CA2241205A1 - Pharmaceutical compositions with vitamin d analogues - Google Patents
Pharmaceutical compositions with vitamin d analogues Download PDFInfo
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- CA2241205A1 CA2241205A1 CA002241205A CA2241205A CA2241205A1 CA 2241205 A1 CA2241205 A1 CA 2241205A1 CA 002241205 A CA002241205 A CA 002241205A CA 2241205 A CA2241205 A CA 2241205A CA 2241205 A1 CA2241205 A1 CA 2241205A1
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- hydrogen atom
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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
- 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
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- 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
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- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
Pharmaceutical preparations that are preferably intended for topical application and that are characterized by having a content of cyclodextrin clathrates and vitamin D analogs. They are suitable for treating psoriasis.
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PCT sheet should not be there PCT sheet should not be there
Description
CA 0224120~ 1998-06-22 Ph~rmaceutical Preparations with Vit~min D Analogs The invention relates to pharmaceutical preparations that contain cyclodextrin clathrates and non-natural vitamin D
analogs.
In particular, the invention relates to pharmaceutical preparations of this type that can be applied topically. Such preparations are preferably suitable for treating psoriasis.
Preparations for treating psoriasis that can be applied topically and that contain a vitamin D analog are already known, for example Psorcutan(R) that contains calcipotriol (Rote Liste [Red List] 1994, Arzneimittelverzeichnis des BDI tBDI List of Pharmaceutical Agents], Editio Cantor, DE Aulendorf, No. 31271).
These preparations have the drawback, however, that they can cause not only skin irritation, such as reddening, itching, or burning, but also serious systemic side-effects, such as hypercalcemias in the case of large-surface application, which require that the therapy be discontinued. It is also disadvantageous that, just like the compounds of the vitamin D
series itself, the vitamin D analogs are easily decomposed by oxygen and/or exposure to light, such that pharmaceutical preparations that contain these compounds have only low stability.
In compounds of the vitamin D series itself and several metabolites of it (such as, for example, in the case of calciferol = vitamin D2, cholecalciferol = vitamin D3 and 25-hydroxyvitamin D3 calcifediol), an attempt was made to improve CA 0224120~ 1998-06-22 their stability and solubility by producing clathrates of these compounds with cyclodextrins (Pharmazie [Pharmaceutics] 35, 1993, 779-787; Acta Pharm. Nord. 2, 1990, 303-312, Drug Dev. and Ind.
Pharm., 19, 1993, 875-885 and GB-A 2,037,773). To our knowledge, no studies have yet been performed to produce preparations that can be applied topically and that contain cyclodextrin clathrates and non-natural vitamin D-analogs that are produced purely synthetically and to study their effectiveness.
It has now been found that such agents of this type that can be applied topically, especially when treating psoriasis vulgaris and other manifestations of this disease, exert a pronounced action in that they seem to cause no serious, undesirable, systemic side-effects, unlike the previously known agents that have the same general action.
Vitamin D analogs that are suitable for the production of the agents according to the invention are, for example, calcitriol (la,25-dihydroxyvitamin D3), calcifediol (25-hydroxyvitamin D3), calcipotriol (CAS-1128-00-9), cholecalciferol (vitamin D3), and tacalcitol (CAS-57333-96-7). Further, the vitamin D analogs that are mentioned in US Patent 5,098,899 are also suitable for, for example, the production of the agents according to the invention.
As suitable vitamin D analogs, especially also the compounds that are described in WO 94/07853 can be mentioned, in which 25-carboxylic acid derivatives in the vitamin D series of general CA 0224120~ 1998-06-22 formula I
analogs.
In particular, the invention relates to pharmaceutical preparations of this type that can be applied topically. Such preparations are preferably suitable for treating psoriasis.
Preparations for treating psoriasis that can be applied topically and that contain a vitamin D analog are already known, for example Psorcutan(R) that contains calcipotriol (Rote Liste [Red List] 1994, Arzneimittelverzeichnis des BDI tBDI List of Pharmaceutical Agents], Editio Cantor, DE Aulendorf, No. 31271).
These preparations have the drawback, however, that they can cause not only skin irritation, such as reddening, itching, or burning, but also serious systemic side-effects, such as hypercalcemias in the case of large-surface application, which require that the therapy be discontinued. It is also disadvantageous that, just like the compounds of the vitamin D
series itself, the vitamin D analogs are easily decomposed by oxygen and/or exposure to light, such that pharmaceutical preparations that contain these compounds have only low stability.
