WO1996037193A1 - Topically applicable agents for treating and preventing alopecia - Google Patents

Topically applicable agents for treating and preventing alopecia Download PDF

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Publication number
WO1996037193A1
WO1996037193A1 PCT/EP1996/002195 EP9602195W WO9637193A1 WO 1996037193 A1 WO1996037193 A1 WO 1996037193A1 EP 9602195 W EP9602195 W EP 9602195W WO 9637193 A1 WO9637193 A1 WO 9637193A1
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Prior art keywords
vitamin
liposome
liposomes
topically applicable
treating
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PCT/EP1996/002195
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German (de)
French (fr)
Inventor
Ralph Lipp
Jutta Riedl
Andreas Sachse
Georg Rössling
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Schering Aktiengesellschaft
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Priority to AU58199/96A priority Critical patent/AU5819996A/en
Priority to EP96919796A priority patent/EP0827395A1/en
Priority to JP8535377A priority patent/JPH11505262A/en
Publication of WO1996037193A1 publication Critical patent/WO1996037193A1/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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/14—Liposomes; Vesicles
    • 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
    • A61K8/67—Vitamins
    • 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
    • A61K9/127—Liposomes
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth

Definitions

  • Topical agents for the treatment and prophylaxis of alopecia Topical agents for the treatment and prophylaxis of alopecia
  • the invention relates to topically applicable agents for the treatment and prophylaxis of alopecia, which is characterized by a content of vitamin D analogs encapsulated in liposomes.
  • vitamin D analogues can be used to treat various forms of alopecia.
  • GB-A 2 260 903 and WO 93/00079 describe topically administrable compositions which contain vitamin D analogues in ointments, creams, gels or lotions. Since these previously known formulations, in particular if they additionally contain penetration-enhancing agents such as ethanol or propylene glycol, also have a systemic activity, they also develop undesirable side effects in addition to the desired therapeutic effect. In particular, they also influence calcium metabolism, which can lead to hypercalcemia and hypercalcuria.
  • topically administrable agents according to the invention which contain vitamin D analogs encapsulated in liposomes, are extremely effective in treating various forms of alopecia, but in contrast to the previously known agents, undesirable systemic side effects are not observed in them.
  • Vitamin D analogs which are suitable for the preparation of the agents according to the invention are, for example, calcitriol (l ⁇ , 25-dihydroyvitamin D3), calcifediol (25-hydroxyvitamin D3), calcipotriol (CAS-1128-00-9) and colecalciferol (Vitamin Ds) and the tacalcitol (CAS-57333-96-7).
  • the vitamin D analogs mentioned in the abovementioned GB-A 2 260 903 and WO 93/00079 are also suitable for producing the agents according to the invention.
  • the compounds described in WO 94/07853 are also suitable as suitable vitamin D analogs, such as, for example, the (5Z, 7E, 22E) - (1S, 3, 24R) -1, 3,24-trihydroxy-9, 10-secocholesta-5,7, 10 (19), 22-tetraen-25-carboxylic acid isopropyl ester.
  • Suitable liposome-forming substances are in particular phospholipids, such as the sphingomyeline, the plasmalogens, the phosphatidylcholines, the phosphatidylethanolamines, the phosphatidylserines, the phosphatidylinosites and the cardiolipins, or else mixtures of these lipids (Dr. Otto-Albert Neumüller: Römpps Chemie-Lexikon; Franksche Verlag Stuttgart, Franksche Verlag Stuttgart (DE), 9th edition, 1991, 3383f) and mixtures of these phospholipids with cholesterol and / or charge carriers, such as, for example, stearylamine, stearic acid or diacetyl phosphate.
  • phospholipids such as the sphingomyeline, the plasmalogens, the phosphatidylcholines, the phosphatidylethanolamines, the phosphatidylserines, the phosphatidylinosites and
  • phospholipid or lipid mixture based on the aqueous phase, is usually used to prepare the liposome suspensions.
  • Suitable mixtures can contain up to 60 percent by weight of cholesterol and up to 30 percent by weight of charge carriers.
  • Ethanol, methanol, isopropanol, diethyl ether, acetone, chloroform and mixtures of these solvents are preferably used as solvents.
  • the process is advantageously carried out under an inert gas atmosphere, such as nitrogen or argon, and the aqueous liposome solutions obtained are stabilized by adding antioxidants, such as sodium ascorbate, tocopherol or sodium bisulfite.
  • aqueous liposome solutions can also contain additional active ingredients, such as bactericides, preservatives and / or buffer substances.
  • the encapsulation of the vitamin D analogs in liposomes can be carried out under the same conditions as the previously known methods of this type (pharmacy in our time ü, 1982, 97-108; Pure Appl. Chem., 53, 1981, 2241-2254) .
  • the encapsulation of the vitamin D analogs can take place both in multilamellar liposomes and in unilamellar liposomes.
  • the active substance-containing liposome suspensions prepared in this way can be diluted with water if necessary and / or thickeners, such as, for example, hydroxyethyl cellulose, methyl cellulose, Aerosil® (Herseller Degussa AG, DE), Carbopol® (BFGoodrich Chem., USA) etc. can be added to make them spreadable To produce gels.
  • thickeners such as, for example, hydroxyethyl cellulose, methyl cellulose, Aerosil® (Herseller Degussa AG, DE), Carbopol® (BFGoodrich Chem., USA) etc.
  • the optimal concentration of active substance in the finished pharmaceutical preparations naturally depends on the type of active substance and the galenical preparation and must be determined in individual cases using the usual preliminary tests. As a rule, it will be sufficient to use pharmaceutical preparations which use 0.001 to 1 mg and preferably 0.005 to 0.1 mg of vitamin D analogs per g of preparation.
  • the liposome suspension obtained contains liposomes with an average size of 112 nm.
  • the phosphatidylcholine content is 9 mg per g; the content of encapsulated! Active ingredient is 0.1 mg per g.
  • the solution is then evaporated to dryness in a 500 ml round-bottom flask on a rotary evaporator, a lipid film forming on the glass wall. This lipid film is removed with 98.9 g of double-distilled water.
  • the suspension obtained is then subjected to high-pressure extrusion, as described in PCT / DE93 / 00997, using Nucleopore® membranes with a decreasing pore size of 5.0, 1.0, 0.4, 0.2, 0.1 and 0.05 ⁇ m is used.
  • the liposome suspension obtained contains liposomes with an average size of 94 nm and otherwise has the same properties as the preparation described in Example 1.
  • the liposome suspension thus obtained contains liposomes with an average size of 106 nm.
  • the phosphatidylcholine content is 9.0 mg per g, the active ingredient content is 0.04 mg per g.
  • the liposome suspension obtained contains liposomes with an average size of 220 nm.
  • the phosphatidylcholine content is 10 mg per g; the content of encapsulated! Active ingredient is 0.2 mg per g.
  • the liposome suspensions prepared according to Examples 1 and 3 are mixed with 0.18%
  • the liposomes are still suspended in the aqueous phase. You are intact.
  • the liposome suspensions prepared according to Examples 1 and 3 are freeze-dried.
  • BHT 2,6-di tert-butyl-4-methylphenol

