NZ232059A - Compositions and use of an alkyl glycerine and azelastine: (4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1h-azepine-4-yl)-1(2h)-phthalazinone; preparatory processes - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £32059 232059 NO DRAWINGS Priority Date(s): loeciftcation mea: "bIKSl /S6-.

Complete Salification Filed: Class: (5)/.

Publication Oater1 2-6.J-UL-.199l.

P.O. Journal, No: ...

Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION - }/ ~ ^ THE USE OF THE ACTIVE SUBSTANCE AZELASTINE IN COMBATTING PSORIASIS DISORDERS AND INElAMffiTORZ DISORDERS /^WE, ASTA-PHARMA AKEIEHSESEEIiSCHAFT, a Gennan ccnpany, of Vfeismullerstrasse 45, 6000 Frankfurt am Main 1, FEDERAL REPUBLIC OF GERMANY, hereby declare the invention, for which^i/We pray that a patent may be granted to ip^us, and the method by which it is to be performed, to be particularly described in and by the following statement: ""-V (followed by Page la) ? 5 2 0 5 9 - la - This invention relates to pharmaceutical compositions that contain azelastine or a pharmaceutically acceptable salt thereof and that are suitable for the treatment of inflammatory disorders and psoriasis disorders. The invention also relates to processes for the production of the compositions.

The substcince azelastine (chemical designation 4-(p-chloro-benzyl) -2- (hexahydro-l-methyl-lH-azepine-4-yl) -1 (2H) -phthalazinone) is known and has been used in asthma prophylaxis and as an anti-allergic agent. The chemical formula of azelastine is However it has now been found that azelastine also has anti-inflammatory effects both against psoriasis and against disorders related thereto. Azelastine is also particularly suitable for the treatment of Colitis ulcerosa. The term psoriasis disorders is understood in the context of the invention as relating to skin disorders which are accompanied by hyperkeratoses, such as in particular psoriasis.

Accordingly, this invention provides a pharmaceutical composition suitable for the treatment of inflammatory disorders and psoriasis disorders, the composition comprising an effective amount of azelastine, or a pharmaceutically acceptable salt thereof, and an alkyl glycerine of the formula I (followed by page lb) ?32059 £ - lb - _ h2c - o - r, i 1 HC - 0 - R2 h2c - oh, in which one of the radicals and R2 is an alkyl group of 2 to 12 carbon atoms and the other radical is a hydrogen atom.

The invention also provides a pharmaceutical composition in topically administrable form that is suitable for the treatment of inflammatory disorders and psoriasis disorders, the composition comprising an effective amount of azelastine, or a pharmaceutically acceptable salt thereof, and conventional pharmaceutical auxiliary substances, carriers and/or diluents that sure topically administrable.

The invention also provides a process for the preparation of a medicament suitable for combating inflammatory disorders and psoriasis disorders, comprising formulating azelastine, or its therapeutically acceptable salts, with an alkyl glycerine of formula I H2C - 0 - Ri HC - 0 - R2 1 H2C - OH, in which one of the radicals and R2 is an alkyl group with 2 to 12 carbon atoms and the other radical is a hydrogen atom; and a pharmaceutically acceptable carrier, auxiliary substance and/or diluent. <-v, -c-v In the process, preferably the azelastine, or the pharmaceutically acceptable salt of azelastine, and the , ■' l Q ! \ Jl (followed by page lc) 232059 lc alkyl glycerine of formula I are mixed together with the conventional carriers, diluents and/or auxiliary substances at temperatures between 0 and 120°C, and the mixture thereby obtained is poured into hollow cells of appropriate size or pressed into tablets or filled into capsules of appropriate size or granulated and then pressed into tablets or filled into capsules, to obtain a composition containing in each dosage unit 2 to 16 mg of azelastine or the pharmaceutically acceptable salt of azelastine.

Preferably the auxiliary substances are selected from starch, cyclodextrin, urea, cellulose, lactose, formalin-casein, modified starch, magnesium stearate, calcium hydrogen phosphate, silicic acid, talcum, and phenoxyethanol, and the mixture obtained is granulated with an aqueous solution that contains one or more of gelatine, starch, polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymerisate and polyoxyethylene sorbitane monooleate.

In another embodiment of the process, preferably the azelastine or the pharmaceutically acceptable salt of azelastine and the alkyl glycerine of formula I is suspended or homogenised with one or more of the following auxiliary substances: soya lecithin, oxynex, and phenoxyethanol, at temperatures between 31 and 65°C in molten hard fat or other mixtures containing fatty acid glycerines and the mixture is then poured into hollow cells or filled into capsules.

In another embodiment of the process, preferably the azelastine or the pharmaceutically acceptable salt of azelastine is homogenized and/or emulsified with 0.05 to 10000 parts by weight of the alkyl glycerine of formula I ^ (related to 1 part by weight of azelastine) at a ' o temperature between 20 and 120°C, optionally in the (followed by page Id) m 232059 Id - © Q presence of one or more emulsifiers and/or complex formers with at least one of the following substances: water, glycerine, paraffin, petroleum jelly, aliphatic alcohol with 12 to 25 carbon atoms, aliphatic monocarboxylic acid with 15 to 20 carbon atoms, sorbitane monopalmitate, polyoxyethylene polyol fatty acid ester, single or multivalent low molecular weight aliphatic alcohol, fatty acid glyceride, wax, silicon, and polyethylene glycol.

