WO2008079312A2

WO2008079312A2 - Compositions for treatment of nasal congestion

Info

Publication number: WO2008079312A2
Application number: PCT/US2007/026107
Authority: WO
Inventors: Melvyn Richard Danzig; Gerald Robert Brian Down
Original assignee: Schering Corporation
Priority date: 2006-12-22
Filing date: 2007-12-19
Publication date: 2008-07-03
Also published as: WO2008079312A3; EP2121022A2

Abstract

Pharmaceutical compositions including a pediatric dosage amount of loratadine and montelukast or a pharmaceutically acceptable salt of montelukast are provided. Compositions are useful for treating, preventing or reducing nasal congestion associated with allergic rhinitis in a pediatric patient.

Description

COMPOSITIONS FOR TREATMENT OF NASAL CONGESTION

BACKGROUND

People around the world frequently suffer from nasal congestion associated with allergies which leads to partially or fully blocked air passages. Nasal congestion and related symptoms generally have undesirable effects for the afflicted person, such as, disruptions of sleep, loss of work and loss of school attendance.

While antihistamines have been shown efficacious for preventing and relieving sneezing, itching, rhinorrhea and other symptoms of allergies, they have not been found to be very effective for relief of the nasal blockage associated with an allergic reaction. Thus, it has been common to concurrently administer sympathomimetic amine decongestant drugs, such as phenylpropanolamine or pseudoephedrine which function as alpha-adrenoceptor agonists. However, not all allergy sufferers should use these decongestant drugs, due to their frequently observed central nervous system and cardiovascular side effects which include agitation, sleeplessness, tachycardia, angina pectoris and hypertension. Phenylpropanolamine has been withdrawn from the US market.

A treatment for nasal congestion associated with allergic conditions which does not exhibit adverse nervous system or cardiovascular effects associated with sympathomimetic amines is needed.

SUMMARY

Provided herein are compositions useful for treating or preventing nasal congestion associated with allergic rhinitis in a pediatric patient.

In certain aspects, the invention provides a pediatric pharmaceutical composition for treating or reducing nasal congestion in a pediatric patient including a therapeutically effective pediatric amount of loratadine and montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof.

In certain embodiments, the pharmaceutically acceptable salt of montelukast is montelukast sodium. In certain embodiments, the composition includes loratadine and montelukast or a pharmaceutically acceptable salt thereof in a ratio of about 1 :2 to about 2:1 mg/mg. In certain embodiments, the composition includes loratadine and montelukast or a pharmaceutically acceptable salt thereof in a ratio of about 2:1 mg/mg, about 1.25:1 mg/mg or about 1 : 1 mg/mg.

In certain embodiments, the composition includes about 10 mg of loratadine and about 5 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof, or about 5 mg of loratadine and about 4 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, the composition may further include at least one taste masking agent and/or at least one additional therapeutic agent.

In certain embodiments the pharmaceutical composition is formulated for oral, nasal, or ophthalmic administration. The pharmaceutical composition may be formulated as a liquid, tablet, capsule, suppository, granule, suspension or film. Suitable tablets, include, for example, orally ingestible, chewable, or fast dissolving tablet forms.

In certain embodiments, the composition is administered to a pediatric patient from 2 to 6 years old or 6 to 12 years old.

In certain embodiments, the composition may be formulated in a single dosage form.

In certain aspects, the invention provides a pediatric pharmaceutical composition for treating or reducing nasal congestion in a pediatric patient including 10 mg of loratadine and 5 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, the invention provides a pediatric pharmaceutical composition for treating or reducing nasal congestion in a pediatric patient including 5 mg of loratadine and 4 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain aspects, the invention provides a method for treating nasal congestion associated with allergic rhinitis in a pediatric patient, including administering to a pediatric patient a pharmaceutical composition including a therapeutically effective pediatric amount of loratadine and montelukast or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

Compositions provided herein include a therapeutically effective amount of an antihistamine and a leukotriene D₄ receptor antagonist for treating, preventing or reducing nasal congestion associated with allergic rhinitis in a pediatric patient.

