WO2008079256A2

WO2008079256A2 - Methods for treating nasal congestion in hypertensive or diabetic patients

Info

Publication number: WO2008079256A2
Application number: PCT/US2007/025992
Authority: WO
Inventors: Melvyn Richard Danzig
Original assignee: Schering Corporation
Priority date: 2006-12-22
Filing date: 2007-12-19
Publication date: 2008-07-03
Also published as: CL2007003750A1; WO2008079256A3; EP2121021A2; TW200838525A

Abstract

Methods for treating, preventing or reducing nasal congestion associated with allergic rhinitis are provided. Methods may involve administering a therapeutically effective amount of a pharmaceutical composition including loratadine and montelukast or a pharmaceutically acceptable salt thereof.

Description

METHODS FOR TREATING 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 Phenylpropanolamine has been withdrawn from the US market.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

In certain aspects, the invention provides a method for treating or reducing nasal congestion associated with allergic rhinitis in a hypertensive patient in need thereof, including administering to said hypertensive patient a therapeutically effective amount of a pharmaceutical composition including loratadine and montelukast or a pharmaceutically acceptable salt thereof.

In certain embodiments, pharmaceutically acceptable salt of montelukast is montelukast sodium. In certain embodiments, side effects associated with a sympathomimetic agent are undesirable for said patient. Exemplary sympathomimetic agents include, for example, pseudoephedrine, ephedrine, phenylpropanolamine or phenylephrine.

In certain embodiments, the patient has blood pressure of at least 140/90, at least 160/95, or at least 200/130. The patient may be suffering from uncontrolled hypertension and/or severe hypertension. The patient may be taking medication to reduce or control blood pressure.

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

In certain embodiments, the pharmaceutical composition includes about 10 mg of loratadine and 10 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof; about 10 mg of loratadine and 5 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof; about 5 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 allergic rhinitis is seasonal allergic rhinitis or perennial allergic rhinitis. In certain embodiments, the patient may be suffering from severe nasal congestion.

In certain embodiments, the pharmaceutical composition further includes at least one additional therapeutic agent.

In certain embodiments, the pharmaceutical composition maybe administered orally, nasally, or ophthalmically. The pharmaceutical composition may be formulated as a liquid, pill, tablet, capsule, suppository, granule, suspension or film. Suitable tablets include, for example, orally ingestible, chewable, or fast dissolving tablet forms. In certain aspects, the invention provides a method for treating or reducing nasal congestion associated with allergic rhinitis in a hypertensive patient in need thereof, including administering to said hypertensive patient a therapeutically effective amount of a pharmaceutical composition including loratadine and montelukast, or a pharmaceutically acceptable salt thereof, wherein administration of said pharmaceutical composition produces a nasal decongestion effect that is substantially the same as the nasal decongestion effect produced by pseudoephedrine.

In certain embodiments, the nasal decongestion effect produced by pseudoephedrine is associated with once daily administration of 240 mg of pseudoephedrine.

In certain aspects, the invention provides a method for treating or reducing nasal congestion associated with allergic rhinitis in a hypertensive patient in need thereof, including administering to said hypertensive patient a therapeutically effective amount of a pharmaceutical composition including loratadine and montelukast or a pharmaceutically acceptable salt thereof, wherein administration of said pharmaceutical composition produces a nasal decongestion effect that is at least 90% of the nasal decongestant effect produced by pseudoephedrine without causing one or more side effects of pseudoephedrine. In certain embodiments, the nasal decongestion effect produced by pseudoephedrine is associated with once daily administration of 240 mg of pseudoephedrine. In certain embodiments, the side effect may be, for example, insomnia, nervousness or dizziness. In certain embodiments, said administering occurs in the evening or at bedtime.

In certain aspects, the invention provides a method for treating or reducing nasal congestion associated with allergic rhinitis in a diabetic patient in need thereof, including administering to said diabetic patient a therapeutically effective amount of a pharmaceutical composition including loratadine and montelukast or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION In certain embodiments, methods described herein include treating, preventing or reducing nasal congestion associated with allergic rhinitis in patients for which administration of sympathomimetic agents may lead to undesirable side effects, exacerbate an existing condition, be contraindicated, or require consultation with a physician before use. For example, such patients may be suffering from a disease or disorder, such as, for example, hypertension, diabetes mellitus, ischemic heart disease, increased intraocular pressure, hyperthyroidism, renal impairment, or prostatic hypertrophy. Other such patients include, for example, patients talcing monoamine oxidase inhibitors (MAOI). In certain embodiments, methods described herein include treating, preventing or reducing nasal congestion associated with allergic rhinitis in patients that have been diagnosed with a disease or disorder, such as, for example, hypertension, diabetes mellitus, ischemic heart disease, increased intraocular pressure, hyperthyroidism, renal impairment, or prostatic hypertrophy.

