WO2005063224A1 - Topical preparations containing dimethyl sulfoxide and dexpanthenol - Google Patents

Topical preparations containing dimethyl sulfoxide and dexpanthenol Download PDF

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WO2005063224A1
WO2005063224A1 PCT/EP2004/014620 EP2004014620W WO2005063224A1 WO 2005063224 A1 WO2005063224 A1 WO 2005063224A1 EP 2004014620 W EP2004014620 W EP 2004014620W WO 2005063224 A1 WO2005063224 A1 WO 2005063224A1
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weight
dexpanthenol
preparations according
contain
dmso
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PCT/EP2004/014620
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German (de)
French (fr)
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Peter Rose
Bernd Ibscher
Peter Schneider
Ruland Fridrich
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Merckle Gmbh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/75—Anti-irritant

Definitions

  • the invention relates to a pharmaceutical topical preparation for the treatment of various indications, containing dimethyl sulfoxide, hereinafter also called DMSO, and dexpanthenol.
  • DMSO is a polar, odorless liquid, for which a variety of physical and therapeutic effects or functions are known. Et al These are radioprotective and cryoprotective effects, as well as membrane penetration, loosening of scar tissue, anti-inflammatory effects and radical trapping.
  • DMSO has been used for around 25 years as a topical medication for the treatment of blunt traumas and diseases from the rheumatic range, as well as a carrier in various antiviral and antifungal preparations.
  • Doloben® gel in an amount of 15% by weight in combination with heparin or Rheumabene® in an amount of 10% by weight.
  • Dexpanthenol is a pantothenic acid derivative which, according to WO 93/21899, is used as an active ingredient in an anti-acne agent, the agent being able to contain DMSO as a penetration aid.
  • DE 196 20 341 describes a geriatricum which can contain dexpanthenol as a absorption mediator and, if appropriate, DMSO to improve percutaneous absorption. According to WO 03/011247, dexpanthenol is also used as a skin penetration enhancer.
  • EP 0 380 989 describes a plaster for transdermal use which contains dexpanthenol in a concentration of 0.1 to 50% by weight as a penetration aid.
  • the object of the present invention is to provide a pharmaceutical topical preparation with a high content of dimethyl sulfoxide and good skin tolerance.
  • the above-mentioned object was achieved by the provision of a pharmaceutical topical preparation which contains 10-60% by weight of dimethyl sulfoxide and 2-15% by weight of dexpanthenol together with conventional auxiliaries and excipients.
  • the weight data are based on the total weight of the preparation.
  • Figure 1 is a graphical representation of transepidermal water loss (TEWL) when using preparations containing DMSO and dexpanthenol.
  • Dexpanthenol the alcohol of pantothenic acid (vitamin B6), is quickly converted into the effective pantothenic acid after dermal absorption in the body. Dexpanthenol has been shown to reduce skin irritation when applied externally and has previously been used primarily for cosmetic applications.
  • a third tolerance study then examined the occurrence of skin irritation depending on the ratio of DMSO and dexpanthenol.
  • the transepidermal water loss (TEWL) determined in a placebo-controlled, double-blind study can be regarded as a sign of tolerance. The higher the transepidermal water loss in the patient at the application site, the less the tolerance of the preparation can be considered.
  • 20 healthy volunteers were given gel preparations containing 10% by weight dexpanthenol and 20, 40 and 60% by weight DMSO. The transepidermal water loss was then measured after 3, 24, 48, 72 and 96 hours. The preparations with dexpanthenol showed a significantly lower water loss than preparations without dexpanthenol.
  • the maximum TEWL for the gel base was 7.2 g / h * m 2 (after 96 hours).
  • the TEWL values of the preparation with 20% by weight DMSO were only slightly higher (max. 10.45 g / h * m 2 after 72 hours) than with the placebo preparation. The results are summarized in Table 1 and shown graphically in FIG. 1.
  • preparations with 20% DMSO in combination with 10% dexpanthenol are particularly advantageous in terms of increased tolerance. It can also be seen that even preparations with 60% DMSO are well tolerated. Furthermore, the preparations can be modified to lower DMSO contents in such a way that the DMSO / dexpanthenol ratio remains approximately constant. For these preparations according to the invention, for example preparations of 20% DMSO with 3.33% dexpanthenol, there is therefore a very particular superiority with regard to good tolerability combined with increased effectiveness.
  • the preparations according to the invention contain DMSO as the active ingredient. In general, they contain no other active ingredient. If desired, the preparations can also contain further active ingredients, for example anti-inflammatory or anti-rheumatic active ingredients, anticoagulants, fibrinolytic active ingredients, etc.
