Classifications

• • 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
  • 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
  • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
• • 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
  • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
  • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

• the invention relates to pharmaceutical preparations containing clathrates of cyclodextrins and unnatural vitamin D analogs.
• the invention relates to topically administrable pharmaceutical preparations of this type.
• Such preparations are preferably suitable for the treatment of psoriasis.
• Preparations for the treatment of psoriasis which can be applied topically and which contain a vitamin D analog are known, for example Psorcutan® containing calcipotriol (Red List 1994, List of Medicines of the BDI, Editio Cantor, DE Aulendorf, No. 31271).
• these preparations not only have the disadvantage that they can cause skin irritation, such as redness, itching or burning, but also serious systemic side effects, such as hypercalcemia in the case of large-scale application, which necessitate discontinuation of the therapy.
• a further disadvantage is that the vitamin D analogs, like the compounds of the vitamin D series, are easily decomposed even by oxygen and / or exposure, so that pharmaceutical preparations which contain these compounds have only a low stability.
• topically administrable agents of this type in particular in the treatment of psoriasis vulgaris and other manifestations of this disease, have an excellent effectiveness and, in contrast to the previously known agents with the same direction of action, do not appear to cause any serious undesirable systemic side effects.
• Vitamin D analogs which are suitable for the preparation of the agents according to the invention are, for example, calcitriol (1 ⁇ , 25-dihydroyvitamin D3), caicifediol (25-hydroxyvitamin 03), calcipotriol (CAS-1128-00-9) and cholecalciferol (Vitamin D3) and the tacalcitol (CAS-57333-96-7).
• the vitamin D analogs mentioned in US Pat. No. 5,098,899 are also suitable for the preparation of the agents according to the invention.
• R 1 , R 2 and R 3 independently of one another each represent a hydrogen atom, a straight-chain or branched-chain saturated alkanoyl group having 1 or 3 to 9 carbon atoms or an aroyl group with -OH- in the meaning of an ⁇ - or ⁇ -hydroxyl group,
• R 4 and R 4a each have a hydrogen atom, a chlorine or fluorine atom, a trifluoromethyl group, a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 4 carbon atoms or R 4 and R 4a together with the carbon atom 25 a 3- to 7-membered
• R5a represents a hydrogen atom or a linear or branched alkyl group with 1 or 3 to 8 carbon atoms and
• cyclodextrins increases the bioavailability of the active ingredient, particularly when applied topically in the upper layers of the skin, and thus enables the active ingredient to be reduced in dose (delayed release).
• cyclodextrin derivatives are not only suitable for the preparation of topically administrable preparations, but they can also advantageously be used for the production of systemically administered dosage forms and also bring the inventive advantage of the delayed release of active ingredient. In this way, the strong systemic side effects of the active ingredient group can be reduced and the substance can be stabilized at the same time.
• R * represents a hydrogen atom, a methyl group, a 2-hydroxyethyl group 25 or a 2-hydroxypropyl group
• R " is a hydrogen atom or, if R * ⁇ represents a methyl group, also one
• Methyl group and r represent a number from 4 to 7.
• Such cyclodextrins are preferably the ⁇ -cyclodextrin, the ⁇ -cyclodextrin, the dimethyl- ⁇ -cyclodextrin, the 2-hydroxyethyl- ⁇ -cyclodextrin, the 2-hydroxypropyl- ⁇ -cyclodextrin and in particular the ⁇ -cyclodextrin (Drug Dev. and Ind. Pharm., 17, 1991, 1503-1549, J. Incl. Phenom., 1, 1983, 135-150 and WO 93 / 13138).
• the vitamin D analogs can be intimately mixed with the cyclodextrin, if appropriate with the addition of further pharmaceutical auxiliaries (for example by stirring, kneading) or one can be obtained from a solution of the components in water and / or a suitable solvent (such as, for example, a Dissolve C1-C4 alcohol such as methanol, ethanol or isopropanol or a C2-C4 ketone such as acetone or methyl ethyl ketone) and then remove the solvent, for example by vacuum distillation, freeze drying or spray drying.
• a suitable solvent such as, for example, a Dissolve C1-C4 alcohol such as methanol, ethanol or isopropanol or a C2-C4 ketone such as acetone or methyl ethyl ketone
• vitamin D analogs dissolved in a suitable solvent such as one of the abovementioned alcohols or ketones
• a suitable solvent such as one of the abovementioned alcohols or ketones
• the ratio of cyclodextrin to vitamin D analogs is chosen so that 1: 1 mokmol complexes are formed, but this does not rule out that it is cheaper in individual cases to choose the molar ratio so that, for example, 2: 1, 3: 1, 3: 2 or 1: 2 complexes are formed.
• topically administrable pharmaceuticals The manufacture of the topically administrable pharmaceuticals is known per se. On the other hand, it is also possible to create new preparations adapted to the special needs of the skin.
• Such topical preparations are produced in a customary manner by converting the active ingredients into the desired application form, for example a solution, a milk, a lotion, a cream, an ointment, a fatty ointment or a paste, using suitable additives.
• the active substance concentration depends on the form of administration.
• An active ingredient concentration of 5 to 30 percent by weight is preferably used.
• the milk, lotion or cream (oil / water emulsions) and the ointment (water / oil emulsion) can be prepared in a conventional manner using conventional emulsifiers (Kirk Othmer: Encyclopedia of Chemical Technology, 3rd edition, 1979; John Wiley & Sons, New York, Vol.
• the topical preparation according to the invention can consist of one or two active ingredients, hydrophilic and / or lipophilic additives, fat phase, oil / water emulsifier, aqueous phase and preservative.
• Moisturizing factors such as propylene glycol, glycerin, polyethylene glycols, urea, vital complexes (such as placenta extracts), enzymes, herbal extracts (such as collagen) can be used as hydrophilic and / or lipophilic additives.
• Suitable as the oily phase or as the fat phase in the oil / water emulsion are hydrocarbons, such as squalene, petroleum jelly, paraffins, triglycerides or stearin, or waxes, such as beeswax or animal or vegetable oils such as olive oil, nut oil, fine bone oil , Almond oil, jojoba oil, lanolin or sunflower oil.
• Suitable oil / water emulsifiers are, for example, stearyl alcohol,
• the aqueous phase can additionally contain buffer substances, such as, for example, the disodium salt of ethylenediamine-N, N, N ' , N' -tetraacetic acid and preservatives, such as benzoic acid, chloroquinaldol, parabee or benzalkonium chloride.
• buffer substances such as, for example, the disodium salt of ethylenediamine-N, N, N ' , N' -tetraacetic acid and preservatives, such as benzoic acid, chloroquinaldol, parabee or benzalkonium chloride.
• the emulsion is additionally mixed with one or two active ingredients) and, if appropriate, with fragrances, such as that of the Crematest® series, and stirred until they are evenly distributed.
• the active substance concentration depends on the form of administration.
• an active ingredient concentration of 0.0001% to 3% is preferably used.
• the complex is weighed into the amount which leads to an active ingredient concentration of 50 ⁇ g / g and supplemented with water to 100 g.
• the complex is dissolved in 99.0 g of water in the amount that leads to an active ingredient concentration of 80 ⁇ g / g and processed with a gel former (e.g. Carbopol®-B.F. Goodrich Chem.) To form a spreadable formulation.
• a gel former e.g. Carbopol®-B.F. Goodrich Chem.
• the complex is weighed in the amount that leads to an active ingredient concentration of 40 ⁇ g / g and rubbed in 20 g petroleum jelly. Subsequently, Vaseline is added proportionately to 100g.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Veterinary Medicine (AREA)
• Nanotechnology (AREA)
• General Engineering & Computer Science (AREA)
• Biotechnology (AREA)
• Medical Informatics (AREA)
• Molecular Biology (AREA)
• Crystallography & Structural Chemistry (AREA)
• Biophysics (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (8)