Abstract

The invention relates to topically applicable agents for the treatment and prevention of alopecia characterised by a content of vitamin D analogues encapsulated in liposomes.

Description

Topisch applizierbare Mittel zur Behandlung und Prophylaxe der Alopezie Topical agents for the treatment and prophylaxis of alopecia
Die Erfindung betrifft topisch applizierbare Mittel zur Behandlung und Prophylaxe der Alopezie, welche durch einen Gehalt in Liposomen verkapselter Vitamin D-Analoga gekennzeichnet ist.The invention relates to topically applicable agents for the treatment and prophylaxis of alopecia, which is characterized by a content of vitamin D analogs encapsulated in liposomes.
Es ist bekannt, daß man Vitamin D-Analoga zur Behandlung verschiedener Alopezieformen verwenden kann. So sind in der GB-A 2 260 903 und der WO 93/00079 topisch applizierbare Mittel beschrieben, die Vitamin D-Analoga in Salben, Cremes, Gelen oder Lotionen enthalten. Da diese vorbekannten Formulierungen, insbesondere wenn sie zusätzlich noch penetrationsverstärkende Mittel, wie Ethanol oder Propylenglycol enthalten, auch eine systemische Wirksamkeit besitzen, entfalten sie neben der erwünschten therapeutischen Wirkung auch unerwünschte Nebenwirkungen. So beeinflussen sie insbesondere auch den Calziumstoffwechsel, was zur Hypercalcämie und Hypercalcurie führen kann.It is known that vitamin D analogues can be used to treat various forms of alopecia. For example, GB-A 2 260 903 and WO 93/00079 describe topically administrable compositions which contain vitamin D analogues in ointments, creams, gels or lotions. Since these previously known formulations, in particular if they additionally contain penetration-enhancing agents such as ethanol or propylene glycol, also have a systemic activity, they also develop undesirable side effects in addition to the desired therapeutic effect. In particular, they also influence calcium metabolism, which can lead to hypercalcemia and hypercalcuria.
Die erfindungsgemäßen topisch applizierbaren Mitteln, die in Liposomen verkapselte Vitamin D-Analoga enthalten entfalten eine ausgezeichnete Wirksamkeit bei der Behandlung verschiedener Alopezieformen, aber im Gegensatz zu den vorbekannten Mitteln werden bei ihnen unerwünschte systemische Nebenwirkungen nicht beobachtet.The topically administrable agents according to the invention, which contain vitamin D analogs encapsulated in liposomes, are extremely effective in treating various forms of alopecia, but in contrast to the previously known agents, undesirable systemic side effects are not observed in them.
Vitamin D-Analoga, die sich zur Herstellung der erfindungsgemäßen Mittel eignen, sind beispielsweise das Calcitriol (lα,25-Dihydroyvitamin D3), das Calcifediol (25- Hydroxyvitamin D3), das Calcipotriol (CAS-1128-00-9), das Colecalciferol (Vitamin Ds) und das Tacalcitol (CAS-57333-96-7). Darüberhinaus sind auch die in der obengenannten GB-A 2 260 903 und WO 93/00079 erwähnten Vitamin D-Analoga zur Herstellung der erfindungsgemäßen Mittel geeignet. Als geeignete Vitamin D-Analoga seien ferner auch die in der WO 94/07853 beschriebenen Verbindungen geeignet, wie zum Beispiel der (5Z,7E,22E)-(1S,3 ,24R)-1 ,3,24-Trihydroxy-9, 10-secocholesta-5,7, 10(19), 22-tetraen-25- carbonsäure-isopropylester.Vitamin D analogs which are suitable for the preparation of the agents according to the invention are, for example, calcitriol (lα, 25-dihydroyvitamin D3), calcifediol (25-hydroxyvitamin D3), calcipotriol (CAS-1128-00-9) and colecalciferol (Vitamin Ds) and the tacalcitol (CAS-57333-96-7). In addition, the vitamin D analogs mentioned in the abovementioned GB-A 2 260 903 and WO 93/00079 are also suitable for producing the agents according to the invention. The compounds described in WO 94/07853 are also suitable as suitable vitamin D analogs, such as, for example, the (5Z, 7E, 22E) - (1S, 3, 24R) -1, 3,24-trihydroxy-9, 10-secocholesta-5,7, 10 (19), 22-tetraen-25-carboxylic acid isopropyl ester.