In compounds of the vitamin D series itself and several metabolites of it (such as, for example, in the case of calciferol = vitamin D2, cholecalciferol = vitamin D3 and 25-hydroxyvitamin D3 calcifediol), an attempt was made to improve CA 0224120~ 1998-06-22 their stability and solubility by producing clathrates of these compounds with cyclodextrins (Pharmazie [Pharmaceutics] 35, 1993, 779-787; Acta Pharm. Nord. 2, 1990, 303-312, Drug Dev. and Ind.
Pharm., 19, 1993, 875-885 and GB-A 2,037,773). To our knowledge, no studies have yet been performed to produce preparations that can be applied topically and that contain cyclodextrin clathrates and non-natural vitamin D-analogs that are produced purely synthetically and to study their effectiveness.
It has now been found that such agents of this type that can be applied topically, especially when treating psoriasis vulgaris and other manifestations of this disease, exert a pronounced action in that they seem to cause no serious, undesirable, systemic side-effects, unlike the previously known agents that have the same general action.
Vitamin D analogs that are suitable for the production of the agents according to the invention are, for example, calcitriol (la,25-dihydroxyvitamin D3), calcifediol (25-hydroxyvitamin D3), calcipotriol (CAS-1128-00-9), cholecalciferol (vitamin D3), and tacalcitol (CAS-57333-96-7). Further, the vitamin D analogs that are mentioned in US Patent 5,098,899 are also suitable for, for example, the production of the agents according to the invention.
As suitable vitamin D analogs, especially also the compounds that are described in WO 94/07853 can be mentioned, in which 25-carboxylic acid derivatives in the vitamin D series of general CA 0224120~ 1998-06-22 formula I
2~ 2~
R
.. , ,. _. ...
il "
in which R1, R2, and R3, independently of one another, each mean a hydrogen atom, a straight-chain or branched-chain saturated alkanoyl group with 1 or 3 to 9 carbon atoms or an aroyl group, with -OH- meaning a hydroxy group in ~- or ~-position, R4 and R4a at the same time each mean 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 R4 and R4a together with carbon atom 25 mean a 3- to 7-member cycloalkyl radical and Y means one of radicals CA 0224120~ 1998-06-22 -C(o)NR5R5a, -C(O)OR6 or -CN, whereby R5, R5a, and R6 each stand for a hydrogen atom or a linear or branched alkyl group with 1 or 3 to 8 carbon atoms, and R6 in addition stands for group (CH2)~C (CH2) n with m = O or 1 and n = 2, 3, 4, 5 or 6 and if m = 1, in addition with n = 1.
Thus, for example, (SZ,7E,22E)-(lS,3R,24R)-1,3,24-trihydroxy-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylic acid-isopropyl ester.
The clathrates of these vitamin D analogs were not previously known, whereas the vitamin D series is distinguished relative to clathrates that are already known by superior properties and are also subjects of this invention. Inclusion into cyclodextrins ensures increased bio-availability of the active ingredient, especially with topical application in the upper skin layers, and thus makes it possible to reduce the dose of the active ingredient (delayed release).
These cyclodextrin derivatives are suitable not only for the production of preparations that can be applied topically, but can also be used advantageously for the production of dosage forms that are to be administered systemically, and here also provide the advantage of the delayed release of active ingredients according to the invention. Thus, the strong systemic side-effects of the active ingredient group can be mitigated, and the substances can be stabilized at the same time.
CA 0224120~ 1998-06-22 In the production of such low-dose forms with calcitriol analogs for oral or systemic application, large fluctuations of the active ingredient concentration almost unavoidably occur in the dosage units (deficient content uniformity), which manifest themselves more powerfully, the lower the dose of the active ingredient.
- In addition, in the storage of such preparations, a decline in the active ingredient concentration is often observed as a result of oxidative degradation reactions of the active ingredient.
In addition, the bio-availability of the respective calcitriol analog at such a low dose is subject to a pronounced first-pass effect and has large interindividual and intraindividual fluctuations.
It has now been found for oral administration that the advantages, which are observed especially in the storage of dosage forms that contain low-dose calcitriol analogs, can be avoided at least to a large extent when dosage forms are prepared that contain powdery cyclodextrin-inclusion compounds of these active ingredients.
Cyclodextrins that are suitable for the production of these CA 0224120~ 1998-06-22 clathrates, for example those of general formula II
CH20RCH2~R CH20R
~ O \) O ' ~-0 Lo ~ /L o 1'~
!oRtlORIl RO
--t o ( ~T) in which R' means a hydrogen atom, a methyl group, a 2-hydroxyethyl group or a 2-hydroxypropyl group R" means a hydrogen atom or, if R1 represents a methyl group, also a methyl group and r means a number from 4 to 7.
