METHODS AND COMPOSITIONS FOR TREATING CHRONIC OBSTRUCTIVE PULMONARY DISEASE, ASTHMA, PNEUMONIA, BRONCHITIS, CYSTIC FIBROSIS, PULMONARY EDEMA, INTERSTITIAL LUNG DISEASE, SARCOIDOSIS, IDIOPATHIC PULMONARY FIBROSIS, ACUTE RESPIRATORY DISTRESS SYNDROME, AND PULMONARY ARTERIAL HYPERTENSION

Abstract

A method of treating COPD, Asthma, Pneumonia, Bronchitis, Cystic Fibrosis, Pulmonary Edema, Interstitial Lung Disease, Sarcoidosis, Idiopathic Pulmonary Fibrosis and PAH in a patient. One embodiment includes administering a vasodilator prostacyclin analogue, such as Beraprost or Iloprost, separately or together with a form of Diethylcarbamazine or Zileuton. Other embodiments may include fluvoxamine. The vasodilator prostacyclin analogue is inhaled. Diethylcarbamazine/Zileuton is inhaled into the lung or administered orally or intravenously. Other embodiments include fluvoxamine. This treatment reduces the progression of the disease, reduces life-threatening exacerbations, and improves the quality of life. The treatment is also for COPD patients with eosinophilia who are incompletely treated with steroids and addresses steroid-unresponsive disease components of COPD including pulmonary hypertension and intravascular inflammation and bronchiectasis. The treatment may include a PDE4 inhibitor and current treatments with existing steroids and beta-adrenergic receptor agonists and/or muscarinic receptor blockers. The treatment is also for ARDS and COVID-19.

Claims

1-52. (canceled)

53. A method of treating COPD and inhibiting further lung damage development in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of diethylcarbamazine or salts thereof (DEC), or Zileuton, wherein the therapeutically effective amount limits or stops the COPD inflammation and inhibits further lung damage development in the patient, and wherein either DEC or Zileuton is administered by inhalation, oral administration, or intravenous administration.

54. The method of claim 53, further comprising administering to the patient a vasodilator selected from group consisting of Beraprost, Beraprost sodium, Iloprost, Treprostinil, Treprostinil Palmitil and Cicaprost.

55. The method of claim 54, wherein DEC or Zileuton and the vasodilator are administered in a manner selected from the group consisting of: (i) the vasodilator is administered by inhalation from one inhaler, and DEC or Zileuton is administered separately by inhalation, oral administration, or intravenous administration; (ii) DEC or Zileuton is administered by inhalation from one inhaler, and the vasodilator is administered separately by inhalation from one inhaler; and (iii) DEC or Zileuton and the vasodilator are administered as a combination together by inhalation from at least one inhaler.

56. The method of claim 55, further comprising administering to the patient at least one other active agent selected from the group consisting of prednisone, salbutamol, formoterol, a muscarinic receptor blocker, and a long-acting beta-adrenergic agonist, wherein the at least one other active agent is administered together with DEC or Zileuton, together with the vasodilator or together with the combination of DEC or Zileuton and vasodilator.

57. The method of claim 54, further comprising administering to the patient a PDE4 inhibitor, wherein the PDE4 inhibitor is administered orally or by inhalation.

58. The method of claim 57, wherein the PDE4 is administered by inhalation, and DEC or Zileuton, the vasodilator, and the PDE4 inhibitor are administered together by inhalation from one inhaler.

59. The method of claim 57, further comprising administering to the patient at least one other active agent selected from the group consisting of prednisone, salbutamol, formoterol, a muscarinic receptor blocker, and a long-acting beta-adrenergic agonist.

60. A pharmaceutical aerosol composition for direct delivery into to the lungs comprising diethylcarbamazine or salts thereof (DEC), or Zileuton and a propellent.

61. The pharmaceutical aerosol composition of claim 60, wherein the DEC or Zileuton has a particle size of 1 to 5 μm, and the pharmaceutical aerosol composition further comprises at least one additional compound selected from the group consisting of: (a) a vasodilator selected from group consisting of Beraprost, Beraprost sodium, Iloprost, Treprostinil, Treprostinil Palmitil and Cicaprost; (b) at least one other active agent selected from the group consisting of prednisone, salbutamol, formoterol, tiotropium, a muscarinic receptor blocker, and a long-acting beta-adrenergic agonis; and (c) a PDE4 inhibitor.

62. The pharmaceutical aerosol composition of claim 61, wherein the at least one additional compound is present in a ratio of 5 μg to 2 mg of DEC or Zileuton.

63. The pharmaceutical aerosol composition of claim 61, wherein the at least one additional compound is a vasodilator having a particle size of 1 to 5 μm.

