MC2025A1 - MEDICINAL PRODUCT CONTAINING AZELASTINE AND CAPABLE OF RELEASING IT IN A CONTROLLED WAY - 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

I

Azelastine is a derivative of phthalazinone which has the following structure:

Cl

15 and whose chemical name is: (4-chlorobenzyl)-4 (1-methyl perhydro-azepinyl-4)-2; (2H)-phthalazinone. It is used particularly for the preventive treatment of asthma. It also has anti-allergic and antihistamine properties (see patent DE 2,164,058). 20 One of the serious drawbacks encountered when applying azelastine is the fatigue it causes as a side effect. Many patients also report drowsiness, lethargy, etc. This side effect is especially noticeable during the first few days of azelastine application, making it impossible for patients to drive vehicles and operate machinery, as their overall alertness is significantly reduced.

It would therefore be extremely interesting to have a form of azelastine administration that did not have fatigue as a side effect, and this would be considered an important medical advance.

In the past, to suppress the side effect, it was common practice to prepare a mixed composition containing both the active substance

5

This method is not applicable to azelastine because the half-lives (tl/2) of azelastine and caffeine differ significantly. (Tl/2 is the time it takes for the blood serum concentration of the active substance, without further administration of the active substance, to fall from a certain initial value to half that value.) The tl/2 value of azelastine is 20 hours, while that of caffeine is only 3.5 hours. Therefore, when azelastine and caffeine are administered together, the effect of caffeine is expected to diminish after a certain time, and the sedative effect of azelastine to reappear. 15 The usual trick is to delay the release of the active ingredient, namely caffeine, in the form of administration, so that the duration of its action is prolonged. Unfortunately, with this method, it is difficult to closely match, in vivo, the changes in blood concentrations of the two active substances.

This is impossible with the techniques available today, because of the large differences in elimination values.

25 Azelastine has an extremely unpleasant taste, at

To such an extent, for example, that azelastine-based compositions, especially liquid ones (such as potions), are difficult for patients to accept or are even refused, particularly by children. Thanks to this invention, it is also possible to prepare azelastine-based compositions with a considerably improved taste.

The technical problem was as follows: to develop a drug containing azelastine as its active ingredient, but with the 35 sedative side effects caused by azelastine mitigated.

to a large extent or even completely eliminated, as well as a process for preparing such a drug.

This technical problem is solved by means of a controlled-release drug of the active substance, 5 drug which contains usual excipients and additives and a delayed component and which is characterized in that the active substance, in this case azelastine or one of its physiologically acceptable salts, is released in a controlled manner, is present in an amount of 1 part 10 by weight of azelastine, relative to the base, for 0.001 to 800 parts by weight of the delayed component, and the release is 0.05 to 5 mg of azelastine per hour, for example 0.05 to 3 mg or even 0.05 to 1 mg of azelastine per hour.

15. When azelastine is in the form of a salt, the amount of azelastine indicated above, relative to the base, is higher because the salt has a higher molecular weight. The amounts of "azelastine" indicated in this memorandum always refer to the base and,

2 0 when dealing with a salt, a correction must be made by calculation taking into account the higher molecular weight.

The invention also includes a method for preparing a controlled-release medicinal product 25 of the active substance, by introducing an active substance into common excipients and additives and a delayed-release component, the method characterized in that azelastine or one of its physiologically acceptable salts is used as the active substance to be released in a controlled manner.

3.0 logically, in a ratio of 1 part by weight of azelastine,

relative to the base, for 0.001 to 800 parts by weight of the retard component, and the release rate is set to a value between 0.05 and 5 mg of azelastine 35 per hour.

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The sub-claims describe preferred embodiments of the invention.

It was found, surprisingly, that to obtain a form of azelastine administration that does not produce the indicated side effect, namely fatigue, it is not necessary to add caffeine—whether in delayed form or not—but simply to delay the azelastine itself. Therefore, when azelastine is introduced in a form of administration that releases the active substance over a longer period (thus achieving a "delay" of the active substance), the side effect, namely fatigue, is no longer observed in individuals treated with this form of administration. This is all the more surprising given that azelastine, as previously mentioned, has an elimination half-life of 20 hours.

In pharmaceutical technology, the delay method has hitherto only been applied to substances with a short half-life, for example, a half-life of at most

2010 hours. Delaying an active substance with a half-life of

Until now, 8 PM was considered the time for pharmacies to open.

simply as professional misconduct.

Moreover, surprisingly, these forms of administration 25 no longer have the bitter taste that was observed until now.

The invention therefore relates to controlled-release forms of administration of the active substance, namely azelastine or one of its physiologically acceptable salts. Suitable salts are

3 0 including chloride, acetate, maleate, lactate, citrate, tartrate, gluconate and embonate.

The invention further relates to a method for manufacturing controlled-release administration forms of the active substance, i.e. aze-35lastine or one of its physiologically acceptable salts.

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The release rate of azelastine, between 0.05 and 5 mg per hour, is determined in an aqueous test solution at a pH of 1.0 and/or 6.8. This test solution is an aqueous solution with one of the indicated pH values. The pH is adjusted by adding an acid or a standard buffer.

Forms of administration may include, for example, delayed-release tablets, delayed-release capsules, pills, potions, implants, injections, plasters, aqueous or oily suspensions, oily solutions, granules, dragees, soft gelatin capsules, or microcapsules.

The compositions according to the invention can be obtained in the following manner:

15

1. By binding azelastine to physiologically acceptable cation exchangers, which may include:

acrylic and methacrylic resins with exchangeable proton 20, acid radicals: COO~, for example Amberliti^ IRP-64,

exchangeable Na+ ion polystyrene resins, SO3~ acid radicals, for example Amberliti® IRP-69.

Ion exchangers are 25 acid ion exchangers. The maximum ratio of azelastine to

The ion exchange ratio is approximately 1:1, with a minimum ratio of approximately 1 part by weight of the active substance to 800 parts of the ion exchange resin. Preferably, for 1 part by weight of the active substance, 30 parts of 1 to 400 parts by weight of the ion exchange resin should be used, or even better, 1 to 100 parts by weight of the ion exchange resin.