Methods provided herein include methods for treating, preventing or reducing nasal congestion associated with allergic rhinitis by administering to a patient a therapeutically effective amount of an antihistamine and a leukotriene D₄ receptor antagonist. 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 used in association with various methods 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, methods described herein include treating, preventing or reducing nasal congestion associated with allergic rhinitis in a hypertensive patient and involve administering to a hypertensive patient a therapeutically effective amount of loratadine and montelukast, or a pharmaceutically acceptable salt of montelukast. A hypertensive patient is a patient having blood pressure which is repeatedly elevated above normal, such as, for example, a patient having a blood pressure of at least 140/90. Hypertensive patients include mildly hypertensive patients, such as, for example, having a blood pressure of about 140/90 to 159/94, moderately hypertensive patients, such as, for example, having a blood pressure from 160/95 to 179/99, and severely hypertensive patients, such as, for example, having a blood pressure of at least 180/100. In certain embodiments, patients having a blood pressure of at least 200/130 may also be treated in accordance with various methods described herein.

Hypertension may be caused by a variety of factors including genetic makeup, disease, diet, or administration of a drug (such as, for example, drug induced hypertension). A clinician skilled in the art can readily identify hypertensive patients using clinical tests, physical examination and medical/family history. In certain embodiments, methods described herein may be used for treating, preventing or reducing nasal congestion in hypertensive patients wherein the hypertension is uncontrolled or controlled with drug therapy. In certain embodiments, hypertensive patients may be treated for nasal congestion associated with allergic rhinitis in conjunction with drug therapy for hypertension. For example, a patient may be undergoing treatment with a beta blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), a diuretic, or a calcium channel blocker concurrently with the administration of loratadine and montelukast, or a pharmaceutically acceptable salt thereof.

In certain embodiments, methods described herein include treating, preventing or reducing nasal congestion associated with allergic rhinitis in a diabetic patient and involve administering to a diabetic patient a therapeutically effective amount of loratadine and montelukast, or a pharmaceutically acceptable salt of montelukast.

Diabetes may be diagnosed using a Fasting Plasma Glucose Test (FPG) and/or an Oral Glucose Tolerance Test (OGTT). Using the FPG test, a person having a fasting blood glucose level of 126 mg/dl or higher is diabetic. Using the OGTT test, a person's blood glucose level is measured after a fast and two hours after drinking a glucose-rich beverage. A person having a two-hour blood glucose level of 200 mg/dl or higher is diabetic. Various methods described herein may be used for treating, preventing, reducing or relieving severe, moderate or mild nasal congestion associated with allergic rhinitis. In certain embodiments, treatment, prevention or reduction of severe nasal congestion is provided. 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. 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 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, methods 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). Various methods also encompass treatment of patients suffering concurrently from both SAR and PAR. Seasonal allergic rhinitis includes allergies that arise in the fall, spring, or winter, or combinations thereof. In certain embodiments, methods include those useful for treating, preventing or reducing 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, a combination of loratadine and montelukast, or a pharmaceutically acceptable salt thereof, 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, patients suffering from nasal congestion associated with allergic rhinitis may also suffer from another disorder, such as asthma.

Various methods described herein permit relief of 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 a combination of loratadine and montelukast results in a side effect profile that is comparable to placebo. In certain embodiments, one or more undesirable side effects of sympathomimetic agents may be avoided 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, methods 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. For example, a therapeutically effective amount of pseudoephedrine may be, for example, 240 mg pseudoephedrine HCl in an extended release formulation for administration once a day. 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 lH-benzo[5,6]cyclohepta[l,2- ό]pyridin-l l-ylidene)-l-piperidinecarboxylic acid ethyl ester, is a nonsedating-type histamine Hi -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-[[[(l/?)-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, moφholine, 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, methods provided herein include coadministration of loratadine and montelukast, or a pharmaceutically acceptable salt thereof.

