DK172235B1 - Azelastine-containing controlled-release drug - Google Patents

Abstract

Azelastine-containing pharmaceutical compositions with controlled release of active substance using a release-delaying component, there being 0.001 to 800 parts of release-delaying component for one part by weight of azelastine (as base), and it also being possible for the azelastine to be in the form of its physiologically tolerated salts, and the rate of azelastine release being between 0.05 and 5 mg per hour.

Description

in DK 172235 B1

Azelastine is a phthalazinone derivative having the following structural formula:

Cl Φ

The chemical term is: 4- (4-chlorobenzyl) -2- (perhydro-1-methyllazepin-4-yl) -1- (2H) phthalazinone. Azelastine is especially used for asthma prophylaxis. Azelastine has 15 antiallergic and antihistamine properties as well, see DE-PS 2,164,058.

One of the major drawbacks of the use of azelastine consists in the side effect fatigue. Many patients also report sleepiness, drowsiness and 20 such. These side effects are especially evident during the first days of the use of azelastine, so that the use of motor vehicles and machines is not possible for patients, and that the general attention of these patients is greatly reduced.

25 Thus, it would be highly desirable and to be considered a medical advance if azelastine preparations were available that did not exhibit the side effect of fatigue.

In order to remove the side effect, it was usually proceeded in the past to develop a combination preparation of the present tiring active substance and caffeine. The caffeine was thereby tasked to abolish the sedative property of the active substance. This method cannot be used with azelastine since the elimination half-lives of the azelastine and caffeine are t 1/2 (t 1/2 is the time taken to halve the serum 2 of the active substance 1 blood at a single initial concentration without further supply of active substance ) differ greatly: t 1/2 for azelastine is 20 hours, t 1/2 for caffeine, however, only 3.5 hours. Thus, by the simultaneous administration of azelastine and caffeine, it can be expected that the effect of caffeine slowly disappears after a certain period of time, whereby the soothing effect of azelastine becomes effective again.

The usual art grip now consists in limiting the release of the active substance caffeine from the composition to such an extent that it results in an extended duration of action. However, this approach is associated with the problem of approximating the blood levels of the two active substances to each other in vivo. This is not possible with the current techniques due to the large differences in elimination values.

The azelastine possesses an unusually unpleasant taste, so that, for example, especially liquid azelastine preparations (e.g., juice) are rejected or not accepted by the patients, especially by children. According to the invention, azelastine preparations whose taste has improved significantly are now also possible.

It is the object of the invention to provide a pharmaceutical composition with the active substance azelastine and a process for its preparation, wherein the sedative effect of azelastine is largely or completely suppressed.

The task is solved with a controlled-release drug preparation, which contains the usual adjuvants and additives and a retardant component, characterized by the release of the active substance azelastine or its physiologically acceptable salts controlled in an amount by weight part of azelastine. with respect to the base, to 0.001 to 800 parts by weight of the retard component, and the release is from 0.05 to 5 mg, or 0.05 mg to 3 mg, or 0.05 mg to 1 mg azelastine / hour.

When the ezelastine is present in the form of a salt, the aforementioned azelastine amount based on the base form is increased accordingly due to the higher molecular weight of the salt. The amount indicated herein herein by "azelastine" is always based on the base form and, if a salt is present, must be converted according to the increased molecular weight.

The object also comprises a process for the preparation of a controlled-release drug preparation by introducing an active substance into usual auxiliaries and additives, and a retard component, which is characterized in that, as an active substance with controlled release. release uses azelastine or its physiologically acceptable salts in the ratio of 1 part by weight of azelastine, with respect to the base form, to 0.001 to 800 parts by weight of retard component, and sets the release rate to 0.05 to 5 mg of azelastine / hour.

In the subclaims, preferred embodiments of the invention are described.

Surprisingly, it was found that to obtain an azelastine form of administration without the side effect fatigue was not at all necessary with the addition of caffeine, delayed or not delayed, but that it was sufficient to delay the active substance azelastine itself. Thus, if the active substance is administered azelastine in a form of administration which releases the active substance over a long period of time (and thus a "delay" of the active substance is implemented), the side effect fatigue of persons treated with this drug is not observed. indgivningsform. This is all the more surprising since azelastine is a substance with the aforementioned elimination half-life of 20 hours.

In the pharmaceutical field, only the delay method was previously applied to drugs with short half-lives, e.g. with up to a maximum of 10 hours.

4 DK 172235 B1

Delay of an active substance having a half-life of 20 hours was previously considered in the field of pharmaceutical science in line with a medical error.

5 in these modes of administration, it is further surprising that the previously observed bitter taste did not occur after ingestion.

Thus, the subject of the invention is controlled release preparations of the active substance azelaastine or physiologically acceptable salts of azelastine.

Suitable salts are, for example, chloride, acetate, maleinate, lactate, citrate, tartrate, gluconate and embonate.

The subject of the invention is a further process for the preparation of controlled release preparations of the active substance azelastine or physiologically acceptable salts of azelastine.

Determination of the release rate of azelastine between 0.05 and 5 mg per day. is made in an aqueous sample solution of pH 1.0 and / or pH 6.8. At this sample solution, it is an aqueous solution of the specified pH. The pH values are adjusted by the addition of acid or by the addition of a usual buffer.

As administration forms are used, for example: retard tablets, retard capsules, pellets, juices, implants, injections, patches, aqueous or oily suspensions, oily solutions, granules, dragees, soft gelatin capsules or microcapsules.

