(19) TZZ ¥__T

(11) EP 2 589 381 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.: 08.05.2013 Bulletin 2013/19 A61K 31/198 (2006.01) A61P 11/00 (2006.01) A61P 11/06 (2006.01) (21) Application number: 11250938.5

(22) Date of filing: 23.12.2011

(84) Designated Contracting States: (72) Inventors: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • Tirouvanziam, Rabindra GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Decatur GA 30030 (US) PL PT RO RS SE SI SK SM TR • Conrad, Carol Designated Extension States: Menlo Park CA 94025 (US) BA ME • Herzenberg, Leonore A. Stanford CA 94305 (US) (30) Priority: 04.11.2011 US 201161555678 P (74) Representative: Beresford, Keith Denis Lewis (71) Applicants: Beresford & Co. • Tirouvanziam, Rabindra 16 High Holborn Decatur GA 30030 (US) London • Conrad, Carol WC1V 6BX (GB) Menlo Park CA 94025 (US) • Herzenberg, Leonore A. Stanford CA 94305 (US)

(54) Compositions for improving or preserving lung function in a patient with a pulmonary disorder

(57) The described invention provides a pharmaceu- ing a therapeutically effective amount ofacetyl- N- tical compositions for use in treatment methods for im- cysteine, a derivative of N-acetylcysteine, or a pharma- proving or preserving lung function in a patient suffering ceutically acceptable salt of N-acetylcysteine, wherein from a pulmonary disorder comprising an inflammatory the therapeutically effective amount is effective to im- component, the pharmaceutical compositions compris- prove or preserve the lung function in the patient. EP 2 589 381 A1

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 589 381 A1 2

Description normal cellular metabolism, is produced mainly in mito- chondriabecause of incomplete reduction of oxygen. The [0001] CROSS REFERENCE TO RELATED APPLI- superoxide radical, although unreactive compared with CATIONS many other radicals, may be converted by biological sys- [0002] This application claims the benefit of priority to 5 tems into other more reactive species, such as peroxyl U.S. Application No. 12/420,577 (filed April 8, 2009), en- (ROO-), alkoxyl (RO-) and hydroxyl (OH-) radicals. titled "N-Acetylcysteine Compositions And Methods For [0010] Themajor cellular sources of free radicals under Treating Acute Exacerbations Of Inflammatory Lung Dis- normal physiological conditions are the mitochondria and ease," which is a continuation- in part of U.S. Application inflammatory cells, such as granulocytes, macrophages, No. 11/507,706 (filed August 22, 2006), which claims the 10 and some T-lymphocytes, which produce active species benefit of priority to U.S. Provisional Application No. of oxygen via the nicotinamide adenine nucleotide oxi- 60/710,807 (filed Aug. 24, 2005) entitled "Methods For dase (NADPH oxidase) system, as part of the body’s Treating And Monitoring Inflammation And Redox Imbal- defense against bacterial, fungal or viral infections. ance In Cystic Fibrosis." The entire contents of each of [0011] Oxidative injury may lead to widespread bio- these applications are incorporated herein by reference. 15 chemical damage within the cell. The molecular mecha- [0003] FIELD OF THE INVENTION nisms responsible for this damage are complex. For ex- [0004] The present invention relates to N-acetyl- ample, free radicals may damage intracellular macromol- cysteine compositions for use in methods of treatment ecules, such as nucleic acids (e.g., DNA and RNA), pro- for improving or preserving lung function in lung disease. teins, and lipids. Free radical damage to cellular proteins [0005] BACKGROUND 20 may lead to loss of enzymatic function and cell death. [0006] Oxidative Stress Associated With GSH De- Free radical damage to DNA may cause problems in rep- pletion lication or transcription, leading to cell death or uncon- [0007] A free radical is a highly reactive and usually trolled cell growth. Free radical damage to cell membrane short-lived molecular fragment with one or more unpaired lipids may cause the damaged membranes to lose their electrons. Free radicals are highly chemically reactive 25 ability to transport oxygen, nutrients or water to cells. molecules. Because a free radical needs to extract a sec- [0012] Biological systems protect themselves against ond electron from a neighboring molecule to pair its single the damaging effects of activated species by several electron, it often reacts with other molecules, which ini- means. These include free radical scavengers and chain tiates the formation of many more free radical species in reaction terminators; "solid-state" defenses, and en- a self-propagating chain reaction. This ability to be self- 30 zymes, such as superoxide dismutase, catalase, and the propagating makes free radicals highly toxic to living or- glutathione peroxidase system. ganisms. [0013] Free radical scavengers/chemical antioxidants, [0008] Living systems under normal conditions pro- suchas vitamin C and vitamin E, counteractand minimize duce the vast majority of free radicals and free radical free radical damage by donating or providing unpaired intermediates. They handle free radicals formed by the 35 electrons to a free radical and converting it to a nonradical breakdown of compounds through the process of metab- form. Such reducing compounds may terminate radical olism. Most reactive oxygen species come from endog- chain reactions and reduce hydroperoxides and epox- enous sources as by-products of normal and essential ides to less reactive derivatives. metabolic reactions, such as energy generation from mi- [0014] The term "solid state defense" as used herein tochondria or detoxification reactions involving the cyto- 40 refers to the mechanism whereby a macromolecule binds chrome P-450 enzyme system. The major sources of free a radical-generating compound, de-excites an excited - - radicals, such as O2 and HNO2 , are modest leakages state species, or quenches a free radical. The most im- - HNO2 , are modest leakages from the electron transport portant solid-state defense in the body is the black pig- chains of mitochondria, chloroplasts, and endoplasmic ment melanin, which scavenges odd electrons to form reticulum. 45 stable radical species, thus terminating radical chain re- [0009] Reactive oxygen species ("ROS"), such as free actions. radicals and peroxides, represent a class of molecules [0015] Enzymatic defenses against active free radical that are derived from the metabolism of oxygen and exist species include superoxide dismutase, catalases, and inherently in all aerobic organisms. The term "oxygen the glutathione reductase/peroxidase system. Superox- radicals" as used herein refers to any oxygen species 50 ide dismutase (SOD) is an enzyme that destroys super- that carries an unpaired electron (except free oxygen). oxide radicals. Catalase, a heme- based enzyme that ca- The transfer of electrons to oxygen also may lead to the talyses the breakdown of hydrogen peroxide into oxygen production of toxic free radical species. The best docu- and water, is found in all living cells, especially in the mented of these is the superoxide radical. Oxygen radi- peroxisomes, which, in animal cells, are involved in the cals, such as the hydroxyl radical (OH-) and the super- 55 oxidation of fatty acids and the synthesis of cholesterol - oxide ion (O2 ) are very powerful oxidizing agents that and bile acids. Hydrogen peroxide is a byproduct of fatty cause structural damage to proteins, lipids and nucleic acid oxidation and is produced by white blood cells to kill acids. The free radical superoxide anion, a product of bacteria.