  • Preferred preparations contain 3 to 15% by weight and in particular 3 to 10% by weight of dexpanthenol.
  • Preferred embodiments of the preparations according to the invention contain:
  • the quantitative ratio (w / w) of DMSO to dexpanthenol is preferably in the range from 10: 1 to 2: 1, in particular 6: 1 to 4: 1.
  • the preparations according to the invention can be in the form of a gel, spray, emulgel, ointment, cream, solution or lotion and can contain customary auxiliaries which are suitable for the preparation of these use forms.
  • the preparations are preferably in the form of a gel.
  • the gels are in particular hydrophilic and generally contain 0.2 to 40% by weight, in particular 0.2 to 10% by weight and particularly preferably 0.2 to 5% by weight, of gel-forming substances.
  • Suitable gel-forming substances are organic gel formers, for example polyacrylic acids, cellulose derivatives, such as hydroxyalkyl celluloses, for example hydroxyethyl cellulose or hydroxypropyl cellulose, methyl cellulose or carboxymethyl cellulose, alginic acid derivatives, polyglycols, such as polyethylene glycol or polypropylene glycol, etc., or inorganic gel formers, for example bentonite silica, for example bentonite silicate , Hydroxyethyl cellulose, hydroxypropyl cellulose and in particular polyacrylic acid are preferred.
  • organic gel formers for example polyacrylic acids, cellulose derivatives, such as hydroxyalkyl celluloses, for example hydroxyethyl cellulose or hydroxypropyl cellulose, methyl cellulose or carboxymethyl cellulose, alginic acid derivatives, polyglycols, such as polyethylene glycol or polypropylene glycol, etc.
  • inorganic gel formers for example bentonite si
  • the gels can contain solvents such as water-miscible alcohols, for example ethanol, isopropanol, ethylene glycol, propylene glycol etc.
  • the gels can also contain humectants, such as glycerin, propylene glycol, sorbitol, polyethylene glycols, polyoxyethylene glycol esters, such as polyoxyethylene glycol trihydroxystearate (macrogol glycerol hydroxystearate) or laurate, polyoxyethylene sorbitan monooleate (polysorbate 80) etc.
  • the preparations according to the invention are useful for the treatment of blunt traumas and diseases of the rheumatic type, inflammation and pain of the musculoskeletal system as well as venous leg disorders and acute neuralgia.

Abstract

The invention relates to pharmaceutical, topical preparations containing 10 to 60 percent by weight of dimethyl sulfoxide and 2 to 15 percent by weight of dexpanthenol. Said preparations are provided with good skin compatibility.

Description

Topische Zubereitungen enthaltend Dimethylsulfoxid und DexpanthenolTopical preparations containing dimethyl sulfoxide and dexpanthenol
Beschreibung:Description:
Gegenstand der Erfindung ist eine pharmazeutische topische Zubereitung zur Behandlung verschiedener Indikationen, enthaltend Dimethylsulfoxid, im Folgenden auch DMSO genannt, und Dexpanthenol.The invention relates to a pharmaceutical topical preparation for the treatment of various indications, containing dimethyl sulfoxide, hereinafter also called DMSO, and dexpanthenol.
DMSO ist eine polare, geruchlose Flüssigkeit, für die eine Vielzahl physikalischer und therapeutischer Wirkungen bzw. Funktionen bekannt ist. U.a. sind das radiopro- tektive und kryoprotektive Wirkungen, sowie Membranpenetration, Lockerung von Narbengewebe, Entzündungshemmung und Radikalfang.DMSO is a polar, odorless liquid, for which a variety of physical and therapeutic effects or functions are known. Et al These are radioprotective and cryoprotective effects, as well as membrane penetration, loosening of scar tissue, anti-inflammatory effects and radical trapping.
DMSO wird seit etwa 25 Jahren als topisches Medikament zur Behandlung von stumpfen Traumen und Erkrankungen aus dem rheumatischen Formenkreis, sowie als Trägersubstanz in verschiedenen antiviralen und antimykotischen Präparaten eingesetzt. Zum Beispiel ist es in den Handelspräparaten Dolobene® Gel in einer Menge von 15 Gew.-% in Kombination mit Heparin oder Rheumabene® in einer Menge von 10 Gew.-%, enthalten.DMSO has been used for around 25 years as a topical medication for the treatment of blunt traumas and diseases from the rheumatic range, as well as a carrier in various antiviral and antifungal preparations. For example, it is contained in the commercial preparations Doloben® gel in an amount of 15% by weight in combination with heparin or Rheumabene® in an amount of 10% by weight.