Examples of suitable antihistamines include, for example, chlorpheniramine maleate (Chlor-trimeton®), dexchlorpheniramine maleate, diphenhydramine hydrochloride (Benadryl®), doxylamine succinate, promethazine hydrochloride, and triprolidine hydrochloride. Low sedating, or nonsedating, antihistamines may also be included in various compositions described herein. Examples of suitable low sedating, or nonsedating, antihistimines include, for example, loratadine (Claritin^®), fexofenadine hydrochloride (Allegra®), cetirizine hydrochloride (Zyrtec®), levocetirizine (Xyzal®), and terfenadine (Teldane®). Examples of suitable leukotriene D₄ receptor antagonist include, for example, Montelukast (Singulair®), Zafirlukast (Accolate®), Zileuton (Zyflo®), and pranlukast.

In certain embodiments, compositions described herein include a therapeutically effective pediatric amount of loratadine and montelukast, or a pharmaceutically acceptable salt thereof, for treating, preventing or reducing nasal congestion associated with allergic rhinitis in a pediatric patient. A pediatric patient as referred to herein means a human patient less than 15 years of age, a patient that is 3 months to 14 years of age, a patient that is 3 months to 12 years of age, a patient that is 3 months to 10 years of age, a patient that is 3 months to 8 years of age, a patient that is 3 months to 6 years of age, a patient that is 3 months to 4 years of age, a patient that is 3 months to 2 years of age, a patient that is 6 months to 14 years of age, a patient that is 6 months to 12 years of age, a patient that is 6 months to 10 years of age, a patient that is 6 months to 8 years of age, a patient that is 6 months to 6 years of age, a patient that is 6 months to 4 years of age, a patient that is 6 months to 2 years of age, a patient that is 2 to 14 years of age, a patient that is 2 to 12 years of age, a patient that is 2 to 10 years of age, a patient that is 2 to 8 years of age, a patient that is 2 to 6 years of age, a patient that is 2 to 4 years of age, a patient that is 6 to 14 years of age, a patient that is 6 to 12 years of age, a patient that is 6 to 10 years of age, a patient that is 6 to 8 years of age, a patient that is 8 to 14 years of age, a patient that is 8 to 12 years of age, a patient that is 8 to 10 years of age, a patient that is 10 to 14 years of age, or a patient that is 10 to 12 years of age.

Various compositions described herein may be used for treating, preventing, reducing or relieving severe, moderate or mild nasal congestion associated with allergic rhinitis. In certain embodiments, compositions may be used for treatment, prevention or reduction of severe nasal congestion.

Types of nasal congestion that can be treated, prevented or reduced include daytime nasal congestion and nighttime nasal congestion. If a patient suffers from congestion which commonly occurs at a particular time of day or night, the timing of administration may be altered to most effectively treat the patient. In certain embodiments, a combination of loratadine and montelukast, or a pharmaceutically acceptable salt thereof, may be administered in the evening or at bedtime for treatment, prevention or reduction of nighttime nasal congestion, hi certain embodiments, a combination of loratadine and montelukast, or a pharmaceutically acceptable salt thereof, may be administered in the morning, upon waking, or at breakfast for treatment, prevention or reduction of daytime nasal congestion. In certain embodiments, a combination of loratadine and montelukast, or a pharmaceutically acceptable salt thereof, may be administered in the morning, upon waking, or at breakfast for treatment, prevention or reduction of nighttime nasal congestion. In certain embodiments, a combination of loratadine and montelukast, or a pharmaceutically acceptable salt thereof, may be administered in the evening or at bedtime for treatment, prevention or reduction of daytime nasal congestion.

In certain embodiments, compositions described herein are useful for treating, preventing or reducing nasal congestion associated with allergic rhinitis, including seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR). Seasonal allergic rhinitis includes allergies that arise in the fall, spring, or winter or combinations thereof. Compositions may also be useful for treating or preventing allergic rhinitis associated with indoor allergens, outdoor allergens, or both. Examples of indoor allergens include, for example, dust, mold and pet dander. Examples of outdoor allergens include, for example, pollen of trees, weeds, grasses, and flowers. Perennial allergic rhinitis is typically associated with indoor allergens and seasonal allergic rhinitis is typically associated with outdoor allergens.

In certain embodiments, compositions described herein may be administered prophylactically to a patient. Prophylactic administration may be of benefit to a variety of patients, such as, for example, patients having a history of allergies associated with nasal congestion, patients susceptible to seasonal allergic rhinitis, and patients susceptible to allergies arising from specific allergens such as, for example, pet dander, grasses, flowers, etc.

