relates to the known process for the preparation of the pharmaceutical composition, which is characterized in that a lipophilic phase consisting of components a) to d) with the aqueous carrier liquid, which optionally contains water-soluble excipients suitable for dermal dosage forms , mixed and, if desired, the available clear, opalescent dispersion based on nanoparticles - nanodispersion - undergoes the following post-operations, adding a further amount of water as carrier liquid and, if appropriate, further water-soluble auxiliaries which are suitable for dermal dosage forms, and, if appropriate, filtration (e.g. Sterile filtration) of the nanodispersion, and / or further processing of the nanodispersion into a dermal preparation
  • a lipophilic phase consisting of components a) to d) with the aqueous carrier liquid, which optionally contains water-soluble excipients suitable for dermal dosage forms , mixed and, if desired, the available clear, opalescent dispersion based
  • a lipophilic phase "oil phase” consisting of component c) - phospholipid (I) -, ethanol, component b), - partial fatty acid ester of polyoxyethylene sorbitan -, component a) - active ingredient, and component d) - triglyceride (II) - forth.
  • the components are mixed at low speed at room temperature using a conventional stirrer with a propeller or a blade, a magnetic stirrer or a static mixer.
  • a combination of different partial fatty acid esters of polyoxyethylene sorbitan is used, in particular the combination consisting of polysorbate 20, 80 and 60. Attention is paid to the sequence by first mixing the phospholipid and the ethanol with one another and then polysorbate 20, 80 in succession and 60 adds. Neutralol is then added by mixing the lipophilic phase ("oil phase") with the aqueous phase which contains water-soluble optional additives, e.g.
  • Preservatives which can contain a low-speed agitator (200 to 1,000 rpm) or a static mixer, form the pharmaceutical composition defined above, which can be defined as a dispersion of colloidal nanoparticles of the lipophilic active ingredient hydrocortisone or simply as nanodispersion due to lasers -Light scatter measurements and electron microscope images distinguish the colloidal particles present in the nanodispersion from other structures such as liquid crystals, micelles, reverse micelles or liposomes.
  • an average particle size is smaller than 50 nm characteristic
  • the nanodispersion can be applied directly after adding the desired amount of water and, if necessary, other auxiliary substances that can be used for dermal dosage forms, e.g. as a dosing spray.
  • auxiliary substances that can be used for dermal dosage forms, e.g. as a dosing spray.
  • a particular advantage over conventional dermal preparations is the possibility of sterile filtration.If desired, sterile filtration can be used to remove all those in the dispersion larger particles with a diameter larger than approx. 200 nm, as well as suspended and solid matter, and so produce a nanodispersion with a fraction of particles of relatively uniform size.
  • Suitable containers are e.g. containers for pump sprays or dosing sprays or plastic containers with a discharge device
  • composition described above with the anti-inflammatory hydrocortisone is suitable as a dermal preparation for the treatment of all diseases of the skin and on the eye.
  • the preparation is used in the prescribed dosage
  • the aqueous phase is prepared by adding (9) in (8) at room temperature.
  • the oil phase is obtained by introducing (1) in (2) until the solution becomes clear.
  • the active ingredient (6) is added in three portions and heated to 60 ° C. until no more crystals are visible. (7) add, mix until the solution becomes clear and cool to room temperature
  • the aqueous phase is combined with the oil phase by introducing the aqueous phase at room temperature and stirring at 300-400 rpm with a magnetic stirrer.
  • the oil phase is then slowly injected into the aqueous phase over a period of about two minutes at a level another 5-10 min avoiding foaming and filters the nanodispersion through a germ filter (0.2 ⁇ m)

Abstract

The present invention relates to a pharmaceutical mixture for the dermal application of hydrocortisone. The active agent is dispersed with the addition of a partial fatty acid ester of polyoxyethylene sorbitan and other auxiliaries like lecithin and neutral oil. This provides a suspension of nanoparticles of the lipophilic agent hydrocortisone.

Description

CORTISOLSPRAY ZUR TOPISCHEN VERABREICHUNG CORTISOL SPRAY FOR TOPICAL ADMINISTRATION
Die vorliegende Erfindung betrifft eine pharmazeutische Zusammensetzung für die dermale Applikation von Hydrocortison oder einem Derivat davon, Verfahren zur Herstellung dieser pharmazeutischen Zusammensetzung sowie ihre Anwendung in der TherapieThe present invention relates to a pharmaceutical composition for the dermal application of hydrocortisone or a derivative thereof, a process for the preparation of this pharmaceutical composition and its use in therapy
Das körpereigene Glucocorticoidhormon Hydrocortison (Cortisol), Merck Index Elevenlh Edition (1989), Nr.47J0, Seite 4711, Chemische Bezeichnung: 11, 17, 21-Trihydroxypregn-4- en-3,20-dion, wird dermal als Antiinflammatorikum zur Behandlung von entzündlichen Hautkrankheiten, z.B. Ekzemen, Psoriasis, Dermatitiden, Kontaktallergien etc , verabreicht Der Index Nominum 1992/93, Swiss Pharmaceutical Society, Medpharm, Sei ent iß c Publ. D- Stuttgari, zählt für den Wirkstoff Hydrocortison 81 dermale Präparate mit eingetragenen Warenzeichen auf. Von den Derivaten, insbesondere dem 21 -Acetat, sind ebenfalls zahlreicheThe body's own glucocorticoid hormone hydrocortisone (cortisol), Merck Index Elevenlh Edition (1989), No. 47J0, page 4711, chemical name: 11, 17, 21-trihydroxypregn-4- en-3,20-dione, is used dermally as an anti-inflammatory agent for treatment of inflammatory skin diseases, e.g. Eczema, psoriasis, dermatitis, contact allergies, etc. administered The Index Nominum 1992/93, Swiss Pharmaceutical Society, Medpharm, Be ent ß c Publ. D-Stuttgari, lists 81 dermal preparations with registered trademarks for the active ingredient hydrocortisone. There are also numerous of the derivatives, especially the 21 acetate
Da die genannten entzündlichen Hautkrankheiten sehr hartnäckig und langwierig sein können, Präparate bekannt sollte sich ein dermales Präparat für die Verabreichung in einem längeren Zeitraum eignen Bei länger andauernder Anwendung von Glucocorticoiden auf der Haut sind trotz guter Wirksamkeit und nachweislichen Heilungserfolgen aber auch systemische Effekte und Nebenwirkungen problematisch, siehe hierzu den Abschnitt G 10 in Rote Liste 1994, Arznemuttelverzeichnis des BPI (Bundesverband der Pharmazeutischen Industrie), ECV Editio Cantor, D-88322 Aulendorf, Nr. 64008. Zahlreiche dermale Präparate enthalten daher anstelle eines der zahlreichen in der Literatur beschriebenen hoch wirksamen, neueren Wirkstoffe vom Glucocorticoidtyp nur das seit langem bekannte, schwächer wirksame Hydrocortison und dieses auch noch in äusserst niedriger Dosierung, z.B meistens 1 mg pro Gramm Formulierung. Man hat daher versucht, die geringe Wirksamkeit solcher Präparate durch eine Dosiserhöhung zu verbessern Präparate mit einer höheren Dosierung selbst von Hydrocortison müssen aber wegen der bekannten Nebenwirkungen und der zahlreichen Kontraindikationen der ärztlichen Kontrolle und der Rezeptpflicht unterstellt werdenSince the inflammatory skin diseases mentioned can be very persistent and lengthy, preparations known to be suitable should be a dermal preparation for administration over a longer period of time.Using glucocorticoids on the skin for a prolonged period of time, systematic effects and side effects are problematic despite good effectiveness and proven healing results , see section G 10 in Rote Liste 1994, list of medicinal products of the BPI (Federal Association of the Pharmaceutical Industry), ECV Editio Cantor, D-88322 Aulendorf, No. 64008. Numerous dermal preparations therefore contain instead of one of the numerous highly effective ones described in the literature , newer active substances of the glucocorticoid type only the long-known, weakly effective hydrocortisone and this also in extremely low doses, eg mostly 1 mg per gram of formulation. Attempts have therefore been made to improve the low efficacy of such preparations by increasing the dose. Preparations with a higher dose even of hydrocortisone must, however, be subject to medical supervision and the prescription obligation because of the known side effects and the numerous contraindications