Bei Präparaten mit höheren DMSO-Konzentrationen als 10-15 % ist eine dauerhafte Anwendung aufgrund der auftretenden Nebenwirkungen wie Juckreiz, Hautirritationen, Pustelbildung sowie Hautablösung bisher nicht ratsam.In the case of preparations with DMSO concentrations higher than 10-15%, long-term use has so far not been advisable due to the side effects that occur, such as itching, skin irritation, pustules and skin detachment.
Medizinisch wünschenswert ist es jedoch, höhere Konzentrationen an DMSO einzusetzen, weil bekanntermaßen die Wirksamkeit von DMSO-haltigen Präparaten mit zunehmender DMSO-Konzentration steigt. Für eine Erhöhung des Wirkstoffspiegels und damit der Wirksamkeit würden sich DMSO-Konzentrationen von oberhalb 20 Gew.-% bis zu 60 Gew.-% eignen. Zur Verringerung der bei diesen Konzentrationen zu erwartenden unerwünschten Nebenwirkungen gab es in der Literatur mehrere Ansätze:However, it is medically desirable to use higher concentrations of DMSO because it is known that the effectiveness of DMSO-containing preparations increases with increasing DMSO concentration. DMSO concentrations of above 20% by weight up to 60% by weight would be suitable for increasing the active ingredient level and thus the effectiveness. There have been several approaches in the literature to reduce the undesirable side effects to be expected at these concentrations:
Gemäß US 4,296,104 wird versucht, die Nebenwirkungen bei höheren DMSO- Konzentrationen durch eine Formulierung mit Harnstoff zu reduzieren. Jedoch ist das Ergebnis kosmetisch inakzeptabel.According to US 4,296,104 an attempt is made to reduce the side effects at higher DMSO Reduce concentrations through a formulation with urea. However, the result is cosmetically unacceptable.
US 4,871 ,767 beschreibt Zubereitungen mit einer DMSO-Konzentration von 10 bis 20 Gew.-% in Kombination mit Etofenamat sowie gegebenenfalls Propylethylengly- kol.No. 4,871,767 describes preparations with a DMSO concentration of 10 to 20% by weight in combination with etofenamate and, if appropriate, propylethylene glycol.
Gemäß DE 19610396 A und US 4,855,294 wird versucht, Hautirritationen und sonstige Nebenwirkungen durch Zugabe von drei- und mehrwertigen Alkoholen, wie Gly- cerin, zurückzudrängen.According to DE 19610396 A and US 4,855,294, attempts are made to suppress skin irritation and other side effects by adding trihydric and polyhydric alcohols, such as glycerol.
Dexpanthenol ist ein Pantothensäurederivat, das gemäß WO 93/21899 als Wirkstoff in einem Antiaknemittel zur Anwendung kommt, wobei das Mittel DMSO als Penetrationshilfsmittel enthalten kann.Dexpanthenol is a pantothenic acid derivative which, according to WO 93/21899, is used as an active ingredient in an anti-acne agent, the agent being able to contain DMSO as a penetration aid.
Die DE 196 20 341 beschreibt ein Geriatricum, das Dexpanthenol als Resorptionsvermittler sowie gegebenenfalls DMSO zur Verbesserung der percutanen Resorption enthalten kann. Auch gemäß WO 03/011247 wird Dexpanthenol als Hautpenetrati- onsenhancer eingesetzt.DE 196 20 341 describes a geriatricum which can contain dexpanthenol as a absorption mediator and, if appropriate, DMSO to improve percutaneous absorption. According to WO 03/011247, dexpanthenol is also used as a skin penetration enhancer.
Schließlich beschreibt die EP 0 380 989 ein Pflaster zur transdermalen Anwendung, das Dexpanthenol in einer Konzentration von 0,1 bis 50 Gew.-% als Penetrationshilfsmittel enthält.Finally, EP 0 380 989 describes a plaster for transdermal use which contains dexpanthenol in a concentration of 0.1 to 50% by weight as a penetration aid.
Die Aufgabe der vorliegenden Erfindung liegt in der Bereitstellung einer pharmazeutischen topischen Zubereitung mit hohem Gehalt an Dimethylsulfoxid und guter Hautverträglichkeit.The object of the present invention is to provide a pharmaceutical topical preparation with a high content of dimethyl sulfoxide and good skin tolerance.
