WO2005077371A1

WO2005077371A1 - Use of levocetirizine for the preparation of a drug

Info

Publication number: WO2005077371A1
Application number: PCT/EP2005/050543
Authority: WO
Inventors: Serge Kouzan
Original assignee: Ucb Farchim Sa
Priority date: 2004-02-12
Filing date: 2005-02-08
Publication date: 2005-08-25

Abstract

The present invention relates to a pharmaceutical use of levocetirizine for the prevention of symptoms or exacerbation of allergic asthma.

Description

Use of levocetirizine for the preparation of a drug

The present invention relates to the use of levocetirizine for the preparation of drugs effective for the prevention of exacerbation of asthma . International patent application 94/06429 describes a meth od utilising levocetirizine for the tre atment of allergic asthma. It has now surprisingly been found that levocetirizine possesses therapeutic properties which render it particularly useful in the prevention of exacerbation of asthma. These activities are not observed in the dextxocetirizin.e . The purpose of the invention concerns the prevention of exacerbation of asthma. The present invention is based on the unexpected recognition that administration of pharmaceutical compositions comprising levocetirizi ne, or a pharmaceutically acceptable s alt thereof to a patient prevents exacerbation of allergic asthma. The present invention encompasses a method for preventing exacerbation of allergic asthma which comprises administering to a patient a therapeutically effective amount of levocetirizine or a pharmaceutically acceptable salt thereof. The present invention also encompasses the use of levocetirizine or a pharmaceutically acceptable salt thereof for the preparation of a medic ament intended for the prevention of the symptoms of exacerbation of allergic asthma. The present invention relates to the use of levocetirizine or a pharmaceutically acceptable salt thereof for the preparation of a medicament intended for reduction of symptoms of allergic asthma, improving quality of life and pre vention of asthma exacerbation. The term "cetirizine" refers to the racemate of [2 -[4-[(4 chlorophenyl)phenylmethyl] -l-piperazinyl]ethoxy] -acetic acid and its dihydrochloride salt which is well known as cetirizine dihydrochl oride; its levorotatory and dextrorotatory enantiomers are known as levocetirizine and dextrocetirizine . Processes for preparing cetirizine, an individual optical isomer thereof or a pharmaceutically acceptable salt thereof have been described in European Patent 0 058 146, Great Britain Patent 2.225.320, Great Britain Patent 2.225.321, United States Patent 5,478,941, European Patent application 0 601 028, European Patent Application 0 801 064 and International Patent Application WO 97/37982. The term "levo cetirizine" as used herein means the levorotatory enantiomer of cetirizine. More precisely, it means that the active substance comprises at least 90% by weight, preferably at least 95% by weight, of one individual optical isomer of cetirizine and at most 10% by weight, preferably at most 5% by weight, of the other individual optical isomer of cetirizine. Each individual optical isomer may be obtained by conventional means, i.e., resolution from the corresponding racemic mixture or by asymmetric synthesis. Each individual optical isomer may be obtained from its racemic mixture by using conventional means such as disclosed in British patent application No. 2,225,3 1. Additionally, each individual optical isomer can be prepared from the racemic mixture by e nzymatic biocatalytic resolution, such as disclosed in U.S. Patents No. 4,800,162 and 5,057,427. The term "pharmaceutically acceptable salts" as used herein refers not only to addition salts with pharmaceutically acceptable non -toxic organic and inorganic acids, such as acetic, citric, maleic, succinic, ascorbic, hydrochloric, hydrobromic, sulfuric, and phosphoric acids and the like, but also its metal salts (for example sodium or potassium salts) or ammonium salts, the amine salts and the aminoacid salts. The best results have been obtained with levocetirizine dihydrochloride. By patient, we understand infant, children, adolescents and adults.

