Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4866—Organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents

Definitions

• the present invention relates to chemically and thermally stable pharmaceutical compositions containing norastemizole .
• a pharmaceutical product including the stability of the therapeutic drug ingredient (s) , the potential interaction between the therapeutic drug ingredient (s) and the inactive ingredient (s) , the manufacturing process, the packaging, the environmental conditions encountered during shipment, storage and handling, the length of time between manufacture and usage and the type of the dosage form.
• the chemical stability of the pharmaceutical product should be considered. Knowledge of the physical and chemical stability of a pharmaceutical formulation is very important for at least three primary reasons .
• a pharmaceutical product preferably, should appear fresh, elegant and professional. Any changes in physical appearance and color including fading, color variation, appearance of haziness and the like can cause the patient to lose confidence in the product.
• uniform dosage of the therapeutic agent (s) over time must be assured. For example, a non-uniform dosage pattern may be indicated by a cloudy solution, a broken emulsion, a discolored tablet, a discolored capsule or the like.
• the therapeutic drug ingredient (s) must be available to the patient throughout the expected shelf life of the dosage form. A breakdown in the physical or chemical integrity of the dosage form can lead to a lack of bioavailability or detrimentally altered bioavailability of the therapeutic drug ingredient (s) .
• Pharmacopeia/National Formulary include, but are not limited to, aerosols, capsules, cachets, collyria, creams, emulsions, extracts, fluid extracts, gels, inhalations, injections, lotions, magmas, milks, ointments, pastes, pellets or implants, powders, solutions, ophthalmic solutions, oral solutions, otic solutions, pastilles, topical solutions, spirits, suppositories, suspensions, sublingual lozenges, syrups, tablets, tinctures, troches, aromatic waters and the like.
• syrups, solutions, suspensions, troches, tablets and capsules are preferred. However, for greater ease of administration, for increased carrying convenience and for improved patient compliance with a prescribed dosage regimen, troches, tablets, and hard and soft gelatin capsules are most preferred. In some cases, tablets are preferred over capsules because tablets are sometimes easier to swallow.
• Troches, tablets and capsules typically, contain the drug ingredient, a diluent and other excipients, such as lubricants and the like, which are well known in the art.
• excipients include, for example, coating agents, colorants, desiccants, emulsifying agents, solubilizing agents, flavors, anti-caking 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 commonly available form of lactose which is widely used as a direct compression excipient. Since the advent of spray-dried lactose, its use as an excipient has expanded. The rapid acceptance of spray-dried lactose is, in part, due to its ease of incorporation in direct compression tablets. In this application, 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 readily and conveniently incorporated into a troche or a capsule dosage form. Spray-dried lactose may be directly added to a drug to yield a desired dilution ratio therewith. Thereafter, for example, the combination of the lactose and the drug may be dry compressed into a tablet or formulated into a troche or a capsule with other excipients, as necessary.
• Lactose whether spray-dried or not, is typically present in equilibrium between its alpha and beta forms, wherein interconversion between these forms is ongoing.
• Alpha-lactose is a disaccharide of beta-D-galactose and alpha-D-glucose .
• Beta-lactose is a disaccharide of beta-D- galactose and beta-D-glucose. Beta-lactose occurs only in its anhydrous form, whereas alpha-lactose may be obtained either in anhydrous form or as a monohydrate.
• aldehyde intermediate is formed which is known to be incompatible with most primary amines.
• Primary amines add to the carbonyl carbon of aldehydes (and ketones) to form imines :
• 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 became 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 (i.e., an imine) in the presence of dextroamphetamine sulfate. Hartauer et al .
• each tablet of Hismanal ® contains 10 mg astemizole, lactose, cornstarch, macrocrystalline cellulose, pre-gelatinized starch, povidone K90, magnesium stearate, colloidal silicon dioxide and sodium lauryl sulfate.
• 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 to be both more potent and less toxic than astemizole.
• norastemizole is an attractive alternative to astemizole for the treatment of allergic disorders. It should be recognized that both astemizole and norastemizole are antihistamines containing secondary amine moieties; however, norastemizole has two secondary amine moieties, whereas astemizole has one.
• the present invention relates to stable pharmaceutical dosage forms of norastemizole that avoid the incompatibility between norastemizole and lactose.
• the present invention relates to a lactose-free pharmaceutical composition which includes norastemizole, or a pharmaceutically acceptable salt thereof, and at least one non-lactose pharmaceutically acceptable excipient.
• 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 said excipient is not lactose .
• At least one non- lactose pharmaceutically acceptable excipient is a binder, a filler, or mixtures thereof.
• at least one pharmaceutical excipient is a binder, a filler, or mixtures thereof.
• the above excipients further include a lubricant, a disintegrant , or mixtures thereof.
• the excipients are croscarmellose, macrocrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
• the disintegrant is a super disintegrant.
• the pharmaceutical composition is substantially free of all mono- or di-saccharide excipients.
• the invention also relates to a thermally stable solid pharmaceutical composition free of lactose comprising norastemizole, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
• the invention relates to a chemically stable solid pharmaceutical composition free of lactose which includes about 1% to about 50% by weight of norastemizole, or a pharmaceutically acceptable salt, and about 99% to about 50% by weight of at least one pharmaceutically acceptable excipient .
• the invention encompasses non-hygroscopic pharmaceutical compositions comprising norastemizole, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
• Non- hygroscopic pharmaceutical compositions of this invention may contain pharmaceutically acceptable excipients that are substantially free of unbound water, i.e., water available to participate in norastemizole/excipient interactions, such as, but not limited to, any interactions between lactose and norastemizole.
• the present invention also provides chemically and thermally stable non-hygroscopic pharmaceutical compositions comprising norastemizole and at least one pharmaceutically acceptable excipient, wherein said excipient can include lactose or other mono- or di- saccharides .
• the norastemizole compositions of the present invention are (a) substantially free of lactose (and preferably substantially free of mono- or disaccharide) , (b) include excipients substantially free of unbound water, which excipients may include lactose, such as alpha-lactose monohydrate or other mono- or di-saccharides, or (c) contain large particles or particles coated with an inert agent, along with excipients that may include lactose, such as alpha-lactose monohydrate or other mono- or di- saccharides.
• lactose such as alpha-lactose monohydrate or other mono- or di- saccharides
• compositions of the invention which are non- hygroscopic may nevertheless include some hygroscopic ingredients; however, the composition overall must be substantially non-hygroscopic.
