MXPA99008710A - Chemically and thermally stable norastemizole formulations - Google Patents

Abstract

The present invention relates to chemically and thermally stable pharmaceutical formulations of the potent antihistamine, norastemizole. The compositions are lactosefree, nonhygroscopic, or anhydrous, or comprise large particles or inertly coated norastemizole, or a pharmaceutically acceptable salt thereof, and are stable and easily manufactured.

Description

CHEMICAL AND THERMALLY STABLE NORASTEMICIOL FORMULATIONS REFERENCE TO THE RELATED APPLICATIONS This application is a continuation in part of the pending application No. 08 / 851,786, filed on May 6, 1997, which is a continuation in part of the pending application No. 08 / 824,477, filed on March 26, 1997, both of which are expressly incorporated herein by reference in their entirety.

FIELD OF THE INVENTION The present invention relates to chemically and thermally stable pharmaceutical compositions containing norastemizole.

BACKGROUND OF THE INVENTION Multiple factors affect the stability of a pharmaceutical product, which include the stability of the therapeutic drug ingredient (s), the potential interaction between the therapeutic drug ingredient (s) and the inactive ingredient (s), the process of manufacturing, packaging, the environmental conditions encountered during shipping, storage and handling, the time between manufacture and use and the type of dosage form.

In addition to the physical stability, the chemical stability of the pharmaceutical product must be considered. Knowledge of the physical and chemical stability of a pharmaceutical formulation is very important for at least three primary reasons. First of all, a pharmaceutical product should preferably look fresh, elegant and professional. Any change in physical appearance and color that includes gradual loss of color, color variation, appearance of turbidity and the like can cause the patient to lose confidence in the product. Secondly, since some products are distributed in multi-dose containers, the uniform dosage of the therapeutic agent (s) should be guaranteed over time. For example, a non-uniform dosing pattern can be indicated by a cloudy solution, a broken emulsion, a discolored tablet, a bleached capsule or the like. Third, the therapeutic drug ingredient (s) must be available to the patient during the expected life in storage of the dosage form. A breakdown in the physical or chemical integrity of the dosage form may result in an absence of bioavailability or modified bioavailability to the detriment of the therapeutic drug ingredient (s). A variety of pharmaceutical dosage forms are available for the satisfactory administration of multiple drugs marketed. Common pharmaceutical dosage forms are mentioned in the United States / National Formulary USP / NF) which includes, but is not limited to, aerosols, capsules, lozenges, eye drops, creams, emulsions, extracts, fluid extracts, gels, inhalations, injections, lotions, magmas, milks, ointments, pastes, pellets or implants, powders, solutions, ophthalmic solutions, oral solutions, otic solutions, pills, topical solutions, spirits, suppositories, suspensions, sublingual tablets, syrups, tablets, tinctures , troches, aromatic waters and the like. For oral administration, syrups, solutions, suspensions, troches, tablets and capsules are preferred. However, to further facilitate administration, to increase convenience in transportation and to improve patient acceptance with a prescribed dosage regimen, troches, tablets and hard and soft gelatin capsules are more preferred. In some cases tablets over capsules are preferred because it is sometimes easier to swallow the tablets. Commonly, the troches, tablets and capsules contain the pharmaceutical ingredient, a diluent and other excipients, such as lubricants and the like, which are well known in the art. Well-known excipients include, for example, coating agents, colorants, desiccants, emulsifying agents, solubilizing agents, flavoring agents, anti-agglutinating agents, plasticizers, suspending agents, viscosity-increasing agents, binders, diluents, wetting agents and the like. Lactose is a commonly used diluent or excipient. Spray-dried lactose is a commercially available form of lactose that is widely used as an excipient for direct compression. Since the arrival of spray-dried lactose, its use as an excipient has spread. The rapid acceptance of spray-dried lactose is due, in part, to its easy incorporation into direct compression tablets. In this application, the spray-dried lactose is in its ready-to-use form and does not require further granulation or introduction of complicated processing steps. Spray-dried lactose can also be easily and conveniently incorporated into a trocisco dosage form or a capsule. Spray-dried lactose can be added directly to a medicament to produce a desired dilution ratio therewith. Then, for example, the combination of the lactose and the drug can be compressed dry in a tablet or formulated in a troche or a capsule with other excipients, as necessary. 'Lactose, whether spray dried or not, is usually present in the balance between its alpha and beta forms where the interconversion between these forms is continuous. Lactose alpha 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 occurs only in its anhydrous form, while alpha lactose can be obtained in its anhydrous form or as a monohydrate. During the interconversion between the alpha and beta forms of lactose an aldehyde intermediate is formed which is known to be incompatible with most primary amines. The primary amines add to the carbonyl carbon of the aldehydes (and ketones) to form imines: H H -C = 0 + RNH2 - C = N-R + H20 (one amine) The incompatibility of most primary amines with lactose is well 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 Indust. Pharm. , 17 (4): 617-630 (1991).

Castello et al. tested the compatibility of amphetamine sulfate (a primary amine salt) with lactose. They found that a mixture of lactose and amphetamine sulfate becomes discolored, especially in the presence of alkaline lubricants such as magnesium stearate. Blaug et al., Tested dextroamphetamine sulfate (a primary amine salt) with spray-dried lactose. They found that the lactose formed a Schiff base (ie, an imine) in the presence of dextroamphetamine sulfate. Hartauer et al., Tested aminophylline with lactose, and found that some incompatibility, evidenced by discoloration, between aminophylline and lactose occurred especially when heat of about 60 ° C was applied. Aminophylline contains a ratio of two molecules of theophylline (a secondary amine) to one molecule of ethylenediamine (a primary amine). However, Hartauer et al. tested these components and found that although theophylline alone (a secondary amine) did not react with lactose in the presence or absence of heat at 60 ° C, ethylenediamine reacted with lactose, especially when heated to 60 ° C. In this way, the incompatibility of aminophylline with lactose appeared to be the result of the incompatibility of the primary amine component of aminophylline, ethylenediamine with lactose. The drug astemizole, a secondary amine, appears to be compatible with lactose, as is commercially available as HISMANAL® in a tablet dosage form containing lactose. According to the Physician's Desk Reference, 50th edition, Medical Economics Co. , Montvale,? J, p. 1293 (1996), each Hismanal® tablet contains 10 mg of astemizole, lactose, corn starch, cellulose, microcrystalline, pregelatinized starch, povidone K90, magnesium stearate, colloidal silicon dioxide, and sodium lauryl sulfate. In the same way, it is expected that norastemizole, another secondary amine and the primary metabolite of astemizole should be compatible with lactose, especially in the absence of applied heat. Norastemizole has been reported as more potent and less toxic than astemizole. In this way, norastemizole is an attractive alternative for astemizole for the treatment of allergic disorders. It should be recognized that astemizole and norastemizole are antihistamines containing secondary amines; however, norastemizole has two secondary amine portions, while astemizole has one.

SUMMARY OF THE INVENTION The present invention relates to the stable pharmaceutical dosage forms of norastemizole which prevents incompatibility between norastemizole and lactose. In one aspect, the present invention relates to a lactose-free pharmaceutical composition that includes norastemizole, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient other than lactose. In another embodiment, the invention relates to a solid pharmaceutical composition that includes norastemizole, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the excipient is not lactose. In a preferred embodiment, at least one pharmaceutically acceptable non-lactose excipient is a binder, a filler or mixtures thereof. In another preferred embodiment, at least one pharmaceutical excipient is a binder, a filler or mixtures thereof. In a preferred embodiment, the above excipients further include a lubricant, a disintegrant or mixtures thereof. In a more preferred embodiment, the excipients are croscarmellose, microcrystalline cellulose, pregelatinized starch and magnesium stearate. In a preferred embodiment, the disintegrant is a super disintegrant. In another embodiment, the pharmaceutical composition is virtually free of all mono- or disaccharide excipients. The invention also relates to a thermally stable, solid, lactose free pharmaceutical composition containing norastemizole or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In another embodiment, the invention relates to a solid, chemically stable, lactose-free pharmaceutical composition that includes from about 1% to about 50% by weight of norastemizole, or a pharmaceutically acceptable salt, and from about 99% to about 50% by weight. Weight of at least one pharmaceutically acceptable excipient. In a second embodiment, the invention comprises non-hygroscopic pharmaceutical compositions containing 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 virtually free of bound water, ie, water available to precipitate norastemizole / excipient interactions, such as, but not limited to, the interactions between lactose and norastemizole. . The present invention also provides non-hygroscopic, chemically and thermally stable pharmaceutical compositions containing norastemizole and at least one pharmaceutically acceptable excipient, wherein the excipient may include lactose or other mono- or disaccharides. In other words, the norastemizole compositions of the present invention are: (a) practically free of lactose (and preferably practically free of mono or disaccharides), (b) include excipients substantially free of bound water, which excipients may include lactose, such as alpha lactose monohydrate or other mono or disaccharides, or (c) contain large particles or particles coated with an inert agent, together with excipients which may include lactose, such as alpha lactose monohydrate or other mono- or di saccharides. In any case, the applicants have discovered highly stable norastemizole formulations. Furthermore, it should be noted that the compositions of the invention that are non-hygroscopic however may include some hygroscopic ingredients; nevertheless, the general composition must be practically non-hygroscopic. In addition, the non-hygroscopic pharmaceutical compositions of the present invention may also utilize hydrated ingredients. In still another embodiment, the present invention comprises anhydrous pharmaceutical compositions, the compositions contain norastemizole or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, which may include lactose. These compositions can be prepared using anhydrous or low moisture containing ingredients using low humidity or low humidity conditions so that the resulting pharmaceutical composition is substantially anhydrous. In addition, the present invention provides chemically and thermally stable anhydrous pharmaceutical compositions containing norastemizole and at least one pharmaceutically acceptable excipient, wherein the excipient may include lactose or other mono- or disaccharides. The invention also encompasses pharmaceutical compositions for the treatment of histamine-induced disorders that contain large particles of norastemizole or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The present invention also provides chemically and thermally stable pharmaceutical compositions having large particles of norastemizole and at least one pharmaceutically acceptable excipient, wherein the excipient may include lactose or other mono- or disaccharides. In a preferred embodiment, about 40% by weight or more of the large particles of norastemizole, or the pharmaceutically acceptable salt thereof, consist of particles having a size of 200 μ or greater. In one embodiment, the pharmaceutical composition of large particles may include lactose as a pharmaceutically acceptable excipient.