The compositions of the invention can be formed in the following manner: 1. By binding azelastine to physiologically acceptable cation exchange. As a cation exchanger, e.g. used: acrylic and methacrylic resin with exchangeable proton, acidic groups: COcP, e.g. Amberlit ^ IRP-64.

polystyrene resins with exchangeable Na +, acidic groups: SO3Q, e.g. Amberliti ^ IRP-69.

5 DK 172235 B1

The ion exchangers are acidic ion exchangers. The maximum ratio of azelastine: ion exchange is approx.

1: 1, the minimum ratio approx. 1 part by weight of active substance to 800 parts of ion exchange resin. Preferably, for 1 to 5 parts by weight of active substance, 1 to 400 parts by weight of ion exchanger is used, in particular 1 to 400 parts by weight of ion exchanger is used.

The binding of azelastine is accomplished by passing an azelastine solution through a bed of the ion exchanger in a column, or suspending the ion exchanger in a solution of azelastine and filtering and washing it after stirring. The filled ion exchanger is dried at temperatures up to approx. 50 ° C. The filled ion exchange particles are preferably equipped with a coating, as described, for example, in US-A-4 212 776. An advantage of the additional coating consists in that the release rate of the active substance can be altered and affected by the coating material wall. The coating of the coated filled ion exchange particles can be dried with hot air at a temperature of 70 ° C to 90 ° C.

The filled ion exchange particles can be filled into hard gelatin capsules or formed into a composition in the form of a suspension by means of water and thickeners, flavoring, stabilizing and preservative agents.

2. Coating of active substance particles, granular or pellet grains or azelastine-containing tablets with coatings of the following substances, these coatings may also be used as a mixture: hydroxypropylmethylcellulose phthalate or acetate succinate; cellulose, starch and polyvinyl acetate phthalate; Carboxymethyl cellulose; polyvinyl acetate; methyl cellulose phthalate, methyl cellulose succinate, methyl cellulose phthalate succinate and methyl cellulose phthalate acid halves; zea; ethyl cellulose and ethyl cellulose succinate; shellac; gluten; ethyl carboxyethyl cellulose; ethacrylate-maleic anhydride copolymer; maleic acid anhydride-vinyl methyl ether copolymer; styrene-maleic acid copolymer; 2-ethyl-hexyl-acrylate maleic acid anhydride; crotonic acid-vinyl acetate copolymer; glutamic acid / glutaminsyreester copolymer; carboxymethylethyl-celluloseglycerinmonooctanoat; cellulose acetate succinate; Polyarginine; fats, oil, wax, fatty alcohol; anionic polymer isates of methacrylic acid and methacrylic acid esters (Eudragi ^^ L, Eudr agii® S); copolymers of acrylic and methacrylic acid esters with a low content of ammonium groups (Eudragil® RS), as well as copolymers of 10 acrylic and methacrylic acid esters and trimethyl ammonium methacrylate (Eudragi & 9RL), copolymer of acrylic acid ethyl and methacrylic acid ethyl (methacrylic acid) NE 30 D), copolymer of acrylic acid, methacrylic acid and their esters (a ratio of the free carboxyl groups 15 to the ester groups of, for example, 1: 1) (Eudragit © L 30 D).

Said substances may further contain conventional plasticizers (e.g., dibutyl sebacate, citric and tartaric ester, glycerine and glycerine ester, 20 phthalic acid ester and similar substances), in addition to the water-soluble substances such as polyethylene glycol, polyvinylpyrrolidone, polyvinylpyrrolidone polyethylene copolymer , hydroxypropylcellulose, hydroxypropylmethylcellulose. Also the addition of 25 fats such as talc and / or magnesium stearate is possible in the coating.

The pellet grains, granules or tablets may also be mixed with additions of organic acids (such as citric, wine, maleic, fumaric and ascorbic acid).

The coating is effected by spraying solutions in organic solvent or suspensions of said substances in organic solvents or water, as further auxiliaries may be added to optimize their processability, such as e.g. surfactants and pigments. The spraying is done e.g. in boiler or in perforated boilers or by the air suspension method (eg smooth fluid bed system WLSD5). The coating can also be by coacervation, forming so-called microcapsules.

The coating may also be effected by coagulating aqueous dispersions of said substances, mixing the active substance with the dispersion and removing the water by drying.

Coated active substance particles and coated granules can be pressed into tablets, coated pellets can be filled into hard gelatin capsules.

When coating active substance particles or granules containing active substance particles, more coating material is usually used than 15 pellets, since the surface to be coated is substantially larger than pellets.

For 1 part by weight of active substance, 0.001 to 800 parts by weight of coating material can be used. Preferred is a weight ratio of 1 part of active substance and 0.005 to 500 parts by weight of coating material, particularly preferably 0.001 to 200 parts by weight of coating material per unit weight. 1 part by weight of active substance. The coating materials are applied at elevated temperature, preferably in an air stream having an inlet temperature of e.g. 70 to 90 ° C; and an exhaust air temperature of e.g. to 40 ° C.

3. Coating small pressed bodies, tablets and granules containing azelastine and one or more osmotically active substances (eg mannitol or sorbitol), with a semipermeable membrane e.g. of 30 to 90 wt% cellulose acetate and hydroxypropyl methyl cellulose (30 to 10 wt%).

As osmotically active substances are used: organic and inorganic compounds or soluble substances which exert an osmotic pressure gradient to the outer liquid over the semipermeable wall. Osmotically active agents or osmotically active compounds include magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium hydrogen phosphate, urea, sucrose and the like. Additional osmotically active substances are known from U.S. Pat. Nos. 3,854,770, 5,077,407 and 4,235,236.

