KR20000052922A - Composition, for the treatment of asthma, containing loratadine and a decongestant - Google Patents

Abstract

PURPOSE: Methods for relieving symptoms of allergic diseases, and more particularly to relieving bronchial asthma symptoms are provided. CONSTITUTION: A preferred decongestant is pseudoephedrine, and a presently preferred daily treatment for obtaining the desired results includes 10 milligrams of loratadine and one of: 240 milligrams of pseudoephedrine, administered in a suitable extended release formulation for 24-hour effectiveness; or two daily doses of 5 milligrams of loratadine and 120 milligrams of pseudoephedrine, administered in an extended release formulation for 12-hour effectiveness; or in up to four divided doses of immediate release formulations during 24 hours, totalling 10 milligrams of loratadine and 240 milligrams of pseudoephedrine.

Description

Composition for the treatment of asthma containing loratadine and decongestant {Composition, for the treatment of asthma, containing loratadine and a decongestant}

The present invention relates to a method for allergic disease, in particular a method for alleviating bronchial asthma symptoms.

Asthma is considered a very serious chronic allergic disease and is typically characterized by airway hypersensitivity, circulating airflow and cough symptoms, asthma and choking. This is one of the most common chronic diseases in children, possibly affecting up to 10% of children. Asthma is economically important because it causes significant loss of time from work and school, and is the most common reason for finding a physician and the reason for going to emergency care facilities and hospitals. In addition, asthma can be a fairly fatal cause, especially if not properly treated.

Asthma is usually characterized by chronic airway inflammation that varies in the degree of reversible airway blockage and increases airway response to various stimuli. Muscle spasm, airway edema, abnormal mucus production and inflammatory cell filtrate can often be observed during acute exacerbations that occur frequently in patients with "asthma attack".

Airway edema and bronchial spasm are typically epinephrine and β ₂ -agonists, such as albuterol (or "salbutamol"), metaproterenol, pybuterol, terbutalin and salmeterol It can be successfully treated with existing dilators. Typically, airway stenosis is blocked by administering a systemic corticosteroid such as prednisone or by inhaling anti-inflammatory drugs such as beclomethasone dipropionate, flunisolid, triamcinolone acetonide, chromoline sodium, and nedocromyl sodium. do. β ₂ -agonists are used as daily maintenance dosing regimens and as “rescue” dosing regimens administered as needed when experiencing worsening symptoms. Systemic corticosteroids are administered therapeutically, usually in large amounts, in the treatment of asthma conditions, while in more serious cases the corticosteroids are administered prophylactically, usually at regular intervals, regardless of current symptoms. The results of these therapeutic actions can be readily quantified by measuring cough, reducing asthma and choking, and improving the patient's Forced Expiratory Volume (FEV) or Peak Expiratory Flow (PEP) rate values. Manifestation of reduced airway narrowing; The measurement and significance of these parameters is described in R. Berkow, Ed., The Merck Manual of Diagnosis and Therapy, Firteenth Edition, Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey, 1987], pages 584-599, in particular 588-9. In addition, for some patients further oral, injection and / or inhalation dosing is required to suppress their disease and the ultimate goal of treatment is to eliminate acute exacerbations.

About 11% of patients with nasal allergy symptoms also suffer from asthma, and studies have shown that 80% of bronchial asthma patients also suffer from allergic rhinitis. Histamine is involved as a mediator of the upper and lower respiratory tract diseases, and studies have been conducted to determine the effect of the histamine H ₁ receptor antagonist "antihistamine" on asthma symptoms. For previous agents, often recognized as "sedative" antihistamines, it was common practice that antihistamines should be contraindicated in asthma patients, as their anticholinergic effects have generally been found to be harmful. Typical recommendations are described in JE Donnelly et al., "Inadequate Parental Understanding of Asthma Medications," Annala of Allergy, Vol. 62, pages 337-341 (1989), of which pages 338-9 are as follows:

A significant percentage of children can be observed by administering antibiotics, antihistamines and decongestants. Drugs in these three groups have not been recognized in the treatment of pediatric hymns.