The invention also comprises solid pharmaceutical compositions for the treatment of histamine-induced disorders, containing a therapeutically effective amount of coated norastemizole, or a pharmaceutically acceptable salt thereof, containing norastemizole, or a pharmaceutically acceptable salt thereof, coated with a Inert coating agent coating agent, and a pharmaceutically acceptable excipient. The present invention further provides chemically and thermally stable pharmaceutical formulations of coated norastemizole which prevents incompatibility between norastemizole and lactose, wherein the excipient may include lactose or other mono- or disaccharides. In one embodiment, the excipient consists of lactose. In another embodiment, the coated norastemizole, or a pharmaceutically acceptable salt thereof, further consists of a granulated formulation of norastemizole, or a pharmaceutically acceptable salt thereof, and a pharmaceutically stable inert excipient, wherein the granulated formulation is coated with an agent inert coating. In a preferred embodiment, the inert agent for the coating consists of an inert film forming agent in a solvent. In a preferred embodiment, the inert film-forming agent is selected from the group consisting of methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose and mixtures thereof. In one embodiment, norastemizole is present in an amount from about 1 mg to about 200 mg. In a more preferred embodiment, norastemizole is present in an amount from about 2 mg to about 100 mg. In another preferred embodiment, norastemizole is present invention in a therapeutic amount effective for the treatment of an allergic disorder. In yet another preferred embodiment, the effective therapeutic amount is sufficient for the prophylaxis or treatment in humans of an allergic disorder. The invention also relates to a pharmaceutical composition that 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 provided in a tablet or capsule dosage form. The invention also relates to a method for the treatment of at least one allergic disorder in a mammal by administering an effective therapeutic amount of one of the above compositions, in a preferred embodiment, the mammal is an ij.ui --- -t -.- o. In a preferred embodiment, the allergic disorder is allergic rhinitis.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 represents the chemical structure of norastemizole. Figure 2 depicts in b & graph format the change in the initial potency of a dosage form of norastemizole and different pharmaceutical excipients when the dosage form is exposed to a temperature of 60 ° C to 75% relative humidity using i non-hermetic containers (ie small bottles with screw cap).