In certain embodiments, compositions described herein are useful for treating, preventing or reducing nasal congestion in pediatric patients that may suffer from both allergic rhinitis and another disorder, such as asthma, hepatic insufficiency, diabetes or hypertension.

In certain embodiments, compositions described herein are useful for relieving nasal congestion while avoiding, or significantly reducing incidence and/or severity of, one or more undesirable side effects associated with sympathomimetic agents such as pseudoephedrine, ephedrine, phenylpropanolamine or phenylephrine. Side effects associated with administration of sympathomimetic amines may include, for example, insomnia, nervousness, jitteriness, restlessness, agitation, dry mouth, hypertension, tachycardia, headache, and dizziness. In certain embodiments, administration of compositions described herein results in a side effect profile that is comparable to placebo.

Various compositions described herein permit avoidance of one or more undesirable side effects of sympathomimetic agents while producing substantially the same nasal decongestant effect as obtained by a therapeutically effective amount of the sympathomimetic agent. Substantially the same nasal decongestant effect as a sympathomimetic agent means that the effect produced is ±30%, ±20%, ±10% or ±5% of the nasal decongestant effect produced by a therapeutically effective amount of a sympathomimetic agent as determined using standard procedures for measuring nasal congestion. In certain embodiments, substantially the same nasal decongestant effect as a sympathomimetic agent means that the effect produced is at least 70%, 80%, 90%, 95%, or greater, of the nasal decongestant effect produced by a therapeutically effective amount of a sympathomimetic agent. In certain embodiments, compositions described herein produce substantially the same nasal decongestant effect as a sympathomimetic agent over a 24 hour dosing period, during the first twelve hours after administration, or during a period 12-24 hours after administration. In certain embodiments, a therapeutically effective amount of a sympathomimetic agent refers to an amount of pseudoephedrine that is effective for treating nasal congestion over a 24 hour period. Such formulations of pseudoephedrine may be prepared by one of skill in the art or may be purchased commercially from Johnson & Johnson, Inc. (New Brunswick, NJ). Loratadine, i.e., 4-(8-Chloro-5,6-dihydro-l li/-benzo[5,6]cyclohepta[l,2- bjpyridin- 11 -ylidene)- 1 -piperidinecarboxylic acid ethyl ester, is a nonsedating-type histamine H] -receptor antagonist. Loratadine is marketed by Schering-Plough Health Care Products, Inc. for the treatment of allergies under the brand name Claritin^® and may be prepared, for example, as described in U.S. Patent No. 4,282,233. Montelukast, i.e., l-[[[(li?)-l-[3-[(lE)-2-(7-Chloro-2- quinolinyl)ethenyl]phenyl]-3-[2-( 1 -hydroxy- 1 - methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, is a selective leukotriene D₄ receptor antagonist. Montelukast sodium is marketed by Merck & Co., Inc. for the treatment of treatment of allergies under the brand name Singulair^® and may be prepared, for example, as described in U.S. Patent No. 5,270,324. Pharmaceutically effective salts of montelukast include, for example, salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. In certain embodiments, the pharmaceutically acceptable salt of montelukast is montelukast sodium. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

As used herein, an equivalent amount of a pharmaceutically acceptable salt of montelukast refers to a milligram amount of a salt form of montelukast that contains essentially the same molar amount of the montelukast anion as contained in a specified milligram amount of montelukast (the free acid). Thus, to determine the equivalent amount of a particular salt form, the specified amount of montelukast (the free acid) is multiplied by the ratio of the molecular weight of the montelukast anion divided by the molecular weight of montelukast (such as, for example, 608.18/586.20 for montelukast sodium/montelukast). For example, 10.4 mg of montelukast sodium is equivalent to 10 mg of montelukast (the free acid).

In certain embodiments, compositions provided herein permit coadministration of loratadine and montelukast, or a pharmaceutically acceptable salt thereof. The active agents may be coformulated as a once a day, single dosage form including a therapeutically effective amount of loratadine and montelukast, or a pharmaceutically acceptable salt thereof. The single daily dosage forms may be useful for both long term or short term treatment regimes. For example, the single daily dosage form may be administered once a day for one or more days, for example, once daily for one day, two days, one week, two weeks, one month, or longer. The single daily dosage form may be administered daily on a regular basis for the treatment of nasal congestion associated with persistent allergies or may be administered sporadically to treat nasal congestion on an as needed basis, such as, for example, acute and/or chronic treatment.