Der vorliegenden Erfindung liegt daher die Aufgabe zugrunde, für den bewahrten Wirkstoff Hydrocortison ein dermales Präparat mit verbesserter Wirksamkeit bei geringer Dosierung herzustellen Der vorliegenden Erfindung liegt daher im engeren Sinne die Aufgabe zugrunde, für den Wirkstoff Hydrocortison eine verbessertes dermales Präparat herzustellen, welches sich für die rezeptfreie Abgabe als sogenanntes OTC-Praparat (Over-the-Counter- Präparat) im Rahmen der sogenannten Selbstmedikation eignetThe present invention is therefore based on the object of producing a dermal preparation for the active ingredient hydrocortisone with improved effectiveness at low dosage. The present invention is therefore based on the object in the narrower sense, to produce an improved dermal preparation for the active ingredient hydrocortisone, which is suitable for over-the-counter dispensing as a so-called OTC preparation (over-the-counter preparation) as part of the so-called self-medication
Die Losung der Aufgabenstellung beruht auf der Überlegung, dass man durch Erhöhung der Löslichkeit des Wirkstoffs Hydrocortison in der Formulierungsgrundlage eine Wirkungs¬ verbesserung bei gleichbleibend niedriger Konzentration erzielen sollte Hydrocortison selbst ist in Wasser, das in dermalen Formulierungen ein wesentlicher Bestandteil ist, schlecht loslich Der Merck Index, loc. eit., gibt eine Wasserloslichkeit von 0,28 mg/ml (25°C) an In Ethanol ist der Wirkstoff besser loslich 15 mg/ml (25°C) Die Zugabe grosserer Mengen Ethanol zur Verbesserung der Löslichkeit des Wirkstoffs ist für dermale Präparate ungunstig, da Ethanol für andere Bestandteile der Formulierung ebenfalls als Solvens wirkt und die Austrocknung der Haut fordert Alternativ zur Verwendung eines ungeeigneten Lösungsmittels schlagen zahlreiche Publikationen wässrige feindisperse Systeme mit Losungseigenschaften auf der Basis von Lipidgemischen vor Darin ist der unlösliche Wirkstoff in Lipidpartikeln mit einer Teilchengrosse kleiner als 1 μm eingeschlossen, welche mit der wässrigen Tragerflussigkeit ein kolloiddisperses oder vorzugsweise ein feindisperses System bilden, das zwar keine echte molekular disperse Losung darstellt, aber für eine dermale Formulierung trotzdem ausreichend homogen ist In der Fachliteratur wird die Verkapselung von lipophilen und/oder schwerlöslichen Wirkstoffen in Mizellen, Mischmizellen, Umkehrmizelien, uniiamellaren, multilamellaren Liposomen, Nanokapseln, Nanopartikeln etc erörtertThe solution to the problem is based on the consideration that by increasing the solubility of the active ingredient hydrocortisone in the formulation base, an improvement in activity should be achieved with a consistently low concentration. Hydrocortisone itself is poorly soluble in water, which is an essential component in dermal formulations. Merck Index, loc. eit., indicates a water solubility of 0.28 mg / ml (25 ° C) The active ingredient is more soluble in ethanol 15 mg / ml (25 ° C) The addition of large amounts of ethanol to improve the solubility of the active ingredient is for dermal preparations unfavorable, since ethanol also acts as a solvent for other components of the formulation and requires the skin to dry out. As an alternative to using an unsuitable solvent, numerous publications suggest aqueous, finely dispersed systems with solution properties based on lipid mixtures. The insoluble active substance in lipid particles with a particle size is smaller included as 1 μm, which form a colloidally disperse or preferably a finely disperse system with the aqueous carrier liquid, which is not a true molecularly disperse solution, but is nevertheless sufficiently homogeneous for a dermal formulation. The encapsulation of lipophilic and / or sparingly soluble active ingredients is known in the specialist literature are discussed in micelles, mixed micelles, reverse micelles, uniiamellar, multilamellar liposomes, nanocapsules, nanoparticles, etc.
Es wurde überraschenderweise gefunden, dass sich eine lipophile Formulierungsgrundlage bestehend aus einem Partialfettsäureester des Polyoxyethylensorbitans, einem Phospholipid und einem Neutralol zur Herstellung einer besonders homogenen feindispersen, Nanodispersion des Wirkstoffs Hydrocortison eignetIt has surprisingly been found that a lipophilic formulation base consisting of a partial fatty acid ester of polyoxyethylene sorbitan, a phospholipid and a neutralol is suitable for producing a particularly homogeneous, finely dispersed, nanodispersion of the active ingredient hydrocortisone
Die vorliegende Erfindung hat eine pharmazeutische Zusammensetzung für die dermale Applikation eines Corticoids zum Gegenstand, welche folgende Bestandteile enthalt a) den Wirkstoff 1 l, 17,21-Trihydroxypregn-4-en-3,20-dion (Hydrocortison) oder ein Derivat davon, gegebenenfalls in Kombination mit einem Wundbehandlungsmittel, b) mindestens einen Partialfettsäureester des Polyoxyethylensorbitans oder eine Kombination davon; c) mindestens ein im wesentlichen reines Phospholipid der Formel:The subject of the present invention is a pharmaceutical composition for the dermal application of a corticoid, which contains the following components: a) the active ingredient 1 l, 17,21-trihydroxypregn-4-en-3,20-dione (hydrocortisone) or a derivative thereof, optionally in combination with a wound treatment agent, b) at least one partial fatty acid ester of polyoxyethylene sorbitan or a combination thereof; c) at least one essentially pure phospholipid of the formula:
11
Figure imgf000005_0001
worin R| Cιo-2o-Acyl, R2 Wasserstoff oder Cιo-2o-Acyl, R3 Wasserstoff, 2-Trimethylamino-l- ethyl, 2- Amino- 1 -ethyl, CM- Alkyl, Cι-5-Alkyl substituiert durch Carboxy, C2.5-Alkyl substi¬ tuiert durch Hydroxy, C2.5-Alkyl substituiert durch Carboxy und Hydroxy oder C∑-s-Alkyl sub¬ stituiert durch Carboxy und Amino, die Inositol- oder die Glycerylgruppe bedeuten, oder Salze dieser Verbindungen; d) ein Triglycerid der Formel:
Figure imgf000005_0001
where R | Cιo- 2 o-acyl, R 2 hydrogen or Cιo- 2 o-acyl, R 3 hydrogen, 2-trimethylamino-1-ethyl, 2-amino-1-ethyl, C M - alkyl, Cι- 5 alkyl substituted by Carboxy, C 2 .5-alkyl substituted by hydroxy, C 2 . 5- alkyl substituted by carboxy and hydroxy or C∑-s-alkyl substituted by carboxy and amino, which mean inositol or the glyceryl group, or salts of these compounds; d) a triglyceride of the formula:
CHjO-COR. CH-O-COR, (||) CH2-0-COR3 CHjO-COR. CH-O-COR, (||) CH 2 -0-COR 3
worin Ri, R2 und R3 Cg.24-Acyl bedeuten; e) Wasser als Trägerflüssigkeit in der für die dermale Applikation erforderlichen Reinheit; und gegebenenfalls f) für dermale Darreichungsformen geeignete Hilfsstoffe.wherein Ri, R 2 and R 3 Cg. 24 is acyl; e) water as carrier liquid in the purity required for dermal application; and optionally f) excipients suitable for dermal dosage forms.
