MXPA06008937A - Combination of anticholinergics and inhibitors of phosphodiesterase type 4 for the treatment of respiratory diseases - Google Patents

Abstract

The present invention relates to a combination of an inhaled / oral PDE 4 inhibitor in combination with inhaled anticholinergic bronchodilators (muscarinic receptor antagonists), preferentially Roflumilast or AWD-12-281 and R,R-glycopyrrolate, for symptomatic or prophylactic treatment of respiratory diseases, especially those accompanied by obstruction or inflammation such as chronic obstructive pulmonary disease (COPD) or asthma. It further comprises the presentation of this combination in a locally applied (inhaled) formulation and application in an inhalation device for instance in the Novolizer®.

Description

COMBINATION OF ANTICOLINERGICOS AND INHIBITORS OF TYPE 4 PHOSPHODESTERASE FOR THE TREATMENT OF RESPIRATORY DISEASES DESCRIPTIVE MEMORY The present invention relates to a combination of an inhaled / oral PDE 4 inhibitor in combination with inhaled anticholinergic bronchodilators (muscarinic receptor antagonists), preferably Roflumílast of AWD-12-281 and R, R-glycopyrrolate, for the symptomatic treatment or prophylactic of respiratory diseases, especially those accompanied by obstruction or inflammation such as chronic obstructive pulmonary disease (COPD) or asthma. It also comprises the presentation of this combination in a locally applied (inhaled) formulation and its application in an inhalation device for example in the Novolizer®. Bronchial asthma, which affects up to 10% of people in industrialized nations, is characterized by bronchoconstriction, chronic inflation of the respiratory tract, hyperreactivity to the respiratory tract and mucosal edema. Airway remodeling and altered non-cholinergic and non-adrenergic neurotransmission can contribute to irreversible airway obstruction and reduced lung function. Bronchial asthma has emerged as a major public health problem throughout the world in the last 20 years. Although the data indicate that current therapies against asthma will lead to a limited decrease in mortality rates, it continues to be a major health care problem (Mannino et al., Surveill Summ 2002; 51: 1-13). It continues to be one of the main causes of preventable hospitalization in the world and adds several million days of work lost. In addition to the increased prevalence of asthma, the costs associated with this disease have also risen dramatically. Chronic obstructive pulmonary disease (COPD) is also very common. This disease is characterized by progressive airflow limitations accompanied by inflammatory reactions. From a review of data from around the world, it is clear that tobacco is not the only cause of COPD. A growing age worldwide is also a certain risk factor. The prevalence of COPD varies, can be between 3% and 10% with a constant upward trend. Although COPD is a major cause of illness and death, its recognition as a public health problem has evolved slowly despite the increasing mortality rate for COPD and the decrease in death rates for most cardiovascular diseases (Hurd, Chest 2000; 117 (2 Suppl): 1S-4S). Additionally, COPD imparts a substantial economic burden on individuals and society. There is now strong evidence that airway inflammation is a predominant underlying problem in patients with asthma. The pathophysiology of asthma involves an intricate network of molecular and cellular interactions, although the contribution of each individual factor is probably different from patient to patient depending on the environment and the stimulus. Important participants in the development of an asthma genotype include the triggering stimulus such as the allergens themselves, cells such as T cells, epithelial cells and mastoid cells that produce a variety of cytosines including IL-5, GM-CSF, IL-3, IL -4 and IL-13 and chemokines such as eotaxin, adhesion molecules, etc. Recent advances in understanding the inflammatory immunological mechanisms of asthma have indicated many potential therapeutic avenues that can prevent or reverse the abnormalities underlying asthma. Currently, pharmacotherapy is the main route for the treatment of asthma. Adrenoreceptor agonists of inhaled ß2 of long and short duration are available. Short-acting ß2 adrenoceptor agonists are now