• the non-hygroscopic pharmaceutical compositions of the present invention may also utilize hydrated ingredients.
• the present invention encompasses anhydrous pharmaceutical compositions, said compositions comprising norastemizole, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, which may include lactose.
• Such compositions may be prepared using anhydrous or low moisture containing ingredients using low moisture or low humidity conditions such that the resulting pharmaceutical composition is substantially anhydrous.
• the present invention provides chemically and thermally stable anhydrous pharmaceutical compositions comprising norastemizole and at least one pharmaceutically acceptable excipient, wherein said excipient can include lactose or other mono- or di- saccharides .
• the invention also encompasses pharmaceutical compositions for the treatment of histamine-induced disorders comprising 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 said excipient can include lactose or other mono- or di- saccharides .
• about 40 weight percent or more of the large particles of norastemizole, or pharmaceutically acceptable salt thereof comprises particles having a size of 200 ⁇ m or larger.
• the large particle pharmaceutical composition may include lactose as a pharmaceutically acceptable excipient.
• the invention also encompasses solid pharmaceutical compositions for the treatment of histamine-induced disorders comprising a therapeutically effective amount of coated norastemizole, or a pharmaceutically acceptable salt thereof, which comprises norastemizole, or a pharmaceutically acceptable salt thereof, coated with an inert coating agent, and a pharmaceutically acceptable excipient.
• the present invention further provides chemically and thermally stable pharmaceutical formulations of coated norastemizole that avoid the incompatibility between norastemizole and lactose, wherein said excipient can include lactose or other mono- or di-saccharides .
• the excipient comprises lactose.
• the coated norastemizole, or a pharmaceutically acceptable salt thereof further comprises a granulated formulation of norastemizole, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable inert excipient, wherein said granulated formulation is coated with an inert coating agent.
• the inert coating agent comprises an inert film-forming agent in a solvent.
• the inert film-forming agent is selected from the group consisting of methylcellulose, hydroxymethyl cellulose, carboxymethyl cellulose, hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, methylhydroxyethylcelluose, sodium carboxymethylcellulose, and mixtures thereof.
• 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 of about 2 mg to about 100 mg. In another preferred embodiment, norastemizole is present in a therapeutically effective amount for treatment of an allergic disorder. In yet another preferred embodiment, the therapeutically effective amount is sufficient for the prophylaxis or treatment in humans of an allergic disorder.
• the invention also relates to a solid pharmaceutical composition that includes norastemizole or a pharmaceutically acceptable salt thereof, macrocrystalline cellulose, pre-gelatinized starch, magnesium stearate, and croscarmellose sodium.
• the solid pharmaceutical composition is provided in a tablet or a capsule dosage form.
• the invention also relates to a method for treating at least one allergic disorder in a mammal by administering a therapeutically effective amount of one of the above compositions.
• the mammal is a human.
• the allergic disorder is allergic rhinitis.
• Figure 2 presents in bar-graph format the change in initial potency of a dosage form of norastemizole and various pharmaceutical excipients when the dosage form is exposed to a temperature of 60°C at 75% relative humidity using non- hermetically sealed containers (i.e., screw-top vials).
• the instability is also initiated and/or accelerated upon exposure to heat at temperatures of greater than about 60°C.
• the instability of lactose and norastemizole may be initiated and/or accelerated by the high surface area of the small particles of norastemizole conventionally used in pharmaceutical compositions upon the exposure of a norastemizole/lactose formulation.
• the instability of lactose and norastemizole may be inhibited or avoided by coating norastemizole particles prior to formulation of the norastemizole with reactive excipients, such as lactose.
• Example 4 a formulation of norastemizole is proposed in Example 4, which happens to lack lactose.
• Formulas A, B and C, of Example 4 each contain 1.0 weight percent of magnesium stearate BP, 94.0, 89.0 and 79.0 weight percent of Starch 1500 (a pre-gelatinized starch commercially available from Colorcon, Ltd.), respectively, and the remainder of the composition is a metabolite of astemizole ( e . g. , norastemizole) .
• Example 4 In practice, one would not prepare or utilize the lactose-free formulations of Example 4 because the magnesium stearate BP and Starch 1500 are incompatible in the weight percents described. In other words, the formulations of Example 4 in this PCT publication are unsuitable for actual pharmaceutical use. Moreover, this publication neither discloses nor suggests that norastemizole and lactose are incompatible, as evidenced by the lactose- containing tablet formulation of norastemizole in Example 5 therein.
• Lactose has been widely accepted and used by the pharmaceutical industry, inter alia , because of its ease of manufacture. 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 to be compatible with lactose, especially at ambient temperatures or where exposure to heat ( e . g. , below about 60°C) is either minimal or altogether avoided. As noted, for example, the drug astemizole is available in a tablet dosage form containing lactose and other excipients under the tradename Hismanal ® .
• norastemizole is provided in lactose-free pharmaceutical compositions. These compositions possess potent antihistaminic activity and are useful in treating a variety of conditions. Some of these conditions include, for example, allergic rhinitis, asthma and other allergic disorders, vertigo, motion sickness, vestibular disturbances ( e . g. , Meniere's disease), diabetic retinopathy, other small vessel disorders associated with diabetes melitis.
• 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 significant shelf-life. Further, the compositions of the invention remain stable even when exposed to mild temperature and humidity changes. Moreover, even though the compositions of the invention are lactose-free, the compositions are still easily manufactured, and the compositions have desirable dosage performance properties.
• the compositions of the invention include solid unit dose formulations comprising norastemizole, or a pharmaceutically acceptable salt thereof, and at least one non-lactose pharmaceutically acceptable excipient.
• compositions may also optionally include other therapeutic ingredients, binders/fillers, disintegrants, lubricants, anti-caking agents, preservatives, film coating agents, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, dispersing agents and/or surface active agents.
• any such optional ingredient must be compatible with norastemizole, a secondary amine, to insure the stability of the formulation.
• the lactose-free dosage form of norastemizole made in accordance with the present invention comprise norastemizole and at least one non-lactose excipient. Examples of such excipients are well known in the art and are listed in the USP (XXI) /NF (XVI), incorporated herein in its entirety by reference thereto. It is further preferred that the lactose-free norastemizole dosage forms made in accordance with the present invention comprise norastemizole, a binder/filler and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. It is even further preferred that the lactose-free norastemizole dosage forms made in accordance with the present invention comprise norastemizole, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
• the lactose-free pharmaceutical compositions comprise norastemizole, or a pharmaceutically acceptable salt thereof, and at least one non-lactose pharmaceutically acceptable excipient, and do not contain any mono- or di-saccharide excipients, including, but not limited to, glucose, sucrose, and fructose.