64. The pharmaceutical aerosol composition of claim 60, further comprising a PDE4 inhibitor, wherein: the DEC or Zileuton is 2.5% to 4% by weight of the pharmaceutical aerosol composition; and the PDE4 inhibitor is 1% to 5% by weight of the pharmaceutical aerosol composition; and the DEC or Zileuton and the PDE4 inhibitor have a particle size of 1 μm to 5 μm.

65. The pharmaceutical aerosol composition of claim 64, further comprising: (a) 0.00125% to 0.002% by weight of a vasodilator selected from group consisting of Beraprost, Beraprost sodium, Iloprost, Treprostinil, Treprostinil Palmitil and Cicaprost; or (b) 0.00125% to 0.002% by weight of a vasodilator selected from group consisting of Beraprost, Beraprost sodium, Iloprost, Treprostinil, Treprostinil Palmitil and Cicaprost, and 1% to 5% by weight of at least one other active agent selected from the group consisting of prednisone, salbutamol, formoterol, a muscarinic receptor blocker, and a long-acting beta-adrenergic agonist.

66. The pharmaceutical aerosol composition of claim 60, further comprises a vasodilator, wherein: the DEC or Zileuton is 2.5% to 4% by weight of the pharmaceutical aerosol composition; the vasodilator is 0.00125% to 0.002% by weight of the pharmaceutical aerosol composition; and the DEC or Zileuton and vasodilator have a particle size of 1 μm to 5 μm.

67. The pharmaceutical aerosol composition of claim 66, further comprising: 1% to 5% by weight of: (i) at least one other active agent selected from the group consisting of prednisone, salbutamol, formoterol, a muscarinic receptor blocker, and a long-acting beta-adrenergic agonist, or (ii) a PDE4 inhibitor.

68. A method of treating COPD, Asthma, Pneumonia, Bronchitis, Cystic Fibrosis, Pulmonary Edema, Interstitial Lung Disease, Sarcoidosis, Idiopathic Pulmonary Fibrosis and PAH and inhibiting further lung damage development in a patient in need thereof, comprising administering by inhalation to the patient a therapeutically effective amount of the pharmaceutical aerosol composition according to claim 64, wherein the therapeutically effective amount limits or stops the COPD Pulmonary or other inflammation and inhibits further lung damage development in the patient.

69. A pharmaceutical composition comprising: (a) at least one of diethylcarbamazine or a salt thereof (DEC) and Zileuton; and (b) at least one of Beraprost or a salt thereof, and Iloprost.

70. The pharmaceutical composition of claim 69, wherein a weight ratio of (a) the at least one of DEC and Zileuton to (b) the at least one of Beraprost and Iloprost is from 2.5-4 to 0.00125:0.002.

71. The pharmaceutical composition of claim 69, further comprising (c) a PDE4 inhibitor.

72. The pharmaceutical composition of claim 69, wherein the pharmaceutical composition is a medical aerosol formulation and further comprise a propellant.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0213] Advantages of embodiments of the present invention will be apparent from the following detailed description of the exemplary embodiments. The following detailed description should be considered in conjunction with the accompanying figures in which:

[0214] FIG. 1 illustrates the progression of the COPD disease in lungs.

[0215] FIG. 2 illustrates the disease manifestation and the role of DEC and Beraprost.

[0216] FIG. 3 illustrates a frequent exacerbator phenotype.

[0217] FIG. 4 is an illustration of smoking as one cause of the disease.

[0218] FIG. 5 in an illustration of the risk factors for the disease.

[0219] FIG. 6 is an illustration of the comparison to the current treatments and this proposed invention.

[0220] FIG. 7 illustrates that DEC treatment significantly inhibited neutrophil infiltration. The figure is reproduced from Ribeiro et al. The authors show in a mouse acute lung injury model that DEC pretreatment prevented the influx of neutrophils into the lung, using the neutrophil and macrophage marker myeloperoxidase.

[0221] FIG. 8 illustrates the effect of DEC on carrageenan-induced TNF-alpha and nitric oxide production in the lung. The figure is reproduced from Ribeiro et al. (a) shows TNF-alpha levels were significantly elevated 4 hours after carrageenan administration in the CAR group in comparison to the sham group. DEC significantly reduced the TNF-alpha levels, but INDO did not reduce the TNF-alpha level in comparison to the CAR group. (b) shows that nitrite and nitrate levels, stable NO metabolites, were significantly increased in the pleural exudates 4 hours after carrageenan administration in comparison to the sham group, and DEC and INDO significantly reduced the nitrite and nitrate level in the exudates. Data expressed as means+/−S. E. M. from n=8 mice for each group *p<0.05 versus carrageenan. This pre-treatment inhibits the inflammation in the lung as shown by reduction in TNF-alpha and Nitric oxide production.