Such cyclodextrins are preferably ~-cyclodextrin, y-cyclodextrin, dimethyl-B-cyclodextrin, 2-hydroxyethyl-B-cyclodextrin, 2-hydroxypropyl-B-cyclodextrin, and especially ~-cyclodextrin (Drug Dev. and Ind. Pharm., 17, 1991, 1503-1549, J.
Incl. Phenom., 1, 1983, 135-150 and WO 93/13138). For the production of clathrates, the vitamin D analogs can be mixed very thoroughly with the cyclodextrin, optionally with the addition of further pharmaceutical adjuvants (for example, by stirring, CA 0224120~ 1998-06-22 kneading), or the analogs can be dissolved from a solution of the components in water and/or a suitable solvent (such as, for example, a C1-C4-alcohol such as methanol, ethanol or isopropanol or a C2-C4 ketone, such as acetone or methylethyl ketone), and the solvent is then removed by, for example, vacuum distillation, freeze-drying, or spray-drying. By contrast, however, it is also possible to feed the vitamin D analogs that are dissolved in a suitable solvent (such as, for example, one of the above-mentioned alcohols or ketone) into an aqueous cyclodextrin solution and to filter and dry the precipitated clathrate.
It is obvious to one skilled in the art that there is a need for some preliminary tests, which are familiar, to ascertain which cyclodextrin is best suited for the inclusion of the desired vitamin D analog. In the case of very small vitamin D-analog molecules, the use of ~-cyclodextrin can be optimum, while in the case of the inclusion of quite large molecules it may be necessary to use y-cyclodextrin or even ~-cyclodextrin as a host molecule. Normally, the ratio of cyclodextrin to vitamin D
analogs is selected in such a way that 1:1 mol:mol complexes are formed, but this does not mean that in individual cases it may not be more advantageous to select the molar ratio in such a way that, for example, 2:1, 3:1, 3:2 or 1:2 complexes are formed.
The production of the pharmaceutical agents that can be applied topically is already known in the art. By contrast, however, it is also possible to create new preparations that are matched to the special needs of the skin.
CA 0224120~ 1998-06-22 The production of such topical preparations is done in the usual way by the active ingredients being converted with suitable additives into the desired form of administration, such as, for example, a solution, a milk, a lotion, a cream, an ointment, a pomade, or a paste. In the preparation that is thus formulated, the active ingredient concentration depends on the form of administration. An active ingredient concentration of S to 30 by weight is preferably used.
The milk, lotion, or cream (oil/water emulsions) and the ointment (water/oil emulsion) can be produced in a conventional way using conventional emulsifiers (Kirk Othmer: Encyclopedia of Chemical Technology, 3rd Edition, 1979; John Wiley & Sons, New York, Vol. 8, pages 900-930, and Dr. Otto-Albrecht Neumuller:
Rompps Chemie Lexikon, 7th Edition, 1973; Frankh'sche Verlagshandlung [Franconian Publishers] Stuttgart, pages 1009-1013). The waxes, emulsifiers, and other additives that are used for these emulsions are the same as those used in conventional contexts (Dr. Otto-Albrecht Neumuller: Rompps Chemie Lexikon, 7th Edition, 1973: Franckh'sche Verlagshandlung Stuttgart, pages 1427-1428).
The topical preparation according to the invention can consist of one or two active ingredients, hydrophilic and/or lipophilic additives, a fatty phase, oil/water emulsifier, an aqueous phase, and preservatives.
As hydrophilic and/or lipophilic additives, moisture-retaining factors (hydrocomplexes), such as, for example, propylene glycol, glycerine, polyethylene glycols, urea, vital CA 0224120~ 1998-06-22 complexes (such as, for example, placenta extracts), enzymes, herbal extracts (such as, for example, collagen) can be used. As oily phases or as fatty phases in oil/water emulsions, hydrocarbons, such as, for example, squalene, vaseline, paraffin, triglycerides, or stearin, or waxes, such as, for example, beeswax or animal or plant oils, such as olive oil, peanut oil, fine bone oil, almond oil, jojoba oil, lanolin, or sunflower seed oil. Suitable oil/water emulsifiers are, for example, stearyl alcohol, polyoxyethylene stearates (such as, for example, MYRJ(~)), complex emulsifiers (such as, for example, Amphoterin(R)), and sorbitan fatty acid esters (such as, for example, Tween 80(R)), carboxyvinylpolymerizates (such as, for example, Carbopol(R)), fatty alcohols, such as, for example, cetyl alcohol, myristyl alcohol or mixed esters (such as, for example, Dehymuls(R)). In addition, the aqueous phase can 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.
In addition, the emulsion is mixed with one or two active ingredient(s) and optionally with perfumes, such as for example, those of the Crematest(R) series, and it is stirred until the distribution is uniform.
