MXPA99003936A - Composition, for the treatment of asthma, containing loratadine and a decongestant - Google Patents

Abstract

The invention encompasses a method for improving pulmonary function of a patient suffering from asthma, comprising administering to the patient customary rhinitis treatment-effective amounts of loratadine and a decongestant such as pseudoephedrine.

Description

ASTHMA TREATMENT INTRODUCTION TO THE INVENTION The invention relates to methods for alleviating the symptoms of allergic diseases and more particularly to alleviating the symptoms of bronchial asthma. The asthma is considered to be a chronic, very qurave allergic disorder, and is typically characterized by airway hypersensitivity, recurrent obstruction of airflow, and symptoms of coughing, wheezing or wheezing, and shortness of breath. It is one of the most common chronic diseases of childhood, affecting not less than 10 percent of children. It is considered that asthma has a significant impact on the economy, since it causes losses of time at work and at school, is one of the most common reasons for visits to the doctor and responsible for many hospital and institution income. emergency treatments. Asthma, moreover, is a serious cause of mortality, especially when it is not treated properly. It is generally accepted that asthma is characterized by chronic inflammation of the respiratory tract, varying degrees of airway obstruction, which is generally reversible, and increases sensitivity from the respiratory tract to a variety of stimuli. During an acute exacerbation, commonly referred to by those who suffer from it as "an asthma attack," muscle spasm, airway edema, abnormal mucosal production, and inflammatory cell filtering can often be observed. Edema and broneospasm of the airways can usually be treated successfully with bronchodilators, such as epinephrine and β2-agonists albuterol. { also called "salbutamol"), metaproterenol, pirbuterol, terbutaline and salmeterol. The narrowing of the airways can usually be blocked by the administration of systemic corticosteroids, such as prednisone, or inhaled anti-inflammatory drugs, such as dipiopionate beclo etasone flunisolide, tria cinolone acetonide, cromolyn sodium and nedocromil sodium. The ß-2 ee agonists are used as daily maintenance medications and as "rescue" medications, when administered, as necessary, in case of experiencing exacerbated symptoms. Systemic corticosteroids are given in therapeutic form, generally in large doses, for the treatment of asthmatic conditions, while corticosteroids are prophylactic and typically administered for the most severe cases in regular spaced doses, regardless of the symptoms currents The action of these treatments results in the relief of cough, asthmatic wheezing and shortness of breath, plus a reduction of the narrowness of the respiratory tract, which can easily be quantified by measuring the improvements in the values of the frequency of the forced expiratory volume of the patient (FF.V) or peak expiratory flow (PEF); the determination and relevance of these parameters are discussed on pages 584-599 of R. Ber ow, ed., The Merck Manual of "Diagnosis and Therapy, Fifteent Edition The Merck Manual of Diagnostics and Therapy, Fifteenth Edition), Merck Sharp &Dohme Research Laboratories, Rahway, New Jersey, 1987, especially on pages 588-9 Some patients also require additional oral, injected and / or inhaled medications to control their disease, with the ultimate goal of treatment being to eliminate exacerbations Acute studies have shown that approximately 11 percent of patients with symptoms of nasal allergies suffer from asthma, and that no less than 80 percent of those with bronchial asthma can also suffer from allergic rhinitis. pathogenic mediator, both in diseases of the upper and lower respiratory tract, and studies have been conducted to determine the effect "antihista "of the histamine receptor antagonist Hi on the symptoms of asthma. With the most ancient drugs, frequently identified as "sedative" antihistamines, it was found that their anticholinergic effects were detrimental to patients suffering from asthma, and so conventional thinking considers that anti-Lysine drugs are contraindicated for asthmatics. The tipleo advice is given by J.E. Donelly et al., "Inadequate parental understanding of Asthma Medications", "Annals of Allergy" (Annals of Allergy), Voi. 62, pages 33 / -3 1 (1989), where he begins on pages 338-9 saying that: "It can be seen that a large percentage of children who had received antibiotics, antihistatain and decongestants for asthma ... These three groups of drugs do not take place in the treatment of childhood