TW200838524A - Methods for treating nasal congestion in hepatically impaired patients - Google Patents

Abstract

Methods for treating, preventing or reducing nasal congestion associated with allergic rhinitis in a hepatically impaired patient are provided. Methods may involve administering to a patient suffering from hepatic insufficiency a therapeutically effective amount of a pharmaceutical composition comprising loratadine and montelukast or a pharmaceutically acceptable salt of montelukast.

Description

200838524 IX. INSTRUCTIONS: [Technical field to which the invention pertains] People around the world are often suffering from allergic-related nasal congestion, which causes partial or complete obstruction of the airway. Nasal congestion and related symptoms often have undesired effects on the tormented person, for example, disruption of sleep, loss of work, and loss of school attendance.

Although antihistamines have been shown to be effective in preventing and relieving sneezing, itching, rhinorrhea and other allergic symptoms, they have not been found to be extremely effective in relieving nasal obstruction associated with allergic reactions. Therefore, a sympathomimetic excitatory amine decongestant is usually administered at the same time, for example, as a phenylpropanolamine or pseudoephedrine agonist of an adrenergic receptor agonist. However, not all patients with allergies should use these decongestants because it is often observed that these decongestants have side effects on the nervous system and cardiovascular, including anxiety, insomnia, tachycardia, angina and hypertension. Phenylpropanolamine has been withdrawn from the US market. There is a need for treatment of nasal congestion associated with allergic conditions, and 1 does not exhibit neurological or cardiovascular effects associated with sympathomimetic excitatory amines. SUMMARY OF THE INVENTION In some aspects, the present invention provides a method for treating or alleviating nasal congestion associated with allergic rhinitis in a patient in need thereof, wherein the patient suffers from (4) A daily dose of medicinally acceptable salt containing about 10 grams of loratadine and about 1 mg of montelukast or equivalent amount of pharmaceutically acceptable salt thereof is administered to the patient. Composition 0 127804.doc 200838524 In certain embodiments, the pharmaceutically acceptable montelukast salt is montelukast. In certain embodiments, the pharmaceutical compositions are administered in a single dosage form. In certain embodiments, the patient may have mild liver function decline, moderate liver function decline, or severe liver function decline. In some embodiments, liver function decline can be associated with diseases such as hepatitis or brewing. Decline in liver function can be a decline in drug-induced liver function. In certain embodiments, 'allergic rhinitis is a seasonal allergic rhinitis. The occupational nose is too or often. In some embodiments, the patient may have severe nasal congestion. Sleeping In certain embodiments, daily administration of a pharmaceutical composition does not induce the patient to be afflicted. In certain embodiments, the pharmaceutical composition further comprises at least one additional therapeutic agent. In addition to the neck, in some embodiments, it can be administered orally, nasally or via: The pharmaceutical composition is formulated into a liquid, a tablet, a capsule, a suppository, a suspension or a film. Suitable binders include, for example, orally, in the form of an edible, or fast-dissolving lozenge. In the smokable state, the present invention provides a method for a patient to be associated with allergic rhinitis, and he is asked to mourn, the method comprising administering to the patient a therapeutically effective amount of the package.

He and montelukast or its pharmaceutically acceptable salt W are administered to the pharmaceutical composition to produce -...5's solution 7" the hyperemia effect is substantially the same as that caused by pseudoephedrine 127804.doc 200838524 to relieve nasal congestion . The effect of removing nasal gold from pseudoephedrine can be associated with a therapeutically effective amount of pseudoephedrine, for example, with a dose of 240 mg of pseudoephedrine per dose. [Embodiment]