• the addition of water ( e . g. , 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e . g. , Jens T. Carstensen, Drug Stabili ty: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and temperature accelerate the study.
• lactose is among the best of all direct compression fillers in fluidity and is very effective for low dose formulations ( e . g. , ⁇ _ 50 mg per dose) where the compactibility of the active ingredient does not play a major role in the formulation. See, e . g. , R.
• the present invention encompasses thermally and chemically stable pharmaceutical compositions, particularly, solid pharmaceutical formulations, which comprise norastemizole, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients, including but not limited to lactose, wherein the lactose containing formulations are anhydrous, i.e., substantially free of unbound water.
• the invention further encompasses thermally and chemically stable non-hygroscopic pharmaceutical compositions which comprise norastemizole, or a pharmaceutically acceptable salt thereof, and one or more excipients or ingredients including, but not limited to, lactose.
• these stable anhydrous or non- hygroscopic pharmaceutical compositions are based, in part, on Applicants' discovery that the incompatibility between norastemizole and lactose, or other mono-or di-saccharides, is accelerated and/or possibly initiated by exposure of such formulations to unbound water.
• preparing pharmaceutical compositions that are substantially free of unbound water will prevent the accelerated degradation of norastemizole that occurs when a reactive excipient is used and unbound water is present .
• non-hygroscopic or anhydrous pharmaceutical compositions comprising norastemizole, lactose and optionally one or more additional excipients or ingredients wherein the resulting pharmaceutical compositions are substantially free of unbound water.
• suitable excipients are selected such that the resulting pharmaceutical compositions are substantially free of unbound water, and processing is conducted using conditions of low humidity.
• Anhydrous norastemizole pharmaceutical composition prepared in accordance with the present invention should be prepared and stored such that the anhydrous nature is maintained. Accordingly, these compositions will be packaged using materials well known in the art for preventing exposure of the pharmaceutical composition to water, allowing them to be included in suitable formulary kits. Such packaging will include, but not be limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, or strip packs.
• a second alternative aspect of the invention encompasses a method of preparing a solid pharmaceutical formulation comprising norastemizole and lactose which method comprises admixing under anhydrous or low moisture/humidity conditions, norastemizole, or a pharmaceutically acceptable salt thereof, and lactose wherein said ingredients are substantially free of unbound water.
• the method may optionally further comprise packaging said anhydrous or non-hygroscopic solid norastemizole formulation under low moisture conditions. By using such conditions, the risk of contact with water is reduced and the degradation of norastemizole is prevented or substantially reduced during processing and storage. Further, the final packaged product has little or no unbound water present which substantially improves stability and prevents degradation.
• Such compositions can be provided in hermetically sealed packages such as vials, sealed packets, blister packs and other vacuum sealed and moisture free containers well known to the skilled artisan.
• the active ingredient or therapeutic agent e.g., norastemizole
• the active ingredient or therapeutic agent is milled and/or screened to decrease the particle size and/or narrow the particle size distribution. Most often, this is done in order to optimize various physicochemical characteristics of the formulation, such as dissolution, content uniformity, bioavailability of the active ingredient, and the like. Dissolution is of particular concern with norastemizole, since the solubility is relatively low (approximately 10 mg/mL) at pH 3-4 and lower above pH 4. Without being limited by any particular theory, however, Applicants believe that the interaction between norastemizole and reactive excipients, such as lactose, may be affected by the surface area of the norastemizole particles in the pharmaceutical composition or formulation.
• compositions for the treatment of histamine-induced disorders which comprise large particles of norastemizole, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
• Pharmaceutically acceptable carriers suitable for use in these compositions include carriers that may comprise one or more excipients selected from the group consisting of inert excipients and reactive excipients, such as lactose or other mono- or di-saccharides.
• These "large particle" pharmaceutical compositions of norastemizole have suitable physicochemical characteristics (in terms of dissolution, content uniformity, bioavailability, and the like) , but do not exhibit incompatibility with reactive recipients, such as lactose .
• 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, comprises particles having a size of 200 ⁇ m or larger, preferably greater than about 250 ⁇ m.
• Another means for inhibiting or preventing 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 manner in which this may be achieved is to coat the norastemizole particles with an inert or non-reactive coating prior to formulation with reactive excipients.
• the inert coating should not significantly influence the pharmacodynamic characteristics (e . g. , time to onset of efficacy, and absorption in vivo) of the composition.
• another embodiment of the present invention relates to solid pharmaceutical compositions for the treatment of histamine-induced disorders comprising a therapeutically effective amount of coated norastemizole, or a pharmaceutically acceptable salt thereof, which comprises norastemizole, or a pharmaceutically acceptable salt thereof, coated with an inert coating agent, and a pharmaceutically acceptable carrier.
• 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. Thereafter, the resulting coated norastemizole may be blended with other excipients, including reactive excipients.
• Suitable inert coating agents, and methods for coating particles or granules, are well known in the art.
• Inert coating agents typically comprise an inert film-forming agent dispersed in a suitable solvent, and may further comprise other pharmaceutically acceptable adjuvants, such as colorants and plasticizers.
• the particles or granules of norastemizole are coated using aqueous or non- aqueous film coating techniques or microencapsulation.
• Suitable inert film-forming agents include, but are not limited to, celluloses, such as methylcellulose, hydroxymethyl cellulose, carboxymethycellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, and sodium carboxymethyl cellulose; vinyls, such as polyvinyl pyrrolidione; glycols, such as polyethylene glycols; acrylics, such as dimethylaminoethyl methacrylate- methacrylate acid ester copolymer, and ethylacrylate- methylmethacrylate copolymer; and other carbohydrate polymers, such as maltodextrins, and polydextrose .
• celluloses such as methylcellulose, hydroxymethyl cellulose, carboxymethycellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, and sodium carboxymethyl cellulose
• the inert coating agent contains a hydrophilic film-forming agent, such as hydroxypropyl methylcellulose, so that absorption in vivo is not significantly delayed.