asthma. " However, the advent of antihistamines that have a reduced sedative effect (such as cetirizine) and anti-seizure antihistamines (such as terfenadine and loratadine) have renewed interest in the treatment of asthma with antihistamines. P.V. Williams and others in the chapter entitled "Asthma m Children" by R. E. Rakel, ed., "Connr s Current Therapy" 1995, W.B. Saunders Co., Philadelphia, Pennsylvania, 1995, pages 682-691, on page 686 states that: "Antihistamines are weak bronchodilators and newer agents, many of which are not available in the United States, have some anti-inflammatory properties, they are not as effective as other medications available for the treatment of asthma, and so do not have A role in the routine management of asthma, they are mentioned here, however, to oppose the expressions inserted in many containers that antihistamines should not be used in patients with asthma.Its use in patients suffering from allergies in the respiratory tract It is not contraindicated if the patient has asthma and they may have a beneficial effect on asthma as well.Developed studies with doses for general treatments of cetiiizine allergic rhinitis of reduced sedative antihistamine drugs include those reported in the following articles: G. Bruttman and others "Protective Effect of Cetirizine in Patie nts Suffering from Folien Asthma ", (" Protective effect of cetirizine in patients suffering from pollen asthma ", Annals of Allergy, Vol. 64, pages 224-228 (1990); J. H. Diikman et al., "Prophylactic Treatment of Grass Pollen-Induced Asma with Cetirizine", (Prophylactic Treatment of Polyacid Asthma with Cetirizine), Clinical and Experimental Allergy, Vol. , pages 483-490 (1990); JA Grant et al., "Cetirizine in patients with seasonal rhinitis and concomitant asthma: Prospective, Randomized, Placebo-controiled trial", (Cetirizine in patients with seasonal rhinitis and concomitant asthma: Probable, a year, controlled, placebo trial) The Journal of Clinical Investigation and Clinical Illness, Vol. 95, pages 923-932 (1995); and DW Aaronson, "Evaluation of Cetirizine in Patients with Allergic Rhinitis and Perennial Asthma", (Evaluation of Cetirizine in patients with allergic rhinitis and perennial asthma) Annals of Allerqy, Asthma and Im unology (Annals of Allergy, Asthma and Immunology) , Vol. 76, pages 440-446 (1996). In general, cetirizine was found to cause some improvement in asthma symptoms, such as chest tightness, asthmatic wheezing, shortness of breath and cough, along with relief of rhinitis symptoms. However, there is no significant progress in lung function, according to measurements of FEV values and other parameters. Terfenadine has also been studied, according to reports by? .Taytard and others, "Treatment of bronchial aeth a with terfenadine; a randomized controlled trial", (Treatment of bronchial asthma with terfenadine: a randomized, controlled trial), Brirish Journal of Clinical Pharmacology (British Bulletin of Clinical Pharmacology), Vol. 24, pages 743-746 (1987); P. Rafferty et al., "Terfenadine, a potent Histamine Hi. Receptor Antagonist in the treatment of grass pollen sensitive asth", (Terfemadine, a potent histamine-receptor antagonist Hi) BriLish Journal of Clinical Pharmacoloqy, Vol. 30, pages 2 9-? 35 (1990); R. Wood-Baker et al., "A doubl e-bl i nd, placebo-controlled study of the effect of the specific histamine Hi-Antagonist Receptor, Terfenadine, in Chronic Severe Asthma", (A double placebo-controlled study of the effect of Histamine H? -receptor antagonist, terfenadine, in severe chronic asthma) British Journal of Clinical Pharmacology, Vol. 39, pages 671-675 (1995). Using twice the normal dose for allergic rhinitis, or 120 milligrams of terfenadine twice a day, a mild positive effect on lung function was obtained, at best. However, the dosing regimen used by Rafferty and others, 180 milligrams three times per day, resulted in higher PEF values at 5.5 percent during the morning and 6.2 percent during the night. Due to the known cardiotoxicity potential of this drug, perhaps routine administration of abnormal high doses is not adequate. A. Dirkesen and others, "Effect of a Non-Sedative Antihistaminic (Loratadine) in Modérate Asthma", (Effect of an anti-seizure antihistamine) (loradatin) Allerqy (Alerqia), Vol. 44, pages 566-571 (1989), reported on the results of a study that administered a treatment dose of normal allergic rhinitis of ~ loratadine (10 milligrams, once a day) to asthmatics. Patients who exhibited a decrease in asthmatic symptoms with the treatment, but who showed only small improvements in lung function, were described as not significant from the statistical point of view.