To fix azelastine, an azelastine solution is passed through a bed of the ion exchanger in a column, or the ion exchanger is suspended in an azelastine solution, and after shaking, it is separated by

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The material is filtered and washed. The charged ion exchanger is dried at a temperature of up to approximately 50°C. It is beneficial to further coat the charged ion exchanger particles, as described, for example, in 5 1'US A 4 221 776. One advantage of coating is that the choice of coating material allows for influencing the release rate of the active substance. The coated and charged ion exchanger particles can be dried with hot air at a temperature of 70 to 90°C.

Charged ion exchange particles can be introduced into hard gelatin capsules, or 15 moreover, a suspension can be prepared with these particles, using water, thickeners, flavorings, stabilizers and preservatives, which constitutes a form of administration.

20

2. By coating particles containing the active substance, granules, pills, or tablets containing azelastine with coating products consisting of 25 substances taken from the following, which may also be used in mixtures: hydroxypropyl methylcellulose phthalate or acetate succinate; cellulose phthalate; starch phthalate and poly-(vinyl acetate phthalate); carboxymethyl cellulose; poly-(vinyl acetate); methylcellulose phthalate; methylcellulose succinate, methylcellulose phthalate succinate, methylcellulose phthalate succinate and methylcellulose phthalic hemiester; zein; ethyl cellulose and ethyl cellulose succinate;

Shellac; gluten; ethyl carboxyethyl cellulose; ethyl acrylate/maleic anhydride copolymer; maleic anhydride/methyl vinyl oxide copolymer; styrene/maleic acid copolymers; ethyl-2-hexyl acrylate/maleic anhydride copolymer; crotonic acid/vinyl acetate copolymer; glutamic acid/ethyl glutamate copolymer; carboxymethyl ethyl cellulose/glycerol monooctanoate; cellulose acetate succinate, polyarginine; fats, oils, waxes and fatty alcohols; anionic polymers of methacrylic acid and methacrylic esters (Eudragir® L, Eudragit® S); acrylic and methacrylic ester copolymers containing a small amount of 15 ammonium radicals (EudragritCB^s), as well as acrylic and methacrylic ester copolymers and trimethylammonium methacrylate (Eudragrt® RL), ethyl acrylate and methyl methacrylate copolymer 70:30 (EudragiiP^E 30D), the copolymer of acrylic acid, methacrylic acid and their esters (ratio of free carboxy radicals to ester radicals equal for example to 1:1) (Eudragii^L 30D).

The substances mentioned may also contain common plasticizers (e.g., dibutyl sebacate 25, citric and tartaric acid esters, glycerol and glycerol esters, phthalic esters, and similar substances); water-soluble substances such as polyethylene glycols, poly(vinylpyrrolidone), copolymers of poly(vinylpyrrolidone) and poly(vinyl acetate), hydroxypropyl cellulose, or hydroxypropyl methylcellulose may also be added. Solid materials, such as talc and/or magnesium stearate, may also be added to the coating material.

35 II There may also be organic acids

(such as citric acid, tartaric acid, maleic acid, fumaric acid or ascorbic acid) incorporated into pills, granules or tablets.

The coating is carried out by spraying solutions in organic solvents, or suspensions of the aforementioned substances in organic solvents or in water, to which additional additives may have been added to optimize their suitability for implementation, for example surfactants or pigments.

Spraying is carried out for example in a coating machine or in perforated containers, or by the method of suspension in air (for example in the Glatt WLSD5 vortex layer apparatus).

The coating can also be carried out by coacervation processes, which gives micro-capsules.

Another way to achieve coating is to coagulate aqueous dispersions of the substances mentioned above: for this, the active substance is mixed with the dispersion and the water is removed by drying.

Coated active substance particles and coated granules can be formed into tablets by pressure molding, and coated pills can be inserted into hard gelatin capsules.

When coating particles of active substance or granules that contain particles of active substance, a larger quantity of coating material is usually used than in the case of pills, because the surface area to be coated is then much larger than in the case of pills.

For 1 part by weight of the active substance, from 0.001 to 800 parts by weight of the coating material can be used. Ideally, the weight ratio should be 1 part of the active substance to 0.005 to 500 parts by weight of the coating material, or even better, 0.01 to 200 parts by weight of the coating material to 1 part of the active substance.

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by weight of the active substance. The coating material is applied at a high temperature, preferably in an air current. The temperature of the incoming air is, for example, 70 to 90°C, and the temperature of the outgoing air is, for example, 40°C.

3. By encapsulating molded objects, tablets or granules containing azelastine and one or more substances with osmotic activity (such as mannitol or sorbitol), with a semi-permeable membrane, made up for example of 70 to 90% by weight of cellulose acetate and hydroxypropyl-methyl-cellulose (30 to 10% by weight).

Substances with osmotic activity can also be considered mineral or organic compounds, or 15 soluble compounds that create an osmotic pressure gradient, relative to the external fluid, on the semi-permeable wall. Agents and compounds with osmotic activity include, in particular, magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, 20 potassium sulfate, potassium hydrogen phosphate, urea, and sucrose.

Other agents with osmotic activity are described in US patents 3,854,770, 4,077,407 and 4,235,236.

Examples of semi-permeable materials known as 25 polymers for osmosis and reverse osmosis include cellulose acylate, cellulose diacetate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, β-glucan acetate, acetaldehyde dimethylacetal, 30 cellulose acetate ethylcarbamate, polyamide, polyurethane, sulfonated polystyrene, cellulose acetate phthalate, cellulose acetate methylcarbamate, cellulose acetate succinate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, 35 cellulose acetate chloroacetate, cellulose dipalmitate, cellulose dioctanoate, and dicaprylate.

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cellulose, cellulose dipentanoate, cellulose acetate valerate, cellulose acetate p-toluene sulfonate, cellulose acetate butyrate, ethyl cellulose, selectively permeable polymers formed by the common precipitation of a polycation and a polyanion, such as those indicated in US patents 3,173,876, 3,276,586, 3,541,005, 3,541,006 and 3,546,142.

