DE19549243A1 - Pharmaceutical preparations containing clathrates of cyclodextrins and unnatural vitamin D analogues - Google Patents

Abstract

Pharmaceutical compositions preferably for topical application are characterised by their content of cyclodextrine clathrates and vitamin D analogues. They are useful for treating psoriasis.

Description

The invention relates to pharmaceutical preparations, the clathrates of cyclodextrins and contain unnatural vitamin D analogues.

In particular, the invention relates to topically administrable pharmaceutical preparations thereof Art. Such preparations are preferably suitable for the treatment of proriasis.

Topical preparations for the treatment of psoriasis that contain a vitamin D Containing analogs are already known, for example those containing calcipotriol Psorcutan® (Red List 1994, List of Medicinal Products of the BDI, Editio Cantor, DE Aulendorf, No. 31271). However, these preparations do 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 large areas Application that necessitates termination of therapy. Another disadvantage is that the vitamin D analogues as well as the compounds of the vitamin D series themselves Oxygen and / or exposure are easily decomposed, so that pharmaceutical preparations, which contain these compounds have little stability.

For compounds of the vitamin D series itself and some of its metabolites (such as Example with calciferol = vitamin D₂, cholecalciferol = vitamin D₃ and 25-hydroxy vitamin D₃ calcifediol) was tried to improve their stability and solubility, by clathrating these compounds with cyclodextrins (Pharmacy 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, none have so far Investigations carried out, topically administrable preparations containing clathrates of Cyclodextrins and unnatural, purely synthetically produced vitamin D analogues to manufacture and examine their effectiveness.

It has now been found that such topically applicable compositions of this type in particular in the treatment of psoriasis vulgaris and other manifestations of it Disease have an excellent efficacy in contrast to that  previously known means of the same direction of action no serious undesirable appear to cause systemic side effects.

Vitamin D analogs which are suitable for the preparation of the agents according to the invention are for example calcitriol (1α, 25-dihydroyvitamin D3), calcifediol (25- Hydroxyvitamin D₃), the calcipotriol (CAS-1128-00-9), the cholecalciferol (vitamin D₃) and the tacalcitol (CAS-57333-96-7). In addition, for example, those in the US Patent 5,098,899 mentioned vitamin D analogs for the preparation of the Invention appropriate means suitable.

Suitable vitamin D analogs are in particular those in WO 94/07853 described compounds in which 25-carboxylic acid derivatives in the vitamin D series of general formula I.

wherein
R¹, R² and R³ each independently represent a hydrogen atom, a straight or ver branched-chain saturated alkanoyl group with 1 or 3 to 9 carbon atoms or an aroyl group, with -OH- in the meaning of an α- or β-hydroxyl group, R⁴ and R ^4a at the same time each a hydrogen atom, a chlorine or fluorine atom, a trifluoromethyl group, a straight or branched chain, saturated or unsaturated carbon hydrogen radical with up to 4 carbon atoms or R⁴ and R ^4a together with the carbon atom 25 a 3- to 7-membered cycloalkyl radical and Y is one of the radicals -C (O) NR⁵R ^5a , -C (O) OR⁶ or -CN, where R⁵, R ^5a and R⁶ each represent a hydrogen atom or a linear or branched alkyl group having 1 or 3 to 8 carbon atoms and R⁶
additionally for the group

with m = 0 or 1 and n = 2, 3, 4, 5 or 6 and if m = 1 additionally with n = 1
stand, mean, are revealed,
such as (5Z, 7E, 22E) - (1S, 3R, 24R) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 22-tetraen-25-carboxylic acid -isopropyl ester.

The clathrates of these vitamin D analogues are not previously known, but stand out previously known clathrates are and are the vitamin D series by superior properties also subject of the present invention.

Inclusion in cyclodextrins increases the bioavailability of the active ingredient achieved, especially with topical application in the upper skin layers, and thus one Dose reduction of the active ingredient enables (delayed release).

These cyclodextrin derivatives are not only for the preparation of topically administrable Preparations are suitable, but they can also be used to produce systemic benefits applying drug forms are used and here also the invention Bring advantage of the delayed release of active ingredient. So the strong systemic Side effects of the drug group are reduced and the substance at the same time be stabilized.

In the manufacture of such low-dose dosage forms with calcitriol analogs for the oral or systemic application almost inevitably fluctuations occur Drug concentration in the dose units based on (lack of content uniformity) appear more strongly, the lower the active ingredient is dosed.

When storing such preparations, one often also observes one Decrease in drug concentration as a result of oxidative degradation reactions of the Active ingredient.