2 3 EP 2 589 381 A1 4

[0016] Glutathione, a tripeptide composed of glycine, tathione available. glutamic acid, and cysteine that contains a nucleophilic [0021] Glutathione reductase, a flavoprotein enzyme thiol (SH) group, is widely distributed in animal and plant of the oxidoreductase class, is essential for the mainte- tissues. It exists in both the reduced thiol form (GSH) and nance of cellular glutathione in its reduced form (Carlberg the oxidized disulfide form (GSSG). In its reduced GSH 5 & Mannervick, J. Biol. Chem. 250: 5475-80 (1975)). It form, glutathione acts as a substrate for the enzymes catalyzes the reduction of oxidized glutathione (GSSG) GSH-S-transferases and GSH peroxidases, both of to reduced glutathione (GSH) in the presence of NADPH which catalyze reactions for the detoxification of xenobi- and maintains a high intracellular GSH/GSSG ratio of otic compounds, and for the reduction of reactive oxygen about 500 in red blood cells. species and other free radicals. The term "xenobiotic" is 10 [0022] Synthesis of GSH requires cysteine, a condi- used herein to refer to a chemical which is not a natural tionally essential amino acid that must be obtained from component of the organism exposed to it. dietary sources or by conversion of dietary methionine [0017] Examples of xenobiotics include, but are not via the cystathionase pathway. If the supply of cysteine limited to, carcinogens, toxins and drugs. The metabo- is adequate, normal GSH levels are maintained. But GSH lism of xenobiotics usually involves two distinct stages. 15 depletion occurs if supplies of cysteine are inadequate Phase I metabolism involves an initial oxidation, reduc- to maintain GSH homeostasis in the face of increased tion or dealkylation of the xenobiotic by microsomal cy- GSH consumption. Acute GSH depletion causes severe tochrome P-450 monooxygenases (Guengerich, F.P. -- sometimes fataloxidative and/or alkylation injury, and Chem. Res. Toxicol. 4: 391-407 (1991); this step is often chronic or slow arising GSH deficiency due to adminis- needed to provide hydroxyl- or amino groups, which are 20 tration of GSH- depleting drugs, such as acetaminophen, essential for phase 11 reactions. Glutathione detoxifies or to diseases and conditions that deplete GSH, may be many highly reactive intermediates produced by cyto- similarly debilitating. chrome P450 enzymes in phase I metabolism. Without [0023] Cysteine is necessary to replenish GSH. Al- adequate GSH, the reactive toxic metabolites produced though various forms of cysteine and its precursors have by cytochrome P- 450 enzymes may accumulate causing 25 been used as nutritional and therapeutic sources of organ damage. cysteine, N-acetylcysteine (NAC) is the most widely used [0018] Phase II metabolism generally adds hydrophilic and extensively studied. NAC is about 10 times more moieties, thereby making a toxin more water soluble and stable than cysteine and much more soluble than the less biologically active. Frequently involved phase II con- stable cysteine disulfide, cystine. Glutathione, glutath- jugation reactions are catalyzed by glutathione S-trans- 30 ione monoethyl ester, and L- 2-oxothiazolidine-4-carbox- ferases (Beckett, G.J. & Hayes, J.D., Adv. Clin. Chem. ylate (procysteine/OTC) also have been used effectively 30: 281-380 (1993), sulfotransferases (Falany, CN, in some studies. In addition, dietary methionine and S- Trends Pharmacol. Sci. 12: 255-59 (1991), and UDP- adenosylmethionine are an effective source of cysteine. glucuronyl-transferases (Bock, KW, Crit. Rev. Biochem. [0024] It is well known that NAC, as a cysteine prodrug, Mol. Biol. 26: 129-50 (1991). Glutathione S- transferases 35 promotes cellular glutathione production, and thus de- catalyze the addition of aliphatic, aromatic, or heterocy- creases, or even prevents, oxidant-mediated damage. clic radicals as well as epoxides and arene oxides to glu- In addition, NAC may act as a direct scavenger for oxi- tathione. These glutathione conjugates then are cleaved dants. Treatment with NAC provides beneficial effects in to cysteine derivatives primarily by renal enzymes and a number of respiratory, cardiovascular, endocrine, in- then acetylated, thus forming N-acetylcysteine deriva- 40 fectious, and other disease settings as described in tives. Examples of compounds transformed to reactive WO05/017094, the contents of which are herein incor- intermediates and then bound to GSH include, but are porated by reference. For example, rapid administration not limited to, bromobenzene, chloroform, and acetami- of NAC is the standard of care for preventing hepatic nophen. Such toxicants may deplete GSH. injury in acetaminophen overdose. NAC administered in- [0019] Depletion of GSH may diminish the body’s abil- 45 travenously in dogs has been shown to protect against ity to defend against lipid peroxidation. Glutathione is a pulmonary oxygen toxicity and against ischemic and cofactor for Glutathione peroxidase (GPx), an enzyme reperfusion damage [Gillissen, A., and Nowak, A., of the oxidoreductase class, which catalyzes the detoxi- Respir. Med. 92: 609-23, 613 (1998)]. NAC treatment fying reduction of hydrogen peroxide and organic perox- also has been shown to decrease NF-κB activation, ides via oxidation of glutathione. GSH is oxidized to the 50 which in turn decreases neutrophilic inflammation in the disulfide linked dimer (GSSG), which is actively pumped lung. out of cells and becomes largely unavailable for recon- [0025] Antioxidant Therapy In Chronic Pulmonary version to reduced glutathione. Loss of large amounts of Diseases GSH results in cell death, while loss of smaller amounts [0026] The lung exists in a high-oxygen environment, can change cell function. 55 and together with its large surface area and blood supply, [0020] Thus, unless glutathione is resynthesized is highly susceptible to injury mediated by oxidative through other pathways, utilization of oxidized glutath- stress. Since reactive oxygen species (ROS) are con- ione is associated with a decrease in the amount of glu- stantly formed in the lung, and since oxygen metabolites

3 5 EP 2 589 381 A1 6 are believed to play a predominant role in the pathogen- treatment (preventive or symptomatic) of exacerbations esis of various pulmonary inflammatory disorders, anti- in a subset of patients with COPD who are not receiving oxidant therapy would seem to be a rational approach to inhaled corticosteroids (Sutherland, E.R., et al., COPD take in pulmonary diseases. Patients with acute respira- Chronic Obstructive Pulmonary Disease 3: 195-202 tory distress syndrome (ARDS), idiopathic pulmonary fi- 5 (2006)). Although treatment with 600 mg oral NAC per brosis (IPF), or chronic obstructive pulmonary disorder day was ineffective at preventing deterioration in lung (COPD) have been the primary targets for clinical studies function and exacerbations in patients with COPD who evaluating the efficacy of NAC in antioxidant therapy. The had frequent exacerbations (i.e., at least two per year for results have been, for the most part, inconclusive. 2 years), these investigators suggested that higher doses [0027] COPD, a syndrome of chronic airway inflamma- 10 of NAC, such as 1200 mg or 1800 mg per day, could be tion, initiated in most cases by chronic tobacco smoke assessed in future trials (Decramer, M., Lancet 365: exposure, which damages the airways and lung paren- 1552-60 (2005)). Oral NAC at high doses (generally 1.2 chyma over many years, has been extensively studied to 1.8 g/day) also has been proposed for the treatment in this regard. An accelerated functional deterioration is (preventive or symptomatic) of exacerbations in chronic accompanied by the development of cough, sputum pro- 15 bronchitis, an inflammation, or irritation, of the airways in duction, dyspnea, and abnormal gas exchange, and the lungs characterized by a chronic cough and chronic leads to an increasing risk of acute flares of disease re- mucus production without another known cause (see ferred to as exacerbations. Exacerbation frequency in- Grandjean, E.M. et al., Clinical Therapeutics (2): 22 creases as the disease progresses, further accelerating 209-21 (2000), and Stey, C., et al., Eur. Resp. J. 16: lung function decline. 20 253-62 (2000)). [0028] The presence of oxidative stress in the airways [0030] Cystic Fibrosis of smokers and patients with COPD has been shown by [0031] Cystic fibrosis (CF) is an inherited autosomal increased products of lipid peroxidation and altered anti- recessive disorder. It is one of the most common fatal oxidant status. Patients with COPD are known to have genetic disorders in the United States, affecting about increased numbers of activated neutrophils in their air- 25 30,000 individuals, and is most prevalent in the Cauca- ways that are believed to be attracted to the airways by sian population, occurring in one of every 3,300 live the cytokines IL-8 and TNF-α, which are present in in- births. The gene involved in cystic fibrosis, which was creased levels in the lungs of patients with stable COPD. identified in 1989, codes for a protein called the cystic Drost, E.M., Skwarski, K.N., Sauleda, J., Soler, N., Roca, fibrosis transmembrane conductance regulator (CFTR). J., Agusti, A., MacNee, W. "Oxidative Stress and Airway 30 CFTR is normally expressed by exocrine epithelia Inflammation in Severe Exacerbations of COPD," Thorax throughout the body and regulates the movement of chlo- 60: 293-300 (2005) disclose that exacerbations of COPD ride ions, bicarbonate ions and glutathione into and out are considered to reflect worsening of the underlying of cells. In cystic fibrosis patients, mutations in the CFTR chronic inflammation in the airways. They reported that gene lead to alterations or total loss of CFTR protein func- increased oxidative stress in the airways of patients with 35 tion, resulting in defects in osmolarity, pH and redox prop- COPD is increased further in severe and very severe erties of exocrine secretions. In the lungs, CF manifests exacerbations of the disease and is associated with in- itself by the presence of a thick mucus secretion which creased neutrophil influx and levels of IL- 8, an inflamma- clogs the airways. In other exocrine organs, such as the tory cytokine associated with airway inflammation in sweat glands, CF may not manifest itself by an obstruc- COPD. The study acknowledged that in COPD, the in- 40 tive phenotype, but rather by abnormal salt composition terpretation of differences between exacerbations and of the secretions (hence the clinical sweat osmolarity test the stable state may actually be a reflection of differences to detect CF patients). in disease severity, because exacerbations were studied [0032] The predominant cause of illness and death in in patients with severe and very severe underlying COPD cystic fibrosis patients is progressive lung disease. The and compared with stable patients with moderate dis- 45 thickness of CF mucus, which blocks the airway passag- ease. es, is believed to stem from abnormalities in osmolarity [0029] While there is some evidence that oral NAC off- of secretions, as well as from the presence of massive sets chronic redox stress when administered in the long amounts of DNA, actin, proteases and prooxidative en- term for chronic respiratory conditions, some studies zymes originating from a subset of inflammatory cells, have demonstrated a beneficial effect, but others have 50 called neutrophils. Indeed, CF lung disease is character- not. For example, NAC has been used for over 20 years ized by early, hyperactive neutrophil-mediated inflamma- to treat COPD, a disease not characterized by glutath- tory reactions to both viral and bacterial pathogens. ione deficiency. Gillissen and Nowak, Respir. Med. 92: [0033] The hyperinflammatory syndrome of CF lungs 609-23, 615 (1998), for example, reported that improve- has several underpinnings, among which an imbalance ments in glutathione levels were seen in patients with 55 between pro-inflammatory chemokines, chiefly IL- 8, and ARDS and IPF, but not COPD, who received 600-1800 anti-inflammatory cytokines, chiefly IL- 10, seems to play mg NAC given daily by mouth. Oral NAC at high doses a major role. See Chmiel et al. Clin Rev Allergy Immunol. (generally 1.2 to 1.8 g/day) has been proposed for the 3(1):5-27 (2002). Chronic oxidative stress in CF patients