Such wraps in semi-permeable membranes can also be made according to DE A 3 310 081 and DE A 3 310 096.

The proportion of the osmotic substance can range, for 1 part by weight of azelastine, from 100 to 800 parts by weight, preferably from 20 to 600 and more, particularly from 50 to 400 parts by weight. The coating materials are applied in such a quantity that the semipermeable membrane has a thickness of 50 to 500 µm, preferably from 100 to 300 µm.

The active substance and substances with osmotic activity can be used at temperatures ranging from ambient to 80°C. To regulate the release rate, a hole is drilled in the membrane wall, for example, using a laser beam, so that after the 25 tablets thus manufactured are introduced into an aqueous liquid, the active substance is either dissolved or suspended by the liquid entering the hole and expelled. The semi-permeable layer is applied, for example, at an intake air temperature of 70 to 900°C.

30 The semi-permeable membrane may also contain a micro-porous layer, or micro-porous substances may be incorporated into it (for this see DE A 3 310 081, for example pages 7 to 17).

Suitable materials for creating the 3.5 microporous layer include polycarbonates.

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consisting of linear carbonic acid polyesters in which carbonate radicals are repeated in the main chain, microporous materials that have been prepared by phosgenation of a dihydro-5 xylated aromatic compound such as bis-phenol, a poly-(vinyl chloride)

microporous, microporous polyamides, such as poly-(hexamethylene-adipamide), microporous modacrylic polymers, including those formed from poly-(vinyl chloride) and acrylonitrile, styrene-acrylic monomers and their microporous copolymers, porous polysulfones characterized by the presence of diphenylene-sulfone motifs in a linear chain, poly-(vinylidene halides), polychloro-ethers, acetal polymers, polyesters prepared by esterification of a dicarboxylic acid or anhydride with an alkylene-polyol, poly-(thio-alkylenes), phenolic polymers, polyesters, microporous polysaccharides with substituted anhydroglucose motifs that have decreasing permeability to water and biological fluids

20 gics, asymmetric porous polymers, crosslinked olefin polymers, hydrophobic or hydrophilic microporous homopolymers, copolymers or interpolymers of reduced density, as well as materials taken from those described in US 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 patent GB 1 126 849 and in Chemical Abstracts, Volume 71, 427F, 22573F, 1969.

Other microporous materials that can be used to create the microporous layer include

30 polyurethanes, cross-linked polyurethanes with elongated chains, polyimides, polybenzimidazoles, collodion, regenerated porteins, semi-solid cross-linked poly(vinylpyrrolidone), microporous materials prepared by diffusion of multivalent cations in poly-electrolyte sols, microporous derivatives of polystyrene, such

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that poly-(sodium styrene sulfonate), polyvinylbenzyltrimethylammonium chloride, microporous cellulose acylates and similar microporous polymers/ such as are described for example in US patents 3,524,753, 3,565,259, 3,276,589, 3,541,055, 3,541,006, 3,546,142, 3,615,024, 3,646,178 and 3,852,224.

Suitable pore generators for forming the microporous layer include solid and liquid materials capable of generating pores. In this document, "pore generators" also refers to substances that form micro-transmissions; the removal of pore generators can be of both types. The term "pore-generating liquids" includes, for the purposes of this description, viscous and semi-solid liquids. Pore generators can be mineral or organic, and the polymer forming the layer typically contains 5 to 70% by weight of pore generators, more specifically 20 to 50% by weight. The term "pore generators," whether solid or liquid, covers substances that can be removed, by dissolution, extraction, or washing, from the microporous membrane precursor by the liquid present in the application area, thereby forming an effective open-cell microporous layer. The solid pore-forming materials have a particle size of approximately 0.1 to 200 µm and include alkali metal salts, such as lithium carbonate, sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, potassium acetate, sodium citrate, etc., and organic compounds, such as saccharides, including sucrose, glucose, fructose, mannitol, mannose, galactose, sorbitol, etc. Soluble polymers, such as Carbouwax, Carbopol, etc., can also be used. Pore-forming materials can also be n

diols, polyols, polyalcohols, polyalkylene glycols, polyglycols, poly-(4,U/-alkylene diols) etc.

4. By incorporating azelastine, which is the active substance, or by binding it to substances taken from the following, or to mixtures of these substances:

- Digestible fats, for example:

triglycerides of saturated fatty acids ranging from CgH16O2 to C18H36O2 and their mixtures, peanut oil and oil

10 of hydrogenated peanut, castor oil and hydrogenated castor oil, olive oil, sesame oil, cottonseed oil and hydrogenated cottonseed oil, corn oil, wheat germ oil, sunflower oil, cod liver oil, mixtures of monoesters, diesters and triesters 15 of palmitic acid and stearic acid - formed with glycerol, glycerol trioleate, diglycol stearate, stearic acid.

- Fats and fat-like substances that are indigestible, for example:

20 esters derived from saturated or unsaturated aliphatic fatty acids (containing from 2 to 22 carbon atoms, more especially from 10 to 18) and aliphatic mono-alcohols (containing from 1 to 20 carbon atoms), camauba wax, beeswax, fatty alcohols (linear or branched) ranging from 25 CgH^yOH to C3qH610H, more particularly from Ci2h25oh to C24H49oh.