However, the emergence of antihistamines (such as cetirizine) and non-sedative antihistamines (such as terfenadine and loratadine) with reduced sedative effects have again made interest in treating asthma with antihistamines. P. V. Williams et al. "Asthma in Children" R. E. Rakel, ed., Conn's Current Therapy 1995, W. B. Saunders Co., Philadelphia, Pennsylvania, 1995], describes:

Antihistamines are weak bronchodilators, and many new drugs not available in the United States are slightly anti-inflammatory. They are not as effective as other agents that can be used to treat asthma and therefore do not serve as conventional asthma treatments. However, in the text, we will refer to antihistamines to replace the phrase "antihistamines should not be used in asthma patients" found in various packaging statements. If patients suffer from asthma, their use in upper respiratory allergy patients is not contraindicated, and they also have a beneficial effect on asthma.

Studies conducted using conventional allergic rhinitis treatment of cetirizine, a reduced sedative antihistamine drug, are reported in G. Bruttman et al., "Protective Effect of Cetirizine in Patients Suffering from Pollen Asthma," Annals of Allergy, Vol. 64, pages 224-228 (1990); J. H. Dijkman et al., "Prophylactic Treatment of Grass Pollen-Induced Asthma with Cetirizine," Clnical and Experimental Allergy, Vol. 20, pages 483-490 (1990); J. A. Grant et al., "Cetirizine in Patients with Seasonal Rhinitis and Concomitant Asthma: Prospective, Randomized, Placed-Controlled Trial," The Journal of Allergy and Clnical Immunology, Vol. 95, pages 923-932 (1995); D. W. Aaronson, "Evaluation of Cetirizine in Patients with Allergic Rhinitis and Perennial Asthma," Annals of Allergy, Asthma and Immunology, Vol. 76, pages 440-446 (1996). In general, it has been found that cetirizine slightly improves asthma symptoms such as chest tightness, asthma, shortness of breath and cough and also relieves rhinitis symptoms. However, measurements of FEV values and other parameters did not show significant improvement in lung function.

Terpenadine has also been studied as reported in A. Taytard et al., "Treatment of Bronchial Asthma with Terfenadine; a Randomised Controlled Trial," British Journal of clinical Pharmacology, Vol. 24, pages 743-746 (1987); P. Rafferty et al., "Terfenadine, a Potent Histamine H ₁ -Receptor Antagonist in the Treatment of Grass Pollen Sensitive Asthma," British Journal of Clinical Pharmacology, Vol. 30, Pages 229-235 (1990); and R. Wood-Baker et al., "A Double-Blind, Placebo Controlled Study of Effect of the Sepecfic Histamine H ₁ -Receptor Antagonist, Terfenadine, in Chronic Severe Asthma," British Journal of Clinical Pharmacology, Vol. 39, pages 671-675 (1995). Two doses of conventional doses for allergic rhinitis or two doses of terfenadine 120 mg daily only have a slight positive effect on lung function. However, the method of administration used by Rafferty et al., Ie three doses of 180 mg per day, increases the PEF value by 5.5% in the morning and 6.2% in the evening. Because of the well-known cardiotoxic potential of the medicament, an unusually large amount of routine administration will not be wise.

A. Dirksen et al., "Effect of a Non-Sedative Antihistaminic (Loratadine) in Moderate Asthma," Allergy, Vol. 44, pages 566-571 (1989) report the results of a study in which a typical dose of loratadine (10 mg, once daily) was administered to an asthma patient. The treatment resulted in relief of symptoms of asthma, but only slight improvement in lung function, which is described as statistically insignificant.

Decongestant medications are often used to treat allergic rhinitis. The most important of these are sympathetic stimulatory amines with α-adrenergic stimulatory activity. More widely used oral dosages include phenylpropanolamine, epihedrin and pseudoephedrine. Decongestants have been used for a long time with antihistamines for the treatment of allergic and other forms of rhinitis, and some of the publications discussed above for the study of cetirizine and terpenadine have been used in patients with clinical trials of antihistamines. It can be used to further reduce symptoms. However, there were no unexpected benefits of using it.

Summary of the Invention

The present invention includes a method for improving lung function in a patient suffering from asthma, characterized by administering to the patient a conventional rhinitis treatment-effective amount of loratadine and a decongestant.

Preferred decongestants are pseudoephedrine, and currently preferred daily therapeutic doses for achieving the desired results of the present invention include 240 mg of pseudoephedrine administered in a sustained release formulation suitable for a 24-hour effect; Two daily doses of loratadine 5 mg and pseudoephedrine 120 mg administered in a sustained release formulation for a 12 hour-effect; Or 10 mg total loratadine and 240 mg pseudoephedrine, administered in up to four times in 24 hours in a fast-acting formulation. In particular, for fast-acting formulations, each agent may be administered independently or in combination dosage forms.