Decongestant drugs are often used to treat allergic rhinitis. The most significant of these are sympathomimetic amines that have an alpha adrenergic stimulating activity. Among the most widely used agents that are administered orally are) phenylpropanolamine, ephedrine and pseudoephedrine. Decongestants have been used for a long time in combination with antihistamines for the treatment of allergic rhinitis and other forms of rhinitis, and some of the publications mentioned above refer to studies of cctirizine and terfenadine which indicate that patients under study were allowed Clinical antihistamines, use pseudoephedrine for additional relief of symptoms. However, there is no unexpected benefit attributed to this use.

Ex act of the Invention The invention comprises a method for improving the lung function of a patient suffering from asthma, including the administration to the patient of a usual treatment for rhinitis, using effective amounts of lorata and a decongestant.

A preferred release is 1 pseudoephedrine, and a daily treatment is preferred to obtain the desired results of the invention, which includes 10 milligrams of loratadine and one of 240 milligrams of pseudoephedrine, administered in a suitable formulation of prolonged release to achieve effectiveness for 24 hours or two daily doses of 5 milligrams of loratadine and 120 milligrams of pseudoephedrine, administered in an extended-release formulation for 12 hours of effectiveness, or in up to four divided doses of immediate-release formulations for 24 hours , totaling 10 milligrams of loratadine and 240 milligrams of pseudoephedrine.

Especially, with the immediate release formulations, the individual drugs can be administered separately or in a combined dose form.

Brief Description of the Figures Figure 1 is a graphic representation of the morning data of PEF obtained in the clinical trial of the example. Figure 2 is a graphic representation of the evening PEF data obtained in the clinical trial of the example. Figure 3 is a graphic representation of the FEV data obtained in the clinical trial of the example.