Coadministration may be conducted by separately formulating the individual drugs and then administering them together (either simultaneously or sequentially). In certain embodiments, loratadine and montelukast, or a pharmaceutically acceptable salt thereof, are administered as a coformulation including both active agents. 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 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 or preventing nasal congestion associated with allergic rhinitis 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.

A combination of loratadine and montelukast, or a pharmaceutically acceptable salt thereof, may be administered in a formulation including 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, or about 1 :1 mg/mg.

Typically, the amount of loratadine and montelukast, or a pharmaceutically acceptable salt thereof, effective for treating, preventing or reducing nasal congestion associated with allergic rhinitis is in the range of about 10 to about 20 mg of loratadine and about 10 to about 20 mg of montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof, about 10 to about 15 mg of loratadine and about 10 to about 15 mg of montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof, about 8 to about 12 mg of loratadine and about 8 to about 12 mg of montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof, in single or divided doses. In certain embodiments, the amount of loratadine and montelukast, or a pharmaceutically acceptable salt thereof, is about 10 mg of loratadine and about 10 mg of montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof; about 10 mg of loratadine and about 5 mg of montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof; about 5 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, methods described herein include administering once daily to a patient suffering from nasal congestion associated with allergic rhinitis a single daily dosage form including about 10 mg of loratadine and about 10.4 mg of montelukast sodium. In certain embodiments, methods described herein involve administration to a patient a combination of loratadine and montelukast, or a pharmaceutically acceptable salt thereof, at a daily dosage level that is equivalent to the daily dosage level that would be administered to a patient of similar age and weight having normal liver function, normal kidney function, and/or normal blood pressure.

Various methods described herein for treating, preventing or reducing nasal congestion associated with allergic rhinitis may include administering 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 anti-inflammatory (such as, for example, aspirin, indomethacin (Indocin^®), ibuprofen (Motrin^®), naproxen (Naprosyn^®), piroxicam (Feldene^®), and nabumetone (Relafen^®), 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.). Such additional therapeutic agent may be separately formulated and separately administered to the patient or may be coformulated together with the loratadine and montelukast, or pharmaceutically acceptable salt thereof.

Coformulations of loratadine and montelukast, or 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.

Any suitable route of administration may be employed for providing the patient with an effective dosage of loratadine and montelukast, or a pharmaceutically acceptable salt thereof, according to various methods described herein. For example, oral, intraoral, rectal, parenteral, epicutaneous, transdermal, subcutaneous, intramuscular, intranasal, sublingual, intradural, intraocular, intrarespiratory, oral or nasal inhalation and like forms of administration may be employed.

A variety of suitable dosage forms may be used for administering loratadine and montelukast, or a pharmaceutically acceptable salt thereof, 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 OF oral sprays, aerosols and the like. Because cf their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. In certain embodiments, 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. The 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. 5,1 12,616 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 propel lant 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 transdermal Iy. Transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

In certain embodiments, pharmaceutical preparations may be in a unit dosage form. In such form, the 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.

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: Efficacy of Loratadine Montelukast Combination (LMC) as Compared to Pseudoephedrine

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. One objective of this study was to assess the efficacy of the fixed-dose combination of loratadine/montelukast (LMC), a once-daily tablet containing 10 mg of loratadine and 10 mg of montelukast, compared with that of placebo in subjects with seasonal allergic rhinitis (SAR) treated for 15 days for the relief of nasal congestion. Other objectives for this study were: (i) to assess the efficacy of LMC vs placebo using health-related quality of life (HrQoL), peak nasal inspiratory flow rate (PNIF), overall condition of SAR, and overall therapeutic response; and (ii) to evaluate the safety profile of LMC relative to that of placebo and pseudoephedrine using subject-reported adverse events (AEs) and vital signs evaluations. This was a Phase 3, multicenter, parallel-group, double-blind, double-dummy, randomized study conducted in conformance with Good Clinical Practices. Subjects were assigned to one of three treatment groups: Group 1 - LMC (10 mg/10 mg); Group 2 - Pseudoephedrine (240 mg); Group 3 - Placebo. Subjects attended four visits: Visit 1 - Screening; Visit 2 - Baseline; Visits 3 and 4 - Treatment Period. Subjects who qualified for the study received their first dose at Visit 2 in the office.