Amounts of loratadine and montelukast, or a pharmaceutically acceptable salt thereof, effective for treating, preventing or reducing nasal congestion associated with allergic rhinitis in a pediatric patient will vary with the age, sex, body weight, general health, severity of the nasal congestion, route of administration, bioavailability of the preparation administered, the dose regimen selected, and the use of concomitant medication. The dose and/or frequency of administration may be adjusted to suit the needs of an individual patient. Suitable total daily dose ranges can be readily determined by those skilled in the art using conventional techniques. A daily dose may be administered in single or divided doses.

Various compositions may include loratadine and montelukast, or a pharmaceutically acceptable salt thereof, in a ratio of about 1 :5 mg/mg to about 5:1 mg/mg, about 1:3 mg/mg to about 3:1 mg/mg, about 1 :2 mg/mg to about 2: 1 mg/mg, about 2:1 mg/mg, about 1.25:1 mg/mg, or about 1 :1 mg/mg.

In certain embodiments, pediatric compositions may include an amount of loratadine and montelukast, or a pharmaceutically acceptable salt thereof, effective for treating, preventing or reducing nasal congestion associated with allergic rhinitis in a pediatric patient. Therapeutically effective pediatric amounts of loratadine and montelukast, or a pharmaceutically acceptable salt thereof, may be in the range of about 1 to about 20 mg of loratadine and about 1 to about 20 mg of montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof, about 2 to about 20 mg of loratadine and about 2 to about 20 mg of montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof, about 2 to about 10 mg of loratadine and about 2 to about 10 mg of montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof, or about 2 to about 5 mg of loratadine and about 2 to about 5 mg of montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof. Such compositions may be formulated so as to provide a therapeutically effective amount in single or divided dosage forms. In certain embodiments, the pediatric compositions described herein include about 10 mg of loratadine and about 5 mg of montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof, about 5 mg loratadine and about 5 mg montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof, or about 5 mg loratadine and about 4 mg montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, pediatric compositions for treatment of pediatric patients suffering from nasal congestion associated with allergic rhinitis are single daily dosage forms including 10 mg loratadine and 5.2 mg montelukast sodium, 5 mg loratadine and 5.2 mg montelukast sodium, or 5 mg loratadine and 4.2 mg montelukast sodium.

In certain embodiments, a single daily dosage form 10 mg loratadine and 5 mg montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof, may be useful for administration to a pediatric patient that is from 6 to 14 years of age, from 8 to 14 years of age, from 10 to 14 years of age, from 12 to 14 years of age, from 6 to 12 years of age, from 8 to 12 years of age, from 10 to 12 years of age, from 6 to 10 years of age, from 8 to 10 years of age, or from 6 to 8 years of age. In certain embodiments, a single daily dosage form including 5 mg loratadine and 5 mg montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof, may be useful for administration to a pediatric patient that is from 2 to 12 years of age, from 2 to 10 years of age, from 2 to 8 years of age, from 2 to 6 years of age, from 2 to 4 years of age, from 4 to 12 years of age, from 4 to 10 years of age, from 4 to 8 years of age, from 4 to 6 years of age, from 6 to 12 years of age, from 6 to 10 years of age, or from 6 to 8 years of age.

In certain embodiments, a single daily dosage form including 5 mg loratadine and 4 mg montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof, may be useful for administration to a pediatric patient that is from 3 months to 8 years of age, from 3 months to 6 years of age, from 3 months to 4 years of age, from 3 months to 2 years of age, from 6 months to 8 years of age, from 6 months to 6 years of age, from 6 months to 4 years of age, from 6 months to 2 years of age, from 3 months to 6 months of age, from 2 to 12 years of age, from 2 to 10 years of age, from 2 to 8 years of age, from 2 to 6 years of age, from 2 to 4 years of age, from 4 to 12 years of age, from 4 to 10 years of age, from 4 to 8 years of age, from 4 to 6 years of age, from 6 to 12 years of age, from 6 to 10 years of age, or from 6 to 8 years of age.