Detailed description of the invention In this reference to the "usual treatment of rhinitis through the use of effective amounts" of a drug, it is intended to indicate those dosages that are approved by any relevant regulatory entity, such as the United States Food and Drug Administration (Department of Food and Drug Administration of the United States), in order to use the drug to treat the symptoms of allergic rhinitis. - References herein to "improve lung function" include an ease of gaseous exchange processes in the lungs, especially as shown clinically by improvements in values of FEV and / or PEF measured in a patient; said meflores will generally be accompanied by a reduction in the patient's perception of shortness of breath. Loratadine, chemically-ethyl-4- (8-chloro-5,6-dihydro-HH-ben or [5, 6] cyclohep- la [1,2-b] pyridin-11-i 1 den]. -pi peri di ncarboxi 1 ato with an empirical formula C22H23CIN2O2 and a molecular weight of 382.89, is a widely used antihistamine anti-seizure drug with an excellent safety profile.The active drug and its preparation are described in US Patent No. 4,282 The drug can be further prepared conveniently according to the process described in U.S. Patent No. 4,731,477 to Schumacher et al. For the purposes of the present invention, loratadine can be administered in any of the different dosage forms, including without limitation, tablet, capsules, syrups or injection, as with most drugs, for the convenience of the patient is preferable to use the tablet or capsule form for oral administration.An effective antihistamine dose of loratadine rocks between approximately 5 to approximately 40 milliqras a day. Due to the systemic average periods of loratadine and its active metabolites, the daily dose can be administered once a day every 24 hours or divided into 2, 3 or 4 equal portions so that the administration is balance with the frequency of a dose of decongestant drug. A typical daily dose of ioratadine to relieve the symptoms of allergic rhinitis is 10 milligrams. Schering Corporation of Kenilworth, New Jersey sells loratadine tablets of 10 milligrams under the CL? RITIN® brand. Useful decongestant drugs include topical decongestants and systemic decongestants. Topical decongestants are typically administered in the form of drops or in aerosols, such as nasal sprays, and contain drugs such as oxymetazoline, phenylephrine, naphazoline, xylometazoline, ephedrine, epinephrine, methylhexaneamine, tetrahydrozoline and xylometazoline. Topical decongestants should not be used for long-term therapies due to the eventual occurrence of rhinitis medicamentosa, which, generally, can only be treated by means of. the discontinued administration of the drug. Systemic decongestant drug compounds suitable for the practice of the invention include the sympathomimetic amines phenylpropanolamine, ephedrine, pseudoephedrine and phenylephrine, a reference herein to the drug specifically including, when necessary, pharmaceutically acceptable salts thereof. Pseudoephedrine is the most used, due to its balance favorable efficacy and safety; typically, hydrochloride, sulfate or other water-soluble salts are used to formulate products. Pseudoephedrine sulfate is chemically sulfate of [S- (R *, R *)] - a- [l (methylamino) ethyl] benzenemethanol, with an empirical formula of (C? 0HibNO) ¿H¿S04 and a molecular weight from 4? 8.54. Extraction of this Ma Huang compound, and chemical synthesis of the compound are well known in the art. For the purposes of the present invention, the pseudoephedrine salts can be administered in any of the various dosage forms, including without limitation, tablets, capsules, syrups or by injection; as with most drugs, oral administration in the form of a tablet or capsule will preferably be for the patient's convenience. Typically, pseudoephedrine sulfate or hydrochloride will be administered to adults in daily doses of 120 to 360 milligrams and to children in daily doses of 60 to 180 milligrams, to relieve the congestion of allergic rhinitis. However, the average systemic period of the pseudoephedrine is considerably shorter than that of the loratadma. In immediate release formulations, individual dosages of 60 milligrams are generally administered to an adult patient four times in a 24 hour period. However, a number of solid sustained release formulations, for example, are known in the art. to make effective the quantity of 120 milliqras of the drug during a period of 12 hours and to make effective the quantity of 240 milligrams during a complete period of 24 hours. It is not essential that loraladine and decongestant be administered together. For example, loratadine can be administered once per day, while the decongestant drug can be administered more frequently to maintain a therapeutic level of systemic drug. Even when the drugs are administered together, it is not necessary that they be present in the same formulation or dosage form. Formulations that combine doses of antihistamine drugs and decongestant drugs are well known in the art. For loratadine, these include a formulation containing 5 milligrams of loratadine and 60 milligrams of pseudoephedrine sulfate for the immediate release of the tablet coating, together with 60 milligrams of pseudoephedrine that is released at a controlled frequency from a matrix of tablet susceptible to dissolution, to provide effectiveness for a period of 12 hours; a useful product that is commercially available in the United States at Schering Corporation of Kenilworth, New Jersey under the brand name CLAR TIN-D® 12 hours. Another formulation incorporates 10 milligrams of loratadma for the immediate release of a tablet coating together with 240 milligrams of pseudoephearin, which is released at a controlled frequency from a tablet matrix susceptible to dissolution in order to provide activity for a period of 24 hours; this technique is described in U.S. Patent No. 5,314,697 to Kwan et al., and a useful product is available in the United States at Schering Corporation under the trademark CLARITIN-D® 24 hours. Said formulations in combination will preferably be for the majority of patients, for their own convenience. This invention will be explained below with reference to the following example, which in no way attempts to limit the scope of the claims expressed herein.