Die vorstehend genannte Aufgabe wurde durch die Bereitstellung einer pharmazeu- tischen topischen Zubereitung gelöst, die als Wirkstoff 10 - 60 Gew.-% Dimethylsulfoxid und 2 - 15 Gew.-% Dexpanthenol zusammen mit üblichen Hilfs- und Trägerstoffen enthält. Die Gewichtsangaben sind im Rahmen der vorliegenden Erfindung auf das Gesamtgewicht der Zubereitung bezogen.The above-mentioned object was achieved by the provision of a pharmaceutical topical preparation which contains 10-60% by weight of dimethyl sulfoxide and 2-15% by weight of dexpanthenol together with conventional auxiliaries and excipients. In the context of the present invention, the weight data are based on the total weight of the preparation.
Figur 1 ist eine graphische Darstellung des transepidermalen Wasserverlustes (TEWL) bei Anwendung von Zubereitungen, die DMSO und Dexpanthenol enthalten.Figure 1 is a graphical representation of transepidermal water loss (TEWL) when using preparations containing DMSO and dexpanthenol.
Dexpanthenol, der Alkohol der Pantothensäure (Vitamin B6), wird nach dermaler Resorption im Körper schnell in die wirksame Pantothensäure umgewandelt. Dexpanthenol führt bei äußerlicher Applikation zur Verminderung von Hautirritationen und wurde bisher vorwiegend für kosmetische Anwendungen eingesetzt.Dexpanthenol, the alcohol of pantothenic acid (vitamin B6), is quickly converted into the effective pantothenic acid after dermal absorption in the body. Dexpanthenol has been shown to reduce skin irritation when applied externally and has previously been used primarily for cosmetic applications.
Eine erste Studie ergab, dass die Applikation einer Zubereitung aus 15 Gew.-% DMSO sowie 2,5% Dexpanthenol zu einem Rückgang unerwünschter Arzneimittelwirkungen um fast 40% führt, verglichen mit einer Kontrollzubereitung aus 15 Gew.- % DMSO ohne Dexpanthenol.A first study showed that the application of a preparation of 15% by weight DMSO and 2.5% dexpanthenol leads to a reduction in adverse drug effects by almost 40% compared to a control preparation of 15% by weight DMSO without dexpanthenol.
In einer zweiten Studie wurde gefunden, dass die Zugabe von 10% Gew.-% Dexpanthenol zu einer Zubereitung, enthaltend 40 Gew.-% DMSO, zu einer verminderten Anzahl und verminderter Stärke von Hautreaktionen führt, verglichen mit einer entsprechenden Zubereitung ohne Dexpanthenol.In a second study, it was found that the addition of 10% by weight dexpanthenol to a preparation containing 40% by weight DMSO leads to a reduced number and strength of skin reactions compared to a corresponding preparation without dexpanthenol.
Daraufhin wurde in einer dritten Verträglichkeitsstudie das Auftreten von Hautirritationen in Abhängigkeit des Verhältnisses von DMSO und Dexpanthenol untersucht. Als Anzeichen der Verträglichkeit kann der in einer placebokontrollierten, doppelblinden Studie bestimmte transepidermale Wasserverlust (TEWL) angesehen werden. Je höher der transepidermale Wasserverlust beim Patienten am Auftragungsort ist, umso geringer kann die Verträglichkeit der Zubereitung angesehen werden. In dieser Studie wurden 20 gesunden Probanden Gel-Zubereitungen appliziert, die 10 Gew.-% Dexpanthenol und 20, 40 sowie 60 Gew.-% DMSO enthielten. Der transepidermale Wasserverlust wurde dann nach 3, 24, 48, 72 und 96 Stunden gemessen. Dabei zeigten die Zubereitungen mit Dexpanthenol einen signifikant geringeren Wasserverlust als Zubereitungen ohne Dexpanthenol. Der TEWL lag bei der Gelgrundlage (Placebo) maximal bei einer Differenz von 7,2 g/h*m2 (nach 96 Stunden). Die TEWL- Werte der Zubereitung mit 20 Gew.-% DMSO lagen nur geringfügig höher (max. 10,45 g/h*m2 nach 72 Stunden) als bei der Placebo-Zubereitung. Die Ergebnisse sind in der Tabelle 1 zusammengestellt und in der Figur 1 graphisch dargestellt.A third tolerance study then examined the occurrence of skin irritation depending on the ratio of DMSO and dexpanthenol. The transepidermal water loss (TEWL) determined in a placebo-controlled, double-blind study can be regarded as a sign of tolerance. The higher the transepidermal water loss in the patient at the application site, the less the tolerance of the preparation can be considered. In this study, 20 healthy volunteers were given gel preparations containing 10% by weight dexpanthenol and 20, 40 and 60% by weight DMSO. The transepidermal water loss was then measured after 3, 24, 48, 72 and 96 hours. The preparations with dexpanthenol showed a significantly lower water loss than preparations without dexpanthenol. The maximum TEWL for the gel base (placebo) was 7.2 g / h * m 2 (after 96 hours). The TEWL values of the preparation with 20% by weight DMSO were only slightly higher (max. 10.45 g / h * m 2 after 72 hours) than with the placebo preparation. The results are summarized in Table 1 and shown graphically in FIG. 1.