The methods provided herein include methods for treating, preventing, or ameliorating nasal congestion associated with allergic rhinitis in a patient with hepatic impairment by administering a therapeutically effective amount of an antihistamine and white to a patient suffering from hepatic impairment. A triene D4 receptor antagonist is achieved. Examples of suitable antihistamines include, for example, chlorpheniramine maleate (Chlor-trimeton positive), dexchlorpheniramine maleate, diphenhydramine hydrochloride (Benadryl®), succinic acid doxylamine succinate, isopropyl hydrazine hydrochloride and triprolidine hydrochloride. Low sedative or non-sedating antihistamines can also be used in conjunction with the various methods described herein. Examples of suitable low-sedating or non-sedating antihistamines include, for example, loratadine (Claritin®), fexofenadine hydrochloride (Allegra®), cetirizine hydrochloride ( Zyrtec®), levocetirizine (Xyzal9) and terfenadine (Teldane®). Examples of suitable leukotriene D4 receptor antagonists include, for example, Singulak®, Zafirlukast (Accolate®), Zileuton (Zyflo®), and Prolenz Pranlukast 某些 In certain embodiments, the methods described herein for treating, preventing, or ameliorating nasal congestion associated with allergic rhinitis in a patient with hepatic impairment involve administration to a liver-damaged disease 127804.doc 200838524 A therapeutically effective amount of loratadine and montelukast or a pharmaceutically acceptable montelukast salt. In certain embodiments, the methods described herein comprise treating, preventing, or ameliorating nasal congestion associated with allergic rhinitis, which have been diagnosed with liver damage, liver disease, or liver disease. The liver is also known to have a disease due to diseases such as alcoholic cirrhosis or hepatitis, or due to techniques such as ketokonazole, y 〇mycin or treleandomycin. A drug that metabolizes the function of the liver and is impaired in liver function. Clinical business people who are familiar with this technology can identify their liver-damaged patients by using clinical tests, physical examinations, and medical history/family history. For example, a liver function assessment method can involve measuring one or more blood or urine markers using standard techniques. Liver function markers include, for example, albumin, alkaline phosphatase (ALp), alanine transaminase (ALT) or serum proline-pyruvate transaminase (SGpT), aspartate transaminase (AST) Or serum glutamate _ oxalic acid transaminase (sg〇t), γ-glutamine transpeptidase (GGT), prothrombin time (ρτ), serum bilirubin and urinary bilirubin. Patients with hepatic impairment include those with mild liver failure, moderate liver function decline, or severe liver function decline. Various scoring systems for determining the severity of liver function decline are known in the art, such as the (3) (iv) 咕 scoring system (see, for example, Pugh, RNH, 1973, 仏J·知rg) 6〇: 646...9). In some embodiments, the methods described herein are useful for treating, preventing, or ameliorating severe, moderate, or mild nasal congestion associated with allergic rhinitis. In certain embodiments, providing treatment or prevention of severe nasal congestion. The type of nasal congestion that is prevented or relieved includes daytime nasal congestion and 127804.doc 200838524 (4) Nasal μ. If the patient has a hyperemia that usually occurs during the daytime or nighttime shirt period, the dosage time can be changed to most effectively treat the patient. In certain embodiments, a combination of loratadine and Meng (4) or its pharmaceutically acceptable salt may be administered at night or at bedtime to treat, prevent, or alleviate nighttime I. In the embodiment, 'in the morning, after waking up, or at breakfast, it will be combined with the gas mine, Meng Guang, illusion 4 main battle, # • 疋 /, 盂 肖, 司特 or its pharmaceutically acceptable salt. Combine to treat, prevent or reduce daytime Congestive. In certain embodiments, a combination of loratadine and montelukast or a pharmaceutically acceptable salt thereof may be administered early, after waking up or at breakfast to treat, prevent or reduce nighttime Nasal congestion. In some embodiments, a combination of loratadine and montelukast or its medicinal granules may be administered at night or at bedtime to treat, prevent or reduce diurnal Nasal congestion. - In certain embodiments, the methods described herein can be used to treat, prevent, or alleviate nasal congestion associated with allergic rhinitis, including seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (pAR). Various methods cover the treatment of patients with concurrent R. Seasonal allergic rhinitis includes allergies that occur in the fall, spring or winter, or in combination. In some conjugate cases, the method includes treatment Or prevent allergic rhinitis associated with indoor allergens, outdoor allergens, or both. Examples of indoor allergens include, for example, dust, mold, and pet dander. Outdoor allergens 7 include (for example) tree flowers Weeds, grasses and flowers. Perennial allergic nasal passages # are related to indoor allergens, and seasonal allergic rhinitis is usually associated with outdoor allergens. In some cases, it can be preventive to patients. Landing with loratadine and Meng 127804.doc 200838524 Ling, 刁te or its medicine can be beneficial for a variety of diseases, n 1 combination. Prophylactic administration may have hang, heart if associated with nasal congestion The history of allergies, the seasonal allergic Lu Hudan # ^ 疋 疋 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Patients with other conditions, such as = liver-impaired patients may also have treatable liver-impaired patients including possible (four) aging, treatment of patients. In some embodiments;: = == The treatments described herein are related to the treatment associated with allergic rhinitis. The various methods described in the article can alleviate the nasal congestion from the sympathomimetic (such as pseudoephedrine test, ephedra test, phenylpropanolamine or phenylephrine) - or a variety of side effects, or significantly reduce The rate of side effects and/or severity. Side effects associated with administration of sympathomimetic excitatory amines can include, for example, insomnia, nervousness, nervousness, restlessness, anxiety, dry mouth, high blood pressure, tachycardia, headache, and dizziness. In certain embodiments, administration of a combination of loratadine and montelukast results in a side effect condition comparable to the administration of a placebo. In certain embodiments, one or more undesirable side effects of the sympathomimetic agent can be avoided while producing substantially the same effect as the nasal congestion-reducing effect obtained by a therapeutically effective amount of the sympathomimetic agent. The same nasal dispelling effect as the sympathomimetic agent means that the effect produced by the therapeutically effective amount of the sympathomimetic agent is ±30%, ±20%, ±10% or ±5%, As measured by the standard procedure for measuring nasal congestion, 127804.doc -10- 200838524. In certain embodiments, the allergic nasal congestion effect, which is substantially the same as the sympathomimetic agent, means that the effect produced is at least 70%, 8%, of the effect of relieving nasal congestion by a therapeutically effective amount of the sympathomimetic agent, 9〇〇/. , 95% or higher. In certain embodiments, the methods described herein produce a relief nasal congestion effect that is substantially the same as the sympathomimetic agent during a 24-hour administration, during the first 12 hours after administration, or 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 to treat nasal congestion during a 24 hour period. For example, a therapeutically effective amount of pseudoephedrine can be, for example, 240 mg of pseudoephedrine HC1 in a one-time extended release formulation. Such formulations of pseudoephedrine may be prepared by those skilled in the art or may be derived from J〇hns〇n &

Purchased by Johnson (New Brunswick, NJ). Loratadine, 4-(8-chloro-5,6-dihydro-indenyl)-benzo[5,6μ裒g,2_b]pyridin-11-ylidene-1-hexahydropyridinecarboxylate Ester is a non-sedating histamine-heavy body antagonist. Used in the treatment of allergies