4 7 EP 2 589 381 A1 8 may severely affect the deformability of blood neutrophils patients weighing more than 30 kg). Ratjen, F., et al., circulating in CF lung capillaries, thereby increasing their Eur. J. Pediatr. 144(4): 374-78 (1985) reported improve- recruitment to the lungs. See Hogg. Physiol Rev. 67 (4): ment in some measures of lung function but saw no sig- 1249-95 (1987). Chronic oxidative stress in CF is linked nificant clinical differences between patients treated with to the overwhelming release of oxidants by inflammatory 5 oral NAC (200 mg 3 times a day), the secretolytic drug lung neutrophils and to abnormal antioxidant defenses ambroxol (30 mg, three times daily), and placebo. A very caused by malabsorption of dietary antioxidants through short fourth study (2 weeks) failed to find any significant the gut and a possible defect in GSH efflux. See Wood difference between the trial arms. See Gotz et al, Eur. J. et al. J. Am. Coll. Nutr. 20 (2 Suppl):157-165 (2001). Resp. Dis. 61 (Suppl) 111: 122-26 (1980). [0034] The hyperinflammatory syndrome at play in CF 10 [0037] Duijvestijn, Y.C. and Brand, P.L. Acta Paediatr. lungs may predispose such patients to chronic infections 88(1): 38-41 (1999) observed, however, that despite the with opportunistic bacterial pathogens. The most com- fact that NAC commonly is used in CF, there is remark- mon bacterium to infect the CF lung isPseudomonas ably little published data on its effects. They tested their aeruginosa, a gram-negative microorganism. The lungs hypothesis that NAC’s antioxidant properties could be of most children with CF become colonized by P. aeru- 15 useful in preventing decline of lung function (defined as ginosa before their third birthday. By their tenth birthday, forced expiratory volume in one second, or FEV1) in cyst- P. aeruginosa becomes dominant over other opportun- ic fibrosis by performing a systematic review of the liter- istic pathogens. See Gibson et al., Am. J. Respir. Crit ature to evaluate whether published evidence supports Care Med., 168 (8): 918-951 (2003). P. aeruginosa infec- the use of NAC administered orally or by nebulization to tions further exacerbate neutrophilic inflammation, which 20 improve lung function in patients with cystic fibrosis. They causes repeated episodes of intense breathing problems identified 23 papers, the majority of which were uncon- in CF patients. Although antibiotics may decrease the trolled clinical observations, of which only three rand- frequency and duration of these attacks, the bacterium omized controlled trials on nebulized NAC were found. progressively establishes a permanent residence in CF None of these studies showed a statistically significant lungs by switching to a so-called "mucoid" biofilm form 25 or clinically relevant beneficial effect of NAC aerosol. of high resistance and low virulence, which never may They found a small beneficial effect of doubtful clinical be eliminated completely from the lungs. The continuous relevance of oral NAC on FEV1 in CF. Although they presence in CF lungs of inflammatory by- products, such suggested that the effects of long-term treatment with as extracellular DNA and elastase, could play a major oral NAC on lung function in CF should be investigated, role in selecting for mucoidP. aeruginosa forms. See 30 they concluded that there is no evidence supporting the Walker et al. Infect Immun. 73(6): 3693-3701 (2005). use of N-acetylcysteine in cystic fibrosis. [0035] Treatments for CF lung disease typically involve [0038] Despite these findings, redox-based therapy is antibiotics, anti-inflammatory drugs, bronchodilators, an attractive idea for CF, since redox imbalance is a and chest physiotherapy to help fight infection, neu- well-recognized aspect of the disease, yet seldom con- trophilic inflammation and obstruction and clear the air- 35 sidered as a therapeutic target. See Cantin, Curr Opin ways. Nevertheless, the persistent, viscous and toxic na- Pulm Med. 10 (6):531-6 (2004). Systemic oxidative stress ture of airway secretions in cystic fibrosis lung disease may affect blood neutrophils by lowering their intracellu- still leads to progressive deterioration of lung function. lar GSH levels, which in turn renders them more prone See Rancourt et al., Am. J. Physiol. Lung Cell Mol. Phys- to lung trapping and dysfunction. See Hogg. Physiol Rev. iol. 286(5): L931-38 (2004). 40 67(4):1249-95 (1987). Besides, systemic oxidative [0036] Although it is characterized by heavy inflamma- stress may alter the chemokine/cytokine balance, favor- tion, CF historically was thought to be a mucus disease. ing inflammation, which systemic NAC treatment may N-acetylcysteine (NAC) is a widely used mucolytic drug help alleviate. See Zafarullah et al. Cell Mol Life Sci. 60 in patients with a variety of disorders, including cystic (1):6-20 (2003). fibrosis. See Rochat,et al.,J. Cell Physiol. 201 (1): 106-16 45 [0039] Acute Exacerbations Of Pulmonary Disease (2004). It has been hypothesized that NAC works as a [0040] A systematic review of randomized controlled mucolytic by rupturing the disulfide bridges of the high trials for established acute oxidative/inflammatory syn- molecular weight glycoproteins present in the mucus, re- dromes, such as Acute Respiratory Distress Syndrome sulting in smaller subunits of the glycoproteins and re- (ARDS), which is characterized by diffuse inflammation duced mucous viscosity. Id. To this end, researchers and 50 of the lung’s alveolar-capillary membrane in response to clinicians have administered NAC to CF patients gener- various pulmonary and extrapulmonary insults, and ally by nebulization, as well as orally. Two placebo- con- Acute Lung Injury (ALI), a milder form of lung injury, trolled studies have reported beneficial effects of oral showed that NAC had no effect on early mortality in these NAC treatment on lung function in cystic fibrosis. See G. diseases (Adhikari, N., Bums, KEA, Meade, MO, The Co- Stafanger, et al., Eur. Respir. J. 1 (2): 161-67 (1988). Ac- 55 chrane Library 1: 1-43, John Wiley & Sons, Ltd., 2008). tive treatment consisted of NAC administered as a 200 [0041] Acute exacerbations of CF are characterized mg oral dose three times daily (for patients weighing less by increased oxidative stress and sputum concentrations than 30 kg) or as a 400 mg oral dose two times daily (for of bioactive lipid mediators. Reid, D. W., et al., Respirol-

