WO2008079257A2 - Procédés pour traiter une congestion nasale chez des patients pédiatriques - Google Patents

Procédés pour traiter une congestion nasale chez des patients pédiatriques Download PDF

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Publication number
WO2008079257A2
WO2008079257A2 PCT/US2007/025993 US2007025993W WO2008079257A2 WO 2008079257 A2 WO2008079257 A2 WO 2008079257A2 US 2007025993 W US2007025993 W US 2007025993W WO 2008079257 A2 WO2008079257 A2 WO 2008079257A2
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Prior art keywords
montelukast
loratadine
pharmaceutically acceptable
acceptable salt
years
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PCT/US2007/025993
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English (en)
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WO2008079257A3 (fr
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Melvyn Richard Danzig
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Schering Corporation
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Publication of WO2008079257A3 publication Critical patent/WO2008079257A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants

Definitions

  • 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.
  • 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.
  • sympathomimetic amine decongestant drugs such as phenylpropanolamine or pseudoephedrine which function as alpha-adrenoceptor agonists.
  • phenylpropanolamine or pseudoephedrine which function as alpha-adrenoceptor agonists.
  • 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.
  • the invention provides a method for treating or reducing nasal congestion associated with allergic rhinitis in a patient in need thereof, wherein said patient is from 2 to 12 years old, including administering to said patient a therapeutically effective amount of a pharmaceutical composition including loratadine and montelukast or pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition including loratadine and montelukast or pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of montelukast is montelukast sodium.
  • the methods may be used to treat a pediatric patient that is from 2 to 6 years old or from 6 to 12 years old.
  • the methods may utilize a pharmaceutical composition including loratadine and montelukast or a pharmaceutically acceptable salt thereof, in a ratio of about 1 :2 to about 2:1 mg/mg.
  • the pharmaceutical 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.
  • the methods may utilize a pharmaceutical composition including about 2 mg to about 10 mg of loratadine and about 2 mg to about 10 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof, hi certain embodiments, the pharmaceutical composition includes 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.
  • the methods may be used for treating or preventing nasal congestion associated with seasonal allergic rhinitis or perennial allergic rhinitis. hi certain embodiments, the methods may be used for treating severe nasal congestion. hi certain embodiments, the methods may utilize a pharmaceutical composition including loratadine and montelukast or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent. hi certain embodiments, the pharmaceutical composition may be administered orally, nasally, or ophthalmically. In certain embodiments, the methods may utilize a pharmaceutical composition that is formulated as a liquid, tablet, capsule, suppository, granule, suspension or film. Tablets may be orally ingestible, chewable, or fast dissolving.
  • the methods may be used for treating or preventing nasal congestion associated with allergic rhinitis in a pediatric patient that is also suffering from asthma.
  • the invention provides a method for treating or reducing nasal congestion associated with allergic rhinitis in a pediatric patient in need thereof, including administering to said pediatric patient a pharmaceutical composition including about 10 mg of loratadine and about 5 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the invention provides a method for treating or reducing nasal congestion associated with allergic rhinitis in a pediatric patient in need thereof, including administering to said pediatric patient a pharmaceutical composition including about 5 mg of loratadine and about 4 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the invention provides a method for treating or reducing nasal congestion associated with allergic rhinitis in a pediatric patient in need thereof, including administering to a pediatric patient of 6 to 12 years of age a chewable tablet including about 10 mg of loratadine and about 5 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the invention provides a method for treating or reducing nasal congestion associated with allergic rhinitis in a pediatric patient in need thereof, including administering to a pediatric patient of 2 to 5 years of age a chewable tablet including about 5 mg of loratadine and about 4 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • Methods provided herein include methods for treating, preventing or reducing nasal congestion associated with allergic rhinitis in a pediatric patient by administering to a pediatric patient a therapeutically effective amount of an antihistamine and a leukotriene D 4 receptor antagonist.
  • 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.
  • Suitable low sedating, or nonsedating, antihistimines include, for example, loratadine (Claritin ® ), fexofenadine hydrochloride (Allegra®), cetirizine hydrochloride (Zyrtec®), levocetirizine (Xyzal®), and terfenadine (Teldane®).
  • suitable leukotriene D 4 receptor antagonist include, for example, Montelukast (Singulair®), Zafirlukast (Accolate®), Zileuton (Zyflo®), and pranlukast.
  • methods described herein for treating or preventing nasal congestion associated with allergic rhinitis in a pediatric patient involve administering to a pediatric patient a therapeutically effective amount of loratadine and montelukast, or a pharmaceutically acceptable salt of montelukast.
  • 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
  • Various methods described herein may be used for treating, preventing, reducing or relieving severe, moderate or mild nasal congestion associated with allergic rhinitis.
  • treatment or prevention 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • Seasonal allergic rhinitis includes allergies that arise in the fall, spring, or winter or combinations thereof.
  • methods include those useful for treating, preventing or reducing allergic rhinitis associated with indoor allergens, outdoor allergens, or both.
  • indoor allergens include, for example, dust, mold and pet dander.
  • 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.
  • 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.
  • 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 phenylepherine.
  • Side effects associated with administration of sympathomimetic amines may include, for example, insomnia, nervousness, jitteriness, restlessness, agitation, dry mouth, hypertension, tachycardia, headache, and dizziness.
  • administration of a combination of loratadine and montelukast results in a side effect profile that is comparable to placebo.
  • 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.
  • 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.
  • 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.
  • 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).
  • methods described herein may be used for treating, preventing or reducing nasal congestion associated with allergic rhinitis in a pediatric patient wherein the side effects of a sympathomimetic agent would be undesirable for said patient.
  • administration of the sympathomimetic agent to said patient may exacerbate an existing condition such as hypertension.
  • administration of a sympathomimetic agent may be contraindicated for said patient.
  • Loratadine i.e., 4-(8-Chloro-5,6-dihydro-l lH-benzo[5,6]cyclohepta[l,2- 6]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-(l-hydroxy-l- methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, is a selective leukotriene D 4 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, mo ⁇ holine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • basic ion exchange resins such as arg
  • 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).
  • 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).
  • 10.4 mg of montelukast sodium is equivalent to 10 mg of montelukast (the free acid).
  • 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, 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.
  • 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, about 2:1 mg/mg, 1.25:1 mg/mg, or about 1:1 mg/mg.
  • the 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 is 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, in single or divided doses.
  • 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 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, hi certain embodiments, methods described herein include administering to a pediatric patient suffering from nasal congestion associated with allergic rhinitis a single daily dosage form including 10 mg loratadine and 10.4 mg montelukast sodium, 10 mg loratadine and 5.2 mg montelukast sodium, 5 mg loratadine and
  • a single daily dose including 10 mg loratadine and 10 mg montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof may be administered to a pediatric patient that is from 10 to 12 years of age, from 10 to 14 years of age, or from 12 to 14 years of age.
  • a single daily dose including 10 mg loratadine and 5 mg montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof may be administered 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.
  • a single daily dose including 5 mg loratadine and 5 mg montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof may be administered 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.
  • a single daily dose including 5 mg loratadine and 4 mg montelukast, or an equivalent amount of a pharmaceutically acceptable salt thereof may be administered 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.
  • Various methods described herein for treating, preventing or reducing nasal congestion associated with allergic rhinitis in a pediatric patient 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 (Indoc ⁇ r), 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
  • 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.
  • 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 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.
  • 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).
  • 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
  • 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 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 disentegrate 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.
  • 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, dichlorotetrafiuoroethane, nitrogen, carbon dioxide or other suitable gas.
  • a suitable propellant such as an inert compressed gas, such as, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafiuoroethane, nitrogen, carbon dioxide or other suitable gas.
  • 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.
  • 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.
  • the pharmaceutical preparation is in a unit dosage form, hi 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.
  • compositions 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.).
  • sugars such as, for example, glucose, sucrose, etc.
  • saccharine such as, for example, glucose, sucrose, etc.
  • dipeptide sweeteners such as, for example, aspartame
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ m to 5000 ⁇ m in diameter.
  • an active agent 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 includes 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.
  • 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 present invention provides among other things methods for treating, preventing or reducing nasal decongestion associated with allergic rhinitis in a pediatric patient. 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.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des procédés pour traiter, prévenir ou réduire une congestion nasale associée à une rhinite allergique chez un patient pédiatrique. Ces procédés peuvent consister à administrer à un patient pédiatrique une dose thérapeutiquement efficace d'une composition pharmaceutique comportant de la loratadine et du montélukast ou un sel pharmaceutiquement acceptable de montélukast.
PCT/US2007/025993 2006-12-22 2007-12-19 Procédés pour traiter une congestion nasale chez des patients pédiatriques WO2008079257A2 (fr)