• a hydrophilic film-forming agent such as hydroxypropyl methylcellulose
• the coated norastemizole may be formulated using standard techniques, including, but not limited to, blending, granulation, compression, or combinations thereof, with other inert and/or reactive excipients, such as lactose, to make various dosage forms, such as tablets, caplets, capsules, troches, and the like.
• the preferred amount of norastemizole in all the dosage forms made in accordance with the present invention should be a therapeutically effective amount thereof, which is also a medically acceptable amount thereof.
• Actual dosage levels of norastemizole in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of norastemizole which is effective to achieve the desired therapeutic response for a particular patient, pharmaceutical composition of norastemizole, and mode of administration, without being toxic to the patient.
• the selected dosage level and frequency of administration of the pharmaceutical compositions of the invention will depend upon a variety of factors including the route of administration, the time of administration, the rate of excretion of the therapeutic agent (s) including norastemizole, the duration of the treatment, other drugs, compounds and/or materials used in combination with norastemizole, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
• the dosage regimen is likely to vary with pregnant women, nursing mothers and children relative to healthy adults.
• a physician having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
• the physician could start doses of norastemizole employed in the pharmaceutical composition of the present invention at levels lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
• a suitable daily dose of norastemizole will be that amount of norastemizole which is the lowest effective dose to produce a desired therapeutic effect.
• Such a therapeutically effective dose will generally depend upon the factors described above.
• the unit dose of lactose-free norastemizole may contain from about 1 mg to about 200 mg and preferably about 2 mg to about 100 mg.
• unit dosages 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.
• the effective daily dose of norastemizole may be administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms as two, three, four, five, six or more sub- doses.
• the preferred dosage forms are tablets, caplets, troches, pastilles, pills, lozenges, syrups, capsules and the like.
• other pharmaceutically acceptable dosage forms such as powders, granules, dragees and the like may be used.
• all components comprising the dosage forms of norastemizole made in accordance with the present invention preferably meet or exceed the standards for pharmaceutical ingredients and combinations thereof in the USP/NF.
• the purpose of the USP/NF is to provide authoritative standards and specifications for materials and substances and their preparations that are used in the practice of the healing arts.
• the USP/NF establish titles, definitions, descriptions, and standards for identity, quality, strength, purity, packaging and labeling, and also, where practicable provide bioavailability, stability, procedures for proper handling and storage and methods for their examination and formulas for their manufacture or preparation.
• lactose-free, non-hygroscopic, anhydrous, large particle, and coated dosage forms of norastemizole described herein and claimed meet the pharmaceutical standards set forth in the USP/NF ( e . g. , USP XXI/NF XVI) for each of the ingredients as well as the lactose-free, non-hygroscopic, anhydrous, large particle, or coated norastemizole dosage forms made with such ingredients.
• norastemizole in effect, the lactose- free, non-hygroscopic, anhydrous, large particle, or coated dosage forms of norastemizole are said to be pharmaceutically acceptable dosage forms made of pharmaceutically acceptable ingredients in pharmaceutically acceptable combinations and pharmaceutically acceptable amounts to at least meet the standards set forth in the USP XXI/NF XVI, incorporated herein in its entirety by reference thereto.
• norastemizole can be made according to methods known in the art, including those disclosed in copending U.S. Application No. 08/182,685, filed January 18, 1994, which is incorporated herein by reference thereto for the express purpose of teaching methods to prepare norastemizole .
• Stability of a pharmaceutical product may be defined as the capability of a particular formulation, in a specific container, to remain within its physical, chemical, microbiological, therapeutic and toxicological specification, although there are exceptions, and to maintain at least about 90% of labeled potency level.
• expiration dating is defined as the time in which the pharmaceutical product will remain stable when stored under recommended conditions .
• Many factors affect the stability of a pharmaceutical product including the stability of the therapeutic ingredient (s) , the potential interaction between therapeutic and inactive ingredient (s) ( e . g. , norastemizole and excipients) and the like. Physical factors such as heat, light and moisture may initiate or accelerate chemical reactions .
• carrier as used herein is synonymous with the term “vehicle.”
• lactose-free as used herein is intended to mean 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 detrimentally affect the potency of the norastemizole below about 90% of initial potency over the shelf life of the dosage form.
• 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, e . g. , alpha lactose monohydrate.
• 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.
• anhydrous as used herein means substantially free of unbound water including moisture.
• non-hygroscopic as used herein means the overall formulation is substantially non- hygroscopic, i.e., does not provide unbound water sufficient to initiate and/or accelerate the incompatibility between norastemizole and reactive excipients, such as lactose.
• additives is synonymous with the term “excipients” as used herein.
• substantially free means less than about 5 weight percent, preferably less than about 1 weight percent, and more preferably less than about 0.1 weight percent.
• large particle as used herein means a composition wherein the norastemizole includes about 40 weight percent or more of particles of norastemizole, or a pharmaceutically acceptable salt thereof, having a size of 200 ⁇ m or larger, preferably greater than about 250 ⁇ m.
• coated preferably means an inert coating agent used to coat norastemizole particles and inhibit the interaction of the particles with reactive excipients, such as lactose.
• 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 reactive excipients.
• pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for administration to and for use in contact with the tissues and fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable medically sound benefit/risk ratio.
• the term "pharmaceutically acceptable" excipient is employed to mean that there are no untoward chemical or physical incompatibilities between norastemizole (or a salt thereof) and any of the excipient components of a given dosage form.
• an untoward chemical reaction is one wherein the potency of the norastemizole (or salt thereof) is detrimentally reduced or increased due to the addition of one or more excipients.
• Another example of an untoward chemical reaction is one wherein the taste of the norastemizole (or salt thereof) dosage form becomes excessively sweet, sour or the like to the extent that the dosage form becomes unpalatable.
• Each excipient must be "acceptable” in the sense of being compatible with the other ingredients of the norastemizole formulation and not injurious to the patient.
• Physical incompatibility refers to incompatibility among the various components of the dosage form such as norastemizole (or salt thereof) and any of the excipient (s) thereof.
• the combination of the excipient (s) and norastemizole may form an excessively hygroscopic mixture or an excessively segregated mixture to the degree that the desired shape of the dosage form ( e . g. , tablet, troche etc.), its stability or the like cannot be sufficiently maintained to be able to administer the dosage form in compliance with a prescribed dosage regimen as desired.
• antihistamines such as astemizole or norastemizole
• solid dosage forms such as tablets, capsules, troches, caplets and the like.