Zur Verkapselung der Vitamin D- Analoga in Liposomen können die Verfahren angewendet werden, die dem Fachmann an sich wohl bekannt sind. So kann man beispielsweise diese Wirkstoffe und die liposomenbildenden Substanzen in einem organischen Lösungsmittel lösen, die Lösung in eine wässrige Phase eintragen und gegebenenfalls nach Homogenisieren das Lösungsmittel destillativ entfernen. Üblicherweise werden die 100- bis 500000-fache Gewichtsmenge Liposomen bildende Substanz oder Substanzgemisch bezogen auf das Vitamin D-Analoga verwendet. Geeignete Liposomen bildende Substanzen sind insbesondere Phospholipide, wie die Sphingomyeline, die Plasmalogene, die Phosphatidylcholine, die Phosphatidylethanolamine, die Phosphatidylserine, die Phosphatidylinosite und die Cardiolipine oder auch Gemische dieser Lipide (Dr. Otto-Albert Neumüller: Römpps Chemie-Lexikon; Franksche Verlagshandlung, Stuttgart(DE), 9te Auflage, 1991, 3383f) und Gemische dieser Phospholipide mit Cholesterin und/oder Ladungsträgern, wie zum Beispiel Stearylamin, Stearinsäure oder Diacetylphosphat.The methods which are known per se to the person skilled in the art can be used to encapsulate the vitamin D analogs in liposomes. For example, these active ingredients and the liposome-forming substances can be dissolved in an organic solvent, the solution added to an aqueous phase and, if necessary, the solvent removed by distillation after homogenization. Usually 100 to 500,000 times the amount by weight of liposome-forming substance or mixture of substances based on the vitamin D analogs are used. Suitable liposome-forming substances are in particular phospholipids, such as the sphingomyeline, the plasmalogens, the phosphatidylcholines, the phosphatidylethanolamines, the phosphatidylserines, the phosphatidylinosites and the cardiolipins, or else mixtures of these lipids (Dr. Otto-Albert Neumüller: Römpps Chemie-Lexikon; Franksche Verlaghandlung, Franksche Verlaghandlung Stuttgart (DE), 9th edition, 1991, 3383f) and mixtures of these phospholipids with cholesterol and / or charge carriers, such as, for example, stearylamine, stearic acid or diacetyl phosphate.
Zur Herstellung der Liposomensuspensionen verwendet man üblicherweise 0,5 bis 10 Gewichtsprozent Phospholipid oder -lipidgemisch bezogen auf die wässrige Phase. Geeignete Gemische können bis zu 60 Gewichtsprozent Cholesterin und bis zu 30 Gewichts¬ prozent Ladungsträger enthalten. Als Lösungsmittel verwendet man vorzugsweise Ethanol, Methanol, Isopropanol, Diethylether, Aceton, Chloroform und Gemische dieser Lösungsmittel.0.5 to 10 percent by weight of phospholipid or lipid mixture, based on the aqueous phase, is usually used to prepare the liposome suspensions. Suitable mixtures can contain up to 60 percent by weight of cholesterol and up to 30 percent by weight of charge carriers. Ethanol, methanol, isopropanol, diethyl ether, acetone, chloroform and mixtures of these solvents are preferably used as solvents.
Da die Lipoide oxidationsempfindlich sind, wird das Verfahren zweckmäßigerweise unter einer Inertgasatmosphäre, wie Stickstoff oder Argon durchgeführt und die erhaltenen wässrigen Liposomenlösungen durch Zugabe von Antioxidantien, wie Natriumascorbat, Tocopherol oder Natriumhydrogensulfit stabilisiert.Since the lipoids are sensitive to oxidation, the process is advantageously carried out under an inert gas atmosphere, such as nitrogen or argon, and the aqueous liposome solutions obtained are stabilized by adding antioxidants, such as sodium ascorbate, tocopherol or sodium bisulfite.
Ferner können die wässrigen Liposomenlösungen noch zusätzliche Wirkstoffe, wie Bactericide, Konservierungsmittel und/oder Puffersubstanzen enthalten.Furthermore, the aqueous liposome solutions can also contain additional active ingredients, such as bactericides, preservatives and / or buffer substances.
