WO1997023242A1

WO1997023242A1 - Pharmaceutical compositions with vitamin d analogues

Info

Publication number: WO1997023242A1
Application number: PCT/EP1996/005856
Authority: WO
Inventors: Karin Hoffmann; Jutta Riedl
Original assignee: Schering Aktiengesellschaft
Priority date: 1995-12-21
Filing date: 1996-12-20
Publication date: 1997-07-03
Also published as: JP2000502733A; AU1306997A; CN1207687A; IS4774A; NO982874L; KR19990076637A; HUP9903935A3; DE19549243A1; EP0869819A1; NO982874D0; CA2241205A1; HUP9903935A2; IL125020A0

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

Pharmaceutical preparations with vitamin D analogues

The invention relates to pharmaceutical preparations containing clathrates of cyclodextrins and unnatural vitamin D analogs.

In particular, 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). However, 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.

Compounds in the vitamin D series itself and some metabolites thereof (such as calciferol = vitamin D2, cholecalciferol = vitamin D3 and 25-hydroxyvitamin D3 caicifediol) have been tried to improve their stability and solubility by producing clathrates of 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 the best of our knowledge, no studies have been carried out to produce topically applicable preparations containing clatrates of cyclodextrins and unnatural, purely synthetically produced vitamin D analogs and to investigate their effectiveness. It has now been found that such 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 (1α, 25-dihydroyvitamin D3), caicifediol (25-hydroxyvitamin 03), calcipotriol (CAS-1128-00-9) and cholecalciferol (Vitamin D3) and the tacalcitol (CAS-57333-96-7). In addition, 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.

The compounds described in WO 94/07853, in which 25-carboxylic acid derivatives in the vitamin D series of the general formula I are particularly suitable, may also be mentioned as suitable vitamin D analogs

OR '

22

21

20 2-- »

23

^R (I) wherein

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 α- or β-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

Cycloalkyl radical and Y one of the radicals

-C (O) NRδR5a _ι -C (O) OR6 or -CN, where R5, R-5a and R each represent a hydrogen atom or a linear or branched alkyl group with 1 or 3 to 8 carbon atoms and

R ⁶ additionally for the group < ^CH 2'm '^"c L ^CH ^ _n with m = 0 or 1 and n = 2, 3, 4, 5 or 6 and if m = 1 additionally with n = 1

stand.

For example, the (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 analogs are not previously known, are distinguished from the known clathrates of the vitamin D series by superior properties and are also an object of the present invention. Inclusion in 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). These 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.

In the manufacture of such low-dosed dosage forms with calcitriol analogs for oral or systemic application, there are almost inevitable strong fluctuations in the active ingredient concentration in the dose units (lack of content uniformity), which become more apparent the lower the active ingredient is dosed. When storing such preparations, a decrease in the concentration of the active substance is also often observed as a result of oxidative degradation reactions of the active substance.

In addition, the bioavailability of the respective calcitriol analogs in such a low dosage is subject to a pronounced first pass effect and has large inter- and intra-individual fluctuations.

It has now been found for oral administration that the advantages which are observed, in particular in the storage of medicaments which contain low-dose calcitriol analogs, can at least largely be avoided by providing medicament forms which contain cyclodextrin in powder form. Inclusion compounds of these active ingredients contain.

15 cyclodextrins which are suitable for the preparation of these clathrates are, for example, those of the general formula II

dl) in which

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 * ι represents a methyl group, also one

Methyl group and r represent 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 in particular the β-cyclodextrin (Drug Dev. and Ind. Pharm., 17, 1991, 1503-1549, J. Incl. Phenom., 1, 1983, 135-150 and WO 93 / 13138). To prepare the clathrates, 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. On the other hand, it is also possible to add the vitamin D analogs dissolved in a suitable solvent (such as one of the abovementioned alcohols or ketones) to an aqueous cyclodextrin solution, to filter off the precipitated clathrate and to dry it.

It is obvious to a person skilled in the art that some preliminary tests, which are common, are required to determine which cyclodextrin is optimally suitable for the inclusion of the desired vitamin D analog. In the case of very small vitamin D-analogous molecules, the use of α-cyclodextrin can be optimal, while with the inclusion of quite large molecules it may be necessary to use γ- or even δ-cyclodextrin as the host molecule.

Normally, 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.