Preferably, the patients are subjects having an history of seasonal allergic rhinitis that became symptomatic du ring annual grass pollen season and/or an history of allergic asthma. More specifically the patients are subjects documented hypersensitive to local seasonal allergens and in particular grass pollen, and / or having documented pollen -induced asthma and in particular with clear exacerbation of symptoms at the grass pollen season . By the term "asthma", we understand a chronic inflammatory disease of the airways associated with an increase in airway hyper -responsiveness, variable airflow lirnitation and respiratory symptoms such as but not limited to, wheezing, breathlessness, difficulty breathing, chest tightness, coughing. By the term "exacerbation of asthma", we understand an increase in the severity of asthma symptoms or characteristics . Exacerbation can be seasonal or not. Asthma exacerbations can be characterized by worsening symptoms, airflow obstruction, and an increased requirement for rescue bronchodilators. By the term "allergic rhinitis", we understand a symptomatic disorder of the nose occurring after allergen exposure . Most frequent symptoms of allergic rhinitis include rhinorrhea, nasal obstruction, nasal itching, nasal pruritus, sneezing, ocular pruritus. By the term "prevention", we understand that the medicament is administered, in allergic asthmatic patients in a prophylactic manner, i.e. before the onset of the asthma exacerbation or before the onset of the asthma symptoms and preferably before the first onset of allergic asthma symptoms at each new potten season, i.e; before the outdoor level of the pollen inducing asthma symptoms or exacerbation starts to increase. Best results have been observed when the treatment takes place before the onset of the pollen season or at the onset of the pollen season . A therapeutically effective amount of levocetirizine or a pharmaceutically acceptable salt thereof is used to prevent or alleviate the effect of exacerbation of asthma. The dosage depends essentially on the specific method of administration and on the purpose of the prevention . The size of the individual doses and the administration program can best be determined based on an individual assessment of the relevant case. The methods required to determine the relevant factors are familiar to the expert. A preferred daily dosage provides from ab out 0,0005 mg to about 1 mg of levocetirizine or a pharmaceutically acceptable salt thereof, per kg of body weight per patient. A particularly preferred daily dosage is from about 0,001 to about 0.5 mg. The best results have been obtained with a daily do sage from about 0,005 to 0.5 mg per kg of body weight per patient. The dosage may be administered once per day of treatment, or divided into smaller dosages, for examples 1 to 4 times a day, and preferably 1' to 2 times a day, and administrated over about a 24 hours time period to reach the total given daily dose . Bests results have been obtained with an administration of a compositions of the invention are twice a day for infants and children; and 5 mg once a day for pre-adolescent, adolescent and adults. The exact dosages in which the compositions are administrated can vary according to the type of use, the mode of use, the requirements of the patient, as determined by a skilled practitioner. The exact dosage for a patient may be specifically adapted by a skilled person in view of the severity of the condition, the specific formulation used, and other drugs which may be involved. Pharmaceutical compositions used according to the present invention may be administered by any conventional means. The rout es of administration include intradermal, transdermal, slow release adininistration, intramuscular, oral and intranasal routes. Any other convenient route of adininistration can be used, for example absorption through epithelial or mucocutaneous linings. The pharmaceutical forms according to the present invention may be prepared according to conventional methods used by pharmacists. The forms can be administered together with other components or biologicaly active agents,- pharmaceuticaUy acceptable surfac tants, excipients, carriers, diluents and vehicles. The pharmaceutical compositions of the invention include any conventional therapeutical inert carrier. The pharmaceutical compositions can contain inert as well as pharmacodynamically active additives. Liquid compositions can for example take the form of a sterile solution which is miscible with water. Furthermore, substances conventionally used as preserving, stabilizing, moisture -retaining, and emulsifying agents as well as substances such as salts f or varying the osmotic pressure, substances for varying pH such as buffers, and other additives can also be present. If desired an antioxidant can be included in the pharmaceutical compositions. Pharmaceutical acceptable excipients or carriers for composi tions include saline, buffered saline, dextrose or water. Compositions may also comprise specific stabilizing agents such a s sugars, including mannose, mannitol and beta cyclodextrin. Carrier substances and diluents can be organic or inorganic substances, for example water, gelatine, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycol and the like. A prerequisite is that all adjuvants and substances used in the manufacture of the pharmaceutical compositions are nontoxic at the proposed dosage. Pharmaceutical compositions can be administered by spray inhalation. Any conventional pharmaceutical composition for spray inhalation administration may be used. Another preferred mode of administration