1 shows a graph of morning PEF data obtained in the clinical trial of the Examples.

2 shows a graph of evening PEF data obtained in the clinical trial of the Examples.

3 shows a graph of morning FEV data obtained in the clinical trial of the Examples.

As used herein, “common rhinitis-effective therapeutic amount” means a dosage approved by certain relevant regulatory agencies, such as the US Food and Drug Administration, for using the medicament to treat allergic rhinitis. As used herein, “improvement of lung function” is meant to include the promotion of the gas exchange process in the lung as seen clinically by, in particular, the improvement of the patient's FEV and / or PEF measurements; Such improvement is usually accompanied by a decrease in the patient's breath awareness.

Loratadine, chemical name ethyl-4- (8-chloro-5,6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b] pyridine-11-ylidene) -1-piperidine Carboxylate (experimental CH ₂₂ H ₂₃ ClN ₂ O ₂ , molecular weight 382.89) is a very widely used non-real antihistamine drug with an excellent safety profile. Such active agents and preparations thereof are described in US Pat. No. 4,282,233 (Vilani). In addition, the medicament may be conveniently prepared according to the methods described in US Pat. No. 4,731,447 to Schumacher et al. For the purposes of the present invention, loratadine can be administered in one of several dosage forms, for example in tablets, capsules, syrups or injections; As with most pharmaceuticals, oral administration in the form of tablets or capsules would be preferred for the convenience of the patient.

The antihistamine effective amount of loratadine is in the range of about 5 mg to about 40 mg per day. Because of the systemic half-life of loratadine and its active metabolites, the daily dose is administered once every 24 hours, or preferably divided into two, three, or four doses in equal fractions according to the frequency of decongestant medication Administration. The typical daily dose of loratadine for the alleviation of allergic rhinitis symptoms is 10 mg. Schering Corporation, Kenilworth, NJ, sells 10 mg of loratadine under the CLARITIN ^R brand. Useful decongestants medicaments include topical decongestants and systemic decongestants. Topical decongestants are usually administered in the form of aerosols, such as drops or nasal sprays, such as oxymethazolin, phenylephrine, napazoline, xylometazoline ephedrine, ephnephrine, methylhexanamine, tetra And drugs such as hydrazolin and xylomethazolin. Because of the eventual occurrence of rhinitis medicamentosa, topical decongestants are not desirable for long-term treatment, and the rhinitis medicamentus can generally be treated only by discontinuous administration of the drug.

Suitable systemic decongestants for the practice of the present invention include stirred neuroexciting amines phenylpropanolamine, ephedrine, pseudoephedrine and phenylephrine, where necessary the medicaments mentioned herein include pharmaceutically acceptable salts thereof. Included. The most widely used of these is pseudoephedrine because of the favorable balance of efficacy and safety; Typically the product is formulated with water soluble hydrochloride, sulfate or other salts. The chemical name of pseudoephedrine sulfate is [S- (R ^* , R ^* )]-α- [1 (methylamino) ethyl] benzenemethanol sulfate (Equation C ₁₀ H ₁₅ NO) ₂ ㆍ H ₂ SO ₄ , molecular weight 428.54) to be. Extraction of the compound from Ma Huang and chemical synthesis of the compound are well known in the art. For the purposes of the present invention, the pseudoephedrine salt may be administered in various dosage forms, such as tablets, capsules, syrups, or injections; As with most pharmaceuticals, oral administration in the form of tablets or capsules would be desirable for the convenience of the patient.

Typically, pseudoephedrine sulfate or hydrochloride will be administered in a daily dose of 120-360 mg in adults and in a daily dose of 60-180 mg in children to alleviate congestion due to allergic rhinitis. However, the systemic half-life of pseudoephedrine is much shorter than that of loratadine. In the case of fast-acting formulations, it is customary to administer each dose of 60 mg four times over a 24-hour period to an adult patient. However, it is known in the art that for many sustained release solid dosage forms, for example, the drug can maintain the effect for 12 hours with 120 mg, and the effect for 24 hours with 240 mg.

It is not necessary to administer loratadine and decongestant together. For example, loratadine may be administered once daily, while decongestant medications are administered more frequently to maintain therapeutic systemic drug levels. Even when the agents are administered together, they do not need to be provided in the same formulation or dosage form.