As semipermeable materials known as polymers for osmosis and reverse osmosis, for example, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, p-glucan acetate, are used. acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, polyamide, polyurethane, sulfonated polystyrene, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethyl amino acetate, 15 cellulose acetate chloroacetate, cellulose dipalmitate, cellulose dioctanoate, cellulose dicaprylate, cellulose dipentanate, cellulose acetate valerate, cellulose acetate p-toluenesulfonate, cellulose acetate butyrate, ethylcellulose, selective permeable formed by 20 co-precipitation of a polycation and a polyanion as disclosed in US-3,173,876, 3,276,586, 3,541,005, 3,541,006 and 3,546,142.

Such coatings with semi-permeable membranes can e.g. also performed according to DE-A-3,310,081 or DE-A-3,310,096.

The proportion of osmotically active substance may range from 10 to 800 parts by weight, preferably 20 to 600 parts by weight, particularly preferably 50 to 400 parts by weight, relative to 1 part by weight of azelastine. The coating is applied in an amount which makes the semipermeable membrane 50 to 500 µm, preferably 100 to 300 µm thick.

The processing of the active substance and the osmotically active substances can take place at temperatures between room temperature and 80 ° C. To adjust the release rate, a hole is drilled into the membrane wall, e.g. by means of a laser beam so that the active substance is dissolved or suspended by penetrating liquid and pressed out of the hole after introduction of the tablets thus prepared in aqueous medium. The application of the semipermeable layer takes place, e.g. at a temperature 5 of the supply air of 70-90 ° C.

Optionally, the semipermeable membrane may also contain a microporous layer, or microporous substances may be incorporated (see, for example, German Publication 3,310,081, for example, page 7-17).

Materials suitable for preparing the microporous layer include e.g. polycarbonates of linear polyesters of carbonic acid, in which carbonate groups form repeat units in the polymer chain, microporous materials prepared by phosgene treatment of a dihydroxyaromatic compound such as bisphenol, a carporous polyvinyl chloride, microporous polyamides such as polyhexamethylene adipic acid, adipic acid formed from polyvinyl chloride and acrylonitrile, microporous styrene-acrylic monomers and their copolymers, porous polysulfones, characterized by linear chain diphenyl sulfone, halogenated polyvinylides, polychloroethers, acetal polymers, polyester prepared by esterification of a dicarboxylic acid or alkylene polyol, polyalkylene sulfides, phenolic polymers, polyesters, microporous polysaccharides with substituted anhydroglucose units having a decreasing permeability to water and biological fluids, asymmetric porous polymers, cross-linked olefin polymers, hydrofoils or hydrophilic microporous homopolymers, copolymers or interpolymers having a reduced density as well as materials disclosed in U.S. Patents 3,595,752, 3,643,178, 3,654,066, 3,709,774, 3,718,532, 3,803. 601, 3,852,224, 3,852,388 and 3,853,601; in UK PS 1,126,849 and in Chemical Abstracts 35 Volume 71, 427F, 22573F, 1969.

Additional microporous materials for preparing the microporous layer include polyurethane, crosslinked chain elongated polyurethanes, polyimides, polybenzimidazole, collodium, regenerated proteins, semi-solid crosslinked polyvinylpyrrolidone, microporous materials prepared by diffusion ----- cations in polyelectrolyte sols, microporose derivatives of polystyrene such as sodium polystyrene sulfonate, polyvinylbenzyl trimethyl ammonium chloride and microporous cellulose acylates and similar microporose polymers known from U.S. Patents 3,524,753, 3,565,259, 3,276. .589, 10 3,541,055, 3,541,006, 3,546,142, 3,615,024, 3,646,178 and 3,852,224.

The pore formers suitable for forming the microporous layer include fats and pore forming liquids. The term pore former as used herein also encompasses substances that make micropassages and the removal of the pore former can lead to both types. The term pore-forming liquid in this specification includes semi-solid and viscous liquids. The pore former may be inorganic or organic, and the layer-forming polymer 20 generally contains 5 to 70 wt% pore former, especially 20 to 50 wt%. The term pore former includes, for solids as well as for liquids, substances which can be dissolved, extracted or extracted from the precursor of the microporous membrane by the liquid present in the environment to form an active open cell porous layer. The pore-forming fats have a particle size of approx. 0.1 to 200 µm and comprises alkali salts such as lithium carbonate, sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium acetate, sodium citrate and the like. Organic compounds include, for example, saccharides including the sugars sucrose, glucose, fructose, mannitol, mannose, glactose, sorbitol and the like. Soluble polymers such as carbowax, carbopol and the like can also be used. The pore formers further comprise diols, polyols, polyhydric alcohols, polyalkylene glycols, polyglycols, poly (α-co) alkylene diols and the like.

4. Embedding of active azelastine in or binding to the following substances or mixtures of these 5 substances: - Digestible fats, for example, triglycerides of saturated fatty acids C8H16 ° 2 to ^ 18 ^ 36 ^ 2 and their mixtures, peanut oil and hydrated peanut oil, ri- 10 castor oil and hydrated castor oil, olive oil, sesame oil, cotton seed oil and hydrated cotton seed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, mixtures of mono-, di- and triesters of palmitic and stearic acid, glycerine, glycerine, glycerine,

- Indigestible fats eg fat-like substances, e.g. esters of aliphatic or unsaturated fatty acids (2 to 22 C atoms, especially 10 to 18 20 C atoms) with monovalent aliphatic alcohols (1 to 20 C atoms), carnauba wax, beeswax, fatty alcohols (straight or branched) the chain length CgH17OH to C1H2H2 OH, especially C2-2H2S ^^ to C2H2 ^ GOH.