In another embodiment of the process, preferably the azelastine or the pharmaceutically acceptable salt of azelastine is dissolved with 0.05 to 10000 parts by weight of an alkyl glycerine of formula I (related to 1 part by weight of azelastine), optionally in the presence of a complex former and/or an emulsifier, at temperatures between 30 and 100°C in water, and physiologically harmless alcohols, polyglycols, polyglycol derivatives, dimethylsulfoxide, triglycerides, partial esters of glycerine, paraffins or oils or mixtures thereof and the solution thereby obtained is optionally made up with the solvents so that the final solution, final suspension or final emulsion contains 0.1 - 10 percent by weight of azelastine or the pharmaceutically acceptable salt. (followed by page 2) 232059 2 The effect of azelastine in psoriasis disorders and dis— orders related thereto (for example psoriasis) was tested by giving mice (average weight 25 g) 1 mg/kg of azelastine daily for -7 -days^ On.day -3 ±he top -Layer jof .skin was removed using sandpaper. This mechanical irritation and removal of the upper layer of skin causes an acute reaction which has morphological similarities with the psoriatic reaction. In addition, the leukotriene content of the dermis and epidermis increases. This is accompanied by a fall in prostaglandin concentration. These changes, too, are typical for psoriasis. These changes did not occur after prior treatment with azelastine. Azelastine normalizes or even lowers dermal and/or epidermal leukotriene concentration and increases prostaglandine concentration.

Currently, psoriasis is principally treated using corticosteroids. In comparison thereto azelastine has only slight or negligible side effects and also inhibits leukotriene synthesis in the skin after systemic administration; in addition azelastine also inhibits the formation of oedema induced by PAF (platelet activating factor).

The ^pharmaceutical compositions- for application in psoriasis disorders and disorders related thereto in Man generally contain between 2 to 16, preferably 4 to 8 mg of azelastine.

Administration may for example be in the form of tablets, capsules, pills, coated tablets, suppositories, ointments, gels, creams, powders, dusting powders, aerosols or in liquid form. Liquid forms of application that may for example be considered are: oils or alcoholic or aqueous solutions as well as suspensions and emulsions. Preferred forms of application are tablets which contain between 4 and 8 mg or solutions which contain between 0.1 to 10 percent by weight of azelastine. • \ t '<> r 232059 The single dose of azelastine for application in psoriasis disorders and disorders related thereto may for example lie: a) in oral medicinal forms between 2 and 16 mg, preferably 8 mg; b) in medicinal forms for local application on the skin and mucous membranes (for example in the form of solutions, lotions, emulsions, ointments and the like) between 0.1 and 10 % by weight, preferably 0.7 - 5 % by weight, in particular 1 - 5 % by weight.

One to 2 tablets 3 times daily containing 4 to 8 mg of azelastine may for example be recommended. In the case of oral administration the minimum daily dose is for example 4 mg; the maximum daily dose in oral administration should not exceed 24 mg.

- (The doses are in each case related to the free base) - 232059 After local application, azelastine inhibits the development of oedema of the ear of the mouse to a dose-related extent after local application of 12-0-tetradecanoylphorbol-acetate (TPA) or arachidonic acid. (Method of Young et al.).

In addition azelastine displays quite generally a good anti-inflammatory effect both after topical (local) and after systemic administration. This effect was for example tested on carrageenin-induced paw oedema of the rat (Method after Morsdorf et: al., Arch. Int. Pharmacodyn. 192 (1971) page 111) or on chemically-induced mouse ear oedema (Method of Young et al., Journal of Investigative Dermatology 80 (1983) page 48-52 as well as 82 (1984) page 367)..

In the experimental model of carrageenin-induced paw oedema of the rat after oral administration (Morsdorf et al. 1971) the test substances are administered orally two hours before administration of the carrageenin using an oesophageal tube (intragastrally). The extent of the increase of paw volume is measured one hour later. Using this process (reduction of the exposure time from the conventional three hours to one hour) the effect of the test substances on the rapidly-released mediators such as leukotriene and PAF (platelet activating factor) can be examined.

For example in the case of arachidonic acid-induced mouse ear oedema a 28 % inhibition of the oedema is achieved with a dose of 3 mg peroral/kg body weight mouse and a 41 % inhibition with topical application of a dose of 0.25 mg/kg mouse ear. In the case of rat paw oedema (induced by carrageenin, determination of paw volume after one hour) a peroral dose of for example 3.9 mg/kg rat inhibited oedema formation by 50%. The lowest already f 0 JUN199 232 059 effective dose in the above mentioned animal experiments is for example 1-2 mg/kg orally or 10 mg/kg with topical use (10 mg/kg correspond to about 0.25 mg/cm body surface.

The general dose range to produce an effect (animal experiments as above) may for example be: 0.1 - 9 mg/kg orally, in particular 0.5-5 mg/kg; 2.5 - 80 mg/kg topically, in particular 5-40 mg/kg.

The direction of the anti-inflammatory effect of azelastine is for example comparable with the effect of the known medicamentous active ingredient indomethacin, but the following differences exist compared thereto: no gastro-intestinal side effects such as gastric erosions, gastric ulcer or gastritis (indeed, azelastine even has>a gastric mucosa-protecting effect), inhibition of leukotriene-synthesis (non-steroidal anti-inflammatory agents, such as indomethacin, promotes this), no influence on the synthesis of prostanoids (the well-known non-steroidal anti-inflammatory agents have an inhibitory effect here). Indications for this anti-inflammatory effect that may for example be considered are: inflammatory and degenerative forms of rheumatism, rheumatoid arthritis, gastritis, gastric and intestinal ulcers).