is by aerosol. The pharmaceutical com position of the invention can also be formulated for topical application. The composition for topical application can be in the form of an aqueous solution, lotion or jelly, an oily solution or suspension or a fatty or emulsion ointment. The pharmaceutic al composition of the invention can also be used for slow prolonged release with a transdermal therapeutic system in polymer matrix or with an appropriate formulation for oral slow release. The pharmaceutical compositions according to the present inventio n may also be administered orally or rectally. They may also be administered by nasal instillation, aerosols or in the form of unguents or creams. The pharmaceutical compositions which can be used for oral administration may be solid or liquid, for example, in the form of uncoated or coated tablets, pills, dragees, gelatine capsules, solutions, syrups , drops and the like. For administration by the rectal route, the compositions containing the compounds of the present invention are generally used in the form of suppositories. The pharmaceutical forms, such as tablets, drops, suppositories and the like, are prepared by conventional pharmaceutical methods. The compounds of the present invention are mixed with a solid or liquid, non -toxic and pharmaceutic ally acceptable carrier and possibly also mixed with a dispersing agent, a disintegration agent, a stabilizing agent and the like. If appropriate, it is also possible to add preservations, sweeteners, coloring agents and the like. Preferably, the pharmac eutical compositions of the invention is administered in traditional form for oral administration, as film coated tablets, lozenges, dragees, and oral liquid preparation such as syrup. Best results have been obtained with an oral dosage form, in particu lar liquid formulations such as syrup or oral drops for children, and film -coated tablet for adults. As an Example of a composition according to the present invention, the following formulation of a film coated tablet is preferred: levocetirizine dihydrochloride, magnesium stearate, cellulose, lactose and silicon dioxide. As an Example of a composition according to the present invention, the following formulation of a syrup is preferred: levocetirizine dihydrochloride, methyl - and propylparaben, sacch arinum, and purified water. Preferably, the treatment is repeated at the onset of each new pollen season. Pharmaceutical compositions of the invention are useful to prevent the symptoms or exacerbation of allergic asthma. These compositions can alleviat e the effects of the symptoms or exacerbation of asthm . Pharmaceutical compositions of the invention are useful to prevent the re - occurence of the symptoms of allergic asthma before the onset of the pollen inducing asthma season. These compositions can alleviate the effects of the symptoms or exacerbation of allergic asthma. Another advantage of the invention is the ability of the process to improve quality of life and major symptoms of allergic rhinitis . The method of the invention is believed particul arly suited to use in patients suffering from allergic asthma. Another advantage of the invention is that levocetirizine dihydrochloride has a preventive treatment (seco ndary prevention) effect on re- occurrence of symptoms of rhinitis when administered before the pollen season onset . Another advantage of the invention is that levocetirizine dihydrochloride can be used for the preparation of a medicament intended for preventing rhinitis crisis Another advantage of the invention is that levocetirizine d ihydrochloride can be used for the preparation of a medicament intended for preventing and decreasing asthma symptoms. It is shown that levocetirizine dihydrochloride has a higher efficacy when administered during at least the 4 to 8 weeks preceding and during 8 weeks following the anticipated onset of the grass pollen season, in subjects suffering from seasonal aUergic rhinitis associated with pollen -induced asthma. An early tre atment of seasonal allergic rhin itis with levocetirizine is effective in improving the major symptoms of rhinitis. When patients are suffering from seasonal allergic rhinitis associated with pollen-induced asthma the benefit can be for both allergic rhinitis and allergic asthma symptoms or exacerbation. According to the invention, the early treatment with an effective amount of levocetirizine prevents the occurrence of allergic asthma symptoms or exacerbation at the pollen season onset. According to the invention, an early treatment with levocetirizine in subjects suffering from seasonal allergic rhinitis associated with pollen -induced asthma decreases severity of symptoms or exacerbation of both rhinitis and asthma. The invention is further defined by refe rence to the following example. Example This trial is a double -blind, paralle 1, placebo controlled, 3 arms, randomized study for evaluation of the efficacy and safety of levocetirizine 5 mg oral tablets, administered more than 4 weeks before and during 8 II propose some weeks not a fixed number e;g; not than 4 weeks following the anticipated onset of the grass pollen season, in subjects suffering from Seasonal Allergic Rhinitis associated with poUen induced Asthma. The pollen season is when the pollen(s) inducing asthma or rhinitis, start to increase in the air. This" study is designed to find out in subjects suffering from Seasonal Allergic Rhinitis associated -with pollen -induced asthma, if an early treatment before the onset of the pollen season could have an impact on the symptoms or exacerbation of rhinitis and asthma. Treatment (LCTZ 5mg/day