Diese pharmazeutische Zusammensetzung zeichnet sich durch günstige Phaseneigenschaften des solubilisierten Wirkstoffs aus. So ist bei vorhandener Opaleszenz und Transparenz im Gegenlicht nur an einer äusserst geringen milchigen Trübung zu erkennen, dass die Suspension noch physikalische Unterschiede gegenüber dem Idealzustand einer echten molekularen Lösung aufweist. Elektronenmikroskopische Abbildungen zeigen, dass eine Population von mehr als 98 % des Wirkstoffs in einer Gaussschen Verteilung als Dispersion von Partikeln (Nanopartikel) mit einer Teilchengrösse kleiner als ca. 50 nm (Nanodispersion) vorliegt. Diese Unterschiede gegenüber einer echten Lösung sind aber aufgrund der besonders guten Homogenitätseigenschaften der Dispersion hinnehmbar, die beispielsweise an einer überraschend hohen Lagerstabilitat, z B keine Entmischung nach mehrmonatiger Lagerung bei Temperaturen bis Raumtemperatur (durch Extrapolation zu erwartende Stabilität langer als zwei Jahre) nachweisbar sindThis pharmaceutical composition is characterized by favorable phase properties of the solubilized active ingredient. With opalescence and transparency in the backlight, it can only be seen from an extremely low milky haze that the suspension still shows physical differences from the ideal state of a real molecular solution. Electron microscopic images show that a population of more than 98% of the active ingredient is in a Gaussian distribution as a dispersion of particles (nanoparticles) with a particle size smaller than approx. 50 nm (nanodispersion). However, these differences compared to a real solution are acceptable due to the particularly good homogeneity properties of the dispersion, for example in one Surprisingly high storage stability, eg no separation after several months of storage at temperatures up to room temperature (stability to be expected by extrapolation longer than two years) can be demonstrated
Eine bevorzugte Ausführungsform betrifft eine pharmazeutische Zusammensetzung enthaltend a) den Wirkstoff Hydrocortison oder das 21 -Acetat, gegebenenfalls in Kombination mit Dexpanthenol, b) die Kombination bestehend aus Polysorbat 20, 80 und 60, c) gereinigtes Lecithin aus Sojabohnen, d) ein Triglycerid aus der Gruppe der Neutralöle, und e) Wasser als Tragerflussigkeit in der für die dermale Applikation erforderlichen Reinheit, und gegebenenfalls f) für dermale Darreichungsformen geeignete HilfsstoffeA preferred embodiment relates to a pharmaceutical composition comprising a) the active ingredient hydrocortisone or the 21 acetate, optionally in combination with dexpanthenol, b) the combination consisting of polysorbate 20, 80 and 60, c) purified lecithin from soybeans, d) a triglyceride the group of neutral oils, and e) water as carrier liquid in the purity required for dermal application, and optionally f) auxiliaries suitable for dermal dosage forms
Der Wirkstoff Hydrocortison - Komponente a) - ist in der weiter vorn definierten pharmazeu¬ tischen Zusammensetzung in der für dermale Applikation zulassigen Dosierung enthalten In den kommerziellen Formulierungen gemäss Rote Liste oder Arzneimittelkompendwm der Schweiz, Documed Basel, Schweiz, ist in rezeptfreien dermalen Präparaten eine Dosis von ca 0,1 bis 0,5 % (umgerechnet auf freies Hydrocortison) enthaltenThe active ingredient hydrocortisone - component a) - is contained in the pharmaceutical composition defined above in the dosage permissible for dermal application. In the commercial formulations according to the Red List or Medicinal Compendium of Switzerland, Documed Basel, Switzerland, there is one dose in non-prescription dermal preparations from about 0.1 to 0.5% (converted to free hydrocortisone)
Ein Derivat des Hydrocortison ist insbesondere das 21 -Acetat, 21 -Acetat- 17-propιonat (Aceponat), 21-Bendazac, 17α-Butyrat, 17α-Butyrat-21 -propionat, 21-Cipιonat (Cyclo- pentanpropionat), 21-Dinatπumphosphat, 21-Hydrogensuccinat, 21 -Natriumsuccιnat, 21 - Tebutat (tert Butylacetat), 17-Valerat oder das XanthogenatA derivative of hydrocortisone is in particular 21-acetate, 21-acetate-17-propionate (aceponate), 21-bendazac, 17α-butyrate, 17α-butyrate-21-propionate, 21-cipionate (cyclopentane propionate), 21-dinatium phosphate , 21-hydrogen succinate, 21 -sodium succιnate, 21 - tebutate (tert-butyl acetate), 17-valerate or the xanthate
Der Wirkstoff Hydrocortison oder eines der genannten Derivate kann in der pharmazeutischen Zusammensetzung in Kombination mit einem bekannten Wundbehandlungsmittel oder Epithelisierungsmittel, z B. Dexpanthenol, enthalten seinThe active ingredient hydrocortisone or one of the derivatives mentioned can be contained in the pharmaceutical composition in combination with a known wound treatment agent or epithelizing agent, for example dexpanthenol
Die Komponente b) - Partialfettsäureester des Polyoxyethylensorbitans - besteht vorzugsweise aus einem im wesentlichen reinen oder dem Gemisch verschiedener Ester des Sorbitans, worin die Struktur der Fettsauregruppen und die Lange der Polyoxyethylenketten variieren Das Sorbitan ist vorzugsweise durch drei hydrophile Polyoxyethylenketten verathert und durch eine hydrophobe Fettsauregruppe verestert Das Sorbitan kann aber auch nur durch ein oder zwei hydrophile Polyoxyethylenketten verathert und entsprechend durch drei oder zwei hydrophobe Fettsäuregruppen verestert sein. Insgesamt ist der Sorbitangrundkorper durch mindestens ein bis maximal drei hydrophile Polyoxyethylengruppen und entsprechend durch maximal drei und mindestens eine hydrophobe Fettsauregruppe substitutiertComponent b) - partial fatty acid ester of polyoxyethylene sorbitan - preferably consists of an essentially pure or a mixture of different esters of sorbitan, in which the structure of the fatty acid groups and the length of the polyoxyethylene chains vary. The sorbitan is preferably etherified by three hydrophilic polyoxyethylene chains and esterified by a hydrophobic fatty acid group But the sorbitan can only be done by one or two hydrophilic polyoxyethylene chains must be etherified and correspondingly esterified by three or two hydrophobic fatty acid groups. Overall, the sorbitan basic body is substituted by at least one to a maximum of three hydrophilic polyoxyethylene groups and accordingly by a maximum of three and at least one hydrophobic fatty acid group
Die Polyoxyethylenkette ist geradkettig und weist vorzugsweise 4-10, insbesondere 4-8, Ethylenoxideinheiten auf. Die Estergruppen am Sorbitangrundkoφer sind von einer gesattigten oder ungesättigten, geradkettigen Carbonsäure und gerader Anzahl von 8-20 C-Atomen abgeleitet Die von dieser Carbonsäure abgleitete Estergruppe ist vorzugsweise geradkettig mit 12, 14, 16 und 18 C-Atomen, z.B n-Dodecanoyl, n-Tetradecanoyl, n-Hexadecanoyl oder n- Octadecanoyl Die von einer ungesättigten Carbonsäure mit gerader Anzahl von 8-20 C- Atomen abgeleitete Estergruppe ist vorzugsweise geradkettig mit 12, 14, 16 und 18 C- Atomen, z.B. Oleoyl. Die genannten Ester des Sorbitans erfüllen die in der Britischen Pharmakopoe (spezielle Monographie) oder Ph. Helv. VII genannten Angaben. Es gelten insbesondere die von den genannten Herstellern publizierten Produktbeschreibungen mit den Angaben auf Datenblättern für das betreffende Produkt, insbesondere Spezifikationen wie Form, Farbe, HLB-Wert, Viskosität, Steigschmelzpunkt und LöslichkeitThe polyoxyethylene chain is straight-chain and preferably has 4-10, in particular 4-8, ethylene oxide units. The ester groups on the sorbitan base are derived from a saturated or unsaturated, straight-chain carboxylic acid and an even number of 8-20 carbon atoms. The ester group derived from this carboxylic acid is preferably straight-chain with 12, 14, 16 and 18 carbon atoms, for example n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl The ester group derived from an unsaturated carboxylic acid with an even number of 8-20 C atoms is preferably straight-chain with 12, 14, 16 and 18 C atoms, for example Oleoyl. The esters of sorbitan mentioned fulfill the information given in the British Pharmacopoeia (special monograph) or Ph. Helv. VII. In particular, the product descriptions published by the named manufacturers with the information on data sheets for the relevant product apply, in particular specifications such as shape, color, HLB value, viscosity, rising melting point and solubility