Azelastine also inhibits the ulcerous intestinal inflammation in the rat triggered by indomethacin (P. Del Soldato et al., Agents and Actions, Volume 16, 5, Publishers: Birkhauser, Basel 1985, pages 393-396). Azelastine inhibits the formation of these intestinal lesions in a dose range of 8-80 mg/kg in a dose-dependent manner. This model demonstrates in particular the effect in Colitis ulcerosa. For example in the above mentioned experimental method with 5 peroral administrations of in each case 50 mg/kg body weight of rat (scheme of application after Del Soldato) inhibition of the inflammation of around 50 % is achieved. 232 059 The lowest already effective oral dose of azelastine in the above mentioned animal experiment is for example 16 mg/kg.

The general dosage range for this intestinal anti-inflammatory action (animal experiment as above) may for example be: 4-80 mg/kg orally, in particular 16-60 mg/kg.

This direction of effect of azelastine is comparable with the effect of the known medicamentous active substance sulphasalazine, although it displays the following differences in comparison therewith: lower dosage, broader pharmacological profile of action (inhibition of leukotriene synthesis and of formation of radicals). In view of this effect the following indications may for example be considered for azelastine: Colitis ulcerosa, Morbus Crohn, inflammatory intestinal disorders (inflammatory bowel disease).

The individual dose of azelastine for use in Colitis ulcerosa and related disorders (for example Morbus Crohn, gastritis, rheumatoid arthritis, inflammatory and degenerative forms of rheumatism) may for example lie: a) in oral medicinal forms between 2 and 24 mg, preferably 4 and 16 mg, in particular 4 and 8 mg; b) in medicinal forms for local application on the skin and mucous membranes (for example in the form of solutions, lotions, emulsions, ointments, enemas and the like) between 0.1 and 10 % by weight, preferably 0.7 - 5 % by weight, in particular 1 - 5 % by weight; c) in the case of suppositories between 4 and 100 mg; preferably 6 and 80 mg, in particular 10 and 50 mg; 232059 d) in the case of parenteral medicinal forms (for example injections, infusions and the like) between 0.1 and 30 mg, preferably 0.5 and 10 mg, in particular 1 and 5 mg.

- (The doses are in each case related to the free base) - r*. w 232059 The individual dose of azelastine for use in gastric and intestinal ulcers may for example lie: a) in the case of oral medicinal forms between 2 and 24 mg, preferably 4 and 16 mg, in particular 4 and 8 mg; b) in the case of parenteral medicinal forms between 0.1 and 30 mg, preferably 0.5 and 10 mg, in particular 1 and 5 mg.

For example 1 to 2 tablets containing 4 to 8 mg of azelastine may be recommended 3 times daily. In the case of oral administration the minimum daily dose is for example 4 mg; the maximum daily dose with oral administration should not exceed 24 mg.

In addition, azelastine also-has a dose-related cytoprotective effect. It has been shown in rats that azelastine inhibits the ethanol-induced formation of mucous membrane damage in the stomach both after systemic and after oral administration and is thus for example indicated in gastritis and gastroduodenal ulceration.

The effect is for example tested in rats in which mucous membrane damage has been provoked in the stomach through administration of ethanol (Szelenyi and Brune, Dig. Dis. Sci., 33 (1988) page 865-871). Azelastine was administered orally (intragastrally) one hour before administration of the ethanol using an oesophageal tube. Azelastine inhibited damage to the gastric mucosa in a dose range of 8-80 mg/kg to a dose-related extent.

The gastric mucosa-protecting effect of azelastine may be compared with that of known medicamentous active substances such as aluminium-containing antacids [AlfOl^)] or sucralfate, although it displays the following differences thereto: lower 232059 dose and more favourable pharmacological profile. Azelastine inhibits leukotriene synthesis, but does not influence prostaglandin synthsis. In addition azelastine also inhibits the formation of radicals.

Pharmaceutical formulations for use in the above mentioned indications generally contain between 2 and 16, preferably 4 to 8 mg of azelastine.

Administration in inflammatory disorders may for example be in the form of tablets, capsules, pills, coated tablets, suppositories, enemas, ointments, clysmas, jellys, gels, creams, powders, dusting powders, suspensions (aerosols) or in liquid form. Liquid forms which may for example be considered are: oils or alcoholic or aqueous solutions as well as suspensions and emulsions. Preferred forms of application are tablets containing between 2 and 16 mg preferably 4 and 10 mg of azelastine. One to 2 tablets containing 4 to 8 mg of azelastine may for example be recommended 3 times daily. In the case of oral administration the minimum daily dose is for example 4 mg; the maximum daily dose in oral administration should not exceed 24 mg.

In the case of Colitis ulcerosa the use of capsules or sachets containing azelastine in the form of sustained release pellets having a release time for the active substance of 6 to 48 hours preferably 12 to 24 hours is particularly preferred.

The acute toxicity of azelastine in mouse (expressed as the LD 50 mg/kg; Method after Miller and Tainter: Proc. Soc. Exper. Biol. a. Med. 57. (1944) 261) is for example between 120 and 170 mg/kg in the case of oral application.

