CN1518448A - Antihistamines for nasal congestion and congestion - Google Patents

Abstract

This invention relates to the use of desloratadine and/or other antihistamines in the treatment and/or prevention of severe nasal congestion and/or obstruction associated with allergic and inflammatory diseases of the upper and lower airways in humans.

Description

Antihistamines for nasal congestion and congestion

field of invention

The present invention relates to the use of desloratadine and/or other antihistamines in the treatment and/or prevention of nasal congestion and/or nasal congestion defined as those associated with allergies and Symptoms of nasal airflow limitation associated with inflammatory conditions such as seasonal allergic rhinitis.

Background of the invention

US Patent 4659716 discloses desloratadine, a nonsedating antihistamine useful in the treatment of allergic reactions in animals, including humans. US Patent 5695997 discloses pharmaceutical compositions comprising desloratadine and methods of using desloratadine for the treatment and prevention of disease conditions such as allergic rhinitis.

Severe nasal congestion/stuffing and/or blockage is a chronic symptom in patients with allergic diseases such as allergic rhinitis. However, existing antihistamines are not yet effective in treating severe nasal congestion and congestion/stiffness associated with allergic disease. Administration of a combination product comprising an antihistamine and the decongestant pseudoephedrine treats congestion associated with allergic rhinitis. For example, the commercially available product Claritin D12 and D24 is a combination of loratadine and pseudoephedrine, and the commercially available product "Allegra-D" is a combination of fenofentin and pseudoephedrine. See PhysiciansDesk Reference 2000.

However, administration of pseudoephedrine may cause unwanted side effects. Side effects associated with pseudoephedrine include insomnia, dizziness, weakness, tremors, or irregular heartbeat. These and other unwanted side effects may cause patients suffering from congestion associated with allergic diseases to avoid or discontinue treatment with pseudoephedrine-containing products.

There is a need for a clinically effective treatment for the treatment or prevention of severe nasal congestion and/or congestion associated with allergic and inflammatory diseases of the human airways using non-sedating antihistamines which do not produce Potential adverse side effects that may be experienced when using products containing pseudoephedrine. That is, there is a need for non-sedating antihistamines that provide a decongestant effect to reduce the need for or eliminate the need for additional decongestants such as pseudoephedrine.

Summary of the invention

The present invention provides a method of treating and/or preventing nasal congestion associated with allergic and inflammatory conditions in a human's airways, the method comprising administering to a human in need thereof a therapeutically and/or prophylactically effective amount of desloratadine.

The present invention also provides a method of treating and/or preventing nasal congestion associated with allergic and inflammatory conditions of the human airways, the method comprising administering to a human in need thereof a therapeutically and/or prophylactically effective amount of desloratadine.

The present invention also provides a method of treating and/or preventing severe nasal congestion associated with allergic and inflammatory symptoms of the human airways, the method comprising co-administering a therapeutically and/or prophylactically effective amount of desloratadine to a human in need thereof with one or more additional decongestants.

The present invention also provides a method of treating and/or preventing nasal congestion associated with allergic and inflammatory symptoms of the human airways, the method comprising administering to a human in need thereof a therapeutically and/or prophylactically effective amount of an antihistamine, wherein The antihistamine is selected from the group consisting of loratadine, cetirizine, fenofenidine, ebastine, astemizole, norastemizole, epinadine, eflurizine or their pharmaceutically acceptable Use salt.

The present invention also provides a method of treating and/or preventing nasal congestion associated with allergic and inflammatory conditions in a human's airways, the method comprising administering to a human in need thereof a therapeutically and/or prophylactically effective amount of an antihistamine in combination with One or more additional decongestants, wherein the antihistamine is selected from the group consisting of loratadine, cetirizine, fenofentin, ebastine, astemizole, norastemizole, epitaxy Nadine, eflurazine or their pharmaceutically acceptable salts.

