RU2214245C2 - Chemically stable and thermostable ready forms of norastemizol - Google Patents

Abstract

FIELD: medicine, pharmacy. SUBSTANCE: invention describes chemically stable and thermostable pharmaceutical compositions of strong anti-histaminic agent norastemizol. Compositions have no lactose, they are non-hygroscopic or anhydrous or comprise large particles of norastemizol or norastemizol covered by an inert coating, or its pharmaceutically acceptable salt. Compositions are stable and can be prepared easily. EFFECT: valuable pharmaceutical properties of compositions. 25 cl, 1 dwg, 7 tbl, 6 ex _

Description

Link to related applications
This application is a partial continuation of application 08/851786, filed May 6, 1997, which is simultaneously under consideration by the US Patent Office, and which, in turn, is a partial continuation of application 08/824477, filed March 26, 1997, with herewith, both applications are expressly incorporated by reference in their entirety into this description.

Field of Invention
The present invention relates to chemically and thermostable pharmaceutical compositions containing norastemizole.

BACKGROUND OF THE INVENTION
The stability of a pharmaceutical product is influenced by many factors, which include the stability of the ingredient (s) of the drug, the possible interaction between the active (s) ingredient (s) and inactive (s) ingredient (s) of the drug, the method of production of such a drug, packaging, conditions environment during the transportation of the drug, its storage and use, the length of time between the production of the drug and its use and the type of dosage form. In addition to physical stability, the chemical stability of the pharmaceutical product should also be taken into account. Knowing the physical and chemical stability of a drug is very important for at least three main reasons.

 First, the pharmaceutical product must be fresh, have an attractive appearance and have the appropriate therapeutic effect. Any physical changes in appearance and color, including fading, discoloration, the appearance of turbidity, etc., can undermine the patient's confidence in the pharmaceutical product. Secondly, since some products are distributed in packages of medicines for repeated use, a standard dosage of the drug (s) should be provided during its shelf life. For example, a cloudy solution, a delaminated emulsion, a discolored tablet, a discolored capsule, or similar deficiencies indicate a non-standard dosage of the drug. Thirdly, the ingredients of the drug should be suitable for the patient throughout the shelf life of the dosage form. The destruction of the physical or chemical integrity of the dosage form may lead to loss of bioavailability of the drug substance or may adversely affect the bioavailability of the ingredient (s) of the drug.

 For the successful administration of many marketed drugs, many pharmaceutical dosage forms are suitable. Conventional pharmaceutical dosage forms listed in the United States Pharmacopeia / National Pharmacological Guide (FSA / NSF, USP / NF) include, but are not limited to, aerosols, capsules, cachets, eye lotions, creams, emulsions, extracts, liquid extracts, gels, dosage forms for inhalation, injection solutions, lotions, mash, suspensions (emulsions), ointments, pastes, granules or implants, powders, solutions, ophthalmic solutions, solutions for oral administration, ear solutions, lozenges, solutions for local use eniya, alcoholic solutions, suppositories, sublingual tablets, syrups, tablets, tinctures, troches, aromatic, aqueous solutions, etc. For oral administration, syrups, solutions, suspensions, lozenges, tablets and capsules are preferred. However, to facilitate the administration of the drug, with a view to its more convenient transportation and for its fullest compliance with the prescribed dosage regimen, lozenges, tablets and hard and soft gelatin capsules are most preferred. In some cases, tablets are preferred over capsules because tablets are sometimes easier to swallow.

 Lozenges, tablets, and capsules typically contain a drug, diluent, and other excipients, for example, lubricants and the like, which are well known to those skilled in the art. Well-known fillers include, for example, coating agents, colorants, desiccants, emulsifiers, solubilizers, flavoring agents, anti-caking agents, plasticizers, suspending agents, viscosity improvers, binders, diluents, wetting agents and the like.

 A commonly used diluent is lactose. A generally accepted form of lactose commonly used as a filler in direct compression is spray dried lactose.

 Since spray dried lactose was obtained, it has been widely used as a filler. The rapid approval of spray-dried lactose is partly due to the ease of incorporation into tablets by direct compression. In this application, spray-dried lactose is contained in a ready-to-use form that does not require additional granulation or the introduction of complex manufacturing operations. Spray dried lactose can also be easily incorporated into a dosage form in the form of lozenges or capsules. Spray dried lactose can be directly added to the drug to obtain the desired ratio. After that, the combination of lactose and the drug can be formulated, when necessary, in the form of lozenges or capsules with other excipients.

 Dried spray or not subjected to such processing, lactose is usually present in the equilibrium state between the alpha and beta forms, in which there is an interaction of these forms. Alpha-lactose is a disaccharide of beta-D-galactose and alpha-D-glucose, beta-lactose is a disaccharide of beta-D-galactose and beta-D-glucose. Beta-lactose is found only in anhydrous form, while alpha-lactose can be obtained either in an anhydrous form or as a monohydrate.

Несовместимость большинства первичных аминов с лактозой является общепризнанной. Смотри Castello et al., J. Pharm. Sci., 51(2):106-108 (Feb. 1962). Смотри также Blaug et al., J. Pharm. Sci, 61(11):1770-1775 (Nov. 1972); Hartauer et al., Drug Dev. And Indust. Pharm., 17(4):617-630 (1991).During the conversion of alpha and beta lactose, an intermediate aldehyde is formed, which is not known to be compatible with most primary amines. Primary amines, when aldehydes (and ketones) are added to carbonyl carbon, form imines

The incompatibility of most primary amines with lactose is widely recognized. See Castello et al., J. Pharm. Sci., 51 (2): 106-108 (Feb. 1962). See also Blaug et al., J. Pharm. Sci 61 (11): 1770-1775 (Nov. 1972); Hartauer et al., Drug Dev. And industries. Pharm., 17 (4): 617-630 (1991).

Castello et al. tested the compatibility of amphetamine sulfate (primary amine salt) with lactose. They found that the mixture of lactose and amphetamine sulfate becomes discolored, especially in the presence of alkaline lubricants, such as magnesium stearate. Blaug et al. tested the compatibility of dextroamphetamine sulfate (primary amine salt) with spray dried lactose. They found that lactose in the presence of dextroamphetamine sulfate forms a Schiff base (i.e., imine). Hartauer et al. checked the compatibility of aminophilin with lactose and found that between aminophilin and lactose there is a certain amount of incompatibility, which is proved by discoloration, especially in the case of applying heat to about 60 ^o C. Aminophilin contains two theophylline molecules (secondary amine) per molecule of ethylenediamine (primary amine) . However, Hartauer et al. tested these components and found that theophylline alone (secondary amine) does not interact with lactose in the presence or absence of heating to 60 ^° C, while ethylenediamine interacts with lactose, especially when heated to 60 ^° C. Thus, the aminophilin is incompatible with lactose is the result of the incompatibility of the component of the primary amine - aminophilin, which is ethylenediamine, with lactose.

The secondary amine astemizole drug is compatible with lactose when it is commercially available in a lactose-containing tablet dosage form in the form of HISMANAL ^® . According to Physician's Desk Reference, 50th Edition Medical Economics Co., Montvale, NJ, p. 1293 (1996), each HISMANAL ^® tablet contains 10 mg of astemizole, lactose, corn starch, microcrystalline cellulose, pregelatinized starch, povidone K90, magnesium stearate, colloidal silicon dioxide and sodium lauryl sulfate.

 Similarly, it is also expected that norastemizole, which is another secondary amine and primary metabolite of astemizole, should be compatible with lactose, especially in the absence of heat. Norastemizole has been reported to be both more potent and less toxic than astemizole. Thus, norastemizole is a worthy alternative to astemizole in the treatment of allergic disorders. It should also be recognized that both astemizole and norastemizole are antihistamines containing secondary amine groups; however, norastemizole has two secondary amine groups, while astemizole has one such group.

SUMMARY OF THE INVENTION
The present invention relates to stable dosage forms of norastemizole in which the incompatibility between norastemizole and lactose is eliminated. In accordance with one aspect, the present invention relates to a lactose-free pharmaceutical composition which comprises norastemizole or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient other than lactose. According to another embodiment, the invention relates to a solid pharmaceutical composition which comprises norastemizole or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient that is not lactose.

 In another preferred embodiment, at least one other than lactose, the pharmaceutically acceptable excipient is a binder, excipient, or a mixture thereof. In another preferred embodiment, the at least one pharmaceutically acceptable excipient is a binder, excipient, or a mixture thereof. In a more preferred embodiment, the above fillers include an additional lubricant, disintegrant, or a mixture thereof. In a more preferred embodiment, the fillers are croscarmellose, microcrystalline cellulose, pregelatinized starch and magnesium stearate. In a preferred embodiment, the disintegrant is a super substance. In another embodiment, the pharmaceutical composition essentially does not contain mono - or disaccharide excipients.

 The invention also relates to thermostable solid pharmaceutical compositions not containing lactose and comprising norastemizole or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In another embodiment, the invention relates to chemically stable solid lactose free pharmaceutical compositions which comprise from about 1 to about 50% by weight of norastemizole or a pharmaceutically acceptable salt thereof and from about 99 to about 50% by weight of at least one pharmaceutically acceptable filler.