-(The doses are in each case related to the free base)- ^ 232059 The pharmaceutical compositions or medicaments contain azelastine or its physiologically acceptable salts as active substance. The active substance is optionally present in a mixture with other pharmacologically or pharmaceutically active ^ substances. The preparation of the medicaments is effected in conventional manner, it also being possible to use conventional and customary pharmaceutical auxiliary substances and other conventional carriers and diluents. '""n, Carrier and auxiliary substances that may for example be considered are those which are recommended or quoted in the following literature references as auxiliary substances for pharmacy, cosmetics and related fields: "Ullmanns Encyklopadie der technischen Chemie", Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 et seq.; H.v.Czetsch-Lindenwald, "Hilfsstoffe fur Pharmazie und angrenzende Gebiete"; Pharm. Ind. issue 2 (1961), page 72 et seq.; Dr. H.P. Fiedler, "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete" Cantor KG, Aulendorf in Wiirttemberg 1981.

Examples hereof are gelatine, natural sugars such as unrefined sugar or lactose, lecithin, pectin, starches (for example corn — starch), cyclodextrines and cyclodextrine derivatives, polyvinyl ' pyrrolidone, polyvinyl acetate, gelatine, gum arabic, alginic acid, tylose, talcum, lycopodium, silica gel (for example colloidal), cellulose, cellulose derivatives (for example cellulose ether in which the cellulose hydroxy groups are partially etherified with lower saturated aliphatic alcohols and/or lower saturated aliphatic oxyalcohols, for example methyloxypropyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate); fatty acids as well as magnesium, calcium or aluminium salts of fatty acids with 12 to 22 carbon atoms, in particular saturated ones (for example stearates), emulsifiers, oils and fats, in particular 232059 vegetable fats (for example peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, in each case also hydrogenated; mono-, di- and triglycerides of saturated fatty acids C-j2h24®2 *-° c18h36°2 an<^ their mixtures, pharmaceutically acceptable single or multivalent alcohols and polyglycols such as polyethylene glycols as well as derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10 - 18 carbon atoms) with monovalent aliphatic alcohols (1 to 20 carbon atoms), or multivalent alcohols such as glycols, glycerine, diethylene glycol, pentaerythritol, sorbitol, mannitol and so on, which may optionally also be etherified, esters of citric acid with primary alcohols, acetic acid, benzylbenzoate, dioxolanes, glycerine formals, tetrahydrofurfuryl alcohol, polyglycol ether with C-| -C-j2-alcohols, dimethylacetamide, lactamides, lactates, ethyl carbonates, silicons (in particular medium-viscous polydimethylsiloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate and the like.

Other auxiliary substances that may be used are substances which aid disintegration (so called disintegrants) such as: cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose or microcrystalline cellulose. Known coating substances may also be used. Those that may for example be considered are: polymerisates as well as copolymerisates of acrylic acid and/or methacrylic acid and/or their esters; copolymerisates of acrylic and methacrylic acid O esters with a low ammonium group content (such as Eudragit RS), copolymerisates of acrylic and methacrylic acid esters and trimethyl ammonium methacrylate (for example Eudragit RL); polyvinylacetate; fats, oils, waxes, fatty alcohols; hydroxypropyl methyl cellulose phthalate or acetate succinate; cellulose-, starch- as well as polyvinylacetate phthalate; 232059 carboxymethyl cellulose; methylcellulose phthalate, -succinate, -phthalate succinate and - phthalate-acid half esters; zein; ethyl cellulose as well as -succinate; schellac, gluten; ethylcarboxyethyl cellulose; ethacrylate-maleic acid anhydride copolymer; maleic acid anhydride-vinylmethyl ether copolymer; styrol-maleic acid copolymerisates; 2-ethyl-hexyl-acrylate maleic acid anhydride; crotonic acid-vinyl acetate copolymer; glutamic acid/glutaminic acid ester-copolymer; carboxymethylethyl-cellulose glycerine monooctanoate; cellulose acetate succinate; polyarginine.

Plasticizing agents for coating substances that may be considered are: Citric and tartaric acid esters (acetyltriethyl-, acetyltributyl-, tributyl-, triethylcitrate); glycerine and glycerine esters (glycerine diacetate, -triacetate, acetylated monoglycerides, castor oil); phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl-phthalate), D-(2-methoxy-or ethoxyethyl)-phthalate, ethylphthalyl-, butylphthalylethyl-and butylglycolate; alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyladipate), di-(2-methoxy- or ethoxyethyladipate); benzophenone; diethyl-and dibutylsebacate, -succinate, -tartrate; diethylene glycol diproprionate; ethylene glycol-diacetate, -dibutyrate, -dipropionate; tributylphosphate, tributyrin; polyethyleneglycol sobitane monooleate (polysorbates such as polysorbate 80); sorbitane monooleate.

For the manufacture of solutions or suspensions it is for example possible to use water or physiologically acceptable organic solvents, such as for example ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols and their derivatives, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerines, paraffins and the like. 232 059 For injectable solutions or suspensions it is for example possible to use non-toxic parenterally acceptable diluents or solvents, such as for example: water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols in mixture with water, Ringer's solution, isotonic salt solution or also solidified oils including synthetic mono- or diglycerides or fatty acids such as oleic acid.

In the manufacture of the formulations it is for example possible to use known and conventional solubilizers or emulsifiers. Solubilizers and emulsifiers which may for example be used are: polyvinyl pyrrolidone, sorbitane fatty acid esters such as sorbitane trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitane monooleate and other ethoxylated fatty acid esters or sorbitane, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolizated oleotriglycerides, polyethyleneoxide condensation products of fatty alcohols, alkylphenols or fatty acids or also 1-methyl-3-(2-hydroxyethyl)-imidazolidone-(2). In this case polyoxyethylated means that the substances in question contain polyoxyethylene chains, the degree of polymerization of which generally lies between 2 and 40 and in particular between 10 and 20.