In certain embodiments, pediatric compositions described herein may include loratadine and montelukast, or a pharmaceutically acceptable salt thereof, in combination with at least one other therapeutic agent. Such therapeutic agents may include, for example, a non-narcotic analgesic (such as, for example, acetaminophen (Tylenol^®) or a cox-2 inhibitor (such as, for example celecoxib (Celebrex^®), valdecoxib (Bextra^®), lumiracoxib (Prexige^®), etoricoxib (Arcoxia^®),etc.)); a non-steroidal antiinflammatory (such as, for example, aspirin, indomethacin (Indocin^®), ibuprofen (Motrin^®), naproxen (Naprosyn^®), piroxicam (Feldene^®), and nabumetone (Relafen¹^, etc.); a long-acting beta 2-adrenergic agonist (LABA) (such as, for example, salmeterol, formoterol, bambuterol, etc.); a corticosteroid (such as, for example prednisone, prednisolone, methylprednisolone, mometasone furoate monohydrate, beclomethasone, flunisolide, triamcinolone acetonide, fluticasone propionate, dexamethasone sodium phosphate, budesonide, etc.); or an antitussive (such as, for example, dextromethorphan, codeine, hydrocodone, etc.). Various pediatric compositions including loratadine and montelukast, or a pharmaceutically acceptable salt thereof, may be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. Techniques and formulations generally may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, PA. In certain embodiments, pediatric compositions described herein may be formulated for any suitable route of administration that provides the patient with an effective dosage of loratadine and montelukast, or a pharmaceutically acceptable salt thereof. For example, formulations suitable for oral, intraoral, rectal, parenteral, epicutaneous, transdermal, subcutaneous, intramuscular, intranasal, sublingual, intradural, intraocular, intrarespiratory, oral or nasal inhalation and like forms of administration are provided.

Various pharmaceutical compositions including loratadine and montelukast, or a pharmaceutically acceptable salt thereof, may be formulated in a variety of suitable dosage forms including, for example, tablets, chewable tablets, fast melt formulations, troches, dispersions, granules, suspensions, solutions, capsules, patches, liquids, syrups, elixirs, gels, powders, magmas, lozenges, ointments, creams, pastes, plasters, lotions, discs, suppositories, films, nasal or oral sprays, aerosols and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. Tablets may be coated by standard aqueous or nonaqueous techniques. In certain embodiments, compositions may be formulated in sustained release form to provide rate controlled release of loratadine and/or montelukast, or a pharmaceutically acceptable salt thereof, to optimize the therapeutic effects. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.

Solid form preparations include powders, tablets, lozenges, dispersible granules, capsules, cachets and suppositories. Such solid dosage forms may be prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (such as, for example, pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (such as, for example, lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (such as, for example, magnesium stearate, talc or silica); disintegrants (such as, for example, potato starch or sodium starch glycolate); or wetting agents (such as, for example, sodium lauryl sulphate). The active ingredient(s) may make up about 5 to about 95 percent of the total weight of the solid dosage form. Tablets, powders, lozenges, cachets and capsules can be used as solid dosage forms suitable for oral administration. Tablets may be coated by methods well known in the art. Tablets may be prepared using standard methods, such as, for example, by compression or molding, optionally, with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

Rapidly disintegrating or dissolving dosage forms (such as, for example, fast melt formulations) are useful for the rapid absorption, particularly buccal and sublingual absorption, of pharmaceutically active agents. Fast melt formulations, such as tablets, may be prepared using standard techniques. For example, granules for fast melt tablets made by either the spray drying or pre-compacting processes may be mixed with excipients and compressed into tablets using conventional tablet making machinery. The granules can be combined with a variety of carriers including low density, high moldability saccharides, low moldability saccharides, polyol combinations, and then directly compressed into a tablet that exhibits an improved dissolution and disintegration profile. Fast melt tablets typically have a hardness of about 2 to about 6 Strong-Cobb units (scu). Tablets within this hardness range disintegrate or dissolve rapidly when chewed. Additionally, the tablets rapidly disintegrate in water. On average, a typical 1.1 to 1.5 gram tablet disintegrates in 1-3 minutes without stirring. This rapid disintegration facilitates delivery of the active material. See, for example, U.S. Patent Nos. 5,112,616 and 5,073,374; U.S. Pat. No. 4,616,047 for further description of fast melt formulations.

Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (such as, for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (such as, for example, lecithin or acacia); non-aqueous vehicles (such as, for example, oils, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (such as, for example, methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavoring, coloring and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound. Parenteral forms to be injected intravenously, intramuscularly or subcutaneously are usually in the form of sterile solutions and may contain tonicity agents (salts or glucose), and buffers. Liquid form preparations may also include solutions for intranasal administration.

For administration by inhalation (such as, for example, pulmonary delivery), the active agents may be delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant such as an inert compressed gas, such as, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, nitrogen, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of such as, for example, gelatin, for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. Combinations of loratadine and montelukast, or a pharmaceutically acceptable salt thereof, may also be deliverable transdermally. Transdermal compositions may include creams, lotions, aerosols and/or emulsions and may be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. hi certain embodiments, pharmaceutical preparations are in a unit dosage form, hi such form, a preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, such as, for example, an effective amount to achieve the desired purpose.

Pharmaceutical formulations of loratadine and montelukast, or a pharmaceutically acceptable salt thereof, may be taste masked to increase patient compliance. Any type of taste masking methodology may be used in association with the pharmaceutical formulations described herein.

One method for taste masking involves the use of sweeteners, flavoring agents or effervescent systems to cover or mask the bitter taste of the active ingredients. For example, flavors that complement the taste of the preparation or which exhibit a longer intensity and stronger taste than the drug can be used. High levels of sweetening agents are often used to overwhelm bitterness with sweetness. Suitable sweeteners include natural and artificial sweeteners such as, for example, sugars (such as, for example, glucose, sucrose, etc.), saccharine, dipeptide sweeteners (such as, for example, aspartame), and sugar alcohols (such as, for example, sorbitol, mannitol, etc.). The taste buds may also be anesthetized by menthol or mint flavors. Many formulations use a raspberry, cherry, orange, or grape flavor that is well liked by both children and adults.

Biochemical methods for taste masking involve the use of lipoproteins to react with bitterness receptor sites, thereby suppressing the response to the drug's bitterness. Other taste masking methods are based on physical means such as agglomeration, coating, and microencapsulation.

Coatings may be used to mask the taste, facilitate swallowing and/or delay release of the active ingredients. The coating prevents the undesirable taste of the drug ingredient from coming through thus making the drug preparation more palatable. In addition, coatings can be designed to act as a time release mechanism to control the rate of release of the medicine in the body. This can be accomplished in various ways such as adjusting the thickness of the coating and selection of the coating polymers/components that are used in these types of specialized coating formulations. Active ingredients may also be processed to pellets or granules in order to reduce the surface area, and then provided with saliva-resistant coatings.

Various types of coatings can be applied to the outside of tablets and drug powders to achieve a specific desired effect. Enteric coatings are designed to be soluble in the intestine, where the pH is 6.5 or higher, but insoluble in the stomach, where the pH is lower. On the other hand, reverse enteric coatings are designed to be partially soluble in the stomach, i.e. under acidic or lower pH conditions, thereby releasing the drug in the stomach.

Microencapsulation is a process by which coatings are applied to small particles of solids, droplets of liquids or dispersions, so as to form microcapsules. This technique differs from other coating procedures in that the size of the particles generally ranges from several tenths of a μm to 5000 μm in diameter.

When an active agent is formulated as a tablet or capsule intended to be swallowed whole, the taste of the active ingredient is usually not an issue since the capsule keeps the active ingredient from contacting the mouth and the tablet can be coated to prevent contact of the active with the mouth for the short time the tablet is present in the mouth. In contrast, masking of the unpleasant taste characteristics of the active agent is an extremely important factor in the formulation of liquid and chewable pharmaceuticals. The palatability of the liquid or chewable dosage form is a critical factor in ensuring patient compliance. U.S. Pat. No. 5,599,556 discloses liquid formulations where the active ingredient is coated with a single outer polymeric coating derived from prolamine cereal grain proteins and a plasticizing agent. The coatings are designed to rapidly degrade once the composition leaves the mouth.

U.S. Pat. No. 5,489,436 discloses chewable tablets made from a coated medicament where the coating is a "reverse enteric coating" designed to be soluble at the acidic pH of the stomach but relatively insoluble in the mouth. The coatings comprise a polymer blend of dimethylaminoethyl methacrylate and neutral methacrylic acid ester and a cellulose ester.