5 9 EP 2 589 381 A1 10 ogy 12 (1): 63-69 (2007). McGrath, L.T. et al, "Oxidative The results of the study showed that NAC plus standard stress during acute respiratory exacerbations in cystic therapy (prednisone plus azothioprine) slows the deteri- fibrosis," Thorax 54: 518-523 (1999) have reported that oration of the primary endpoints vital capacity and DL CO during acute respiratory exacerbations, patients with CF in patients with IPF better than does the standard therapy are subject to acute oxidative attack in addition to the 5 (prednisone plus azothioprine) alone. chronic systemic oxidative stress found in this condition. [0046] Episodes of idiopathic acute respiratory deteri- Such acute respiratory exacerbations in CF are charac- oration have been termed acute exacerbations of IPF. terized by increased respiratory symptoms, reduction in Collard, H.R. et al., Am. J. Respir. Crit. Care med. 176 forced expiratory volume in one second ("FEV1") of more (7): 636-43 (2007). The etiology of acute exacerbations than 10%, and a decision to treat with intravenous anti- 10 of IPF is unknown. There are several competing hypoth- biotics. As reported, although almost all of the antioxidant eses, including, but not limited to, the hypothesis that scavengers developed to cope with the acute attack were acute exacerbations of IPF represents a distinct, patho- partially depleted during infection, antibiotic treatment of biological manifestation of the primary disease process, the acute infection tended to reduce measures of free characterized by idiopathic lung injury; the hypothesis radical damage by moderating the infection and hence 15 that acute exacerbations of IPF may represent clinically the immune response. occult but biologically distinct conditions that go undiag- [0042] Like in CF, it is known that chronic phase and nosed, such as viral infection, or aspiration; and the hy- acute pathological flares of such chronic pulmonary dis- pothesis that acute exacerbations of IPF may be the se- eases as Acute Respiratory Distress Syndrome (ARDS), quelae of an acute direct stress to the lung, with a sub- Acute Lung Injury (ALI), Chronic Bronchitis (CB), and 20 sequent acceleration of the already abnormal fibroprolif- Chronic Obstructive Pulmonary Disease (COPD) share erative process intrinsic to IPF. a common feature, i.e., their chronic phase and acute [0047] Asthma is an inflammatory disease of the lungs pathological flares are associated with redox and inflam- characterized by reversible (in most cases) airway ob- matory dysfunctions and an increased proteolysis of lung struction due to narrowing of the conducting airways, hy- tissue. 25 per-responsiveness/hyper-reactivity, and chronic inflam- [0043] Unlike CF, ARDS, ALI, CB, and COPD, both mation characterized by an influx and activation of in- Idiopathic Pulmonary Fibrosis (IPF) and Asthma are flammatory cells, generation of inflammatory mediators, characterized by considerable matrix thickening/deposi- and epithelial cell shedding. In chronic asthma, there is tion in the mucosa/lumen of the airways. The effect of an increased sequestration within the lungs of leukocytes high-dose oral NAC has not been tested against acute 30 from the peripheral microcirculation. Since many chronic exacerbations in either IPF or asthma. asthma patients have eosinophilic infiltrates, eosinophils [0044] Idiopathic Pulmonary Fibrosis (IPF), a syn- are thought to play a critical role in the inflammatory re- drome regrouping several diseases with progressive fi- sponse inchronic asthma. Indeed, it isbelieved thatmuch brosis of the alveoli, is a chronic, progressive, incurable of the lung problems in chronic asthma relates to the lung disease characterized by deposition of fibers in the 35 eosinophil disease. In addition, neutrophils isolated from lung through the hyperproliferation of myofibroblasts. peripheral blood of asthmatic patients generate greater Causative factors remain unknown. In some individuals, amounts of reactive oxygen species than cells from nor- it develops quickly, while others have cryptic disease. An mal subjects, may be involved in acute exacerbations of oxidant-antioxidant imbalance that depletes glutathione asthma. (Kirkham, P., Rahman, I., Pharmacology & Ther- levels has been described in IPF. 40 apeutics 111: 476-94 (2006)). [0045] A clinical study reported by Demedts, Maurits, [0048] Oxidative stress is believed to play a key role et al., New England J. Med. 353 (21): 2229-42 (2005) in the pathogenesis of clinically stable (chronic) bronchial has suggested that NAC may be beneficial when com- asthma. It also has been shown that acute exacerbations bined with standard therapies for chronic IPF, but the of asthma [meaning a sudden increase in breathlessness study was not powered to show the impact of NAC on 45 over the preceding 48 hours and presence of one of the survival, did not address use of NAC as a primary therapy following signs: tachypnea (meaning a respiratory rate in IPF patients, and did not address the effect of high- of >18), use of accessory muscles or respiration, audible dose oral NAC on acute exacerbations of IPF. The dou- wheezing, prolonged expiration with rhonchi (meaning a ble-blind, randomized, placebo-controlled multicenter sound occurring during inspiration or expiration caused study assessed the effectiveness over one year of 600 50 by air passing through bronchi that are narrowed by in- mg NAC administered three times daily added to stand- flammation, spasm of smooth muscle, or presence of mu- ard therapy with prednisone plus azothioprine to test cus in the lumen heard on auscultation (meaning a diag- whether this regimen would slow the functional deterio- nostic method of listening to the sounds made) of the ration in patients with IPF has been reported. The primary chest] are associated with increased inflammation in the endpoints were changes between baseline and month 55 airways and with increased oxidative stress. Nadeem, 12 in vital capacity (meaning the total amount of air that A., et al., J. Asthma 1:45-50 (2005). may be exhaled after a maximum inspiration) and in sin- [0049] Asthmatic exacerbations commonly occur in gle-breath carbon monoxide diffusing capacity ("DL CO"). two phases: an immediate phase, caused by release of