Die Verkapselung der Vitamin D- Analoga in Liposomen kann unter den gleichen Bedingungen durchgeführt werden, wie die vorbekannten Verfahren dieser Art (Pharmazie in unserer Zeit ü, 1982, 97-108; Pure Appl. Chem., 53, 1981, 2241-2254). Die Verkapselung der Vitamin D-Analoga kann sowohl in multilamellarer Liposomen als auch in unilamellaren Liposomen erfolgen.The encapsulation of the vitamin D analogs in liposomes can be carried out under the same conditions as the previously known methods of this type (pharmacy in our time ü, 1982, 97-108; Pure Appl. Chem., 53, 1981, 2241-2254) . The encapsulation of the vitamin D analogs can take place both in multilamellar liposomes and in unilamellar liposomes.
Bei dem erfindungsgemäßen Verfahren ist es aber auch andererseits möglich, das Lösungsmittel nicht durch Destillation sondern mittels der bekannten Verfahren der trans- membranen Destillation (Chem. Ing. Techn. 56, 1984, 514-521; J. of Membran Sei., 39, 1988, 45-51; DE-A 33 12 359) oder Pervaporation (Swiss Chem., 10, 1988, 45-51; ACS Symposium 281., 1985, 467-478; Chem. Ing. Techn., 60, 1988, 590-603) zu entfernen.In the process according to the invention, however, it is also possible, on the other hand, not to use solvents by distillation but by means of the known methods of transmembrane distillation (Chem. Ing. Techn. 56, 1984, 514-521; J. of Membrane Sei., 39, 1988, 45-51; DE-A 33 12 359) or pervaporation (Swiss Chem., 10, 1988, 45-51; ACS Symposium 281., 1985, 467-478; Chem. Ing. Techn., 60, 1988, 590-603).
Die so hergestellten wirkstoffhaltigen Liposomensuspensionen können bei Bedarf mittels Wasser verdünnt und/oder mit Verdickungsmitteln, wie beispielsweise Hydroxyethyl- cellulose, Methylcellulose, Aerosil® (Herseller Degussa AG, DE) Carbopol® (B.F.Goodrich Chem., USA) etc. versetzt werden um so streichfähige Gele herzustellen. Andererseits ist es aber auch beispielweise möglich, die Suspensionen mittels Gefrier¬ trocknung zur Trockne einzuengen und den erhaltenen Rückstand in eine Salbengrundlage oder Creme einzuarbeiten.The active substance-containing liposome suspensions prepared in this way can be diluted with water if necessary and / or thickeners, such as, for example, hydroxyethyl cellulose, methyl cellulose, Aerosil® (Herseller Degussa AG, DE), Carbopol® (BFGoodrich Chem., USA) etc. can be added to make them spreadable To produce gels. On the other hand, it is also possible, for example, to freeze the suspensions to dryness by means of freeze drying and to incorporate the residue obtained into an ointment base or cream.
Die optimale Wirkstoffkonzentration in den fertigen pharmazeutischen Präparaten ist naturgemäß von der Art des Wirstoffes und der galenischen Zubereitung abhängig und muß im Einzelfall mittels der üblichen Vorversuche ermittelt werden. In der Regel wird es ausreichend sein, wenn man pharmazeutische Präparate anwendet, die 0,001 bis 1 mg und vorzugsweise 0,005 bis 0,1 mg Vitamin D-Analoga pro g Präparat verwendet.The optimal concentration of active substance in the finished pharmaceutical preparations naturally depends on the type of active substance and the galenical preparation and must be determined in individual cases using the usual preliminary tests. As a rule, it will be sufficient to use pharmaceutical preparations which use 0.001 to 1 mg and preferably 0.005 to 0.1 mg of vitamin D analogs per g of preparation.
Die nachfolgenden Ausführungsbeispiele dienen zur näheren Erläuterung der Erfindung. The following exemplary embodiments serve to explain the invention in more detail.
Beispiel 1example 1
(Filmmethode mit anschließender Hochdruck-Homogenisation)(Film method with subsequent high pressure homogenization)
0,9 g PC S 100 (Hersteller Lipoid KG, DE-Ludwigshafen), 0,1 g Cholesterin und 10 mg (5Z,7E,22E)-(lS,3R,24R)-l,3,24-Trihydroxy-9,10-seco-cholesta-5,7,10(19),22-tetraen-25- carbonsäure-isopropylester werden in 50 ml 95%igem Ethanol gelöst. Dann wird die Lösung in einem 500 ml Rundkolben am Rotationsverdampfer zur Trockne eingeengt, wobei sich ein Lipidfilm an der Glaswand bildet. Dieser Lipidfilm wird mit 98,9 g bidestilliertem Wasser abgelöst. Anschließend wird die erhaltene Liposomensuspension mit einem Hochdruckhomogenisator (Microfluidizer® der Firma Microfluid Corp. USA) bei 400 MPA und 25 °C homogenisiert und