• capsule dosage forms such as hard gelatin capsules, soft gelatin capsules and the like may also be used.
• tablets remain a preferred dosage form because of the advantages afforded both to the patient (e . g. , accuracy of dosage, compactness, portability, blandness of taste as well as ease of administration) and to the manufacturer (e.g., simplicity and economy of preparation, stability as well as convenience in packaging, shipping and dispensing) .
• Tablets are solid pharmaceutical dosage forms containing therapeutic drug substances with or without suitable additives.
• tablets and similar dosage forms may contain a number of materials referred to as additives. These additives are classified according to the role they play in the formulation of the dosage form such as a tablet, a caplet, a capsule, a troche or the like.
• additives include, but are not limited to, binders, diluents (fillers), disintegrants and lubricants.
• additives for use in the present invention specifically refers to lactose- free dosage forms
• the skilled artisan will readily understand that a subset of each category includes additives suitable for use in non-hygroscopic, anhydrous, large particle, or coated pharmaceutical compositions of the present invention.
• the non-hygroscopic, anhydrous, large particle, or coated pharmaceutical compositions of the present invention may also include lactose or other mono- or di-saccharides as excipients.
• inorganic bisulfites may be used to improve the stability of any of the norastemizole compositions herein.
• excipients and additives For non-hygroscopic formulations, special precautions must be exercised in choosing excipients and additives, such that overall, there is no propensity for moisture sorption (absorption or adsorption) in the absence of suitable environmental controls.
• excipients for use in such formulations include, but are not limited to, alpha lactose monohydrate, mannitol and the like.
• suitable anhydrous or low moisture forms of the below identified excipients or additives should be used, for example, AVICEL-PH-103TM and Starch 1500 LM.
• a binder is used to provide a free-flowing powder from the mix of tablet ingredients so that the material will flow when used on a tablet machine .
• the binder also provides a cohesiveness to the norastemizole tablet. Too little binder will give flow problems and yield tablets that do not maintain their integrity. Too much may adversely affect the release (dissolution rate) of the drug from the tablet. Thus, a sufficient amount of binder should be incorporated into the tablet to provide a free-flowing mix of the tablet ingredients without adversely affecting the dissolution rate of the drug ingredients from the tablet . With lower dose tablets, the need for good compressibility can be eliminated to a certain extent by the use of suitable diluting excipients called compression aids.
• the amount of binder used varies upon the type of formulation and mode of administration, and is readily discernible to those of ordinary skill in the art .
• Binders suitable for use with the lactose-free, non-hygroscopic, anhydrous, large particle, or coated dosage formulations of norastemizole made 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, powdered tragacanth, guar gum, cellulose and its derivatives (e.gr., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose) , polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, ( e .
• macrocrystalline cellulose g. , Nos. 2208, 2906, 2910
• macrocrystalline cellulose or mixtures thereof.
• Suitable forms of macrocrystalline cellulose are, for example, the materials sold as AVICEL-PH-101, AVICEL-PH- 103 and AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA., U.S.A.) .
• An exemplary suitable binder is a mixture of macrocrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581 by FMC Corporation.
• a filler comprises a large portion of the tablet.
• Fillers e . g. , diluents
• diluents are used to give the powder (e.g., in the tablet or capsule) bulk so that an acceptable size tablet, capsule or other desirable dosage form is produced.
• therapeutic ingredients are formed in a convenient dosage form of suitable size by the incorporation of a diluent therewith. As with the binder, binding of the drug to the filler may occur and affect bioavailability.
• lactose should not be used with norastemizole to form the dosage forms of norastemizole made in accordance with the present invention if precautions have not been taken to eliminate unbound water. It is also preferable that the lactose-free dosage forms of norastemizole according to the present invention do not include mono- or di-saccharides, such as, but not limited to, glucose, sucrose and fructose.
• the amount of filler used varies upon the type of formulation and mode of administration, and is readily discernible to those of ordinary skill in the art .
• suitable fillers for use with the lactose-free dosage forms of norastemizole made in accordance with the present invention include, but are not limited to, talc, calcium carbonate ( e . g. , granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre- gelatinized starch, or mixtures thereof.
• the binder/filler in pharmaceutical compositions of the present invention is typically present in about 50 to about 99 weight percent of the pharmaceutical composition.
• Disintegrants are used to cause the tablet to disintegrate when exposed to an aqueous environment . Too much of a disintegrant will produce tablets which may disintegrate in the bottle due to atmospheric moisture and provide unbound water sufficient to initiate and/or accelerate norastemizole lactose interaction. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the drug ingredient (s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the drug ingredient (s) should be used to form the dosage forms of norastemizole made according to the present invention. The amount of disintegrant used varies based upon the type of formulation and mode of administration, and is readily discernible to those of ordinary skill in the art.
• Suitable disintegrants that may be used to form the lactose-free dosage forms of norastemizole made in accordance with 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 or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof .
• the lactose-free, non-hygroscopic, anhydrous, large particle, or coated pharmaceutical compositions of norastemizole such that they dissolve fairly rapidly upon administration to the subject, e . g. , in the subject's stomach.
• 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, croscarmellose sodium or sodium starch glycolate .
• adhesion of the dosage form ingredients to the punches of the tableting machine must be avoided.
• drug e . g. , norastemizole
• sticking of drug or other dosage form ingredients in this way requires unnecessarily high ejection forces when removing the tablet from the die. Excessive ejection forces may lead to a high breakage rate and increase the cost of production not to mention excessive wear and tear on the dies.
• selection of a drug salt with good anti-adhesion properties also minimizes these problems.
• the lubricant is used to enhance the flow of the lactose-free norastemizole tableting powder mix to the tablet machine and to prevent sticking of the tablet in the die after the tablet is compressed. Too little lubricant will not permit satisfactory tablets to be made and too much may produce a tablet with a water-impervious hydrophobic coating. Because lubricants are usually hydrophobic materials such as stearic acid, magnesium stearate, calcium stearate and the like, a water-impervious hydrophobic coating may be formed by the use of too much lubricant. Further, a water-impervious hydrophobic coating can inhibit disintegration of the tablet and dissolution of the drug ingredient (s) .
• a sufficient amount of lubricant should be used that readily allows release of the compressed tablet from the die without forming a water-impervious hydrophobic coating that detrimentally interferes with the desired disintegration and/or dissolution of the drug ingredient (s) .