In addition, the bioavailability of the respective calcitriol analogue is so low Dosage is subject to a pronounced first pass effect and large inter and shows intra-individual fluctuations.

It has now been found for oral administration that the benefits which one especially in the storage of drug forms, the low-dose calcitriol analogs contain, observed, at least largely avoid, if one takes dosage forms provides the powdery cyclodextrin inclusion compounds of these active ingredients contain.

Cyclodextrins which are suitable for producing these clathrates are, for example, those of the general formula II

wherein
R 'is a hydrogen atom, a methyl group, a 2-hydroxyethyl group or a 2-hydroxypropyl group
R '' is a hydrogen atom or, if R₁ represents a methyl group, also a methyl group and
n is a number from 4 to 7.

Such cyclodextrins are preferably the α-cyclodextrin, the γ-cyclodextrin, the Dimethyl-β-cyclodextrin, the 2-hydroxyethyl-β-cyclodextrin, the 2-hydroxypropyl-β- cyclodextrin and especially β-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 the clathrate you can take the vitamin D analogues with the cyclodextrin if necessary Mix the addition of other pharmaceutical excipients thoroughly (for example by stirring, Kneading) or you can from a solution of the components in water and / or suitable solvents (such as a C1-C4 alcohol such as methanol, ethanol or isopropanol or a C₂-C₄ ketone such as acetone or methyl ethyl ketone) and then the solvent, for example by vacuum distillation, freeze drying or Remove spray drying. On the other hand, it is also possible to do this in a suitable Solvent (such as one of the above alcohols or ketone) dissolved To enter vitamin D analogues in an aqueous cyclodextrin solution, the failed Filter off and dry the clathrate.

It is obvious to the person skilled in the art that some common preliminary tests are required in order to determine which cyclodextrin is optimal for inclusion of the desired vitamin D analogue is suitable. With very small vitamin D-analogous molecules, the Use of α-cyclodextrin may be optimal while being quite large in inclusion Molecules may be required to have γ- or even δ-cyclodextrin as host molecules  use. Usually you choose the ratio of cyclodextrin to vitamin D- Analogs so that 1: 1 mol: mol complexes are formed, but this does not rule out that it is more favorable in individual cases to choose the molar ratio so that, for example, 2: 1, 3: 1, 3: 2 or 1: 2 complexes are formed.

The manufacture of the topically administrable pharmaceuticals is known per se. On the other hand But it is also possible to create new ones that are adapted to the special needs of the skin To prepare preparations.

Such topical preparations are prepared in the usual way by the Active ingredients with suitable additives in the desired application form, such as a solution, a milk, a lotion, a cream, an ointment, a fatty ointment or one Paste transferred. In the formulation so formulated, the active ingredient concentration is of Application form dependent. An active ingredient concentration of 5 to 30 is preferred Weight percent used.

The milk, lotion or cream (oil / water emulsions) and the ointment (water / oil Emulsion) can be used in a conventional manner using conventional emulsifiers be produced (Kirk Othmer: Enzyclopedia of Chemical Technology, 3rd edition, 1979; John Wiley & Sons, New York, Vol. 8, pages 900-930, and Dr. Otto Albrecht Neumüller: Römpps Chemie Lexikon, 7th edition, 1973; Frankh'sche publishing company Stuttgart, pages 1009-1013). The waxes used for these emulsions, Emulsifiers and other additives are the same as you would conventionally used (Dr. Otto-Albrecht Neumüller: Römpps Chemie Lexikon, 7th edition, 1973; Franckh'sche Verlaghandlung Stuttgart, pages 1427-1428).

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 preservatives exist.

As hydrophilic and / or lipophilic additives, moisturizing factors (hydro complexes), such as propylene glycol, glycerin, polyethylene glycols, urea, vital complexes (such as placenta extracts), enzymes, herbal extracts (such as collagen) be used. Suitable as an oily phase or as a fat phase in the oil / water emulsion 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, Polyoxyethylene stearates (such as MYRJ®), complex emulsifiers (such as  Amphoterin®) and sorbitan fatty acid esters (such as Tween 80®), Carboxyvinyl polymers (such as Carbopol®), fatty alcohols such as Cetyl alcohol, myristyl alcohol or mixed esters (such as Dehymuls®). The aqueous phase can additionally buffer substances, such as the disodium salt the ethylenediamine-N, N, N ', N'-tetraacetic acid and preservatives, such as Benzoic acid, chloroquinaldol, parabee or benzalkonium chloride.