Schering-Plough Health Care Products

Claritm® is sold and can be prepared, for example, as described in U.S. Patent No. 4,282,233. Montelukast, ie (into chloro-2-quinolinyl)vinyl]phenyl]-3-[2-(l-hydroxy·1_methylethyl)phenyl]propyl]thio]methyl ] Cyclopropylacetate, a selective leukotriene 4 receptor antagonist. The montelukast sodium used to treat allergies is sold by the company Merck & Co. under the trade name Smgulair® and can be prepared, for example, as described in U.S. Patent No. 5,27,324. 127804.doc •11- 200838524

Pharmaceutically effective montelukast salts include, for example, those prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, divalent manganese salts, potassium salts, sodium salts, zinc salts, and the like. . In certain embodiments, the pharmaceutically acceptable montelukast salt is montelukast sodium. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, substituted amines (including naturally substituted amines), cyclic amines and salts of basic ion exchange resins, such as arginine, beets Alkali, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine , Ethyl hexahydropyridine, reduced glucosamine, glucosamine, histidine, hydrabamme, isopropylamine, lysine, methyl glucosamine, morpholine, hexahydropyrazine, hexahydro Pyridine 'polyamine resin, procaine (Pr〇Caine) ... ticket, cocoa, triethylamine, trimethylamine, tripropylamine, amine butanediol specific test salt. A syllabus: the equivalent amount of pharmaceutically acceptable montelukast salt refers to the sulphate containing 4 grams of i Meng 4 sitter (free acid) containing substantially the same amount of anionic moles. Special salt form. Therefore, to determine the equivalent ΐ of a particular salt form, multiply the specified amount of 1 russel (free acid) by the ratio of the montelukast anion knife divided by the molecular weight of montelukast (for example, 1 Russner /Monu Sute is 608·18/586·20). For example, 1 〇·4 mg of montelukast sodium corresponds to 10 mg of montelukast (free acid). In certain embodiments, the methods provided herein comprise co-administering a salt of loratadine and montelukast per pot, which is acceptable for each pot. The individual can be dosed by separately dispensing the drug 127804.doc 12 - 200838524 and then administering it to (7) or by: owing. In some embodiments, loratadine and montelukast or a pharmaceutically acceptable salt thereof are administered as a co-formulation comprising (iv) an active agent. It may comprise: a therapeutically effective amount of talatide and montelukast or a pharmaceutically acceptable salt thereof: a single-dosage form of each of the active agents may be dispensed once per day or in a few days Inject a single daily dosage form, for example, 〆^ acupoint, two days, one week, two weeks, one month or longer. A single-day dosage form may be administered on a daily basis to treat hyperemia associated with persistent allergies or may be sporadicly administered as needed to treat nasal congestion, such as acute and/or chronic treatment. "The amount of loratadine and montelukast or its pharmaceutically acceptable salt that can be used to effectively treat or prevent nasal congestion associated with allergic rhinitis can vary with age, sex, weight, and The health, the degree of nasal congestion, the fish stalk, the bioavailability of the formulation administered, the selected dosage regimen, and the use of the concomitant medication. The dosage and/or frequency of administration can be adjusted to meet the needs of the individual patient. Those skilled in the art will be able to determine the appropriate total dose range using conventional techniques. The dose can be administered in a single dose or in divided doses. It can range from about 1:5 mg/mg to about 5:1 mg/ The ratio of milligrams, from about gram/mg to about 3:1 mg/mg, from about 1:2 mg/mg to about 2:1 mg/mg, or about 1:1 mg/mg, includes loratadine and montelukast a combination of loratadine and montelukast or a pharmaceutically acceptable salt thereof, administered in a single-dose or divided dose, for effective treatment , prevention or reduction 127B04.doc -13- 200838524 Light and allergic rhinitis Guandu's nasal congestion of loratadine and montelukast or its pharmaceutically acceptable salt is usually from about 10 to about 20 mg of loratadine and from about 10 to about 20 mg of montelukast or equivalent. A pharmaceutically acceptable salt thereof, from about 10 to about 15 mg of loratadine and from about 10 to about 15 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof, from about 8 to about 12 mg "He will determine from about 8 to about 12 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, it is atravastatin and montelukast or its medicinal

The amount of salt that can be forked is about 10 mg of gas rituximab and about 1 mg of montelukast or an equivalent amount of its pharmaceutically acceptable salt; about 10 mg of lorata and about 5 mg of monro Or a comparable 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 a chlorine mine He will give about 4 mg of montelukast or equivalent: its pharmaceutically acceptable salt. In certain embodiments, the methods described herein comprise administering a daily-to-day dosage form to a liver-impaired patient suffering from nasal congestion associated with allergic rhinitis, comprising about 10 mg of loratadine. And about 1 4 mg of montelukast sodium. In certain embodiments, the methods described herein involve administering to a liver-impaired patient a dose equivalent to a daily dose level that can be administered to a patient having a normal liver machine of age and weight. A combination with loratadine and a pharmaceutically acceptable salt of Monroe. In some embodiments, the method for preventing or alleviating the allergic rhinitis associated with allergic rhinitis in a liver-acquired patient by using a mouthwash as described herein may include administering chlorhexidine and Montelusk. Special or its medical doctors are connected to /, the milk of the eight hundred 杲 杲 τ τ τ 与 与 与 与 与 与 与 与 与 与 与 与 与 与These treatments are available in the form of #/0 摩乐月! including, for example, non-narcotic analgesics (eg 127804.doc •14- 200838524