DETAILED DESCRIPTION

[0222] Aspects of the present invention are disclosed in the following description directed to specific embodiments of the invention. Those skilled in the art will recognize that alternate embodiments may be devised without departing from the spirit or the scope of the claims. Additionally, well-known elements of exemplary embodiments of the invention will not be described in detail or will be omitted so as not to obscure the relevant details of the invention. Further, to facilitate an understanding of the description discussion of several terms used herein follows.

[0223] As used herein, the word “exemplary” means “serving as an example, instance or illustration.” The embodiments described herein are not limiting, but rather are exemplary only. It should be understood that the described embodiments are not necessarily to be construed as preferred or advantageous over other embodiments. Moreover, the terms “embodiments of the invention”, “embodiments” or “invention” do not require that all embodiments of the invention include the discussed feature, advantage, or mode of operation.

[0224] The present invention is based on the discovery that DEC or Zileuton combined with a vasodilator such as Beraprost or Beraprost sodium or Iloprost, will address COPD disease and Asthma, Pneumonia, Bronchitis, Cystic Fibrosis, Pulmonary Edema, Interstitial Lung Disease, Sarcoidosis, Idiopathic Pulmonary Fibrosis and PAH mechanisms of action that steroids and other current medications do not effect. The present invention is also based on the discovery that Fluvoxamine has an additional mechanism of action to reduce inflammation. Specifically, Asthma, Pneumonia, Bronchitis, Cystic Fibrosis, Pulmonary Edema, Interstitial Lung Disease, Sarcoidosis, Idiopathic Pulmonary Fibrosis, and PAH and COPD disease, which is often described as a smoldering inflammation, requires a treatment that (1) reduces inflammation (2) lowers contraction of airway smooth muscles and of lung vessels (3) prevents the dysfunction of endothelial cells (4) inhibits pulmonary vasoconstriction (5) protects the lung vascular endothelial cells thereby Decreasing intra-vascular inflammation and (6) inhibits or retards Inhibition of interstitial fibrosis in the COPD subtype that is characterized by emphysema, lung fibrosis and pulmonary hypertension and (6) prevents pulmonary emboli.

[0225] The present inventors understood in order to prevent patients affected with Asthma, Pneumonia, Bronchitis, Cystic Fibrosis, Pulmonary Edema, Interstitial Lung Disease, Sarcoidosis, Idiopathic Pulmonary Fibrosis and PAH and COPD from progressing and develop ever worsening symptoms and then possible death, administration of drugs that inhibit steroid-resistant inflammation and protect the lung vascular endothelium must be selected. Such drugs must intervene early enough to prevent disease progression and also treat this disease and protect the lung from developing further damage. To do so, they realized the mechanisms of action these drugs have to provide is as follows: [0226] (i) Inhibit chemotaxis of inflammatory cells into the lung and the heart. [0227] (ii) Decrease vascular permeability and airway edema. [0228] (iii) Decrease the activity of the master inflammatory mediator transcription factor NFkappaB activation in various cell types, including endothelial cells which likely develop an inflammatory phenotype (one characteristic of which is NFkappaB expression). [0229] (iv) Avoid the inherent risk of current treatments whereby patients become susceptible to pneumonia or Haemophilus influenzae airway infections, or susceptible to developing osteoporosis. [0230] (v) Provide a treatment that has anti-inflammatory properties and is also an antioxidant to inhibit the intravascular inflammatory and procoagulant mechanisms that pave the way to lung damage and heart failure. [0231] (vi) Address LTB4, as it is of critical importance in the development of organ failure due to activation of chemotaxis and causing direct damage to the endothelium resulting in vascular leakage and in addition to address the synthesis of LTC4, a peptido-leukotriene that is vaso- and bronchospastic. The actions of vasospastic and bronchospastic in the context of chronic pulmonary inflammation are important in that these leukotriene-driven disease components contribute to the airflow limitation and shortness of breath and to pulmonary hypertension. [0232] (vii) Inhibit the formation of leukotriene B4 that then inhibits the chemotaxis of neutrophils and macrophages into the injured lung and also endothelial cell damage. [0233] (viii) Address cytokines that play an important part in the manifestation of the inflammatory response; of particular interest are IL-1, IL-6 and TNF-alpha. [0234] (ix) Prevent the 5-lipoxygenase (5-LO) dependent expression signature and that 5-LO may work as a co-transcription factor IL-1beta, IL-6, BC12, ET, beta catenin, c-Myc. IL-1 and IL-6 are likely involved in COPD, in chronic lung infections and organ damage. [0235] (x) Inhibit pulmonary vasoconstriction and provide protection against lung tissue fibrosis. [0236] (xi) The inhaled drugs need to be deposited deep into the lungs-reaching the alveolar level—for maximum benefit.