used on a demand basis for rapid relief of symptoms. In recent years, long-acting inhaled β2-adrenoreceptor agonists have played an increasing role in the management of asthma, particularly in patients with moderate to severe asthma. Antimuscarinic drugs are less effective in relieving an asthma attack than adrenoreceptor agonists of ß2 (Rodrigo and Rodrigo, Chest 2002).; 121: 1977-87). However, with the introduction of the new anticholinergic tiotropium, the use of anticholinergics in respiratory diseases will increase enormously. Inhaled glucocorticoids have become the main route of therapy in chronic asthma. They are the most clinically effective treatment but can produce serious side effects and, even more, be inefficient in asthmatics resistant to corticosteroids. In general, much less is known about the pathogenesis of COPD than asthma. Recent studies have greatly expanded the understanding of underlying pathogenetic mechanisms of COPD. Thus, there is a consensus that COPD is also an inflammatory disease. From the current pathogenetic point of view, neutrophil granulocytes, CD8 + lymphocytes and macrophages with their mediators play a probably crucial role in the pathogenesis of COPD. The current administration focuses on improving the lung function of patients suffering from COPD. The first step in this procedure is cessation of smoking. There is evidence that the reduction or cessation of smoking may result in improvement of certain respiratory parameters. Bronchodilators (β2-adrenoreceptor agonists and anticholinergics) are now the main route of symptomatic therapy. Adrenoreceptor agonists of short and long acting ß2 such as salbutamol, fenoterol, salmeterol, formoterol are established therapeutic in the management of symptomatic COPD. Of the short-acting antimuscarinic drugs, sponsorship is widely used. Recently, triotopium, a long acting anticholinergic with a certain preference to M3 muscarinic receptors has been introduced worldwide (Hansel and Barnes, Drugs Today (Barc) 2002; 38: 585-600). Anticholinergic agents can be used effectively in the treatment of COPD in horses in the same way. Ipratropium in a dose of 2400 μg / horse is an effective bronchodilator in horses with COPD (Duvibier et al., Equine Vet J 1999; 31: 20-4, Bayly et al, Equine Vet J. 2002 Jan; 34 (1): 36-43). Currently, COPD anti-inflammatory therapy is unresolved. The use of systemic and inhaled glucocorticoids for COPD has increased significantly in the last 20 years. They have been tested under the premise that interference with inflammation in COPD should alter the course of the disease. Although inhaled corticosteroids have a proven benefit in the management of asthma, but until recently, their efficacy in non-asthmatic COPD related to smoking had no evidence (Bonay et al., Drug Saf 2002; 25: 57-71). Inhaled glucocorticoids have a relatively short impact on the inflammatory processes that characterize COPD (Adcock and Cheng, Curr Opin Investing Drugs 2002; 3: 58-60). Therefore, it is indicated whether there is an important bronchodilator response or the patient has a more severe disease with frequent exacerbations (Alsaeede et al Am J Med 2002; 113: 59-65). Airway obstruction and airway inflammation are characteristic of asthma as well as COPD. Although airway inflammation in asthma and COPD, respectively, involves different types of cells, both diseases are of a chronic inflammatory nature associated with cell infiltration and activation. Although bronchial asthma is predominantly characterized by eosinophils and CD4 lymphocytes, neutrophil granulocytes, CD8 lymphocytes and macrophages appear to play an important role in the pathogenesis of COPD. Thus, PDEs that are involved in smooth muscle relaxation and that are also found in eosinophils as well as neutrophils and other inflammatory and immunocompetent cells are probably an essential element of the advancement of both diseases. Many of the segments and mechanisms involved in the pathogenesis of these diseases are inhibited by activating the cyclic nucleotide signaling pathway. Thus, an increase in intracellular cAMP interferes with the activation of eosinophilic lymphocytes, neutrophils and mastoid cells, and blocks the production of cytosine, cell replication and cellular chemotaxis at sites of inflammation.