 In a second embodiment, the invention includes non-hygroscopic pharmaceutical compositions comprising norastemizole or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The non-hygroscopic pharmaceutical compositions of this invention may contain pharmaceutically acceptable excipients that are substantially free of unbound water, i.e. water that can take part in the interactions of norastemizole and filler, for example, in any interactions between lactose and norastemizole, but not only in them. The present invention also provides chemically and thermostable non-hygroscopic drugs containing norastemizole and at least one pharmaceutically acceptable excipient, which may include lactose or other mono- or disaccharides.

In other words, the norastemizole compositions of the present invention
(a) essentially do not contain lactose (and preferably essentially do not contain mono - or disaccharide),
(b) include excipients substantially free of unbound water, which may include lactose, for example alpha-lactose monohydrate or other mono- or disaccharides, or
(c) contain large particles or particles coated with an inert substance, and fillers that may include lactose, for example alpha-lactose monohydrate or other mono- or disaccharides. In any case, the applicants found highly stable norastemizole preparations. In addition, it should be noted that compositions of the invention that are non-hygroscopic may nevertheless include some hygroscopic ingredients; however, the compositions as a whole should be substantially non-hygroscopic. Moreover, hydrated ingredients may also be used in the non-hygroscopic pharmaceutical compositions of the present invention.

 In yet another embodiment, the present invention includes anhydrous pharmaceutical compositions comprising norastemizole or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients, which may include lactose. Such compositions can be prepared using anhydrous or low moisture ingredients in low humidity environments so that the resulting drug is substantially anhydrous. In addition, the present invention provides chemically and thermostable anhydrous pharmaceutical compositions comprising norastemizole and at least one pharmaceutically acceptable excipient, which may include lactose or other mono- or disaccharides.

 The invention also includes pharmaceutical compositions for treating histamine disorders, comprising large particles of norastemizole or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The present invention also provides chemically and thermostable pharmaceutical compositions having coarse particles of norastemizole and at least one pharmaceutically acceptable excipient, which may include lactose or other mono- or disaccharides.

 In a preferred embodiment, about 40 weight. % or larger particles of norastemizole or its pharmaceutically acceptable salt are particles of 200 microns or more. In one embodiment, a pharmaceutical composition containing large particles may include lactose as a pharmaceutically acceptable excipient.

 The invention also includes solid pharmaceutical compositions for treating histamine disorders, comprising a therapeutically effective amount of norastemizole or a pharmaceutically acceptable salt thereof coated and comprising norastemizole or a pharmaceutically acceptable salt thereof, coated with an inert agent, and a pharmaceutically acceptable excipient. The present invention further provides chemically and thermostable pharmaceutical compositions of coated norastemizole in which the incompatibility between norastemizole and lactose is eliminated, wherein the excipient may include lactose or other mono- or disaccharides.

 In one embodiment, the filler comprises lactose. In another embodiment, the coated norastemizole or its pharmaceutically acceptable salt further comprises a granular composition of norastemizole or its pharmaceutically acceptable salt and a pharmaceutically acceptable inert carrier, the granular composition being coated with an inert agent. In a preferred embodiment, the inert coating agent comprises an inert film-forming agent in a solvent. More preferably, the inert film forming agent is selected from the group consisting of methyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose sodium carboxymethyl cellulose and mixtures thereof.

 In one embodiment, norastemizole is present in an amount of from about 1 to about 200 mg. In a more preferred embodiment, norastemizole is present in an amount of from about 2 to about 100 mg. In another preferred embodiment, norastemizole is present in a therapeutically effective amount necessary to treat an allergic disorder. In yet another preferred embodiment, a therapeutically effective amount is sufficient to prevent or treat people with allergic disorders.

 The invention also relates to a solid pharmaceutical composition which includes norastemizole or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, pregelatinized starch, magnesium stearate and croscarmellose sodium. In one embodiment, the solid pharmaceutical composition is presented in dosage form in the form of tablets or capsules.

 The invention also relates to a method for treating mammals of at least one allergic disorder by administering a therapeutically effective amount of one of the above compositions. In a preferred embodiment, the mammal is a human. In a more preferred embodiment, the allergic disorder is allergic rhinitis.

Brief Description of the Drawings
In FIG. 1 shows the chemical structure of norastemizole.

In FIG. 2 are presented in the form of diagrams of changes in the initial activity of the dosage form, consisting of norastemizole and various pharmaceutical excipients, in the case of exposure to the dosage form in sealed containers (i.e. vials with a screw cap), a temperature of 60 ^o C and a relative humidity of 75% .

DETAILED DESCRIPTION OF THE INVENTION
Applicants have unexpectedly discovered that even in the absence of applied heat, the bleaching reaction that was found for primary amine and lactose was also found for norastemizole. Thus, the previously incompatible incompatibility between the secondary amine norastemizole and lactose was determined. Therefore, it is desirable to formulate dosage forms of norastemizole that do not contain lactose. In addition, applicants have also found that the instability of lactose and norastemizole can be initiated and / or accelerated by exposing the composition of norastemizole / lactose to water, including atmospheric moisture, such as humidity. Instability is also initiated and / or accelerated by heating the composition above about 60 ^° C. Moreover, applicants have also found that the instability of lactose and norastemizole can be initiated and / or accelerated by the high specific surface area of small particles of norastemizole commonly used in pharmaceutical compositions. Applicants have also found that the instability of lactose and norastemizole can be inhibited or eliminated by coating the particles of norastemizole before formulating norastemizole with reactive excipients such as lactose.

 In PCT / US 93/08349 published by WO 94/07495, Example 4 proposes a lactose-free norastemizole formulation. Each of the formulations A, B and C of example 4 contains 1.0 wt.% Magnesium stearate BP, respectively 94.0, 89.0 and 79.0 weight. % starch 1500 (pregelatinized starch commercially available from Colorcon, Ltd), the rest of the composition is a metabolite of astemizole (for example, norastemizole).

 However, this publication does not disclose or suggest that norastemizole and lactose are incompatible, as evidenced by the composition of the norastemizole tablets containing lactose in Example 5.

 In view of previously unaddressed drug problems, including the secondary amine norastemizole and lactose, it is desirable to obtain stable solid drugs norastemizole in which the incompatibility between norastemizole and lactose is eliminated. The present invention recognizes and provides lactose-free norastemizole drugs.

 Based on the pharmacological advantages of norestemizole over astemizole, a need arose for stable dosage forms of norestemizole with high efficacy. To date, there is no commercially available sustainable drug norastemizole. However, the inventors found that when lactose was eliminated and the alternative ingredients described were described, the lactose-free dosage forms of norastemizole became unexpectedly chemically, physically and thermostable. Such stability can be achieved by the present invention, without loss of ease of manufacture or activity of the dosage forms.

 One feature of the present invention is to provide chemically and thermostable medications that include norastemizole or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient, and which do not include or do not use any form of lactose. Lactose, due to the simplicity of its production, in addition, was widely used in the pharmaceutical industry. However, applicants have found that formulations containing norastemizole and lactose are unstable and decompose more rapidly when exposed to heat and moisture.

Было также обнаружено, что несовместимость существует даже при температуре окружающей среды (например, при температурах ниже около 60^oС) и при относительной влажности окружающей среды. Кроме того, заявители также обнаружили высокостабильные фармацевтические композиции, содержащие норастемизол, в которых не применяют широко признанный наполнитель лактозу.It was previously believed that secondary amines are compatible with lactose, especially at ambient temperature or when the effect of heat (for example, at a temperature below about 60 ^{° C.} ) is either minimal or can be avoided altogether. As noted, for example, previously, the drug astemizole is available in dosage form in the form of tablets containing lactose and other excipients, under the trade name HISMANAL ^® .
It has now been discovered that there is a physical and / or chemical incompatibility between the secondary amine norastemizole and lactose. Without intending to be - associated with any theory, the applicant believes that the incompatibility of norastemizole with lactose is the result of the formation of enamines due to the reaction between the aldehyde intermediate of lactose and the secondary amine

It was also found that incompatibility exists even at ambient temperature (for example, at temperatures below about 60 ^{° C.} ) and at relative humidity. In addition, applicants have also discovered highly stable pharmaceutical compositions containing norastemizole that do not use the widely recognized lactose excipient.

 In accordance with one feature of the present invention, norastemizole is provided in pharmaceutical compositions not containing lactose. These compositions have high antihistamine activity and are useful in the treatment of many conditions. Some of these conditions include, for example, allergic rhinitis, asthma and other allergic disorders, dizziness, motion sickness, vestibular disorders (e.g., Meniere's disease), diabetic retinopathy, and other small vessel disorders associated with diabetes mellitus.

 More importantly, such lactose-free compositions provide stable and convenient dosage forms for the delivery of norestemizole to humans. Lactose-free compositions of the invention have a significant shelf life, inter alia, also because they are stable. In addition, the compositions of the invention remain stable even when they are exposed to moderate temperatures and humidity. Moreover, despite the fact that the compositions of the invention do not contain lactose, their production is still feasible and the compositions have the desired performance.