[0237] It follows during treatment of Asthma, Pneumonia, Bronchitis, Cystic Fibrosis, Pulmonary Edema, Interstitial Lung Disease, Sarcoidosis, Idiopathic Pulmonary Fibrosis and PAH and COPD, patients with DEC or Zileuton provide some of the critical mechanisms of action needed.

[0238] The proposed mechanisms of action DEC are several fold: reduction of leukotriene production, protection against oxidative stress and inhibition of cytokine production via the interference with NFkappaB signaling, prevention of scar formation and in the case of DEC, antiviral benefits. Zileuton is not known to have anti-oxidant or anti-viral properties.

[0239] Based on this research and trials for other indications using DEC, with an antioxidant, anti-inflammatory, anti-viral, antifibrotic and NFkappaB activity blocking properties, it is designated by the present inventors that treatment with DEC (or Zileuton) will provide the required mechanisms of action and together with Beraprost or Beraprost sodium or Iloprost will provide the other required mechanisms of action to arrest this disease.

[0240] In addition, the present inventors determined that DEC and Beraprost influence vascular inflammation. This discovery is based on the results of experiments conducted, by the inventor Norbert F. Voelkel, in rat models.

[0241] One of the present inventors, Norbert F. Voelkel, determined that these mechanisms involved in inflammation are amenable to modification by DEC and it is proposed by Norbert F. Voelkel to treat intravascular inflammation.

[0242] In some exemplary embodiments, COPD in a patient is treated by administering a therapeutically effective amount of a DEC (or Zileuton), the same applying to Asthma, Pneumonia, Bronchitis, Cystic Fibrosis, Pulmonary Edema, Interstitial Lung Disease, Sarcoidosis, Idiopathic Pulmonary Fibrosis and PAH. In one exemplary embodiment, Diethylcarbamazine (C.sub.10H.sub.21N.sub.3O) (or Zileuton C.sub.11H.sub.12N.sub.2O.sub.2S) is administered. In an exemplary embodiment, the therapeutically effective amount of the DEC (or Zileuton) delivers 4 to 12 mg of DEC (or Zileuton) per day. In other exemplary embodiments, the therapeutically effect amount of DEC (or Zileuton) is 4 to 8 mg of DEC (or Zileuton) per day. This amount may be administered, for example, in some embodiments, in 4 to 1 doses delivered via an inhaler as 1 mg of DEC (or Zileuton) per “puff”, or in other embodiments, in 4 to 12 doses delivered by an inhaler as 1 mg of DEC (or Zileuton) per “puff”. In alternative embodiments, a single dose may include 2 puffs, each puff delivering 1 mg of DEC (or Zileuton). In further exemplary embodiments, the therapeutically effect amount of DEC (or Zileuton) can be greater than 6 mg of DEC (or Zileuton) per day, such 6 to 12 mg of DEC (or Zileuton) per day, and may be delivered by an inhaler in doses of 1 or 2 or 3 puffs, each puff delivering each puff delivering 1 mg of DEC (or Zileuton). The amount of DEC (or Zileuton) is adjusted according to the degree of reduction in sputum Leukotrienes.

[0243] The DEC or Zileuton may be administered in a composition comprising pharmaceutically acceptable carriers and/or excipients. The compositions may be administered in an intravenous form, in and inhaled form or an oral form, such as a tablet or a capsule. In some exemplary embodiments the composition is an inhaled form, either alone as DEC (or Zileuton) only or together with either Beraprost (or Beraprost sodium) or Iloprost, or combined with current inhalers that deliver (1) beta-adrenergic receptor agonists (bronchodilators), (2) inhaled corticosteroids to treat airway inflammation, (3) muscarinic receptor blockers-anticholinergics, and/or (4) a phosphodiesterase 4 inhibitor which has anti-inflammatory actions, such as roflumilast or CHF6001.

[0244] In addition to DEC or Zileuton, Beraprost (or Beraprost sodium) or Iloprost is to be used for the COPD disease and Asthma, Pneumonia, Bronchitis, Cystic Fibrosis, Pulmonary Edema, Interstitial Lung Disease, Sarcoidosis, Idiopathic Pulmonary Fibrosis and PAH treatment strategy. Beraprost (or Beraprost sodium) or Iloprost are vasodilator drugs designed for pulmonary arterial hypertension that have additional mechanisms of action that will improve the effectiveness of DEC (or Zileuton) through improvement of gas exchange, decrease in the production of inflammatory cytokines, prevention of the dysfunction of endothelial cells, inhibition of pulmonary vasoconstriction, protection of the lung vascular endothelial cells, decreasing intra-vascular inflammation, and inhibition or retarding Inhibition of interstitial fibrosis. In some exemplarily embodiments, Beraprost (or Beraprost sodium) or Iloprost may be delivered in a daily therapeutically effective amount of 20 to 60 μg. This amount may be administered, for example, by 3 to 6 doses or 4 to 8 doses delivered via an inhaler as 5 μg of Beraprost (or Beraprost sodium) or Iloprost per “puff”. In some embodiments, a single dose may include 2 puffs, each puff delivering 5 μg of Beraprost (or Beraprost sodium) or Iloprost.