EXAMPLE A clinical trial was conducted, in which 193 adult patients suffering from asthma and rhinitis were randomly chosen to receive, either the product described above, CIARITIN-D® 12 hours or a placebo twice daily for six weeks, during the fall of the allergic season. All the patients had been using and They continued to use the albuterol bronchodilator during the study using a pressurized aerosol dispensing inhaler prescribed by doctors to control the symptoms of asthma. However, patients were not allowed to administer any other medication for rhinitis or asthma during that study. Patients were evted before starting the study by, inter alia, measurements with FEV and PEF indices to generate baseline data and evtions were repeated twice a week during the study. It was found that patients receiving the drug combination experienced a marked reduction, both in asthma symptoms and in rhinitis, compared to patients who only received placebo. Figure 1 shows the results of morning measurements of the PEF indices for patients receiving loratadine and pseudoephedrine sulfate (full line) and placebo (dotted line). The ordinate is ~ the average change of the PEF indices from the vs of the baseline, expressed in liters per minute. There was a very clear, statistically significant improvement during the study due to the administration of the drug combination. Figure 2 is a similar representation of the results of an evening measurement of the PEF indices for the patients, being the groups identified as was done previously. The visible, statistically significant improvement obtained during the study is the result of the administration of the combination of drugs. Figure 3 is a representation of the additional results, generated by measurements of FKV in the first second ("FEVi"). The oate shows the mean change of the FEVj values from the baseline, expressed in liters. Data from patients receiving pseudoephedrine sulfate and ioratadine are identified by the full line while data from patients receiving only placebo are represented by the dotted line. The improvement observed very clearly, statistically significant, in lung function during the study is due to the administration of the combination of drugs. - The magnitude of improvements in lung function shown herein will be important for the well-being of an asthmatic patient, regardless of whether or not the patient suffers from rhinitis.

Claims (12)

1. The use of loratadine and a decongestant for the preparation of medications to improve the lung function of a patient suffering from asthma, where the drugs contain customary amounts of loratadine and decongestant, effective for the treatment of rhinitis.

The use of claim 1, wherein the decongestant is selected from the group consisting of phenylpropanolamine, ephedrine, phenylephrine, pseudoephedrine or a combination of any two or more thereof.

3. The use of claim 1, wherein the decongestant consists of pseudoephedrine. .

The use of claim 3, wherein the pseudoephedrine is administered in an amount of about 60 to about 360 milligrams per day.

5. The use of claim 3, wherein the pseudoephedrine is administered in an amount of about 120 to about 240 milligrams per day.

6. The use of claim 1, wherein the loratadine is administered in an amount of about 5 to about 40 milligrams per day.

7. The use of claim 3, wherein the loratadine is administered in an amount of about 10 milligrams per day.

8. The use of claim 1, consists in administering approximately 10 milligrams of loratadine daily and approximately 120 to approximately? 40 milligrams of pseudoephedrine daily.

The use of claim 1, wherein loratadine and the decongestant are administered in separate compositions.

The use of claim 1, wherein loratadine and the decongestant are administered in a single composition.

The use of claim 1, wherein loratadine and the decongestant are administered in a single composition in which loratadine and a portion of the decongestant are present in a coating, and the remainder of the decongestant is present in an erodible matrix.

12. The use of claim 1, wherein loratadine and decongestant are administered in a single solid composition in which the loratadine is present in a coating and the decongestant is present in an erodible matrix. RESTRICTION OF THE INVENTION The invention encompasses a method for improving the lung function of a patient suffering from asthma, comprising the administration to the patient of effective amounts customary for the treatment of rhinitis, of loratadine and a decongestant Cal as pseudoeedin.