- Polymers, for example:

poly-(vinyl alcohol), poly-(vinyl chloride), poly-(acrylic acid) (Carbopol); anionic polymers derived from methacrylic acid and methacrylic acid esters (Eudragil® L, Eudragil® S), copolymers of an acrylic or methacrylic ester with trimethylammonium methacrylate (Eudragil® RL, Eudragil® RS), copolymers of

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Ethyl acrylate and methyl methacrylate (Eudragit^ 35 NE 30D), copolymers of acrylic acid, methacrylic acid and their esters (ratio of radicals

carboxy-free to ester radicals 1:1) (Eudragit® L 30D), polyethylene, poly-(glycolic acid), poly-(hydroxybutyric acid), poly-(lactic acid), copolymers of lactic acid and glycolic acid (manufacturer: Boehringer 5 Ingelheim), copolymers of lactic acid and ethylene oxide, copolymers of glycolic acid and ethylene oxide, copolymers of lactic acid and hydroxybutyric acid, phthalate or acetate succinate of hydroxypropyl methylcellulose; acetate phthalate of cellulose, acetate phthalate of starch, and polyacetate-

vinyl phthalate) .. . ; carboxymethyl cellulose; methyl cellulose phthalate, succinate and phthalate succinate, methyl cellulose phthalic hemi-ester; zein; ethyl cellulose; shellac, gluten; ethyl carboxyethyl 15 cellulose; ethyl acrylate/maleic anhydride copolymer; maleic anhydride/vinyl methyl oxide copolymer; styrene/maleic acid copolymers; ethyl-2-hexyl acrylate/maleic anhydride copolymer; crotonic acid/vinyl acetate copolymer; glu-20 tamic acid/glutamic acid ester copolymer; carboxymethyl cellulose glycerol monooctanoate; cellulose acetate succinate; polyarginine; cross-linked alginate; cross-linked gelatin.

- Thickeners ("blowing agents"), for example: 25 methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (Pharmacoat, Methocel E = ether formed by propylene glycol and methyl cellulose), alginic acid and its salts (salt of Na, salt of Ca, also mixtures of sodium alginate and calcium salts, such as CaHP04), 3 0 starch, carboxymethyl starch, carboxymethyl cellulose and their salts (for example salts of Na), galactomannan, acacia gum, karaya gum, ghatti gum, agar, carrageenan, xanthan gum, guar gum and its derivatives, locust bean gum, propylene glycol alginate, pectins, tragacanth.

35

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For 1 part by weight of azelastine, 1 to 800 parts by weight of one of these retarding components are used, preferably 1.5 to 600 parts by weight or, even better, 2.0 to 400 parts by weight. These compositions are prepared at temperatures between 18 and 80°C.

To create these forms of administration, one can proceed in the following way:

a) Azelastine or one of its salts is dissolved or dispersed in the aforementioned fats or fat-like substances, or in mixtures thereof, by melting the aforementioned substances, then cooling them again, grinding them, possibly adding other substances, for example, the water-soluble or swellable substances mentioned above, and then compressing them into tablets. The cooling and grinding of the molten mass can also be carried out in a single step. The molten mass is then dispersed in cold water or subjected to solidification by spraying.

When using the oils mentioned above as retarding agents, azelastine or its salt is dissolved or suspended in the oil and, possibly after adding a proportion of aluminium monostearate of up to 2%, it is put into ampoules and then sterilized, or, possibly after adding flavourings and/or sedimentation retardants such as highly dispersed silica (for example Aerosil), it is homogenised and put into bottles.

b) Azelastine is mixed with the aforementioned fats, polymers, or thickeners, or with mixtures of these substances, also by applying heat, and the mixtures are molded, possibly after adding

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additional additives are used to make tablets, or they are molded to make pills.

(c) Azelastine is mixed with solutions of the fats 5 or polymers mentioned, in water or in organic solvents, such as ethanol, ethyl acetate, acetone or isopropanol, possibly mixed with carriers, such as celluloses, then the solvents are driven off by evaporation, the coated product containing the active substance obtained is mixed with other 10 adjuvants and, with the mixture, molded articles are made, for example tablets or pills.

A mixture consisting of azelastine and the aforementioned thickeners is moistened with organic solvents, such as ethanol, ethyl acetate, acetone or isopropanol, possibly with the addition of binders, such as poly-(vinylpyrrolidone) or copolymers of poly-(vinylpyrrolidone) and poly-(vinyl acetate), the resulting mixture is granulated, then dried, additional adjuvants are possibly added and the mixture is molded to make tablets.

Azelastine is mixed with a solution of natural or synthetic resins, such as shellac or poly(vinyl acetate), in a polyethylene glycol of molecular weight between 200 and 1500, possibly with the addition of further adjuvants, such as stearates or thickeners, and the resulting mixture is encapsulated in soft or hard gelatin capsules.

In a completely general way, the manufacture of medicines can be carried out in a known manner: 35 can then be used, in addition to the delayed components, the d)

15

20

e)

25

30

known and common pharmaceutical adjuvants as well as other common excipients and diluents, the adjuvants mentioned as retarder components may also perform other functions, for example act as release agents or as disintegrating agents.

Examples of such excipients and adjuvants include substances recommended or indicated as adjuvants for pharmaceuticals, cosmetics, and related fields in the following literature: Ullmanns Encyklopädie der technischen Chemie, vol. 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, vol. 52 (1963), pages 918 sqq.; H.v.Czetsch-Lindenwald, Hilfsstoffe für Pharmazie und angrenzende Gebiete; Pharm. Ind., fascicle 2, 1961, pages 72 sqq.; 15 Dr. H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, 2nd ed., Editio Cantor, Aulendorf in Württemberg 1981.

Common adjuvants, excipients and diluents include, for example, gelatin, natural sugars such as sucrose or lactose, lecithin, pectins, starch (e.g., corn starch), and starch derivatives, cyclodextrins or cyclodextrin derivatives, poly-(vinylpyrrolidone), gelatin, gum arabic, alginic acid, tylose, talc, lycopo-25 de- powder, . silica (e.g. colloidal silica), levulose, tragacanth, sodium chloride, stearates, magnesium and calcium salts derived from fatty acids containing 12 to 22 carbon atoms, more particularly saturated fatty acids (such as stearates), poly-30 (ethylene glycols) with an average molecular weight between 200 and 20,000, preferably between 200 and 5,000, more especially between 200 and 1,000, or mixtures thereof, and/or vinyl-pyrrolidone polymers and/or vinyl-pyrrolidone-vinyl acetate copolymers, es-35 ters derived from saturated or unsaturated aliphatic fatty acids

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turates (containing from 2 to 22 carbon atoms, more specifically from 10 to 18) and aliphatic mono-alcohols (containing from 1 to 20 carbon atoms) or polyols, such as glycols, glycerol, diethylene glycol, penta-5-erythritol, sorbitol, or mannitol, which may also be etherified, benzyl benzoate, dioxolans, forms of glycerol, tetrahydrofurfuryl alcohol, polyglycol ethers containing from 1 to 12 carbon atoms, dimethylacetamide, lactamides, 10 lactates, ethyl carbonates, silicones (more specifically medium-viscosity poly-(dimethylsiloxanes)), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, carbonate of magnesium, gum arabic, alginic acid, 15 stearates, fats and similarly acting substances.