[0245] Thus, it is expected that Beraprost (or Beraprost sodium) (or Iloprost), and DEC (or Zileuton) work synergistically in preventing intravascular inflammation. While Beraprost (or Beraprost sodium) or Iloprost is expected to reduce inflammation, improve gas exchange, protect endothelial cells, inhibit vasoconstriction, DEC (or Zileuton) is expected to decrease inflammation, inhibit neutrophil chemotaxis and NFkappaB-dependent gene transcription and DEC will provide virus protection by inhibiting viral replication. FIG. 7 illustrates that that DEC treatment significantly inhibited inflammatory cell infiltration (myeloperoxidase is produced by neutrophils and macrophages). The 5-LO enzyme that is expressed in activated lung vessel endothelial cells acts in the context of pulmonary vascular disease as an activator of gene expression. 5-LO leads to the production of leukotriene C4, which is the first and well-established action of 5-LO, and of leukotriene C4 which increases bronchoconstriction and pulmonary vasoconstriction by contracting smooth muscle cells in the bronchial airways and in the lung vessels. Thus, inhibiting 5-LO would also inhibit leukotriene C4 synthesis, which would remove a pulmonary vessel constricting substance. A second action is a non-enzymatic function of binding to the 5-LO activating protein (FLAP) on the envelope of the cell nucleus. Fitzpatrick and Lepley showed in 1998 that 5-LO co-precipitated with a subunit of the transcription factor NF-kappaB when they examined nuclear extracts. NF-kappaB controls the expression of genes encoding several inflammatory mediators. Thus, 5-LO, by binding to NF-kappaB in the cell nucleus would activate transcription of a number of genes in control of cell growth and genes encoding inflammatory mediators such as IL-1beta and IL-6—and also TNF alpha. FIG. 8 illustrates the effect of DEC on carrageenan-induced TNF-alpha and nitric oxide production in the lung and that DEC will inhibit TNF Alpha production. As a result of 5-LO inhibitor treatment, there would be a reduction in the vascular inflammation leading to halting of disease progression and assist disease reversal. LTB4 is important chemotactic leukotriene that is a product of the enzyme leukotriene A4 hydrolase—which is downstream from 5-LO. LTB4-has recently been studied in rats and it was demonstrated that LTB4 caused pulmonary-endothelial cell apoptosis (Tian W. et al Sci Transl Med. 2013 Aug. 28; 5(200):200ra117). Because effective inhibition of the 5-LO would also block LTB4 production, it is expected that 5-LO inhibitors in the treatment of COPD and Asthma, Pneumonia, Bronchitis, Cystic Fibrosis, Pulmonary Edema, Interstitial Lung Disease, Sarcoidosis, Idiopathic Pulmonary Fibrosis and PAH would also target LTB4-dependent pathomechanisms.

[0246] In exemplary embodiments, a PDE4 inhibitor may be included in the treatment with DEC (or Zileuton) with or without Beraprost (or Beraprost sodium) (or Iloprost) as described above. By including a PDE4 inhibitor, the invention employs a strategy of adding the benefits of DEC (or Zileuton) with or without the added benefits of a vasodilator drug Beraprost (or Beraprost sodium) (or Iloprost), and gain the PDE4 inhibitor benefit of additional inflammation reduction. When an inhalable PDE4 inhibitor used, for example, CHF6001, as developed by Chiesi Pharma (Lee J H, Kim H J, Lung 20015), it may be delivered in a daily therapeutically effective amount of 4 to 12 mg. This amount may be administered, for example, by 3 to 6 or 4 to 8 doses delivered via an inhaler, with has 1 mg of CHF6001 per “puff”.