DETAILED DESCRIPTION OF THE INVENTION Applicants have discovered that, even in the absence of applied heat, surprisingly, the discoloration reaction found with the primary amines and lactose also encounters norastemizole. In this way, there seems to be an incompatibility hitherto unappreciated between the secondary amine, norastemizole and lactose. Therefore, it is desirable to formulate norastemizole dosage forms that are lactose free. In addition, applicants have also discovered that lactose and norastemizole instability can be initiated and / or accelerated upon exposure of a norastemizole / lactose formulation to water, including atmospheric moisture., for example, humidity. Instability also starts and / or accelerates with exposure to heat at temperatures greater than about 60 ° C. In addition, applicants have also discovered that the lactose and norastemizole instability can be initiated and / or accelerated by the high surface area of the norastemizole small particles traditionally used in pharmaceutical compositions with the exposure of a norastemizole / lactose formulation. In addition, applicants have also discovered that the lactose and norastemizole instability can be inhibited or prevented by coating the norastemizole particles prior to the formulation of norastemizole with the reactive excipients such as lactose. In the PCT application PCT / US93 / 08349, published as WO 94/07495, a formulation of norastemizole which lacks lactose is proposed in Example 4. The formulas A, B and C, of Example 4, each contain 1.0 wt% of magnesium stearate BP, 94.0, 89.0 and 79.0 by weight of 1500 starch (a pregelatinized starch commercially available from Colorcon Ltd), respectively, and the rest of the composition is a metabolite of astemizole (e.g., norastemizole). However, in practice it would not be possible to prepare or use the lactose-free formulations of Example 4 because the magnesium stearate BP and the starch 1500 are incompatible in the percent by weight described. In other words, the formulations of Example 4 in this PCT publication are unsuitable for actual pharmaceutical use. Furthermore, this publication neither discloses nor suggests that norastemizole and lactose are incompatible, as evidenced by the formulation of norastemizole-containing lactose tablets in Example 5 herein. In view of the problems not hitherto appreciated, associated with pharmaceutical formulations including secondary amines, norastemizole and lactose, it is desired to prepare solid, stable, norastemizole pharmaceutical formulations that avoid incompatibility between norastemizole and lactose. The present invention advantageously recognizes and provides lactose-free norastemizole dosage formulations. Based on the pharmacological benefits of norastemizole over astemizole, there is a need for high performance and stable norastemizole dosage forms. To date, there is no formulation of norastemizole, stable, available commercially. However, the inventors have found that by eliminating lactose and using the alternative ingredients described herein, the lactose-free norastemizole dosage forms are surprisingly chemically, physically and thermally stable. This stability can be obtained by the present invention without losing the ease of manufacture or the operation of the dose. A feature of the present invention, thus refers to chemically and thermally stable pharmaceutical formulations that include norastemizole, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient that does not include or utilize any form of lactose. Lactose has been widely accepted and used by the pharmaceutical industry, among others, due to its ease of handling. However, applicants have advantageously found that formulations containing norastemizole and lactose are unstable over time and degrade more rapidly upon exposure to heat and moisture. Secondary amines were previously considered compatible with lactose, especially at ambient temperatures or where exposure to heat (eg, below about 60 ° C) is minimal or avoided altogether. As noted, for example, the drug astemizole is available in a tablet dosage form containing lactose and other excipients under the Hismanal® brand. It has now been discovered that physical and / or chemical incompatibility exists between the secondary amine, nora = te izol and lactose. Without being limited by theory, it is considered that the incompatibility of norastemizole with lactose results from the formation of enamines due to the reaction between the intermediate aldehyde of lactose and a secondary amine: C - CH = 0 + HN R2 - C = C NR2 + H20 (one amine) It has also been found that the incompatibility still exists at ambient temperatures (e.g., temperatures less than about 60 ° C) and at the relative humidity of the environment. In addition, applicants have also discovered highly stable pharmaceutical compositions containing norastemizole without the use of widely accepted excipient lactose. In accordance with a feature of the present invention, norastemizole is provided in lactose-free pharmaceutical compositions. These compositions have potent antihistamine activity and are useful in the treatment of various conditions. Some of these conditions include, for example, allergic rhinitis, asthma and other allergic disorders, vertigo, movement disease, vestibular disturbances (e.g., Meniere's disease), diabetic retinopathy, other disorders of small spleens associated with diabetes mellitus. It is important to note that these lactose-free compositions provide a stable and convenient dosage form for delivering norastemizole to humans. The lactose-free compositions of the invention are stable, inter alia, in that they have a significant shelf life. In addition, the compositions of the invention remain stable even when exposed to moderate temperature and humidity changes. In addition, although the compositions of the invention are free of lactose, the compositions are still easily manufactured, and the compositions have the desirable properties for the operation of the dosage. The compositions of the invention include solid unit dose formulations containing norastemizole, or a pharmaceutically acceptable salt thereof, and at least one other pharmaceutically acceptable lactose excipient. The compositions may also optionally include other therapeutic ingredients, binders / fillers, disintegrants, lubricants anti-caking agents, preservatives, film-forming agents, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, dispersing agents and / or agents surface assets. However, any optional ingredient may be compatible with norasteir-izcl, a secondary amine, to ensure the stability of the formulation. It is preferred that the lactose-free dosage form of norastemizole prepared according to the present invention contains norastemizole and at least one non-lactose excipient. Examples of these excipients are well known in the art and are mentioned in USP (XXI) / NF (XVI), incorporated herein by reference to their completeness. Furthermore, it is preferred that the lactose-free norastemizole dosage forms prepared according to the present invention contain norastemizole, a binder / filler and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. It is even more preferable that the lactose-free norastemizole dosage forms prepared according to the present invention contain norastemizole, microcrystalline cellulose, pregelatinized starch and magnesium stearate. It has also been discovered that other sugars such as fructose and sucrose, cause degradation similar, although not as severe, to that caused by lactose when used in combination with formulations containing norastemizole. Thus, in another embodiment, the lactose-free pharmaceutical compositions contain norastemizole, or a pharmaceutically acceptable salt thereof, and at least one non-lactose pharmaceutically acceptable excipient, and do not contain any mono- or disaccharide excipients, including, but not limited to, to glucose, sucrose and fructose. As already mentioned, formulations of norastemizole containing lactose that are exposed to unbound water, eg, moisture, degrade more easily. The addition of water (for example 5%) is widely accepted in the pharmaceutical art as a means of simulating long-term storage to determine the characteristics as shelf life or the stability of the formulations over time. See, Jens T. Carstensen, Drug Stability: Principies &; Practice, 2a. ed. Marcel Dekker, NY, NY, 1995 pp. 379-80. In effect, water and temperature accelerate e_U study. In addition, the effect of water on a formulation is of great importance since favorable conditions for hygroscopicity, for example, moisture, are commonly encountered during the manufacture, handling, packaging, storage, shipping and use of the formulation. Thus, it is evident that the use of lactose in pharmaceutical compositions or formulations containing norastemizole should be avoided due to the substantial contact with moisture that the compositions have under normal manufacturing, packaging and storage conditions. In addition, although the excipients other than lactose can be readily used for the manufacture of the lactose-free pharmaceutical compositions of norastemizole described above without affecting the therapeutic performance and ease of manufacture of the compositions, the spray-dried lactose remains an excipient of choice . In the spray-dried form, lactose is among the best loading materials for direct compression and is very effective for low dose formulations (eg, <50 mg per dose) where the compatibility of the active ingredient does not play an important role in the formulation. See, for example, R. Shangraw, Selection of Manufacturing Process and Excipients with and Emphasis on Direct Compression, Course material from Granulation, Tableting, and Capsule Technology, Center for Professional Advancement, East Brunswick, NJ, 1996. Therefore, when possible, it is desirable to include lactose among the available excipients, possible for the solid dosage forms or the pharmaceutical composition of norastemizole. Thus, as an alternative, the present invention comprises chemically and thermally stable pharmaceutical compositions, in particular solid pharmaceutical formulations containing norastemizole, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients, including but not limited to they are limited to lactose, wherein formulations containing lactose are anhydrous, ie, virtually free of bound water. The invention further comprises non-hygroscopic, stable, thermally and chemically stable pharmaceutical compositions containing norastemizole or a pharmaceutically acceptable salt thereof, and one or more excipients or ingredients including, but not limited to, lactose. Without adhering to any theory, these stable, anhydrous or non-hygroscopic pharmaceutical compositions are based, in part, on the discovery of applicants that the incompatibility between norastemizole and lactose, or other mono- or disaccharides, is accelerated and / or possibly begins by exposing these formulations to unbound water. In this way, the preparation of pharmaceutical compositions that are virtually free of unbound water will prevent the accelerated degradation of norastemizole that occurs when a reactive excipient is used and unbound water is present. Thus, if the lactose is a desired excipient, another aspect of the invention relates to non-hygroscopic or anhydrous pharmaceutical compositions containing norastemizole, lactose and optionally one or more additional excipients or ingredients wherein the resulting pharmaceutical compositions are practically free. of unbound water. It should be recognized that non-hygroscopic or anhydrous formulations can be prepared by standard methods, provided that the suitable excipients are selected so that the resulting pharmaceutical compositions are virtually free of unbound water, and the process is carried out using low-water conditions. humidity. The norastemizole pharmaceutical composition, anhydrous, prepared according to the present invention must be prepared and stored so as to maintain the anhydrous nature. Therefore, these compositions will be packaged using materials well known in the art to avoid exposure of the pharmaceutical composition to water, allowing them to be included in suitable formulation equipment. This packaging shall include, but not be limited to, hermetically sealed sheets, plastics or the like, unit dose containers, blister packs or packets of strips. Accordingly, a second alternative aspect of the invention comprises a method of preparing a solid pharmaceutical formulation containing norastemizole and lactose which method comprises mixing under anhydrous or low-moisture conditions, norastemizole, or a pharmaceutically acceptable salt thereof, and lactose. , where these ingredients are practically free of unbound water. The method can optionally further comprise packaging the solid, anhydrous or non-hygroscopic norastemizole formulation under low humidity conditions. By using these conditions, the risk of contact with water is reduced and the degradation of norastemizole is prevented or practically reduced during processing and storage. In addition, the final packaged product has little or no unbound water present that substantially improves stability and prevents degradation. These compositions may be provided in hermetically sealed packages such as vial vials, sealed packages, blister packs and other vacuum sealed and moisture-free containers well known to the skilled artisan in the pharmacy. Traditionally, when preparing pharmaceutical compositions or formulations, the active ingredient or therapeutic agent, (eg, norastemizole) is screened to decrease the particle size and / or narrow the particle size distribution. More often, this is done to optimize the different physicochemical characteristics of the formulation, such as dissolution, content uniformity, bioavailability of the active ingredient, and the like. The solution is of particular interest with norastemizole, since the solubility is relatively low (approximately 10 mg / tt-1 at pH 3/4 and lower than above pH 4. Without being limited to any particular theory, however, applicants consider that the interaction between norastemizole and reactive excipients, such as lactose, can be affected by the surface area of the norastemizole particles in the pharmaceutical composition or formulation.Therefore, another embodiment of the present invention comprises the pharmaceutical compositions for the treatment of histamine-induced disorders containing large norastemizole particles, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier: Pharmaceutically acceptable carriers, suitable for use in these compositions include carriers which may consist of one or more excipients selected from the group consisting of inert excipients and exci reactive teeth, such as lactose or other mono- or disaccharides. These pharmaceutical compositions of "large particles" of norastemizole have suitable physical and chemical characteristics (in terms of dissolution, uniformity of content, bioavailability and the like), but they do not present incompatibility with reactive containers, such as lactose [sic]. In a preferred embodiment, the norastemizole, or a pharmaceutically acceptable salt thereof, present in the composition has a particle size distribution in which about 40% by weight or more of norastemizole, or a pharmaceutically acceptable salt thereof, consists of particles which have a size of 200 μ or greater, preferably greater than approximately 250 μ. Another means to inhibit or prevent the interaction between norastemizole and reactive excipients, such as lactose, in a pharmaceutical composition is to prevent norastemizole from coming into contact with any reactive excipients in the composition. One way in which this can be achieved is to coat the norastemizole particles with an inert or non-reactive coating before the formulation with the reactive excipients. Preferably, the inert coating should not significantly influence the pharmacodynamic characteristics (e.g., the time of onset of efficacy, and in vivo absorption) of the composition. Accordingly, another embodiment of the present invention relates to solid pharmaceutical compositions for the treatment of histamine-induced disorders containing a therapeutically effective amount of coated norastemizole, or a pharmaceutically acceptable salt thereof, containing norastemizole, or a pharmaceutically salt acceptable thereof, coated with an inert coating agent, and a pharmaceutically acceptable carrier. In a preferred embodiment, the norastemizole, or a pharmaceutically acceptable salt thereof, is first granulated with an inert excipient (e.g., starch), and then the resulting granules are coated with an inert or non-reactive coating agent. Then, the resulting coated norastemizole can be mixed with other excipients, including the reactive excipients. Suitable inert coating agents, and methods for coating the particles or granules, are well known in the art. Inert coating agents usually consist of an inert film former, dispersed in a suitable solvent, and may also contain other pharmaceutically acceptable adjuvants, such as colorants and plasticizers. Preferably, the norastemizole particles or granules are coated using aqueous or non-aqueous film coating or microencapsulation techniques. Suitable inert film-forming agents include, but are not limited to, celluloses such as methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose and sodium carboxymethylcellulose.; vinyls such as polyvinyl pyrrolidione [sic]; glycols such as polyethylene glycols; acrylics such as dimethyl aminoethyl methacrylate copolymer methacrylate acid ester, and ethylacrylate methyl methacrylate copolymer; and other carbohydrate polymers such as maltodextrins and polydextrose. Preferably, the inert coating agent contains a hydrophilic film-forming agent such as hydroxypropylmethylcellulose, so that in vivo absorption is not significantly delayed. Once the particles or granulated formulations of norastemizole are coated with the inert coating agent, the coated norastemizole can be formulated using standard techniques, including, but not limited to, mixing, granulation, compression or combinations