For acetaminophen (Tylenol®) or cyclooxygenase-2 inhibitors (eg celecoxib (Celebrex, valdecoxib (Bextra®), lumiracoxib (Prexige8) , etoricoxib (Arcoxia®), etc.); non-steroidal anti-inflammatory drugs (eg aspirin, indomethacin (Indocin®), ibuprofen) (Motrin8), naproxen (Naprosyn®), piroxicam (Feldene8), and nabumetone (Relafen®); long-acting β2-adrenergic agonists (LABA) (eg salmeterol, formoterol, bambuterol, etc.); corticosteroids (eg prednisone, prednisolone, nail) Mometasone furoate monohydrate, beclomethasone, flimisolide, triamcinolone acetonide, fluticasone propionate ), dexamethasone sodium dexametha Sonne sodium phosphate), budesonide, etc.; or antitussives (eg, dextromethorphan, codeine, hydrocodone, etc.). The additional therapeutic agent can be formulated separately and administered separately to the patient or co-formulated with loratadine and montelukast or a pharmaceutically acceptable salt thereof. One or more physiologically acceptable carriers or excipients may be used in a conventional manner to formulate co-modulations of raltreline and montelukast or a pharmaceutically acceptable salt thereof. For general techniques and formulations, see A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th ed., (1990), 127804.doc -15- 200838524

Mack Publishing Company, Easton, PA 〇 Any of the methods described herein can be used to provide an effective dosage of loratadine and montelukast or a pharmaceutically acceptable salt thereof to any patient. For example, έ 'can be used orally, intraorally, rectally, parenterally, transepidermally, transdermally, subcutaneously, intramuscularly, intranasally, sublingually, intradurally, intraocularly, in the respiratory organs, orally or via Nasal inhalation and similar forms of administration. Various suitable dosage forms can be used to administer loratadine and montelukast or a pharmaceutically acceptable salt thereof, including, for example, lozenges, chewable lozenges, quick-melt formulations, tablets, dispersions Liquid, granules, suspensions, solutions, capsules, patches, liquids, syrups, elixirs, gels, powders, troches, lozenges, ointments, emulsions, pastes, plasters, lotions, Disc shaped, suppository, film, nasal or oral spray, aerosol, and the like. Because of their ease of administration, lozenges and capsules represent the best oral dosage form, in which case solid pharmaceutical carriers may be employed. In some embodiments, the tablet may be coated by standard aqueous or non-aqueous techniques. In certain embodiments, the composition can be formulated in a sustained release form to control the rate of release of loratadine and/or montelukast or a pharmaceutically acceptable salt thereof to optimize therapeutic effects. Dosage forms suitable for sustained release include: a tablet 2 comprising a plurality of layers having a different rate of disintegration or having a controlled release polymer matrix impregnated with the active ingredient and shaped into a tablet; or comprising such impregnation Or a capsule of an embedded porous polymer matrix. Oral/tanned sputum includes powders, lozenges, diamond-shaped lozenges, dispersible granules, capsules, cachets, and suppositories. The solid dosage forms can be prepared by conventional methods using pharmaceutically acceptable excipients, such as binders (for example, 127804.doc -16 - 200838524 gelatinized corn starch, polyvinyl sigma biloba or Propyl methylcellulose), a filler (such as lactose, microcrystalline cellulose or calcium hydrogen phosphate lubricant starch or sodium starch glycolate); or a wetting agent (such as sodium lauryl sulfate). « The active ingredient may constitute from about 5% to about 95% of the total weight of the solid dosage form. Tablets, powders, lozenges, cachets and capsules can be used as solid dosage forms for oral administration. The tablets can be coated by methods well known in the art. ^ _ A tablet can be prepared using standard methods, for example by pressing (or as needed) with one or more (4)* aiding ingredients. The compressed tablet can be prepared by compressing the active in a free-flowing form (such as a powder or granule) in a suitable machine 1 §, which may optionally be combined with a binder, a lubricant, an inert diluent, or a surface active agent. Mixing agents or dispersing agents. Molded tablets may be prepared by molding in a suitable and advantageous manner a mixture of powdered compounds moistened with an inert liquid diluent. Rapidly disintegrating or dissolving dosage forms (e.g., fast-melting formulations) can be used for rapid absorption of pharmaceutical active agents, especially for intra-cheek and sublingual absorption. Rapid-melting formulations such as lozenges can be prepared using standard techniques. For example, the granules of the fast-melting agent prepared by the T-drying or pre-compacting process can be mixed with an excipient and compressed into a tablet using a conventional tablet preparation machine. The particles may be combined with various carriers (including low density high mold processing sugars, low mold processing sugars, polyols) and then directly compressed to exhibit improved solubility and disintegration conditions. Lozenges. Fast melt tablets typically have a hardness of from about 2 to about 6 Strong-Cobb units (scu). Recorded within this hardness range during chewing: the agent disintegrates or dissolves rapidly. In addition, the recordings; the agent disintegrated rapidly in water 127804.doc -17- 200838524. On average, hl to 15 g of the spinning agent usually disintegrates in 1-3 minutes without stirring. This rapid disintegration facilitates the delivery of the active material. See, for example, U.S. Patent No. 5,112,616 and U.S. Patent No. 4,616,047; The liquid preparation for oral administration can be in the form of, for example, a solution, syrup, emulsion or suspension, or it can be present as an anhydrous product to be constructed by water or other suitable vehicle before use. These liquid methods are prepared with pharmaceutically acceptable additives, such as suspensions;: sorbitol syrup, fiber-cutting organisms or hydrogenated edible fats; emulsifiers (such as linum or gum arabic); #water vehicles (eg ", by oil, ethanol or refined vegetable oils"; and preservatives (for example methyl or propyl paraben or sorbic acid). The preparation may also contain buffer salts, flavoring agents, coloring agents, and sweeteners, as appropriate. The orally administered preparation can be suitably formulated to control the release of the active compound. The parenteral form which can be administered intravenously, intramuscularly or subcutaneously is usually in the form of a sterile solution and may contain osmo-regulators (salts or glucose) and buffers. Liquid form preparations may also include solutions for nasal administration. For inhaled administration (eg, pulmonary delivery), by a gas (eg, difluorodichloromethane, fluorine = gas, sputum, methane, tetrafluorodichloroethane = helium, carbon dioxide, or other suitable Suitable propellant, such as gas), can be delivered in the form of a sol spray from a pressurized pack or sprayer. If an aerosol is added, the metered amount can be delivered by a valve. Gum 2 such as gelatin for use in an inhaler or insufflator!) is formulated as a powder mixture comprising the compound and a suitable powder base such as a cream and a tert. 127804.doc -18- 200838524 A combination of loratadine and montelukast or a pharmaceutically acceptable salt thereof may also be deliverable transdermally. The transdermal compositions may be in the form of emulsions, lotions, aerosols and/or emulsions and may be included in conventional or conventional transdermal patches for use in the art. In certain embodiments, the pharmaceutical preparations are in unit dosage form. In this form, the preparation can be subdivided into unit dosages containing suitable quantities of the active ingredient in an appropriate amount (e.g., effective amount for the intended purpose). The present invention will be more readily understood by the following examples of the invention, which are set forth by way of example only, and are not intended to limit the invention in any way. . Example 1 ···································································································· For example, a double-blind, placebo-controlled trial evaluated montelukast, loratadine, and combination therapy with montelukast and loratadine for the treatment of seasonal allergic rhinitis in the fall. Effectiveness and tolerance (see Nayak, AS et al., and 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 the use of montelukast alone or in combination with loratadine is well tolerated in patients with seasonal allergic rhinitis. 127804.doc •19- 200838524