A total of 1095 subjects were randomized into the study: LMC, 363 subjects; pseudoephedrine, 369 subjects; and placebo, 363 subjects. All subjects received at least one dose of study medication. The mean duration of treatment was 15 days for all groups with at least 91% of subjects in each group receiving study medication for the protocol-specified treatment period of 15 days. Of the 1095 randomized subjects, 1057 (96.5%) completed the study.

The treatment groups were generally well matched with regard to demographics and baseline characteristics. Across the three treatment groups, the subject population was 60% to 66% female and the mean age was 35.7 to 36.6 years. The study population was comprised primarily of Caucasian (78% to 79%) subjects. Major inclusion criteria included: (i) at least a 2-year documented history of SAR, which exacerbated during the study season, (ii) a positive skin-prick test response to at least two appropriate seasonal allergens at Visit 1 (Screening), (iii) clinical symptomatology at the Screening visit (assessed by the subject) (symptom scores must have met the following criteria: nasal rhinorrhea > 2, nasal congestion > 2, total nasal symptoms > 6, total non-nasal symptoms > 4, and overall evaluation > 2), and (iv) clinical symptomatology at the Baseline visit (Visit 2) (the total of the seven run-in diary reflective (PRIOR) scores for the 3 days prior to the baseline visit and the AM score of the baseline visit must have been: nasal congestion > 14, total nasal symptoms > 42, and total non-nasal symptoms > 28). During the Screening, Baseline, and Treatment Period visits, severity of congestion/stuffiness was scored twice daily (AM and PM) by the subject as reflective (PRIOR) (i.e., the subject's status over the previous 12 hours) according to the scale below. Also, twice daily during the Screening and Treatment Periods, subjects measured and recorded their peak nasal inspiratory flow rate (using PNIF meters dispensed at the screening visit). At all visits (Days 1, 8, 15), the investigator or designee, and the subject, assessed the overall condition of SAR according to that same scale: 0 = None (no symptoms evident); 1 = Mild (symptoms are clearly present but minimal awareness; easily tolerated and not bothersome to daily living and/or sleeping); 2 = Moderate (definite awareness of symptoms, which are bothersome but tolerable); 3 = Severe (symptoms are hard to tolerate; may cause interference with activities of daily living and/or sleeping). Evaluations included the entire time period since the previous visit.

For the primary efficacy variable and the only symptom assessed during the treatment period, nasal congestion, the mean baseline scores for the mean AM PRIOR, PM PRIOR, and AM/PM PRIOR assessments were comparable among the three treatment groups. AMPRIOR Nasal Congestion Score

The primary efficacy endpoint, change from Baseline in AM PRIOR nasal ^•congestion score, measures the symptom relief overnight, which is 12 to 24 hours after dosing. Results are summarized in Table 1 which shows that the LMC and pseudoephedrine effects parallel each other over the entire study period. The analysis demonstrated that LMC was statistically significantly more effective than placebo in decreasing AM PRIOR nasal congestion score from Baseline averaged over the 15 days of treatment. The mean decrease in nasal congestion score over Days 2 to 15 (the primary time point) for LMC was 0.12 point greater than the placebo decrease (P=O.009). Since this assessment was made before dosing in the morning, LMC had maintained its effect over the entire dosing interval.

Pseudoephedrine was also statistically significantly more effective than placebo in decreasing AM PRIOR nasal congestion score from Baseline over Days 2 to 15 (0.13 decrease in scores greater than placebo; P=O.004). However, there were no significant differences between LMC and pseudoephedrine in the change from Baseline in nasal congestion score at the primary time point of Days 2 to 15 or at any other time point analyzed. The effect of LMC (0.12 point) was 92% of the effect of pseudoephedrine (0.13 point).

LMC=loratadine 10 mg/montelukast 10 mg combination tablet, PSE=pseudoephedπne 240 mg tablet a LS Means and Pstd (pooled standard deviations) are obtained from the two way ANOVA model with treatment and site effects b Mean percent changes are raw means

AMJPM PRIOR Nasal Congestion Score

AM/PM PRIOR nasal congestion score measures the symptom relief over the 24-hour period post-dose. LMC was statistically significantly more effective than placebo in decreasing AM/PM PRIOR nasal congestion score from Baseline over the average of Days 1 to 15 (Table 2). The mean decrease in nasal congestion score was 0.61 point for LMC and 0.49 point for placebo. The difference of -0.12 point between LMC and placebo was statistically significant (P=O.003).