6 11 EP 2 589 381 A1 12 mediators, that often is characterized by bronchocon- the pharmaceutical composition is individually wrapped striction resulting in wheezing and coughing, and an in- to avoid oxidation. According to another embodiment, flammatory or late phase, that includes increasing airway the pharmaceutical composition is formulated for oral ad- inflammation, which leads to hyper-responsiveness. ministration. According to another embodiment, the phar- [0050] There are many published guidelines for man- 5 maceutical composition is formulated for parenteral, in- agement of asthma available, but there is little if any doc- travenous, intratracheal, intramuscular, or intraperito- umented objective data to support their usefulness in neal administration. According to another embodiment, acute care of asthma. the therapeutically effective amount comprises at least [0051] Although chronic redox and inflammatory 200 mg ofN-acetylcysteine, the derivative of N-acetyl- stresses in asthma (Nadeem, 2005; Kirkham 2006) have 10 cysteine, or the pharmaceutically acceptable salt of N- been documented, the effect of high-dose oral NAC has acetylcysteine but less than 20,000 mg acetyl- ofN- not been tested against acute exacerbations in asthma. cysteine, the derivative of N- acetylcysteine, or the phar- [0052] Tuberculosis (TB), once believed to have been maceutically acceptable salt of N-acetylcysteine. Ac- almost eradicated, has shown a resurgence and a sub- cording to another embodiment, the therapeutically ef- stantial increase in drug resistance. Human immunode- 15 fective amount ranges from about 900 mg per day of N- ficiency virus (HIV) infection is a major risk factor for the acetylcysteine, the derivative ofN-acetylcysteine, or the development of TB, and TB seems to make HIV infection pharmaceutically acceptable salt of N-acetylcysteine to worse [Sacchetini, J.C., et al. Nat. Rev. Microbiol. 6(1): about 2,700 mg per day of N-acetylcysteine, the deriva- 41-52 (2008)]. Immune reconstitution inflammatory syn- tive of N- acetylcysteine, or the pharmaceutically accept- drome (referred to herein as IRS or IRIS), is an adverse 20 able salt of N-acetylcysteine. According to another em- consequence of the restoration of pathogen- specific im- bodiment, the therapeutically effective amount for oral mune responses in HIV infected patients during the initial administration is about 900 mg of N-acetylcysteine, the months of highly active anti- retroviraltherapy. Symptoms derivative ofN-acetylcysteine, or the pharmaceutically include fever, lymphadenopathy, and worsening of res- acceptable salt of N-acetylcysteine each time, three piratory and other TB symptoms. Although the patho- 25 times a day. The method of treatment using the pharma- physiology of IRIS is unknown, preliminary investigations ceutical composition of the invention further comprises suggest that an acute exacerbation of mycobacterium- monitoring at least one lung function before and at a plu- specific Th1 responses against mycobacterial antigens rality of time points during treatment. Preferably, moni- after HIV infection control by this therapy may cause IRIS toring at least one lung function is carried out at 4, 8, 12, in HIV/TB patients. See Bougarit, A. et al., AIDS 20: FI- 30 16, 20, and 24 weeks following treatment. According to F7 (2006); Shankar, E.M., AIDS Research & Therapy 4: another embodiment, improved lung function of the pa- 29 (2007). tient is maintained for at least 6 months following admin- [0053] The present invention describes use of NAC as istration of the therapeutically effective amount ofN- ace- a primary therapy to improve or preserve lung function tylcysteine, the derivative ofN-acetylcysteine, or the in patients suffering from a pulmonary disorder that in- 35 pharmaceutically acceptable salt of N-acetylcysteine. cludes an inflammatory component. According to another embodiment, the pharmaceutical [0054] SUMMARY OF THE INVENTION composition increases Forced Expiratory Volume in one [0055] According to one aspect, the described inven- second (FEV1) of the patient compared to the Forced tion provides a pharmaceutical composition for improving Expiratory Volume in one second (FEV1) of an untreated or preserving a lung function in a patient suffering from 40 control patient. According to another embodiment, the a pulmonary disorder comprising an inflammatory com- pharmaceutical composition increases Forced Expirato- ponent, the pharmaceutical composition comprising a ry Volume in one second (FEV1) of the patient by at least therapeutically effective amount of N-acetylcysteine, a 4% over the Forced Expiratory Volume in one second derivative of N-acetylcysteine, or a pharmaceutically ac- (FEV1) of the untreated control patient. According to an- ceptable salt of N-acetylcysteine and a carrier, wherein 45 other embodiment, the pharmaceutical composition in- the therapeutically effective amount is effective to im- creases Forced Expiratory Volume in one second (FEV1) prove or preserve the lung function in the patient. of the patient by at least 0.15% over a baseline Forced [0056] The pulmonary disorder comprising an inflam- Expiratory Volume in one second (FEV1) value of the matory component may be cystic fibrosis, chronic ob- patient measured before treatment. According to another structive pulmonary disorder (COPD), idiopathic pulmo- 50 embodiment, the pharmaceutical composition increases nary fibrosis, or a bacterial infection in the lung. The pul- Forced Expiratory Volume in one second (FEV1) of the monary disorder comprising an inflammatory component patient by at least 2% over a baseline Forced Expiratory may be tuberculosis. According to an embodiment, the Volume in one second (FEV1) value of the patient meas- compositionis capable of acute or chronic administration. ured before treatment. According to another embodi- According to another embodiment, the pharmaceutical 55 ment, the pharmaceutical composition increases time composition is a tablet. According to another embodi- between exacerbations in the patient compared to a con- ment the pharmaceutical composition is an effervescent trol. According to another embodiment, the pharmaceu- tablet. According to another embodiment, each dose of tical composition reverses at least one symptom associ-

7 13 EP 2 589 381 A1 14 ated with the pulmonary disorder. According to another cysteine-treated and placebo-treated groups. embodiment, the pharmaceutical composition further [0070] DETAILED DESCRIPTION OF THE INVEN- comprises an anti- infective agent, bronchodilating agent, TION or anti-inflammatory agent. According to another embod- [0071] The present invention describes compositions iment, the pharmaceutical composition increases Forced 5 and methods for improving or preserving lung function in

Expiratory Volume in one second (FEV1) of a patient a patient suffering from an inflammatory lung disease. In treated with the pharmaceutical composition by a pro- some embodiments, the inflammatory lung disease is portion in the range from 4% to 6% over the FEV 1 value bronchial asthma. In some embodiments, the inflamma- of an untreated control patient. According to another em- tory lung disease is Idiopathic Pulmonary Fibrosis (IPF). bodiment, the pharmaceutical composition increases10 In some embodiments, the inflammatory lung disease is

Forced Expiratory Volume in one second (FEV 1) of a pa- cystic fibrosis (CF). In some embodiments, the inflam- tient treated with the pharmaceutical composition by a matory lung disease is tuberculosis, with or without co-in- proportion in the range from 0.15% to 2% over a baseline fection with HIV.

Forced Expiratory Volume in one second (FEV1) value [0072] The term "acute" as used herein refers to a rapid of the patient measured before treatment. 15 onset, brief (not prolonged), and severe health-related [0057] BRIEF DESCRIPTION OF THE DRAWINGS state, and to a plan of treatment designed to achieve [0058] FIGURE 1 shows a diagram of a multi-center certain results over a brief term. phase IIB randomized placebo-controlled, double-blind [0073] The term "fibroblast growth factor (FGF)" refers study designed for assessing the effects of oral N-ace- to a family of over a dozen structurally related members. tylcysteine in cystic fibrosis patients. 20 FGF1 is also known as acidic FGF; FGF2 is sometimes [0059] FIGURE 2 shows baseline characteristics of called basic FGF (bFGF); and FGF7 sometimes goes by cystic fibrosis patients enrolled in the phase IIB clinical the name keratinocyte growth factor. FGFs can activate study. a set of receptor tyrosine kinases called the fibroblast [0060] FIGURE 3 shows baseline pulmonary function growth factor receptors (FGFRs). Receptor tyrosine ki- of cystic fibrosis patients enrolled in the phase IIB clinical 25 nases are proteins that extend through the cell mem- study. brane. When the FGF receptor binds an FGF (and only [0061] FIGURE 4 shows primary and secondary out- when it binds an FGF), the dormant kinase is activated, comes of the oral administration of N-acetylcysteine in and phosphorylates certain proteins within the respond- cystic fibrosis patients as compared to a placebo-treated ing cell, activating those proteins. FGFs are associated group. 30 with several developmental functions, including angio- [0062] FIGURE 5 shows a graph plotting the change genesis (blood vessel formation), mesoderm formation, in neutrophil elastase activity (ml/ml) measured at and axon extension. While FGFs often can substitute for screening, week 12 and week 24 for NAC-treated (dark one another, their expression patterns give them sepa- grey) and placebo-treated (light grey). rate functions. FGF2, for example, is especially important [0063] FIGURE 6 shows a graph plotting the relative 35 in angiogenesis. % change in functional expiratory volume in liters meas- [0074] The term "chronic" refers to a persistent, ured at screening, week 12 and week 24 for NAC-treated long-term, health-related state of 3 months duration or (dark grey) and placebo-treated (light grey). longer and to a plan of treatment designed to achieve [0064] FIGURE 7 shows a graph plotting the relative certain results over a long term. % change in functional expiratory volume in liters meas- 40 [0075] The term "condition," as used herein, refers to ured at screening, week 12 and week 24 forNAC+inhaled a varietyof health states andis meant to include disorders antibiotics-treated (solid dark grey), treated NAC- or diseases, and inflammation caused by any underlying (dashed dark grey), placebo + inhaled antibiotics- treated mechanism or disorder. (solid light grey) and placebo- treated (dashed light grey). [0076] The term "disease" or "disorder," as used here- [0065] FIGURE 8shows a graph plottingthe proportion 45 in, refers to an impairment of health or a condition of of event-free pulmonary exacerbation over 24 weeks for abnormal functioning. NAC-treated (dark grey) and placebo- treated (light grey). [0077] The terms "event" or "adverse event" are used [0066] FIGURE 9 shows adverse events measured in interchangeably to refer to any undesirable experience N-acetylcysteine-treated and placebo-treated groups. associated with the use of a medical product in a patient. [0067] FIGURE 10 shows cystic fibrosis respiratory 50 [0078] The term "exacerbations" as used herein refers symptoms diary ("CFRSD") results in N-acetyl-to an increase in the severity of a disease or any of its cysteine-treated and placebo-treated groups. signs or symptoms. A pulmonary exacerbation, for ex- [0068] FIGURE 11 shows cystic fibrosis questionnaire ample, is a worsening of respiratory signs and symptoms. revised ("CFQ-R") respiratory score in N-acetyl-The term "event free exacerbation" as used herein there- cysteine-treated and placebo-treated groups. 55 fore refers to an exacerbation that is not connected to an [0069] FIGURE 12 shows exacerbations (pulmonary adverse event. and sinus) and related events (hospitalized, antibiotic [0079] The term "hypoxia-inducible factor (HIF-1) re- treatment -oral, inhaled and IV antibiotics) in N-acetyl- fers to an inducible transcriptional complex that plays an