thereof, with other inert excipients. and / or reagents such as lactose, to be the different dosage forms such as tablets, caplets, 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 thereof, which is also a medically acceptable amount thereof. The actual dosage levels of norastemizole in the pharmaceutical compositions of the present invention may be varied to obtain an amount of norastemizole which is effective to achieve the desired therapeutic response for a specific patient, the pharmaceutical composition of norastemizole and the administration cdc, without being toxic to the patient. The dose level selected and the frequency of administration of the pharmaceutical compositions of the invention will depend on a variety of factors including the route of administration, the time of administration, the rate of excretion of the therapeutic agent (s) including norastemizole, duration of treatment, other medications, compounds and / or materials used in combination with norastemizole, age, sex, weight, condition, general health and previous medical history of the patient who is being treated, and well-known similar factors in the medical technique. For example, it is very likely that the dosage regimen varies with pregnant women, nursing mothers and children in relation to healthy adults. A physician with ordinary skill in the art can easily determine and prescribe the effective therapeutic amount of the necessary pharmaceutical composition. For example, the physician could initiate doses of norastemizole used in the pharmaceutical composition of the present invention at levels lower than those required to obtain the desired therapeutic effect and gradually increase the dose until the desired effect is obtained. An adequate daily dose of norastemizole will be the amount of norastemizole which is the lowest effective dose to produce a desired therapeutic effect. This effective therapeutic dose will generally depend on the factors described above. For example, the unit dose of lactose-free norastemizole may contain from about 1 mg to about 200 mg and, preferably, from about 2 mg to about 100 mg. For example, unit doses may be formulated with 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, or 62.5 mg of norastemizole If desired, the effective daily dose of norastemizole can be administered separately at suitable intervals during the day, optionally, in unit dosage forms such as two, three, four, five, six or more sub-doses. As already noted, the preferred dosage forms are tablets, capsules, troches, lozenges, pills, wafers, syrups, capsules and the like. However, other pharmaceutically acceptable dosage forms such as powders, granules, dragees and the like can be used. It will be noted that all components containing the norastemizole dosage forms prepared according to the present invention preferably meet or exceed the standards for the ingredients and pharmaceutical combinations thereof in the USP / NF. The purpose of the USP / NF is to provide authorized standards and specifications for materials and substances and their preparations that are used in the practice of healing techniques. The USP / NF establishes titles, definitions, descriptions and standards for identity, quality, concentration, purity, packaging and labeling, and also, where practicable, provide bioavailability, stability, proper handling and storage procedures and methods for their examination and formulas for their manufacturing or preparation. The lactose-free, non-hygroscopic, anhydrous, large-particle, and norastemizole-coated dosage forms described herein and claimed comply with the pharmaceutical standards set forth in the USP / NF (eg, USP XXI / NF XVI) for each of the ingredients, as well as the dosage forms of norastemizole without lactose, non-hygroscopic, anhydrous, large-particle or coated, prepared with these ingredients. In effect, the lactose-free, non-hygroscopic, anhydrous, large-particle or coated dosage forms are said to be pharmaceutically acceptable dosage forms prepared from pharmaceutically acceptable ingredients in pharmaceutically acceptable combinations and pharmaceutically acceptable amounts to at least meet the standards established in USP XXI / NF XVI that are incorporated in their integrity as reference herein. In addition, it should be noted that norastemizole can be prepared according to methods known in the art, including those described in copending application of United States No. 08 / 182,685 filed January 18, 1994, which is incorporated in the present as reference to it for the express purpose of teaching the methods to prepare norastemizole. The stability of a pharmaceutical product can be defined as the ability of a specific formulation, in a specific container, to remain within its physical, chemical, microbiological, therapeutic and toxicological specification although there are exceptions, and to remain at least approximately 90% of the marked power level. In this way, for example, the expiration date is defined as the time in which the pharmaceutical product will remain stable when stored under the recommended conditions. Multiple factors affect the stability of a pharmaceutical product, including the stability of the therapeutic ingredient (s), the potential interaction between the therapeutic ingredient (s) and inactive (s) (eg norastemizole and the excipients) and the like. Physical factors such as heat, light and humidity can initiate or accelerate chemical reactions. For convenience, certain terms used herein are defined as follows. The term "carrier" as used herein is synonymous with the term "vehicle." The term "lactose free" as used herein is intended to understand that the amount of lactose present, if any, in the dosage form of norastemizole is insufficient to cause the incompatibility between norastemizole and lactose discovered by the inventors to affect detrimentally the potency of norastemizole below about 90% of the initial potency over 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 pharmaceutical composition, for example alpha lactose monohydrate. In the same way, the term "anhydrous" as used herein means the amount of unbound water present, if any, in the dosage form of norastemizole is insufficient to initiate and / or accelerate the incompatibility between norastemizole and lactose. . In addition, "anhydrous", "anhydrous conditions" or "anhydrous nature" as used herein means practically free of unbound water including moisture. The term "non-hygroscopic" as used herein means that the total formulation is practically non-hygroscopic, ie, it does not provide enough unbound water to initiate and / or accelerate the incompatibility between norastemizole and reactive excipients such as lactose. The term "additives" is synonymous with the term "excipients" as used herein. The term "practically free" means less than about 5% by weight, preferably less than about 1% by weight, and more preferably less than about 0.1% by weight. The term "large particle" as used herein means a composition wherein the norastemizole includes about 40% by weight or more of norastemizole particles, or a pharmaceutically acceptable salt thereof, with a size of 200 μ or greater, of preference greater than about 250 μ. The terms "coated", "inert coating" or "inherently coated" as used herein preferably means an inert coating agent used to coat norastemizole particles and inhibit the interaction of the particles with reactive excipients, such as lactose. Although non-inert coatings suitable for use in conventional pharmaceutical applications are also suitable for use with the lactose-free, non-hygroscopic, anhydrous and large-particle formulations of the invention, it is preferred that any coating used be inert and inhibit the interaction of norastemizole with any of the reactive excipients. The term "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that are, within the scope of medical judgment, suitable for administration to and for use in contact with tissues and fluids. of humans and animals without excessive toxicity, irritation, allergic response or other problem or complication, in proportion to a reasonable medical benefit / risk ratio. In addition, the term "pharmaceutically acceptable" excipient is used to understand that there are no adverse chemical or physical incompatibilities between norastemizole (or a salt thereof) and any of the excipient components of a given dosage form. For example, an adverse chemical reaction is one in which the potency of norastemizole (or a salt thereof) is reduced or increased in a deleterious manner 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 the norastemizole (or the salt thereof) becomes excessively sweet, sour or the like to the extent that the dosage form becomes unpleasant. Each of the excipients must be "acceptable" in the sense of being compatible with the other ingredients of the norastemizole formulation and not injuring the patient. The physical incompatibility refers to the incompatibility between the different components of the dosage form such as norastemizole (or the salt thereof) and any of the excipients thereof. For example, the combination of the excipients and norastemizole can form an excessively hygroscopic mixture or an excessively segregated mixture to the extent that the desired form of the dosage form (eg, tablet, troche, etc.), its stability or the like can not be maintained sufficiently to allow the dosage form to be administered in compliance with a prescribed dosage regimen as desired. More often, antihistamines such as astemizole or norastemizole are administered orally by means of a solid dosage form such as tablets, capsules, troches, caplets and the like. In addition, capsule dosage forms such as hard gelatin capsules, soft gelatin capsules and the like can also be used. However, tablets retain their preferred dosage form due to the advantages they provide to the patient (eg, dosing accuracy, compact shape, ease of transport, for its taste as well as the ease of administration) and for the manufacturer (for example, the simplicity and economy of the preparation, the stability as well as the convenience in packaging, shipping and distribution). The tablets are solid pharmaceutical dosage forms containing therapeutic drug substances with or without suitable additives. For the medicinal substances or therapeutic ingredients of the present invention (ie, the dosage forms of lactose-free, non-hygroscopic, anhydrous, large-particle or coated norastemizole) with or without diluents, to be prepared in dosage form solid (for example tablets) with pressure, using available equipment, it is necessary that the material, in its crystalline form or powder, possess diverse physical characteristics. These features include, for example, the ability to flow freely, like a powder, or have consistency with compaction, and be easily released from the machine. Since most materials have none or only some of these properties, tablet formulation and preparation methods have been developed to impart these desirable characteristics to the materials to be compressed in a tablet or similar dosage form. As noted, in addition to the pharmaceutical or therapeutic ingredient the tablets and similar dosage forms may contain different materials known as additives. These additives are classified according to the function they perform in formulating the dosage form as a tablet, a caplet, a capsule, a troche or the like. A group of additives includes, but is not limited to, binders, diluents (fillers), disintegrants and lubricants. Although the following description of the different additives for use in the present invention relates specifically to the lactose-free dosage forms, those skilled in the art will readily understand that a sub-series of each category includes suitable additives for use in non-pharmaceutical compositions. hygroscopic, anhydrous, large particle or coated particles of the present invention. In addition, the non-hygroscopic, anhydrous, large-particle or coated pharmaceutical compositions of the present invention may also include lactose or other mono- or disaccharides as excipients. In another embodiment, the inorganic bisulfites can be used to improve the stability of any of the norastemizole compositions herein. For non-hygroscopic formulations special precautions can be taken in the choice of excipients and additives, so that in general, there is no propensity for moisture solution (absorption or adsorption) in the absence of adequate environmental controls. For example, excipients for use in these formulations include, but are not limited to, alpha lactose monohydrate, mannitol and the like. For anhydrous formulations, suitable anhydrous or low moisture forms of suitable excipients or additives identified below should be used, for example, AVICEL-PH-103 ™ and Starch 1500 LM. A binder is used to provide a free flowing powder from the mixture of the ingredients of the tablet so that the material flows when used in a tabletting machine. The binder also provides cohesiveness for the norastemizole tablet. Too little agglutinating will give flow problems and produce tablets that do not maintain their integrity. Too much can adversely affect the release (dissolution rate) of the tablet drug. In this manner, a sufficient amount of binder must be incorporated into the tablet to provide a free-flowing mixture of the tablet ingredients without adversely affecting the rate of dissolution of the pharmaceutical ingredients of the tablet. With lower dose tablets the need for good compressibility can be eliminated to some extent by the use of suitable diluent excipients called compression aids. The amount of binder used varies with the type of formulation and the mode of administration, and is easily discernible by those skilled in the art. Binders suitable for use with lactose-free, non-hygroscopic, anhydrous, large particle or norastemizole coating dosage preparations prepared in accordance with the present invention include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth powder, guar gum, cellulose and their derivatives (for example, ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, carboxymethylcellulose) sodium), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropylmethyl cellulose (for example, Nos. 2208, 2906, 2910), microcrystalline cellulose or mixtures thereof. Suitable forms of microcrystalline cellulose are, for example, materials marketed as AVICEL-PH-101, AVICEL-PH-103 and AVICEL-PH-105 (available from FMC Corporation, American Viscoce Division, Avicel Sales, Marcus Hook, PA. , EU). An exemplary binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose marketed as AVICEL RC-581 by FMC Corporation. Most commercial tablets weigh from about 100 mg to about 500 mg. Thus, for multiple potent drugs including the dosage forms of norastemizole, a loading material consists of a large portion of the tablet. The fillers (for example the diluents) are used to bulge the powder (for example, in the tablet or capsule) so that a tablet, capsule or other desirable dosage form of acceptable size can be produced. Commonly, the therapeutic ingredients are formed in a convenient dosage form of suitable size by the incorporation of a diluent therewith. As with the binder, agglutination of the drug with the filler material can occur and affect bioavailability. Accordingly, a sufficient amount of filler material must be used to obtain a desired dilution ratio without detrimentally affecting the release of the drug ingredient (s) from the dosage form containing the filler. In addition, a filler material that is physically and chemically compatible with the therapeutic ingredient (s) of the dosage form must be used. Thus, as already noted, the lactose should not be used with norastemizole to form the dosage forms of norastemizole prepared according to the present invention if no precautions have been taken to remove the unbound water. It is also preferable that the lactose-free dosage forms of norastemizole according to the present invention does not include mono- or disaccharides, such as, but not limited to, glucose, sucrose and fructose. The amount of filler used varies with the type of formulation and the mode of administration, and is readily discernible by those skilled in the art. Examples of fillers suitable for use with the lactose-free dosage forms of norastemizole prepared according to the present invention include, but are not limited to, talc, calcium carbonate (eg, granules or powder), cellulose microcrystalline, cellulose powder, dextrates, kaolin, mannitol, salicylic acid, sorbitol, starch, pregelatinized starch or mixtures thereof. The binder / filler in the pharmaceutical compositions of the present invention is usually present in about 50 to about 99% by weight of the pharmaceutical composition. Disintegrants are used to cause the tablet to disintegrate when exposed to an aqueous environment. Too much disintegrant will produce tablets that can disintegrate in the bottle due to atmospheric humidity and provide enough unbound water to initiate and / or accelerate the norastemizole lactose interaction. Too little may be insufficient for disintegration to occur and may thus alter the rate and degree of release of the active ingredient (s) from the dosage form. In this way, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally modify the release of the active ingredients should be used to form the norastemizole dosage forms prepared in accordance with the present invention. The amount of disintegrant used varies based on the type of formulation and mode of administration, and is readily discernible by those skilled in the art. Typically, about 0.5 to about 15% by weight of the disintegrant, preferably about 1 to about 5% by weight of the disintegrant can be used in the pharmaceutical composition. Suitable disintegrants that can be used to form the lactose-free dosage forms of norastemizole prepared according to the present invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium , crospovidone, polacrilin potassium, sodium starch glycolate, potato starch or tapioca, other starches, pregelatinized starch and other starches, clays, or other algin, other celluloses, gums or mixtures thereof.