- Polymers such as polyvinyl alcohol, polyvinyl chloride, polyacrylic acid (Carbopol®); anionic polymerizers of methacrylic acid and methacrylic acid esters (Eudragil® L,

Eudragi (ES), acrylic and methacrylic acid ester copolymers with trimethylammonium methacrylate (Eudragitör, 30 Eudragi® RS).

Copolymerates of acrylic acid ethyl and methacrylic acid methyl esters (Eudragit® NE 30 D), as well as of acrylic acid, methacrylic acid and their esters (ratio of the 35 free carboxylic groups to the 1: 1 ester groups) (Eudra-giÆ> - L30 D), polyethylene, polyglycolic acid, polyhydroxy butyric acid, polylactic acid, lactic acid copolymers 12 DK 172235 B1 and glycolic acid (manufacturer: Boehringer Ingelheim), lactic acid and ethylene oxide copolymers or acetate succinate; cellulose acetate phthalate, starch acetate phthalate, and polyvinyl acetate phthalate; carboxymethyl cellulose; methylcellulose phthalate, succinate, phthalate succinate, methylcellulose phthalic acid halves; zea; ethyl cellulose; shellac, 10 gluten; ethylcarboxyethylcellulose; ethacrylate-maleic anhydride copolymer; maleic acid anhydride-vinyl methyl ether copolymer; styrene-maleic acid copolymer in sat; 2-ethyl-hexyl-acrylate maleic acid anhydride; crotonic acid-vinyl acetate copolymer; glutamic acid / glutamic acid ester copolymer; carboxymethyl cellulose glycerine monooctanoate; cellulose acetate succinate; poly-arginine; crosslinked alginate; crosslinked gelatin.

Nitrogen such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (Pharma coat, Methocel E = methylcellulose propylene glycol ether), alginic acid and its salts (Na, Ca salt, also mixtures of sodium alginate and calcium salts e.g.

CaHPO 4), starch, carboxymethyl starch, carboxymethyl cellulose and its salt (e.g., Na salt), galactomannan, gum arabic, karaya gum, ghatti gum, agar agar, carrageenan, xanthan gum, guar gum and its derivatives, locust bean meal, propylene glycol alginate, pectin and tragacanth.

30

For one part by weight of azelastine, in these retarding components, 1 to 800 parts by weight of the retarding component, preferably 1.5 to 600 parts by weight, in particular 2.0 to 400 parts by weight, are used. The preparation of these preparations is carried out at temperatures between 18 ° C and 80 ° C. The preparation of the composition may be carried out, for example, as follows: (a) by dissolving or dispersing azelastine or its salts in said fats or fat-like substances or mixtures thereof, by melting said substances and subsequent re-cooling, comminution, possibly adding of additional substances such as e.g. the above water-soluble or water-swellable substances and pressing for tablets. The cooling of the melt and comminution can also be summarized in one step, the melt being dispersed in cold water and subjected to spray drying. Using the above oil as a retarding component, azelastine or its salt is dissolved or suspended in the oil and optionally after addition of 15 up to 2% aluminum monostearate filled in ampoules and then sterilized or optionally after the addition of flavoring and / or sedimentation delay agents such as high dispersed silicon dioxide (e.g., AerosiJ®) homogenized and filled into bottles; (b) by mixing azelastine with the said fats, polymers or swelling substances or mixtures of these substances, including by the use of heat and compression. c) by mixing azelastine with solutions of said fats or polymers in water or organic solvents, such as e.g. ethanol, ethyl acetate, acetone or isopropanol, optionally admixture with carrier materials such as celluloses, and subsequent evaporation of the solvent and admixture of the obtained active ingredient mixture with additional excipients and processing for drugs such as e.g. tablets or pellets, d) by wetting a mixture of azelastine and said swelling agents with organic solvent such as ethanol, ethyl acetate, acetone or isopropanol, optionally by the addition of binders such as polyvinylpyrrolidone or copolymers of polyvinylpyrrolidone and polyvinylacetate, polyvinylacetate the mixture formed followed by drying, optionally adding additional excipients and pressing the mixture to tablets, or e) by mixing azelastine with a solution of natural or artificial resin such as shellac or polyvinyl acetate in polyethylene glycol having a molecular weight of 200 to 1500, optional addition of additional excipients such as e.g. stearates or toxins and encapsulating the formed mass into soft or hard gelatin capsules.

In general, the preparation of the compositions is carried out in a manner known per se, in addition to the delayed components, the known and usual pharmaceutical auxiliaries and an additional 25 usual carriers and diluents can be used, the auxiliaries mentioned as secondary components also being able to exert other features, e.g. act as mold release agent or as explosive agent. As the kind of carriers and excipients used e.g. such substances that are recommended or listed in the following literature references as auxiliaries to pharmacy, cosmetics and adjoining areas: Ullmann's Encyclopedia of Technology Chemie, Vol. 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), pages 918 et seq., 35 H.V. Czétsch-Lindenwald, auxiliaries for pharmaceuticals and adjoining areas; Pharm. Ind., Booklet 2, 1961, page 15 DK 172235 B1 72 and the following pages; Dr. Η. P. Fiedler, Lexikon der Auxiliary for Cl r Pharmacy, Cosmetics and Adjacent Areas, 2nd edition, Editio Cantor, Aulendorf in Wilrttem-berg 1981.