In the pharmaceutical agents that are thus formulated, the active ingredient concentration depends on the form of administration. In the case of lotions and ointments, an active ingredient concentration of 0.0001% to 3% is preferably used.
The following embodiments are used to provide a more detailed explanation of the invention:
Example 1 200 mg of dimethyl-B-cyclodextrin (0.15 mmol) in 1.00 ml of water is added drop by drop to a solution of 50 mg of (5Z,7E,22E)-(lS,3R,24R)-1,3,24-trihydroxy-9,10-seco-cholesta-5,7,10(19),22-tetraene-carboxylic acid-isopropyl ester (0.10 mmol) in 0.5 ml of dioxane while being stirred vigorously. After another 15 minutes of stirring and the addition of 1.2 ml of dioxane, the clear solution is frozen in a dry ice-methanol bath and then freeze-dried for 36 hours.
For the production of the solution, the complex is weighed in in an amount that produces an active ingredient concentration of 50 ~g/g, and it is made up with water to 100 g.
Example 2 3.93 g of dimethyl-~-cyclodextrin and 0.209 g of (5Z,7E,22E)-(lS,3R,24R)-1,3-trihydroxy-9,10-seco-cholesta-5,7,10(19),22-tetraene-25-carboxylic acid isopropylester are suspended in 100 ml of water by means of at least 5 minutes of ultrasonic irradiation. The suspension is stirred for 48 hours and then filtered. The filtrate is frozen in an acetone/dry ice bath and freeze-dried for 24 hours.
For the production of the hydrogel, the complex is dissolved in an amount that produces an active ingredient concentration of 80 ~g/g, in 99.0 g of water, and processed into an easily spreadable formulation with a gel former (e.g., Carbopol(R)-B.F.
Goodrich Chem.).
Example 3 680 mg (0.6 mmol) of native B-cyclodextrin is dissolved in 40 ml of 60% aqueous ethanol by means of ultrasound at a temperature of 38~C. Then, a solution of 100 mg of (5Z,7E,22E)-(lS,3$,24R)-1,3,24-trihydroxy-9,10-seco-cholesta-5,7,10(19),22-tetraene25-carboxylic acid-isopropyl ester in 10 ml of 60%
aqueous ethanol is added drop by drop within 3 minutes while being stirred constantly and being exposed to nitrogen gassing.
It is stirred for another 15 minutes at 38~C and cooled within one hour to 13~C.
The precipitate that is produced is filtered off, washed with the mother liquor, and dried in a vacuum.
For the production of the lipa gel, the complex is weighed in in an amount that produces an active ingredient concentration of 40 ~g/g and pasted in 20 g of vaseline. Subsequently, vaseline is to be added proportionately to make the solution up to 100 g.
R
.. , ,. _. ...
il "
in which R1, R2, and R3, independently of one another, each mean a hydrogen atom, a straight-chain or branched-chain saturated alkanoyl group with 1 or 3 to 9 carbon atoms or an aroyl group, with -OH- meaning a hydroxy group in ~- or ~-position, R4 and R4a at the same time each mean 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 R4 and R4a together with carbon atom 25 mean a 3- to 7-member cycloalkyl radical and Y means one of radicals CA 0224120~ 1998-06-22 -C(o)NR5R5a, -C(O)OR6 or -CN, whereby R5, R5a, and R6 each stand for a hydrogen atom or a linear or branched alkyl group with 1 or 3 to 8 carbon atoms, and R6 in addition stands for group (CH2)~C (CH2) n with m = O or 1 and n = 2, 3, 4, 5 or 6 and if m = 1, in addition with n = 1.
Thus, for example, (SZ,7E,22E)-(lS,3R,24R)-1,3,24-trihydroxy-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylic acid-isopropyl ester.
The clathrates of these vitamin D analogs were not previously known, whereas the vitamin D series is distinguished relative to clathrates that are already known by superior properties and are also subjects of this invention. Inclusion into cyclodextrins ensures increased bio-availability of the active ingredient, especially with topical application in the upper skin layers, and thus makes it possible to reduce the dose of the active ingredient (delayed release).
These cyclodextrin derivatives are suitable not only for the production of preparations that can be applied topically, but can also be used advantageously for the production of dosage forms that are to be administered systemically, and here also provide the advantage of the delayed release of active ingredients according to the invention. Thus, the strong systemic side-effects of the active ingredient group can be mitigated, and the substances can be stabilized at the same time.
CA 0224120~ 1998-06-22 In the production of such low-dose forms with calcitriol analogs for oral or systemic application, large fluctuations of the active ingredient concentration almost unavoidably occur in the dosage units (deficient content uniformity), which manifest themselves more powerfully, the lower the dose of the active ingredient.