Detailed description of the invention

The phrase "allergic and inflammatory conditions of the airflow passages" refers to those allergic and inflammatory diseases and conditions found in the upper and lower airways from the nose to the lungs. Typical allergic and inflammatory diseases of the upper and lower airways include seasonal and common allergic rhinitis, non-allergic rhinitis, asthma (both allergic and non-allergic), sinusitis, and colds .

The term "congestion" refers to an obstruction with reduced nasal cavity diameter and increased nasal airflow resistance, thus reducing obstruction, non-ventilation or blockage of the upper airways from the nose to the lungs and/or constriction of the lower airways, including severe nasal congestion and congestion.

The term "nasal congestion" refers to a subject with congestion who suffers from moderate to severe nasal congestion and nasal airflow obstruction, typically with minor rhinorrhea. For example, at the initial visit, the subject should provide seven twice-daily (in the morning and afternoon) follow-up (in the morning and afternoon) diary reflection scores, which include scores for the three calendar days before the initial visit and the morning of the first visit day . The scores are as follows: the total rhinorrhea score should be at least equal to 14; the total nasal congestion score should exceed the total rhinorrhea score by at least 2 points; the total nasal symptoms score should be at least equal to 42; the total non-nasal symptoms should be at least equal to 28.

The primary efficacy variable was the mean score for morning-afternoon "reflective" nasal congestion symptoms, represented by the mean change over the treatment period (Days 1 to 8) compared to initial visit. The main comparison for this variable will be eg desloratadine versus placebo.

Secondary efficacy parameters included the morning "instantaneous" nasal congestion score and the mean morning-afternoon "reactive" and "instantaneous" total symptom scores minus nasal congestion (sum of the six individual symptom scores); the total symptom score (including seven individual symptom scores including nasal congestion); nasal symptom score (sum of four nasal symptom scores); total nasal symptom score minus nasal congestion/airflow; nonnasal symptom score (three individual nonnasal symptom scores and ); each of seven individual symptom scores and assessments of treatment response to treatment by subjects and investigators/designers.

In addition, on the basis of the probing, the subjects will objectively measure the degree of nasal breathing freedom/nasal congestion twice a day, using the In-Check nasal inspiratory flow meter device, and record the results in the recipient's diary. Any subjective symptoms related to nasal congestion will also be evaluated.

Safety assessments will include routine subject and investigator-assessed adverse events; investigator-assessed vital signs and ECG; laboratory evaluations of blood chemistry, hematology, and urinalysis.

Subjects can be of any gender and of any race, at least 12 years of age; at least 2 years of moderate/severe vernal seasonal allergic rhinitis history documenting that the patient is sensitive to the prevalent vernal seasonal allergen skin Positive sting test (history of allergy/skin test reactivity to perennial allergens and molds can also be obtained from analysis for demographic purposes and possibly specific subfamily).

As stated above, in order to qualify for screening for this study, subjects must demonstrate the following reflective (before 12 hours) sign/symptom scores: Rhinorrhea (either preceding or following) score of at least Moderate degree (minimum 2 points), nasal congestion must be at least moderate (minimum 2 points), total nasal symptom score must be at least 6, and total non-nasal score must be at least equal to 4. To qualify for randomization at the initial visit, the seven twice-daily (morning and afternoon) follow-up diary "reflexive" scores (which include the three calendar days prior to baseline and the morning of the baseline day) must be as follows: Rhinorrhea Symptom Score Must equal at least 14; Total Nasal Congestion score must exceed Total Rhinorrhea score by at least 2 points; Total Nasal Symptoms score must equal at least 42; and Total Non-Nasal Symptoms must equal at least 28.

Subjects must be healthy and free of any clinically significant disease other than SAR that may interfere with the study plan, evaluation of SAR, or interpretation of data obtained from the study. Rescue treatment is not provided. Group I will receive desloratadine 5.0 mg; Group II will receive placebo. Desloratadine placebo tablet 5.0 mg. This study was double-blind, parallel group and at multicenter.