Additionally, the activation of the cAMP signaling pathway in the smooth muscle cell of the respiratory tract promotes relaxation and blocks the replication of smooth muscle cells (Tomlinson et al., Biochem Pharmacol 1995; 49: 1809-19), thus avoiding remodeling of the respiratory tract observed in the chronic stage of diseases. PDE4 belongs to a superfamily of at least 11 isozymes that catalyze the hydrolysis of cAMP and / or cGMP. PDE4 is a major cAMP metabolizing enzyme in immune and inflammatory cells, smooth muscle of the respiratory tract and pulmonary nerves. Based on their cellular and tissue distribution, selective inhibitors of this enzyme suppress the release of mediator from inflammatory cells (Hatzelmann and Schudt, J Pharmacol Exp Ther 2001; 297: 267-79, Marx ei ai, Pulm Pharmacol Ther 2002; 15: 7-15, Kuss et al, J Pharmacol Exp Ther 2003; 307: 373-85). They show a broad spectrum of activity in animal models of COPD (Billah ef ai, J. Pharmacol Exp Ther 2002; 302: 127-37, Kuss ei ai, J Pharmacol Exp Ther 2003; 307: 373-85). Side effects associated with the class, mainly nausea and emesis, seem to have been at least overcome by so-called "second generation" PDE4 inhibitors. Current clinical studies convincingly indicate the therapeutic utility of PDE4 inhibitors in both asthma and COPD (Dyke and Montana, Expert Opin Investing Drugs 2002; 11: 1-13, Grootendorst et al., Pulm Pharmacol Ther 2003; 16: 341-7 , Spina, Drugs 2003; 63: 2575-94). Efforts to minimize or eliminate the adverse events mentioned above sometimes associated with PDE4 inhibitors have included creating inhibitors that do not penetrate the central nervous system and administer PDE4 inhibitors by inhalation rather than orally. The inhibitors of the PDE4 isoenzyme reduce inflammatory processes in both asthma and COPD. Thus, these effects of PDE4 inhibitors result in improved bronchial function in patients suffering from bronchial asthma or COPD. Anticholinergic medications have been accepted as an important treatment modality in COPD and in chronic asthma. The anticholinergic bronchodilator, the muscarinic receptor antagonist, used in this invention will be a long-acting compound. Any compound of this type can be used in this combination therapy approach. By long acting it is meant that the drug will have an effect on the bronchi that lasts about 12 hours or more, up to 24 hours. The recently approved long-acting inhaled anticholinergic drug, tiotropium, produces sustained bronchodilation over 24 hours a day (Calverley et al., Thorax 2003; 58: 855-60). Glycopyrrolate belongs to drugs called anticholinergics and antagonizes the neurotransmitter acetylcholine at its receptor site. This effect leads to considerable bronchodilation and a lower secretion of mucus. Glycopyrrolate, a quaternary ammonium compound, consists of four stereoisomers. It is efficiently absorbed from mucous membranes, thus reducing anticholinergic side effects (Ali-Melkkila et al., Acta Anaesthesiol Scand 1993; 37: 633-42). Glycopyrrolate has no selectivity in its binding to M3 receptors. However, kinetic studies showed that glycopyrrolate slowly dissociates from M3 muscarinic receptors (Haddad et al., Br J Pharmacol 1999; 127: 413-20). Similar to tiotropium, this behavior explains the relative selectivity of the glycopyrrolate receptor and its prolonged duration of action. Undoubtedly, there is evidence that racemic glycopyrrolate produces considerable and long-lasting bronchodilator effects in both asthmatic and COPD patients (Walter et al., Chest 1987; 91: 49-51, Schroeckenstein et al., J Allergy Clin Immunol 19881; : 115-9, Gilman et al., Chest 1990; 98: 1095-8, Cydulka and Emerman, Ann Emerg Med 1995; 25: 470-3). Since asthma and COPD are characterized by major mucus secretions, the antisecretory effect of anticholinergics such as glycopyrrolate is an additional advantage for its use in the therapy of these diseases. Current treatments for asthma and COPD are not satisfactory. Due to the high prevalence of these diseases, more effective and more convenient therapeutic interventions are highly desirable. The problem underlying the present invention was to provide such improved therapeutic alternatives with greater efficiency and fewer side effects. The problem is solved by a new combination drug comprising a PDE4 inhibitor and an anticholinergic, which is superior to monocompounds with respect to therapeutic efficacy, onset and duration of action, or side effects. Surprisingly it has been revealed that the use of a combination comprising topical (inhaled) anticholinergics such as racemic glycopyrrolate, or its enantiomers, especially R, R-glycopyrrolate, or their diastereomers or their physiologically acceptable salts and inhaled / oral phosphodiestearase inhibitors (PDE) ) 4 as AWD12-81 or roflumilast or its physiologically acceptable salts results in a more effective and safe treatment of bronchial asthma and chronic obstructive pulmonary diseases (COPD) that allows lower doses or decreases side effects. The pharmacodynamic properties of both classes of drug, anticholinergics (especially R, R-glycopyrrolate) and PDE4 inhibitors complement each other and result in a more effective treatment of the aforementioned diseases. Additionally, patient compliance also increases. The PDE4 inhibitor useful in this invention can be any compound known to inhibit the PDE4 enzyme and which has been found to act as highly specific PDE4 inhibitors and which is preferably used for inhalation. For example, preclinical and clinical studies with the highly potent and selective PDE4 inhibitor AWD 12-281 showed that this compound has good preclinical and clinical efficacy. In Brown Norway rats, AWD 12-281 suppressed airway eosinophilia induced by allergens with an ID50 of 7 μg / kg when administered intrapulmonary. The ID50 value of the known corticosteroid beclomethasone was comparable (0.1 μg / kg). Due to its unique metabolic profile, the compound has an adequate safety profile after topical administration (nasal or inhaled). When AWD 12-281 is given to dogs by inhalation, no emesis was induced to the highest feasible dose (15 mg / kg) which indicates that AED 12-281 is useful for the inhaled treatment of asthma and COPD (Kuss et al. , J Pharmacol Exp Ther 2003; 307-373-85).