durch ein Filter von 0,2 μm filtriert.0.9 g PC S 100 (manufacturer Lipoid KG, DE-Ludwigshafen), 0.1 g cholesterol and 10 mg (5Z, 7E, 22E) - (lS, 3R, 24R) -l, 3,24-trihydroxy-9 , 10-seco-cholesta-5,7,10 (19), 22-tetraen-25-carboxylic acid isopropyl ester are dissolved in 50 ml of 95% ethanol. The solution is then evaporated to dryness in a 500 ml round-bottom flask on a rotary evaporator, a lipid film forming on the glass wall. This lipid film is removed with 98.9 g of double-distilled water. The liposome suspension obtained is then homogenized with a high-pressure homogenizer (Microfluidizer® from Microfluid Corp. USA) at 400 MPA and 25 ° C. and filtered through a filter of 0.2 μm.
Die erhaltene Liposomensuspension enthält Liposomen mit einer mittleren Größe von 112 nm. Der Gehalt an Phosphatidylcholin liegt bei 9 mg pro g; der Gehalt an verkapselten! Wirkstoff beträgt 0,1 mg pro g.The liposome suspension obtained contains liposomes with an average size of 112 nm. The phosphatidylcholine content is 9 mg per g; the content of encapsulated! Active ingredient is 0.1 mg per g.
Beispiel 2Example 2
0,9 g PC S 100, 0,1 g Cholesterin und 10 mg (5Z,7E,22E)-(1S,3R,24R)-1,3,24~ Trihydroxy-9, 10-seco-cholesta-5,7, 10(19),22-tetraen-25-carbonsäure-isopropylester werden in 50 ml 95% igen Ethanol gelöst.0.9 g PC S 100, 0.1 g cholesterol and 10 mg (5Z, 7E, 22E) - (1S, 3R, 24R) -1,3,24 ~ trihydroxy-9, 10-seco-cholesta-5, 7, 10 (19), 22-tetraen-25-carboxylic acid isopropyl ester are dissolved in 50 ml of 95% ethanol.
Dann wird die Lösung in einem 500 ml Rundkolben am Rotationsverdampfer zur Trockne eingeengt, wobei sich ein Lipidfilm an der Glaswand bildet. Dieser Lipidfilm wird mit 98,9 g bidestilliertem Wasser abgelöst. Die erhaltene Suspension wird dann einer Hochdruck- extrusion unterworfen, wie in der PCT/DE93/00997 beschrieben, wobei man Nucleopore®- Membrane mit absteigender Porenweite von 5,0, 1,0, 0,4, 0,2, 0,1 und 0,05 μm verwendet.The solution is then evaporated to dryness in a 500 ml round-bottom flask on a rotary evaporator, a lipid film forming on the glass wall. This lipid film is removed with 98.9 g of double-distilled water. The suspension obtained is then subjected to high-pressure extrusion, as described in PCT / DE93 / 00997, using Nucleopore® membranes with a decreasing pore size of 5.0, 1.0, 0.4, 0.2, 0.1 and 0.05 μm is used.
Die erhaltene Liposomen-Suspension enthält Liposomen mit einer mittleren Größe von 94 nm und hat ansonsten die gleichen Eigenschaften, wie das in Beispiel 1 beschriebene Präparat.The liposome suspension obtained contains liposomes with an average size of 94 nm and otherwise has the same properties as the preparation described in Example 1.
Beispiel 3Example 3
(Herstellung von Liposomen-Suspensionen und anschließende Beladung mit Wirkstoff) 0,9 g PC S 100 und 0,1 g DSPG,Na (Hersteller Sygena LTD, CH-Liestal) werden in 50 ml 95%igem Ethanol gelöst, zur Trockne eingeengt und der entstandene Lipidfilm mit 99 g bidestilliertem Wasser abgelöst. Dann führt man eine Hochdruckextrusion durch, wie in Beispiel 2 beschrieben.(Preparation of liposome suspensions and subsequent loading with active ingredient) 0.9 g PC S 100 and 0.1 g DSPG, Na (manufacturer Sygena LTD, CH-Liestal) are dissolved in 50 ml 95% ethanol, evaporated to dryness and the resulting lipid film is detached with 99 g bidistilled water. A high pressure extrusion is then carried out as described in Example 2.
50,0 g der so hergestellten Liposomen-Suspension werden in einem Jodzahlkolben vorgelegt, mit 2 mg (5Z,7E,22E)-(lS,3R,24R)-l,3,24-Trihydroxy-9,10-seco-Cholesta- 5,7, 10(19),22-tetraen-25-carbonsäure-isopropylester versetzt, 18 Stunden lang bei Raumtemperatur gerührt und dann durch einen Filter von 0,2 μm Porenweite filtriert.50.0 g of the liposome suspension thus prepared are placed in an iodine number flask, with 2 mg (5Z, 7E, 22E) - (IS, 3R, 24R) -l, 3,24-trihydroxy-9,10-seco-cholesta - 5.7, 10 (19), 22-tetraen-25-carboxylic acid isopropyl ester, stirred for 18 hours at room temperature and then filtered through a filter with a pore size of 0.2 μm.