Applications Claiming Priority (2)

Publications (1)

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Country Status (12)

Cited By (7)

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Citations (6)

• 1995
  • 1995-12-21 DE DE19549243A patent/DE19549243A1/de not_active Withdrawn
• 1996
  • 1996-12-20 KR KR1019980704745A patent/KR19990076637A/ko not_active Application Discontinuation
  • 1996-12-20 WO PCT/EP1996/005856 patent/WO1997023242A1/de not_active Application Discontinuation
  • 1996-12-20 HU HU9903935A patent/HUP9903935A3/hu unknown
  • 1996-12-20 CN CN96199734A patent/CN1207687A/zh active Pending
  • 1996-12-20 CA CA002241205A patent/CA2241205A1/en not_active Abandoned
  • 1996-12-20 AU AU13069/97A patent/AU1306997A/en not_active Abandoned
  • 1996-12-20 JP JP9523335A patent/JP2000502733A/ja active Pending
  • 1996-12-20 EP EP96944669A patent/EP0869819A1/de not_active Withdrawn
  • 1996-12-20 IL IL12502096A patent/IL125020A0/xx unknown
• 1998
  • 1998-06-15 IS IS4774A patent/IS4774A/is unknown
  • 1998-06-19 NO NO982874A patent/NO982874L/no not_active Application Discontinuation

Patent Citations (6)

Non-Patent Citations (3)

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