Based on the physicochemical properties of norastemizole, it is usually desirable to formulate lactose-free, non-hygroscopic, anhydrous, large-particle or norastemizole-coated pharmaceutical compositions such that they dissolve very rapidly upon administration to the individual, by example, in the stomach of the individual. Thus, in a preferred embodiment, the lactose-free, non-hygroscopic, anhydrous, large-particle or coated pharmaceutical compositions of the present invention include a super-disintegrant such as, but not limited to, sodium croscarmellose or sodium starch glycolate. sodium. Whatever the dosage, adhesion of the ingredients of the dosage form to the punches of the tabletting machine should be avoided. For example, when the drug (eg, norastemizole) accumulates on the surface of the punch, it causes the surface of the tablet to be chopped and therefore unacceptable. Also, adhesion of the drug or other ingredients of the dosage form in this manner requires unnecessarily high ejection forces when the tablet is removed from the matrix. Excessive ejection forces can give rise to a high breakage rate and increase in the cost of production without mentioning the excessive wear of the dies. In practice it is possible to reduce the adhesion by wet kneading or by the use of high levels of lubricants, for example, magnesium stearate. However, the selection of a drug salt with good anti-adhesion properties also minimizes these problems. As noted, lubricant is used to improve the flow of the lactose-free norastemizole tableting powder mixture for the tableting machine and prevent adhesion of the tablet in the matrix after the tablet is compressed. Very little lubricant will not allow to prepare satisfactory tablets and too much will produce a tablet with a hydrophobic coating impervious to water. Because the lubricants are usually hydrophobic materials such as stearic acid, magnesium stearate, calcium stearate and the like, a hydrophobic coating impervious to water can be formed by the use of too much lubricant. In addition, a hydrophobic water-impermeable coating can inhibit the disintegration of the tablet and the dissolution of the drug ingredients. In this manner, a sufficient amount of lubricant should be used that facilitates the release of the compressed tablet from the matrix without forming a hydrophobic coating impervious to water that interferes in a detrimental manner with the desired disintegration and / or dissolution of the ingredient (s). s) of the drug.