Geeignete Partialfettsäureester des Polyoxyethylensorbitans sind unter dem Wortzeichen Tween*81 der Fa.ICI kommerziell erhältlich und den chemischen Bezeichnungen Polyoxyethylen- (20 oder 4)-sorbitanmonolaurat (TWEEN 20 und 21), Polyoxyethylen-(20)-sorbitanmono- palmitat oder -monostearat (TWEEN 40 und 60), Polyoxyethylen-(4 oder 20)-sorbitan- monostearat oder -tristearat (TWEEN 61 und 65), Polyoxyethylen-(20 oder 5)-sorbitanmono- oleat (TWEEN 80 oder 81) oder Polyoxyethylen-(20)-sorbitantrioleat (TWEEN 85) bekanntSuitable partial fatty acid esters of polyoxyethylene sorbitan are commercially available under the word symbol Tween * 81 from ICI and have the chemical names polyoxyethylene (20 or 4) sorbitan monolaurate (TWEEN 20 and 21), polyoxyethylene (20) sorbitan monopalmitate or monostearate ( TWEEN 40 and 60), polyoxyethylene (4 or 20) sorbitan monostearate or tristearate (TWEEN 61 and 65), polyoxyethylene (20 or 5) sorbitan mono oleate (TWEEN 80 or 81) or polyoxyethylene (20) -sorbitan trioleate (TWEEN 85) known
In einer besonders bevorzugten Ausführungsform der Erfindung verwendet man als Komponente b) eine Kombination bestehend aus TWEEN 20, TWEEN 80 und TWEEN 60, bzw Polysorbat 20, 80 und 60In a particularly preferred embodiment of the invention, a combination consisting of TWEEN 20, TWEEN 80 and TWEEN 60 or polysorbate 20, 80 and 60 is used as component b)
Die Komponente b) ist in in der pharmazeutischen Zusammensetzung in einem Mengenanteil (bezogen auf das Gesamtgewicht der Formulierung) von ca 1 ,0 % bis 5,0 %, vorzugsweise 1,0 % bis 3,0 %, enthalten Komponente c) - Phospholipid der Formel I Die Nomenklatur der Phosphohpide (I) und die Bezifferung der C-Atome erfolgt anhand der in Eur J ofBiochem 79, 1 1-21 ( 1977) "Nomenclature of Lipids" von der IUPAC-IUB Commission on Biochemical Nomenclature (CBN) gegebenen Empfehlungen (sn-Nomenkiatur, stereospecific numbeπng)Component b) is contained in the pharmaceutical composition in a proportion (based on the total weight of the formulation) of approximately 1.0% to 5.0%, preferably 1.0% to 3.0% Component c) - Phospholipid of the formula I The nomenclature of the phosphohpides (I) and the numbering of the C atoms is carried out using the "Nomenclature of Lipids" from the IUPAC-IUB Commission on in Eur J ofBiochem 79, 1 1-21 (1977) Biochemical Nomenclature (CBN) given recommendations (sn-nomenclature, stereospecific numbeπng)
Ri und R2 mit den Bedeutungen C]0-2o-Acyl sind vorzugsweise geradkettiges C 10.20- Alkanoyl mit einer geraden Anzahl an C-Atomen und geradkettiges Cιo-2o-AJkenoyl mit einer Doppelbindung und einer geraden Anzahl an C-AtomenR 1 and R 2 with the meanings C ] 0-2 o-acyl are preferably straight-chain C 10 . 2 0- alkanoyl with an even number of carbon atoms and straight-chain Cιo- 2 o-AJkenoyl with a double bond and an even number of carbon atoms
Geradkettiges C 10-20- Alkanoyl Ri und R2 mit einer geraden Anzahl an C-Atomen sind beispielsweise n-Dodecanoyl, n-Tetradecanoyl, n-Hexadecanoyl oder n-OctadecanoylStraight-chain C 10-20 alkanoyl R 1 and R 2 with an even number of C atoms are, for example, n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl
Geradkettiges Cιo-2o-Alkenoyl Ri und R2 mit einer Doppelbindung und einer geraden Anzahl an C-Atomen sind beispielsweise 6-cis- oder 6-trans-, 9-cis- oder 9-trans-Dodecenoyl, -Tetradecenoyl, -Hexadecenoyl, -Octadecenoyl oder -Icosenoyl, insbesondere 9-cis-Octa- decenoyl (Oleoyl), ferner 9,12-cis-Octadecadienoyl oder 9, 12,15-cis-OctadecatrienoylStraight-chain Cιo- 2 o-alkenoyl R 1 and R 2 with a double bond and an even number of carbon atoms are, for example, 6-cis or 6-trans, 9-cis or 9-trans-dodecenoyl, tetradecenoyl, hexadecenoyl , Octadecenoyl or icosenoyl, in particular 9-cis-octa-decenoyl (oleoyl), further 9,12-cis-octadecadienoyl or 9, 12,15-cis-octadecatrienoyl
Ein Phospholipid (I), worin R3 2-Trimethylamino- 1-ethyl bedeutet, wird mit dem Trivialnamen Lecithin und ein Phospholipid (I), worin R3 2- Amino- 1-ethyl bedeutet, mit dem Trivialnamen Kephalin bezeichnet Geeignet sind beispielsweise naturlich vorkommendes Kephalin oder Lecithin, z B Kephalin oder Lecithin aus Sojabohnen oder Huhnerei mit verschiedenen oder identischen Acylgruppen Ri und R2, oder Mischungen davonA phospholipid (I) in which R 3 denotes 2-trimethylamino-1-ethyl is designated with the trivial name lecithin and a phospholipid (I) in which R 3 denotes 2-amino-1-ethyl with the trivial name cephalin are suitable, for example naturally occurring cephalin or lecithin, for example cephalin or lecithin from soybeans or chicken eggs with different or identical acyl groups R 1 and R 2 , or mixtures thereof
Das Phospholipid (I) kann aber auch synthetischen Ursprungs sein Unter dem Begriff synthetisches Phospholipid definiert man Phosphohpide, welche bezuglich Ri und R2 eine einheitliche Zusammensetzung haben. Solche synthetischen Phosphohpide sind vorzugsweise die weiter vorn definierten Lecithine und Kephaline, deren Acylgruppen Ri und R2 eine definierte Struktur haben und von einer definierten Fettsaure mit einem Reinheitsgrad hoher als ca 95% abgeleitet sind Ri und R2 können gleich oder verschieden und ungesättigt oder gesattigt sein Bevorzugt ist Rj gesattigt, z B n-Hexadecanoyl, und R2 ungesättigt, z B 9-cιs- Octadecenoyl (Oleoyl)The phospholipid (I) can also be of synthetic origin. The term synthetic phospholipid is used to define phosphohpides which have a uniform composition with respect to R 1 and R 2 . Such synthetic phosphohpides are preferably the lecithins and cephalins defined above, whose acyl groups R 1 and R 2 have a defined structure and are derived from a defined fatty acid with a purity higher than about 95%. R 1 and R 2 can be the same or different and unsaturated or saturated Rj is preferably saturated, for example n-hexadecanoyl, and R 2 is unsaturated, for example 9-cιs- octadecenoyl (oleoyl)
Der Begriff "natürlich vorkommendes" Phospholipid (I) definiert Phosphohpide, welche bezüglich Rj und R2 keine einheitliche Zusammensetzung haben Solche naturlichen Phos- pholipide sind ebenfalls Lecithine und Kephaline, deren Acylgruppen Ri und R2 strukturell undefinierbar und von naturlich vorkommenden Fettsauregemischen abgeleitet sindThe term "naturally occurring" phospholipid (I) defines phosphohpides which have no uniform composition with respect to Rj and R 2 . Pholipids are also lecithins and kephalins, the acyl groups R 1 and R 2 of which are structurally indefinable and derived from naturally occurring fatty acid mixtures
Die Forderung "im wesentlichen reines" Phospholipid (I) definiert einen Reinheitsgrad von mehr als 90%(Gew ), vorzugsweise mehr als 95%, des Phospholipids (I), welcher anhand geeigneter Bestimmungsmethoden, z B papierchromatographisch, mit Dunnschichtchroma- tographie, mit HPLC oder enzymatischen. Farbtest, nachweisbar istThe requirement "essentially pure" phospholipid (I) defines a degree of purity of more than 90% (by weight), preferably more than 95%, of the phospholipid (I), which can be determined using suitable determination methods, for example paper chromatography, with thin-layer chromatography HPLC or enzymatic. Color test, is detectable
In einem Phospholipid (I) ist R3 mit der Bedeutung CM-Alkyl beispielsweise Methyl oder Ethyl Die Bedeutung Methyl ist bevorzugtIn a phospholipid (I), R 3 is C M alkyl, for example methyl or ethyl. The meaning methyl is preferred
R3 mit den Bedeutungen Cι_5-Alkyl substituiert durch Carboxy, C2.5- Alkyl substituiert durch Hydroxy oder C2.5-Alkyl substituiert durch Carboxy oder Hydroxy sind beispielsweise 2- Hydroxyethyl, 2,3-Dihydroxy-n-propyl, Carboxymethyl, 1- oder 2-Carboxyethyl, Dicarboxy- methyl, 2-Carboxy-2-hydroxyethyl oder 3-Carboxy-2,3-dihydroxy-n-propylR 3 with the meanings Cι_ 5 alkyl substituted by carboxy, C 2 . 5 - Alkyl substituted by hydroxy or C 2 .5-alkyl substituted by carboxy or hydroxy are for example 2-hydroxyethyl, 2,3-dihydroxy-n-propyl, carboxymethyl, 1- or 2-carboxyethyl, dicarboxymethyl, 2-carboxy -2-hydroxyethyl or 3-carboxy-2,3-dihydroxy-n-propyl