Polyoxyethylated substances of this kind may for example be obtained through reaction of hydroxyl group-containing compounds (for example mono- or diglycerides or unsaturated compounds such as those containing oleic acid residues) with ethylene oxide (for example 40 mol ethylene oxide per mol glyceride).

Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil. See also Dr. H.P. Fiedler "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete" 1971, pages 191-195. 232 0 59 In addition it is also possible to add preservatives, stabilizers, buffer substances for example calcium hydrogen phosphate, colloidal aluminium hydroxide, flavour correcting substances, sweeteners, colourants, antioxidants and complex formers for example ethylene diamino-tetra-acetic acid) and the like. Adjustment to a pH range of ca. 3 to 7 is optionally possible using physiologically acceptable acids or buffers to stabilize the molecule of active substance. In general a neutral to weakly acidic (up to pH 5) pH value is preferred.

For the preparation of dermally applied formulations it is possible to use the above mentioned substances and spreadable or liquid hydrocarbons such as Vaseline or paraffin or gels of paraffin hydrocarbons and polyethylene, fats and oils of plant or animal origin which may in part also be hydrated or synthetic fats such as glycerides of the Cg-C-jg fatty acids, as well as beeswax, cetylpalmitate, wool wax, wool wax alcohols; fatty alcohols such as cetyl alcohol, stearyl alcohol, polyethylene glycols of molecular weight 200 to 20,000; liquid waxes such as isopropylmyristate, isopropylstearate, ethyloleate; emulsifiers such as sodium, potassium and ammonium salts of the stearic acids or palmitic acids as well as triethenolamine stearate, alkali salts of the oleic acids, ricinic acid, salts of sulfurated fatty alcohols such as sodium lauryl sulphate, sodium acetyl sulphate, sodium stearyl sulphate, salts of gallic acid, sterols such as cholesterol, partial fatty acid esters of multivalent alcohols such as ethylene glycol monostearate, glycerol monostearate, pentaerythrit monostearate, partial fatty acid esters of sorbitan, partial fatty acid esters of polyoxyethylene sorbitan, sorbitol ethers of polyoxyethylene, fatty acid esters of polyoxyethylene, fatty alcohol ethers of polyoxyethylene, fatty acid esters of saccharose, fatty acid esters of polyglycerol, lecithin. 232059 Antioxidants that may for example be considered are sodium metabisulphite, ascorbic acid, gallic acid, gallic acid alkyl ester, butylhydroxyanisol, nordihydroguaiaretic acid, tocopherols as well as tocopherols + synergists (substances which bind heavy metals through complex formation, for example lecithin, ascorbic acid, phosphoric acid). The addition of synergists substantially enhances the antioxygenic effect of the tocopherols.

The conserving agents that may for example be considered are sorbic acid, p-hydroxybenzoic acid esters (for example lower alkyl esters), benzoic acid, sodium benzoate, trichloroiso-butylalcohol, phenol, cresol, benzethonium chloride and formalin derivatives.

The pharmaceutical and galenic treatment of the compounds of the invention is effected according to the conventional standard methods. For example active substance(s) and auxiliary and/or carrier substances are well mixed by means of stirring or homogenizing (for example using conventional mixing devices), working generally taking place at temperatures between 20 and 80°C, preferably 20 to 50°C, particularly at room temperature. In this connection reference is also made to the following standard work: Sucker, Fuchs, Speiser, "Pharmazeutische Technologie", publishers: Thieme-Verlag Stuttgart, 1978.

Application may be to the skin or mucous membrane or to the inside of the body, for example oral, enteral, pulmonal, rectal, nasal, vaginal, lingual, intravenous, intra-arterial, intracardial, intramuscular, intraperitoneal, intracutaneous or subcutaneous. The parenteral forms of preparation are in particular sterile or sterilized preparations. 232059 For the treatment of psoriasis azelastine is used locally, for example in the form of solutions, tinctures, suspensions, emulsions, ointments, gels, creams, pastes, lotions or shampoos. Anhydrous formulations are preferably used, facilitating thereby the concommitant use of salicylic acid and/or urea. Formulations of this type, which may also be made washable through the addition of surfactants, are for example described in German published patent 36 03 859. The urea may either be present as a surfactant-urea inclusion compound or also in free form. Formulations containing neither urea nor salicylic area may of course also be used.

The concentrations of azelastine used in this case may for example be 0.1 to 10 % (weight/weight), preferably 0.5 to 8 %, in particular 1 to 5 %. The concentrations of salicylic acid are for example 0.1 to 10 %, preferably 0.2 to 8 %, in particular 0.5 to 5 %. The concentrations of urea used are for example 1 to 20 %, preferably 3 to 18 %, in particular 5 to 15 %.

For topical application and also for formulation as a medicament for other forms of application it has for example been found advantageous to use azelastine together with at least one alkyl glycerine with 2 to 12 carbon atoms in the alkyl radical which may be present in the form of an ether group bound to one of the primary or secondary OH groups of the glycerine. Alkyl glycerines of this type boost or improve the effect of azelastine. Alkyl glycerines with 3 to 9 carbon atoms are preferably used here alone or in a mixture.