- In addition, in the storage of such preparations, a decline in the active ingredient concentration is often observed as a result of oxidative degradation reactions of the active ingredient.
In addition, the bio-availability of the respective calcitriol analog at such a low dose is subject to a pronounced first-pass effect and has large interindividual and intraindividual fluctuations.
It has now been found for oral administration that the advantages, which are observed especially in the storage of dosage forms that contain low-dose calcitriol analogs, can be avoided at least to a large extent when dosage forms are prepared that contain powdery cyclodextrin-inclusion compounds of these active ingredients.
Cyclodextrins that are suitable for the production of these CA 0224120~ 1998-06-22 clathrates, for example those of general formula II
CH20RCH2~R CH20R
~ O \) O ' ~-0 Lo ~ /L o 1'~
!oRtlORIl RO
--t o ( ~T) in which R' means a hydrogen atom, a methyl group, a 2-hydroxyethyl group or a 2-hydroxypropyl group R" means a hydrogen atom or, if R1 represents a methyl group, also a methyl group and r means a number from 4 to 7.
Such cyclodextrins are preferably ~-cyclodextrin, y-cyclodextrin, dimethyl-B-cyclodextrin, 2-hydroxyethyl-B-cyclodextrin, 2-hydroxypropyl-B-cyclodextrin, and especially ~-cyclodextrin (Drug Dev. and Ind. Pharm., 17, 1991, 1503-1549, J.
Incl. Phenom., 1, 1983, 135-150 and WO 93/13138). For the production of clathrates, the vitamin D analogs can be mixed very thoroughly with the cyclodextrin, optionally with the addition of further pharmaceutical adjuvants (for example, by stirring, CA 0224120~ 1998-06-22 kneading), or the analogs can be dissolved from a solution of the components in water and/or a suitable solvent (such as, for example, a C1-C4-alcohol such as methanol, ethanol or isopropanol or a C2-C4 ketone, such as acetone or methylethyl ketone), and the solvent is then removed by, for example, vacuum distillation, freeze-drying, or spray-drying. By contrast, however, it is also possible to feed the vitamin D analogs that are dissolved in a suitable solvent (such as, for example, one of the above-mentioned alcohols or ketone) into an aqueous cyclodextrin solution and to filter and dry the precipitated clathrate.
It is obvious to one skilled in the art that there is a need for some preliminary tests, which are familiar, to ascertain which cyclodextrin is best suited for the inclusion of the desired vitamin D analog. In the case of very small vitamin D-analog molecules, the use of ~-cyclodextrin can be optimum, while in the case of the inclusion of quite large molecules it may be necessary to use y-cyclodextrin or even ~-cyclodextrin as a host molecule. Normally, the ratio of cyclodextrin to vitamin D
analogs is selected in such a way that 1:1 mol:mol complexes are formed, but this does not mean that in individual cases it may not be more advantageous to select the molar ratio in such a way that, for example, 2:1, 3:1, 3:2 or 1:2 complexes are formed.
The production of the pharmaceutical agents that can be applied topically is already known in the art. By contrast, however, it is also possible to create new preparations that are matched to the special needs of the skin.
CA 0224120~ 1998-06-22 The production of such topical preparations is done in the usual way by the active ingredients being converted with suitable additives into the desired form of administration, such as, for example, a solution, a milk, a lotion, a cream, an ointment, a pomade, or a paste. In the preparation that is thus formulated, the active ingredient concentration depends on the form of administration. An active ingredient concentration of S to 30 by weight is preferably used.
The milk, lotion, or cream (oil/water emulsions) and the ointment (water/oil emulsion) can be produced in a conventional way using conventional emulsifiers (Kirk Othmer: Encyclopedia of Chemical Technology, 3rd Edition, 1979; John Wiley & Sons, New York, Vol. 8, pages 900-930, and Dr. Otto-Albrecht Neumuller:
Rompps Chemie Lexikon, 7th Edition, 1973; Frankh'sche Verlagshandlung [Franconian Publishers] Stuttgart, pages 1009-1013). The waxes, emulsifiers, and other additives that are used for these emulsions are the same as those used in conventional contexts (Dr. Otto-Albrecht Neumuller: Rompps Chemie Lexikon, 7th Edition, 1973: Franckh'sche Verlagshandlung Stuttgart, pages 1427-1428).
The topical preparation according to the invention can consist of one or two active ingredients, hydrophilic and/or lipophilic additives, a fatty phase, oil/water emulsifier, an aqueous phase, and preservatives.