R3 mit der Bedeutung C2-5-Alkyl substituiert durch Carboxy und Amino ist z B 3-Amιno-3- carboxy-n-propyl oder 2-Amino-2-carboxy-n-propyl, vorzugsweise 2-Amιno-2-carboxyethy! Phosphohpide (I) mit diesen Gruppen können in Salzform, z B als Natrium- oder Kaliumsalz, vorliegenR 3 with the meaning C 2 - 5 alkyl substituted by carboxy and amino is for example 3-Amιno-3-carboxy-n-propyl or 2-amino-2-carboxy-n-propyl, preferably 2-Amιno-2- carboxyethy! Phosphohpides (I) with these groups can be in salt form, for example as the sodium or potassium salt
Phosphohpide (1), worin Ri die Inositol- oder die Glycerylgruppe bedeutet, sind unter den Bezeichnungen Phosphatidylinositol und Phosphatidylglycerol bekanntPhosphohpides (1), in which Ri denotes the inositol or glyceryl group, are known under the names phosphatidylinositol and phosphatidylglycerol
Für die Acylreste in den Phospholipiden (I) sowie in den Tπglyceriden (II) sind auch die in Klammern angegebenen Bezeichnungen gebrauchlichFor the acyl residues in the phospholipids (I) and in the Tπglyceriden (II), the names given in brackets are also useful
9-cis-Dodecenoyl (Lauroleoyl), 9-cis-Tetradecenoyl (Myristoleoyl), 9-cis-Hexadecenoyl (Palmitoleoyl), 6-cis-Octadecenoyl (Petroseloyl), 6-trans-Octadecenoyl (Petroselaidoyl), 9-cιs- Octadecenoyl (Oleoyl), 9-trans-Octadecenoyl (Elaidoyl), 9,12-cis-Octadecadienoyl (Linoleoyl), 9,12, 15-cis-Octadecatrienoyl (Linolenoyl),l l-cis-Octadecenoyl (Vaccenoyl), 9-cis-Icosenoyl (Gadoleoyl), 5,8, 11,14-cis-Eicosatetraenoyl (Arachidonoyl), n-Dodecanoyl (Lauroyl), n- Tetradecanoyl (Myristoyl), n-Hexadecanoyl (Palmitoyl), n-Octadecanoyl (Stearoyl), n- Icosanoyl (Arachidoyl), n-Docosanoyl (Behenoyl), n-Tetracosanoyl (Lignoceroyl) Ein Salz des Phospholipids (I) ist vorzugsweise pharmazeutisch annehmbar Salze definieren sich durch die Existenz von salzbildenden Gruppen im Substituenten R3 sowie durch die freie Hydroxygruppe am Phosphor Möglich ist ebenfalls die Bildung von inneren Salzen Bevorzugt sind Alkalimetallsalze, insbesondere Natriumsalze9-cis-dodecenoyl (lauroleoyl), 9-cis-tetradecenoyl (myristoleoyl), 9-cis-hexadecenoyl (palmitoleoyl), 6-cis-octadecenoyl (petroseloyl), 6-trans-octadecenoyl (petroselecoyoyl), 9 (Oleoyl), 9-trans-octadecenoyl (Elaidoyl), 9,12-cis-octadecadienoyl (Linoleoyl), 9,12, 15-cis-octadecatrienoyl (Linolenoyl), l l-cis-octadecenoyl (Vaccenoyl), 9-cis Icosenoyl (gadoleoyl), 5,8, 11,14-cis-eicosatetraenoyl (arachidonoyl), n-dodecanoyl (lauroyl), n-tetradecanoyl (myristoyl), n-hexadecanoyl (palmitoyl), n-octadecyloyl (stearo - Icosanoyl (arachidoyl), n-docosanoyl (behenoyl), n-tetracosanoyl (lignoceroyl) A salt of the phospholipid (I) is preferably pharmaceutically acceptable. Salts are defined by the existence of salt-forming groups in the substituent R 3 and by the free hydroxyl group on the phosphorus. The formation of internal salts is also possible. Alkali metal salts, in particular sodium salts, are preferred
Die Komponente c) wird in einer bevorzugten Konzentration von ca 0,05 bis 1 ,0 Gew -%, vorzugsweise 0,05 bis 0,1 Gew -%, bezogen auf das Gesamtgewicht der Formulierung, hinzugesetzt In einer besonders bevorzugten Ausführungsform verwendet man gereinigtes Lecithin aus Sojabohnen der Qualität LIPOID S 100Component c) is added in a preferred concentration of about 0.05 to 1.0% by weight, preferably 0.05 to 0.1% by weight, based on the total weight of the formulation. In a particularly preferred embodiment, purified is used Lecithin from soybeans of the quality LIPOID S 100
Komponente d) In einem als Komponente d) verwendeten Triglycerid der Formel II bedeuten Ri, R2 und R3 geradkettiges Cs-24-Acyl mit gerader Anzahl an C-Atomen, insbesondere n- Octanoyl, n-Dodecanoyl, n-Tetradecanoyl, n-Hexadecanoyl, n-Octadecanoyl, 9-cis- Dodecenoyl, 9-cis-Tetradecenoyl, 9-cis-Hexadecenoyl, 9-cis-Octadecenoyl oder 9-cis- Icosenoyl Die Bedeutungen von Ri, R2 und R3 können identisch oder verschieden sein, wobei die individuellen Gruppen R|, R2 und R3 selbst strukturell einheitlich definiert sind Dies ist für synthetische oder halbsynthetische Triglyceride charakteristisch Ri, R2 und R-, können aber auch aus verschiedenen Acylgruppen unterschiedlicher Struktur bestehen Dies ist für Triglyceride naturlichen Ursprungs charakteristischComponent d) In a triglyceride of the formula II used as component d), R 1, R 2 and R 3 are straight-chain Cs- 24- acyl with an even number of C atoms, in particular n-octanoyl, n-dodecanoyl, n-tetradecanoyl, n -Hexadecanoyl, n-octadecanoyl, 9-cis-dodecenoyl, 9-cis-tetradecenoyl, 9-cis-hexadecenoyl, 9-cis-octadecenoyl or 9-cis- icosenoyl. The meanings of Ri, R 2 and R 3 can be identical or different The individual groups R 1 , R 2 and R 3 are themselves structurally uniformly defined. This is characteristic of synthetic or semisynthetic triglycerides, R 1, R 2 and R-, but can also consist of different acyl groups of different structure. This is for triglycerides of natural origin characteristic
Ein Triglycerid der Formel II ist ein halbsynthetisches oder synthetisches, im wesentlichen reines Triglycerid oder ein pharmazeutisch gebrauchliches Triglycerid naturlichen Ursprungs Bevorzugt ist ein Triglycerid naturlichen Ursprungs, z B Erdnuss-, Sesam-, Sonnenblumen-, Oliven-, Maiskeim-, Soja-, Rizinus-, Baumwollsamen-, Raps-, Distel-, Traubenkern-, Fisch¬ oder Kokosöl In einer besonders bevorzugten Ausführungsform der Erfindung verwendet man ein mit dem Begriff Neutralol definiertes Triglycerid mit verschiedenen Acylgruppen unterschiedlicher Struktur, z.B ein Triglycerid der fraktionierten Kokosfettsauren C8-Cιo vom Typ Migiyol®, z B MIGLYOL 812A triglyceride of the formula II is a semisynthetic or synthetic, essentially pure triglyceride or a pharmaceutically usable triglyceride of natural origin. A triglyceride of natural origin is preferred, eg peanut, sesame, sunflower, olive, corn germ, soybean, castor -, Cottonseed, rapeseed, safflower, grape seed, fish or coconut oil In a particularly preferred embodiment of the invention, a triglyceride defined by the term neutralol with different acyl groups of different structure is used, for example a triglyceride of the fractionated coconut fatty acids C 8 -Cio of the Migiyol ® type, for example MIGLYOL 812
Das Triglycerid (II) ist in der weiter vorn definierten pharmazeutischen Zusammensetzung in einem bevorzugten Konzentrationsbereich von ca 0, 1 bis 2,0 Gew -%, vorzugsweise 0, 1 bis 1,0 Gew -%, bezogen auf das Gesamtgewicht der Formulierung, enthalten Die Komponente e) - Wasser als Tragerflüssigkeit in der für die dermale Applikation erforderlichen Reinheit - ist nach den Vorschriften der nationalen Pharmakopoen keim- und pyrogenfreiThe triglyceride (II) is contained in the pharmaceutical composition defined above in a preferred concentration range of approximately 0.1 to 2.0% by weight, preferably 0.1 to 1.0% by weight, based on the total weight of the formulation Component e) - water as carrier liquid in the purity required for dermal application - is germ and pyrogen free according to the regulations of the national pharmacopoeia
Die Komponente f) - für dermale Formulierungen geeignete Hilfsstoffe - ist als fakultative Komponente enthalten Solche Hilfsstoffe sind in Cremen, Salben, Gelen, Lotionen, Pasten, Schäumen, Tinkturen oder Lotionen enthaltenComponent f) - auxiliaries suitable for dermal formulations - is contained as an optional component. Such auxiliaries are contained in creams, ointments, gels, lotions, pastes, foams, tinctures or lotions