8 15 EP 2 589 381 A1 16 essential role in cellular responses to hypoxia. By hy- pressed as liters. The term "FEV1/FVC" or "FEV1 Per- droxylation of specific prolyl and asparinyl residues in the cent (FEV1%)" as used herein refers to the ratio of FEV1 α subunit of HIF by a series of non-haem iron- dependent to FVC. It indicates what percentage of the total FVC was dioxygenases, transduces the oxygen-sensitive signal. expelled from the lungs during the first second of forced [0080] The term "idiopathic" refers to a disease of un- 5 exhalation. This number is called FEV1%, %FEV1 or known cause. FEV1/FVC ratio. The term "FEV3" or "Forced Expiratory [0081] The term interstitial lung disease ("ILD") in- Volume in Three Seconds" as used herein refers to the cludes a variety of chronic lung disorders in which lung volume of air which can be forcibly exhaled in three sec- tissue is damaged in some known or unknown way, the onds, which is measured in Liters. This volume usually walls of the air sacs in the lung become inflamed; and 10 is fairly close to the FVC since, in the normal individual, scarring (or fibrosis) begins in the interstitium (or tissue most of the air in the lungs can be forcibly exhaled in between the air sacs) and the lung becomes stiff. When three seconds. The term "FEV3/FVC" or "FEV3%" as all known causes of interstitial lung disease have been used herein refers to the ratio of FEV3 to the FVC. It ruled out, the condition is called idiopathic pulmonary fi- indicates what percentage of the total FVC was expelled brosis. 15 during the first three seconds of forced exhalation. This [0082] The term "inflammation" as used herein refers is called "%FEV3" or "FEV3%". to the physiologic process by which vascularized tissues [0087] The term "FEF" or "Forced Expiratory Flow" as respond to injury. See, e.g., FUNDAMENTAL IMMU- used herein refers to a measure of how much air can be NOLOGY, 4th Ed., William E. Paul, ed. Lippincott- Raven expired from the lungs. It is a flow rate measurement and Publishers, Philadelphia (1999) at 1051-1053, incorpo- 20 is measured as liters/second or liters/minute. The FVC rated herein by reference. During the inflammatory proc- expiratory curve is divided into quartiles and therefore ess, cells involved in detoxification and repair are mobi- there is a FEF that exists for each quartile. The quartiles lized to the compromised site by inflammatory mediators. are expressed as FEF25%, FEF50%, and FEF75% of Inflammation is often characterized by a strong infiltration FVC. of leukocytes at the site of inflammation, particularly neu- 25 [0088] The term "FVC" or "Forced Vital Capacity" as trophils (polymorphonuclear cells). These cells promote used herein refers to the volume of air, which can be tissue damage by releasing toxic substances at the vas- forcibly and maximally exhaled out of the lungs until no cular wall or in uninjured tissue. Traditionally, inflamma- more can be expired. FVC is usually expressed in units tion has been divided into acute and chronic responses. called liters. [0083] The term "acute inflammation" as used herein 30 [0089] The terms "lung function" or "pulmonary func- refers to the rapid, short-lived (minutes to days), relatively tion" are used interchangeably herein refers to the func- uniform response to acute injury characterized by accu- tional status of the lungs. The primary instrument used mulations of fluid, plasma proteins, and neutrophilic leu- in pulmonary function testing is the spirometer. It is de- kocytes. Examples of injurious agents that cause acute signed to measure changes in volume and can only inflammation include, but are not limited to, pathogens 35 measure lung volume compartments that exchange gas (e.g., bacteria, viruses, parasites), foreign bodies from with the atmosphere. Spirometers with electronic signal exogenous (e.g. asbestos) or endogenous (e.g., urate outputs (pneumotachs) also measure flow (volume per crystals, immune complexes), sources, and physical unit of time). A device is usually attached to the spirom- (e.g., bums) or chemical (e.g., caustics) agents. eter, which measures the movement of gas in and out of [0084] The term "chronic inflammation" as used herein 40 the chest and is referred to as a spirograph. Exemplary refers to inflammation that is of longer duration and which endpoints that reflect lung function include, but are not has a vague and indefinite termination. Chronic inflam- limited to, FEV1, FEF, FVC, etc. mation takes over when acute inflammation persists, ei- [0090] The term "MVV" or "Maximal Voluntary Venti- ther through incomplete clearance of the initial inflamma- lation" as used herein refers to a value determined by tory agent or as a result of multiple acute events occurring 45 having the patient breathe in and out as rapidly and fully in the same location. Chronic inflammation, which in- as possible for 12 - 15 seconds. The total volume of air cludes the influx of lymphocytes and macrophages and moved during the test can be expressed as L/sec or fibroblast growth, may result in tissue scarring at sites of L/min. This test parameter reflects the status of the res- prolonged or repeated inflammatory activity. piratory muscles,compliance of thethorax- lungcomplex, [0085] A "control," as used herein, can refer to an ac- 50 and airway resistance. tive, positive, negative or vehicle control. As will be un- [0091] The term "PEFR" or "Peak Expiratory Flow derstood by those of skill in the art, controls are used to Rate" as used herein refers to a maximum flow rate establish the relevance of experimental results, and pro- achieved by the patient during the forced vital capacity vide a comparison for the condition being tested. maneuver beginning after full inspiration and starting and [0086] The term "FEV1" or "Forced Expiratory Volume 55 ending with maximal expiration. It can either be meas- in One Second" as used herein refers to the volume of ured in L/sec or L/min. air, which can be forcibly exhaled from the lungs in the [0092] As used herein, the term "modulate" or "modu- first second of a forced expiratory maneuver. It is ex- lating" refers to adjusting, changing, or manipulating the