It also provides clinical and quality of life benefits. Another study evaluated the combination of loratadine and montelukast in the treatment of seasonal allergic rhinitis patients with severe nasal congestion: therefore [refer to I? on behalf of the father-in-law, B · special rule, 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 page 30) (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, page 31) (2003)). The study concluded that the use of the combination was comparable to the effect of loratadine alone. Another randomized, double-blind study compared the combination of fensapride-pseudoephedrine with loratadine-monucut in the treatment of seasonal allergic rhinitis (see, 3⁄4 Moinuddin, » 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)) 〇 This study concluded that fesoteine-pseudoephedrine and loratadine in seasonal allergic rhinitis - Montelukast is equally effective in improving symptoms, rhinitis and conjunctivitis quality of life survey (RQLQ) scores and nasal congestion. One of the goals of this study was to evaluate a fixed-dose of chlorella in a subject with seasonal allergic rhinitis (SAR) who was treated for 15 days to relieve nasal congestion. 127804.doc -20- 200838524 Teddy / Monroe The efficacy of the combination (LMC) (containing 10 mg of loratadine and 10 mg of montelukast daily) was compared with the efficacy of placebo. Other objectives of the study were: (i) to evaluate the efficacy of LMC on placebo using health-related quality of life (HrQoL), nasal maximum inspiratory flow (PNIF), overall SAR condition, and overall treatment response; and (Η) Subject-reported adverse events (AEs) and vital signs were used to assess the safety of LMC relative to placebo and pseudoephedrine. This is a phase 3, multicenter, parallel group, double-blind, double-simulated, randomized study based on good clinical trial specifications. Subjects were assigned to one of three treatment groups • Group 1-LMC (10 mg/10 mg); Group 2_ pseudoephedrine (24 mg mg group 3 - placebo. Subjects participated in 4 visits: the first visit) - Screening; 2nd visit - baseline; 3rd and 4th visits - Treatment period. Subjects meeting the study conditions received their first dose at the clinic at the 2nd visit. A total of 1095 subjects will be tested Randomly assigned to the study: 363 subjects, pseudo-yellow test, 369 subjects; and placebo, 363 subjects

Of the trials, 1057 (96.5%) completed the study.

The study population consisted primarily of subjects with a Caucasian age and an average age of S. cerevisiae (78% to 127804.doc 21 200838524 79%). The main criteria include: (1) a history of SAR recorded at least 2 years, and aggravated in the 9th year of the study, (1)) at the i-th visit (screening) with at least two upper-quarter bM allergens with skin spots The thorn test positive reaction, (4) the bed syndrome at the time of screening k (measured by the subject) (symptom score must meet the following criteria. Nasal leak 22, nasal congestion U, total nasal symptoms 总, total non-nasal Symptom M, and overall assessment (4)) and (iv) Clinical Symptoms at Baseline Jane (2nd Visit) (reported in 7 rounds of logs 3 days prior to baseline visit (pR leg) score and AM for baseline visits The score must be a total of: nasal congestion..., total nasal symptoms 242, and total non-nasal symptoms > 28). Subjects were assessed for hyperemia/non-ventilation severity as a response (PRIOR) (ie, subjects within the previous 12 hours) during the baseline and during the treatment visit, according to the following scale twice (10) and PM) status). Similarly, during the screening and treatment periods, subjects measured and recorded their nasal maximum inspiratory flow twice a day (using the pNIF meter assigned at the time of the visit). At all visits (1, 8, and 15), the investigator or assignee and subject estimated the overall condition of the SAR based on the same table: 〇 = no (no obvious symptoms); 1 = mild (symptoms) Obvious but minimally detectable; easily tolerated and does not interfere with normal life and/or sleep); 2 = moderate (can clearly detect symptoms, these symptoms are anxious but still tolerable); 3 = severe ( Symptoms are difficult to tolerate; can cause disturbances in twins/tongue activity and/or sleep). The evaluation included the entire period since the previous visit.