or Placebo) is initiated 8 weeks before the anticipated onset of grass pollen season, and pursued for 8 weeks thereafter. In the third arm the LCTZ administration started only at the anticipated onset of the grass pollen season, a placebo being administered during the 8 weeks before the anticipated onset of the grass pollen season. LCTZ means levocetirizine d ihydrochloride . The primary objective of the study is to evaluate the efficacy of LCTZ 5 mg/day, as an early started treatment, versus pi acebo to reduce some of the majors symptoms of rhinitis observed over the 12 ^■week period following the randomization visit. The evaluation of the efficacy was done by the analysis of the T4SS (sum of the scores of the severity of sneezing, rhinorrhea, nasa 1 pruritus and ocular pruritus). The secondary objective is to evaluate the efficacy of LCTZ 5 mg/day, as an early started treatment, versus placebo to allevia te the pollen-induced symptoms or exacerbation of asthma, observed over the 12 weeks after rando mization. It is also to evaluate the efficacy of LCTZ 5 mg/day, as an early started treatment, versus placebo to reduce the symptoms of rhinitis and asthma over the first 4 season weeks and during the entire observation period following the actual onset of the grass pollen season. It is also to evaluate the efficacy of LCTZ 5 mg/day, as an early started treatment, versus placebo to delay the onset of pollen -induced symptoms /exacerbation of rhinitis and asthma. It is also to evaluate the efficacy of LCTZ 5 mg/day, as an early started treatment, versus placebo to reduce the symptoms of rhinitis as assessed through the T5SS (including nasal congestion), over the 12 weeks after randomization, over the first 4 season weeks (each week and overall) and during t he entire observation period following the actual onset of the grass pollen season . It is also to evaluate the efficacy of LCTZ 5 mg/day, as an early started treatment, versus placebo to reduce the use of rescue tre atment for rhinitis and allergic asthma symptoms or exacerbations . The objectives are also to compare the efficacy of LTCZ 5mg/day started 8 weeks before the anticipated onset of the grass pollen season versus LTCZ 5mg/day started at the anticipated onset of the grass pollen season, to evaluate the effect of LCTZ 5mg/day on direct and indirect cost parameters for rhinitis, asthma and other co-morbidities before and after the actual on set of the grass pollen season. Subjects included in the study are aged 12 or more, male or female; having at least 2-year history'of Seasonal Allergic Rhinitis that became symptomatic during annual grass pollen season; are documented (within the year) hyp ersensitivity (RAST ≥ Class 3 or skin test ++) to local seasonal allergens (grass pollen); having documented pollen -induced Asthma (clear exacerbation of symptoms at the grass pollen season). The subjects had at least one asthma exacerbation over the last 3 years. The subjects are without acute ongoing exacerbation of asthma or allergic rhinitis present at the entry into the study. Primary and secondary variables were used to compare arm A (placebo / placebo) versus arm B (levocetirizine / levocetirizine). The primary efficacy variable is the mean Total 4 rhinitis Symptoms Score (T4SS: sum of the scores for the severity of sneezing, rhinorrhea, nasal pruritus and ocular pruritus) over the first 12 weeks after randomization. For rhinitis, the evaluation is dealt with mean T5SS (T4SS + nasal congestion), mean individual symptoms of rhinitis, t ime to onset of the first rhinitis episode, percentage of days with acute rhinitis symptoms (T4SS ≥ 6 or T5SS ≥ 8) and use of (yes/no) and percentage of days with rescu e treatment for rhinitis. For asthma, the evaluation is dealt with mean TASS (sum of scores for the severity of coughing, whe ezing and breathing difficulty), p ercentage of days with nocturnal asthma, mean individual symptoms of asthma, p ulmonary function test FEV1 measured at each visit, pulmonary function test: mean P EF-morning and mean PEF-evening, time to onset of the first asthma exacerbation, p ercentage of asthma symptoms free days, u se of (yes/no) and percentage of days wi th rescue treatment for asthma., mean number of short -acting β2-agonists puffs per day. Rhinitis and asthma variables (related to the TASS, nocturnal asthma and use of short-acting β2-agonists) are evaluated within the following time frame: Over the first 12 weeks after randomizatio n: primary variable for rhinitis ; over each of the first 4 season weeks after the actual onset of the grass pollen season (season week 1, season week 2, season week 3 and season week 4) ; over the first 4 season weeks (season week 1 through season week 4) after the actual onset of the grass pollen season; over the entire observation period following the actual onset of the grass pollen seaso . With the present results, it is demonstrated that levocetirizine treatment in patients with already established allergic asthma and/ or seasonal allergic rhinitis can reduce the severity of allergic asthma symptoms :exacerbations , delay the onset, reduce the number and the severity of allergic asthma symptoms/ exacerbations. It is demonstrated that levocetirizine dihydrochloride is able to reduce allergic asthma symptoms severity by prophylactic treatment starting before the presumed dnset^'bf the ^"allergic season (and "continued treatment during the season) in patients suffering from seasonal allergic rhinitis and/ or allergic asthma. It is demonstrated that levocetirizine dihydrochloride is able to reduce asthma disease burden in patients suffering from asthma .