Suitable lubricants for use with the norastemizole lactose-free dosage forms prepared according to 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, talcum, hydrogenated vegetable oil (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil) and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar or mixtures thereof. Additional lubricants include, for example, a silica gel, Syloide (AEROSIL 200, manufactured by WR Grace Co. of Baltimore MD), a synthetic silica coagulated aerosol (marketed by Deaussa Co. of Plano, Texas) CAB-O-SIL (a pyrogenic silicon dioxide product marketed by Cabot Co., Boston, Mass.) or mixtures thereof. Optionally, a lubricant may be added, usually in an amount of less than about 1% by weight of the pharmaceutical composition. Another class of additives for use with norastemizole dosage forms includeBut not limited to, anti-caking agents, antimicrobial preservatives, coating agents, colorants, desiccants, flavors and perfumes, plasticizers, viscosity increasing agents, sweeteners, buffering agents, humectants and the like. Suitable anti-caking agent for use with free dosage forms of lactose norastemizole made in accordance with the present invention include, but are not limited to, calcium silicate, magnesium silicate, silicon dioxide, colloidal silicon dioxide, talc or mixtures thereof. Antimicrobial preservatives for use with the free dosage forms of lactose norastemizole made in accordance with the present invention include, but not are limited to, solution benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butyl paraben, cetylpyridinium chloride, chlorobutanol, cresol, dihydroacetic acid, ethylparaben, methylparaben, phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, potassium sorbate, propylparaben, sodium benzoate, dehydroacetate, sodium propionate, sodium sorbic acid, thimersol, thymol or mixtures thereof. Suitable for use with free dosage forms of lactose norastemizole made in accordance with the present invention include, but are not limited to, sodium carboxymethyl cellulose, cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceutical glaze, hydroxypropyl cellulose coating agents , methylcellulose hidroxipropi1 (eg, Nos .: 2208, 2906, 2910), hydroxypropyl methylcellulose phthalate (e.g., Nos .: 2,007,731, 220824), methylcellulose, polyethylene glycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, Carnauba wax, microcrystalline wax or mixtures thereof. The amount of the coating agent and carrier vehicle (aqueous or non-aqueous) used varies with the type of formulation and the mode of administration, and is easily discernable by those skilled in the art. cold on the bed of the tablet in a continuous or alternate mode with a spray cycle for drying; . Ar the solution for film coating. For non-hygroscopic, anhydrous, large-particle or coated pharmaceutical compositions of the invention containing reactive excipients such as lactose, non-aqueous operations are preferred, for example non-aqueous coatings should be used. The covering solution can be atomized using positive pneumatic displacement systems or peristaltic pump in a continuous or intermittent spray drying cycle. The specific type of spray application is selected depending on the drying efficiency of the drum for the coating. In most cases the coating material is atomized until the non-hygroscopic, large-particle, anhydrous or coated lactose-free norastemizole tablets until the desired thickness and desired appearance of the tablet is obtained. Many different types of coatings can be applied as enteric coatings, slow release coatings or fast dissolution type for fast action tablets. Preferably, fast dissolving type coatings are used to allow faster release of the active ingredients, giving rise to an accelerated onset. The thickness of the coating of the film-forming polymer applied to the tablet, for example, can vary. However, it is preferred that the thickness simulate appearance, texture (tactile and taste in the mouth) and the function of a gelatin capsule. When a more rapid or delayed release of the therapeutic agent (s) is desired, one skilled in the art should readily recognize the type of film and thickness, if any, for use based on characteristics such as desired blood levels of the active ingredient, release rate, solubility of the active ingredient and the desired functioning of the dosage form. Different film-forming agents suitable for use in the coating of a final dosage form, such as tablets containing the norastemizole formulations present free of lactose, non-hygroscopic, anhydrous, large-particle or coated include, for example, methylcellulose , hydroxypropyl methylcellulose (PHARMACOAT 606 6 cps), polyvinylpyrrolidone (povidone), ethylcellulose (ETHOCEL 10 cps), different methacrylic acid derivatives and methacrylic acid esters, cellulose acetate phthalate or mixtures thereof. Colorants suitable for use with the lactose-free norastemizole dosage forms prepared in accordance with the present invention include, but are not limited to, pharmaceutically acceptable colorants and lacquers, caramel, red ferric oxide, yellow ferric oxide or mixtures thereof. same. Desiccants suitable for use with lactose-free, anhydrous, large-particle or coated-free norastemizole dosage formulations prepared in accordance with the present invention include, but are not limited to, calcium chloride, calcium sulfate, silica gel or mixtures thereof. Flavors suitable for use with the lactose-free norastemizole dosage forms prepared in accordance with the present invention include, but are not limited to, acacia, tragacanth, almond oil, anethole, anise oil, benzaldehyde, caraway, oil. caraway, cardamom oil, cardamom seed, tincture composed of cardamom, cherry juice, cinnamon, cinnamon oil, clove oil, cocoa, coriander oil, eriodiction, eriodiction fluid extract, ethyl acetate, ethyl vanillin, oil eucalyptus, fennel oil, glycyrrhiza, pure glycyrrhiza extract, glycyrrhiza fluid extract, lavender oil, lemon oil, menthol, methyl salicylate, monosodium glutamate, nutmeg oil, orange flower oil, orange flower water, orange oil, sweet orange peel tincture, spirit composed of orange, mint, peppermint oil, mint spirit, pine oil, oil rose, strong rose water, spearmint, spearmint oil, spearmint, tincture of tolu balm, vanilla, vanilla and vanilla tincture or mixtures thereof. Plasticizers suitable for use with the lactose-free norastemizole dosage forms prepared in accordance with the present invention include, but are not limited to, castor oil, monoglycerides, diacetylated, diethyl phthalate, glycerin, monoglycerides, mono- and diacetylated , polyethylene glycol, propylene glycol and triacetin or mixtures thereof. Suitable viscosity-increasing agents for use with the norastemizole lactose-free dosage forms prepared according to the present invention include, but are not limited to, acacia, agar, allymic acid, aluminum monostearate, bentonite, bentonite magma. , carbomer 934, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium carboxymethylcellulose 12, carrageenan, microcrystalline cellulose, gelatin, guar gum, hydroxyethylcellulose, hydropropylcellulose, hydroxypropyl methylcellulose (Nos. 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. Sweetening agents suitable for use with the lactose-free norastemizole dosage forms prepared according to the present invention include, but are not limited to, aspartame, dextrata, mannitol, saccharin, calcium saccharin, sodium saccharin, sorbitol, solution of sorbitol or mixtures thereof. Buffering agents suitable for use with the lactose-free norastemizole dosage forms prepared according to the present invention include, but are not limited to, magnesium hydroxide, aluminum hydroxide and the like, or mixtures thereof. Suitable wetting agents include, but are not limited to, glycerol, other humectants or mixtures thereof. The norastemizole dosage forms of the present invention may also include one or more of the following: (1) dissolving retarding agents such as paraffin; (2) absorption accelerators such as quaternary ammonium compounds; (3) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (4) absorbers such as kaolin and bentonite clay (5) antioxidants as water-soluble antioxidants (eg, ascorbic acid, cysteine hydrochloride, sodium disulfate, sodium metabisulfate, sodium sulfite and the like), oil-soluble antioxidants (eg eg, ascorbyl palmitate, hydroxyanisole (BHA), hydroxybutyl toluene (BHT), lecithin, propyl gallate, alpha tocopherol and the like, and (6) metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, aridic acid , phosphoric acid and the like The non-hygroscopic, anhydrous, particle or coated lactose-free norastemizole dosage forms 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 mentioned above with respect to the tablets For the formation of tablets, norastemizole is combined with one or more excipients (e.g., diluents, binders, disintegrants, dispersing agents, surface active agents, lubricants, coating materials, flavoring agents, coloring agents, solvents, viscosity-increasing agents, suspending agents, sweeteners, colorants, dyes and similar) and the different proportions used by the traditional rattling equipment such as double cover or "V" mixers by known methods for manufacturing chemically and thermally stable dosage forms (eg, tablets, caplets and the like) with a content of uniform and mixed distribution of the therapeutic agents. The exact amounts of each of the different excipients can be easily determined by those skilled in the pharmaceutical art. The large-scale production of the dosage form of lactose-free, non-hygroscopic, anhydrous, large-particle or coated norastemizole prepared in accordance with the present invention may require, in addition to the therapeutic active ingredient (s), additives, including, but are not limited to diluents, binders, lubricants, disintegrants, colorants, flavorants, sweetening agents and the like or mixtures thereof. By incorporating these and other additives it is possible to prepare a variety of dosage forms (e.g., tablets, capsules, caplets, troches and the like) These include, for example, hard gelatin capsules, caplets, sugar-coated tablets, tablets enteric coated for delayed action, multiple compression tablets, long-acting tablets, solution tablets, effervescent tablets, oral and sublingual tablets, trociscos and similars. The sugar coating preferably does not include lactose or mono- or disaccharides, except in the formulations of norastemizole practically free of unbound water. Lactose-free, non-hygroscopic, anhydrous, large-particle or coated tablets of the present invention are usually prepared by compression molding or by generally accepted tablet-forming methods. Accordingly, compressed tablets are generally prepared by large-scale production methods while molded tablets often include small-scale operations. For example, there are three general methods of preparing tablets to make the dosage forms of norastemizole: (1) the wet granulation method; (2) the dry granulation method; and (3) direct compression. These methods are well known to those skilled in the art. See Remington's Pharmaceutical Sciences, 16th and 18th Eds., Mack Publishing Co., Easton, Pennsylvania (1980 and 1990). See, also the U.S. Pharmacopeia XXI, U.S. Pharmacopeial Convention, Inc., Rockville, Maryland (1985). Preferably, wet granulation is not used for non-hygroscopic or anhydrous dosage forms. The different tablet formulations of the lactose-free, non-hygroscopic, anhydrous, large-particle or coated norastemizole dosage forms can be prepared according to the present invention. These include dosage forms of tablets such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, multiple-compression tablets, long-acting tablets and the like. Sugar coated (TRA) tablets of norastemizole without lactose, non-hygroscopic, anhydrous, particle or with inert coating are compressed tablets containing a sugar coating. These coatings can be colorful and are beneficial in the coating of drug substances that have unpleasant tastes or odors and in the protection of materials sensitive to oxidation. Lactose-free, non-hygroscopic, anhydrous, large-particle or coated tablets with film coating (TRP) are compressed tablets that are covered with a thin layer or film of a water-soluble material. It is possible to use different polymeric substances with film-forming properties. The film coating imparts the same general characteristics as the sugar coating with the additional advantage of greatly reducing the time required for coating operation. Enteric coated tablets are also suitable for use in the present invention. Enteric-coated tablets (TRE) of lactose-free, non-hygroscopic, anhydrous, particulate or coated tablets are compressed tablets coated with substances that resist dissolution in the gastric fluid but disintegrate in the intestine. The enteric coating can be used for tablets containing drug substances that are inactivated or destroyed in the stomach, for those that irritate the mucosa or as a delayed release medium for the medication. Multiple compressed tablets (TCM) of norastemizole without lactose, non-hygroscopic, anhydrous, large-particle or coated are compressed tablets prepared by more than one compression cycle, such as compression-coated tablets or tablets. Layered tablets are prepared by compressing additional tablet granulation over a previously compressed granulation. The operation can be repeated to produce tablets of multiple layers, of two three or more layers. Typically, special tabletting machines are required to make the tablets with layers. See, for example, U.S. Patent No. 5 213 738, incorporated herein by reference in its entirety. The tablets with compression coating are another form of tablets with multiple compression. These tablets, also known as dry-coated tablets, are prepared by feeding tablets previously compressed in a tabletting machine and compressing another layer of granulation around the preformed tablets. These lactose-free, non-hygroscopic or anhydrous norastemizole tablets have all the advantages of compressed tablets, ie, granulate, monogravure, disintegration rate, etc., while maintaining the attributes of the sugar-coated tablets in the taste masking. of the active substance in the core tablet. Compression coated tablets can also be used to separate incompatible active substances. further, these can be used to provide an enteric coating to the core tablets. Both types of norastemizole tablets (ie, layer tablets and compression-coated tablets) can be used, for example, in the design of long-acting dosage forms. The lactose-free, non-hygroscopic, anhydrous, large-particle or coated, long-acting norastemizole tablets may contain compressed tablets formulated to release the active substance in a form to provide medication for a time. There are different types of tablets that include the delayed action tablets in which the release of the active substance is prevented during a time interval after the administration or until certain physiological conditions exist. Repeated action tablets can be formed that periodically release a full dose of the active substance to the gastrointestinal fluids. Also, extended release tablets that continuously release increases of the active substance contained in the gastrointestinal fluids can be formed. The preparation method and the additives that they incorporate into the lactose-free, non-hygroscopic, anhydrous, large-particle or coated tablets are selected to give the tablet formulation the desirable physical characteristics while permitting rapid compression of the tablets. After compression, preferably the tablets should have different additional attributes such as appearance, hardness, speed of disintegration and uniformity that are influenced by the method of preparation and by the additives present in the formulation of the tablet. The basic unit in all tablet compression equipment includes a lower punch that fits into a matrix from the bottom and an upper punch, having a head of generally the same shape and dimensions as the lower punch, which enters the cavity of the matrix from the top after the rattling material fills the cavity of the matrix. The tablet is formed by pressure applied to the punches. Subsequently, the tablet is ejected from the matrix. The weight of the tablet is determined by the volume of the material that fills the cavity of the matrix. The capacity of the norastemizole tablets or the granulation of the lactose-free, non-hygroscopic, anhydrous, large-particle or coated dosage form to flow freely into the die cavity is important to ensure uniform filling. The fluidity of the granulation is also important to ensure a continuous movement of the granulate from the supply source or feed hopper. In addition, if the granulation for tablets does not have cohesive properties, after compression the tablet will separate! and it will crumble with the handling. Furthermore, since the punches must move freely within the die and the tablet must be easily expelled from the faces of the punches, the material for the rattle must have a degree of lubrication to minimize friction and allow the separation of the compressed tablet. It is possible to add a granulation agent to facilitate the granulation. The amount of the granulating agent used varies with the type of formulation and the mode of administration, and is readily discernible by those skilled in the art. Usually, about 5 to about 15% by weight of the granulating agent is used in the pharmaceutical formulation. Preferably, when the lactose is present in the anhydrous or non-hygroscopic compositions of the present invention, the granulating agent must be non-aqueous. In addition, it should be noted that stable, lactose-free, non-hygroscopic, anhydrous, large-particle or coated tablets or other dosage forms thereof retain their original size, shape, weight and color under normal handling and storage conditions. through its storage life. In this way, for example, excessive powder or solid particles in the bottom of the container crack or shatter the face of a tablet, or the appearance of the crystals on the surface of the tablets or on the walls of the container indicate physical instability of the uncoated tablets. Therefore, the effect of moderate, uniform and reproducible stirring and rolling of the tablets should be considered to ensure that they have sufficient physical stability. The hardness of the tablet can be determined by commercially available hardness testers. In addition, the in vitro availability of the active ingredient should not change appreciably over time. The lactose-free pharmaceutical compositions of the present invention can also be formulated in a soft elastic gelatin capsule unit dosage form using conventional methods well known in the art (see, for example, Eberet, Pharm. Tech., 1 (5): 44-50 (1977), soft, elastic gelatin capsules have a gelatin shell, soft globular somewhat thicker than hard gelatin capsules, where a gelatin is plasticized by the addition of glycerin, sorbitol or a similar polyol. The hardness of the capsule shell can change varying the type of gelatin and the amounts of plasticizer and water. The soft gelatin covers may contain a preservative (such as methyl and propylparabens and sorbic acid) to prevent fungal growth. The active ingredient may be dissolved or suspended in a liquid vehicle or carrier, such as vegetable or mineral oils, glycols such as polyethylene glycol and propylene glycol, triglycerides, surfactants such as polysorbates or a combination thereof. The tablets and other dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, can optionally be classified or prepared with coatings and layers such as enteric coatings and other coatings well known in the pharmaceutical formulating art. The pharmaceutical compositions of the present invention can also be formulated to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to produce the desired release profile, other polymer matrices, liposomes and / or microspheres Unless indicated otherwise, all percentages set forth herein are percentages by weight based on the total weight of all components of a particular dosage form. The lactose-free, non-hygroscopic, anhydrous, large-particle or coated compositions of the present invention may also contain, for example, an analgesic, a decongestant, a cough suppressant or an expectorant. The incompatibility of norastemizole with lactose is illustrated in Table 1 below. The effect of lactose on norastemizole at different temperatures (eg, 25 ° C, 40 ° C and 60 ° C), at different levels of relative humidity (for example, 60% and 75% relative humidity) and at different times (for example, 0, 1 week, 1 month, 2 months, 3 months, 6 months, and 9 months) was evaluated. The results of this evaluation are presented in Table 1. The level of impurities within the tested capsules was measured using high performance liquid chromatography (HPLC), and is presented in Table 1 as a percentage of the dosage form tested. Note that the discoloration of the initial opaque white appearance is an indication of the incompatibility between norastemizole and lactose, which is corroborated by the increased percentages of the impurities detected by HPLC.