Tabelle 1Table 1
Figure imgf000006_0001
Figure imgf000006_0001
Aus Tabelle 1 und Figur 1 geht hervor, dass Zubereitungen mit 20 % DMSO in Kombination mit 10% Dexpanthenol bezüglich einer erhöhten Verträglichkeit besonders vorteilhaft sind. Weiterhin ist ersichtlich, dass selbst Zubereitungen mit 60% DMSO gute Verträglichkeit besitzen. Weiterhin können die Zubereitungen hin zu niedrigeren DMSO-Gehalten derart abgewandelt werden, dass das DMSO/Dexpanthenol- Verhältnis in etwa konstant bleibt. Für diese ebenfalls erfindungsgemäßen Zubereitungen, beispielsweise Zubereitungen von 20% DMSO mit 3,33% Dexpanthenol, ergibt sich daher eine ganz besondere Überlegenheit bezüglich einer guten Verträglichkeit in Verbindung mit einer erhöhten Wirksamkeit.It can be seen from Table 1 and FIG. 1 that preparations with 20% DMSO in combination with 10% dexpanthenol are particularly advantageous in terms of increased tolerance. It can also be seen that even preparations with 60% DMSO are well tolerated. Furthermore, the preparations can be modified to lower DMSO contents in such a way that the DMSO / dexpanthenol ratio remains approximately constant. For these preparations according to the invention, for example preparations of 20% DMSO with 3.33% dexpanthenol, there is therefore a very particular superiority with regard to good tolerability combined with increased effectiveness.
Die erfindungsgemäßen Zubereitungen enthalten als Wirkstoff DMSO. Im Allgemeinen enthalten sie keinen weiteren Wirkstoff. Gewünschtenfalls können die Zuberei- tungen auch weitere Wirkstoffe enthalten, beispielsweise antiinflammatorische oder antirheumatische Wirkstoffe, Antikoagulantien, fibrinolytische Wirkstoffe etc.The preparations according to the invention contain DMSO as the active ingredient. In general, they contain no other active ingredient. If desired, the preparations can also contain further active ingredients, for example anti-inflammatory or anti-rheumatic active ingredients, anticoagulants, fibrinolytic active ingredients, etc.
Bevorzugte Zubereitungen enthalten 3 bis 15 Gew.-% und insbesondere 3 bis 10 Gew.-% Dexpanthenol. Bevorzugte Ausführungsformen der erfindungsgemäßen Zubereitungen enthalten:Preferred preparations contain 3 to 15% by weight and in particular 3 to 10% by weight of dexpanthenol. Preferred embodiments of the preparations according to the invention contain:
15 bis 30 Gew.-% DMSO und 2,5 bis 5 Gew.-% Dexpanthenol;15 to 30% by weight DMSO and 2.5 to 5% by weight dexpanthenol;
15 bis 25 Gew.-% DMSO und 3,3 bis 4,5 Gew.-% Dexpanthenol;15 to 25% by weight DMSO and 3.3 to 4.5% by weight dexpanthenol;
18 bis 22 Gew.-% DMSO und 3,6 bis 4,3 Gew.-% Dexpanthenol;18 to 22% by weight DMSO and 3.6 to 4.3% by weight dexpanthenol;
45 bis 65 Gew.-%, insbesondere 45 bis 60 Gew.-%, DMSO und 8 bis 12 Gew.-%, insbesondere 8 bis 10 Gew.-%, Dexpanthenol.45 to 65% by weight, in particular 45 to 60% by weight, DMSO and 8 to 12% by weight, in particular 8 to 10% by weight, dexpanthenol.
Das Mengenverhältnis (G/G) von DMSO zu Dexpanthenol liegt vorzugsweise im Bereich von 10:1 bis 2:1 , insbesondere 6:1 bis 4:1.The quantitative ratio (w / w) of DMSO to dexpanthenol is preferably in the range from 10: 1 to 2: 1, in particular 6: 1 to 4: 1.