The forms of administration may also contain surfactants. Examples include alkali metal soaps, such as alkali metal salts of higher fatty acids (e.g., sodium palmitate or sodium stearate) or their derivatives (e.g., sodium ricinoleate sulfuric acid); sulfur compounds or sulfonated compounds formed by the reaction of higher fatty alcohols with sulfuric acid or chlorosulfonic acid and used, for example, in the form of their sodium salts (e.g., sodium lauryl sulfate, sodium cetyl sulfate, sodium stearyl sulfate,

sodium cetylsulfonate); bile acid salts; saponins; quaternary ammonium compounds; partial fatty acid esters of sorbitan; partial fatty acid esters and fatty acid esters of poly-(oxyethylene)sorbitans; polyethoxylation products of sorbitol; fatty acid esters of polyethylene glycols; fatty alcohol ethers of

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polyethylene glycols; fatty acid esters of sucrose; fatty acid esters of polyglycerols; proteins; lecithins.

The dosage forms may also contain cellulose, especially when preparing tablets. Examples of suitable cellulose include purified cellulose (for example, in the form of the commercial product known as Elcema®).

or microcrystalline cellulose, such as that which

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10 is found commercially under the name Avicel^. However, other fillers acting as binders can be used, such as calcium hydrogen phosphate, lactose, starches (for example potato starch, corn starch, modified starches, among others 15 Starch ST 1500/Colorcon), glucose, mannitol or sucrose.

The forms of administration may also contain sedimentation retardants, for example highly dispersed silicas which have a surface area (determined by the BET method) of 50 to 500 m²/g, more specifically of 100

2

at 400 m/g." eR- can be found commercially, for example under

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the name Aerosil.

It may also be recommended to use release agents in the form of administration. Examples of such agents include talc, silicone talc, calcium stearate, magnesium stearate, stearic acid, paraffins, hydrogenated fats and oils, and silicone oil emulsion.

Other adjuvants can also be considered 30 substances that cause disintegration (disintegrating agents or "delitescence" agents), such as cross-linked poly-(vinylpyrrolidone), sodium derivative of carboxymethyl starch, sodium derivative of carboxymethyl cellulose, formaldehyde gelatin, formaldehyde-35 casein, poly-(acrylic acid) and ultra-aminopectins.

To prepare solutions or suspensions, one can use, for example, water or physiologically acceptable organic solvents, such as ethanol, 1,2-propylene glycol, polyglycols and their derivatives. For injectable solutions or suspensions, one can use, for example, non-toxic diluents or solvents that are acceptable for parenteral administration, such as water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer's solution 10, or an isotonic sodium chloride solution.

It is also possible to add stabilizers, colorants, antioxidants and complexing agents (such as ethylenediaminetetraacetic acid) etc., as well as acids, such as citric acid, 15-tartaric acid, maleic acid or fumaric acid.

Examples of antioxidants include sodium metabisulfite, cysteine, ascorbic acid and its esters (e.g., palmitate), flavonoids, gallic acid, alkyl gallates, butyl-hydroxy-20 anisole, nor-dihydro-guajaretic acid, tocopherols, and tocopherols with added synergistic agents (substances that bind heavy metals by forming complexes, such as lecithin, ascorbic acid, citric acid, or phosphoric acid).

25 As preservatives, one could consider, for example, sorbic acid, p-hydroxybenzoic acid esters (among others, lower alkyl esters), benzoic acid, sodium benzoate, trichloroisobutyl alcohol, phenol, cresols, benzethonium chloride 3O and formaldehyde derivatives.

As plasticizers for the materials constituting the envelope, one can consider esters of citric acid or tartaric acid (triethyl or tributyl acetyl citrate, tributyl citrate, triethyl citrate); i.e., 35% glycerol and esters of glycerol (diacetate and triacetate of

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glycerol, acetylated monoglycerides, castor oil); esters of phthalic acid [dibutyl, dipentyl, diethyl, dimethyl, dipropyl or bis-(2-methoxy- or 2-ethoxy-ethyl), ethyl-phthalyl or butyl-phthalyl-glycolates of ethyl and butyl]; alcohols (propylene glycol,

polyethylene glycols of different chain lengths), adipates (diethyl adipate, bis-(2-methoxy-2-ethoxyethyl) adipate); benzophenone; diethyl and dibutyl sebacate, succinate and tartrate; diethylene glycol dipro-10 pionate; ethylene glycol diacetate, dibutyrate and dipropionate; tributyl phosphate; tributyrin; mono-oleate of a polyethoxylation product of sorbitan; sorbitan mono-oleate.

15 To apply the retarder components or the wrapping materials, solvents from the group of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic, aromatic 20 or heterocyclic solvents and their mixtures may be used. Typical solvents include, among others, acetone, diacetone alcohol, methanol, ethanol, isopropanol, butanol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl ether acetate, dichloromethane, ethylene dichloride, propylene dichloride, tetrachloromethane, nitroethane, nitropropane, tetra-3-chloroethane, diethyl oxide, diisopropyl oxide, cyclohexane, cyclooctane, benzene, toluene, naphtha, dioxane-1,4, tetrahydrofuran, diethylene glycol dimethyl ether, water and mixtures thereof, for example mixtures of acetone and water, acetone and methanol, acetone and ethanol, methylene dichloride and methanol, and ethylene dichloride and

H-

methanol, as well as mixtures thereof. During the wrapping process, these solvents are again removed.