 Compositions of the invention include solid unit dosage forms comprising norastemizole or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient that is not lactose. The compositions may also optionally include other medicinal ingredients, binders / fillers, disintegrating agents, lubricants, anti-caking agents, preservatives, film-forming agents, sweeteners, pigments, flavoring agents, desiccants, plasticizers, colorants, dispersants and / or surfactants. However, to ensure the stability of the composition, any such optional ingredient must be compatible with the secondary amine norastemizole.

 Preferably, the lactose-free dosage forms of norastemizole obtained in accordance with the present invention include norastemizole and at least one excipient that is not lactose. Examples of such excipients are well known in the art and are listed in the United States Pharmacopeia (XXI) / National Pharmacological Guide (XVI), USP (XXI) / NF (XVI), which are incorporated herein by reference. It is also preferred that the lactose-free dosage forms of norastemizole obtained in accordance with the present invention include norastemizole, a binder / excipient and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. In addition, it is also preferred that the lactose-free dosage forms of norastemizole prepared in accordance with the present invention include norastemizole, microcrystalline cellulose, pregelatinized starch and magnesium stearate.

 It was also found that other sugars, such as fructose and sucrose, cause a similar, although not so strong degradation compared with degradation caused by lactose, when it is used in combination with formulations containing norastemizole. Thus, in another embodiment, the lactose-free pharmaceutical compositions include norastemizole or a pharmaceutically acceptable salt thereof and at least one non-lactose pharmaceutically acceptable excipient, but do not contain mono- and disaccharide excipients, including but not limited to glucose, sucrose and fructose.

 As mentioned above, norastemizole formulations that contain lactose and are exposed to unbound water, such as moisture or moisture, degrade faster. In order to determine properties such as shelf life or drug stability over time, in the pharmaceutical field, water is widely used (for example, in the amount of 5%) as a means of modeling long-term storage. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d ed. Marcel Dekker, NY, NY 1995, pp. 379-380. In fact, water and temperature accelerate research.

 The effect of water on the composition is very important, since during the production, packaging, storage, transportation and use of the drug, conditions favorable for hygroscopicity, such as moisture and / or humidity, are often found. Therefore, it is obvious that the use of lactose should be avoided in pharmaceutical preparations or compositions containing norastemizole, since the compositions under normal conditions of production, packaging and storage have significant contact with moisture and / or humidity.

 Moreover, although excipients other than lactose can be used to produce known lactose-free norestemizole pharmaceutical compositions without affecting the processability and therapeutic efficacy of the compositions, spray dried lactose will continue to be an alternative excipient. Spray-dried lactose has the highest fluidity among direct compression fillers and is very effective for low-dose formulations (e.g. ≤50 mg per dose) in which the compressibility of the active ingredients is not particularly important. See, for example, R. Shangraw, Selection of Manufacturing Process and Excipients with Emphasis on Direct Compression, Course material from Granulation, Tableting and Capsule Technology, Center for Proffessional Advancement, East Brunswick, NJ, 1996. Therefore, when possible, it is advisable to include in solid dosage forms or drugs of norastemizole along with other available lactose excipients.

 Thus, as an alternative, the present invention includes chemically and thermostable pharmaceutical compositions, in particular solid formulations, which contain norastemizole or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients, including, but not limited to, lactose, wherein lactose-containing preparations are anhydrous, i.e. essentially free of unbound water.

 In addition, the invention includes thermo- and chemically stable non-hygroscopic pharmaceutical compositions that contain norastemizole or a pharmaceutically acceptable salt thereof and one or more excipients or ingredients including, but not limited to, lactose. Without intending to confine themselves to any theory, it is believed that such stable anhydrous or non-hygroscopic pharmaceutical compositions are based in part on the discovery that the incompatibility between norastemizole and lactose or other mono- or disaccharides is accelerated and / or possibly triggered when exposed to unbound water. Thus, the preparation of pharmaceutical compositions that are substantially free of unbound water will prevent the accelerated degradation of norastemizole, which occurs when a reactive excipient is used and unbound water is present.

 If lactose is the desired excipient, another aspect of the invention relates to non-hygroscopic or anhydrous drugs, including norastemizole, lactose and optionally one or more additional excipients or ingredients that are substantially free of unbound water. It should be recognized that non-hygroscopic or anhydrous formulations can be obtained by conventional methods, provided that suitable excipients are selected so that the resulting drugs do not contain unbound water, and the treatment is carried out under conditions of low humidity.

 The anhydrous pharmaceutical composition of norastemizole obtained in accordance with the present invention should be obtained and stored in such a way that the anhydrous nature of the preparation is preserved. These compositions, in order to prevent exposure to water and to ensure inclusion in suitable pharmacological kits, can be suitably packaged using materials well known in the art. Such packaging will include, but is not limited to, hermetically sealed foil, plastics, or similar materials, containers containing a unit dose of medication, blister packs, or tape packs.

 Accordingly, a second alternative aspect of the invention includes a method for preparing a solid formulation containing norastemizole and lactose, which comprises mixing in anhydrous conditions or under low moisture / humidity conditions of norastemizole or its pharmaceutically acceptable salt and lactose, wherein the ingredients are substantially free of water . The method may optionally further include packaging an anhydrous or non-hygroscopic solid preparation of norastemizole in low humidity conditions. When these conditions are applied during processing and storage, the risk of contact with water is reduced and the decomposition of norastemizole is prevented or significantly reduced. In addition, the final packaged product does not contain water or has a small amount of unbound water, which essentially increases stability and prevents degradation of the drug. Such preparations can be provided in hermetically sealed packages, for example vials, ampoules, sealed bags, blister packs, and other moisture-free vacuum packs well known to those skilled in the art.

 By tradition, when drugs or formulations are prepared, the active ingredient or drug (eg, norastemizole) is ground and / or sieved to reduce particle size and / or narrow the size distribution. This is usually carried out to optimize the various physicochemical properties of the composition, for example, dissolution, uniformity of content, bioavailability of the active ingredient and similar properties. Of particular concern is the solubility of norastemizole, since the solubility is relatively low (about 10 mg / ml) at a pH of 3-4 and even lower at a pH of about 4. Not limited to any particular theory, the applicants, however, suggest that the interaction between norastemizole and reactive excipients, for example lactose, are influenced by the specific surface of the particles of norastemizole in the pharmaceutical composition or the finished form.

 Accordingly, another embodiment of the present invention includes medicaments for the treatment of disorders caused by histamine, which include large particles of norastemizole or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers for use in such preparations include carriers, which may include one or more carriers selected from the group consisting of inert excipients and reactive excipients, for example, lactose or other mono- and disaccharides. Such “coarse particles” medicinal pharmaceutical compositions of norastemizole have suitable physicochemical properties (in terms of dissolution, uniformity of content, bioavailability and similar properties), but do not show incompatibility with reactive excipients, for example lactose.

 In a preferred embodiment, the norastemizole or its pharmaceutically acceptable salt present in the preparation has a particle size distribution in which 40 wt.% Or more of norastemizole or its pharmaceutically acceptable salt comprises particles of 200 microns or more, preferably more than about 250 microns.

 Another method of inhibiting or preventing the interaction between norastemizole and reactive excipients, for example lactose, in a pharmaceutical composition is to prevent contact of norastemizole with any reactive excipient of the composition. One way this can be achieved is by coating the particles of norastemizole before formulating it with reactive excipients, an inert or non-reactive coating. The inert coating should preferably not significantly affect the pharmacodynamic characteristics of the composition (for example, the period of time before the onset of action and the adsorption capacity in vivo).

 Accordingly, another embodiment of the present invention relates to solid pharmaceutical compositions for treating histamine disorders, comprising a therapeutically effective amount of a coated norastemizole or a pharmaceutically acceptable salt thereof, which include norastemizole or a pharmaceutically acceptable salt coated with an inert agent, and a pharmaceutically acceptable carrier. In a preferred embodiment, norastemizole or a pharmaceutically acceptable salt thereof is first granulated with an inert filler (e.g., starch) and then the granules obtained are coated with an inert or non-reactive agent. After that, the resulting coated norastemizole can be mixed with other excipients, including reactive excipients.

 Suitable inert coating agents and methods for coating particles or granules are well known in the art. Inert coating agents typically include an inert film-forming agent dispersed in an appropriate solvent, and may further include other pharmaceutically acceptable adjuvants, such as dyes and plasticizers. Particles or granules of norastemizole are preferably coated using aqueous film coating or microencapsulation techniques. Suitable inert film-forming agents include, but are not limited to, celluloses such as methyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl; vinyls, for example polyvinylpyrrolidone; glycols, for example polyethylene glycols; acrylics, for example a copolymer of dimethylaminoethyl methacrylate and a methacrylic acid ester and a copolymer of ethyl acrylate and methyl methacrylate, and other carbohydrate polymers, for example maltodextrins and polydextrose. The inert coating agent contains a hydrophilic film-forming agent, for example, hydroxypropyl methylcellulose, and therefore in vivo absorption is not significantly delayed.