Applications Claiming Priority (2)

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US87165606P 2006-12-22 2006-12-22
US60/871,656 2006-12-22

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WO2008079257A2 true WO2008079257A2 (fr) 2008-07-03
WO2008079257A3 WO2008079257A3 (fr) 2008-09-12

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TW (1) TW200838523A (fr)
WO (1) WO2008079257A2 (fr)

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
KESKIN O ET AL: "Do the leukotriene receptor antagonists work in children with grass pollen-induced allergic rhinitis?" PEDIATRIC ALLERGY AND IMMUNOLOGY 200606 DK, vol. 17, no. 4, June 2006 (2006-06), pages 259-268, XP002483380 ISSN: 0905-6157 1399-3038 *
LAI L ET AL: "Pediatric allergic rhinitis: Treatment" IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA 200505 US, vol. 25, no. 2, May 2005 (2005-05), pages 283-299, XP009101253 ISSN: 0889-8561 *
PERONI D G ET AL: "The combination of single-dose montelukast and loratadine on exercise-induced bronchospasm in children" EUROPEAN RESPIRATORY JOURNAL 2002 CH, vol. 20, no. 1, 2002, pages 104-107, XP002483381 ISSN: 0903-1936 *
WALIA MANDEEP ET AL: "Montelukast in pediatric asthma management" INDIAN JOURNAL OF PEDIATRICS, vol. 73, no. 4, April 2006 (2006-04), pages 275-282, XP009101260 ISSN: 0019-5456 *

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CL2007003749A1 (es) 2008-08-01
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