Examples of common excipients, carriers and diluents are gelatin, natural sugars such as cane sugar or milk sugar, lecithin, pectin, starch (eg corn starch) as well as starch derivatives, cyclodextrins and cyclodextrin , tylose, talc, lycopodium, silicic acid (e.g., colloidal), fructose, tragacanth, sodium chloride, stearate, magnesium and calcium salts of fatty acids with 12 to 22 C atoms, especially those saturated (e.g. stearate) , polyethylene glycol having an average molecular weight between 200 and 20,000, preferably between 200 and 5,000, especially between 200 and 1,000, or mixtures thereof and / or polymers of vinylpyrrolidone and / or blend polymers of vinylpyrrolidone and vinyl acetate, esters of ali -20 fatty saturated or unsaturated fatty acids (2 to 22 C atoms, especially 10 to 18 C atoms) with monovalent aliphatic alcohols (1 to 20 C atoms) or multivalent alcohols such as gl ycols, glycerin, diethylene glycol, pentaerythritol, sorbitol, mannitol, etc., which may also be etherified, benzyl benzoate, dioxolane, glycerine formaldehyde, tetrahydrofurfuryl alcohol, polyglycol ether with C x to C 12 alcohols, dimethyl acetate, dimethyl acetate ethyl carbonate, silicone (especially medium-viscous poly-dimethylsiloxane), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate, gum arabic, alginic acid, stearate, fats and substances that work in the same way.

In addition, the forms of administration may contain surfactants. Examples are: alkali soaps, such as higher fatty acid alkali salts (e.g., Na palmitate, Na stearate) or their derivatives (e.g.

16 DK 172235 B1

Na-ricinolat-sulfuric acid ester); sulphated compounds or sulphonated compounds which arise from the reaction of higher fatty alcohols with sulfuric acid or chlorosulphonic acid and e.g. are used as nitrate salts (e.g.

Sodium lauryl sulfate, sodium cetyl sulfate, sodium stearyl sulfate, sodium cetyl sulfonate); salts of bile acid; saponin; quaternary ammonium compounds; sorbitan partial fatty acid ester; partial fatty acid ester and fatty acid ester of polyoxyethylene sorbitan; sorbitol ether of polyoxyethylene; fatty acid esters of polyoxyethylene; fatty alcohol ether of polyoxyethylene; fatty acid esters of sucrose; fatty acid ester of polyglycerol; proteins; lecithin.

The forms of administration may also contain celluloses, especially when preparing pressed preparations.

As such, purified cellulose (e.g., as commercially available ElcemaR) is used; or microcrystalline cellulose, such as e.g. is available commercially under the name AvicelR. However, other binder functional fillers such as calcium hydrogen phosphate, milk sugar, starch (e.g. potato starch, corn starch, modified starch such as Starch ST 1500 / Colorcon), glucose, mannitol and sucrose can also be used.

The compositions may further contain sediment ring retardants, such as e.g. high-dispersed silica having a surface of 50 to 500 m2 / g, in particular 100 to 400 m2 / g (determined by the BET method). These are commercially available e.g. under the name Aerosil R.

Further, the use of mold release agents in the form of administration may make sense. As such, talc or silicone-treated talc, calcium and magnesium stearate, stearic acid, paraffin, hydrated fats and oils and silicone oil emulsion.

35 Further auxiliaries are also used which cause degradation (so-called explosives), such as: cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethylcellulose, formaldehyde gelatin, formaldehyde casein, polyacrylic acid and ultramylic acid.

For example, for preparing solutions and suspensions, water or physiologically acceptable organic solvents such as e.g. ethanol, 1,2-propylene glycol, polyglycol and their derivatives. For injectable solutions or suspensions, e.g. non-toxic parenterally acceptable diluents or solvents such as: water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycol in admixture with water.d Ringer's solution and isotonic boiling salt solution.

Further, the addition of stabilizers, dyes, antioxidants and complexing agents (eg ethylenediaminotetraacetic acid) and the like is possible as well as the addition of acid such as citric acid, tartaric acid, maleic acid and fumaric acid.

As antioxidants, for example, sodium metabisulphite, cysteine, ascorbic acid and its esters (e.g. palmitate), flavonoid, gallic acid, gallic acid alkyl ester, butylhydroxyanisole, norihydroguanic acid, tocopherol and tocopherol + synergists (substances that bind together) are used. (for example, lecithin, ascorbic acid, citric acid, phosphoric acid).

As a preservative, for example, sorbic acid, p-hydroxybenzoic acid ester (e.g. lower alkyl ester), benzoic acid, sodium benzoate, trichloroisobutyl alcohol, phenol, cresol, benzethonium chloride and formaldehyde derivatives are used.

For example, as a coating plasticizer, citric and tartaric esters (acetyl triethyl, acetyl tributyl, tributyl, triethyl citrate) are used; glycerine and glycerine ester (glycerine diacetate, triacetate, acetylated monoglycerides, castor oil); DK 172235 B1 1Θ phthalic acid esters (dibutyl, diamyl, diethyl, dimethyl, dipropyl, D- (2-methoxy or ethoxyethyl) phthalate, ethyl phthalyl and butyl phthalyl ethyl and butyl glycolate); alcohols (propylene glycol, polyethylene glycol of different chain lengths), adipate (diethyl, di (2-methoxy- or ethoxy-ethyl) adipate); benzoephenon; diethyl and dibutyl sebacate, succinate, tartrate; di-ethylene glycol dipropionate; ethylene glycol diacetate, dibutyrate, dipropionate; tributyl phosphate, tributyrin; Polyethylene glycol sorbitan monooleate; sorbitanmonooleate.

