Asthma is a major cause of chronic morbidity and mortality, with an estimated 300 million affected individuals worldwide and 2, 50,000 annual deaths attributed to the disease. People of all ages in most countries are affected by this chronic disease.
Asthma is a chronic inflammatory disorder of the airways associated with airway hyper responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. An increased inflammatory response is a major part of the pathophysiology of acute asthma, and regular preventive treatment is important.
Chronic obstructive pulmonary disease (COPD) is a severe respiratory condition that is increasing in prevalence worldwide. In India, the estimated prevalence is about 12.36 million. It is currently the fourth leading cause of death in the UK & US, and predicted to rank third in the global impact of disease by the year 2020.
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease state characterized by air flow limitation that is not fully reversible. The airflow obstruction is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs it also produces significant systemic consequences. COPD is associated with mucus hyper secretion, emphysema, bronchiolitis.
Therapy for the treatment and/or prevention of asthma and chronic obstructive pulmonary disease (COPD) currently includes the use of bronchodilators such as beta2-agonists, anticholinergics and steroids.
More specifically asthma, COPD and other related disorders have been known to be treated with beta2-agonist as they provide a bronchodilator effect, resulting in relief from the symptoms of breathlessness. Beta2-agonists can be short acting for immediate relief, or long acting for long term prevention of asthma symptoms.
Long acting β2-agonists improve lung function, reduce symptoms and protect against exercise-induced dyspnea in patients with asthma and COPD. Long acting β2-agonists induce bronchodilation by causing prolonged relaxation of airway smooth muscle. In addition to prolonged bronchodilation, long acting β2-agonists (LABAs) exert other effects such as inhibition of airway smooth-muscle cell proliferation and inflammatory mediator release, as well as non smooth-muscle effects, such as stimulation of mucociliary transport, cytoprotection of the respiratory mucosa and attenuation of neutrophil recruitment and activation.
Further use of a long acting β2-agonist reduces the frequency of drug administration. Currently available long acting beta2-agonists (LABAs) include salmeterol and formoterol.
Even though it is known that beta2-agonists provide a symptomatic relief in bronchoconstriction, another component of asthma, which is inflammation, requires separate treatment such as steroid. Most of the inhaled corticosteroids need to be administered in multiple dosage regimens.
Corticosteroids exhibit inhibitory effects on inflammatory cells and inflammatory mediators involved in the pathogenesis of respiratory disorders. Treatment with a corticosteroid/glucocorticoid is considered one of the most potent and effective therapies currently available for persistent asthma.
However, a considerable proportion of patients treated with inhaled corticosteroids (ICS) have been found to remain symptomatic, despite the use of low to moderate doses of inhaled corticosteroids (ICS).
Also, use of these corticosteroids, especially in children, has been limited due to their potential side effects. In children and teenagers, these medicines can prohibit or slow down growth and may affect the function of adrenal glands. Another possible problem in children is that these corticosteroids may cause infections such as chickenpox and measles.
Other side effects with the use of corticosteroids are that they cause suppression of the Hypothalamic-Pituitary-Adrenal (HPA) axis, produces adverse effects on the bone growth in children and on the bone density in the elderly, ocular complications (cataract formation and glaucoma) and skin atrophy. In elderly people, corticosteroids may seem to increase the risk of high blood pressure and bone diseases. Bone associated diseases by using corticosteroids are especially more likely to occur in elderly females.
Thus the therapeutic options in the treatment of asthma chronic obstructive pulmonary disease (COPD) which are not adequately controlled by the use of low to moderate doses of ICS are either to increase the dose of the inhaled corticosteroid (ICS) or to combine the therapy of an inhaled corticosteroid (ICS) with bronchodilators such as beta2-agonists and/or anticholinergics.
Currently available corticosteroids include beclomethasone, budesonide, fluticasone, mometasone, ciclesonide and triamcinolone.
Anticholinergic agents also act as bronchodilators and are potential alternatives to beta agonists. However, anticholinergics can also be administered along with beta2-agonists (LABAs) for the management of asthma. Anticholinergics act by competing with acetylcholine for the receptor sites at vagus nerve or nerve-muscle junctions. This prevents the transmission of reflexes that are induced by asthma stimuli.
The use of anticholinergics provides an advantage in elderly patients as the responsiveness of β2-agonists declines with old age. Further it would be advantageous to use in patients who are intolerant to the use of beta2-agonists.