For the primary efficacy variable and the only symptom evaluated during the treatment period _ nasal congestion, the mean AM PRIOR 'PM pRI〇R& AM/pM 127804.doc -22· 200838524 average score for the PRIOR assessment was comparable between the two treatment groups. AM PRIOR nasal congestion score The primary efficacy index is the change in the AM PRI0R nasal congestion score from baseline, which is characterized by overnight symptom relief at 12 to 24 hours after administration. The results are summarized in Table 1, which shows that the effects of LMC and pseudoephedrine tests are similar to each other throughout the study. Analysis shows that during the 15-day treatment period, lmc^am

The mean reduction in PRIOR nasal congestion scores from baseline was statistically significantly more effective than placebo. On days 2 to 15 (major time points), the mean reduction in the LMC nasal congestion score was greater than the placebo reduction by 2 points (1 > = 〇〇〇 9). Since the assessment was performed prior to administration in the morning, LMC maintained its efficacy throughout the dosing period. During the second to fifteenth day period, the decrease in the AM PRIOR nasal congestion score for pseudoephedrine from baseline was statistically significantly more effective than placebo. (The score is lower than the comfort of the sword 〇·13 points; p = 〇〇〇4). However, there was no significant difference between LMC and pseudoephedrine in the change in nasal congestion score from baseline at the main day-to-day stagnation on days 2 to 15 or at any other time point analyzed. The effect of LMC (0.12 points) is 92% of the pseudoephedrine effect (0.13 points). 127804.d〇i •23- 200838524 Table 1. Results of nasal congestion analysis: Subjects evaluated AM PRIOR for 12 hours (all random subjects). LMC(A) PSE(B) Placebo (c) Pstda N LS Mean a (Average % change) b N LS Mean a (Average % change) b N LS Mean a (Average % change) b Baseline 362 2.66 366 2.67 360 2.69 Change from baseline Day 2 358 -0.30 (-10.3) 363 -0.30 (-10.6) 358 -0.23 (-8.1) 0.672 Day 3 361 -0.44 (15.7) 364 -0.42 (15.0) 359 - 0.30 (-10.4) 0.728 Day 4 360 -0.48 (-17.4) 363 -0.41 (-14.4) 359 -0.33 (-11.4) 0.759 Day 2 to 8 361 -0.48 (-17.4) 365 -0.45 (-16.3) 359 -0.37 (-13.2) 0.581 Days 9 to 15 356 -0.65 (-23.6) 357 -0.70 (-25.3) 358 -0.52 (-18.6) 0.690 Days 2 to 15 362 -0.56 (-20.4) 366 -0.57 (-20.6) 360 -0.44 (-15.8) 0.595 Pairwise comparison P value 95% confidence interval AB AC BC AB AC BC From baseline change Day 2 0.915 0.208 0.171 (-0.09,0.10) (-0.16,0.04) (- 0.17, 0.03) Day 3 0.764 0.011 0.024 (-0.12, 0.09) (-0.25, -0.03) (-0.23, -0.02) Day 4 0.202 0.007 0.150 (-0.18, 0.04) (-0.27, -0.04) ( -0.19,0.03) Days 2 to 8 0.587 0.013 0.052 (-0.11,0.06) (-0.19, -0.02) (-0.17,0.00) Days 9 to 15 0.317 0.016 ≪•001 (-0.05,0.15) (-0.23, -0.02) (-0.28, -0.08) Days 2 to 15 0.790 0.009 0.004 (-0.08, 0.10) (-0.20, -0.03) (-0.21, - 0.04)

LMC = 10 mg loratadine/10 mg montelukast combination lozenge; PSE = 240 mg pseudoephedrine money detector. a : LS mean and Pstd (total standard deviation) were obtained from a two-way ANOVA model with treatment and site effects. b: The average percentage change is the original average. AM/PM PRIOR nasal congestion score The AM/PM PRIOR nasal congestion score characterizes the symptom relief during the 24 hour period after administration. During the first to fifteenth days, the mean reduction in AM/PM PRIOR nasal congestion scores from LMC from baseline was statistically significantly more effective than placebo (Table 2). The mean reduction in nasal congestion score for LMC was 0.61 points, compared with 0.49 for placebo -24-127804.doc 200838524. The difference between the LMC and placebo-0.12 points was statistically significant (Ρ=0.003). During the first to fifteen days, the mean PRIOR nasal congestion score for pseudoephedrine decreased from baseline to the mean of placebo. It was also significantly more effective (the score was lower than the placebo by 〇·16 points; Ρ<0·001). However, there was no significant difference between LMC and pseudoephedrine in terms of the average of days 1 to 15. Table 2. Nasal congestion analysis results: Subjects evaluated AM/PM PRIOR 12 hours (all random subjects).