Claims

1. Use of levocetirizine or a pharmaceutically acceptable salt thereof for the preparation of a m edicament intended for preventing symptoms or exacerbation of allergic asthma.

2. Use of levocetirizine or a pharmaceutically acceptable salt thereof for the preparation of a medicament intended for decreasing the symptoms of exacerbation of allergic asthma.

3. Use of levocetirizine or a pharmaceutically acceptable salt thereof for the preparation of a medicament inte nded for delaying the onset and reducing number and severity of allergic asthma symptoms/ exacerbations in subjects with already established allergic asthma and/ or seasonal allergic rhinitis.

4. Use of levocetirizine or a pharmaceutically acceptable salt thereof for the preparation of a medicament intended fo r treating subjects suffering from seasonal allergic rhinitis associated with pollen -induced asthma.

5. Use of levocetirizine or a pharmaceutically acceptable salt thereof for the preparation" of a medicament intende d for reducing asthma symptoms severity by prophylactic treatment starting weeks before the presumed onset of the allergic season in patients suffering from seasonal allergic rhinitis and/or allergic asthma.

6. Use of levocetirizine or a pharmaceutically acceptable salt thereof for the preparation of a medicament in tended for reducing asthma disease burden in patients suffering from asthma.

7. Use according to any one of claims 1 to claim 6 , wherein the salt is the levocetirizine dihydrochloride.

8. Use according to any one of claims 1 to 7 , wherein the medicament is adapted for administration of a daily dosage from about 0, 0005 mg to about 1 mg of said levocetirizine or said pharmaceutically acceptable salt thereof, per kg of body weight per patient.

9. Use according to any one of claims 1 to 8, wherein the treatment takes place before the onset of the pollen season .

10. Use according to any one of claims 1 to 8, wherein the treatment takes place at the onset of the pollen season .