U.S. Pat. No. 6,136,347 discloses taste-masked microcapsules for use in liquid suspension formulations, particularly in oil-based juices or a suitable liquid such as water. The microcapsule includes an active ingredient granule coated with a single outer polymeric coating derived from film-forming agents such as neutral methyl and ester compounds of polymethacrylic acid. The coatings are designed to be water- insoluble and rapidly degrade once the composition reaches the acidic environment of the stomach. U.S. Patent No. 6,027,746 discloses a chewy, soft gelatin capsule within which a drug adsorbate is dispersed in a solid or liquid fill material. The drug is absorbed onto flake-like particles of an adsorbate such as magnesium trisilicate, silicate dioxide or a mixture thereof. The fill material of the capsule within which the adsorbate is dispersed comprises flavors, sweeteners, corn syrup, solvents and other food-grade excipient that assist in the stabilizing and taste-masking of bitter tasting drugs.

U.S. Patent No. 7,067,116 discloses fast dissolving orally consumable films containing a taste masking agent such as an ion exchange resin to mask the taste of a pharmaceutically active agent formulated in the film.

U.S. Patent No. 4,581,232 discloses the use of magnesium trisilicates for formation of medicament adsorbates to render bitter drugs tasteless in liquid, tablet and chewable dosage forms which become readily bioavailable when the adsorbate reaches the low pH environment of the stomach.

Various studies evaluating combination therapy with montelukast and loratadine have been published. For example, a double-blind, placebo-controlled trial evaluated the effectiveness and tolerability of montelukast, loratadine, and combination therapy with montelukast and loratadine for treating patients with fall seasonal allergic rhinitis (see Nayak, A.S., et al., Efficacy and tolerability of montelukast alone or in combination with loratadine in seasonal allergic rhinitis: a multicenter, randomized, double-blind, placebo-controlled trial performed in the fall, Annals of Allergy, Asthma & Immunology 88: 592-600 (2002)). The study concluded that montelukast alone or in combination with loratadine is well tolerated and provides clinical and quality-of-life benefits for patients with seasonal allergic rhinitis. Another study assessed the efficacy of a loratadine and montelukast combination in seasonal allergic rhinitis subjects with severe nasal congestion (see Prenner, B. et al., Assessment of the efficacy of loratadine (L) -Montelukast (M) combination (LMC) in seasonal allergic rhinitis (SAR) subjects with severe nasal congestion (NC) without a history of perennial allergic rhinitis

(PAR), Annals of Allergy, Asthma & Immunology 90: 122 (Abstract P30) (2003); and Rachelefsky, G. et al., Assessment of the efficacy of loratadine (L) -Montelukast (M) combination (LMC) in seasonal allergic rhinitis (SAR) subjects with severe nasal congestion (NC), Annals of Allergy, Asthma & Immunology 90: 123 (Abstract P31) (2003)). The study concluded that the effects of the combination and loratadine alone were comparable. Another randomized, double-blind study compared the combinations of fexofenadine-pseudoephedrine and loratadine-montelukast in the treatment of seasonal allergic rhinitis (see Moinuddin, R. et al., Comparison of the combinations of fexofenadine-pseudoephedrine and loratadine-mnontelukast in the treatment of seasonal allergic rhinitis, Annals of Allergy, Asthma & Immunology 92: 73-79 (2004)). The study concluded that fexofenadine-pseudoephedrine and loratadine- montelukast have comparable efficacy in improving symptoms, Rhinoconjuctivitis Quality of Life Questionnaire (RQLQ) scores, and nasal obstruction in seasonal allergic rhinitis.

EXEMPLIFICATION

The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way. EXAMPLE 1: Preparation ofChewable Tablets of Loratadine (10 mg) and Montelukast (5 mg)

A wet granulation process has been used to manufacture

Montelukast/Loratadine chewable tablets in a 5/10 mg dose strength. The process consists of the following steps: (1) Wet Granulating: Prepare a solution by dissolving Montelukast sodium salt in purified water. Dry blend microcrystalline cellulose, loratadine, croscarmellose sodium, hydroxypropyl cellulose and mannitol in a high shear granulator. Spray the drug solution onto the dry blended materials. Granulate to a satisfactory endpoint. (2) Fluid Bed Drying: Dry the granulation in a fluid bed dryer. (3) Milling: mill the dry granulation using a cone mill. (4) Sweetener and flavor addition: Blend the sized granulation with screened orange flavor and aspartame. (5) Lubricating: Blend screened magnesium stearate with the granulation. (6) Compressing: compress the lubricated blend using a tablet press. Inspect tablets for defects and store in suitable containers.