N baseline 362 change from baseline LMC (A) PSE (B) placebo (C) LS mean a (average % change) b

N LS average a (average % change) b

N LS average 2 (average % change) b

Pstda 2.65 368 2.65 360 2.67 Day 1 354 -0.36 Day 2 361 -0.44 Day 3 361 -0.50 Day 4 361 -0.56 Days 1 to 8 361 -0.54 Days 9 to 15 356 -0.71 Numbers 1 to 15 Day 362 -0.61 \ly \)/ X)/ \)y \iy \—/ 8 ο 5·7·1·0·8 2.6.8.0.0.6.2. -1-1-1-2-2- 2-2 /^v 5 5 5 4 7 7 8 5 6 6 6 6 5 6 -0.48 -0.44 -0.49 -0.53 -0.54 -0.78 -0.65

\ly ΧΪ/ \ly \»y 8’ 236.2.91· 7.6.89.0.8.4. 11112 2 2 G G G G G G

0.650 0,621 0.642 0.671 0.554 0.663 0.572

Pairwise comparison P value 95% confidence interval AB AC BC AB AC BC Change from baseline Day 1 0.011 0.510 0.001 (0.03, 0.22) (-0.13, 0.06) (-0.25, -0.06) Day 2 0.921 0.007 0.005 (- 0.09, 0.10) (-0.22, -0.03) (-0.22, -0,04) Day 3 0.904 0.006 0.009 (-0.10, 0.09) (-0.23, -0.04) (-0.22, -0.03) Day 4 0.613 0.006 0.024 (-0.12, 0.07) (-0.24, -0.04) (-0.21,-0.01) Days 1 to 8 0.928 0.004 0.003 (-0.08, 0.08) (-0.20, -0.04) (-0.20, -0.04) Days 9 to 15 0.149 0.005 <.001 (-0.03, 0.17) (-0.24, -0.04) (-0.31, -0.11) Days 1 to 15 0.422 0.003 <.001 (-0.05, 0.12) (- 0.21, -0.04) (-0.24, -0.08) LMO 10 mg of thunderidine/10 mg of montelukast combination tablet; PSE = 240 mg of pseudoephedrine tablet. a : LS mean and Pstd (total standard deviation) were obtained from a two-way ANOVA model with treatment and site effects. b: The average percentage change is the original average. -25- 127804.doc 200838524 PM PRIOR nasal congestion score The PM PRIOR nasal congestion score characterizes the symptom relief after the administration of the drug to the day of the sputum. This analysis confirmed the primary analysis, that is, the mean reduction in nasal sweating from the baseline in LMC was more statistically significant (P=G._) than in placebo, and LMC and pseudoephedrine were examined. No significant difference. Other efficacy variables The results of AM PNIF changes from baseline are summarized in Table 3, which shows that the effects of LMC and pseudoephedrine tests are similar to each other throughout the study period. The pNiF砰 estimate is a transient assessment that characterizes the nasal airflow at the Society. AM evaluation was performed at the 24-hour investment interval. During the second to fifteenth day (major time point), the average increase in PNIF from baseline was melon liters/minute for stains, 1 G.G6 liters/minute for maize, and 5 minutes for placebo. The analysis showed that the increase in the AM p curtain from the baseline during the 2nd to 15th day was statistically significantly more effective ((4) fine). Since this is an instantaneous assessment performed immediately prior to administration in the morning, LMC maintains its effect throughout the administration interval. During the second to isday period, the increase in AM pNIF from baseline in pseudoephedrine was statistically significantly more effective than placebo ((4) thanks). However, there was no significant difference between LMC and pseudoephedrine at the major time points on days 2 to 15 or at any other time point analyzed, ΑΜρΝιρ from baseline changes. 127804.doc -26 - 200838524 Table 3. Maximum nasal inspiratory flow (liters per minute) analysis results · Subject - evaluation AM (all random subjects). LMC (Α) PSE (B) Placebo (c) Pstda Ν LS mean a ί mean change) b Ν LS mean a (average % change) b Ν LS mean a ί mean % change) b Baseline 361 91.80 366 96.27 360 94.99 Change from baseline day 2 361 5.15 (9.1) 362 3.68 (5.8) 358 1.19 (3.6) 23.36 Day 3 361 6.87 (11.5) 365 6.35 (9.7) 358 1.81 (4.6) 23.45 Day 4 361 7.47 ( 12.9) 364 7.53 (10.9) 358 1.09 (4.4) 24.23 Days 2 to 8 361 8.56 (13.3) 365 7.85 (11.1) 358 3.43 (7.0) 19.97 Days 9 to 15 355 12.85 (19.2) 357 12.70 (16.9) 357 6.92 (11.4) 24.68 Days 2 to 15 361 10.64 (16.2) 366 10.06 (13.7) 360 5.05 (9.0) 20.54 Pairwise comparison of P values __95% confidence interval AB AC BC AB AC BC From baseline change day 2 0.399 0.023 0.153 (-1.95, 4.89) (0.54, 7.39) (-0.93, 5.92) Day 3 0.766 0.004 0.009 (-2.91, 3.95) (1.62, 8.51) (1.11, 7.98) Day 4 0.974 <.001 < .001 (-3.60, 3.48) (2.83, 9,94) (2.89, 9.99) Days 2 to 8 0.633 <•001 0.003 (-2.21, 3.63) (2.20, 8.06) (1.50, 7.34) Section 9 to 15 days 0.933 0.001 0.002 (-3.49, 3.80) (2.29, 9.57 (2.14, 9.41) Days 2 to 15 0.703 <.001 0.001 (-2.42, 3.58) (2.59, 8.60) (2.01, 8.01)