Die erfindungsgemäßen Zubereitungen können als Gel, Spray, Emulgel, Salbe, Creme, Lösung oder Lotion vorliegen und übliche Hilfsstoffe enthalten, die für die Herstellung dieser Anwendungsformen geeignet sind. Vorzugsweise liegen die Zubereitungen in Form eines Gels vor. Die Gele sind insbesondere hydrophil und enthalten im allgemeinen 0, 2 bis 40 Gew.-%, insbesondere 0,2 bis 10 Gew.-% und beson- ders bevorzugt 0,2 bis 5 Gew.-%, gelbildende Substanzen. Geeignete gelbildende Substanzen sind organische Gelbildner, beispielsweise Polyacrylsäuren, Cellulose- derivate, wie Hydroxyalkylcellulosen, beispielsweise Hydroxyethylcellulose oder Hydroxypropylcellulose, Methylcellulose oder Carboxymethylcellulose, Alginsäurede- rivate, Polyglykole, wie Polyethylenglykol oder Polypropylenglykol, etc. oder anorga- nische Gelbildner, beispielsweise Bentonit oder kolloidale Kieselsäure. Bevorzugt sind Hydroxyethylcellulose, Hydroxypropylcellulose und insbesondere Polyacrylsäu- re. Zusätzlich können die Gele Lösungsmittel, wie mit Wasser mischbare Alkohole, beispielsweise Ethanol, Isopropanol, Ethylenglykol, Propylenglykol etc. enthalten. Die Gele können auch Feuchthaltemittel enthalten, wie Glycerin, Propylenglykol, Sorbit, Polyethylenglykole, Polyoxyethylenglykolester, wie Polyoxyethylenglykol- trihydroxystearat (Macrogol-Glycerol-Hydroxystearat) oder -laurat, Polyoxyethylen- sorbitanmonooleat (Polysorbat 80) etc. Die erfindungsgemäßen Zubereitungen sind brauchbar zur Behandlung von stumpfen Traumen und Erkrankungen des rheumatischen Formenkreises, Entzündungen und Schmerzen des Bewegungsapparates sowie von venösen Beinleiden und akuten Neuralgien.The preparations according to the invention can be in the form of a gel, spray, emulgel, ointment, cream, solution or lotion and can contain customary auxiliaries which are suitable for the preparation of these use forms. The preparations are preferably in the form of a gel. The gels are in particular hydrophilic and generally contain 0.2 to 40% by weight, in particular 0.2 to 10% by weight and particularly preferably 0.2 to 5% by weight, of gel-forming substances. Suitable gel-forming substances are organic gel formers, for example polyacrylic acids, cellulose derivatives, such as hydroxyalkyl celluloses, for example hydroxyethyl cellulose or hydroxypropyl cellulose, methyl cellulose or carboxymethyl cellulose, alginic acid derivatives, polyglycols, such as polyethylene glycol or polypropylene glycol, etc., or inorganic gel formers, for example bentonite silica, for example bentonite silicate , Hydroxyethyl cellulose, hydroxypropyl cellulose and in particular polyacrylic acid are preferred. In addition, the gels can contain solvents such as water-miscible alcohols, for example ethanol, isopropanol, ethylene glycol, propylene glycol etc. The gels can also contain humectants, such as glycerin, propylene glycol, sorbitol, polyethylene glycols, polyoxyethylene glycol esters, such as polyoxyethylene glycol trihydroxystearate (macrogol glycerol hydroxystearate) or laurate, polyoxyethylene sorbitan monooleate (polysorbate 80) etc. The preparations according to the invention are useful for the treatment of blunt traumas and diseases of the rheumatic type, inflammation and pain of the musculoskeletal system as well as venous leg disorders and acute neuralgia.