This is pilot research. As such, sample sizes were chosen to provide reasonable estimates and trends for possible treatment effects. Thus, for a sample size of 150 patients per treatment group, with a two-tailed alpha level of 0.05, the pooled standard deviation of change from baseline was 0.6 points, and a difference between treatment groups of about 0.19 units or greater was detected (power at least 80%).

300 subjects will be enrolled at approximately 10 sites with approximately 30 subjects enrolled at each site. The ratio of subjects assigned to treatment was 1:1 (desloratadine: placebo).

Subjects will be randomly assigned to one of two treatment randomization plans. Randomization will be done within appropriately sized groups using random numbers generated by the clock-time-based SAS function Uniform (SAS function UNIFORM). Those who drop out will not be replaced.

This is a one-week pilot Phase II study consisting of a total of 300 enrolled subjects. Each subject was screened during the US spring allergy season. Subjects must have adequate symptoms associated with both nasal and non-nasal symptoms at both screening and initial visit. To ensure the first dose of a randomized treatment unit, subjects in both treatment groups will be present at the clinic for an initial visit, usually 3 to 14 days after the screening visit. In each treatment group, subjects were required to visit the clinic for their next visit, on day 8 (7 days after baseline).

The amount of desloratadine effective for treating or preventing congestion associated with allergic and inflammatory conditions of the airways will vary with the age, sex, weight, and severity of the allergic and inflammatory conditions of the patient. Variety. Typically, the amount of desloratadine effective for treating or preventing such allergic and inflammatory conditions ranges from about 2.5 mg/day to about 45 mg/day, preferably from about 2.5 mg/day to about 20 mg /day, or about 5.0mg/day-about 15mg/day, or about 5.0mg/day-about 10mg/day, more preferably about 5.0mg/day to about 7.5mg/day, and most preferably single dose or divided dose About 5.0mg/day, or a single dose of 5.0mg/day.

US Patent No. 4,659,716 discloses a method for preparing desloratadine, a pharmaceutical composition containing it and a method for treating allergic reactions in mammals by using desloratadine and the pharmaceutical composition containing it. US Patent 5595997 discloses pharmaceutical compositions comprising desloratadine and methods of using desloratadine for the treatment and prevention of various disease states such as allergic rhinitis. Desloratastat was purchased from Schering Company, Kenilworth, N.J.

Antihistamines that may also be used in the present invention include loratadine, cetirizine, levocetirizine, mizolastine for seasonal allergic rhinitis, fenofentin, ebazan Tine, astemizole, norastemizole, epinadine, eflurazine or their pharmaceutically acceptable salts. The use of desloratadine, loratadine, fenofentine and cetirizine is most preferred.

It is reported that US Patent 4525358 discloses cetirizine. A preferred pharmaceutically acceptable salt is the hydrochloride, also known as cetirizine hydrochloride. The amount of cetirizine that can be used in the unit dosage form of the composition of the present application ranges from about 2.5-20 mg, may also be about 5-about 10 mg, preferably about 10 mg.

According to reports, U.S. Patent 4,254,129 discloses Fenofentine (MDL 16,455A). A preferred pharmaceutically acceptable salt is the hydrochloride, also known as fenofenidine hydrochloride. The amount of fenofenidine that can be employed in the unit dosage form of the composition of the present application ranges from about 40-200 mg, or about 60-about 180 mg, preferably about 120 mg.

Ebastine is reported to be described in EP134124. Ebastine can be employed in a unit dosage form in an amount ranging from about 5 to about 20 mg, preferably about 10 mg.

Astemizole is reportedly described in US Patent 4,219,559. Astemizole can be employed in a unit dosage form in an amount ranging from about 5 to about 20 mg, preferably about 10 mg.

It is reported that norastemizole is an antihistamine, and its professional name is 1-((4-fluorophenyl)methyl)-N-4-piperidinyl-1H-benzimidazol-2-amine. This compound is the active metabolite of astemizole. Norastemizole can be employed in unit dosage forms in amounts ranging from about 5 to about 40 mg, or from about 10 mg to about 20 mg.