[0247] In exemplary embodiments, Fluvoxamine may be included in the treatment with DEC (or Zileuton) with or without Beraprost (or Beraprost sodium) (or Iloprost) or with or without a PDE4 inhibitor as described above. By including Fluvoxamine, the invention employs a strategy of adding the benefits of DEC (or Zileuton) with or without the added benefits of a vasodilator drug Beraprost (or Beraprost sodium) (or Iloprost), and with or without a PDE4 inhibitor and gain the Fluvoxamine benefit of additional inflammation reduction. When an inhalable Fluvoxamine it may be delivered in a daily therapeutically effective amount of 1 to 5 mg, This amount may be administered, for example, by 3 to 6 or 4 to 8 doses delivered via an inhaler, with has 0.5 to 2 mg of Fluvoxamine per “puff”.

TABLE-US-00001 TABLE 2 Expected Effect On COPD and other Lung Diseases, such as Asthma, Pneumonia, Bronchitis, Cystic Fibrosis, Pulmonary Edema, Interstitial Lung Disease, Sarcoidosis, Idiopathic Pulmonary Drug Agent Fibrosis and PAH Expected Combined Beraprost or Iloprost, that can be Improved Gas Synergism in reducing airway and substituted with Treprostinil, Exchange intravascular inflammation. Treprostinil Palmitil, or Decrease in the Greater reduction in pulmonary Cicaprost production of hypertension than the reduction inflammatory cytokines achieved by Beraprost or Iloprost prevention the alone. dysfunction of endothelial cells inhibition of pulmonary vasoconstriction protection the lung vascular endothelial cells Decreasing intra- vascular inflammation inhibition or retarding interstitial fibrosis DEC or Zileuton. Anti-inflammation A vasodilator, such as Beraprost or Antioxidant Iloprost combined with DEC or reduction in pulmonary Zileuton are synergistic. artery pressure In addition to their complementary Anti-viral mechanisms of action, the vasodilation of Beraprost or Iloprost allow DEC or Zileuton to be more effective. A PDE4 Inhibitor Reduced Inflammation Reduced Inflammation Fluvoxamine Reduced Inflammation Reduced Inflammation Reduced Depression Reduced Depression

[0248] In terms of administration, some exemplary embodiments concerning the administration of both DEC (or Zileuton) and a co-drug comprising of Beraprost (or Beraprost sodium) (or Iloprost) in a single dose form or composition delivered by inhalation. In other exemplary embodiments DEC or Zileuton and co-drug of Beraprost (or Beraprost sodium) (or Iloprost are administered in separate compositions, which may be administered via the same route. Alternatively, these separate compositions may be administered by different routes. For example, the co-drug of Beraprost (or Beraprost sodium) and Iloprost may be in an inhalable form and the DEC (or Zileuton) may be in composition of an intravenous, oral, or inhalable form. If Fluvoxamine is added to the treatment, it may also be delivered as an injectable, oral or inhalable form.

[0249] In some exemplary embodiments, the DEC (or Zileuton)—with or without a co-drug of Beraprost (or Beraprost sodium) or Iloprost—is administered: DEC (or Zileuton) in a dose of 4-12 mg/day, which is a dose that can be shown to reduce sputum LTB4 and sputum eosinophilia.

[0250] In some exemplary embodiments, the Beraprost or Beraprost sodium or Iloprost—with or without a co-drug of DEC (or Zileuton) and with or without the co-drug of Fluvoxamine—is administered: Beraprost or Beraprost sodium in a dose of 20 to 60 microgram/day, which is a dose that does not cause systemic hypotension.

[0251] The compositions for DEC (or Zileuton) may comprise pharmaceutically acceptable carriers and/or excipients. The compositions may be in an intravenous form, and inhalable or an oral form, such as a tablet, a microtablet formulation, or a capsule. For compositions comprising Beraprost or Iloprost, with or without DEC or Zileuton, specific carriers and/or excipients may be added to provide the proper format for inhalable pumps. For compositions comprising Fluvoxamine, with or without DEC or Zileuton and with or without Beraprost or Iloprost, specific carriers and/or excipients may be added to provide the proper format for inhalable pumps.

[0252] In other exemplary. embodiments, any of the above oral forms of DEC or Zileuton may also be taken with one or more of the following current treatments as part of a single dose, as an additional oral form or as an additional component to one of the oral forms, for example: (1) prednisone (2) beta-adrenergic receptor agonists (bronchodilators), (3) inhaled corticosteroids to treat airway inflammation, (4) muscarinic receptor blockers-anticholinergics, and/or (5) a phosphodiesterase 4 inhibitor which has anti-inflammatory actions.

[0253] In other exemplary embodiments, any of the foregoing combinations with or without Beraprost or Beraprost sodium or Iloprost or with or without DEC or Zileuton may also be administered in concert with orally administered drugs currently prescribed to treat COPD and Asthma, Pneumonia, Bronchitis, Cystic Fibrosis, Pulmonary Edema, Interstitial Lung Disease, Sarcoidosis, Idiopathic Pulmonary Fibrosis and PAH such as prednisone or a PDE4 inhibitor.