Ausführungsbeispieleembodiments
Zubereitungen zur topischen Applikation wurden durch Zusammengeben von Substanzen gemäß Tab. 2 hergestellt. Diese Zubereitungen sind exemplarisch und nicht limitierend:Preparations for topical application were prepared by combining substances according to Table 2. These preparations are exemplary and not limiting:
Tabelle 2Table 2
Figure imgf000008_0001
' Trometamol: 2-Amino-2-(hydroxymethyl)-propan-1,3-diol
Figure imgf000008_0001
'Trometamol: 2-amino-2- (hydroxymethyl) propane-1,3-diol
Vergleichsbeispiel 1 :Comparative Example 1:
In einer klinischen Studie bei 581 Patienten wurde die lokale Verträglichkeit einer erfindungsgemäßen Zubereitung (A) aus 15% DMSO und 2,5% Dexpanthenol mit einer Zubereitung (B) aus 15% DMSO ohne Dexpanthenol verglichen. Dabei wurde lediglich bei 6,2% der mit der Zubereitung (A) behandelten Patienten Nebenwirkungen dokumentiert. In der Vergleichsgruppe der Patienten, die mit dem Präparat ohne Dexpanthenol behandelt wurden, traten dagegen bei 15,6% Nebenwirkungen auf. Das relative Risiko einer unerwünschten Arzneimittelwirkung ist bei Anwendung der erfindungsgemäßen Zubereitung (A) demnach rund 40% niedriger als bei Anwendung der Zubereitung (B).In a clinical study in 581 patients, the local tolerance of a preparation (A) of 15% DMSO and 2.5% dexpanthenol according to the invention was compared with a preparation (B) of 15% DMSO without dexpanthenol. It was Side effects were only documented in 6.2% of the patients treated with preparation (A). In contrast, in the comparison group of patients treated with the preparation without dexpanthenol, side effects occurred in 15.6%. The relative risk of an undesirable drug effect when using the preparation (A) according to the invention is accordingly around 40% lower than when using the preparation (B).
Vergleichsbeispiel 2:Comparative Example 2:
Im Rahmen einer doppelblinden klinischen Prüfung wurde an 20 gesunden Probanden die Verträglichkeit einer erfindungsgemäßen Zubereitung aus 40% DMSO mit 10% Dexpanthenol mit einer Zubereitung aus 40% DMSO ohne Dexpanthenol verglichen. 18 Probanden berichteten bei beiden Prüfpräparaten über Juckreiz, wobei der Juckreiz bei Auftragen von DMSO ohne Dexpanthenol deutlich stärker ausgeprägt war. Bei 4 Probanden (20%) wurden bei Auftragen von DMSO ohne Dexpanthenol Quaddelbildungen beobachtet, die bei Auftragen von DMSO mit Dexpanthenol nicht auftraten. Bei 3 Probanden (15%) wurden nach Auftragen von DMSO ohne Dexpanthenol Erytheme festgestellt, die bei Auftragen von DMSO mit Dexpanthenol nicht auftraten. Es wurde abschließend festgestellt, dass Hautreaktionen bei Behandlung mit der erfindungsgemäßen Zubereitung aus 40% DMSO und 10% Dexpanthenol insgesamt weniger häufig und weniger stark ausfallen als bei der Kontrollzubereitung. In the context of a double-blind clinical trial, the tolerance of a preparation according to the invention made from 40% DMSO with 10% dexpanthenol was compared with a preparation made from 40% DMSO without dexpanthenol in 20 healthy volunteers. 18 subjects reported itching in both test products, the itching when applying DMSO without dexpanthenol was significantly more pronounced. In 4 subjects (20%) wheals were observed when DMSO was applied without dexpanthenol, which did not occur when DMSO was applied with dexpanthenol. In 3 subjects (15%) erythema was found after application of DMSO without dexpanthenol, which did not occur when application of DMSO with dexpanthenol. It was finally found that skin reactions when treated with the preparation according to the invention consisting of 40% DMSO and 10% dexpanthenol are overall less frequent and less severe than with the control preparation.

Claims

Patentansprüche claims
1. Pharmazeutische topische Zubereitungen enthaltend 10 bis 60 Gew.-% Dimethylsulfoxid (DMSO) und 2 bis 15 Gew.-% Dexpanthenol sowie übliche Hilfs- und Trägerstoffe.1. Pharmaceutical topical preparations containing 10 to 60% by weight of dimethyl sulfoxide (DMSO) and 2 to 15% by weight of dexpanthenol as well as customary auxiliaries and carriers.
2. Zubereitungen nach Anspruch 1 , dadurch gekennzeichnet, dass sie 15 Gew.-% bis 30 Gew.-% DMSO und 2,5 Gew.-% bis 5 Gew.-% Dexpanthenol enthalten.2. Preparations according to claim 1, characterized in that they contain 15% by weight to 30% by weight of DMSO and 2.5% by weight to 5% by weight of dexpanthenol.
3. Zubereitungen nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass sie 20 Gew.-% bis 25 Gew.-% DMSO und 3,3 Gew.-% bis 4 Gew.-% Dexpanthenol enthalten.3. Preparations according to claim 1 or 2, characterized in that they contain 20 wt .-% to 25 wt .-% DMSO and 3.3 wt .-% to 4 wt .-% dexpanthenol.