 After the particles or granular compositions of norastemizole are coated with an inert coating agent, the coated norastemizole using conventional methods including, but not limited to, mixing, granulating, compressing, or combinations thereof, can be formulated with other inert and / or reactive excipients, for example lactose, to produce various dosage forms, for example tablets, caplets, drops, capsules, troches and the like.

 The preferred amount of norastemizole in all dosage forms made in accordance with the present invention should be a therapeutically effective amount, which is also an amount acceptable from a medical point of view. Doses of norastemizole in the pharmaceutical compositions of the present invention can be varied so that an amount of norastemizole can be obtained that is effective to achieve the desired therapeutic effect for a particular patient, to obtain a pharmaceutical composition of norastemizole and to provide a route of administration, while they do not have a toxic effect on the patient .

 The selected dose and frequency of administration of the pharmaceutical compositions of the invention will depend on many factors, including the method of administration of the drug, time of administration, rate of excretion of the active substance (s), including norastemizole, duration of treatment, other drugs, compounds and / or substances used in combination with norestemizole, age, gender, weight, condition, health and medical history of the patient being treated, and similar factors well known in the medical field. For example, the drug regimen for treating pregnant women, nursing mothers, and children compared with healthy adults will probably be changed.

 The attending physician can easily determine and prescribe the necessary therapeutically effective amount of the pharmaceutical composition. For example, the attending physician may prescribe lower initial doses of norastemizole in the pharmaceutical composition of the present invention than those required to achieve the desired therapeutic effect, and then gradually increase the dose until the desired effect is achieved.

 A suitable daily dose of norastemizole is such an amount of norastemizole that is the lowest dose effective to obtain the desired therapeutic effect. Such a therapeutically effective dose will usually depend on the factors described above. Thus, for example, a unit dose of lactose-free norastemizole may contain from about 1 to about 200 mg, and preferably from about 2 to about 100 mg. Dosage units may be prepared using 2.5, 5, 10, 12.5, 15, 20, 25, 30, 35, 40, 45, 50, or 62.5 mg of norastemizole. If necessary, an effective daily dose of norastemizole can be taken at regular intervals in separate doses in an amount of 1 to 6. As noted earlier, the preferred dosage forms are tablets, caplets, capsules, troches, lozenges, pills, syrups, capsules and the like. forms. However, other pharmaceutically acceptable dosage forms may be used, for example, powders, granules, dragees, etc.

 It should be noted that all the components that make up the dosage forms of norastemizole made in accordance with the present invention, preferably satisfy all the standards and requirements for medicinal ingredients and their combinations contained in USP / NF or even exceed such requirements. The purpose of the USP / NF is to provide authoritative standards and specifications for materials and substances and methods for their preparation, which are used in the field of healthcare. USP / NF establishes names, definitions, descriptions and standards for identifying authenticity, quality, efficiency, purity, packaging and labeling, and also provides in practice bioavailability, stability, handling and storage procedures and methods for checking and formulating them for production or preparation.

 The lactose-free, non-hygroscopic, anhydrous, coarse particles and coated dosage forms of norastemizole presented in the description and claims satisfy the pharmaceutical standards set forth in USP / NF (e.g., USP XXI / NF XVI) for each of the ingredients, as well as those not containing lactose, non-hygroscopic, anhydrous large particles or coated dosage forms of norastemizole made using such ingredients. In fact, lactose-free, non-hygroscopic, anhydrous, containing large particles and coated dosage forms of norastemizole are pharmaceutically acceptable dosage forms made from pharmaceutically acceptable ingredients in pharmaceutically acceptable combinations and in pharmaceutically acceptable amounts that meet the standards set forth in USP XXI / NF XVI, included in this description in its entirety as a reference. In addition, it should be noted that norastemizole can be obtained in accordance with methods known in this field, including those methods that are disclosed in pending application by the US Patent Office application 08/182685, filed January 18, 1994, which is included in this description as a reference for the purpose of teaching methods for producing norastemizole.

 The stability of a pharmaceutical product can be defined as the ability of a particular composition to remain within the physical, chemical, microbiological, therapeutic and toxicological specifications, although there are exceptions, as well as maintain at least about 90% of the activity level indicated on the label for the drug packaging facilities. Thus, the expiration date is defined as the time at which the pharmaceutical product remains stable if it is stored under the recommended conditions.

 The stability of a pharmaceutical product is influenced by many factors, including the stability of the therapeutic ingredient (s), the possible interaction between the therapeutic (s) and inactive (s) ingredient (s) (for example, between norastemizole and excipients) and similar factors. Physical factors, such as heat, light, and moisture, can initiate or accelerate chemical reactions.

 For convenience, the specific terms used in this description are defined as follows. The term “carrier,” as used herein, is synonymous with the term “vehicle” (solvent). The term “lactose-free” as used herein means the amount of lactose present, if present, in a dosage form of norastemizole that is insufficient to cause incompatibility between norastemizole and lactose, which the inventors have found to have an adverse effect on activity norastemizole, the value of which will be less than about 90% of the initial activity throughout the shelf life of the dosage form. The term “unbound water” as used herein means water that is not present in the form of a stable hydrate of one or more components of the drug, for example in the form of alpha-lactose monohydrate. Similarly, the term “anhydrous,” as used herein, means that the amount of unbound water present in the dosage form of norastemizole is insufficient to initiate and / or accelerate the incompatibility between norastemizole and lactose. Further, the term "anhydrous", "anhydrous conditions" or "anhydrous nature (nature)", as used here, means essentially the absence of unbound water, including moisture. The term “non-hygroscopic” as used here means that the entire composition is essentially non-hygroscopic, that is, does not provide unbound water in an amount sufficient to initiate and / or accelerate the incompatibility between norastemizole and reactive excipients, for example lactose. The term "additives" is synonymous with the term "filler", which is used here. The term "essentially free" means less than about 5 wt.%, Preferably less than about 1 weight. % or more, preferably less than about 0.1 wt.%. The term "coarse particle" as used herein means a composition in which norastemizole comprises about 40 wt.% Or more particles of norastemizole or a pharmaceutically acceptable salt thereof, 200 microns or more, preferably more than about 250 microns. The terms “coated,” “inert coating,” or “inert coating,” as used herein, preferably mean an inert coating agent used to coat norastemizole particles and inhibit the interaction of particles with reactive excipients such as lactose. Although inert coatings suitable for use in conventional pharmaceutical applications are also suitable for use with lactose-free, non-hygroscopic anhydrous compositions of the invention comprising large particles, it is preferred that any coating used be inert and inhibit the interaction of norastemizole with reactive excipients.

 The term "pharmaceutically acceptable", as used herein, refers to those compounds, materials, compositions and / or dosage forms that, within generally accepted medical reasoning, are suitable for administration and use in contact with tissues and fluids of the human body and animals and do not cause excessive toxicity, irritation, an allergic reaction, or other problems or complications, with a reasonable ratio of benefits / risk.

 In addition, the term “pharmaceutically acceptable excipient” is used to mean that there are no adverse chemical or physical incompatibilities between norastemizole (or its salt) and any excipients of this dosage form. So, for example, an adverse chemical reaction is one in which the activity of norastemizole (or its salt) is significantly reduced or increased due to the addition of one or more excipients. Another example of an adverse chemical reaction is one in which the taste of the dosage form of norastemizole (or its salt) becomes excessively sweet, acidic, and the like. to such an extent that the dosage form becomes unpleasant. Each excipient should be "acceptable" in the sense of its compatibility with other ingredients of the norastemizole composition and should not be harmful to the patient.

 Physical incompatibility refers to incompatibility between the various components of a dosage form, for example, norastemizole (or its salt) and any of its excipients. For example, a combination of excipient (s) and norestemizole may form an excessively hygroscopic mixture or a mixture segregated to such an extent that the desired form of the dosage form (e.g. tablets, lozenges, etc.), its stability or similar properties becomes impossible save, as a result of which the dosage form cannot be used in accordance with the dosage regimen prescribed by the attending physician.

 Most often, antihistamines, for example astemizole or norastemizole, are administered orally by solid dosage forms, for example tablets, capsules, troches, caplets and the like. In addition, capsule dosage forms may be used, for example, hard gelatine capsules, soft gelatine capsules, etc.

 However, tablets remain the preferred dosage form due to their advantages obtained both for the patient (for example, dosage accuracy, compactness, portability, soft taste, and ease of administration) and for the manufacturer (for example, simplicity and cost-effectiveness of preparation, stability, and convenience during packaging, transportation and distribution). Tablets are pharmaceutical dosage forms containing a drug substance with or without suitable additives.

 In order for the drug substances or therapeutic ingredients of the present invention (i.e., not containing lactose, non-hygroscopic, anhydrous, large particles and coated dosage forms of norastemizole) with or without diluents to be transformed into solid dosage forms (e.g. tablets) using pressure and suitable equipment, it is necessary that the material in crystalline or powder form, has many physical properties. These properties include, for example, the ability to flow freely when the powder adheres during compaction, and easy release from the tool. Since most materials do not have these properties or have only some of these properties, methods have been developed to formulate and prepare tablets to give the material that is to be compressed into tablets or a similar dosage form the desired properties.