Experimental part We investigated the influence of R, R-glycopyrrolate in combination with PDE4 inhibitors on TNF secretion when using human peripheral blood mononuclear cells (PBMC). The study was approved by our Institutional Ethics Committee in accordance with the International Declarations of Helsinki and Tokyo. PBMC were isolated from heparinized blood samples from healthy donors by density gradient centrifugation. An equal volume of Hanks pH regulator (Life Technologies, Heidelberg, Germany) is added to heparinized whole blood samples. 15 ml of Histopaque-1077 (Sigma, Deisenhofen, Germany) were coated with a maximum of 40 ml of blood / Hanks mixture which was centrifuged for 30 minutes at room temperature (2000 rpm). A visible band containing PBMC is transferred to a fresh tube and washed twice with Hanks pH regulator. Finally, the cells were seeded in RPMl 1640 medium (Life Technologies, Heidelberg, Germany) with Glutamax I (Gibco BRL, Eggenstein) and 10% fetal calf serum (Boehringer Mannheim, Penzberg, Germany). After being isolated, the PBMC were cultured in RPMl 1640 medium supplemented with 10% fetal calf serum (FCS) at 37 ° C, 5% CO2 overnight. The PBMC were isolated from other cells by an adhesion method, the non-adherent cells were removed by changing the medium. Cells were resuspended at 10 6 cells / ml and incubated in 500 μl volumes in 24-well tissue culture plates (Falcon Becton Dickinson Labware) at 37 ° C, 5% CO2. After pre-incubation with test substances (0.5 μl / 500 μl medium) for 30 minutes, the cells were stimulated with lipopolysaccharide (LPS) (1 μg / ml). At the indicated times the cells were pelleted by centrifugation, the supernatants were harvested and kept frozen at -80 ° C until the determination of the protein; the cells were used by RLT lysis pH regulator (Quiagen, Hilden, Germany) and frozen at -80 ° C until analysis. Cytokine measurements in culture supernatants are performed by sandwiching ELISA using adapted antibody pairs (Pharmingen, Heidelberg, Germany). The ELISA plates (Maxisorb, Nunc) were coated overnight with an anti-cytosine monoclonal antibody (mAb) in 0.1 M carbonate pH buffer, pH 9.5. After washing, the plates are blocked with a test diluent (Pharmingen, Heidelberg, Germany) for 1 hour and washed again. Samples of appropriately diluted and standard supernatants are distributed in duplicate and the plates are incubated for 2 hours at room temperature. The plates are washed, incubated for 1 hour with a support detector (biotinylated anti-cytokine antibody and Avidin-horseradish peroxidase conjugate). After washing, the substrate is added (TMB and hydrogen peroxide). The reaction is stopped by adding 1 M HsPO. The plates are read at 450 nm (reference 570 nm) in a microplate reader (Dynatech). The results are expressed as a percentage of the level of control of cytokine production by cells stimulated in the absence of the compound. After stimulation with LPS, the release of basal TNFa from monocytes increased from 328 pg / ml to 7,258 pg / ml. R, R-glycopyrrolate only did not influence the release of TNFα induced by LPS up to 10 μmoles / l. The PDE4 inhibitor rolipram inhibited the release of TNFa in a concentration-dependent manner. The CI35 value of rolipram gave an amount of 68.9 ± 15.2 nmoles / l. The simultaneous addition of 10 μmoles / l of R, R-glycopyrrolate surprisingly and significantly reduced CI35 to 1.70 ± 1.18 nM (p = 0.0151). These results show that R, R-glycopyrrolate improves the anti-inflammatory activity of PDE4 inhibitors significantly and surprisingly in an additive manner. Both inhaled / oral PDE4 inhibitors and anticholinergic inhibitors can be effectively used in the treatment of various diseases of the respiratory tract of horses. Activated neutrophils are grouped in the lungs of horses with COPD which can contribute to inflammation and damage to the lungs. It has been shown that PDE4 inhibitors can reduce