• Suitable lubricants for use with the lactose-free dosage forms of norastemizole made in accordance with the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil) , zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof.
• Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore MD) , a coagulated aerosol of synthetic silica (marketed by Deaussa Co. of Piano, Texas), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass) or mixtures thereof.
• a lubricant may optionally be added, typically in an amount of less than about 1 weight percent of the pharmaceutical composition.
• Another class of additives for use with the dosage forms of norastemizole include, but are 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 agents for use with the lactose-free dosage forms of norastemizole made in accordance with the present invention include, but are not limited to, calcium silicate, magnesium silicate, silicon dioxide, colloidal silicon dioxide, talc or mixtures thereof.
• Suitable antimicrobial preservatives for use with the lactose-free dosage forms of norastemizole made in accordance with the present invention include, but are not limited to, benzalkonium chloride solution, benzethonium chloride, benzoic acid, benzyl alcohol, butyl paraben, cetylpyridinium chloride, chlorobutanol, cresol, dehydroacetic acid, ethylparaben, methylparaben, phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, potassium sorbate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimersol, thymol or mixtures thereof.
• Suitable coating agents for use with the lactose- free dosage forms of 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, hydroxypropyl methylcellulose (e.g., Nos . : 2208, 2906, 2910), hydroxypropyl methyl cellulose phthalate (e.g., Nos.: 200731, 220824), methylcellulose, polyethylene glycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax or mixtures thereof.
• the amount of coating agent and the carrier vehicle (aqueous or non-aqueous) used varies upon the type of formulation and mode of administration, and is readily discernible to those of ordinary skill in the art.
• a coating of a film forming polymer may optionally be applied to the norastemizole tablet (e.g., a capsule shaped tablet often referred to as a caplet) in accordance with the present invention by using one of several types of equipment such as a conventional coating pan, Accelacota, High-Cola or Worster air suspension column. Such equipment typically has an exhaust-system to remove dust and solvent or water vapors to facilitate quick drying. Spray guns or other suitable atomizing equipment may be introduced into the coating pans to provide spray patterns conducive to rapid and uniform coverage of the tablet bed. Normally, heated or cold drying air is introduced over the tablet bed in a continuous or alternate fashion with a spray cycle to expedite drying of the film coating solution.
• a conventional coating pan Accelacota, High-Cola or Worster air suspension column.
• Spray guns or other suitable atomizing equipment may be introduced into the coating pans to provide spray patterns conducive to rapid and uniform coverage of the tablet bed. Normally, heated or cold drying air is introduced over the tablet bed in a continuous or
• non-hygroscopic, anhydrous, large particle, or coated pharmaceutical compositions of the invention containing reactive excipients, such as lactose, non-aqueous operations are preferred, e.g., non-aqueous coating should be used.
• the coating solution may be sprayed by using positive pneumatic displacement or peristaltic pump systems in a continuous or intermittent spray-dry cycle. The particular type of spray application is selected depending upon the drying efficiency of the coating pan.
• the coating material is sprayed until the lactose-free, non-hygroscopic, large particle, anhydrous, or coated norastemizole tablets are uniformly coated to the desired thickness and the desired appearance of the tablet is achieved.
• Many different types of coatings may be applied such as enteric, slow release coatings or rapidly dissolving type coatings for fast acting tablets.
• rapidly dissolving type coatings are used to permit more rapid release of the active ingredients, resulting in hastened onset.
• the thickness of the coating of the film forming polymer applied to a tablet may vary. However, it is preferred that the thickness simulate the appearance, feel (tactile and mouth feel) and function of a gelatin capsule.
• the film type and thickness if any, to use based on characteristics such as desired blood levels of active ingredient, rate of release, solubility of active ingredient, and desired performance of the dosage form.
• a number of suitable film forming agents for use in coating a final dosage form, such as tablets comprising the present lactose-free, non-hygroscopic, anhydrous, large particle or coated formulations of norastemizole include, for example, methylcellulose, hydroxypropyl methyl cellulose (PHARMACOAT 606 6 cps) , polyvinylpyrrolidone (povidone) , ethylcellulose (ETHOCEL 10 cps) , various derivatives of methacrylic acids and methacrylic acid esters, cellulose acetate phthalate or mixtures thereof.
• Suitable colorants for use with the lactose-free dosage forms of norastemizole made in accordance with the present invention include, but are not limited to, pharmaceutically acceptable dyes and lakes, caramel, red ferric oxide, yellow ferric oxide or mixtures thereof.
• Suitable desiccants for use with the lactose-free, anhydrous, large particle, or coated norastemizole dosage formulations made in accordance with the present invention include, but are not limited to, calcium chloride, calcium sulfate, silica gel or mixtures thereof.
• Suitable flavors for use with the lactose-free dosage forms of norastemizole made in accordance with the present invention include, but are not limited to, acacia, tragacanth, almond oil, anethole, anise oil, benzaldehyde, caraway, caraway oil, cardamom oil, cardamom seed, compound cardamom tincture, cherry juice, cinnamon, cinnamon oil, clove oil, cocoa, coriander oil, eriodictyon, eriodictyon fluidextract , ethyl acetate, ethyl vanillin, eucalyptus oil, fennel oil, glycyrrhiza, pure glycyrrhiza extract, glycyrrhiza fluidextract , lavender oil, lemon oil, menthol, methyl salicylate, monosodium glutamate, nutmeg oil, orange flower oil, orange flower water, orange oil, sweet orange peel tincture
• Suitable plasticizers for use with the lactose-free dosage forms of norastemizole made in accordance with the present invention include, but are not limited to, castor oil, diacetylated monoglycerides, diethyl phthalate, glycerin, mono-and di-acetylated monoglycerides, polyethylene glycol, propylene glycol, and triacetin or mixtures thereof.
• Suitable viscosity increasing agents for use with the lactose-free dosage forms of norastemizole made in accordance with the present invention include, but are not limited to, acacia, agar, alamic acid, aluminum monostearate, bentonite, bentonite magma, carbomer 934, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethylcellulose sodium 12, carrageenan, cellulose, microcrystalline cellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (Nos.
• magnesium aluminum silicate magnesium aluminum silicate
• methylcellulose pectin
• polyvinyl alcohol povidone
• silica gel colloidal silicon dioxide, sodium alginate, tragacanth and xanthan gum or mixtures thereof .