Further, anticholinergics can also be used in patients suffering from nocturnal asthma, chronic asthma with concurrent fixed way obstruction, intrinsic asthma and also in patients with asthma of longer duration.
Although a combination therapy of a bronchodilator with an inhaled corticosteroid improves pulmonary efficiency, reduces inflammatory response and provides symptomatic relief as compared to higher doses of inhaled corticosteroid alone in patients affected by respiratory disorders such as asthma, the selection of a specific bronchodilator and inhaled corticosteroid can also play a very important role in formulation of fixed dose combinations.
Additionally it simplifies the therapy, reduces the cost and also provides control of respiratory disorders. Reducing the dose frequency to the minimum is an important step in simplifying asthma management for improving patient adherence to the therapy.
Currently, there are several approved combinations of long-acting beta agonist (LABA) and inhaled corticosteroid (ICS). Some of these approved combinations for the treatment of asthma and chronic obstructive pulmonary disease (COPD) are salmeterol/fluticasone propionate (Advair diskus, Advair HFA), and formoterol fumarate dehydrate/budesonide (Symbicort).
Most of the available combinations of a long-acting beta agonist (LABA) with inhaled corticosteroid (ICS) have to be administered twice daily.
Even from the patient compliance point of view, the treatment calls for the patient to comply with different dosage regimens, different frequencies of administration, etc.
Efforts to improve compliance have been aimed at by, simplifying the medication packaging, providing effective medication reminders, improving patient education, and limiting the number of medications prescribed simultaneously.
U.S. Pat. No. 7,008,951 discloses a pharmaceutical composition comprising indacaterol and a corticosteroid for simultaneous, sequential or separate administration in the treatment of inflammatory or obstructive airway diseases and in a ratio of 100:1 to 1:300.
U.S. Pat. No. 7,622,483 discloses a combination comprising indacaterol and a steroid.
U.S. Pat. No. 6,800,643 discloses a medicament comprising separately or together indacaterol and a corticosteroid in a ratio from 100:1 to 1:300.
U.S. Pat. No. 7,622,484 discloses a composition in inhalable form comprising indacaterol and mometasone furoate for simultaneous administration in the treatment of inflammatory or obstructive airway diseases and in a ratio of 3:1 to 1:7.
U.S. Pat. No. 6,030,604 discloses a dry powder composition comprising glucocorticoids and beta-2 agonist.
WO0178745 discloses compositions containing a combination of formoterol and fluticasone propionate.
U.S. Pat. No. 7,172,752 discloses inhalation particles comprising a combination of a beta2-agonist and a glucocorticosteroid in a predetermined and constant ratio.
WO02083113 discloses pharmaceutical compositions comprising formoterol and a steroidal anti-inflammatory agent in a pharmacologically suitable fluid.
WO2004028545 discloses a combination of a long-acting beta2-agonist and a glucocorticosteroid in the treatment of fibrotic diseases.
US2005053553 discloses methods for administration by inhalation of a metered dry powder having combined doses of formoterol and fluticasone.
US2005042174 discloses a combination comprising indacaterol and of doses of a beta2-agonist, an anticholinergic agent and an anti-inflammatory steroid.
US2009088408 discloses pharmaceutical compositions of anticholinergics, corticosteroids and betamimetics and their use in the treatment of respiratory diseases.
WO2006105401 discloses anticholinergic in combination with a corticosteroid, and a long acting beta agonist, for simultaneous or sequential administration in the prevention or treatment of a respiratory, inflammatory or obstructive airway disease.
Further selecting a combination of a long-acting beta2 agonist (LABA) and an inhaled corticosteroid (ICS) is critical since both drugs should be capable of being administered once daily. A treatment method where a long-acting beta2 agonist (LABA) is required to be administered once daily and an inhaled corticosteroid (ICS) is required to be administered twice daily or vice versa will not be useful since the purpose of once a day treatment is defeated.
However, none of the above prior art specifically discloses the combination of indacaterol with fluticasone furoate, formoterol with fluticasone furoate or indacaterol with ciclesonide and indacaterol with fluticasone furoate and tiotropium. Moreover, none of these prior arts mention or disclose that the combination of indacaterol and fluticasone furoate, formoterol with fluticasone furoate or indacaterol with ciclesonide and indacaterol with fluticasone furoate and tiotropium can be administered once daily for the prevention or treatment of respiratory, inflammatory or obstructive airway disease.
Hence, there still remains a need to formulate a pharmaceutical composition which simplifies the dosage regimen by administering a once a day composition for the treatment of these respiratory disorders.