[0254] One exemplary device for delivery of the drug combinations is an inhaler and may be a dry powder inhaler or aerosol, of which there are many designs. The drug delivery device (inhaler) is the device that delivers an adequate dose of the drugs deep into the airways, which in one exemplary embodiment delivery is to the alveolar level. In exemplary embodiments, the inhalation delivery device may be a dry powder inhaler (DPI), metered dose inhaler (MDI), soft mist inhaler, or a nebulizer.

[0255] In exemplary embodiments, the inhaler compositions may be pre-packaged in an inhalation delivery device.

[0256] The inhaler composition comprises the drug combinations, a pharmaceutically acceptable carrier, diluent, or excipient, which may include solubilizing agent, and antioxidant, a stabilizing agent or a combination thereof, and, in some exemplary embodiments, a propellant.

[0257] Exemplary embodiments of the inhaler compositions include a composition for direct delivery into to the lungs by inhalation with 2.5-4% by weight DEC or Zileuton, 1% to 5% by weight of a PDE4 inhibitor, and a propellent for inhalation delivery from an inhaler. The weight ratio is 5 μg of PDE4 inhibitor to 2 mg of DEC or Zileuton, or 10 μg to 4 mg. In some exemplary embodiments, the PDE4 inhibitor is CHF6001, as developed by Chiesi Pharma (Lee J H, Kim H J, Lung 20015). The DEC or Zileuton and PDE4 inhibitor have a particle size of 1 μm to 5 μm for suitable dispensing by the inhaler. The composition may further comprise a pharmaceutically acceptable carrier, diluent, or excipient, which may include solubilizing agent, and antioxidant, a stabilizing agent or a combination thereof.

[0258] In other exemplary embodiments the inhaler composition may further comprise, in addition to DEC or Zileuton and the PDE4 inhibitor, 0.00125% to 0.002% by weight of a vasodilator selected from group consisting of Beraprost, Beraprost sodium, Iloprost, Treprostinil, Treprostinil Palmitil and Cicaprost. In some exemplary embodiments, the vasodilator is Beraprost (or Beraprost sodium) or Illoprost. The weight ratio is 5 μg of vasodilator to 2 mg of DEC or Zileuton, or 10 μg to 4 mg. The vasodilator has a particle size of 1 μm to 5 μm for suitable dispensing by the inhaler.

[0259] In other exemplary embodiments the inhaler composition may further comprise, in addition to DEC or Zileuton and Fluvoxamine and the PDE4 inhibitor, 0.00125% to 0.002% by weight of a vasodilator selected from group consisting of Beraprost, Beraprost sodium, Iloprost, Treprostinil, Treprostinil Palmitil and Cicaprost. In some exemplary embodiments, the vasodilator is Beraprost (or Beraprost sodium) or Iloprost. The weight ratio is 5 μg of vasodilator to 2 mg of DEC or Zileuton, or 10 μg to 4 mg. The vasodilator has a particle size of 1 μm to 5 μm for suitable dispensing by the inhaler.

[0260] In other exemplary embodiments the inhaler composition may further comprise, in addition to DEC or Zileuton and Fluvoxamine, 0.00125% to 0.002% by weight of a vasodilator selected from group consisting of Beraprost, Beraprost sodium, Iloprost, Treprostinil, Treprostinil Palmitil and Cicaprost. In some exemplary embodiments, the vasodilator is Beraprost (or Beraprost sodium) or Illoprost. The weight ratio is 5 μg of vasodilator to 2 mg of DEC or Zileuton, or 10 μg to 4 mg. The vasodilator has a particle size of 1 μm to 5 μm for suitable dispensing by the inhaler.

[0261] In other exemplary embodiments the inhaler composition may further comprise, in addition to DEC or Zileuton and the PDE4 inhibitor and/or a vasodilator, 0.00125% to 0.002% by weight of at least one other active agent selected from the group consisting of prednisone, salbutamol, formoterol, a muscarinic receptor blocker, and a long-acting beta-adrenergic agonist. The at least one other active agent has a particle size of 1 μm to 5 μm for suitable dispensing by the inhaler.

[0262] In other exemplary embodiments the inhaler composition may further comprise, in addition to DEC or Zileuton and Fluvoxamine the PDE4 inhibitor and/or a vasodilator, 0.00125% to 0.002% by weight of at least one other active agent selected from the group consisting of prednisone, salbutamol, formoterol, a muscarinic receptor blocker, and a long-acting beta-adrenergic agonist. The at least one other active agent has a particle size of 1 μm to 5 μm for suitable dispensing by the inhaler.