Pseudoephedrine was also statistically significantly more effective than placebo in decreasing AM/PM PRIOR nasal congestion score from Baseline over the average of Days 1 to 15 (0.16 point decrease in scores greater than placebo; P<0.001 ). However, there were no significant differences between LMC and pseudoephedrine over the average of Days 1 to 15.

LMC=loratadine 10 mg/montelukast 10 mg combination tablet, PSE=pseudoephedπne 240 mg tablet a LS Means and Pstd (pooled standard deviations) are obtained from the two way ANOVA model with treatment and site effects 5 Mean percent changes are raw means

PM PRIOR Nasal Congestion Score

The PM PRIOR nasal congestion score measures the symptom relief during the daytime, which is 0 to 12 hours after dosing. This analysis confirmed the results of the primary analysis, in that LMC was statistically significantly (P=0.004) more effective than placebo for decreasing nasal congestion scores from Baseline over the average of Days 1 to 15, and that there were no significant differences between LMC and pseudoephedrine. Other Efficacy Variables

Results for the change from Baseline in AM PNIF are summarized in Table 3 which shows that the LMC and pseudoephedrine effects parallel each other over the entire study period. The PNIF assessment is an instantaneous one, measuring the nasal airflow at the time of assessment. The AM evaluation is performed at the end of the 24-hour dosing interval. Mean increases from Baseline in PNIF over Days 2 to 15 (the primary time point) were 10.64 L/min for LMC, 10.06 L/min for pseudoephedrine, and 5.05 L/min for placebo. The analysis demonstrated that LMC was statistically significantly more effective than placebo in increasing AM PNIF from Baseline over Days 2 to 15 (P<0.001). Since this is an instantaneous assessment that was made immediately before dosing in the morning, LMC had maintained its effect over the entire dosing interval.

Pseudoephedrine was also statistically significantly more effective than placebo in increasing AM PNIF from Baseline over Days 2 to 15 (P=0.001). However, there were no significant differences between LMC and pseudoephedrine in the change from Baseline in AM PNIF at the primary time point of Days 2 to 15 or at any other time point analyzed.

Table 3. Peak Nasal Inspiratory Flow Rate (L/min) Analysis Results Subject - Evaluated AM (All Randomized

Subjects).

LMC (A) PSE (B) Placebo (C)

LS (Mean % LS (Mean % LS (Mean °/c

N Mean³ Change)" N Mean³ Change)" N Mean³ Change)' Pstd"

Baseline 361 91 80 366 9627 360 94 99

Change from Baseline

Day 2 361 5 15 (9 1) 362 3 68 (5 8) 358 I 19 (3 6) 23 36

Day 3 361 6 87 (1 1 5) 365 6 35 (9 7) 358 1 81 (4 6) 23 45

Day 4 361 747 (12 9) 364 7 53 (109) 358 1 09 (4 4) 2423

Days 2 to 8 361 8 56 ( 13 3) 365 7 85 (1 1 1) 358 3 43 (7 0) 1997

Days 9 to 1 5 355 12 85 (19 2) 357 12 70 (169) 357 692 (1 1 4) 24 68

Days 2 to 1 5 361 1064 (16 2) 366 1006 (13 7) 360 5 05 (9 0) 20 54

Pairwise Comparisons P-Values 95% Confidence Interval

A-B A-C B-C A-B A-C B-C

Change from Baseline

Day 2 0399 0023 0 153 (- 1 95,4 89) (0 54, 7 39) (-093, 5 92)

Day3 0 766 0004 0009 (-2 91 ,3 95) ( 1 62,8 51 ) ( 1 1 1 ,7 98)

Day 4 0974 <001 < 00l (-3 60, 3 48) (2 83, 994) (2 89, 999)

Days 2 to 8 0633 < 001 0003 (-2 21 ,: 63) (2 20, 8 06) ( 1 50,7 34)

Days 9 to 15 0933 0001 0002 (-3 49, 3 80) (2 29, 9 57) (2 14,9 41 )

Days 2 to 15 0 703 < 001 0001 (-2 42, 3 58) (2 59, 8 60) (2 01 ,8 01 )

LMC=loratadιne 10 mg/montelukast 10 mg combination tablet, PSE=pseudoephedπne 240 mg tablet a LS (least significant) Means and Pstd (pooled standard deviations) are obtained from the two way ANOVA model with treatment and site effects Mean percent changes are raw means Analyses of the other secondary efficacy variables (ie, RQLQ, the joint evaluation of therapeutic response, and the joint evaluation of overall condition of SAR) demonstrate that LMC was statistically significantly (PO.005) more effective than placebo and that there were no significant differences between LMC and pseudoephedrine.