 As noted, in addition to the drug substance or therapeutic ingredient, tablets and similar dosage forms may contain a number of materials classified as additives. These additives are classified according to the role they play in formulating a dosage form, for example, tablets, caplets, capsules, troches, or the like. One group includes, but is not limited to, binders, diluents (fillers), disintegrants, and lubricants.

 Although the following discussion of various additives intended for use in the present invention specifically relates to lactose-free dosage forms, those skilled in the art will recognize that the subgroup of each category includes additives suitable for use in non-hygroscopic, anhydrous, coarse particles or coated Norastemizole medicaments of the present invention. In addition, non-hygroscopic, anhydrous, containing large particles and coated drugs of the present invention may also include lactose or other mono - or disaccharides as fillers. In another embodiment, inorganic bisulfites may be used to increase the stability of the norastemizole compositions.

 When choosing fillers and additives for hygroscopic compositions, special precautions should be taken so that, in the absence of control of environmental conditions, there is no tendency to moisture sorption (absorption or adsorption). For example, excipients used in such formulations include, but are not limited to, alpha-lactose monohydrate, mannitol, and the like.

For anhydrous formulations, anhydrous or low moisture forms of the following excipients or additives, for example AVICEL-PH-103 ^TM and Starch 1500LM, should be used.

 In order to provide a free-flowing powder from a mixture of the ingredients that make up the tablets and the free flow of the material when used in a tablet machine, a binder is used. The binder also gives cohesive ability to the norastemizole tablets. Too little binder will cause fluidity problems, as a result, the resulting tablets will not be able to maintain their integrity. Too much binder can have an adverse effect on the release (dissolution rate) of a drug from a tablet. Thus, to ensure a free-flowing mixture of the ingredients of the tablets and to eliminate the possibility of an adverse effect on the dissolution rate of the medicinal ingredients from the tablets, a sufficient amount of binder should be included in them. At a reduced dose, the need for a high degree of compressibility can be eliminated to a certain extent by the use of suitable diluent fillers, called compression aids. The amount of binder used will vary depending on the type of composition and method of administration of the drug, and it can be easily determined by a person skilled in the art.

 A binder suitable for use in lactose-free, non-hygroscopic, anhydrous, large-particle, or coated norastemizole formulations made in accordance with the present invention include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic resins, for example, gum arabic, sodium alginate, alginic acid, other alginates, tragacanth powder, guar gum, cellulose and its derivatives (for example, ethyl cellulose, acetate cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose (e.g. 2208, 2906, 2910), microcrystalline cellulose, or mixtures thereof.

 Suitable forms of microcrystalline cellulose are, for example, materials sold under the trade names AVICEL-PH-101, AVICEL-PH-103 and AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA., USA). An example of a natural binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold by FMC Corporation under the trade name AVICEL-RC-581.

 Most tablets sold on the market range in weight from about 100 mg to about 500 mg. Therefore, in most potent drugs, including dosage forms of norastemizole, a significant portion of the tablets is excipient. In order to obtain an acceptable size of tablets, capsules or other preferred dosage forms and to give the powder (e.g., tablets or capsules) volume, fillers (e.g., diluents) are used. Typically, the active ingredients form a suitable dosage form having an appropriate size when a diluent is included. When using a binder, binding of the drug to the excipient may occur, which will affect the bioavailability. Therefore, in order to achieve the desired degree of dilution and the absence of an adverse effect on the degree of release of the active ingredient (s) of their dosage form containing an excipient, a sufficient amount of excipient should be used. In addition, an excipient that is physically and chemically compatible with the active ingredient (s) of the dosage form should be used. Therefore, for the formation of dosage forms of norastemizole made in accordance with the present invention, in the absence of precautions for eliminating unbound water, lactose should not be used together with norastemizole. It is also preferred that the lactose-free dosage forms of norastemizole in accordance with the present invention do not include mono- or disaccharides such as glucose, sucrose and fructose, but not only them. The amount of excipient used will vary depending on the type of composition and method of administration of the drug, and it can be easily determined by a person skilled in the art.

 Examples of suitable excipients used in lactose-free norestemizole dosage forms made in accordance with the present invention include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol , silicic acid, sorbitol, starch, pregelatinized starch, or mixtures thereof.

 The proportion of the binder / excipient in the medicaments of the present invention is usually from about 50 to about 99% by weight of the weight of the pharmaceutical composition.

 For the disintegration of tablets when exposed to an aqueous medium, substances that contribute to the disintegration of the dosage form are used. Too much disintegrant will lead to tablets that can break down in containers due to atmospheric moisture and providing unbound water sufficient to initiate and / or accelerate the interaction between norastemizole and lactose. Too small an amount of such a substance may be insufficient for the disintegration of the dosage form and therefore may change the rate and degree of release of the drug (s) substance (s) from the dosage form. Thus, in order to obtain dosage forms of norestemizole made in accordance with the present invention, a sufficient amount of a disintegration promoting substance dosage form that is neither too small nor too large should be used, as a result of which it will not adversely change the rate and degree of drug release (s) ) substance (c). The amount of substance contributing to the disintegration of the dosage form varies depending on the type of composition and method of administration of the drug, and it can be easily determined by a person skilled in the art. Typically, from about 0.5 to about 15% by weight of a disintegrating agent can be used in the drug, preferably from about 1 to about 5% by weight.

 Disintegrating agents that can be used to form lactose-free norestemizole dosage forms made in accordance with the present invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium polacryline, sodium starch glycolate, potato starch or cassava starch, other starches, pregelatinized starch, clays, other alginines , other celluloses, resins or mixtures thereof.

 It is usually desirable to formulate lactose-free, non-hygroscopic, anhydrous, containing large particles and coated drugs of norastemizole, based on the physicochemical properties of norastemizole so that they dissolve quickly when administered to a person, for example, in a person’s stomach. Therefore, in a preferred embodiment, lactose-free, non-hygroscopic, anhydrous, coarse particles and coated drugs of the present invention include super-substances that contribute to the disintegration of the dosage form, including, for example, but not limited to, croscarmellose sodium or sodium starch glycolate.

 At any dose, sticking of the ingredients of the dosage form to the punch of the tablet machine should be avoided. So, for example, when a drug substance (for example, norastemizole) accumulates on the surface of the punch, the surface of the tablet is covered with pits and therefore it becomes unacceptable. In addition, the adhesion of the drug substance or other ingredients of the dosage form in this case inevitably requires the application of significant pushing forces to remove the tablet from the mold. Excessive ejection forces can lead to a high rate of failure and increase the cost of production, not to mention excessive wear and mold. In practice, adhesion can be reduced by wetting or by applying high levels of lubricants, such as magnesium stearate. However, choosing a medicinal salt with good release properties will also minimize these problems.

 As noted above, a lubricant is used to increase the fluidity of the lactose-free norestemizole tablet powder mixture in the tablet machine and to prevent the tablet from sticking to the mold after it is compressed. Too small a quantity of lubricant will not provide tablets of satisfactory quality, and too large a quantity of such substance may result in tablets with a permeable hydrophobic coating. Since lubricants are usually hydrophobic materials, for example stearic acid, magnesium stearate, calcium stearate and the like, a waterproof hydrophobic coating can be formed by using too much lubricant. In addition, a waterproof hydrophobic coating can inhibit the disintegration of the tablets and the dissolution of the drug (s) ingredient (s). Thus, to easily remove the compressed tablet from the mold without forming a waterproof hydrophobic coating that adversely affects the desired disintegration of the dosage form and / or dissolution of the drug (s) ingredient (s), a sufficient amount of lubricant should be used.

 Such lubricants used in the lactose-free dosage forms of norastemizole made in accordance with the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g. peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), st arat zinc, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, silica gel silica gel (AEROSIL 200 manufactured by WRGrade Co. of Baltimore MD), synthetic silica coagulated aerosol (sold by Deaussa Co. of Piano, Texas), CAB-0-SIL (fumed silica product) sold by Cabot Co. of Boston, Mass.) or mixtures thereof. A lubricant may optionally be added to the drug in an amount of less than about 1% by weight based on the drug.

 Another class of additives used in dosage forms of norastemizole includes, but is not limited to, anti-caking agents, antimicrobial preservatives, coating agents, colorants, desiccants, flavoring agents, perfumes, plasticizers, viscosity enhancers, sweeteners, buffers, moisturizers and similar additives.

 Suitable anti-caking agents used in the lactose-free dosage forms of norastemizole made in accordance with the present invention include, but are not limited to, calcium silicate, magnesium silicate, silicon dioxide, colloidal silicon dioxide, talc and mixtures thereof.

 Suitable antimicrobial preservatives used in the lactose-free dosage forms of norestemizole made in accordance with the present invention include, but are not limited to, a solution of benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben, cetylpyridinium chloride, chlorobutanolidenecres, debronolene, methylparaben, phenol, phenylethyl alcohol, phenylmercury (II) acetate, phenylmercury (II) nitrate, potassium sorbate, propylparaben, sodium benzoate, sodium dehydroacetate, pronionate n Tria, sorbic acid, timersol, thymol or mixtures thereof.