Particularly favourable effects are therefore displayed by a medicament which a) contains azelastine and b) an alkyl glycerine of the general formula I 232059 H2<f " 0 - R1 HC - O - R-> I 2 H2C - OH, in which one of the radicals R-j and R2 represents an alkyl group with 2 to 12 carbon atoms and the other radical represents a hydrogen atom, as well as optionally other conventional pharmacological additives and diluents.

Use may preferably be made of a mixture of water and an alkyl glycerine mixture of nonyl or octyl glycerine, hexyl or pentyl glycerine and propyl or ethyl glycerine. A corresponding formulation for topical use contains for example 1 to 100 mg of azelastine per ml of alkyl glycerine of Formula I or a corresponding alkyl glycerine mixture with water.

A mixture of this type is hereinafter also referred to as a cascade.

The amount of azelastine in mg/ml of cascade is designated by an index shown thereafter in such a manner that for example a cascade mixture containing 40 mg/ml of azelastine is termed a cascade 40 and a mixture with 60 mg of azelastine per ml of cascade is termed a cascade 60.

The manufacture of the alkyl glycerines is known for example from DE-OS 33 43 530.8. Preference is for example given to alkyl glycerine-water mixtures which contain for example nonyl glycerine, octyl glycerine, hexyl glycerine, pentyl glycerine, propyl glycerine and ethyl glycerine. Aqueous mixtures of this kind contain for example 3 of the glycerine ethers mentioned, namely a lower (ethyl, propyl), a middle (pentyl, hexyl) and a higher one (octyl, nonyl) whereby the amount by weight of the 232059 lower ether is about as large as the sum of the amounts by weight of the two other glycerine ethers. The amount of water is about equal to the amount of the lower glycerine ether and is for example half the total amount of the glycerine ethers present. Examples of glycerine ether-water mixtures of this type are listed below: Water Glycerine propyl- Glycerine hexyl- Glycerine-nonyl ether ether ether Parts 2 : 2 : 1 : 1 by wt.

Water Glycerine ethyl- Glycerine pentyl-Glycerine-octyl ether ether ether Parts 2 : 2 : 1 : 1 by wt.

Medicaments containing alkyl glycerines of Formula I are particularly suitable for topical application. In order to treat for example psoriasis and related disorders, cascade 1 to cascade 100 is for example rubbed into the skin areas affected two to three times daily. No harmful side effects have been observed to date.

Topical treatments with an azelastine-cascade mixture can, however, also be applied in the treatment of for example internal inflammatory disorders through rubbing into a large area of the skin. Resorption through the skin then leads to the attainment of therapeutically effective blood levels. An 232059 advantage of this form of application lies in the fact that the cascade formulations are tolerated by the skin without difficulty.

Presentation of the azelastine in the form of a cascade formulation (for example in the form of the solutions cascade 1 to cascade 100) is also suitable for the manufacture of suppositories for rectal insertion. This is also an effective method of treating internal inflammatory disorders.

A particularly favourable carrier mixture for azelastine consists of a mixture of about 4 parts by weight of water, 4 parts by weight of propyl glycerine and 2 parts by weight each of hexyl glycerine and nonyl glycerine.

To manufacture medicaments containing azelastine in the presence of a glycerine ether of Formula I or of a mixture of glycerine ethers of this type of Formula I, the azelastine is for example used with 10000 to 0.05, for example 1000 to 5 or 700 to 7, preferably 30 to 10 parts by weight (related in each case to one part by weight of azelastine) of at least one glycerine ether of Formula I or a mixture of such glycerine ethers as well as optionally 10000 to 0.05, for example 400 to 2, preferably 20 to 3 parts by weight of water (also related to one part by weight of azelastine). This mixture with the glycerine ethers can be effected at the beginning of the manufacture of the corresponding medicament, but optionally also during a later stage in manufacture.

Examples 232 0 59 1 . Example of a formulation for the topical treatment of psoriasis '' \ This relates to a solution of 8.8 % of azelastine hydrochloride in a mixture of solvents referred to as cascade 0 (azelastine 8 %).

Preparation of the cascade 0 1000 g of water, 1000 g of glycerine-1-n-propyl ether, 500 g of glycerine-1-n-hexyl ether and 500 g of glycerine-1-n-nonyl ether are mixed in a suitable vessel.

Preparation of the azelastine solution About 2.5 litres of cascade 0 are measured into a suitable vessel and 264 g of azelastine hydrochloride dissolved in this mixture of solvents. The result is then made up to 3 litres with cascade 0.

The density of the solution of 1.023 g/ml at 22°C. This solution is sterile filtered under aseptic conditions into a sterile recipient through a membrane filter having a pore size of 0.2 /am and filled into sterile dropper bottles of 10 ml each. 1 ml of solution contains 80 mg of azelastine (corresponding to 88 mg of azelastine-HCl). 2. Azelastine film-coated tablets for oral application Preparation of the tablets A premix is prepared of 440 g of azelastine-HCl, 360 mg of microcrystalline cellulose and 200 g of talcum. This premix together with 6000 g of lactose monohydrate, 2870 g of 232 0 59' microcrystalline cellulose and 100 g of highly disperse silicon dioxide are passed through a sieve and homogenized in a suitable mixer. 30 g of magnesium stearate are sieved into the mixture so obtained and the result homogenized one more. The mass so obtained is pressed into tablets weighing 100 mg having a diameter of 6 mm and a radius of curvature of 5.5 mm. 232059 Preparation of the film-coated tablets The tablets are continuously sprayed in a vessel suitable for this purpose with 1.2 kg of a film suspension.