The emulsion is additionally with one or two active ingredient (s) and optionally with fragrances, such as that of the Crematest® series, added and up to even distribution of the same stirred.

In the pharmaceuticals formulated in this way, the active substance concentration is of Application form dependent. For lotions and ointments, one is preferred Drug concentration from 0.0001% to 3% used.

The following exemplary embodiments serve to explain the invention in more detail:

example 1

200 mg of dimethyl-β-cyclodextrin (0.15 mmol) in 1.00 ml of water are added dropwise with vigorous stirring a solution of 50 mg (5Z, 7E, 22E) - (1S, 3R, 24R) -1,3,24- Trihydroxy-9,10-seco-Cholesta-5,7,10 (19), 22-tetraenecarboxylic acid isopropyl ester (0.10 mmol) in 0.5 ml of dioxane. After stirring for a further 15 minutes and adding 1.2 ml of dioxane, the clear solution is frozen in a dry ice-methanol bath and then freeze-dried for 36 hours.

To prepare the solution, the complex is weighed into the amount that results in a Active ingredient concentration of 50 µg / g leads and supplemented with water to 100 g.

Example 2

3.93 g dimethyl-β-cyclodextrin and 0.209 g (5Z, 7E, 22E) - (1S, 3R, 24R) -1,3-trihydroxy- 9,10-seco-Cholesta-5,7,10 (19), 22-tetraen-25-carboxylic acid-isopropyl ester in 100 ml Suspended water with the help of at least 5 min ultrasonic radiation. The suspension is stirred for 48 hours and then filtered. The filtrate is in one Acetone / dry ice bath frozen and freeze-dried for 24 hours.

To produce the hydrogel, the complex is used in the amount that results in a Active ingredient concentration of 80 µg / g, dissolved in 99.0 g of water and with a Gelling agent (e.g. Carbopol®-B.F. Goodrich Chem.) To form a spreadable formulation processed.

Example 3

680 mg (0.6 mmol) of native β-cyclodextrin are dissolved in 40 ml of 60% aqueous ethanol solved with the help of ultrasound at a temperature of 38 ° C. Then one Solution of 100 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 in 10 ml of 60% aqueous ethanol dropwise within 3 min with constant stirring and gassing with nitrogen admitted. The mixture is stirred at 38 ° C. for a further 15 minutes and cooled to 13 ° C. within one hour from.

The resulting precipitate is filtered off, washed with the mother liquor and in Vacuum dried.  

To produce the lipagel, the complex is weighed in the amount that results in a Active ingredient concentration of 40 µg / g leads and rubbed in 20 g petroleum jelly. In connection Vaseline is added proportionally to 100 g.

Claims (7)

1. Pharmaceutical preparations, characterized by a content of clathrates of cyclodextrins and vitamin D analogues. 2. Topically applicable pharmaceutical preparations according to claim 1. 3. Topically administrable pharmaceutical preparations according to claim 2 Treatment of psoriasis. 4. Pharmaceutical preparations according to claim 1 to 3 containing as vitamin D Analogously the calcitriol. 5. Clathrates of cyclodextrins containing a vitamin D analog of the general formula I. wherein
R¹, R² and R³ 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,
OH is an α or β hydroxyl group,
R⁴ and R ^4a are each a hydrogen atom, a chlorine or fluorine atom, a trifluoromethyl group, a straight or branched chain, saturated or unsaturated hydrocarbon radical with up to 4 carbon atoms or R⁴ and R ^4a together with the carbon atom 25 a 3- to 7-membered Cycloalkyl radical and Y one of the radicals -C (O) NR⁵R ^5a , -C (O) OR⁶ or -CN, where R⁵, R ^5a and R⁶ each represent a hydrogen atom or a linear or branched alkyl group having 1 or 3 to 8 carbon atoms and R⁶
additionally for the group with m = 0 or 1 and n = 2, 3, 4, 5 or 6 and if m = 1 additionally with n = 1 mean. 6. Clathrates of cyclodextrins according to claim 5, containing the (5Z, 7E, 22E) - (1S, 3R, 24R) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 22-tetrae-n-25- carboxylic acid isopropyl ester. 7. Pharmaceutical preparations according to claims 1 to 6, containing a cyclodextrin of the general formula II wherein
R ′ is a hydrogen atom, a methyl group, a 2-hydroxyethyl group or a 2-hydroxypropyl group,
R '' is a hydrogen atom or, if R₁ represents a methyl group, also a methyl group and
n is a number from 4 to 7.