Regardless of their method of manufacture, the administration forms according to the invention are characterized in that they release into body fluids or cause to penetrate into these fluids the active substance, i.e. azelastine or one of its physiologically acceptable salts, at a release rate of between 0.05 and 5 mg per hour.

10 The dosage indications always refer to azelastine in its basic form; when using azelastine salts, a correction must be made taking into account the molecular mass.

The contents of the active substance, i.e., 15-azelastine, in the compositions according to the invention are:

a) in the case of forms of administration to be applied orally:

from 0.1 to 50 mg, preferably from 0.2 to 30 mg or, more specifically,

20 of 0.5 to 20 mg of azelastine (active substance).

The indicated unit doses can be administered 1 to 5 times a day, preferably 1 to 3 times or, even better, 1 or 2 times.

b) in the case of forms of administration to be applied by 25 the parenteral route (intravenous, intramuscular,

subcutaneous, intraperitoneal):

from 0.1 to 500 mg, preferably from 0.2 to 400 mg or, more specifically,

from 0.5 to 250 mg of azelastine (active substance). 30 The indicated unit doses may be administered from once a month (for example, in the case of implants to be applied subcutaneously) to 3 times a day, preferably from once a month to twice a day, more particularly from once a month to once a day, 35 c) in the case of forms of administration to be applied by

-Hf.-

the dermal route (for example, plasters):

from 5 to 5000 mg, preferably from 10 to 3000 mg or, more specifically,

from 30 to 2000 mg of azelastine (active substance).

The indicated unit doses can be administered from once a day to once a month, preferably from once every 3 days to once every 3 weeks, more particularly from once a week to every two weeks.

The following retarding components are particularly valued:

a) Cation exchangers:

Sodium salt of a poly-(styrene- or divinylbenzene-sulfonic acid) (for example Amberlite® IRP 69). For 1 part of azelastine (base), for example, 3 to 10 parts of Amberlite® 69 are used.

b) Wrapping materials:

Hydroxypropyl methylcellulose phthalate:

for 1 part azelastine, 1.5 to 3 parts phthala-hydroxypropyl-methyl-cellulose 55.

Ethylcellulose:

for 1 part of azelastine, from 0.1 to 1 part of ethylcellulose.

(R)

Eugragit resins such as EudragitwRS:

.for the part of azelastine, from 0.01 to 0.1 part of Eudra-

git® RS.

c) Semi-permeable layers equipped with a core containing a substance with osmotic activity and an outlet opening:

Envelope made of a layer 100 to 300 µm thick which is made up of 82% cellulose acetate and 18% hydroxypropyl-Hydroxy-1-cellulose.

d) Coating substances:

Hydrocolloids, for example hydroxypropyl-methyl-cellulose:

for 1 part azelastine, 2 to 10 parts hydro-

colloid.

Eudragit ®RS:

for 1 part of azelastine, 10 to 15 parts of Eudragit^ 5 RS.

Glycerol ditripalmitostearate (e.g., Precirol Ato 5):

for 1 part of azelastine, from 1 to 10 parts of Precirol Ato 5'.

10 The rate of release of the active substance which it is necessary to achieve, i.e. a rate between 0.05 and 5 mg per hour, is regulated within the required range by the measures described in the process claims, considered in association with the corresponding indications given in the description.

When we want to obtain a specific release velocity located within this interval, we can operate, for example, in the following way:

1. The active substance of the ma-

20 last described.

2. The release rate of the active substance from the administration form is determined using, as the release medium, 0.1N hydrochloric acid (2 hours) and a phosphate buffer at pH 6.8 (by the

25 continued).

3. a) If the release velocity is too high:

The proportion of the retardant component is increased and/or the proportion of water-soluble adjuvants is decreased. The proportion of the substance to be ac-

3.0 osmotic activity.

b) If the release velocity is too low:

The proportion of the retarding component is reduced and/or the proportion of water-soluble adjuvants is increased. The proportion of the substance with osmotic activity is increased.

- «< -

Generally, the aim is to achieve a release rate of 1 mg of azelastine per hour.

Example 1

5 100 mg of azelastine hydrochloride is mixed with 960 mg of hydroxypropyl-methyl-cellulose (viscosity of a 2% aqueous solution: 4000 mPa.s (commercial product: for example Methocel K4M Premium)), 1320 g of spray-dried lactose and 20 mg of magnesium stearate, 10 and the mixture is molded by compression to make tablets each weighing 120 mg, having a diameter of 6 mm and a radius of curvature of 6 mm.

A film soluble in gastric juice 15, permeable to gastric juice, or resistant to gastric juice can then be applied to the tablets using the usual methods.

To create a coating resistant to gastric juices, approximately 1000 g of the following suspension is sprayed onto 1000 g of tablets, for example, in a coated container: 20. 63 g of cellulose acetate phthalate is dissolved in 480 g of acetone. 21 g of diethyl phthalate, 30 g of dichloromethane, and 131 g of methanol are added to this solution. 4.4 g of titanium dioxide is then homogeneously suspended in the resulting solution. 25. The spraying is carried out intermittently:

between spraying phases heated drying air is blown in.

The delayed-release tablet contains 5 mg of azelastine hydrochloride.

30 Example 2

Mix 12 g of azelastine hydrochloride, 20 g of Eudragit®RS PM, 250 g of talc, and 200 g of lactose, and moisten the mixture with approximately 140 g of a mixture of 12.7 g of glycerol triacetate (trade name: e.g., triacetin) and 127.3 g of Eudragi®RS 12.5. Granulate

The moist mixture is passed through a 1 mm mesh sieve, and, after drying at room temperature in a coating machine, a mixture of 909 g of Eudragit® RS 12.5 and 91 g of triacetin is sprayed using a spray gun. Without the addition of any further additives, the resulting dried granulated product is molded into biconvex tablets, each weighing 300 mg and having a diameter of 10 mm.

One tablet contains 5 mg of aze-10 lastin hydrochloride in a delayed composition.