[0263] In other exemplary embodiments the inhaler composition may further comprise, in addition to DEC or Zileuton and Fluvoxamine and/or a vasodilator, 0.00125% to 0.002% by weight of at least one other active agent selected from the group consisting of prednisone, salbutamol, formoterol, a muscarinic receptor blocker, and a long-acting beta-adrenergic agonist. The at least one other active agent has a particle size of 1 μm to 5 μm for suitable dispensing by the inhaler.

[0264] In other exemplary embodiments the inhaler composition may further comprise, Fluvoxamine the PDE4 inhibitor and/or a vasodilator, 0.00125% to 0.002% by weight of at least one other active agent selected from the group consisting of prednisone, salbutamol, formoterol, a muscarinic receptor blocker, and a long-acting beta-adrenergic agonist. The at least one other active agent has a particle size of 1 μm to 5 μm for suitable dispensing by the inhaler.

[0265] Exemplary embodiments of the inhaler composition also include a composition for direct delivery into to the lungs by inhalation with 2.5% to 4% by weight DEC or Zileuton and 0.00125% to 0.002% by weight of a vasodilator selected from group consisting of Beraprost, Beraprost sodium, Iloprost, Treprostinil, Treprostinil Palmitil and Cicaprost, and a propellent for inhalation delivery from the inhaler. The weight ratio is 5 μg of vasodilator to 2 mg of DEC or Zileuton, or 10 μg to 4 mg. The DEC or Zileuton and vasodilator have a particle size of 1 μm to 5 μm for suitable dispensing by the inhaler. In some exemplary embodiments, the vasodilator is Beraprost (or Beraprost sodium) or illoprost. The composition may further comprise a pharmaceutically acceptable carrier, diluent, or excipient, which may include solubilizing agent, and antioxidant, a stabilizing agent, or a combination thereof.

[0266] In other embodiments, the inhaler composition may further comprise, in addition to DEC or Zileuton and the vasodilator, 1% to 5% by weight of at least one other active agent selected from the group consisting of prednisone, salbutamol, formoterol, a muscarinic receptor blocker, and a long-acting beta-adrenergic agonist. The at least one other active agent has a particle size of 1 μm to 5 μm for suitable dispensing by the inhaler.

[0267] In other embodiments, the inhaler composition may further comprise, in addition to DEC or Zileuton, Fluvoxamine and the vasodilator, 1% to 5% by weight of at least one other active agent selected from the group consisting of prednisone, salbutamol, formoterol, a muscarinic receptor blocker, and a long-acting beta-adrenergic agonist. The at least one other active agent has a particle size of 1 μm to 5 μm for suitable dispensing by the inhaler.

[0268] In other embodiments, the inhaler composition may further comprise, in addition to DEC or Zileuton and the vasodilator and/or the at least one other active agent, 1% to 5% by weight of a PDE4 inhibitor. The weight ratio is 5 μg of PDE4 inhibitor to 2 mg of DEC or Zileuton, or 10 μg to 4 mg. In some exemplary embodiments, the PDE4 inhibitor is CHF6001, as developed by Chiesi Pharma (Lee J H, Kim H J, Lung 20015). The PDE4 inhibitor have a particle size of 1 μm to 5 μm for suitable dispensing by the inhaler.

[0269] In other embodiments, the inhaler composition may further comprise, in addition to DEC or Zileuton and Fluvoxamine and the vasodilator and/or the at least one other active agent, 1% to 5% by weight of a PDE4 inhibitor. The weight ratio is 5 μg of PDE4 inhibitor to 2 mg of DEC or Zileuton, or 10 μg to 4 mg. The weight ratio is 5 μg of PDE4 inhibitor to 1 mg of Fluvoxamine, or 5 μg to 5 mg. In some exemplary embodiments, the PDE4 inhibitor is CHF6001, as developed by Chiesi Pharma (Lee J H, Kim H J, Lung 20015). The PDE4 inhibitor have a particle size of 1 μm to 5 μm for suitable dispensing by the inhaler.

[0270] The at least one other active agent has a particle size of 1 μm to 5 μm for suitable dispensing by the inhaler 1% to 5% by weight of at least one other active agent selected from the group consisting of prednisone, salbutamol, formoterol, a muscarinic receptor blocker, and a long-acting beta-adrenergic agonist.

[0271] The foregoing description and accompanying figures illustrate the principles, preferred embodiments, and modes of operation of the invention. However, the invention should not be construed as being limited to the particular embodiments discussed above. Additional variations of the embodiments discussed above will be appreciated by those skilled in the art.

[0272] Therefore, the above-described embodiments should be regarded as illustrative rather than restrictive. Accordingly, it should be appreciated that variations to those embodiments may be made by those skilled in the art without departing from the scope of the invention as defined by the following claims.