Geeignet sind insbesondere Ethanol, insbesondere in geringen Mengenanteilen von ca 0,1 bis 5 %, Isopropanol, ferner Konservierungsmittel, z.B Benzalkoniumchlorid, Phenoxyethanol, ferner Benzoesaure oder deren Salze, 4-Hydroxy-benzoesaureester (PHB-Ester), Phenole, z B tert -Butyl-4-methoxy- oder Di-tert.-butyl-4-methylphenol, Benzylalkohol, 4-Chlor- oder 2,4- Dichlorbenzylalkohol, 2-Phenylethanol, Chlorhexidindiacetat oder -digluconat, Thiabendazol, Cetyltriammoniumbromid, Cetylpyridiniumbromid, Phenododeciniumbromid oder Sorbinsaure, Antioxidantien, z.B. Ascorbinsaure, Cystein, Sulfite, z.B Natriumbisulfit, Thioglycol oder Glutathion, ätherische Öle zur Verbesserung des Geruchs, z B Menthol, Orangen- Pomeranzen-, Mandarinen- oder Citronenöl, oder Fliessmittel oder Mittel zur Verhinderung von Verdunstung, z.B. Polyalkohole, z.B Propylenglycol, Polyethylenglycol oder GlycerinParticularly suitable are ethanol, in particular in small amounts of approx. 0.1 to 5%, isopropanol, furthermore preservatives, for example benzalkonium chloride, phenoxyethanol, furthermore benzoic acid or its salts, 4-hydroxy-benzoic acid ester (PHB ester), phenols, eg tert -Butyl-4-methoxy- or di-tert-butyl-4-methylphenol, benzyl alcohol, 4-chloro- or 2,4-dichlorobenzyl alcohol, 2-phenylethanol, chlorhexidine diacetate or digluconate, thiabendazole, cetyltriammonium bromide, cetylpyridinium bromidium bromide, phenododecarboxylic acid, phenodinodinodromide , Antioxidants, e.g. Ascorbic acid, cysteine, sulfites, e.g. sodium bisulfite, thioglycol or glutathione, essential oils to improve the smell, e.g. menthol, orange-orange, mandarin or lemon oil, or flow agents or agents to prevent evaporation, e.g. Polyalcohols, e.g. propylene glycol, polyethylene glycol or glycerin
Ebenfalls Gegenstand der vorliegenden Erfindung ist das an sich bekannte Verfahren zur Herstellung der pharmazeutischen Zusammensetzung, welches dadurch gekennzeichnet ist, dass man eine lipophile Phase bestehend aus den Komponenten a) bis d) mit der wässrigen Tragerflussigkeit, welche gegebenenfalls für dermale Darreichungformen geeignete wasserlösliche Hilfsstoffe enthält,vermischt und, falls erwünscht, die erhaltliche klare, opal- eszente Dispersion auf der Basis Nanopartikel - Nanodispersion - folgenden Nachoperationen unterzieht Zusatz einer weiteren Menge Wasser als Tragerflussigkeit sowie gegebenenfalls weiterer wasserlöslicher Hilfsstoffe, welche für dermale Darreichungsformen geeignet sind, und gegebenenfalls Filtration (z.B. Sterilfiltration) der Nanodispersion, und/oder Weiter¬ verarbeitung der Nanodispersion zu einem dermalen PräparatThe present invention also relates to the known process for the preparation of the pharmaceutical composition, which is characterized in that a lipophilic phase consisting of components a) to d) with the aqueous carrier liquid, which optionally contains water-soluble excipients suitable for dermal dosage forms , mixed and, if desired, the available clear, opalescent dispersion based on nanoparticles - nanodispersion - undergoes the following post-operations, adding a further amount of water as carrier liquid and, if appropriate, further water-soluble auxiliaries which are suitable for dermal dosage forms, and, if appropriate, filtration (e.g. Sterile filtration) of the nanodispersion, and / or further processing of the nanodispersion into a dermal preparation
Gemäss diesem Verfahren stellt man eine lipophile Phase "Ölphase" bestehend aus der Komponente c) - Phospholipid (I) -, Ethanol, Komponente b), - Partialfettsäureester des Polyoxyethylensorbitans -, Komponente a) - Wirkstoff, und der Komponente d) - Triglycerid (II) - her. Das Vermischen der Komponenten erfolgt bei Raumtemperatur niedertourig mit konventionellem Rührer mit Propeller oder Flugelblatt, einem Magnetruhrer oder statischem Mischer.According to this process, a lipophilic phase "oil phase" consisting of component c) - phospholipid (I) -, ethanol, component b), - partial fatty acid ester of polyoxyethylene sorbitan -, component a) - active ingredient, and component d) - triglyceride (II) - forth. The components are mixed at low speed at room temperature using a conventional stirrer with a propeller or a blade, a magnetic stirrer or a static mixer.
In einer bevorzugten Ausführungsform des Verfahrens verwendet man eine Kombination verschiedener Partialfettsäureester des Polyoxyethylensorbitans, insbesondere die Kombination bestehend aus Polysorbat 20, 80 und 60 Dabei achtet man auf die Reihenfolge, indem man zunächst das Phospholipid und den Ethanol miteinander vermischt und dazu nacheinander Polysorbat 20, 80 und 60 hinzusetzt. Anschliessend setzt man Neutralol hinzu Durch Vermischen der lipophilen Phase ("Ölphase") mit der wässrigen Phase, welche wasserlösliche fakultative Zusätze, z.B. Konservierungsmittel, enthalten kann, mit einem niedertourigen Rührwerk (200 bis 1 '000 Upm) oder statischem Mischer, bildet sich die weiter vorn definierte phamazeutische Zusammensetzung, welche sich als Dispersion von kolloidalen Nanopartikeln des lipophilen Wirkstoffs Hydrocortison oder vereinfacht als Nanodispersion definieren lasst Aufgrund von Laser-Lichtstreumessungen und Aufnahmen im Elektronenmikroskop sind die in der Nanodispersion vorhandenen kolloidalen Partikel von anderen Gebilden wie Flussig- kristallen, Mizellen, Umkehrmizellen oder Liposomen unterscheidbar Für die statistische Mehrzahl von mehr als 95%, vorzugsweise mehr als 98%, ist eine mittlere Partikelgrosse kleiner als 50 nm charakteristischIn a preferred embodiment of the process, a combination of different partial fatty acid esters of polyoxyethylene sorbitan is used, in particular the combination consisting of polysorbate 20, 80 and 60. Attention is paid to the sequence by first mixing the phospholipid and the ethanol with one another and then polysorbate 20, 80 in succession and 60 adds. Neutralol is then added by mixing the lipophilic phase ("oil phase") with the aqueous phase which contains water-soluble optional additives, e.g. Preservatives, which can contain a low-speed agitator (200 to 1,000 rpm) or a static mixer, form the pharmaceutical composition defined above, which can be defined as a dispersion of colloidal nanoparticles of the lipophilic active ingredient hydrocortisone or simply as nanodispersion due to lasers -Light scatter measurements and electron microscope images distinguish the colloidal particles present in the nanodispersion from other structures such as liquid crystals, micelles, reverse micelles or liposomes. For the statistical majority of more than 95%, preferably more than 98%, an average particle size is smaller than 50 nm characteristic
Zur Charakterisierung der erhältlichen Nanodispersion sind an sich bekannte Methoden geeignet, z B optische Beurteilung schwache bis starke Opaleszenz des Präparates ist leicht erkennbar (Hinweis auf durchschnittliche Partikelgrosse kleiner als 50 nm), Laser- Lichtstreuung (Bestimmung der Partikelgrosse und Homogenität), Elektronenmiskroskopie (Gefrierbruch- und Negativkontrasttechnik)Methods known per se are suitable for characterizing the available nanodispersion, for example optical assessment of weak to strong opalescence of the preparation is easily recognizable (indication of average particle size smaller than 50 nm), laser light scattering (determination of the particle size and homogeneity), electron microscopy (freeze fracture and negative contrast technique)
Der Nanodispersion ist nach Zusatz der gewünschten Menge Wasser und gegebenenfalls weiterer Hilfsstoffe, die für dermale Darreichungsformen verwendbar sind, z.B als Dosierspray direkt applizierbar Ein besonderer Vorteil gegenüber konventionellen dermalen Präparaten ist die Möglichkeit der Sterilfiltration Falls erwünscht kann man durch Sterilfiltration, alle in der Dispersion befindlichen grösseren Partikel mit einem Durchmesser grösser als ca 200 nm, sowie Schweb- und Feststoffe, abtrennen und so eine Nanodispersion mit einer Fraktion von Partikeln mit relativ einheitlicher Grosse herstellen.The nanodispersion can be applied directly after adding the desired amount of water and, if necessary, other auxiliary substances that can be used for dermal dosage forms, e.g. as a dosing spray.A particular advantage over conventional dermal preparations is the possibility of sterile filtration.If desired, sterile filtration can be used to remove all those in the dispersion larger particles with a diameter larger than approx. 200 nm, as well as suspended and solid matter, and so produce a nanodispersion with a fraction of particles of relatively uniform size.