 Suitable coating agents used in the lactose-free dosage forms of norestemizole made in accordance with the present invention include, but are not limited to, sodium carboxymethyl cellulose, cellulose acetate phthalate, ethyl cellulose, gelatin, pharmaceutical glaze, hydroxypropyl cellulose, hydroxypropyl cellulose 29, e.g. 2910), hydroxypropyl methyl cellulose phthalate (e.g. 200731, 220824), methyl cellulose, polyethylene glycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, wax carnauba, microcrystalline wax or mixtures thereof. The amount of coating agent and carrier (diluent) (aqueous or non-aqueous) used depends on the type of composition and method of administration of the drug, and it can be easily determined by a person skilled in the art.

 Norastemizole tablets (e.g., capsule-shaped tablets, which are often referred to as caplets) made in accordance with the present invention may optionally be coated with a film-forming polymer using one or more types of equipment, for example a conventional coating tank, air Accelacota, High-Cola or Worster suspension columns. Such equipment typically has an exhaust system designed to remove dust and solvent or water vapor to facilitate quick drying. Spray guns or other suitable equipment for spraying liquids can be introduced into the coating tanks to provide spraying patterns that result in a quick and uniform coating of the tablet layer. Typically, heated or cooled air is fed continuously or intermittently to the tablet layer to accelerate the drying of the film-forming solution. For non-hygroscopic, anhydrous, large-particle containing or coated medicaments of the invention containing reactive excipients, for example lactose, non-aqueous processes are preferred, for example, a non-aqueous coating should be used.

 The coating solution may be spray applied using a pneumatic conveying system or peristaltic pump system and a continuous or intermittent spray drying cycle. The particular type of spray coating is selected depending on the drying efficiency of the coating tub.

 In most cases, the coating material is sprayed until lactose-free, non-hygroscopic, anhydrous, containing large particles or coated tablets of norastemizole are uniformly coated to obtain a coating of the desired coating thickness and appearance. To obtain high-speed tablets, many different types of coatings can be applied, for example, enteric coating, slowly releasing or rapidly dissolving coatings for fast-acting tablets. To provide a faster release of the active ingredients, a rapidly dissolving type of coating is preferred that accelerates the onset of the process. The thickness of the coating of the film-forming polymer applied to the tablet may vary. However, it is preferred that the thickness corresponds to the appearance, sensation (touch and taste) and function of the gelatin capsules. Depending on whether a faster or slower release of the drug (s) is desired, those skilled in the art can easily determine the type of film and thickness based on characteristics such as the desired levels of the active ingredient in the blood, release rate, solubility active ingredient and the desired effectiveness of the dosage form.

 Suitable film-forming agents used in the coating of the final dosage form, for example tablets including lactose-free, non-hygroscopic, anhydrous, large particles or coated tablets of norastemizole, include, for example, methylcellulose, hydroxypropylmethyl cellulose, (PHARMACOAT 606 6 centipoise), polyvinylpyrrolone , ethyl cellulose (ETHOCEL 10 centipoise), various methacrylic acid derivatives and methacrylic acid esters, cellulose acetate phthalate or mixtures thereof.

 Suitable colorants used in the lactose-free dosage forms of norastemizole made in accordance with the present invention include, but are not limited to, pharmaceutically acceptable colorants and varnishes, caramel, red ferric oxide, yellow ferric oxide, or mixtures thereof. Suitable desiccants used in the lactose-free dosage forms of norastemizole made in accordance with the present invention include, but are not limited to, calcium chloride, calcium sulfate, silica gel, or mixtures thereof.

 Suitable flavoring agents used in the lactose-free dosage forms of norestemizole made in accordance with the present invention include, but are not limited to, gum arabic, tragacanth, almond oil, anethole, anise oil, benzaldehyde, cumin, caraway seeds, cardamom oil, cardamom seed , tincture of cardamom, which has a complex composition, cherry juice, cinnamon, cinnamon oil, clove oil, cocoa, coriander oil, eriodictin, liquid extract of eriodictin, ethyl acetate, ethyl vanillin, eucalyptus oil, fennel fresh oil, licorice root, pure licorice extract, liquid licorice extract, lavender oil, lemon oil, menthol, methyl salicylate, monosodium glutamate, nutmeg oil, orange flower oil, orange oil, sweet tincture of orange peel, alcohol tincture of orange, which has a complex composition of orange , peppermint, peppermint oil, peppermint alcohol, needle needles oil, rose oil, concentrated rose water, spikelet mint, spikelet peppermint oil, thymol, tincture of balsam, vanilla, tincture of vanilla and vanillin, or a mixture thereof.

 Suitable plasticizers used in the lactose-free dosage forms of norastemizole made in accordance with the present invention include, but are not limited to, castor oil, diacetylated monoglycerides, diethyl phthalate, glycerin, mono-and diacetylated monoglycerides, polyethylene glycol, propylene glycol and tri.

 Suitable viscosity increasing agents used in the lactose-free dosage forms of norestemizole made in accordance with the present invention include, but are not limited to, gum arabic, agar, alamic acid, aluminum monostearate, bentonite, a thick aqueous suspension of bentonite, carbomer 934, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium 12-carboxymethyl cellulose, carrageenan (Irish or pearl moss), cellulose, microcrystalline cellulose, gelatin, guar gum, hydra ksietiltsellyulozu, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208; 2906; 2910), magnesium aluminum silicate, methylcellulose, pectin, polyvinyl alcohol, povidone, silica gel, colloidal silicon dioxide, sodium alginate, tragacanth and xanthan gum or mixtures thereof.

 Suitable sweeteners used in the lactose-free dosage forms of norastemizole made in accordance with the present invention include, but are not limited to, aspartame, dextrates, mannitol, saccharin, calcium saccharin, sorbitol, sorbitol solution, or mixtures thereof.

 Suitable buffers used in lactose-free dosage forms of norastemizole made in accordance with the present invention include, but are not limited to, magnesium hydroxide, aluminum hydroxide and the like, or mixtures thereof. Suitable humectants include, but are not limited to, glycerin, other humectants, or mixtures thereof. Dosage forms of norastemizole of the present invention further include one or more of the following additives: (1) dissolution retardants, for example paraffin; (2) absorption accelerators, for example quaternary ammonium compounds; (3) wetting agents, for example, such as cetyl alcohol and glycerol monostearate; (4) absorbents, for example kaolin and bentonite clay; (5) antioxidants, e.g., water-soluble antioxidants (e.g., ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate, sodium sulfite and the like), oil-soluble antioxidants (e.g., ascorbyl palmitate, hydroxyanisole (HA), butylated hydroxytoluene, lebol (B) , alpha-tocopherol and the like) and (6) chelating agents, e.g. citric acid, ethylenediaminetetraacetic acid (EDTA) (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

 Lactose-free, non-hygroscopic, anhydrous, containing large particles or coated dosage forms of norastemizole of the present invention can also be provided in the form of hard or soft capsules, for example gelatin or other suitable materials, together with various excipients previously indicated for tablets. For the formation of tablets, norastemizole is combined in various proportions with one or more excipients (for example, diluents, binders, disintegrating agents, dispersing agents, surfactants, lubricants, coating agents, flavoring agents, colorants, viscosity increasing agents, suspending agents, sweeteners, colorants, pigments, etc.) using conventional tabletting equipment, such as double-shell mixers or mixers V-shaped, by known methods for the production of chemically and thermostable dosage forms (e.g., tablets, caplets and the like) having a uniform distribution and containing a mixture of drug substances. The exact amounts of each of the various excipients can be easily determined by a person skilled in the art.

 For large-scale production of lactose-free, non-hygroscopic, anhydrous, large particles or coated dosage forms of norastemizole made in accordance with the present invention, in addition to the active drug (s) substance (s), additives may be required, including, but not limited to, diluents, binders, lubricants, substances that contribute to the disintegration of dosage forms, colorants, flavoring agents, sweeteners and the like, or mixtures thereof. When these and other additives are included, many dosage forms can be made (for example, tablets, capsules, caplets, troches, etc.). These include, for example, hard gelatine capsules, droplets, sugar-coated tablets, enteric-coated tablets to slow them down, multi-pressed tablets, sustained release tablets, dissolution tablets, effervescent tablets, slow dissolution tablets in the buccal pocket and sublingual tablets, lozenges, and the like. Sugar-coated tablets preferably do not include lactose and mono- or disaccharides, with the exception of norastemizole formulations essentially free of unbound water.

 Tablets of lactose-free, non-hygroscopic, anhydrous, large particles of norastemizole or coated dosage forms of norastemizole of the present invention are usually made by molding, compression, or by conventional tablet formation methods. Accordingly, compressed tablets are usually obtained by large-scale production methods, while the formation of molded tablets is carried out using small-scale operations. So, for example, there are three main methods for preparing tablets for the manufacture of dosage forms of norastemizole: (1) wet granulation method; (2) dry granulation method; and (3) direct compression method. These methods are well known to those skilled in the art. See Remington's Pharmaceutical Sciences, 16th and 18th Eds., Mask Publishing Co. , Easton, Pennsylvania (1980 and 1990). See also US Pharmacopeia XXI, US Pharmacopeial Convention, Inc., Rockville, Maryland (1985). To obtain non-hygroscopic or anhydrous dosage forms, wet granulation is not used.