Epinatine is reported to be described in DE3008944 or Jpn.J.Clin.Pharmocol.Ther., 1991, 22, p.617. Epinatine can be employed in a unit dosage form in an amount ranging from about 1 to about 20 mg, preferably from about 2 mg to about 18 mg.

Ethchlorizine (UCB-28754) is reported to be an antihistamine, and its professional name is [2-[4-[bis(p-fluorophenyl)methyl]-1-piperidinyl]ethoxy] acetic acid. CAS registry number 140756-35-7. Ethchlorizine can be employed in a unit dosage form in an amount ranging from about 4 to about 60 mg.

US Patent 4282233 discloses a method for preparing loratadine, a pharmaceutical composition containing it and a method of using loratadine and a pharmaceutical composition containing it to affect the antiallergic response of a mammal. Claritin was purchased from Schering-Plough Company (Kenilworth, NJ) under the trade name Claritin ^™ .

Pharmaceutical compositions of desloratadine and/or other antihistamines may be administered by any means, e.g., oral, parenteral, e.g., subcutaneous ("SC"), intramuscular ("IM"), intravenous ("IV") and intraperitoneal ("IP"), topically or intravaginally or by inhalation (by oral or intranasal). Preferably, desloratadine and/or other antihistamines are administered orally.

This medicine is formulated by combining desloratadine and/or other antihistamines or equivalent amounts of their pharmaceutically acceptable salts with a suitable inert pharmaceutically acceptable carrier or diluent (which may be solid or liquid) combination. Desloratadine can be converted into a pharmaceutically acceptable acid addition salt by mixing with a corresponding amount of a pharmaceutically acceptable acid. Typically, suitable pharmaceutically acceptable acids include mineral acids such as HNO ₃ , H ₂ SO ₄ , H ₃ PO ₄ , HCI, HBr, organic acids including but not limited to acetic acid, trifluoroacetic acid, propionic acid, lactic acid, malic acid acid, succinic acid, tartaric acid, glucuronic acid and citric acid as well as alkyl or aryl sulfonic acids such as p-toluenesulfonic acid, 2-naphthalenesulfonic acid or methanesulfonic acid. Preferred pharmaceutically acceptable salts are trifluoroacetate, tosylate, mesylate and chloride. Desloratadine free base is more stable than its acid addition salts, and the use of desloratadine free base in the pharmaceutical composition of the present invention is more preferred.

Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets may contain from about 5% to about 95% active substance. Suitable solid carriers are known in the art, for example magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods for preparing various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition (1990), Mack Publishing Company, Easton, PA.

Liquid form preparations include solutions, suspensions and emulsions. Examples that may be mentioned are water or water-propylene glycol solutions for parenteral injection. Solid form preparations can be converted to liquid preparations prior to oral or administration. Parenteral forms for intravenous, intramuscular or subcutaneous injection are usually in the form of sterile solutions and may contain tonicity agents (saline or dextrose) and buffering agents. Oral solutions, suspensions and emulsions may contain opacifying agents. Liquid form preparations may also include solutions for intranasal administration.

Aerosol formulations suitable for administration by inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as an inert compressed gas, eg nitrogen.

Also included are solid form preparations which are to be converted, shortly before use, to liquid form preparations for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the present invention may also be administered transdermally. Transdermal compositions may be in the form of creams, lotions, aerosols and/or emulsions and may be contained in matrix or reservoir transdermal patches conventional in the art for this purpose.

Additionally, the present invention includes desloratadine and/or other antihistamines in combination with other decongestants. Due to the decongestant effect of desloratadine and/or other antihistamines, the amount of other decongestants may be reduced in comparison to other combinations of antihistamines and decongestants. Other decongestants that may be used in combination with desloratadine and/or other antihistamines include pseudoephedrine, phenylephrine, and phenylpropanolamine.