Solvents from the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic, aromatic, heterocyclic solvents and their mixtures may be used to introduce the retard components or coatings. Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethyl glycol monoethyl ether , ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, tetrachlorocarbon, nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxide furan, diethylene glycol dimethyl ether, water and mixtures thereof such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol and ethylene dichloride and methanol and their mixtures. During the coating process, this solvent is removed again. Irrespective of the method of preparation, the forms of administration according to the invention are peculiar in that they release the active substance azelastine or its physiologically acceptable salts to, or allow it to pass into, body fluids at a release rate between 0.05 and 5 mg per day. hour.

DK 172235 Pg 19

Dosage indications are always expressed with respect to azelastine in base form; If salts of azelastine are used, the molecular weight must be converted accordingly.

The content of active azelastine in the compositions of the invention is a) in the case of orally applicable preparations 0.1 mg to 50 mg, preferably 0.2 mg to 30 mg, in particular 10 0.5 mg to 20 mg of active azelastine.

Said single doses may be used 1 to 5 times, preferably 1 to 3 times, especially 1 to 2 times daily, 15 b) in parenterally usable preparations (intravenous, intramuscular, subcutaneous, intraperitoneal): 0.1 mg to 500 mg, preferably 0 , 2 mg to 400 mg, especially 0.5 to 250 mg of active azelastine.

Said single doses may be administered once monthly (e.g., for implants for subcutaneous use) to 3 times daily, preferably once monthly to 2 times daily, especially once monthly to once daily.

(C) in preparations for dermal use (e.g., plastics) 5 mg to 5000 mg, preferably 10 mg to 3000 mg, especially 30 mg to 2000 mg of active azelastine.

Said single doses may be administered once daily to once monthly, preferably once every three days to once every three weeks, especially once a day. week to once every two weeks.

Particularly preferred retarding components are: a) Cation exchange.

Poly (styrene, divylnylbenzenesulfonic acid sodium 5 (eg Amberlite® IRP 69). For 1 part azelastine (base), for example, 3 to 10 parts Amberlite® IRP 69 is used).

(b) Coatings.

Hydroxypropyl methyl cellulose phthalate.

For 1 part azelastine 1.5 to 3 parts hydroxypropyl methyl cellulose phthalate 55.

Ethyl cellulose.

15 to 1 part azelastine 0.1 to 1 part ethyl cellulose.

Eudragith resin such as e.g. Eudragit® RS.

For 1 part azelastine 0.01 to 0.1 part Eudragit® RS.

C) Semipermeable layers with osmotically active core containing active substance and release orifice:

Coat with 100 to 300 µm thick layer of 82% cellulose acetate and 18% hydroxypropylmethyl cellulose.

25 d) Embedding fabrics.

Hydrocolloids, e.g. hydroxypropyl:

To 1 part azelastine 2 to 10 parts hydrocolloid.

Eudragit ® RS:

For 1 part azelastine 10 to 15 parts Eudragit® RS.

Glycerine dithripalmito stearate (eg Precirol Ato 5).

For 1 part azelastine 1 to 10 parts precirol Ato 5.

The desired release rate of 0.05 to 5 mg per hour to the desired range at 35 21 DK 172235 B1 using the procedure precautions in connection with the corresponding information in the description. In the event that a particular release rate is desired within this range, e.g. Proceed as follows: 1. Preparation of the coating or embedding of the active substance in the manner described.

2. Testing the release of the active substance from the composition using 0.1 N HCl (2 hours) and phosphate buffer pH 6.8 (thereafter) as the release medium.

15 (a) the release is found to be too high:

Increase in retard component proportion and / or decrease in the proportion of water-soluble excipients. Decrease in the proportion of osmotic active substance.

B) If the release turns out to be too low:

Decrease of retard component and / or increase of water soluble excipient. Increase in the proportion of osmotically active substance.

In general, a release rate of 1 mg azelastine per dose is sought. hour.

Example 1 100 g of azelastine hydrochloride are mixed with 960 g of hydroxypropyl methyl cellulose (viscosity of a 2% aqueous solution: 4000 cP (commercial product: eg Met-35 Hocel K4M Premium)), 1320 g of spray-dried lactose and 20 g of magnesium stearate, and the mixture is pressed into tablets DK 172235 B1 22 of 120 mg with a diameter of 6 mm and a vault radius of 6 mm.

In addition, the tablets may be equipped with a gastric juice-soluble, gastric juice-permeable or mesh-resistant film coating according to conventional methods.

To form a stomach-resistant coating, approx. 1000 g tablets with approx. 1000 g of the following suspension, e.g. in a coating ring boiler: in 480 g of acetone is dissolved 63 g of cellulose acetate-10 phthalate. To this solution are added 21 g of phthalic acid diethyl ester, 30 g of dichloromethane and 131 g of methanol. 4.4 g of titanium dioxide are homogeneously suspended in the resulting solution. The spraying is discontinuous, with hot air being blown in between the spray phases.

IS A retard tablet contains 5 mg of azelastine hydrochloride.