Example 3

50 g of azelastine hydrochloride is mixed with 100 g of tartaric acid, 250 g of lactose, 10 g of microcrystalline cellulose (Avicel PH 101), and 7 g of hydroxypropyl-15 cellulose (viscosity of the 5% solution: 75 to 150 mPa·s (e.g., the product with the trade name: Klucel LF)). The mixture is then coated with 60 g of a 6.25% aqueous solution of hydroxypropyl cellulose (viscosity of the 5% aqueous solution: 75 to 150 mPa·s (e.g., the product with the trade name: Klucel LF)). The wet mixture is forced through a perforated plate with 1 mm diameter holes, and the resulting strands are cut and rounded in the usual way by processing on a Sphero-nizer plate. The resulting pills are dried and sieved. 300 g of pills from the sieving fraction ranging from 800 to 1200 pu are coated, in the usual way, by spraying in a vortex layer apparatus, with a solution of 42.5 g of ethylcellulose (trade name: Ethocel Type N22) and 37.5 g of polyethylene-30 glycol 1500 (trade name: for example Carbowax 1540).

in 720 g of chloroform.

50 mg of the coated pills obtained as described above are introduced into hard gelatin capsules of size 3.

35 One hard gelatin capsule contains 4.4 mg of

1

2

3

50

50

50

480

192

96

660

948

1044

10

10

10

n azelastine hydrochloride in a retardant composition. Example 4

Forms of administration conforming to the invention are manufactured by coating in swelling substances (thickeners).

The following substances are mixed together (quantities expressed in grams):

Composition No.

10 Azelastine hydrochloride

Hydroxypropyl-methyl-cellulose (= Methocel K 4 M)

Lactose

Magnesium stearate 15. With the mixture, we manufacture, on a special press

ciale, flat-faced tablets weighing 120 mg each and having a diameter of 6 mm.

These tablets have the following characteristics: Thickness (in mm) 3.25 3.15 3.05

20 Tensile strength (in N) 47 48 50

(Heberlein's test apparatus for measuring tensile strength)

One tablet contains 5 mg of azelastine hydrochloride. The release of the active substance, in the USP XXI apparatus (dissolution test apparatus No. 2, solvent medium: 500 ml of 0.1 N hydrochloric acid, rotation speed: 120 revolutions per minute), occurs as follows (the release of the active substance is given as a percentage):

30 K' of the composition

35

1

2

3

AT

end of

5

minutes

4

31

50

At the end of

60

minutes

20

76

100

At the end of

120

minutes

36

96

At the end of

180

minutes

55

After 240 minutes 74

After 300 minutes, 86

After 3, 60 minutes, 93

Example 5

5. Mix 100 g of azelastine hydrochloride,

200 g of tartaric acid, 500 g of lactose, and 700 g of microcrystalline cellulose are mixed with approximately 700 g of purified water. The moist mixture is forced through a perforated plate with holes 10 1 mm in diameter, and the resulting strands are fragmented and rounded in the usual manner by processing on a Spheronizer plate. The resulting pills are then dried and sieved.

On 1000 g of the pills corresponding to the sieving fraction ranging from 800 to 1250 pm, a suspension-15 sion which has been prepared in the following way is sprayed:

0.6 g of Polysorbate 80 is dissolved in 190 g of purified water and emulsified in a 40 g solution of triethyl citrate. 800 g of a 30% aqueous dispersion of an es- copolymer is added to the resulting emulsion.

2 0 ters of acrylic acid and methacrylic acid containing a small amount of (chloro-trimethylammonio)-ethyl acrylate (= Eudragit® RS 30D), and shake for about 10 minutes.

In 860 g of purified water, 25,109.2 g of talc and 0.2 g of an antifoaming silicone oil (Simethicone) are suspended. This suspension is then introduced, while stirring, into the dispersion obtained above.

The resulting varnish suspension is applied to the pills in the usual way, for example-

3.0 pie using a rotating layer spray granulator

The pills are dried under the same conditions: the intake air temperature is 40 to 50°C and the exhaust air temperature is no more than 40°C.

The varnish suspension mentioned above is sprayed in such a quantity that the total weight of

)»

dried pills weighing 1042 g.

The glazed pills are introduced, in a quantity of 78.1 mg, into size 3 hard gelatin capsules. One hard gelatin capsule contains 5 mg of azelastine hydrochloride in a delayed-release formulation. The release of the active substance from the capsule, in the USP XXI apparatus (dissolution test apparatus No. 2, dissolution medium: 500 mL of 0.1 N hydrochloric acid, rotation speed: 120 rpm), is carried out as follows:

after one hour 3.0 mg, or 60%

after 2 hours 4.5 mg, or 90%.

The rate of release of the active substance is therefore 3 mg per hour.

15 Example 6

The procedure is carried out as described in example 5, with the difference that a quantity of the varnish suspensions mentioned in example 5 is sprayed onto the pills such that the total weight of the dried pills is 1127 g.

2.0 The varnished pills are then introduced in a quantity of

84.5 mg, in size 3 hard gelatin capsules. One hard gelatin capsule contains 5 mg of azelastine hydrochloride in a delayed-release formulation. The release of the active substance from one capsule, in the USP XXI apparatus (the conditions applied during the test are the same as in Example 5), occurs as follows:

after one hour 0.25 mg, or 5%

after 2 hours 0.50 mg, or 10%.

3 0 The rate of release of the active substance is therefore 0.25 mg per hour.

Example 7:

We proceed as described in example 6.

16.9 mg of the pills obtained according to example 6 are introduced into hard gelatin capsules of the dimension

Si sion 3. Thus, a hard gelatin capsule contains 1 mg of azelastine hydrochloride in a delayed-release formulation. The release of the active substance from one capsule,

in the USP XXI apparatus (same conditions as in the test of example 5), is done as follows: after one hour 0.05 mg, or 5%

after 2 hours 0.10 mg, or 10%.

The release rate of active substance 10 is therefore 0.05 mg per hour.

Example 8:

6 mg azelastine capsules, or 6 mg azelastine suspension in 5 ml, each time bound to a highly acidic cation exchanger.