The film suspension is prepared by dissolving 60 g of polyethylene glycol 6000, 12 g of polysorbate 80 and 9.6 g of carboxymethyl cellulose sodium in 787.2 g of water. 120 g of talcum, 120 g of titanium dioxide and 1.2 g of simethicone* are dispersed into this solution and then 90 g of a copolymerisate based on dime thy laminoe thy 1 methacrylate and neutral methacrylic acid esters added with gentle stirring in the form of a 30 % aqueous dispersion (EudragitR E 30 D). 1 film tablet contains 4 mg of azelastine (corresponding to 4.4 mg of azelastine hydrochloride).

Simethicone is a mixture of polydimethyl siloxan (predominantly 90 - 99 % by weight) and silicon dioxide (for example 4-7 % by weight); U.S. Pharmacopoeia, 21st edition 232059 Azelastine 8 mg film-coated tablets Preparation of film-coated tablets for the treatment of Colitis ulcerosa 88 g of azelastine hydrochloride, 701 g of lactose monohydrate and 701 g of microcrystalline cellulose are sieved, mixed and moistened with 1440 g of a ph-independent acrylic resin lacquer substance which forms poorly permeable coatings (EudragitR RS 12.5). The moist mass is granulated through a sieve and dried.

The dry granulate, 100 g of talcum and 30 g of magnesium stearate are sieved again and homogenized in a suitable mixture. This mass is pressed into tablets weighing 180 mg having a diameter of 8 mm and a radius of curvature of 6 mm. To prepare the film-coated tablets the tablets are sprayed in an apparatus conventionally used for this purpose with a film suspension manufactured as follows. 18 g of magnesium stearate are dispersed in 664 g of isopropanol with stirring; 18 g of 1,2 propylene glycol and 800 g of an anionic polymerisate of methacrylic acid and methacrylic acid esters that contains a softener, is gastric juice resistant and only soluble beyond pH 7 (EudragitR S 12.5) are then worked into this suspension. 1 film-coated tablet contains 8 mg of azelastine (corresponding to 8.8 mg of azelastine hydrochloride). 232059 Azelastine 8 mg capsules (preferably for the treatment of Colitis ulcerosa) 100 g of azelastine hydrochloride/ 200 g of tartaric acid, 500 g of lactose and 700 g of microcrystalline cellulose are mixed and pasted with about 700 g of purified water. The moist mass is pressed through a perforated place having a hole diameter of 1 mm and the resultant strands divided and rounded in the conventional manner by treatment on a spheronizer disc. The pellets obtained are dried and sieved. 1000 g of pellets of the sieve fraction 800 to 1200 ^tim are sprayed with a suspension that is prepared as follows: 0.6 g of polysorbate 80 are dissolved in 190 g of purified water and 40 g of triethyl citrate are emulsified into the solution. 800 g of a 30% aqueous dispersion of a copolymerisate of acrylic and methacrylic acid esters having a low content of trimethyl ammonium methacrylate chloride (= EudragitR RS 30 D) are added to the emulsion thereby obtained and stirred for about 10 minutes. 109.2 g of talcum and 0.2 g of silicon anti-foaming oil (Simethicone) are suspended in 860 g of purified water. This suspension is stirred into the above obtained dispersion.

The lacquering suspension so obtained is applied to the pellets in the conventional manner, for example using a fluidized bed spray granulator at an inlet air temperature of 40-50°C and a maximum outlet air temperature of 40°C. The pellets are dried under the same conditions.

The lacquering suspension is sprayed onto the pellets until the total weight of the dried pellets is 1127 g. 232 059 The lacquered pellets are filled in batches of 148.7 mg into size 1 hard gelatine capsules. One hard gelatine capsule contains 8.8 mg of azelastine hydrochloride corresponding to 8 mg of azelastine in sustained release formulation. The release of azelastine hydrochloride from this pharmaceutical form is tested according to the process given in the US Pharmacopoeia, 21st edition (USP XXI) using the Dissolution Test Apparatus 2. The release of azelastine hydrochloride in 500 ml of test solution at 37°C is determined at a paddle speed of 100 revolutions per minute. The test solution consists for the first 2 hours of 0.1 molar hydrochloric acid after which the pellets are transferred to phosphate buffer solution of pH 6.8 of the European Pharmacopoeia. In each case the release of azelastine hydrochloride is measured from the test solutions.

The release is after 3 hours after 4 hours after 5 hours 21.7 % after 6 hours 31.7 % in phosphate after 7 hours 39.2 % buffer pH 6.8 after 1 hour after 2 hours in 0.1 m HCl after 8 hours 48.5 % after 9 hours 56.1 % after 10 hours 64.0 % after 11 hours 74.5 % after 12 hours 81.2 % 232059

Claims (20)

WHAT WE CLAIM IS;

1. A pharmaceutical composition suitable for the treatment of inflammatory disorders and psoriasis disorders, the composition comprising an effective amount of azelastine, or a pharmaceutically acceptable salt thereof, and an alkyl glycerine of the formula I H,C - 0 - R, 1 T HC - 0 - R? 1 I 2 H2C - OH, in which one of the radicals R^ and R£ is an alkyl group of 2 to 12 carbon atoms and the other radical is a hydrogen atom.

2. A pharmaceutical composition according to claim 1 further comprising conventional pharmaceutical auxiliary substances, carriers and/or diluents.