Die so erhaltene Liposomen-Suspension enthält Liposomen mit einer mittleren Größe von 106 nm. Der Gehalt an Phosphatidylcholin liegt bei 9,0 mg pro g, der Gehalt an Wirkstoff liegt bei 0,04 mg pro g.The liposome suspension thus obtained contains liposomes with an average size of 106 nm. The phosphatidylcholine content is 9.0 mg per g, the active ingredient content is 0.04 mg per g.
Beispiel 4Example 4
(Eine modifizierte reverse-phase-evaporation Methode)(A modified reverse phase evaporation method)
0,5 g PC E 100 und 10 mg (5Z,7E,22E)-(lS,3R,24R)-l,3,24-Trihydroxy-9,10-seco-- cholesta-5,7,10(19),22-tetraen-25-carbonsäure-isopropylester werden in 100 ml Dietylether gelöst und mit 50 ml 0,015 M wässrigem Tris-Puffer von pH 7,4 versetzt. Dann homogenisiert man das Zweiphasengemisch im Hochdruckhomogenisator (Microfluidizer®) bei 20Pa und 23 °C. Die entstandene Emulsion wird am Rotationsverdampfer bei 4000Pa und 23 °C vom Diethylether befreit und die erhaltene Liposomen-Suspension durch ein Filter von 0,45 μm filtriert.0.5 g PC E 100 and 10 mg (5Z, 7E, 22E) - (lS, 3R, 24R) -l, 3,24-trihydroxy-9,10-seco-- cholesta-5,7,10 (19th ), 22-tetraen-25-carboxylic acid isopropyl ester are dissolved in 100 ml of dietyl ether and mixed with 50 ml of 0.015 M aqueous Tris buffer of pH 7.4. Then the two-phase mixture is homogenized in a high-pressure homogenizer (Microfluidizer®) at 20Pa and 23 ° C. The resulting emulsion is freed from diethyl ether on a rotary evaporator at 4000 Pa and 23 ° C. and the liposome suspension obtained is filtered through a 0.45 μm filter.
Die erhaltene Liposomen-Suspension enthält Liposomen mit einer mittleren Größe von 220 nm. der Gehalt an Phosphatidylcholin liegt bei 10 mg pro g; der Gehalt an verkapselten! Wirkstoffbeträgt 0,2 mg pro g.The liposome suspension obtained contains liposomes with an average size of 220 nm. The phosphatidylcholine content is 10 mg per g; the content of encapsulated! Active ingredient is 0.2 mg per g.
Beispiel 5 und 6Examples 5 and 6
Die gemäß Beispiel 1 und 3 hergestellten Liposomen-Suspensionen werden mit 0,18 %The liposome suspensions prepared according to Examples 1 and 3 are mixed with 0.18%
p-Hydroxybenzylmethylester, 0,02 % p-Hydroxybenzylpropylester und 2% Hydroxyethylcellulose versetzt und 5 Minuten lang mit 600 Umdrehungen pro Minute und dann kurzfristig mit 1000 Umdrehungen pro Minute gerührt. Dann läßt man die Mischungen 24 Stunden ruhen. Die Zubereitungen haben eine mittelweiche Konsistenz, der Viskositätswert liegt bei etwap-Hydroxybenzylmethylter, 0.02% p-Hydroxybenzylpropylester and 2% Hydroxyethylcellulose added and stirred for 5 minutes at 600 revolutions per minute and then briefly at 1000 revolutions per minute. The mixtures are then left to stand for 24 hours. The preparations have a medium-soft consistency, the viscosity value is approximately
30000 mPa/s. In den Zubereitungen sind die Liposomen weiterhin in der wässrigen Phase suspendiert. Sie sind intakt.30000 mPa / s. In the preparations, the liposomes are still suspended in the aqueous phase. You are intact.
Beispiel 7 und 8Examples 7 and 8
(Herstellung eines liposomalen Lipogels)(Preparation of a Liposomal Lipogel)
Die gemäß Beispiel 1 und 3 hergestellten Liposomen-Suspensionen werden gefriergetrocknet. Der getrocknete Liposomen-Kuchen wird mit einer Schlagzeugmühle zerkleinert und das entstandene Pulver portionsweise mit soviel einer Salbengrundlage verrieben, die aus Vaseline besteht, welche 0,02 % 2,6-Di tert.-butyl-4-methylphenol (=BHT) als Antioxidanz enthält, daß die Wirkstoffkonzentration in der fertigen Salbe bei 0,05 mg pro g liegt. The liposome suspensions prepared according to Examples 1 and 3 are freeze-dried. The dried liposome cake is crushed with a drum mill and the resulting powder is triturated in portions with an ointment base consisting of petroleum jelly which contains 0.02% 2,6-di tert-butyl-4-methylphenol (= BHT) as an antioxidant contains that the active ingredient concentration in the finished ointment is 0.05 mg per g.