neutrophil activation in vivo in horses with COPD (Rickards et al., J Vet Pharmacol Ther 2001 24: 275-81). The combination therapy contemplated by this invention comprises administering a PDE4 inhibitor with a long-acting anticholinergic bronchodilator to prevent the onset of a pulmonary disease event or to treat an existing condition and to reduce inflammation of the airways. The compounds can be administered together in a single dose form. Or they can be administered in different dosage forms. These can be administered at the same time. Or these may be administered close or separately, so that a drug is administered in the morning and the second drug is administered at night. The combination can be used prophylactically or after the onset of symptoms. In some cases the combination or combinations can be used to prevent the progression of a lung disease or to stop the consumption of a function such as lung function. These drugs, the anticholinergics and the PDE4 inhibitors, are generally administered as an aerosol with or without propellants, or as an inhaled powder, for example with the Novolizer®. This invention contemplates the co-administration of drugs in a delivery form such as an inhaler, which places the drugs in the same inhaler. The formulations are within the skill of the person skilled in the art (for example, they contain excipients such as lactose monohydrate). The active ingredients can be given 1 to 8 times a day, enough to present the desired activity. Preferably, the active components are given about once or four times a day, more preferably once or twice a day. The PDE4 inhibitor can be administered in an amount between 200 and 5,000 μg / day to an adult human, preferably from 500 to 2,000 μg / day depending on the intensity of airway inflammation. The PDE4 inhibitor, for example roflumilast, can be administered in an inhaled or oral form. The inhaled anticholinergic drug, racemic glycopyrrolate, one of its enantiomers, especially R, R-glycopyrrolate or one of its diastereoisomers or mixtures thereof and their salts, solvates and hydrates can be administered in an amount of between 5 and 500 μg / day in human adults preferably 15 to 300 μg / day. A dose scale between 5 and 100 μg / day is especially preferred. It is contemplated that both active agents can be administered at the same time, or very close in time. Alternatively, a drug can be taken in the morning and one later during the day. Or in another scenario, a drug can be taken twice a day and the other once a day, either at the same time while a dose occurs twice a day, or separately. Preferably both drugs can be taken together at the same time. For veterinary use, the anticholinergic, especially R, R-glycopyrrolate can be given to horses in an amount of 1-32 μg / kg / day, preferably between 4 and 16 μg / kg / day alone or in combination with an inhaled PDE4 inhibitor administered in an amount of between 4 and 100 μg / day in adult humans, preferably 10 to 40 μg / day depending on the intensity of airway inflammation. The invention is illustrated but not restricted to the following example. Inhalation powder with 50 μg of R, R-glycopyrrolate and 500 μg AWD 12-281 per individual dose. An amount of 50 g of R, micronized R-glycopyrrolate is mixed with 100 g of alpha lactose monohydrate, the mixture is given in a sieve of a mesh size of 0.5 mm and again finely mixed. 500 g of AWD 12-281 micronized is mixed with 1000 g of alpha lactose monohydrate, the mixture is given in a sieve of a mesh size of 0.8 mm and again mixed finally. The two mixtures received are mixed and filled with alpha lactose monohydrate at 12000 g. Subsequently, it is mixed again and the powder mix received is filled into powder inhalers that release 12 mg of powder per individual dose. Per individual dose, 50 μg of R, R-glycopyrrolate and 500 μg of AWD 12-281 are released from a powder inhaler and delivered to the patient's airway.