9 17 EP 2 589 381 A1 18 function or status of at least one measure. Such modu- a pharmaceutically acceptable salt of NAC and a phar- lation may be any change, including an undetectable maceutically acceptable carrier. The therapeutically ef- change. fective amount is effective to preserve pulmonary func- [0093] The term "oxidative stress" as used herein re- tion or to improve lung function by, for example, reducing fers to a condition caused by an imbalance between re- 5 inflammation, reducing or reversing symptoms, extend- activeoxygen species and the antioxidant defense mech- ing the time between exacerbations or a combination anisms of a cell, leading to an excess production of ox- thereof. The term "improving or preserving lung function" ygen metabolites. Skaper, et al., Free Radical Biol. & in its various grammatical forms as used herein means Med. 22(4): 669-678 (1997). increasing or maintaining the performance of the lung in [0094] The term "redox" as used herein refers to re- 10 a patient affected by a pulmonary disorder. For example, duction and oxidation. Reduction may occur , for exam- lung function can be measured by pulmonary function ple, by (a) acceptance of one or more electrons by an tests using equipment designed for this purpose. Known atom or ion; (b) removal of oxygen from a compound; (c) techniques used in the art to monitor lung function in- addition of hydrogen to a compound. Oxidation may oc- clude, but are not limited to, spirometry, which provides cur, for example, by (a) loss of one or more electrons; 15 information about airflow limitation and lung volumes; (b) addition of oxygen to a compound; (c) loss of hydro- plethysmography, which provides information about air- gen from a compound. Oxidation and reduction generally way resistance, total lung size, and trapped gas; transfer occur simultaneously (redox reactions); the substance factor, which provides information about alveolar func- that gains electrons is terms the oxidizing agent, while tion; gas washout tests, which provide information about the substance that loses electrons is termed the reducing 20 gas mixing, small airway function, and heterogeneous agent. changes in compliance; computational tomography, [0095] The term "redox imbalance" as used herein re- which provides information about large and small airway fers to an imbalance between reactive oxygen species deterioration; and oscillometry, which may provide infor- and the antioxidant defense mechanisms of a cell. mation about small airways. [0096] The term "solid state defense" as used herein 25 [0101] As used herein the terms ""therapeutically ef- refers to the mechanism whereby a macromolecule binds fective amount" or "pharmaceutically effective a radical-generating compound, de-excites an excited amount" refer to the amount of the compositions of the state species, or quenches a free radical. invention that result in a therapeutic or beneficial effect [0097] The term "syndrome," as used herein, refers to following its administration to a subject. The concentra- a pattern of symptoms indicative of some disease or con- 30 tion of the substance is selected so as to exert its thera- dition. peutic effect, but low enough to avoid significant side [0098] As used herein the term "treating" includes ab- effects within the scope and sound judgment of the skilled rogating, substantially inhibiting, slowing or reversing the artisan. The effective amount of the composition may progression of a disease, condition or disorder, substan- vary with the age and physical condition of the biological tially ameliorating clinical or symptoms of a disease, con- 35 subject being treated, the severity of the condition, the dition or disorder, and substantially preventing the ap- duration of the treatment, the nature of concurrent ther- pearance of clinical or symptoms of a disease, condition apy, the specific compound, composition or other active or disorder. Treating further refers to accomplishing one ingredient employed, the particular carrier utilized, and or more of the following: (a) reducing the severity of the like factors. According to one embodiment, the therapeu- disease, condition or disorder; (b) limiting development 40 tically effective amount comprises at least 200 mg of of symptoms characteristic of the disease, condition or N-acetylcysteine, the derivative of N-acetylcysteine, or disorder(s) being treated; (c) limiting worsening of symp- the pharmaceutically acceptable salt of N- acetylcysteine toms characteristic of the disease, condition or disorder but less than 20,000 mg thereof. (s) being treated; (d) limiting recurrence of the disease, [0102] A skilled artisan may determine a therapeutical- condition or disorder(s) in patients that have previously 45 ly effective amount of the compositions described herein had the disease, condition or disorder (s); and (e) limiting by determining the unit dose. As used herein, a "unit recurrence of symptoms in patients that were previously dose" refers to the amount of a composition required to asymptomatic for the disease, condition or disorder(s). produce a response of 50% of maximal effect (i.e. ED50). [0099] The terms "VEGF-1" or "vascular endothelial The unit dose may be assessed by extrapolating from growth factor-1" are used interchangeably herein to refer 50 dose-response curves derived from in vitro or animal to a cytokine that mediates numerous functions of en- model test systems. The amount of the NAC compounds dothelial cells including proliferation, migration, invasion, in the compositions of the present invention which will be survival, and permeability. Although VEGF is a critical effective in the treatment of a particular disorder or con- regulator in physiological angiogenesis, it also plays a dition will depend on the nature of the disorder or condi- significant role in skeletal growth and repair. 55 tion, and may be determined by standard clinical tech- [0100] In one embodiment of the present invention, the niques. (See, for example, Goodman and Gilman’s THE composition of the present invention comprises a thera- PHARMACOLOGICAL BASIS OF THERAPEUTICS, peutically effective amount of NAC, a NAC derivative, or Joel G. Harman, Lee E. Limbird, Eds.; McGraw Hill, New

10 19 EP 2 589 381 A1 20

York, 2001; THE PHYSICIAN’S DESK REFERENCE, treatment. According to another embodiment, the meth- Medical Economics Company, Inc., Oradell, N.J., 1995; od further comprises monitoring at least one lung function and DRUG FACTS AND COMPARISONS, FACTS AND during chronic treatment. According to another embodi- COMPARISONS, INC., St. Louis, Mo., 1993). The pre- ment, the method further comprises monitoring at least cise dose to be employed in the formulation will also de- 5 one lung function before acute treatment. According to pend on the route of administration, and the seriousness another embodiment, the method further comprises of the disease or disorder, and should be decided ac- monitoring at least one lung function at intervals following cording to the judgment of the practitioner and each pa- acute treatment. According to another embodiment, the tient’s circumstances. method further comprises monitoring at least one lung [0103] The term "pharmaceutical composition," as10 function during acute treatment. used herein, refers to a composition that has under gone [0107] The terms "drug carrier", "carrier", or "vehicle" federal regulatory review, which prevents, reduces in in- as used herein refers to a pharmaceutically acceptable tensity, cures, ameliorates, or otherwise treats a target inert agent or vehicle for delivering one or more active disorder or disease. agents to a mammal, and often is referred to as "excipi- [0104] According to another embodiment, the pharma- 15 ent." As used herein the term "a pharmaceutically ac- ceutical composition is a tablet. According to another em- ceptable carrier" refers to any substantially non-toxic car- bodiment, N-acetylcysteine is formulated as an efferves- rier conventionally useable for NAC administration in cent tablet dosage form. Effervescent tablets allow for which NAC will remain stable and bioavailable. The car- an even distribution of N-acetylcysteine concentration rier suitable for NAC administration must be of sufficiently and create a balanced buffered solution for easy absorp- 20 high purity and of sufficiently low toxicity to render it suit- tion. According to some such embodiments, in order to able for administration to the mammal being treated. Car- protect each N-acetylcysteine effervescent tablet from riers and vehicles useful herein include any such mate- degradation and oxidation, each dose of the N-acetyl- rials known in the art which are nontoxic and do not in- cysteine composition is vacuum- wrapped in foil packag- teract with other components. The (pharmaceutical) car- ing. According to another embodiment, each dose of the 25 rier may be, without limitation, a binding agent (e.g., N-Acetylcysteine composition is vacuum- wrapped in pa- pregelatinized maize starch, polyvinylpyrrolidone or hy- per packaging. According to another embodiment, each droxypropyl methylcellulose, etc.), a filler (e.g., lactose dose of the N-acetylcysteine composition is vacuum- and other sugars, microcrystalline cellulose, pectin, gel- wrapped in plastic packaging. According to some such atin, calcium sulfate, ethyl cellulose, polyacrylates, cal- embodiments, each tablet contains about 900 mg of N- 30 cium hydrogen phosphate, etc.), a lubricant (e.g., mag- acetylcysteine. According to another embodiment, each nesium stearate, talc, silica, colloidal silicon dioxide, tablet contains about 600 mg of N-acetylcysteine. stearic acid, metallic stearates, hydrogenated vegetable [0105] According to another embodiment, the thera- oils, corn starch, polyethylene glycols, sodium benzoate, peutically effective amount for oral administration ranges sodium acetate, etc.), a disintegrant (e.g., starch, sodium from about 900 mg of N-acetylcysteine, the derivative of 35 starch glycolate, etc.), or a wetting agent (e.g., sodium N-acetylcysteine, or the pharmaceutically acceptable lauryl sulphate, etc.). Other suitable (pharmaceutical) salt of N-acetylcysteine per day to about 2,700 mg of N- carriers for the compositions of the present invention in- acetylcysteine, the derivative of N-acetylcysteine or the clude, but are not limited to, water, salt solutions, alco- pharmaceutically acceptable salt of N- acetylcysteine per hols, polyethylene glycols, gelatins, amyloses, magnesi- day. Ranges, in various aspects, are expressed herein 40 um stearates, talcs, silicic acids, viscous paraffins, hy- as from "about" or "approximately" one particular value droxymethylcelluloses, polyvinylpyrrolidones and the and/or to "about" or "approximately" another particular like. value. When values are expressed as approximations by [0108] In some embodiments, the carrier of the com- use of the antecedent "about," it will be understood that position of the present invention includes a release agent some amount of variation is included in the range. 45 such as sustained release or delayed release carrier. In [0106] According to another embodiment, the patient such embodiments, the carrier may be any material ca- is administered orally about 900 mg of N-acetylcysteine, pable of sustained or delayed release to provide a more the derivative ofN-acetylcysteine or the pharmaceutically efficient administration, e.g., resulting in less frequent acceptable salt of N-acetylcysteine each time, three and/or decreased dosage, improve ease of handling, and times a day. According to another embodiment, the meth- 50 extend or delay effects on diseases, disorders, condi- od further comprises monitoring at least one lung function tions, syndromes, and the like, being treated. Non- limit- before treatment and at intervals (e.g., 4, 8, 12, 16, 20, ing examples of such carriers include liposomes, micro- and 24 weeks) following treatment. According to another sponges, microspheres, or microcapsules of natural and embodiment, the method further comprises monitoring synthetic polymers and the like. Liposomes may be at least one lung function before chronic treatment. Ac- 55 formed from a variety of phospholipids such as choles- cording to another embodiment, the method further com- terol, stearylamines or phosphatidylcholines. prises monitoring at least one lung function at intervals [0109] The NAC used should be substantially free of (e.g., 4, 8, 12, 16, 20, and 24 weeks) following chronic sulfones or other chemicals that interfere with the me-