 In accordance with the present invention, various lactose-free, non-hygroscopic, non-hygroscopic, tableted tablets containing large particles or coated dosage forms of norastemizole can be made. These include tablet dosage forms, for example, sugar-coated tablets, film-coated tablets, enteric-coated tablets, disintegrating in the intestines, multi-pressed tablets, sustained release tablets, and the like. Lactose-free, non-hygroscopic, anhydrous, coarse particles or sugar coated tablets of norastemizole are sugar coated tablets. Such coatings can be colored, and they are advantageous in coating medicinal substances having an unpleasant taste or smell, and in protecting materials sensitive to oxidation. Lactose-free, non-hygroscopic, anhydrous, coarse particles or film-coated tablets of norastemizole are compressed tablets that are coated with a thin layer or film of water-soluble material. Many polymeric substances with film-forming properties can be used. The film coating gives the same general properties as the sugar coating, however, in the case of the film coating, an additional advantage is achieved consisting in a significant reduction in the period of time required for the coating operation. Enteric-coated tablets disintegrating in the intestine are also suitable for use in the present invention. Lactose-free, non-hygroscopic, anhydrous, coarse particles or enteric coated tablets of norastemizole are compressed tablets coated with substances that resist dissolution in the gastric fluid but break down in the intestines. Enteric coating can be used for tablets containing drugs that are inactivated or destroyed in the stomach, for tablets that irritate the mucous membrane, or as a drug with prolonged action.

 Lactose-free, non-hygroscopic, anhydrous, coarse particles or multi-pressed coated norestemizole tablets are compressed tablets obtained from more than one compression cycle, for example multilayer tablets or compressed tablets. Laminated tablets are prepared by compressing additional tablet granulate onto previously compressed granulate. To obtain multilayer tablets consisting of two, three or more layers, the operation can be repeated. Typically, special tablet presses are needed for the manufacture of multilayer tablets. See, for example, US Pat. No. 5,213,738, incorporated herein by reference in its entirety.

 Compressed coated tablets are another form of multi-pressed tablets. Such tablets, which can also be classified as dry-coated tablets, are prepared by feeding previously compressed tablets to a tablet machine and compressing another granular layer around previously formed tablets. These lactose-free, non-hygroscopic or anhydrous norastemizole tablets have all the advantages of compressed tablets, i.e. a cut, a monogram, disintegration rate, etc., and at the same time they preserve the properties of sugar-coated tablets, masking the taste of the drug substance in the tablet core. Compressed tablets may also be used to separate incompatible drugs. In addition, they can be used to provide an enteric coating on the tablet core. Both types of norastemizole tablets (i.e. multilayer tablets and compressed coated tablets) can be used, for example, in the modeling of sustained release dosage forms.

 Lactose-free, non-hygroscopic, anhydrous, coarse particles or sustained release coated norestemizole tablets may include compressed tablets formulated to isolate a drug substance in a manner that provides drug therapy for a period of time. There are also other types of tablets that include sustained release tablets in which the release of the drug is prevented for the period following the administration of the drug or until certain physiological conditions exist. Sustained-release tablets may be formed that periodically release a dose of the drug into the gastrointestinal fluid. Sustained-release tablets can also be formed that continuously release the increments of the drug substance into the gastrointestinal fluid.

 The production method and additives to be included in lactose-free, non-hygroscopic, anhydrous, containing large particles or coated tablets of norastemizole are chosen so as to obtain a tablet composition with the desired physical properties and at the same time ensure rapid compression of the tablets. After pressing, the tablets will preferably have a number of additional properties, such as the corresponding appearance, hardness, disintegration ability and uniformity, which are affected by both the preparation method and the additives present in the tablet composition.

 The main component of the tablet pressing equipment includes a lower punch that is inserted from the bottom into the die, and an upper punch having a head of the same shape and the same size as the lower punch, and which enters the die cavity from the upper part afterwards as the cavity of the stamp is filled with tabletting material. The tablet is formed by pressure applied to the punches. Then the tablets are removed from the stamp. The weight of the tablets is determined by the volume of material that fills the die cavity.

 The ability of lactose-free, non-hygroscopic, anhydrous, containing large particles or coated with tablet or granular dosage forms of norastemizole to freely flow into the die cavity is important to ensure uniform filling of its cavity. The flowability of the granulate is also important to ensure continuous movement of the granulate from a power source or feed bin. In addition, if the tablet granulate does not have cohesive properties, after pressing, the tablets crumble and break when handled. Moreover, since the punches should move freely in the die and the tablets should be easily removable from the front of the puncheon, the tablet material should have a degree of lubrication such that friction can be minimized and the pressed tablet removed. A granulating agent may be added to facilitate granulation. The amount of granulating agent used will vary depending on the type of composition and method of administering the drug, and it will be readily determined by one skilled in the art. Typically, about 5 to about 15% by weight of a granulating agent is used in a medicine. Preferably, if lactose is present in the anhydrous or non-hygroscopic compositions of the present invention, the granulating agent is anhydrous.

 In addition, it should be noted that stable, lactose-free, non-hygroscopic, anhydrous, containing large particles or coated tablets of norastemizole or its other dosage forms retain their original size, shape, weight and color under normal conditions of handling and storage throughout the shelf life . Therefore, for example, excessively fine powder or solid particles located in the bottom of the package, cracks or crumbs on the front side of the tablets or the appearance of crystals on the surface of the tablets or on the packaging walls are an indicator of the physical instability of the uncoated tablets. Therefore, to ensure sufficient physical stability of the tablets, moderate, uniform and reproducible shaking and dropping of the tablets should be carried out. The hardness of the tablets can be determined using commercially available test instruments. In addition, the in vitro availability of the active ingredient should not change over time.

 The lactose-free pharmaceutical compositions of the present invention can also be formulated as unit dosage forms, in the form of soft, flexible gelatin capsules, using generally accepted methods well known in the art (see, for example, Ebert, Pharm. Tech., 1 (5): 44-50 (1977)). Soft elastic gelatin capsules have a soft, spherical gelatin shell, somewhat thicker than the shell of hard gelatin capsules, the gelatin being plasticized by the addition of glycerol, sorbitol or the like polyol. The hardness of the capsule shell can be changed by changing the type of gelatin and the amounts of plasticizer and water. To prevent the growth of fungi, soft gelatin shells may contain a preservative (for example, methyl and propyl parabens and sorbic acid). The active ingredient may be dissolved or suspended in a liquid vehicle or carrier, for example, vegetable or mineral oils, glycols, for example polyethylene glycol and propylene glycol, triglycerides, surfactants, for example polysorbates, or a combination thereof.

 Tablets and other dosage forms of the pharmaceutical compositions of the present invention, for example dragees, capsules, pills and granules, may optionally have nicks or may be prepared with coatings and shells, for example, enteric coatings and other coatings well known in the art of drug preparation.

 The pharmaceutical compositions of the present invention can also be formulated so that it is possible to provide a slow or controlled release of the active ingredient from them using, for example, in various proportions of hydroxypropyl methylcellulose, which provides the desired release profile, other polymer matrices, liposomes and / or microspheres.

 In the present description, unless otherwise indicated, all percentages are presented in percent by weight based on the total weight of all components of a particular dosage form.

 Lactose-free, non-hygroscopic, anhydrous, containing large particles or coated with norastemizole compositions may additionally contain, for example, an analgesic, decongestant, cough suppressant or expectorant.

The incompatibility of norestemizole with lactose is illustrated in table 1. The effect of lactose on norestemizole was evaluated at various temperatures (for example, at 25, 40 and 60 ^o С), various levels of relative humidity (for example, at relative humidity of 60 and 75%) and at different times (for example, at zero point, after 1 week, 1 month, 2 months, 3 months, 6 months and 9 months). The results of this assessment are presented in table 1. Using high performance liquid chromatography (HPLC), the level of impurities in the test capsules was measured and presented in table 1 as a percentage in the test dosage form. It should be noted that the appearance of discoloration of the capsules, which were initially white and opaque, served as an indicator of incompatibility between norastemizole and lactose, which was confirmed by increased percentages of impurities detected by HPLC.

Thus, the results show that when norastemizole is formulated with lactose, enclosed in hard gelatin capsules, and they are stored in sealed containers, the composition is chemically unstable at elevated temperature and humidity. Moreover, even at 25 ^° C and 60% relative humidity, norastemizole / lactose capsules had an increased content of impurities and decreased in vitro activity after six (6) and nine (9) months, indicating an incompatibility between norastemizole and lactose.

In an attempt to identify excipients suitable for use with norestemizole that are other than lactose, excipient studies were performed using various classes of other excipients. Examples of test excipients included corn starch, calcium sulfate dihydrate, calcium stearate, sucrose, fructose, calcium carbonate, microcrystalline cellulose, maltodextrin, CaHPO ₄ • 2H ₂ O, CaHPO ₄ , magnesium stearate, starch 1500 ^® , croscarmelli sodium and mixtures.