Claims (17)

NOVELTY OF THE INVENTION CLAIMS

1. - Combination of topical R, R-glycopyrrolate or its physiologically acceptable salts with phosphodiesterase (PDE) 4 inhibitors or their physiologically acceptable salts for the treatment of respiratory diseases, including bronchial asthma and chronic obstructive pulmonary disease (COPD).

2. The combination according to claim 1, further characterized in that the phosphodiesterase (PDE) 4 inhibitors are selected from the group comprising Roflumilast or AWD12-281 or their physiologically acceptable salts.

3. The combination according to claim 2, further characterized in that the phosphodiesterase inhibitor (PDE) 4 is Roflumilast or its physiologically acceptable salts.

4. The combination according to claim 2, further characterized in that the phosphodiesterase inhibitor (PDE) 4 is AWD 12-281 or its physiologically acceptable salts.

5. The combination according to any of claims 1 to 4, further characterized in that the daily dose of R, R, -glycopyrrolate is from 5 to 500 μg, preferably from 15 to 300 μg and the daily dose of the PDE4 inhibitor is it finds between 200 to 5,000 μg / day preferably 500 to 2,000 μg / day.

6. The combination according to any of claims 1 to 4, further characterized in that the daily dose of R, R-glycopyrrolate is from 5 to 100 μg, and the daily dose of the PDE4 inhibitor is between 200 and 5,000 μg. / day, preferably 500 to 2,000 μg / day.

7. Pharmaceutical compound for the treatment of asthma or respiratory diseases containing topical R, R-glycopyrrolate or its physiologically acceptable salts and at least one inhibitor of phosphodiesterase type 4 or its physiologically acceptable salts.

8. The pharmaceutical composition according to claim 7, characterized in that the two active substances are available in a dispersion of appropriate particle size when inhaled.

9. The pharmaceutical compound according to claim 7, further characterized in that it is a. inhalable spray with or without propellant.

10. The pharmaceutical composition according to claim 7, further characterized in that it is an inhalable dry powder.

11. The pharmaceutical composition according to claim 7, further characterized in that it is a suspension or an inhalable solution.

12. The pharmaceutical composition according to any of claims 7-11, further characterized in that it contains R, R-glycopyrrolate or its physiologically acceptable salts and at least one phosphodiesterase type 4 inhibitor or its physiologically acceptable salts, presented in an inhaler.

13. The pharmaceutical composition according to claim 12, further characterized in that it contains R, R-glycopyrrolate and AWD 12-281 or its physiologically acceptable salts.

14. The pharmaceutical composition according to claim 12, further characterized in that it contains R, R-glycopyrrolate and Roflumilast or their physiologically acceptable salts.

15. The pharmaceutical composition according to any of claims 7-14, further characterized in that the active substances are present in a fixed or free combination for simultaneous, sequential or separate administration together with the usual excipients and additives in a pharmaceutical form suitable for application by inhalation.

16. The use of a combination of topical R, R-glycopyrrolate or its physiologically acceptable salts and at least one phosphodiesterase type 4 inhibitor or its physiologically acceptable salts to prepare a medicament for the treatment of asthma / allergies and / or respiratory diseases in mammals.

17. - The use as claimed in claim 16, wherein the mammal is a human or a horse.