Table 1 * STABILITY OF NORASTEMIZOL CAPSULES * stability of norastemizole when filled in hard gelatin capsules with lactose, approximately 25 mg of norastemizole and 4,975 g of lactose; even at 25 ° C, the capsules showed an increase in ii-purities (impurities by HPLC) and in vitro potency (HPLC assay) was reduced after 6 months and 9 months indicating incompatibility between lactose and norastemizole.

In this way, the results show that when norastemizole was formulated with lactose, filled into hard gelatin capsules and stored in a non-sealed container, the formulation was not chemically stable at elevated temperatures and humidity. In addition, even at 25 ° C with 60 ° relative humidity, the norastemizole / lactose capsules showed increase in impurities and reduced potency in vitro after six (6) and nine (9) months, indicating the incompatibility between norastemizole and lactose . In an effort to identify excipients, in addition to lactose, suitable for use with norastemizole, a study of excipients was conducted using a variety of other excipient classes. Examples of tested excipients include corn starch, calcium sulfate dihydrate, calcium stearate, sucrose, fructose, calcium carbonate, microcrystalline cellulose, maltodextrin, CaHP04 »2H20, CaHP04, magnesium stearate, starch 1500®, croscarmellose sodium or mixtures thereof. The effect of the different excipients on norastemizole degradation is represented in Figure 2, where the norastemizole / excipient combination was exposed to a temperature of 60 ° C and 75% relative humidity, and stored in a hermetically sealed container, which are the common conditions for compatibility studies of excipients. As is evident in Figure 2, norastemizole and lactose are clearly incompatible due to the drop in the potency of the drug. However, such a drastic drop in potency between norastemizole and the other tested excipients is not observed. However, the daily dosage may need to be adjusted to take into account the variations in potency between the excipients that are observed and illustrated in Figure 2. Figure 2 also provides some indication that the mono- and disaccharide excipients also preference should be avoided in the formulations of norastemizole, for example, as shown] by the degradation observed with the conditions of norastemizole and sucrose. The above results were obtained using containers with screw cap, temperature and high humidity which is a widely accepted means to determine the interactions of the compounds with the excipients under accelerated conditions. Applicants have also found that norastemizole alone, when stored under high humidity conditions (thus exposed to significant unbound water), is extremely stable for prolonged periods. Another study was conducted to evaluate the effects of moisture changes on the interactions lactose and norastemizole.