Claims

Patentansprüche: Claims:
1.) Topisch applizierbares Mittel zur Behandlung und Prophylaxe der Alopezie, dadurch gekennzeichnet, daß es in Liposomen verkapselte Vitamin D-Analoga enthält.1.) Topically applicable agent for the treatment and prophylaxis of alopecia, characterized in that it contains vitamin D analogs encapsulated in liposomes.
2.) Topisch applizierbares Mittel gemäß Anspruch 1, dadurch gekennzeichnet, daß es in Form eines Hydrogels oder Oleogels vorliegt. 2.) Topically applicable agent according to claim 1, characterized in that it is in the form of a hydrogel or oleogel.
PCT/EP1996/002195 1995-05-22 1996-05-22 Topically applicable agents for treating and preventing alopecia WO1996037193A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU58199/96A AU5819996A (en) 1995-05-22 1996-05-22 Topically applicable agents for treating and preventing alopecia
EP96919796A EP0827395A1 (en) 1995-05-22 1996-05-22 Topically applicable agents for treating and preventing alopecia
JP8535377A JPH11505262A (en) 1995-05-22 1996-05-22 Topically applicable drug for hair loss treatment and hair loss prevention

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19519273.7 1995-05-22
DE19519273A DE19519273A1 (en) 1995-05-22 1995-05-22 Topical agents for the treatment and prophylaxis of alopecia

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997037637A1 (en) * 1996-04-04 1997-10-16 Ortho Pharmaceutical Corporation Liposome-based topical vitamin d formulation
WO2003028674A2 (en) * 2001-10-02 2003-04-10 Cedars-Sinai Medical Center Method for stimulating hair growth by administering vitamin d analogs
EP2464357A2 (en) * 2009-08-14 2012-06-20 Berg Biosystems, LLC Vitamin d3 and analogs thereof for treating alopecia
EP3969005A4 (en) * 2019-05-17 2023-10-04 The Trustees of The University of Pennsylvania Methods and compositions for treating obesity and/or skin disorders