• Suitable sweetening agents for use with the lactose-free dosage forms of norastemizole made in accordance with the present invention include, but are not limited to, aspartame, dextrates, mannitol, saccharin, saccharin calcium, saccharin sodium, sorbitol, sorbitol solution, or mixtures thereof .
• Suitable buffering agents for use with the lactose- free dosage forms of norastemizole made in accordance with the present invention include, but are not limited to, magnesium hydroxide, aluminum hydroxide and the like, or mixtures thereof.
• Suitable humectants include, but are not limited to, glycerol, other humectants or mixtures thereof.
• the dosage forms of norastemizole of the present invention may further include one or more of the following: (1) dissolution retarding agents, such as paraffin; (2) absorption accelerators, such as quaternary ammonium compounds; (3) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (4) absorbents, such as kaolin and bentonite clay; (5) antioxidants, such as water soluble antioxidants (e.g., ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate, sodium sulfite and the like), oil soluble antioxidants (e.g., ascorbyl palmitate, hydroxyanisole (BHA) , butylated hydroxy toluene (BHT) , lecithin, propyl gallate, alpha-tocopherol and the like) ; and (6) metal chelating agents, such as citric acid, ethylenediamine tetracetic acid (EDTA) , sorbi
• lactose-free, non-hygroscopic, anhydrous, large particle, or coated norastemizole dosage forms of the present invention may also be provided in the form of hard or soft capsules, for example, of gelatin or other suitable materials together with various excipients previously noted with regard to tablets.
• the 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 the like) in various proportions using traditional tableting equipment such as twin shell or "v" blenders by known procedures to manufacture chemically and thermally stable dosage forms (e.g., tablets, caplets and the like) containing a uniform distribution and blending of therapeutic agents.
• 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 the like
• traditional tableting equipment such as twin shell or "v" blenders by known procedures to manufacture chemically and thermally stable dosage
• sugar-coated tablets include, for example, hard gelatin capsules, caplets, sugar-coated tablets, enteric- coated tablets to delay action, multiple compressed tablets, prolonged-action tablets, tablets for solution, effervescent tablets, buccal and sublingual tablets, troches and the like.
• Sugar-coating preferably does not include lactose or mono- or di-saccharides, except in norastemizole formulations substantially free of unbound water.
• Tablets of the lactose-free, non-hygroscopic, anhydrous, large particle, or coated dosage forms of norastemizole of the present invention are typically made by molding, by compression or by generally accepted tablet forming methods. Accordingly, compressed tablets are usually prepared by large-scale production methods while molded tablets often involve small-scale operations. For example, there are three general methods of tablet preparation for making 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 U.S. Pharmacopeia
• lactose-free, non-hygroscopic, anhydrous, large particle, or coated dosage forms of norastemizole may be made in accordance with the present invention.
• tablet dosage forms such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, multiple-compressed tablets, prolonged action tablets and the like.
• Lactose-free, non-hygroscopic, anhydrous, large particle, or inert coated norastemizole sugar-coated tablets (SCT) are compressed tablets containing a sugar coating.
• Such coatings may be colored and are beneficial in covering up drug substances possessing objectionable tastes or odors and in protecting materials sensitive to oxidation.
• Lactose-free, non-hygroscopic, anhydrous, large particle, or coated norastemizole film- coated tablets are compressed tablets which are covered with a thin layer or film of a water-soluble material. A number of polymeric substances with film-forming properties may be used. The film coating imparts the same general characteristics as sugar coating with the added advantage of a greatly reduced time period required for the coating operation. Enteric-coated tablets are also suitable for use in the present invention. Lactose-free, non-hygroscopic, anhydrous, large particle or coated norastemizole enteric- coated tablets (ECT) are compressed tablets coated with substances that resist dissolution in gastric fluid but disintegrate in the intestine.
• ECT norastemizole enteric- coated tablets
• Enteric coating can be used for tablets containing drug substances which are inactivated or destroyed in the stomach, for those which irritate the mucosa or as a means of delayed release of the medication.
• Lactose-free, non-hygroscopic, anhydrous, large particle, or coated norastemizole multiple compressed tablets (MCT) are compressed tablets made by more than one compression cycle, such as layered tablets or press-coated tablets. Layered tablets are prepared by compressing additional tablet granulation on a previously compressed granulation. The operation may be repeated to produce multilayered tablets of two, three or more layers. Typically, special tablet presses are required to make layered tablets. See, for example, U.S. Pat. No. 5,213,738, incorporated herein in its entirety by reference thereto.
• Press coated tablets are another form of multiple compressed tablets. Such tablets, also referred to as dry- coated tablets, are prepared by feeding previously compressed tablets into a tableting machine and compressing another granulation layer around the preformed tablets. These lactose-free, non-hygroscopic, or anhydrous norastemizole tablets have all the advantages of compressed tablets, i.e., slotting, monogramming, speed of disintegration, etc., while retaining the attributes of sugar coated tablets in masking the taste of the drug substance in the core tablet. Press- coated tablets can also be used to separate incompatible drug substances. Further, they can be used to provide an enteric coating to the core tablets. Both types of norastemizole tablets (i.e., layered tablets and press-coated tablets) may be used, for example, in the design of prolonged-action dosage forms .
• Lactose-free, non-hygroscopic, anhydrous, large particle, or coated norastemizole prolonged-action tablets may comprise compressed tablets formulated to release the drug substance in a manner to provide medication over a period of time.
• tablet types that include delayed-action tablets in which the release of the drug substance is prevented for an interval of time after administration or until certain physiological conditions exist.
• Repeat action tablets may be formed that periodically release a complete dose of the drug substance to the gastrointestinal fluids.
• extended release tablets that continuously release increments of the contained drug substance to the gastrointestinal fluids may be formed.
• the method of preparation and the additives to be incorporated into a lactose-free, non-hygroscopic, anhydrous, large particle, or coated norastemizole tablet are selected in order to give the tablet formulation the desirable physical characteristics while allowing the rapid compression of tablets.
• the tablets preferably should have a number of additional attributes such as appearance, hardness, disintegration ability and uniformity which are influenced both by the method of preparation and by the additives present in the tablet formulation.
• the basic unit in all tablet compression equipment includes a lower punch which fits into a die from the bottom and an upper punch, having a head of generally the same shape and dimensions as that of the lower punch, which enters the die cavity from the top after the tableting material fills the die cavity.