Abgemessene Mengen Nanodispersion füllt man, gegebenenfalls als Konzentrat, in geeignete Behalter für eine Dosiseinheit ab Geeignete Gefasse sind z.B Gefasse für Pumpsprays oder Dosiersprays oder Kunststoffgefasse mit AuslaufvorrichtungMeasured quantities of nanodispersion are filled into suitable containers for one dose unit, if necessary as a concentrate. Suitable containers are e.g. containers for pump sprays or dosing sprays or plastic containers with a discharge device
Die weiter vorn beschriebene pharmazeutische Zusammensetzung mit dem Antiinflamma- torikum Hydrocortison ist als dermales Präparat zur Behandlung sämtlicher Krankheiten der Haut und am Auge geeignet Dabei wendet man das Präparat in der vorgeschriebenen Dosierung anThe pharmaceutical composition described above with the anti-inflammatory hydrocortisone is suitable as a dermal preparation for the treatment of all diseases of the skin and on the eye. The preparation is used in the prescribed dosage
Das folgende Beispiel illustriert die Erfindung:The following example illustrates the invention:
Rezeptur für eine Hydrocortison 0.1%-Nanokolloid-Dosierspray-FormulierungFormula for a hydrocortisone 0.1% nanocolloid dosing spray formulation
Figure imgf000013_0001
Man stellt durch Zugabe von (9) in (8) bei Raumtemperatur die wässrige Phase her Die Ölphase erhalt man durch Vorlegen von (1) in (2), bis die Losung klar wird Anschliessend gibt man nacheinander (3), (4) und (5) - Polysorbat 20, 80 und 60 - hinzu und rührt, bis das Gemisch klar wird Den Wirkstoff (6) fügt man in drei Portionen hinzu, und erwärmt auf 60°C, bis keine Kristalle mehr sichtbar sind Man gibt (7) hinzu, mischt bis zum Klarwerden der Losung und kühlt auf Raumtemperatur ab
Figure imgf000013_0001
The aqueous phase is prepared by adding (9) in (8) at room temperature. The oil phase is obtained by introducing (1) in (2) until the solution becomes clear. Then (3), (4) and (5) - Polysorbate 20, 80 and 60 - and stir until the mixture becomes clear. The active ingredient (6) is added in three portions and heated to 60 ° C. until no more crystals are visible. (7) add, mix until the solution becomes clear and cool to room temperature
Man vereinigt die wässrige Phase mit der Ölphase, in dem man die wässrige Phase bei Raumtemperatur vorlegt und bei 300 - 400 Upm mit einem Magnetruhrwerk rührt Anschliessend injiziert man über einen Zeitraum von ca zwei Minuten lang langsam unter Niveau die Ölphase in die wässrige Phase Man rührt weitere 5-10 Min unter Vermeidung von Schaumbildung und filtriert die Nanodispersion durch einen Keimfilter (0,2 μm) The aqueous phase is combined with the oil phase by introducing the aqueous phase at room temperature and stirring at 300-400 rpm with a magnetic stirrer. The oil phase is then slowly injected into the aqueous phase over a period of about two minutes at a level another 5-10 min avoiding foaming and filters the nanodispersion through a germ filter (0.2 μm)

Claims

AnsprücheExpectations
1 Pharmazeutische Zusammensetzung für die dermale Applikation eines Corticoids enthaltend a) den Wirkstoff 1 l,17,21-Trihydroxypregn-4-en-3,20-dion (Hydrocortison) oder ein Derivat davon, gegebenenfalls in Kombination mit einem Wundbehandlungsmittel, b) mindestens einen Partialfettsäureester des Polyoxyethylensorbitans oder eine Kombination davon, c) mindestens ein im wesentlichen reines Phospholipid der Formel1 pharmaceutical composition for the dermal application of a corticoid containing a) the active ingredient 1 l, 17,21-trihydroxypregn-4-en-3,20-dione (hydrocortisone) or a derivative thereof, optionally in combination with a wound treatment agent, b) at least a partial fatty acid ester of polyoxyethylene sorbitan or a combination thereof, c) at least one essentially pure phospholipid of the formula
11
Figure imgf000015_0001
worin R] Cιo-20-Acyl, R2 Wasserstoff oder Cιo-2o-Acyl, R3 Wasserstoff, 2-Trimethylamino-l- ethyl, 2- Amino- 1-ethyl, CM- Alkyl, C 1.5- Alkyl substituiert durch Carboxy, C2.s- Alkyl substi¬ tuiert durch Hydroxy, C2.5-Alkyl substituiert durch Carboxy und Hydroxy oder C2.5-Alkyl sub¬ stituiert durch Carboxy und Amino, die Inositol- oder die Glycerylgruppe bedeuten, oder Salze dieser Verbindungen, d) ein Triglycerid der Formel
Figure imgf000015_0001
wherein R] Cιo- 20 -acyl, R 2 hydrogen or Cιo- 2 o-acyl, R 3 hydrogen, 2-trimethylamino-l-ethyl, 2-amino-1-ethyl, C M - alkyl, C 1 . 5 - alkyl substituted by carboxy, C 2 .s-alkyl substituted by hydroxy, C 2 . 5- alkyl substituted by carboxy and hydroxy or C 2 .5-alkyl substituted by carboxy and amino, which mean inositol or the glyceryl group, or salts of these compounds, d) a triglyceride of the formula
CH2-0-COR. CH -0-COR2 0l)ι CH2-0-COR3 CH 2 -0-COR. CH- 0 -COR 2 0l) ι CH 2 -0-COR 3
worin Ri, R2und R3 Cg.24- Acyl bedeuten, e) Wasser als Tragerflüssigkeit in der für die dermale Applikation erforderlichen Reinheit, und gegebenenfalls f) für dermale Darreichungsformen geeignete Hilfsstoffewherein Ri, R 2 and R 3 Cg. 24 -acyl mean e) water as carrier liquid in the purity required for dermal application, and optionally f) auxiliaries suitable for dermal dosage forms
2 Pharmazeutische Zusammensetzung gemäss Anspruch 1 enthaltend als Komponente a) den Wirkstoff Hydrocortison oder das 21-Acetat, 21 -Acetat- 17-propionat (Aceponat), 21- Bendazac, 17α-Butyrat, 17α-Butyrat-21 -propionat, 21-Cipionat (Cyclopentanpropionat), 21 - Dinatriumphosphat, 21-Hydrogensuccinat, 21-Natriumsuccinat, 21-Tebutat (tert -Butylacetat), 17-Valerat oder das Xanthogenat, gegebenenfalls in Kombination mit einem Epithelisierungsmittel2 Pharmaceutical composition according to claim 1 containing as component a) the active ingredient hydrocortisone or the 21-acetate, 21-acetate-17-propionate (aceponate), 21-bendazac, 17α-butyrate, 17α-butyrate-21-propionate, 21-cipionate (Cyclopentane propionate), 21 - disodium phosphate, 21-hydrogen succinate, 21-sodium succinate, 21-tebutate (tert-butyl acetate), 17-valerate or the xanthate, optionally in combination with an epithelizing agent
3 Pharmazeutische Zusammensetzung gemäss Anspruch 2 enthaltend als Komponente a) den Wirkstoff Hydrocortison oder das 21 -Acetat, gegebenenfalls in Kombination mit Dexpanthenol3 Pharmaceutical composition according to claim 2 containing as component a) the active ingredient hydrocortisone or the 21 acetate, optionally in combination with dexpanthenol
4 Pharmazeutische Zusammensetzung gemäss einem der Ansprüche 1 -3 enthaltend als Komponente b) eine Kombination verschiedener Partialfettsäureester des Polyoxy¬ ethylensorbitans4 Pharmaceutical composition according to one of claims 1-3 containing as component b) a combination of different partial fatty acid esters of polyoxyethylene sorbitan
5 Pharmazeutische Zusammensetzung gemäss Anspruch 4 enthaltend als Komponente b) die Kombination bestehend aus Polysorbat 20, 80 und 605 Pharmaceutical composition according to claim 4 containing as component b) the combination consisting of polysorbate 20, 80 and 60
6 Pharmazeutische Zusammensetzung gemäss einem der Ansprüche 1 -5 enthaltend als Komponente c) gereinigtes Lecithin aus Sojabohnen und als Komponente d) ein Triglycerid aus der Gruppe der Neutralöle6 Pharmaceutical composition according to one of claims 1 -5 containing as component c) purified lecithin from soybeans and as component d) a triglyceride from the group of neutral oils