15. 8.48 g of azelastine hydrochloride is dissolved in 4 liters of purified water. 71.5 g of a styrene-sulfonic acid-divinylbenzene copolymer (degree of crosslinking: 8%) (commercial product: e.g., Amberlite® IR 120) is suspended in the resulting solution, and the suspension is stirred for 3 hours. Afterward, the suspension is filtered through a glass filter, the resulting filter cake is washed twice, each time with 300 ml of purified water, and the wash water is carefully removed by squeezing.

25. 5 g of gelatin is dissolved (isoelectric point:

6-7.6; molecular mass of 25,000 to 35,000) (commercial product

(5)

cial: Gelita"^ Collagel, Deutsche Gelatinefabriken, Eberbach/ Neckar) in a solution, contained in a beaker, of 5 g of hydrochloric acid IN in 800 g of purified water. The filter cake obtained above is suspended in the solution, and the suspension is stirred for one hour. The suspension is then filtered through a glass filter, the resulting filter cake is washed twice, each time with 200 ml of purified water, and the wash water is removed by squeezing.

"J

The filtration cake is dried at 60°C. The dried product is placed in size 4 hard gelatin capsules, at a rate of 62 mg of the product per capsule.

A hard gelatin capsule contains 6 mg of aze-5-lastine, bound to a highly acidic cation exchanger.

A liquid containing 6 mg of azelastine, bound to an ion exchanger, is prepared in 5 ml, by proceeding as follows:

10. 7.4 kg of purified water is heated to 90-95°C and 0.002 kg of propyl 4-hydroxybenzoate and 0.013 kg of methyl 4-hydroxybenzoate are dissolved in it. In the solution, cooled to 70°C, 0.02 kg of hydroxyethylcellulose (average degree of polymerization: 250) and 3.0 kg of sucrose are dissolved. 15. After cooling to 25°C, 3 g of raspberry flavoring and 0.2 kg of modified starch (Starch 1500/Colorcon) are dissolved or suspended while stirring. 124 g of dried, azelastine-loaded ion exchanger are then added to the suspension while stirring. The suspension is then extended to 11.0 kg (i.e., 10 litres) with purified water.

The release of the active substance from a capsule or 5 ml of the suspension, in the USP XXI apparatus (dissolution test apparatus 2, medium 25, dissolution: 500 ml of a 0.9% sodium chloride solution, rotation speed: 100 revolutions per minute), is carried out as follows:

At the end of

1 hour

25%

At the end of

2 hours

40%

At the end of

3 hours

50%

At the end of

4 hours

58%

At the end of

5 hours

65%

At the end of

6 hours

69%

At the end of

7 hours

72%

At the end of

8 hours

75%

ii-

The dissolution medium is then renewed every hour. Each time, the values obtained for the release are summed.

5

*

Claims (6)

DEMANDS 1. A medicinal product containing azelastine and capable of releasing the active substance at a controlled rate thanks to a delayed-release component; a medicinal product in which it 5 y a, for 1 part by weight of azelastine (relative to the base), of 0.001 to 800 parts of the retard component, and azelastine may also be found in the form of one of its physiologically acceptable salts, and the azelastine release rate of which is between 0.05 and 5 mg per hour, the release rate being determined in an aqueous test solution of pH equal to 1.0 and/or 6.8. 2. Medicinal product according to claim 1 characterized in that the active substance, i.e. azelastine or 15 one of its physiologically acceptable salts, possibly supplemented with other usual adjuvants and additives; a) is wrapped with line or multiple delay components, or 20 b) is bound to a cation exchanger, or c) is supplemented with one or more substances with osmotic activity and is enveloped in a semi-permeable membrane, in which a hole is drilled, or d) is coated in or bound to one or more substances taken from 25 the whole consisting of digestible fats, indigestible fats, indigestible fat-like substances, polymers and blowing agents (thickeners), in such a way that the release is controlled. 30 3. Medicinal product according to claim 1 characterized in that the forms of administration contain from 0.1 to 50 mg of the active substance (azelastine) when intended for oral administration, from 0.1 to 500 mg when intended for parenteral administration, and from 5 to 5000 mg when intended for dermal administration. 4. A process for manufacturing a controlled-release medicinal product containing azelastine as the active substance, characterized in that 1 part by weight of azelastine (relatively 5 at the base), this can also be in the form of one of its physiologically acceptable salts, with 0.001 to 800 parts by weight of a retarder component and, possibly, other usual pharmaceutical adjuvants and additives, and the release rate is set to a value between 0.05 and 5 mg of azelastine per hour. 5. A method for manufacturing "a medicinal product according to claim 4, characterized in that the active substance, i.e. azelastine or one of its physiologically acceptable salts: 15 a) is wrapped with one or more retarding components, or b) is linked to a cation exchanger, or c) is enriched with one or more substances with osmotic activity and is wrapped with a semi-permeable membrane 2. Permeable, in which a hole is drilled, or (d) is coated in one or more substances taken from the whole consisting of digestible fats, indigestible fats, indigestible fat-like substances, polymers and blowing agents 25 (thickeners), or is related to these substances, Furthermore, in the operating procedures indicated above, other common adjuvants and additives can also be used. 6. Method for manufacturing a medicinal product according to the 3.0 claim 4 and/or claim 5, method characterized The form of administration contains from 0.1 to 50 mg of the active substance (azelastine) when intended for oral administration, from 0.1 to 500 mg when intended for parenteral administration, and from 5 to 5000 mg 35 when intended for dermal administration. -36 - A drug containing azelastine and capable of releasing it in a 'controlled' manner. ABRIDGED DESCRIPTION Drugs that contain azelastine and release the active substance in a controlled manner, using a delayed-release component. These medications contain, for every part by weight of azelastine (relative to the base), from 0.001 to 800 parts of the sustained-release component, and azelastine may also be present in the form of one of its physiologically acceptable salts. The release rate of azelastine is between 0.05 and 5 mg per hour. No drawing. ^ .}< »?r\ tu*;\ •> ~r;~ ——* in I Industrial 27, Boulevard des Moulins MO - 98000 MONTE CAULO (