• the tablet is formed by pressure applied on the punches. Subsequently, the tablet is ejected from the die. The weight of the tablet is determined by the volume of the material which fills the die cavity.
• the ability of the lactose-free, non-hygroscopic, anhydrous, large particle, or coated norastemizole tablet or dosage form granulation to flow freely into the die cavity is important in insuring an uniform fill.
• the flowability of the granulation is also important to insure continuous movement of the granulation from the source of supply or feed hopper. Further, if the tablet granulation does not possess cohesive properties, after compression the tablet will crumble and fall apart on handling. Even further, as the punches must move freely within the die and the tablet must be readily ejected from the punch faces, the tableting material must have a degree of lubrication to minimize friction and to allow for the removal of the compressed tablet. A granulating agent may be added to facilitate granulation.
• the amount of granulating agent used varies upon the type of formulation and mode of administration, and is readily discernible to those of ordinary skill in the art. Typically, about 5 to about 15 weight percent of granulating agent is used in the pharmaceutical formulation. Preferably, when lactose is present in the anhydrous or non-hygroscopic compositions of the present invention, the granulating agent should be non-aqueous.
• stable lactose-free, non- hygroscopic, anhydrous, large particle, or coated norastemizole tablets or other dosage forms thereof retain their original size, shape, weight and color under normal handling and storage conditions throughout their shelf life.
• excessive powder or solid particles at the bottom of the container, cracks or chips on the face of a tablet, or appearance of crystals on the surface of tablets or on container walls are indicative of physical instability of uncoated tablets.
• the effect of mild, uniform and reproducible shaking and tumbling of tablets should be undertaken to insure that the tablets have sufficient physical stability.
• Tablet hardness can be determined by commercially available hardness testers.
• the in vi tro availability of the active ingredient should not change appreciably with time.
• the lactose-free pharmaceutical compositions of the present invention may also be formulated in a soft elastic gelatin capsule unit dosage form by using conventional methods, well-known in the art (see, e.g., Ebert, Pharm . Tech . , 1(5) :44-50 (1977)).
• Soft elastic gelatin capsules have a soft, globular, gelatin shell somewhat thicker than that of hard gelatin capsules, wherein a gelatin is plasticized by the addition of glycerin, sorbitol, or a similar polyol .
• the hardness of the capsule shell may be changed by varying the type of gelatin and the amounts of plasticizer and water.
• the soft gelatin shells may contain a preservative (such as methyl-and propylparabens and sorbic acid) to prevent the growth of fungi.
• 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.
• 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, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art.
• compositions of the present invention may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres .
• lactose-free, non-hygroscopic, anhydrous, large particle, or coated norastemizole compositions of the present invention may further contain, for example, an analgesic, a decongestant , a cough suppressant, or an expectorant.
• excipients tested include corn starch, calcium sulfate dihydrate, calcium stearate, sucrose, fructose, calcium carbonate, microcrystalline cellulose, maltodextrin, CaHP0 4 «2H 2 0, CaHP0 4 , magnesium stearate, starch 1500 ® , croscarmellose sodium or mixtures thereof.
• Figure 2 also provides some indication that mono- and di-saccharide excipients should also preferably be avoided in norastemizole formulations, e.g., as shown by the degradation observed with norastemizole/sucrose combinations.
• the crimped vials were held at 60°C for 14 days and assayed for norastemizole.
• a lactose-free, non-hygroscopic, anhydrous, large particle, or coated norastemizole dosage formulation such as a troche, a tablet or a capsule may be formed by combining norastemizole, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically compatible excipients, as described above, in pharmaceutically compatible amounts to yield 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.
• the tablet, troche or capsule dosage formulation may be formed, 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, may be used. However, compression molding is preferred for the formulation of tablets and troches. For capsules, hard gelatin capsule shells are preferred which are filled with norastemizole and one or more excipients. STARCH 1500 ® is a pre-gelatinized starch manufactured by Colorcon Ltd. that is not recommended for use in amounts exceeding 75 weight percent.
• magnesium stearate when magnesium stearate is used as a lubricant with STARCH 1500 ® , amounts greater than 0.25 weight percent of magnesium stearate should not be used, as this may have an adverse effect on dissolution.
• This adverse effect on dissolution in formulations of STARCH 1500 ® and greater than 0.25 weight percent of magnesium stearate is particularly important for compounds having relatively low water-solubility, such as norastemizole .
• Example 1 Hard Gelatin Capsule Unit Dosage Forms (Lactose-Free)
• the active ingredient is sieved and blended with the excipients listed.
• the mixture is filled into suitably sized two-piece hard gelatin capsules using suitable machinery and methods well known in the art. See Remington's Pharmaceutical Sciences, 16th or 18th Editions, each incorporated herein in its entirety by reference thereto.
• Other doses may be prepared by altering the fill weight and, if necessary, changing the capsule size to suit. Any of the stable, non-lactose, non-hygroscopic, and anhydrous hard gelatin capsule formulations above may be formed.
• the active ingredient is sieved through a suitable sieve and blended with the non-lactose excipients until a uniform blend is formed.
• the dry blend is screened and blended with the magnesium stearate.
• the resulting powder blend is then compressed into tablets of desired shape and size. Tablets of other strengths may be prepared by altering the ratio of the active ingredient (i.e., norastemizole) to the excipient (s) or modifying the tablet weight.
• Example 5 Wet Granulation (Lactose-Free)
• the active ingredient is sieved through a suitable screen and blended with the non-lactose excipients (excluding half of the croscarmellose (or sodium starch glycolate) and all of the microcrystalline cellulose) until a uniform blend is formed. Suitable volumes of water are added and the powder granulated. After drying, the granules are screened and blended with the microcrystalline cellulose, the remainder of croscarmellose or sodium starch glycolate, and briefly with the magnesium stearate. The resulting free- flowing powder is then compressed into tablets of desired shape and size. Tablets of other strengths may be prepared by altering the ratio of the active ingredient (i.e., norastemizole) to the excipients or modifying the tablet weight .
• Example 6 Direct Compression
• the active ingredient is passed through a suitable sieve and blended with the non-lactose excipients (except magnesium stearate) until a uniform blend is formed.
• the dry blend is screened and blended briefly with magnesium stearate.
• the resulting powder blend is then compressed into tablets of desired shape and size. Tablets of other strengths may be prepared by altering the ratio of the active ingredient (i.e., norastemizole) to the excipients or modifying the tablet weight .

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