Example 2 20 g of azelastine hydrochloride, 20 g of Eudragit® PM PM, 250 g of talc and 200 g of lactose are mixed and the mixture is wetted with approx. 140 g of a mixture of 12.7 g of glycerine triacetate (trade name eg triacetin) and 127.3 g of Eudragit® RS 12.5. The moist mass is granulated through a 1 mm mesh screen in the usual manner and, after drying at room temperature, is sprayed with a mixture of 909 g Eudragit Φ RS 12.5 and 91 g triazetin using a spray gun in a kettle ring boiler. The formed, dried granules are pressed without the addition of additional excipients to biconvex tablets weighing 300 mg and 10 mm in diameter.

One tablet contains 5 mg azelastine hydrochloride as a retarding preparation.

35 DK 172235 B1 23

Example 3

50 g of azelastine hydrochloride are mixed with 100 g of tartaric acid, 250 g of lactose, 10 g of microcrystalline cellulose (Avicel PH 101) and 7 g of hydroxypropyl cellulose (viscosity of a 5% solution: 75 to 150 cP

(trade name eg Klucel LF)) and the mixture is kneaded with 60 g of a 6.25% aqueous solution of hydroxypropyl cellulose (viscosity of 5% aqueous solution: 75 to 10 150 cP (trade name eg Klucel LF )). The moist mass is pressed through a hollow leaf having a hole diameter of 1 mm and the strands formed are cut and rounded by treatment on a Spheronizer disc in the usual manner.

The pellets formed are dried and sieved. 300 g pellets of the 15 sieve fraction 800 to 1200 µm are coated in the usual manner with a solution of 42.5 g of ethyl cellulose (trade name: Ethocel type N 22) and 37.5 g of polyethylene glycol 1500 (trade name eg Carbowax 1540) in 720 g of chloroform by spraying into the fluid bed apparatus.

50 mg of the above-coated coated pellets were loaded into size 3 hard gelatin capsules.

A hard gelatin capsule contains 4.4 mg of azelaine hydrochloride as a retarding preparation.

25

Example 4

Preparation of the forms of administration according to the invention takes place by embedding in swelling substances: 30 The following substances are mixed: (indications in grams) DK 172235 B1 24

Recipe 12 3

Azelastine Hydrochloride 50 50 50 5 Hydroxypropyl methylcellulose (= Methocel K 4 M) 480 192 96

Lactose 660 948 1044

Magnesium stearate 10 10 10 10 The mixture is pressed into plant tablets weighing 120 mg and 6 mm in diameter on a tablet press.

There were obtained

Thickness mm 3.25 3.15 3.05 15 Break strength (N) 47 48 50 (Heberlein tensile strength tests)

One tablet contains 5 mg azelastine hydrochloride. The release of active substance in the apparatus from USP XXI 20 (disolution tester apparatus 2, dissolution medium: 500 ml 0.1 N HCl, rpm: 120 rpm) is as follows: (release of active substance is given in%)

Recipe 25 12 3

After 5 minutes 4 31 50

After 60 minutes 20 76 100

After 120 minutes 36 96 30 After 180 minutes 55

After 240 minutes 74

After 300 minutes 86

After 360 minutes 93 35 DK 172235 B1 25

Example 5 100 g of azelastine hydrochloride, 200 g of tartaric acid, 500 g of milk sugar and 700 g of microcrystalline cellulose 5 are mixed and kneaded with approx. 700 g of purified water. The moist mass is pressed through a hollow blade having a hole diameter of 1 mm and the strands formed are cut and rounded in the usual manner by treatment on a Spheronizer disc. The pellets formed are dried and sieved.

10 1000 g pellets of the sieve friction 800 to 1250 µm are sprayed with a suspension prepared as follows: In 190 g of purified water, 0.6 g of Polysorbate 80 is dissolved and in the solution 40 g of triethyl citrate is emulsified. To the resulting emulsion is added 800 g of a 30% aqueous dispersion of a copolymer of acrylic and methacrylic acid esters with a low content of trimethylammonium ethacrylate chloride (= Eudragit R RS 30 D) and stirred for approx. 10 minutes.

In 860 g of purified water, 109.2 g of talc and 0.2 g of silicone antifoam oil (Simethicone) are suspended. This suspension is stirred into the dispersion formed above.

Application of pellets with the coating suspension thus formed takes place in the usual manner e.g. using a fluid bed spray granulator at an inlet temperature of 40-50 ° C and an exhaust air temperature of maximum 40 ° C. Drying of pellets is done under the same conditions .. · '

The above coating suspension is sprayed in until the total weight of the dried pellets is 1042 g.

The lacquered pellets are filled into size 3 hard gelatin capsules in an amount of 78.1 mg. A hard gelatin capsule contains 5 mg of azelastine hydrochloride as a retarding preparation. The release of the active substance 35 from a capsule in the apparatus of USP XXI (dissolution tester, apparatus 2, dissolution medium: 500 ml of 0.1 N HCl, speed of revolution: 120 rpm) is:

After 1 hour 3.0 mg »60%

After 2 hours 4.5 mg 2 90%.

5

The release of active substance is thus 3 mg per day.

t ime.

Example 6 10

Work is carried out in the same manner as in Example 5, except that the pellets are sprayed with so much of the coating suspension mentioned in Example 5 that the total weight of the dried pellets is 1127 g.

Next, the lacquered pellets are filled into size 3 hard gelatin capsules in an amount of 84.5 mg. A hard gelatin capsule contains 5 mg of azelastine hydrochloride as a retarding preparation. The release of the active substance from a capsule in the apparatus of USP XXI is (the same test conditions as in Example 5):

After 1 hour 0.25 mg = 5%

After 2 hours 0.50 mg = 10%.