Preferably, the pharmaceutical formulations are presented in unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active ingredient, eg, an effective amount to achieve the desired purpose.

Desloratadine is especially indicated for the treatment and prophylaxis of nasal symptoms (stuff/congestion, rhinorrhea, nasal itching, sneezing) and non-nasal symptoms of seasonal allergic rhinitis in patients in need of such treatment and/or prophylaxis (itchy/burning eyes, watery/watery eyes, red eyes, itchy ears/palate) including nasal congestion.

The clinical effect and safety of desloratadine have been proved in four double-blind, randomized clinical trials by 3200 patients with seasonal allergic rhinitis. The results of these clinical studies demonstrate the effectiveness of desloratadine in the treatment of adult and adolescent patients with seasonal rhinitis.

Efficacy endpoints for all studies were total symptom score, total nasal symptom score, total non-nasal symptom score, and health quality of life (HQOL) analysis in the efficacy trial. Desloratadine (5 mg once daily) significantly reduced the total symptom scores (rhinorrhea, sneezing, congestion/stiffness, itchy nose, itchy/burning eyes, watery eyes, red eyes, and itchy ears/palate) Sum). Desloratadine (5 mg) was significantly more effective than placebo in reducing nasal symptoms (p<0.01). An important efficacy endpoint analyzed in the desloratadine study was the morning and present total symptom scores. This parameter measures the reduction in the patient's overall symptoms after 24 hours before taking the next day's dose. Statistically significant (p<0.05) reductions were maintained throughout the 24-hour dose interval over the dose range of 5 mg to 20 mg.

The effect of desloratadine on nasal congestion/ventilation is described by using data pooled from a randomized, parallel group, double-blind, placebo-controlled study of desloratadine in patients with SAR. Patients (12-75 years old; pooled n-659-662/group) with a history of ≥2 years of seasonal allergic rhinitis and moderate-severe symptoms at enrollment received (PO) desloratadine ( 5mg or 7.5mg) or placebo once daily for 14 days. The severity of congestion/ventilation was rated by the patients during the study (0=none, 1=mild, 2=moderate, 3=severe). The mean change in symptom severity score over 14 days from baseline was evaluated. The mean symptom severity score for nasal congestion/ventilation in each treatment group at baseline was 2.4, indicating that patients had moderate-to-severe nasal congestion prior to treatment. Desloratadine significantly reduced nasal congestion/stiffness (5 mg and 7.5 mg desloratadine vs. placebo, P equal to 0.02 and 0.01, respectively) and total symptom severity.

These data suggest that desloratadine has the added benefit of significantly reducing persistent allergic symptoms (eg, nasal congestion/stiffness) in patients with SAR.

Claims (41)