3. A pharmaceutical composition according to claim 2 containing 0.05 to 10000 parts by weight of the alkyl glycerine and 0.05 to 10000 parts by weight water per part by weight of azelastine.

4. A pharmaceutical composition according to claim 3 containing 5 to 700 parts by weight of the alkyl glycerine and 5 to 700 parts by weight water per part by weight of azelastine.

5: A pharmaceutical composition according to any one of claims 1 to 4 containing 0.1 to 10% by weight of azelastine.

6. A pharmaceutical composition according to any one claims 1 to 5 comprising a mixture of alkyl glycerines formula I. 232059 - 27 -

7. A pharmaceutical composition according to claim 1 and substantially as described in this specification with reference to example 1.

8. A pharmaceutical composition in topically administrable form that is suitable for the treatment of inflammatory disorders and psoriasis disorders, the composition comprising an effective amount of azelastine, or a pharmaceutically acceptable salt thereof, and conventional pharmaceutical auxiliary substances, carriers and/or diluents that are topically administrable.

9. A pharmaceutical composition according to claim 8 containing between 0.1 to 10% by weight azelastine.

10. A pharmaceutical composition according to claim 9 containing between 1 to 5% by weight azelastine.

11. A pharmaceutical composition according to any one of claims 1 to 10 further comprising urea and/or salicylic acid.

12. A process for the preparation of a medicament suitable for combating inflammatory disorders and psoriasis disorders, comprising formulating azelastine, or its therapeutically acceptable salts, with an alkyl glycerine of formula I h2c -0-^1 HC - O - &2 h2c - OH, in which one of the radicals and R2 is an alkyl group with 2 to 12 carbon atoms and the other radical is a hydrogen atom; and a pheirmaceutically acceptcible carrier // auxiliary substance and/or diluent. /, v' 232059 - 28 -

13. A process according to claim 12 further including water so that the medicament comprises 0.05 to 10000 by weight of the alkyl glycerine and 0.05 to 10000 parts by weight of water, in each case related to one paxt by weight of azelastine.

14. A process according to claim 12 in which the azelastine, or the pharmaceutically acceptable salt of azelastine, and the alkyl glycerine of formula I are mixed together with the conventional carriers, diluents and/or auxiliary substances at temperatures between 0 and 120°C, and the mixture thereby obtained is poured into hollow cells of appropriate size or pressed into tablets or filled into capsules of appropriate size or granulated and then pressed into tablets or filled into capsules, to obtain a composition containing in each dosage unit 2 to 16 mg of azelastine or the pheirmaceutically acceptable salt of azelastine.

15. A process according to claim 14 in which the auxiliary substances axe selected from starch, cyclodextrin, urea, cellulose, lactose, formalin-casein, modified starch, magnesium stearate, calcium hydrogen phosphate, silicic acid, talcum, and phenoxyethanol, and the mixture obtained is granulated, with an aqueous solution that contains one or more of gelatine, starch, polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymerisate and polyoxyethylene sorbitane monooleate.

16. A process according to claim 14 in which the azelastine or the pharmaceutically acceptable salt of azelastine and the alkyl glycerine of formula I is # y u. i * t suspended or homogenised with one or more of the following^ auxiliary substances: soya lecithin, oxynex, and '.'.-j phenoxyethanol, at temperatures between 31 and 65°C in u2 J Q JUN1991 molten hard fat or other mixtures containing fatty acid glycerines and the mixture is then poured into hollow eel or filled into capsules. - 29 -

17. A process according to claim 12 in which the azelastine or the pharmaceutically acceptable salt of azelastine is homogenized and/or emulsified with 0.05 to 10000 parts by weight of the alkyl glycerine of formula I (related to 1 part by weight of azelastine) at a temperature between 20 and 120°C, optionally in the presence of one or more emulsifiers and/or complex formers, with at least one of the following substances: water, glycerine, paraffin, petroleum jelly, aliphatic alcohol with 12 to 25 carbon atoms, aliphatic monocarboxylic acid with 15 to 20 carbon atoms, sorbitane monopalmitate, polyoxyethylene polyol fatty acid ester, single or multivalent low molecular weight aliphatic alcohol, fatty acid glyceride, wax, silicon, and polyethylene glycol.

18. A process according to claim 12 in which the azelastine or the pharmaceutically acceptable salt of azelastine is dissolved with 0.05 to 10000 parts by weight of an alkyl glycerine of formula I (related to 1 part by weight of azelastine), optionally in the presence of a complex former and/or an emulsifier, at temperatures between 30 and 100°C in water, and physiologically harmless alcohols, polyglycols, polyglycol derivatives, dimethylsulfoxide, triglycerides, partial esters of glycerine, paraffins or oils or mixtures thereof and the solution thereby obtained is optionally made up with the solvents so that the final solution, final suspension or final emulsion contains 0.1 - 10 percent by weight of azelastine or the pharmaceutically acceptable salt.

1-9. A process according to claim 12 and substantially as described in this specification with reference to example 1. f '^10 JUN1991 232059 - 30

20. The use of azelastine or a pharmaceutically acceptable salt thereof in combination with an alkyl glycerine of formula I in which one of the radicals and R£ is an alkyl group having 2 to 12 carbon atoms and the other radical is a hydrogen atom or a mixture of such alkyl glycerines for the preparation of a pharmaceutical composition according to any one of claims 1 to 7. ASTA-PHARMACEUTICAL AKTIENGEffgT-T.firw&yp to ju,\'?99ri