7 Pharmazeutische Zusammensetzung gemäss einem der Ansprüche 1 -6 enthaltend a) den Wirkstoff Hydrocortison als freie Base oder das 21 -Acetat, gegebenenfalls in Kombination mit Dexpanthenol, b) die Kombination bestehend aus Polysorbat 20, 80 und 60, c) gereinigtes Lecithin aus Sojabohnen, d) ein Triglycerid aus der Gruppe der Neutralole, und e) Wasser als Tragerflussigkeit in der für die dermale Applikation erforderlichen Reinheit, und gegebenenfalls f) für dermale Darreichungsformen geeignete Hilfsstoffe7 Pharmaceutical composition according to one of claims 1-6 containing a) the active ingredient hydrocortisone as free base or the 21 acetate, optionally in combination with dexpanthenol, b) the combination consisting of polysorbate 20, 80 and 60, c) purified lecithin from soybeans , d) a triglyceride from the group of neutralols, and e) water as carrier liquid in the purity required for dermal application, and optionally f) auxiliaries suitable for dermal dosage forms
8 Verfahren zur Herstellung einer pharmazeutischen Zusammensetzung gemäss Anspruch 1 für die dermale Applikation eines Corticoids, dadurch gekennzeichnet, dass man eine lipophile Phase bestehend aus den Komponenten a) bis d) mit der wässrigen Tragerflussigkeit, welche gegebenenfalls für dermale Darreichungformen geeignete wasserlösliche Hilfsstoffe enthalt, vermischt; und, falls erwünscht, die erhaltliche klare opaleszente Dispersion auf der Basis Nanopartikel - Nanodispersion - folgenden Nachoperationen unterzieht Zusatz einer weiteren Menge Wasser als Tragerflüssigkeit sowie gegebenenfalls weiterer wasserlöslicher Hilfsstoffe, welche für dermale Darreichungsformen geeignet sind, und gegebenenfalls Filtration der Nanodispersion, und/oder Weiterverarbeitung der Nanodispersion zu einem dermalen Präparat8. A process for the preparation of a pharmaceutical composition according to claim 1 for the dermal application of a corticoid, characterized in that a lipophilic phase consisting of components a) to d) is mixed with the aqueous carrier liquid, which optionally contains water-soluble excipients suitable for dermal dosage forms ; and, if desired, the available clear opalescent dispersion based on nanoparticles - nanodispersion - is subjected to the following subsequent operations by adding a further amount of water as carrier liquid and, if appropriate, further water-soluble auxiliaries which are suitable for dermal dosage forms, and if appropriate Filtration of the nanodispersion, and / or further processing of the nanodispersion into a dermal preparation
9 Verfahren gemäss Anspruch 8, dadurch gekennzeichnet, dass man als Komponente b) die Kombination bestehend aus Polysorbat 20, 80 und 60 verwendet9. The method according to claim 8, characterized in that the combination consisting of polysorbate 20, 80 and 60 is used as component b)
10 Verfahren gemäss Anspruch 9, dadurch gekennzeichnet, dass man nacheinander Polysorbat 20, Polysorbat 80 und Polysorbat 60 zur lipophilen Phase hinzufügt10. The method according to claim 9, characterized in that polysorbate 20, polysorbate 80 and polysorbate 60 are added in succession to the lipophilic phase
11. Die nach dem Verfahren gemäss Anspruch 7 erhältliche Dispersion auf der Basis Nanopartikel11. The dispersion based on nanoparticles obtainable by the process according to claim 7
12 Das nach dem Verfahren gemäss Anspruch 7 erhaltliche Konzentrat, Filtrat oder Trockenpraparat enthaltend Nanopartikel mit dem Wirkstoff Hydrocortison12 The concentrate, filtrate or dry preparation obtainable by the process according to claim 7 containing nanoparticles with the active ingredient hydrocortisone
13 Dispersion auf der Basis Nanopartikel mit dem Wirkstoff Hydrocortison oder einem Derivat davon zur Anwendung in einem therapeutischen Verfahren 13 Dispersion based on nanoparticles with the active ingredient hydrocortisone or a derivative thereof for use in a therapeutic process
PCT/CH1996/000434 1995-12-12 1996-12-09 Cortisone spray for topical administration WO1997021428A1 (en)

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EP0852941A1 (en) * 1996-12-13 1998-07-15 Vesifact Ag Nanodispersion cosmetic composition
EP0956851A1 (en) * 1998-05-11 1999-11-17 Ciba SC Holding AG Use of nanotopes in cosmetic products
EP0956853A2 (en) * 1998-05-11 1999-11-17 Ciba SC Holding AG Use of nanodispersions in pharmaceutical compositions
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EP0852941A1 (en) * 1996-12-13 1998-07-15 Vesifact Ag Nanodispersion cosmetic composition
US7381423B2 (en) 1998-05-11 2008-06-03 Ciba Specialty Chemicals Corp. Use of nanodispersions in cosmetic end formulations
US7008638B2 (en) 1998-05-11 2006-03-07 Ciba Specialty Chemicals Corporation Use of nanodispersions in cosmetic end formulations
US7081253B2 (en) 1998-05-11 2006-07-25 Ciba Specialty Chemicals Corporation Use of nanodispersions in pharmaceutical end formulations
EP0956853A2 (en) * 1998-05-11 1999-11-17 Ciba SC Holding AG Use of nanodispersions in pharmaceutical compositions
US7871642B2 (en) 1998-05-11 2011-01-18 Ciba Specialty Chemicals Corporation Use of nanodispersions in pharmaceutical end formulations
EP0956851A1 (en) * 1998-05-11 1999-11-17 Ciba SC Holding AG Use of nanotopes in cosmetic products
AU767896B2 (en) * 1998-05-11 2003-11-27 Ciba Specialty Chemicals Holding Inc. Use of nanodispersions in pharmaceutical end formulations
EP0956853A3 (en) * 1998-05-11 2000-01-05 Ciba SC Holding AG Use of nanodispersions in pharmaceutical compositions
WO2000015763A1 (en) * 1998-09-14 2000-03-23 Vesifact Ag Utilization of nanocells in final culture medium products
US7175850B2 (en) 1998-12-23 2007-02-13 Idea Ag Formulation for topical non-invasive application in vivo
FR2820320A1 (en) * 2001-02-02 2002-08-09 Oreal SUSPENSION OF NANOSPHERES OF ACTIVE LIPOPHILIC PRINCIPLE STABILIZED BY HYDRODISPERSIBLE POLYMERS
EP1228746A1 (en) * 2001-02-02 2002-08-07 L'oreal Suspension of nanospheres of lipophilic active ingredients stabilised with water-dispersible polymers
EP1256337A1 (en) * 2001-05-08 2002-11-13 Vesifact Ag Method and compositions for applying an agent to a substrate
WO2002089769A3 (en) * 2001-05-08 2003-11-27 Vesifact Ag Method for applying an active ingredient to a substrate, compositions for said method, container containing a composition and use of said compositions
EP2000131A2 (en) 2001-05-08 2008-12-10 Vesifact Ag Method for applying an active ingredient to a substrate, compositions for said method, receptacle containing a composition and use of said compositions
WO2002089769A2 (en) * 2001-05-08 2002-11-14 Vesifact Ag Method for applying an active ingredient to a substrate, compositions for said method, container containing a composition and use of said compositions
KR100772327B1 (en) 2004-04-22 2007-10-31 주식회사유한양행 Nanoemulsion Compositions Containing Hydrocortisone or Its Salts
EP2099410A2 (en) * 2006-11-29 2009-09-16 Malvern Cosmeceutics Limited Compositions comprising macromolecular assemblies of lipid and surfactant
JP2017105808A (en) * 2006-11-29 2017-06-15 マルベルン コスメセウチクス リミテッド Compositions comprising macromolecular assemblies of lipid and surfactant
WO2008086953A1 (en) * 2007-01-16 2008-07-24 Bayer Consumer Care Ag Colloidal solution
RU2449776C2 (en) * 2007-01-16 2012-05-10 Байер Конзюмер Кер АГ Colloidal solution

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