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030219465A1 (en) * 2002-05-23 2003-11-27 Suresh Kumar Gidwani Composition for delivery of dithranol
WO2013072929A2 (en) * 2011-09-23 2013-05-23 Indian Institute Of Technology Nanop article based cosmetic composition
FR3017290B1 (en) * 2014-02-10 2017-05-12 Dermaconcept Jmc COMPOSITION FOR CONTROLLING THE FALL OF HAIR
MX2021006750A (en) 2018-12-06 2021-11-17 Lipicare Life Sciences Ltd Vitamin d micro-emulsions and uses thereof.

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5116605A (en) * 1989-03-09 1992-05-26 Alt John P Composition and skin treatment method therewith for mitigating acne and male-pattern baldness
US5190935A (en) * 1989-07-10 1993-03-02 Leo Pharmaceutical Products Ltd. Vitamin d analogues
US5374629A (en) * 1990-03-30 1994-12-20 Leo Pharmaceutical Products Ltd. A/S Lovens Kemiske Fabrik Produktionsaktieselskab Vitamin D analogues
US5401731A (en) * 1989-06-29 1995-03-28 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Productionsaktieselskab) Vitamin D analogues
EP0664287A1 (en) * 1994-01-20 1995-07-26 Duphar International Research B.V Vitamin D Compounds and method of preparing these compounds
US5447924A (en) * 1990-08-15 1995-09-05 Leo Pharmaceutical Products Ltd. Vitamin D analogues

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5116605A (en) * 1989-03-09 1992-05-26 Alt John P Composition and skin treatment method therewith for mitigating acne and male-pattern baldness
US5401731A (en) * 1989-06-29 1995-03-28 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Productionsaktieselskab) Vitamin D analogues
US5190935A (en) * 1989-07-10 1993-03-02 Leo Pharmaceutical Products Ltd. Vitamin d analogues
US5374629A (en) * 1990-03-30 1994-12-20 Leo Pharmaceutical Products Ltd. A/S Lovens Kemiske Fabrik Produktionsaktieselskab Vitamin D analogues
US5447924A (en) * 1990-08-15 1995-09-05 Leo Pharmaceutical Products Ltd. Vitamin D analogues
EP0664287A1 (en) * 1994-01-20 1995-07-26 Duphar International Research B.V Vitamin D Compounds and method of preparing these compounds

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997037637A1 (en) * 1996-04-04 1997-10-16 Ortho Pharmaceutical Corporation Liposome-based topical vitamin d formulation
US5834016A (en) * 1996-04-04 1998-11-10 Cilag Ag Liposome-based topical vitamin D formulation
WO2003028674A2 (en) * 2001-10-02 2003-04-10 Cedars-Sinai Medical Center Method for stimulating hair growth by administering vitamin d analogs
WO2003028674A3 (en) * 2001-10-02 2003-12-11 Cedars Sinai Medical Center Method for stimulating hair growth by administering vitamin d analogs
EP2464357A2 (en) * 2009-08-14 2012-06-20 Berg Biosystems, LLC Vitamin d3 and analogs thereof for treating alopecia
EP2464357A4 (en) * 2009-08-14 2013-08-14 Berg Pharma Llc Vitamin d3 and analogs thereof for treating alopecia
AU2010282731B2 (en) * 2009-08-14 2015-08-13 Berg Llc Vitamin D3 and analogs thereof for treating alopecia
AU2010282731C1 (en) * 2009-08-14 2016-04-21 Berg Llc Vitamin D3 and analogs thereof for treating alopecia
AU2015238850B2 (en) * 2009-08-14 2017-08-24 Berg Llc Vitamin D3 and analogs thereof for treating alopecia
US9901637B2 (en) 2009-08-14 2018-02-27 Berg Llc Vitamin D3 and analogs thereof for treating alopecia
US11305016B2 (en) 2009-08-14 2022-04-19 Berg Llc Vitamin D3 and analogs thereof for treating alopecia
EP3969005A4 (en) * 2019-05-17 2023-10-04 The Trustees of The University of Pennsylvania Methods and compositions for treating obesity and/or skin disorders

Also Published As

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CA2222061A1 (en) 1996-11-28
AU5819996A (en) 1996-12-11
JPH11505262A (en) 1999-05-18
DE19519273A1 (en) 1996-11-28
EP0827395A1 (en) 1998-03-11
KR19990021864A (en) 1999-03-25

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