As hydrophilic and/or lipophilic additives, moisture-retaining factors (hydrocomplexes), such as, for example, propylene glycol, glycerine, polyethylene glycols, urea, vital CA 0224120~ 1998-06-22 complexes (such as, for example, placenta extracts), enzymes, herbal extracts (such as, for example, collagen) can be used. As oily phases or as fatty phases in oil/water emulsions, hydrocarbons, such as, for example, squalene, vaseline, paraffin, triglycerides, or stearin, or waxes, such as, for example, beeswax or animal or plant oils, such as olive oil, peanut oil, fine bone oil, almond oil, jojoba oil, lanolin, or sunflower seed oil. Suitable oil/water emulsifiers are, for example, stearyl alcohol, polyoxyethylene stearates (such as, for example, MYRJ(~)), complex emulsifiers (such as, for example, Amphoterin(R)), and sorbitan fatty acid esters (such as, for example, Tween 80(R)), carboxyvinylpolymerizates (such as, for example, Carbopol(R)), fatty alcohols, such as, for example, cetyl alcohol, myristyl alcohol or mixed esters (such as, for example, Dehymuls(R)). In addition, the aqueous phase can 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.
In addition, the emulsion is mixed with one or two active ingredient(s) and optionally with perfumes, such as for example, those of the Crematest(R) series, and it is stirred until the distribution is uniform.
In the pharmaceutical agents that are thus formulated, the active ingredient concentration depends on the form of administration. In the case of lotions and ointments, an active ingredient concentration of 0.0001% to 3% is preferably used.
The following embodiments are used to provide a more detailed explanation of the invention:
Example 1 200 mg of dimethyl-B-cyclodextrin (0.15 mmol) in 1.00 ml of water is added drop by drop to a solution of 50 mg of (5Z,7E,22E)-(lS,3R,24R)-1,3,24-trihydroxy-9,10-seco-cholesta-5,7,10(19),22-tetraene-carboxylic acid-isopropyl ester (0.10 mmol) in 0.5 ml of dioxane while being stirred vigorously. After another 15 minutes of stirring and the addition of 1.2 ml of dioxane, the clear solution is frozen in a dry ice-methanol bath and then freeze-dried for 36 hours.
For the production of the solution, the complex is weighed in in an amount that produces an active ingredient concentration of 50 ~g/g, and it is made up with water to 100 g.
Example 2 3.93 g of dimethyl-~-cyclodextrin and 0.209 g of (5Z,7E,22E)-(lS,3R,24R)-1,3-trihydroxy-9,10-seco-cholesta-5,7,10(19),22-tetraene-25-carboxylic acid isopropylester are suspended in 100 ml of water by means of at least 5 minutes of ultrasonic irradiation. The suspension is stirred for 48 hours and then filtered. The filtrate is frozen in an acetone/dry ice bath and freeze-dried for 24 hours.
For the production of the hydrogel, the complex is dissolved in an amount that produces an active ingredient concentration of 80 ~g/g, in 99.0 g of water, and processed into an easily spreadable formulation with a gel former (e.g., Carbopol(R)-B.F.
Goodrich Chem.).
Example 3 680 mg (0.6 mmol) of native B-cyclodextrin is dissolved in 40 ml of 60% aqueous ethanol by means of ultrasound at a temperature of 38~C. Then, a solution of 100 mg of (5Z,7E,22E)-(lS,3$,24R)-1,3,24-trihydroxy-9,10-seco-cholesta-5,7,10(19),22-tetraene25-carboxylic acid-isopropyl ester in 10 ml of 60%
aqueous ethanol is added drop by drop within 3 minutes while being stirred constantly and being exposed to nitrogen gassing.
It is stirred for another 15 minutes at 38~C and cooled within one hour to 13~C.
The precipitate that is produced is filtered off, washed with the mother liquor, and dried in a vacuum.
For the production of the lipa gel, the complex is weighed in in an amount that produces an active ingredient concentration of 40 ~g/g and pasted in 20 g of vaseline. Subsequently, vaseline is to be added proportionately to make the solution up to 100 g.