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. In the preparation formulated in this way, 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. 8, pages 900 - 930, and Dr. Otto-Albrecht Neumüller: Römpps Chemie Lexikon, 7th edition, 1973; Frankh'sche Verlagshandlung Stuttgart, pages 1009 - 1013). The waxes, emulsifiers and other additives used for these emulsions are the same as are used conventionally (Dr. Otto-Albrecht Neumüller: Römpps 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, fat phase, oil / water emulsifier, aqueous phase and preservative.

Moisturizing factors (hydro complexes) 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,

Polyoxyethylene stearates (such as MYRJ®), complex emulsifiers (such as Amphoterin®) and sorbitan fatty acid esters (such as Tween 80®), carboxy vinyl polymers (such as Carbopol®), fatty alcohols such as cetyl alcohol, myristyl alcohol or mixed esters (such as Dehymuls®). 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.

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. In the pharmaceuticals formulated in this way, the active substance concentration depends on the form of administration. For lotions and ointments, an active ingredient concentration of 0.0001% to 3% is preferably used.

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

example 1

200 mg of dimethyl-ß-cyclodextrin (0.15 mmol) in 1.00 ml of water are added dropwise with vigorous stirring to a solution of 50 mg (5Z.7E.22E) - (1 S, 3R, 24R) -1, 3.24- Trihydroxy-9, 10-seco-Cholesta-5,7, 10 (19), 22-tetra-carboxylic acid isopropyl ester (0.10 mmol) in 0.5 ml of dioxane was added. 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 which leads to an active ingredient concentration of 50 μg / g 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) Propyl 22-tetraen-25-carboxylic acid are suspended in 100 ml of water with the aid of at least 5 min of ultrasound radiation. 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.

To produce the hydrogel, the complex is dissolved in 99.0 g of water in the amount that leads to an active ingredient concentration of 80 μg / g and processed with a gel former (e.g. Carbopol®-B.F. Goodrich Chem.) To form a spreadable formulation.

Example 3

680 mg (0.6 mmol) of native β-cyclodextrin are dissolved in 40 ml of 60% aqueous ethanol using ultrasound at a temperature of 38 ° C. Then a solution of 100 mg (5Z, 7E, 22E) - (1S, 3R, 24R) -1, 3,24-trihydroxy-9,10-seco-cholesta-5,7,10 (19), 22- Tetraen25-carboxylic acid isopropyl ester in 10 ml of 60% aqueous ethanol with constant stirring and nitrogen gassing added dropwise within 3 min. The mixture is stirred at 38 ° C. for a further 15 minutes and cooled to 13 ° C. within one hour. The resulting precipitate is filtered off, washed with the mother liquor and dried in vacuo.

To produce the lipagel, the complex is weighed in the amount that leads to an active ingredient concentration of 40 μg / g and rubbed in 20 g petroleum jelly. Subsequently, Vaseline is added proportionately to 100g.

Claims

claims

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. Topical pharmaceutical preparations according to claim 2 for the treatment of psoriasis.

4. Pharmaceutical preparations according to claim 1 to 3 containing as a vitamin D analog, the calcitriol.

5. Clathrates of cyclodextrins containing a vitamin D analog of the general formula I.

CR '

22

21 'V

20 ² *

4 a ^R

R

3 ^N ^ ^' "OR ¹

R (D wherein R ¹ , R ² and R ³ each independently represent 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 is an α or β-hydroxyl group,

R ⁴ and R ^4a are each a hydrogen atom, a chlorine or fluorine atom, one

Trifluoromethyl group, a straight 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

Cycloalkyl radical and Y one of the radicals

-C (O) NR5R5a_ -C (O) OR6 or -CN, where R ⁵ , R ^ ^a and R *> each for a hydrogen atom or a linear or branched alkyl group with 1 or 3 to 8 carbon atoms and R ⁶ additionally for the group < ^CH 2 * m ^{~ c} | ^CH 2 * _n with m = 0 or 1 and n = 2, 3, 4, 5 or 6 and if m = 1 also with n = 1 mean.

6. Clathrates of cyclodextrins according to claim 5, containing the (5Z, 7E, 22E) - (1 S, 3R, 24R) -1, 3,24-trihydroxy-9, 10-secocholesta-5,7, 10 (19) , 22-tetraen-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 R-] represents a methyl group, also one

Methyl group and r is a number from 4 to 7.