In small vials of amber colored glass, corrugated at the top, of 20 ml, the following samples were prepared: Norastemizole pure Norastemizole 20% / lactose 80% Norastemizole 20% / lactose 80% with H20 5% Norastemizole 1% / lactose 99% Norastemizole 1% / lactose 99% with H20 5% The vials were maintained at 60 ° C for 14 days and norastemizole was assessed. The results show that the incompatibility of norastemizole and lactose is greatly reduced when unbound water is not present and the container is hermetically sealed. Actually, the effect of moisture on the reaction rate is significant. When the unbound water was not purposely added to the well sealed containers, the differences were not practically different from that of the control, that is, pure norastemizole. Reduced potency was observed in the presence of unbound water, while reductions in potency were observed compared to norastemizole without lactose and pure in the absence of unbound water. ? ozol oraz (test results) Norastemizole pure 96.90 Norastemizole 20% / lactose 80% 98.33 Norastemizole 20% / lactose 80% with H20 5% 65.16 Norastemizole 1% / lactose 99% 92.59 Norastemizole 1% / lactose 99% with H20 5% 77.22 A lactose-free, non-hygroscopic, anhydrous, large-particle or coated formulation formulation of norastemizole such as a troche, tablet or capsule can be formed by combining norastemizole, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically compatible excipients, as already described, in pharmaceutically acceptable amounts to produce a unit dose norastemizole dosage formulation containing from about 1 mg to about 200 mg of norastemizole, and preferably containing from about 2 mg to about 100 mg of norastemizole It is possible to form the dosage formulation in tablets, troches or capsules, for example, by methods well known in the art including wet granulation, dry granulation or compression molding. Again, wet granulation is not useful for non-hygroscopic or anhydrous formulations. Other methods for forming tablets, troches and capsules, well known in the art can also be used. However, compression molding is preferable for the formulation of tablets and troches. For capsules, hard gelatin capsules filled with norastemizole and one or more excipients are preferred. STARCH 1500® is a pregelatinized starch manufactured by Colorcon Ltd that is not recommended for use in amounts exceeding 75% by weight. In addition, when magnesium stearate is used, as a lubricant with STARCH 1500®, no greater than 0.25 wt% of magnesium stearate should be used, as this may have an adverse effect on the solution. This adverse effect on the dissolution in STARCH 1500® formulations and greater than 0.25% by weight of magnesium stearate is particularly important for compounds having relatively low water solubility such as norastemizole. Having described the invention, the following examples illustrate the preferred embodiments according to the invention currently claimed. It will be understood that the examples are illustrative and do not limit the scope or scope of the appended claims.

Example 1: Unit dosage forms in hard gelatine capsule (lactose free) Example 2: Unit dosage forms in hard gelatin capsule (non-hygroscopic) Example 3: Unit dosage forms in hard gelatin capsule (anhydrous) The active ingredient is sifted and mixed with the excipients mentioned. The mixture is filled into two-piece hard gelatin capsules of suitable size using suitable machinery and methods well known in the art. See, Remington's Pharmaceutical Sciences, 16th or 18th eds., Each incorporated herein in its entirety as a reference thereto. Other doses can be prepared by modifying the filling weight and, if necessary, changing the size of the capsule to adapt it. It is possible to form any of the formulations of hard gelatin capsules without lactose, non-hygroscopic and suitable anhydrous.

Example 4: Formulations of compressed tablets (without lactose) The active ingredient is screened through a suitable screen and mixed with the non-lactose excipients until a uniform mixture is formed. The dried mixture is sifted and mixed with the magnesium stearate. The resulting powder mixture is then compressed into tablets of desired shape and size. Tablets of other concentrations can be prepared by modifying the ratio of the active ingredient (i.e., norastemizole) to the excipients or by modifying the weight of the tablet.

Example 5: Wet granulation (lactose free) The active ingredient is sifted through a suitable mesh and mixed with the non-lactose excipients (excluding half of croscarmellose (or sodium starch glycolate) and all microcrystalline cellulose) until a uniform mixture is formed. Suitable volumes of water are added and the powder is granulated. After drying the granules are sieved and mixed with microcrystalline cellulose, the rest of the croscarmellose or sodium starch glycolate and briefly with magnesium stearate.

The resulting free-flowing powder is then compressed into tablets of desired size and shape. Tablets of other concentrations can be prepared by modifying the ratio of the active ingredient (i.e., norastemizole) to the excipients or by modifying the weight of the tablet.

Example 6: Direct compression The active ingredient is passed through a suitable screen and mixed with the non-lactose excipients (except magnesium stearate) until a uniform mixture is formed. The dry mixing is screened and mixed briefly with magnesium stearate. The resulting powder is then compressed into tablets of desired size and shape. Tablets of other concentrations can be prepared by modifying the ratio of the active ingredient (i.e., norastemizole) to the excipients or by modifying the weight of the tablet. Although the present invention has been described with respect to the specific embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the claims.

Claims (42)

1. A lactose-free pharmaceutical composition containing norastemizole, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable non-lactose excipient.

2. A solid pharmaceutical composition containing norastemizole, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the excipient is not lactose.

3. The composition of claim 1 or 2, which further contains a lubricant, disintegrant or mixtures of both.

The composition of claim 1, wherein at least one pharmaceutically acceptable non-lactose excipient consists of croscarmellose sodium, microcrystalline sodium cellulose, pregelatinized starch and magnesium stearate.

The composition of claim 1 or 2, wherein the pharmaceutical composition is practically free of ono- or disaccharides.

6. A solid, thermally stable, lactose-free pharmaceutical composition consisting essentially of norastemizole, a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

7. A solid, chemically stable, lactose-free pharmaceutical composition containing about 1% to about 50% by weight of norastemizole, or a pharmaceutically acceptable salt thereof, and about 99% to about 50% by weight of at least one pharmaceutically acceptable excipient .

The composition of claim 1 or 2, wherein the norastemizole is present in an amount from about 1 mg to about 200 mg.

The composition of claim 8, wherein norastemizole is present in an amount from about 2 mg to about 100 mg.

The composition of claim 1 or 2, wherein norastemizole is present in a therapeutic amount effective for the treatment of an allergic disorder.

11. A solid pharmaceutical composition containing norastemizole or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, pregelatinized starch, magnesium stearate and croscarmellose sodium.

12. The solid pharmaceutical composition of claim 11, wherein the solid composition is provided with a tablet or capsule dosage form.

13. The pharmaceutical composition according to claim 2 further comprising an enteric coating.

14. A method for the treatment of allergies in a mammal, which consists in administering an effective therapeutic amount of a composition according to claims 1 to 6.

15. The method of claim 14, wherein the mammal is a human.

16. The method of claim 14, wherein the allergic disorder is allergic rhinitis.

17. An anhydrous pharmaceutical composition containing norastemizole, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

18. An anhydrous pharmaceutical composition of claim 17, wherein at least one pharmaceutically acceptable excipient is lactose.

19. A solid pharmaceutical composition containing norastemizole, or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable excipient, and lactose, wherein the composition is substantially free of unbound water.

The pharmaceutical composition of claim 17 or 19 wherein at least one pharmaceutically acceptable excipient is selected from the group consisting of low moisture or anhydrous excipients.

21. An anhydrous pharmaceutical composition containing about 1% to about 50% by weight of norastemizole, or a pharmaceutically acceptable salt thereof and 99% to about 50% by weight of one or more pharmaceutically acceptable excipients.

22. A solid unit dosage form containing an anhydrous composition of claim 20 or 21 contained in a hermetically sealed sheet, a hermetically sealed container, a package bliste, r or packages by layers.

23. A non-hygroscopic pharmaceutical composition containing norastemizole, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

24. The non-hygroscopic pharmaceutical composition of claim 23, wherein the one or more pharmaceutically acceptable excipients is lactose.

25. A non-hygroscopic pharmaceutical composition containing norastemizole, or a pharmaceutically acceptable salt thereof, lactose and one or more pharmaceutically acceptable excipients, wherein the composition is substantially free of unbound water.

26. A non-hygroscopic, solid pharmaceutical composition containing norastemizole, or a pharmaceutically acceptable salt, at least one pharmaceutically acceptable excipient and lactose.

27. The pharmaceutical composition of claim 24 or 25, wherein one or more pharmaceutically acceptable excipients are selected from the group consisting of non-hygroscopic or low-moisture excipients.

28. The pharmaceutical composition of claim 23, 24, 25 or 26 wherein the lactose is hydrated.

A method for the treatment of an allergic disorder in a mammal consisting of administering an effective therapeutic amount of a composition according to claim 24 or 25.

30. The method of claim 29, wherein the mammal is a human .

31. The method of claim 29, wherein the allergic disorder is allergic rhinitis.

32. A pharmaceutical composition for the treatment of histamine-induced disorders contains large particles of norastemizole, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

33. The large-particle pharmaceutical composition of claim 32, wherein at least one excipient consists of lactose.

34. The large-particle pharmaceutical composition of claim 38, wherein about 40% by weight or more of the large particles of norastemizole, or the pharmaceutically acceptable salt thereof, consists of particles with a size of 200 microns or larger.

35. A solid pharmaceutical composition for the treatment of histamine-induced disorders contains an effective therapeutic amount of coated norastemizole, or a pharmaceutically acceptable salt thereof, containing norastemizole, or a pharmaceutically acceptable salt thereof, coated with an inert coating agent, and an acceptable pharmaceutical excipient.

36. The solid pharmaceutical composition of claim 35, wherein the excipient consists of lactose.

37. The solid pharmaceutical composition of claim 35, wherein the coated norastemizole or a pharmaceutically acceptable salt thereof consists of a granulated formulation of norastemizole or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable inert excipient, wherein the granulated formulation is coated with an inert coating agent.

38. The solid pharmaceutical composition of claim 35 or 37, wherein the inert coating agent consists of an inert film-forming agent in a solvent.

39. The solid pharmaceutical composition of claim 38, wherein the inert film-forming agent is selected from the group consisting of: methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose, and mixtures thereof.

40. A method for the treatment of an allergic disorder in a mammal, which consists in administering an effective therapeutic amount of a composition according to claim 32 or 35.

41. The method of claim 40, wherein the mammal is a human.

42. The method of claim 40, wherein the allergic disorder is allergic rhinitis.