Formulations in combination with dosages of antihistamines and decongestants are known in the art. These include, for example, 5 hours of loratadine released immediately from the tablet coating and 60 mg of pseudoephedrine released at a controlled rate from the corrosive tablet matrix along with 60 mg of pseudoephedrine sulfate to provide an effect for 12 hours. Formulations will be included; Useful products are available under the trade name CLARITIN-D ^R 12 HOUR from Schering Corporation, Kenilworth, NJ. Another formulation provides an effect for 24 hours including 10 mg of loratadine released immediately from the tablet coating together with 240 mg of pseudoephedrine released at a controlled rate from the corrosive tablet matrix; This technique is described in US Pat. No. 5,314,697 (Kwan et al), and useful products are commercially available from Schering Corporation, Kenilworth, NJ, under the trade name CLARITIN-D ^R 24 HOUR. Such combination formulations will be preferred for convenience to most patients.

The invention will be further illustrated through the following examples, which are not intended to limit the appended claims in any way.

A clinical trial is conducted in 193 adult patients suffering from both asthma and rhinitis, randomly receiving the aforementioned CLARITIN-D ^R 12 HOUR product or placebo twice daily for six weeks during the fall allergy season. All patients have been using albuterol, a bronchodilator drug, via a pressurized aerosol-measured dose inhaler as prescribed by a physician to continue asthma symptoms and continue to use it in this study. No other rhinitis or asthma medications are allowed for use in patients during this study.

Prior to commencing this study, in particular, FEV and PEF rate measurements are evaluated to generate baseline data and the assessment is repeated weekly during the study.

It has been found that patients receiving this combination drug experience a significant reduction in both rhinitis and asthma compared to patients receiving only placebo.

1 shows the results of morning PEF rate measurements for patients receiving loratadine and pseudoephedrine sulfate (solid line) and patients receiving placebo only (dashed line). The ordinate in liters per minute is the average change from the reference value. Due to the combined administration of the agents, very clear and statistically significant improvements appear during this study.

2 shows similar results of evening PEF rate measurements for patients in the groups classified as described above. Similar clear and statistically significant improvements during this study are the result of combined administration of the agent.

3 shows additional study results, as indicated by FEV measurements (“FEV ₁ ”) for 1 second. The vertical census in liters shows the average change from the baseline FEV ₁ value. Data from patients receiving loratadine and pseudoephedrine sulfate are indicated by hatched bars, while data from patients receiving only placebo are shown as open bars. A very clear and statistically significant improvement in lung function during this study is due to the combined administration of the agent.

The degree of improvement in pulmonary function as shown herein will be important for the health of asthma patients regardless of whether they are a patient with rhinitis.

Claims (16)

A conventional rhinitis treatment-effective amount of loratadine and decongestant is administered to an asthma patient, thereby improving lung function in the patient with asthma. The method of claim 1, wherein the decongestant is selected from the group consisting of phenylpropanolamine, ephedrine, phenylephrine, pseudoephedrine, or combinations thereof. The method of claim 1, wherein the decongestant comprises pseudoephedrine. The method of claim 3, wherein the pseudoephedrine is administered in an amount of about 60 to about 360 mg per day. The method of claim 3, wherein the pseudoephedrine is administered in an amount of about 120 to about 240 mg per day. The method of claim 1, wherein loratadine is administered in an amount of about 5 to about 40 mg per day. The method of claim 1, wherein loratadine is administered in an amount of about 10 mg per day. The method of claim 1, wherein 10 mg of loratadine and about 120 mg to about 240 mg of pseudoephedrine per day are administered. The method of claim 1, wherein the loratadine and the decongestant are administered in separate formulations. The method of claim 1, wherein the loratadine and the decongestant are combined in a single dosage form. A method for improving pulmonary function in a patient with asthma, characterized by administering about 5 to about 40 mg of loratadine and about 60 to about 360 mg of pseudoephedrine per day to an asthmatic patient. The method of claim 11, wherein loratadine and pseudoephedrine are administered in separate formulations. The method of claim 11, wherein loratadine and pseudoephedrine are combined in a single dosage form. The method of claim 11, wherein loratadine and pseudoephedrine are in a single tablet formulation, wherein a portion of pseudoephedrine and loratadine are present in the coating and the remaining pseudoephedrine is present in the corrosive matrix. The method of claim 11, wherein loratadine and pseudoephedrine are in a single tablet formulation, wherein loratadine is in the coating and pseudoephedrine is in the corrosive matrix. A method for improving pulmonary function in a patient with asthma, characterized by administering about 10 mg of loratadine and about 240 mg of pseudoephedrine per day to an asthmatic patient.