1. A method for treating and/or preventing nasal congestion associated with human airway allergic and inflammatory symptoms, the method comprising administering a treatment and/or prevention effective amount of desloratadine to a person in need thereof. 2. according to the method for claim 1, wherein the consumption of desloratadine is about 2.5mg/ day-about 45mg/ day. 3. The method according to claim 2, wherein desloratadine is used in an amount of about 5 mg/day to about 15 mg/day. 4. The method according to claim 3, wherein desloratadine is used in an amount of about 5 mg/day to about 10 mg/day. 5. The method according to claim 1, wherein the allergic and inflammatory condition is seasonal allergic rhinitis, perennial allergic rhinitis, sinusitis or allergic asthma. 6. A method of treating and/or preventing nasal congestion associated with allergic and inflammatory airway diseases in humans, the method comprising administering a therapeutically and/or prophylactically effective amount of desloratadine to a human in need thereof. 7. The method according to claim 6, wherein desloratadine is used in an amount ranging from about 2.5 mg/day to about 45 mg/day. 8. The method according to claim 7, wherein desloratadine is used in an amount of about 5 mg/day to about 15 mg/day. 9. The method according to claim 8, wherein desloratadine is used in an amount of about 5 mg/day to about 10 mg/day. 10. A method for treating and/or preventing severe nasal congestion associated with human allergic and inflammatory diseases, the method comprising administering in combination a therapeutically and/or preventively effective amount of desloratadine and a or more additional decongestants. 11. The method according to claim 10, wherein desloratadine is used in an amount of about 2.5 mg/day to about 45 mg/day. 12. The method according to claim 11, wherein desloratadine is used in an amount of about 5 mg/day to about 15 mg/day. 13. The method according to claim 12, wherein desloratadine is used in an amount of about 5 mg/day to about 10 mg/day. 14. The method according to claim 10, wherein said decongestant is pseudoephedrine. 15. The method according to claim 14, wherein said pseudoephedrine is present in an amount to provide a decongestant effect at which deleterious side effects associated with such decongestant effect are eliminated or lessened. 16. The method according to claim 15, wherein said side effect is insomnia, dizziness, weakness, tremor or arrhythmia. 17. The method according to claim 10, wherein desloratadine is administered in an amount of about 5 mg/day. 18. The method according to claim 10, wherein the amount of desloratadine is about 6 mg/day. 19. A method of treating and/or preventing nasal congestion associated with allergic and inflammatory diseases of the human airways, the method comprising administering to a human in need thereof a therapeutically and/or prophylactically effective amount of an antihistamine. 20. The method according to claim 19, wherein the antihistamine is selected from the group consisting of loratadine, cetirizine, fenofentin, ebastine, astemizole, norastemizole, epinadine , eflurazine or their pharmaceutically acceptable salts. 21. The method according to claim 20, wherein the antihistamine is loratadine. 22. The method according to claim 21, wherein the amount of loratadine is about 10 mg/day. 23. The method according to claim 19, wherein the allergic response is seasonal allergic rhinitis, perennial allergic rhinitis, sinusitis or allergic asthma. 24. A method of treating and/or preventing nasal congestion associated with seasonal allergic rhinitis in a human, the method comprising administering to a human in need thereof a therapeutically and/or prophylactically effective amount of an antihistamine. 25. The method according to claim 24, wherein the antihistamine is selected from the group consisting of loratadine, cetirizine, fenofentin, ebastine, astemizole, norastemizole, epinadine , eflurazine or their pharmaceutically acceptable salts. 26. The method according to claim 25, wherein the antihistamine is loratadine. 27. The method according to claim 26, wherein the amount of loratadine is about 10 mg/day. 28. A method of treating and/or preventing severe nasal congestion associated with allergic and inflammatory symptoms in humans, the method comprising administering to a human in need thereof a therapeutically and/or prophylactically effective amount of an antihistamine in combination with a or more additional decongestants. 29. The method according to claim 28, wherein the antihistamine is selected from the group consisting of loratadine, cetirizine, fenofentin, ebastine, astemizole, norastemizole, epinadine , eflurazine or their pharmaceutically acceptable salts. 30. The method according to claim 29, wherein the antihistamine is loratadine. 31. The method according to claim 30, wherein the amount of loratadine is about 10 mg/day. 32. The method according to claim 28, wherein said decongestant is pseudoephedrine. 33. The method according to claim 32, wherein said pseudoephedrine is present in an amount to provide a decongestant effect at which deleterious side effects associated with such decongestant effect are eliminated or lessened. 34. The method according to claim 28, wherein said side effect is insomnia, dizziness, weakness, tremor or arrhythmia. 35. The method of claim 28, wherein the antihistamine is cetirizine. 36. The method according to claim 35, wherein the amount of cetirizine is about 5 mg/day. 37. The method according to claim 35, wherein the amount of cetirizine is about 10 mg/day. 38. The method according to claim 28, wherein the antihistamine is fenofenidine. 39. The method according to claim 38, wherein the amount of fenofenidine is about 180 mg/day. 40. The method according to claim 38, wherein the amount of fenofenidine is about 60 mg/day. 41. The method according to claim 38, wherein the amount of fenofenidine is about 30 mg/day.