The effect of various excipients on the destruction of norastemizole is shown in FIG. 2, where the combination of norestemizole and the excipient was subjected to a temperature of 60 ^° C and a relative humidity of 75% and stored in a sealed packaging, these conditions were typical for studying the compatibility of the excipient.

 As clearly follows from FIG. 2, due to a sharp drop in the activity of the drug substance, norastemizole and lactose are undoubtedly incompatible. However, for norastemizole and other test excipients, such a sharp drop was not observed. However, in view of the changes in activity of various excipients, which are shown in FIG. 2, it may be necessary to adjust the daily dose.

 FIG. 2 also provides an indication that the use of mono- and disaccharide excipients in the norastemizole formulations should preferably be avoided, as follows, for example, from the degradation observed when using combinations of norastemizole and sucrose. The above results were obtained using screw caps, high temperature and humidity packages, which are widely used to determine the interactions of compounds with fillers under conditions that accelerate such interactions. Applicants also found that norastemizole alone, when stored in high humidity conditions (i.e. when exposed to unbound water), is extremely stable over an extended period of time. Another study was conducted to evaluate the effect of moisture changes on the interaction of lactose and norastemizole. The following samples were obtained in 20 mm amber glass vials with a screw cap.

Pure norastemizole:
20% norastemizole / 80% lactose
20% norastemizole / 80% lactose with 5% H ₂ O
1% norastemizole / 99% lactose
1% norastemizole / 99% lactose with 5% H ₂ O
Bubbles with a screwed top were kept at 60 ^o C for 14 days and analyzed for the content of norastemizole.

 The results show that the incompatibility of norastemizole and lactose is significantly reduced in the absence of unbound water and hermetically sealed packaging. In fact, the effect of moisture on the reaction rate is significant. When unbound water was intentionally not added to well-sealed packages, there is a significant difference compared to control, i.e. pure norastemizole was not found. In the presence of unbound water, reduced activity was observed, while in the absence of unbound water, a decrease in activity was observed compared to lactose-free or pure norastemizole.

% norastemizole - Analysis Results
Pure norastemizole - 96.90
20% norastemizole / 80% lactose - 98.33
20% norastemizole / 80% lactose with 5% H ₂ O - 65.16
1% norastemizole / 99% lactose - 92.59
1% norastemizole / 99% lactose with 5% H ₂ O - 77.22
Lactose-free, non-hygroscopic, anhydrous, containing large particles or coated dosage forms of norastemizole, for example lozenges, can be formed by combining norastemizole or its pharmaceutically acceptable salt with one or more pharmaceutically compatible excipients as described above, in pharmaceutically compatible amounts to form a drug a norastemizole preparation containing unit doses in an amount of from about 1 to 200 mg of norastemizole and preferably from about 2 to an eye lo 100 mg norastemizole. Dosage forms in the form of tablets, lozenges or capsules can be formed, for example, by methods known in the art, including wet granulation, dry granulation or direct compression. Wet granulation, on the other hand, is not suitable for non-hygroscopic or anhydrous compositions. Other methods well known in the art may be used to form tablets, lozenges, and capsules. However, direct compression is preferred for the formulation of tablets and lozenges. For capsules, hard gelatine capsules are preferred which are filled with norastemizole and one or more excipients.

STARCH 1500 ^® is a pregelatinized starch manufactured by Colorcon Ltd., which is not recommended for use in amounts exceeding 75 wt.%. In addition, when magnesium stearate is used as a lubricant with STARCH 1500 ^® , magnesium stearate should not be used in amounts greater than 0.25 wt.%, As this may have an adverse effect on dissolution. Such an adverse effect on the dissolution of formulations containing STARCH 1500 ^® and magnesium stearate in amounts of more than 0.25 wt.%, Is especially important for compounds having relatively low solubility in water, for example, such as norastemizole.

 The following examples illustrate preferred embodiments of the claimed invention. It should be understood that the examples are for illustrative purposes only and do not limit the nature or scope of the appended claims.

 The active ingredient was sieved and mixed with the listed excipients. The mixture was enclosed in suitable, two-part bonded hard gelatine capsules using equipment and methods well known in the art. See Remington's Pharmaceutical Sciences, 16th and 18th Editions, incorporated by reference in their entireties. Other doses can be obtained by changing the weight of the composition enclosed in capsules and, if necessary, by changing the size of the capsule. Any of the above stable, lactose-free, non-hygroscopic and anhydrous formulations in the form of gelatin capsules can be prepared.

 The active ingredient was sieved through a suitable sieve and mixed with lactose-free fillers to form a homogeneous mixture. The dry mixture was sieved and mixed with magnesium stearate. Then, the resulting powder mixture was compressed into tablets of the desired shape and size. Tablets of other activity can be prepared by changing the ratio of the active ingredient (i.e., norastemizole) to the vehicle (s) or by modifying the weight of the tablet.

 The active ingredient was sieved through a suitable sieve and mixed with lactose-free fillers (excluding half the amount of croscarmellose (or sodium starch glycolate) and all microcrystalline cellulose) until a uniform mixture formed. Appropriate volumes of water were added and the powder was granulated. After drying, the granules were sieved and mixed with microcrystalline cellulose, residues of croscarmeloe or sodium starch glycolate and quickly with magnesium stearate. Then the obtained free-flowing powder was pressed into tablets of the desired shape and size. Tablets of other activity can be obtained by changing the ratio of the active ingredient (i.e., norastemizole) to excipients or by modifying the weight of the tablet.

 The active ingredient was sieved through a suitable sieve and mixed with lactose-free fillers (except magnesium stearate) until a homogeneous mixture was formed. The dry mixture was sieved and quickly mixed with magnesium stearate. Then, the resulting powder mixture was pressed into tablets of the desired shape and size. Tablets of other activity can be obtained by changing the ratio of the active ingredient (i.e., norastemizole) to excipients or modifying the weight of the tablet.

 Although the present invention has been described with reference to specific options, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the scope and spirit of the invention as defined in the claims.

Claims (25)

 1. A solid lactose-free pharmaceutical composition comprising norestemizole or a pharmaceutically acceptable salt, solvent, binder, disintegrant, lubricant, the solvent, binder, disintegrant, lubricant are not the same substance.  2. The composition according to claim 1, characterized in that the disintegrant is present in an amount of from about 0.5 to about 15% and the lubricant is present in an amount of up to about 1%.  3. The composition according to p. 1, characterized in that it is a dosage form in the form of tablets or capsules.  4. The composition according to claim 1, characterized in that norastemizole or its pharmaceutically acceptable salt is present in an amount of from about 1 mg to about 200 mg.  5. The composition according to claim 1, characterized in that norastemizole or its pharmaceutically acceptable salt is present in an amount of from about 2 mg to about 100 mg.  6. A solid pharmaceutical composition comprising norastemizole or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium and magnesium stearate.  7. The composition according to claim 6, characterized in that it is a dosage form in the form of tablets or capsules.  8. The composition of claim 6, wherein norastemizole or a pharmaceutically acceptable salt thereof is present in an amount of about 1 mg to about 200 mg.  9. The composition of claim 8, wherein norastemizole or a pharmaceutically acceptable salt thereof is present in an amount of from about 2 mg to about 100 mg.  10. A method of treating allergic disorders in a mammal, which comprises administering to said mammal a therapeutically effective amount of a composition according to claim 1.  11. The method of claim 10, wherein said mammal is a human.  12. The method of claim 10, wherein the allergic disorder is allergic rhinitis.  13. A method of treating allergic disorders in a mammal, comprising administering to said mammal a therapeutically effective amount of a composition according to claim 6.  14. The method according to item 13, in which the mammal is a human.  15. The method according to item 13, in which the allergic disorder is allergic rhinitis.  16. A solid pharmaceutical composition comprising a therapeutically effective amount of particles of norastemizole or a pharmaceutically acceptable salt coated thereon, wherein said particles are coated with an inert coating and a pharmaceutically acceptable excipient.  17. The solid pharmaceutical composition according to clause 16, in which the particles of norastemizole or its pharmaceutically acceptable salt coated include granular particles of norastemizole or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.  18. The composition according to clause 16, in which the inert coating comprises an inert film-forming agent in a solvent.  19. The composition of claim 18, wherein the inert film-forming agent is selected from the group consisting of methyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof.  20. A method of treating an allergic disorder in a mammal, comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition according to claim 16.  21. The method according to claim 20, in which the mammal is a human.  22. The method according to claim 20, in which the allergic disorder is allergic rhinitis.  23. A solid pharmaceutical composition comprising norastemizole or a pharmaceutically acceptable salt thereof, a solvent, a binder, a disintegrant, a lubricant, the disintegrant being a super disintegrant.  24. The composition according to p. 23, characterized in that the super-disintegrant is sodium croscarmellose or sodium starch glycolate.  25. The composition according to paragraph 24, wherein the super-disintegrant is croscarmellose sodium. Priority on points:
03/26/1997 and 05/06/1997 - according to claims 1-15, 23-25;
03/25/1998 - according to PP.16-22.

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