Claims (7)
1. Pharmaceutical preparations, characterized by having a content of cyclodextrin clathrates and vitamin D analogs.
2. Topically applied pharmaceutical preparations according to claim 1.
3. Topically applied pharmaceutical preparations according to claim 2 for treating psoriasis.
4. Pharmaceutical preparations according to claims 1 to 3 that contain calcitriol as a vitamin D analog.
5. Cyclodextrin clathrates that contain a vitamin D analog of general formula I
in which R1, R2, and R3, independently of one another, each mean a hydrogen atom, a straight-chain or branched-chain saturated alkanoyl group with 1 or 3 to 9 carbon atoms, or an aroyl group, OH means a hydroxy group in .alpha.- or .beta.-position, R4 and R4a at the same time each mean 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 R4 and R4a together with carbon atom 25 mean a 3- to 7-member cycloalkyl radical and Y means one of radicals -C(O)NR5R5a, -C(O)OR6 or -CN, whereby R5, R5a, and R6 each stand for a hydrogen atom or a linear or branched alkyl group with 1 or 3 to 8 carbon atoms, and R6 in addition stands for group with m = 0 or 1 and n = 2, 3, 4, 5 or 6 and if m = 1, in addition with n = 1.
in which R1, R2, and R3, independently of one another, each mean a hydrogen atom, a straight-chain or branched-chain saturated alkanoyl group with 1 or 3 to 9 carbon atoms, or an aroyl group, OH means a hydroxy group in .alpha.- or .beta.-position, R4 and R4a at the same time each mean 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 R4 and R4a together with carbon atom 25 mean a 3- to 7-member cycloalkyl radical and Y means one of radicals -C(O)NR5R5a, -C(O)OR6 or -CN, whereby R5, R5a, and R6 each stand for a hydrogen atom or a linear or branched alkyl group with 1 or 3 to 8 carbon atoms, and R6 in addition stands for group with m = 0 or 1 and n = 2, 3, 4, 5 or 6 and if m = 1, in addition with n = 1.
6. Cyclodextrin clathrates according to claim 5, containing (5Z,7E,22E)-(1S,3R,24R)-1,3,24-trihydroxy-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylic acid-isopropyl ester.
7. Pharmaceutical preparations according to claims 1 to 6, containing a cyclodextrin of general formula II, in which R' means a hydrogen atom, a methyl group, a 2-hydroxyethyl group or a 2-hydroxypropyl group R" means a hydrogen atom or, if R1 represents a methyl group, also a methyl group and r means a number from 4 to 7.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19549243.9 | 1995-12-21 | ||
| DE19549243A DE19549243A1 (en) | 1995-12-21 | 1995-12-21 | Pharmaceutical preparations containing clathrates of cyclodextrins and unnatural vitamin D analogues |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2241205A1 true CA2241205A1 (en) | 1997-07-03 |
Family
ID=7781710
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002241205A Abandoned CA2241205A1 (en) | 1995-12-21 | 1996-12-20 | Pharmaceutical compositions with vitamin d analogues |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0869819A1 (en) |
| JP (1) | JP2000502733A (en) |
| KR (1) | KR19990076637A (en) |
| CN (1) | CN1207687A (en) |
| AU (1) | AU1306997A (en) |
| CA (1) | CA2241205A1 (en) |
| DE (1) | DE19549243A1 (en) |
| HU (1) | HUP9903935A3 (en) |
| IL (1) | IL125020A0 (en) |
| IS (1) | IS4774A (en) |
| NO (1) | NO982874L (en) |
| WO (1) | WO1997023242A1 (en) |
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|---|---|---|---|---|
| US20100048511A1 (en) * | 2006-11-06 | 2010-02-25 | Hanmi Pharm Co., Ltd. | Complex formulation for preventing or treating osteoporosis which comprises solid dispersion of vitamin d or its derivative and bisphosphonate |
| US8207149B2 (en) | 2007-04-25 | 2012-06-26 | Cytochroma, Inc. | Method for treating secondary hyperparathyroidism in CKD |
| US8329677B2 (en) | 2006-06-21 | 2012-12-11 | Cytochroma, Inc. | Method of treating and preventing secondary hyperparathyroidism |
| US8426391B2 (en) | 2006-02-03 | 2013-04-23 | Proventiv Therapeutics, Llc | Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 |
| US8592401B2 (en) | 2007-04-25 | 2013-11-26 | Proventiv Therapeutics, Llc | Methods and compounds for vitamin D therapy |
| US9861644B2 (en) | 2013-03-15 | 2018-01-09 | Opko Ireland Global Holdings, Ltd. | Stabilized modified release vitamin D formulation and method of administering same |