4. Zubereitungen nach Anspruch 1 , dadurch gekennzeichnet, dass sie 45 Gew.-% bis 60 Gew.-% DMSO und 8 Gew.-% bis 10 Gew.-% Dexpanthenol enthalten.4. Preparations according to claim 1, characterized in that they contain 45 wt .-% to 60 wt .-% DMSO and 8 wt .-% to 10 wt .-% dexpanthenol.
5. Zubereitungen nach einem der vorhergehenden Ansprüche, dadurch ge- kennzeichnet, dass Gewichtsverhältnis von DMSO zu Dexpanthenol im Bereich von 10:1 bis 2:1 liegt.5. Preparations according to one of the preceding claims, characterized in that the weight ratio of DMSO to dexpanthenol is in the range from 10: 1 to 2: 1.
6. Zubereitungen nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass sie in Form eines Gels, eines Sprays, eines Emulgels, einer Salbe, einer Creme, einer Lösung oder einer Lotion vorliegen.6. Preparations according to one of the preceding claims, characterized in that they are in the form of a gel, a spray, an emulsifier, an ointment, a cream, a solution or a lotion.
7. Zubereitungen nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass sie in Form eines Gels vorliegen.7. Preparations according to one of the preceding claims, characterized in that they are in the form of a gel.
8. Zubereitungen nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass sie in Form eines hydrophilen Gels vorliegen und 0,2 - 40 Gew.-% gelbildende Substanzen enthalten. 8. Preparations according to one of the preceding claims, characterized in that they are in the form of a hydrophilic gel and contain 0.2-40% by weight of gel-forming substances.
9. Zubereitungen nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass sie gelbildende Substanzen, wie Polyacrylsäure, Hydroxyethylcellulose und/oder Hydroxypropylcellulose, mit einem Anteil von 0,2- 10 Gew.-% enthalten.9. Preparations according to one of the preceding claims, characterized in that they contain gel-forming substances, such as polyacrylic acid, hydroxyethyl cellulose and / or hydroxypropyl cellulose, in a proportion of 0.2-10% by weight.
10. Zubereitungen nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass sie als gelbildende Substanz Polyacrylsäure mit einem Anteil von 0,2-5 Gew.-% enthalten.10. Preparations according to one of the preceding claims, characterized in that they contain as a gel-forming substance polyacrylic acid in a proportion of 0.2-5 wt .-%.
1 1. Zubereitungen nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass sie ein Feuchthaltemittel, beispielsweise 1 ,2 Propandiol oder hydrophile Emulgatoren, enthalten.1 1. Preparations according to one of the preceding claims, characterized in that they contain a humectant, for example 1, 2 propanediol or hydrophilic emulsifiers.
12. Zubereitungen nach einem der vorhergehenden Ansprüche, dadurch ge- kennzeichnet, dass sie als Feuchthaltemittel hydrophile Emulgatoren, wie Macrogol-Glycerol-Hydroxystearat oder Polysorbat 80, mit einem Anteil von 1-3 Gew.-% enthalten.12. Preparations according to one of the preceding claims, characterized in that they contain, as humectants, hydrophilic emulsifiers, such as macrogol glycerol hydroxystearate or polysorbate 80, in a proportion of 1-3% by weight.
13. Zubereitungen nach einem der vorhergehenden Ansprüche, dadurch ge- kennzeichnet, dass sie Aromastoffe mit einem Anteil von 0,2-4 Gew.-% enthalten.13. Preparations according to one of the preceding claims, characterized in that they contain flavorings in a proportion of 0.2-4% by weight.
14. Zubereitungen nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass sie überdies übliche Hilfsstoffe mit einem Anteil von 0,5- 50 Gew.-% enthalten.14. Preparations according to one of the preceding claims, characterized in that they also contain customary auxiliaries in a proportion of 0.5-50% by weight.
15. Verwendung einer pharmazeutischen topischen Zubereitung nach einem oder mehreren der Ansprüche 1 bis 14 zur Behandlung von Entzündungen und Schmerzen, insbesondere des Bewegungsapparates, stumpfen Trau- men und Erkrankungen des rheumatischen Formenkreises, venösen Beinleiden und akuten Neuralgien. 15. Use of a pharmaceutical topical preparation according to one or more of claims 1 to 14 for the treatment of inflammation and pain, in particular of the musculoskeletal system, blunt dreams and diseases of the rheumatic type, venous leg disorders and acute neuralgia.
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