Table 4 summarizes the adverse events that occurred in 2% or more of subjects in any treatment group. LMC-treated subjects had an overall incidence of adverse events (15.2%) that was lower than for PSE-treated subjects (23.0%) and comparable to that of placebo-treated subjects (17.6%). Except for dry mouth, nausea, headache, and insomnia, no adverse event was reported for more than 2% of subjects in any treatment group. Dry mouth and nausea occurred at a notably higher incidence in the PSE treatment group (4.9%, 2.2%) than in the LMC group (0.6%, 0.3%) or the placebo group (0.6%, 0%). Dizziness occurred only in PSE-treated subjects (6, 1.6%). Insomnia, a common side effect of PSE, occurred in 8 (2.2%) PSE-treated subjects compared with none of the LMC-treated subjects and 2 (0.6%) placebo-treated subjects.

A summary of all adverse events is shown below.

Table 4 Summary of Treatment-Emergent Adverse Events Reported for 2% or More of Subjects in Any Treatment Group (All Randomized Subjects)

Number (%) of Subjects

Body System/Organ Class LMC PSE Placebo

Adverse Event (n=363) (n=369) (n=363)

Any Adverse Event 55 (15.2) 85 (23.0) 64 (17.6)

Gastrointestinal Disorders

Dry mouth 2 (0.6) 18 (4.9) 2 (0.6)

Nausea 1 (0.3) 8 (2.2) 0

Nervous System Disorders

Headache 8 (2.2) 7 (1.9) 9 (2.5)

Psychiatric Disorders

Insomnia 0 8 (2.2) 2 (0.6)

LMC=loratadine 10 mg/montelukast 10 mg combination tablet; PSE=pseudoephedrine 240 mg tablet.

In addition, specific adverse events associated with sympathomimetic amines (except insomnia) were extracted from the overall table of adverse events to determine the relative incidence of these events among treatment groups. These are summarized in Table 5. The incidence of these events is higher in the PSE group than in the LMC or placebo groups. Almost all of these adverse events were considered by the investigator to be treatment related.

Table 5 Incidence of Adverse Events (Except Insomnia) Related to Sympathomimetic Amines

LMC=loratadine 10 mg/montelukast 10 mg combination tablet, PSE=pseudoephedπne 240 mg tablet

EQUIVALENTS The present invention provides among other things methods for treating, reducing or preventing nasal congestion associated with allergic rhinitis. 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 method for treating or reducing nasal congestion associated with allergic rhinitis in a hypertensive patient in need thereof, comprising administering to said hypertensive patient a therapeutically effective amount of a pharmaceutical composition comprising loratadine and montelukast or a pharmaceutically acceptable salt thereof.

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

3. The method of claim 1 , wherein at least one side effect associated with pseudoephedrine is undesirable for said patient.

4. The method of claim 3, wherein said side effect is insomnia, nervousness or dizziness.

5. The method of claim 1, wherein said therapeutically effective amount of a pharmaceutical composition comprising loratadine and montelukast or a pharmaceutically acceptable salt thereof produces a nasal decongestant effect that is at least 90% of the nasal decongestant effect produced by pseudoephedrine.

6. The method of claim 1 , wherein the patient has blood pressure of at least 140/90.

7. The method of claim 1, wherein the patient has blood pressure of at least 160/95.

8. The method of claim 1, wherein the patient has blood pressure of at least 200/130.

9. The method of claim 1 , wherein the patient is suffering from uncontrolled hypertension.

10. The method of claim 1, wherein the patient is suffering from severe hypertension.

1 1. The method of claim 1 , wherein the patient is taking medication to reduce or control blood pressure.

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

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

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

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

16. The method of claim 1, wherein the allergic rhinitis is seasonal allergic rhinitis.

17. The method of claim 1, wherein the allergic rhinitis is perennial allergic rhinitis.

18. The method of claim 1, wherein the nasal congestion is severe.

19. The method of claim 1, wherein the pharmaceutical composition further comprises at least one additional therapeutic agent.