Thus, the release of the active substance is 0.25 mg per ml. hour.

Example 7 30 Work as described in Example 6. If 16.9 g of the pellets formed in Example 6 are filled into size 3 gelatin capsules, a hard gelatin capsule contains 1 mg of azelastine hydrochloride as a retarding preparation. The release of the active substance from a capsule in the USP XXI 35 apparatus (under test conditions as in Example 5) is: 27 DK 172235 B1

After 1 hour 0.05 mg * 5%

After 2 hours 0.10 mg £ 10%.

Thus, the release of active substance is 0.05 mg per day.

5 hours.

Example 8

Capsules with 6 mg azelastine or suspension 10 with 6 mg azelastine in 5 ml, each bound to strong cation exchangers.

Dissolve 8.48 g of azelastine hydrochloride in 4 liters of purified water. In the solution, 71.5 g of styrene sulphonic acid ivinylbenzene copolymer (crosslinking grade 8%) (commercial product: eg Amberlite IR 120) is suspended and the suspension is stirred for 3 hours. The suspension is then filtered through a glass filter nozzle and the resulting filter cake is washed twice with 300 ml of purified water and the wash water is well sucked off.

5 g of gelatin (isoelectric point 6-7.6, molecular weight 25,000-35,000) (commercial product: Gelita® Collagel, Deutsche Gelatin factory, Eberbach / Neckar) are dissolved in a solution of 5 g of 1 N hydrochloric acid in 800 g of purified water. wear glasses. The filter cake formed above is suspended in the solution and the suspension is stirred for 1 hour. Next, the suspension is filtered through a glass filter nug and the filter cake formed is washed twice with 200 ml of purified water and the wash water is suctioned off.

The filter cake is dried at 60 ° C. The dried product 30 is filled into hard gelatin capsules of size 4 in an amount of 62 mg.

A hard gelatin capsule contains 6 mg of azelastine bound to strong acidic cation exchange.

A juice containing 5 mg of azelastine 35 bound to ion exchange in 5 ml is obtained as follows.

7.4 kg of purified water is heated to 90-95 ° C and dissolved 0.002 kg of propyl 4-hydroxybenzoate and 0.013 kg of methyl 4-hydroxybenzoate. In the cooled to 70 ° C solution, 0.020 kg of hydroxyethyl cellulose (average polymerization degree: 250) and 3.0 kg of sucrose are unlocked.

After cooling to 25 ° C, 3 g of raspberry flavor and 0.2 kg of modified starch (Starch 1500 ® / Colorcon) are dissolved or suspended with stirring. Into the suspension is stirred 124 g of the dried azelastine-filled ion exchanger. The suspension is then filled with purified water to 11.0 kg (corresponding to 10 L).

10 The release of the active substance from a capsule or 5 ml suspension into the USP XXI apparatus (disolution tester, apparatus 2, solubility medium 500 ml sodium chloride 0.9%, speed: 100 rpm) is: 15 After 1 hour 25%

After 2 hours 40%

After 3 hours 50%

After 4 hours 58%

After 5 hours 65% 20 After 6 hours 69%

After 7 hours 72%

After 8 hours 75%

Also, the solubility medium is renewed every 25 hours; the values obtained for the release are added together.

Claims (6)

1. Controlled release azelastine-containing drug, characterized in that a retard component is used, in which, for one part by weight of azelastine (based on the base form), 0.001 to 800 parts retard component is used, and that azelastine may also be in the form of its physiologically acceptable salts, and that azela-! 0 strain release rate is between 0.05 and 5 mg per per hour (determining the release rate in an aqueous sample solution of pH 1.0 and / or pH 6.8). A medicament according to claim 1, characterized in that the active substance azelastine or its physiologically acceptable salts is optionally added by one or more additional auxiliaries and additives a) coated with one or more retard components, or b) bound to a cation exchanger. or (c) added one or more osmotically active substances and coated with a semi-permeable membrane into which a hole is drilled; or d) embedded in or bonded to one or more digestible fats, indigestible fats or 25 fats-like substances, polymers or swelling substances, to achieve controlled release. Drug according to claim 1, characterized in that the oral dosage forms contain 0.1 to 50 mg, for the parenteral use 0.1 to 500 mg and for the dermal use 5 to 5000 mg of the active azelastine. . Process for the preparation of a drug containing the active substance azelastine, with controlled release of the active substance, characterized by mixing one part by weight of azelastine DK 172235 B1 (based on the base form), the azelastine also being available. in the form of its physiologically acceptable salts, with 0.001 to 800 parts by weight of retard component and optionally additional usual pharmaceutical adjuvants and additives, setting the release rate to 0.05 to 5 mg azelastine per ml. hour. Process for the preparation of a medicament according to claim 4, characterized in that the active substance azelastine or its physiologically acceptable salts a) is coated with one or more retard components or b) is bound to a cation exchanger, or c) is added one or more osmotically active substances and are coated with a semipermeable membrane, drilling a hole in the membrane, or d) embedding in or bonding to one or more digestible fats, indigestible fats or fat-like substances, polymers or swelling substances, which may also be used. additional usual auxiliaries and additives. Process for the preparation of a medicament according to claim 4 and / or 5, characterized in that the oral dosage forms contain 0.1 to 50 mg, for the parenteral use 0.1 to 500 mg and for the dermal use. contains 5 to 5,000 mg of the active substance azelastine.