Quantitative and Qualitative Composition:

Quantity of excipients may vary + 10%

** The water is removed during processing

EQUIVALENTS The present invention provides among other things compositions including therapeutically effective pediatric amounts of loratadine and montelukast, or a pharmaceutically acceptable salt thereof. While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

What is claimed is:

1. A pediatric pharmaceutical composition for treating or reducing nasal congestion in a pediatric patient comprising a therapeutically effective pediatric amount of loratadine and montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof.

2. The composition of claim 1, wherein the pharmaceutically acceptable salt of montelukast is montelukast sodium.

3. The composition of claim 1, wherein the pediatric patient is from 2 to 6 years old.

4. The composition of claim 1, wherein the pediatric patient is from 6 to 12 years old.

5. The composition of claim 1, wherein the composition comprises loratadine and montelukast or a pharmaceutically acceptable salt thereof in a ratio of about 1 :2 to about 2:1 mg/mg.

6. The composition of claim 1, wherein the composition comprises loratadine and montelukast or a pharmaceutically acceptable salt thereof in a ratio of about 1.25:1 mg/mg.

7. The composition of claim 1, wherein the composition comprises loratadine and montelukast or a pharmaceutically acceptable salt thereof in a ratio of about 2:1 mg/mg.

8. The composition of claim 1, wherein the composition comprises about 10 mg of loratadine and about 5 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof.

9. The composition of claim 1, wherein the composition comprises about 5 mg of loratadine and about 4 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof.

10. The composition of claim 1, wherein the composition is formulated in a single dosage form.

11. The composition of claim 1, wherein the composition further comprises at least one taste masking agent.

12. The composition of claim 1, further comprising at least one additional therapeutic agent.

13. The composition of claim 1, wherein the composition is formulated for oral, nasal, or ophthalmic administration.

14. The composition of claim 1 , wherein the composition is formulated as a liquid, tablet, capsule, suppository, granule, suspension or film.

15. The composition of claim 14, wherein the tablet is orally ingestible, chewable, or fast dissolving.

16. A pediatric pharmaceutical composition for treating or reducing nasal congestion in a pediatric patient comprising 10 mg of loratadine and 5 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof.

17. The composition of claim 16, wherein the pharmaceutically acceptable salt of montelukast is montelukast sodium.

18. The composition of claim 16, wherein the composition further comprises at least one taste masking agent.

19. The composition of claim 16, further comprising at least one additional therapeutic agent.

20. The composition of claim 16, wherein the pharmaceutical composition is formulated for oral, nasal, or ophthalmic administration.

21. The composition of claim 16, wherein the pharmaceutical composition is formulated as a liquid, tablet, capsule, suppository, granule, suspension or film.

22. The composition of claim 21, wherein the tablet is orally ingestible, chewable, or fast dissolving.

23. The composition of claim 16, wherein the pediatric patient is from 6 to 12 years old.

24. A pediatric pharmaceutical composition for treating or reducing nasal congestion in a pediatric patient comprising 5 mg of lόratadine and 4 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof.

25. The composition of claim 24, wherein the pharmaceutically acceptable salt of montelukast is montelukast sodium.

26. The composition of claim 24, wherein the composition further comprises at least one taste masking agent.

27. The composition of claim 24, further comprising at least one additional therapeutic agent.

28. The composition of claim 24, wherein the pharmaceutical composition is formulated for oral, nasal, or ophthalmic administration.

29. The composition of claim 24, wherein the pharmaceutical composition is formulated as a liquid, tablet, capsule, suppository, granule, suspension or film.

30. The composition of claim 29, wherein the tablet is orally ingestible, chewable, or fast dissolving.

31. The composition of claim 24, wherein the pediatric patient is from 2 to 6 years old.

32. A method for treating nasal congestion associated with allergic rhinitis in a pediatric patient, comprising administering to a pediatric patient the pharmaceutical composition of claim 1, 16 or 24.