20. The method of claim 1, wherein the pharmaceutical composition is administered orally, nasally, or ophthalmically.

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

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

23. A method for treating or reducing nasal congestion associated with allergic rhinitis in a hypertensive patient in need thereof, comprising administering to said hypertensive patient a therapeutically effective amount of a pharmaceutical composition comprising loratadine and montelukast or a pharmaceutically acceptable salt thereof, wherein administration of said pharmaceutical composition produces a nasal decongestion effect that is substantially the same as the nasal decongestion effect produced by pseudoephedrine.

24. The method of claim 23, wherein the nasal decongestion effect produced by pseudoephedrine is associated with once daily administration of 240 mg of pseudoephedrine.

25. The method of claim 23, wherein administration of said pharmaceutical composition produces a nasal decongestion effect that is at least 70% of the nasal decongestion effect produced by pseudQephedrine.

26. The method of claim 23, wherein the nasal decongestion effect is determined over a period from about 12 to about 24 hours after administration of said pharmaceutical composition.

27. A method for treating or reducing nasal congestion associated with allergic rhinitis in a hypertensive patient in need thereof, comprising administering to said hypertensive patient a therapeutically effective amount of a pharmaceutical composition comprising loratadine and montelukast or a pharmaceutically acceptable salt thereof, wherein administration of said pharmaceutical composition produces a nasal decongestion effect that is at least 90% of the nasal decongestant effect produced by pseudoephedrine without causing one or more side effects of pseudoephedrine.

28. The method of claim 27, wherein the side effect is insomnia, nervousness or dizziness.

29. The method of claim 27, wherein said administering occurs in the evening or at bedtime.

30. The method of claim 27, wherein the nasal decongestion effect is determined over a period from about 12 to about 24 hours after administration of said pharmaceutical composition.

31. The method of claim 27, wherein the nasal decongestion effect produced by pseudoephedrine is associated with once daily administration of 240 mg of pseudoephedrine.

32. A method for treating or reducing nasal congestion associated with allergic rhinitis in a diabetic patient in need thereof, comprising administering to said diabetic patient a therapeutically effective amount of a pharmaceutical composition comprising loratadine and montelukast or a pharmaceutically acceptable salt thereof.

33. The method of claim 32, wherein said therapeutically effective amount of a pharmaceutical composition comprising loratadine and montelukast or a pharmaceutically acceptable salt thereof produces a nasal decongestant effect that is at least 90% of the nasal decongestant effect produced by pseudoephedrine without causing one or more side effects of pseudoephedrine.

34. The method of claim 32, wherein the pharmaceutically acceptable salt of montelukast is montelukast sodium.

35. The method of claim 32, wherein the pharmaceutical composition comprises about 10 mg of loratadine and 10 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof.

36. The method of claim 32, wherein the pharmaceutical composition is administered orally, nasally, or ophthalmically.

37. The method of claim 32, wherein the pharmaceutical composition is formulated as a liquid, pill, tablet, capsule, suppository, granule, suspension or film.

38. The method of claim 37, wherein the tablet is orally ingestible, chewable, or fast dissolving. ^:

39. A method for treating or reducing nasal congestion associated with allergic rhinitis comprising administering to a patient in need of treatment, a therapeutically effective amount of a pharmaceutical composition comprising loratadine and montelukast or a pharmaceutically acceptable salt thereof, wherein administration of said pharmaceutical composition produces a nasal decongestion effect that is substantially the same as the nasal decongestion effect produced by pseudoephedrine.

40. The method of claim 39, wherein administration of sympathomimetic agents may lead to undesirable side effects, exacerbate an existing condition, be contraindicated, or require consultation with a physician before use.

41. The method of claim 39, wherein administration of said pharmaceutical composition produces a nasal decongestion effect that is at least 70% of the nasal decongestion effect produced by pseudoephedrine.

42. The method of claim 39, said therapeutically effective amount of said pharmaceutical composition produces a nasal decongestant effect that is at least 90% of the nasal decongestant effect produced by pseudoephedrine.

43. The method of claim 39, wherein the nasal decongestion effect is determined over a period from about 12 to about 24 hours after administration of said pharmaceutical composition.

44. The method of claim 39, wherein the nasal decongestion effect produced by pseudoephedrine is associated with once daily administration of 240 mg of pseudoephedrine.