LMO 10 mg loratadine/10 mg montelukast combination lozenge; PSE = 240 mg pseudoephedrine lozenge. a : LS (least significant) mean and Pstd (total standard deviation) were obtained from a two-way ANOVA model with treatment and site effects. b: The average percentage change is the original average. Analysis of other secondary efficacy variables (ie, RQLQ, combined evaluation of treatment response, and combined assessment of overall SAR conditions) showed that LMC was statistically significant (Ρ<0·005) more effective than LMO and LMC was There was no significant difference between pseudoephedrine. Table 4 summarizes the adverse events that occurred in 2% or more of the subjects in either treatment group. The overall incidence of adverse events in subjects treated with LMC (15.2%) was lower than that in subjects treated with PSE (23.0%) and in placebo-treated subjects -27-127804.doc 200838524 rate ( 17.6%) equivalent. No adverse events were reported except for dry mouth, nausea, headache, and insomnia in more than 2% of subjects in either treatment group. Oral dryness and nausea occurred in the PSE treatment group at a significantly higher incidence (4.9%, 2.2%) than the LMC group (0.6%, 0.3%) or the placebo group (0.6%, 0%). Dizziness occurred only in subjects treated with PSE (6, 1.6%). Insomnia, the general side effects of PSE, occurred in 8 (2.2%) subjects treated with PSE, compared with none of the subjects treated with LMC and insomnia and 2 (0.6%) via placebo The subject was treated for insomnia. • The summary of all adverse events is shown below. Table 4 Reports of 2% or more subjects (all random subjects) in any treatment group. Summary of body system/organ class adverse events (%) LMC (n=363) PSE (n=369) Placebo (n=363) Any adverse event 55 (15.2) 85 (23.0) 64 (17.6) Dry mouth of gastrointestinal disorders 2 (0.6) 18 (4.9) 2 (0.6) Nausea 1 (0.3) 8 (2.2) 0 Neurological Disorder Headache 8 (2.2) 7 (1.9) 9 (2.5) Psychiatric Insomnia 0 8 (2.2) 2 (0.6) LMO 10 mg loratadine/10 mg montelukast combination lozenge; PSE = 240 mg pseudoephedrine lozenge. In addition, specific adverse events associated with sympathomimetic excitatory amines (except insomnia) were selected from the Summary of Adverse Events to determine the relative incidence of such events between treatment groups 127804.doc -28- 200838524. These incidences are summarized in Table 5. The incidence of such events in the PSE group was higher than in the LMC or placebo group. Researchers treat almost all of these events as treatment-related. Table 5 Adverse events associated with sympathomimetic excitatory amines (except insomnia) Incidence number (%) Adverse events LMC (n=363) PSE (n=369) Placebo (n=363) Any bad Event 3 (0.8) 14(3.8) 4(1.1) Stun 0 0 1 (03) Tension 0 2 (0.5) 0 Easy irritation 2 (0.6) 1 (0.3) 0 Dizziness 0 6 (1.6) 0 Psychomotor function hyperactivity 0 1 (0.3) 1 (0.3) Tremor 0 0 1 (0.3) Neurotic 0 3 (0.8) 1 (0.3) Disturbance 1 (0.3) 1 (0.3) 0 LMC = 10 mg loratadine/10 mg Menglu Tablet combination tablet; PSE = 240 mg pseudoephedrine lysine. Equivalents The present invention provides, inter alia, a method for treating, preventing or ameliorating nasal congestion associated with ≥ sensitive rhinitis in patients with hepatic impairment. While the invention has been described in connection with the specific embodiments of the embodiments Many variations of the invention will become apparent to those skilled in the art after reading this description. The full scope of the invention, as well as the full scope of its equivalents, and the full scope of such modifications are intended to be 127804.doc -29-

Claims (1)

200838524 X. The scope of application for patents · · For the treatment of patients in need of reading & π filling gold ... The nose associated with allergic rhinitis, wipes the patient with liver dysfunction 次 - secondary to the disease Suffering from the inclusion of the qi: including (l〇raUdin^ from a priest) [7] Mao Kechao ruding its medicine. Acceptable 2. The method of claim 1 is montelukast sodium. For the method of claim 1, 4. for the method of claim 1, 5. for the method of claim 1, 6. for the method of claim 1, 7. for the method of claim 1, 8. Method, 9. The method of claim 1, 10. The method of claim 1, rhinitis 0 11. The method of claim 1, the rhinitis 〇 12 · the method of claim 1, 13. The request 1 Method, the patient is lethargic 14. An additional therapeutic agent according to the method of claim 1. 127804.doc salt wherein the pharmaceutically acceptable montelukast wherein the patient has mild liver function decline. The patient has moderate liver function decline. The sputum patient has severe liver function decline. The liver function decline is related to the disease. The liver function decline is related to hepatitis. The method of claim 1, wherein the pharmaceutical composition is oral or鲁〆16. The method of claim 16, wherein the pharmaceutical composition is formulated as a liquid, a troche, a capsule, a elixirs, a granule, a suspension or a film. 17. The method of claim 16, wherein the tablet system Oral, chewable or fast-dissolving. 18 - A method for treating or alleviating allergic rhinitis associated with allergic rhinitis, nasal congestion, method comprising administering to the liver-impaired patient An anti-drug comprising loratadine and montelukast or a pharmaceutically acceptable salt thereof, and a buccal substance, wherein the anti-nasal congestion effect produced by administering the pharmaceutical composition and the pseudo-ephedra test are produced The nasal congestion effect is the same. 19. According to the method of claim 18, the anti-nasal congestion effect produced by pseudoephedrine is related to the daily-time administration of 24G mg pseudo-ephedrine. 18 methods' The effect of releasing the nasal congestion A produced by the pharmaceutical composition is at least 70% of the effect of releasing the nasal sputum by the pseudoephedrine test. 21. The method of claiming the item 18, wherein the method of relieving the nasal filling effect The measurement is carried out during the period of about 12 to about 24 hours after administration of the pharmaceutical composition. 127804.doc 200838524 VII. Designation of representative drawings: (1) The representative representative of the case is: (none) (2) The symbol of the representative figure Brief Description: 8. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: (none) 127804.doc