| US10220047B2 (en) | 2014-08-07 | 2019-03-05 | Opko Ireland Global Holdings, Ltd. | Adjunctive therapy with 25-hydroxyvitamin D and articles therefor |
| US10302660B2 (en) | 2008-04-02 | 2019-05-28 | Opko Renal, Llc | Methods useful for vitamin D deficiency and related disorders |
| US11173168B2 (en) | 2016-03-28 | 2021-11-16 | Eirgen Pharma Ltd. | Methods of treating vitamin D insufficiency in chronic kidney disease |
| US11672809B2 (en) | 2010-03-29 | 2023-06-13 | Eirgen Pharma Ltd. | Methods and compositions for reducing parathyroid levels |
| US11752158B2 (en) | 2007-04-25 | 2023-09-12 | Eirgen Pharma Ltd. | Method of treating vitamin D insufficiency and deficiency |
| US11801253B2 (en) | 2007-04-25 | 2023-10-31 | Opko Renal, Llc | Method of safely and effectively treating and preventing secondary hyperparathyroidism in chronic kidney disease |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6538037B2 (en) | 1991-01-08 | 2003-03-25 | Bone Care International, Inc. | Methods for preparation and use of 1α,24(S)-dihydroxyvitamin D2 |
| US6566353B2 (en) | 1996-12-30 | 2003-05-20 | Bone Care International, Inc. | Method of treating malignancy associated hypercalcemia using active vitamin D analogues |
| US6503893B2 (en) | 1996-12-30 | 2003-01-07 | Bone Care International, Inc. | Method of treating hyperproliferative diseases using active vitamin D analogues |
| US6573256B2 (en) | 1996-12-30 | 2003-06-03 | Bone Care International, Inc. | Method of inhibiting angiogenesis using active vitamin D analogues |
| GB9826656D0 (en) | 1998-12-03 | 1999-01-27 | Novartis Ag | Organic compounds |
| DE102005017775A1 (en) * | 2005-04-13 | 2006-10-19 | Schering Ag | New complex of vitamin-D-compounds with 5Z,7E,10(19)-triene system and methylene derivatives of beta-cyclodextrin, useful for the preparation of medicament and to treat psoriasis |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU177586B (en) * | 1978-12-19 | 1981-11-28 | Chinoin Gyogyszer Es Vegyeszet | New process for preparing stable inclusion complexes of vitamine d with cyclodextrin |
| JPS5910562A (en) * | 1982-07-07 | 1984-01-20 | Teijin Ltd | Preparation of pre-1alpha-hydroxycholecalciferol compound |
| JPS5936656A (en) * | 1982-08-23 | 1984-02-28 | Teijin Ltd | Novel clathrate compound and drug containing said compound as active component |
| JPS60120812A (en) * | 1983-12-02 | 1985-06-28 | Teijin Ltd | Remedy for diabetic osteopenia |
| ATE104554T1 (en) * | 1990-01-10 | 1994-05-15 | Hoffmann La Roche | TOPICAL PREPARATIONS. |
| IL107185A (en) * | 1992-10-06 | 1998-02-22 | Schering Ag | Vitamin d, 25-carboxylic acid derivatives and pharmaceutical compositions containing the same |
-
1995
- 1995-12-21 DE DE19549243A patent/DE19549243A1/en not_active Withdrawn
-
1996
- 1996-12-20 WO PCT/EP1996/005856 patent/WO1997023242A1/en not_active Application Discontinuation
- 1996-12-20 JP JP9523335A patent/JP2000502733A/en active Pending
- 1996-12-20 HU HU9903935A patent/HUP9903935A3/en unknown
- 1996-12-20 CN CN96199734A patent/CN1207687A/en active Pending
- 1996-12-20 CA CA002241205A patent/CA2241205A1/en not_active Abandoned
- 1996-12-20 KR KR1019980704745A patent/KR19990076637A/en not_active Application Discontinuation
- 1996-12-20 IL IL12502096A patent/IL125020A0/en unknown
- 1996-12-20 AU AU13069/97A patent/AU1306997A/en not_active Abandoned
- 1996-12-20 EP EP96944669A patent/EP0869819A1/en not_active Withdrawn
-
1998
- 1998-06-15 IS IS4774A patent/IS4774A/en unknown
- 1998-06-19 NO NO982874A patent/NO982874L/en not_active Application Discontinuation
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Also Published As
| Publication number | Publication date |
|---|---|
| NO982874D0 (en) | 1998-06-19 |
| EP0869819A1 (en) | 1998-10-14 |
| WO1997023242A1 (en) | 1997-07-03 |
| HUP9903935A2 (en) | 2000-03-28 |
| AU1306997A (en) | 1997-07-17 |
| KR19990076637A (en) | 1999-10-15 |
| HUP9903935A3 (en) | 2000-05-29 |
| CN1207687A (en) | 1999-02-10 |
| IS4774A (en) | 1998-06-15 |
| NO982874L (en) | 1998-08-20 |
| JP2000502733A (en) | 2000-03-07 |
| IL125020A0 (en) | 1999-01-26 |
| DE19549243A1 (en) | 1997-06-26 |
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Legal Events
| Date | Code | Title | Description |
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| FZDE | Discontinued |