11 21 EP 2 589 381 A1 22 tabolism of anyco-administered drug in its bioactiveform, [0113] The determination of reduced and oxidized spe- substantially free of its oxidized form,N- acetyl- di- cies present in a sample may be determined by various cysteine, and the composition should be prepared in a methods known in the art, including, but not limited to, manner that substantially prevents oxidation of the NAC for example, capillary electrophoresis, and high perform- during preparation or storage. 5 ance liquid chromatography as described by Chassaing [0110] It may be noted that the effectiveness of NAC et al. J. Chromatogr. B. Biomed. Sci. Appl. 735 (2):219-27 depends on the presence of the reduced form, which (1999).. may, for example, liberate the reduced form of glutath- [0114] The compositions of the present invention may ione from homo- and hetero- disulfide derivatives in thiol- be administered systemically either orally, parenterally, disulfide exchange reactions. A typical unit dosage may 10 or rectally in dosage unit formulations containing conven- be a solution suitable for oral or intravenous administra- tional nontoxic pharmaceutically acceptable carriers, ad- tion; an effervescent tablet suitable for dissolving in wa- juvants, and vehicles as desired. ter, fruit juice, or carbonated beverage and administered [0115] The compositions of the present invention may orally; a tablet taken from two to six times daily, or one be in a form suitable for oral use, for example, as tablets, time-release capsule or tablet taken several times a day 15 troches, lozenges, aqueous or oily suspensions, dispers- and containing a proportionally higher content of active ible powders or granules, emulsions, hard or soft cap- ingredient, etc. The time-release effect may be obtained sules or syrups or elixirs. Compositions intended for oral by capsule materials that dissolve at different pH values, use may be prepared according to any known method, by capsules that release slowly by osmotic pressure, or and such compositions may contain one or more agents by any other known means of controlled release. Unit 20 selected from the group consisting of sweetening agents, dosage forms may be provided wherein each dosage flavoring agents, coloring agents, and preserving agents unit, for example, teaspoonful, tablespoonful, gel cap- in order to provide pharmaceutically elegant and palata- sule, tablet or suppository, contains a predetermined ble preparations. Tablets may contain the active ingre- amountof the compositions of the present invention.Sim- dient(s) in admixture with non- toxic pharmaceutically-ac- ilarly, unit dosage forms for injection or intravenous ad- 25 ceptable excipients which are suitable for the manufac- ministration may comprise the compound of the present ture of tablets. These excipients may be, for example, invention in a composition as a solution in sterile water, inert diluents, such as calcium carbonate, sodium car- normal saline or another pharmaceutically acceptable bonate, lactose, calcium phosphate or sodium phos- carrier. The specifications for the unit dosage forms of phate; granulating and disintegrating agents, for exam- the present invention depend on the effect to be achieved 30 ple, corn starch or alginic acid; binding agents, for exam- and the intended recipient. Thus, in some embodiments, ple, starch, gelatin or acacia; and lubricating agents, for NAC is formulated at high doses as an effervescent tablet example, magnesium stearate, stearic acid or talc. The or in granular form in a single dose packet to be dissolved tablets may be uncoated or they may be coated by known in water to prevent untoward stomach effects. techniques to delay disintegration and absorption in the [0111] Over-the-counter NAC may be variably pro-35 gastrointestinal tract and thereby provide a sustained ac- duced and packaged. Because the production and pack- tion over a longer period. For example, a time delay ma- aging methods generally do not guard against oxidation, terial such as glyceryl monostearate or glyceryl distear- the NAC may be significantly contaminated with bioactive ate may be employed. They also may be coated for con- oxidation products. These may be particularly important trolled release. in view of data indicating that the oxidized form of NAC 40 [0116] Compositions of the present invention also may has effects counter to those reported for NAC and is bi- be formulated for oral use as hard gelatin capsules, oactive at doses roughly 10-100 fold less than NAC. See where the active ingredient(s) is (are) mixed with an inert Samstrand et al., J. Pharmacol. Exp. Ther. 288: 1174-84 solid diluent, for example, calcium carbonate, calcium (1999). phosphate or kaolin, or soft gelatin capsules wherein the [0112] The distribution of the oxidation states of NAC 45 active ingredient(s) is (are) mixed with water or an oil as a thiol and disulfide depends on the oxidation/reduc- medium, for example, peanut oil, liquid paraffin, or olive tion (redox) potential. The half-cell potential obtained for oil. the NAC thiol/disulfide pair is about +63 mV, indicative [0117] The compositions of the present invention may of its strong reducing activity among natural compounds be formulated as aqueous suspensions wherein the ac- [see Noszal et al. J. Med. Chem. 43:2176-2182 (2000)]. 50 tive ingredient(s) is (are) in admixture with excipients suit- In one embodiment of the invention, the preparation and able for the manufacture of aqueous suspensions. Such storage of the formulation is performed in such a way excipients are suspending agents, for example, sodium that the reduced form of NAC is the primary form admin- carboxymethylcellulose, methylcellulose, hydroxy-pro- istered to the patient. Maintaining NAC containing formu- pylmethylcellulose, sodium alginate, polyvinylpyrro- lation in solid form is preferable for this purpose. When 55 lidone, gum tragacanth, and gum acacia; dispersing or in solution, NAC containing formulations are preferably wetting agents may be a naturally- occurring phosphatide stored in a brown bottle that is vacuum sealed. Storage such as lecithin, or condensation products of an alkylene in cool dark environments is also preferred. oxide with fatty acids, for example, polyoxyethylene stea-

12 23 EP 2 589 381 A1 24 rate, or condensation products of ethylene oxide with curring gums, for example, gum acacia or gum traga- long chain aliphatic alcohols, for example, heptadecae- canth,naturally- occurring phosphatides, for example soy thyl-eneoxycetanol, or condensation products of ethyl- bean, lecithin, and esters or partial esters derived from ene oxide with partial esters derived from fatty acids and fatty acids and hexitol anhydrides, for example sorbitan a hexitol such as polyoxyethylene sorbitol monooleate, 5 monooleate, and condensation products of the partial es- or condensation products of ethylene oxide with partial ters with ethylene oxide, for example, polyoxyethylene esters derived from fatty acids and hexitol anhydrides, sorbitan monooleate. The emulsions also may contain for example polyethylene sorbitan monooleate. The sweetening and flavoring agents. aqueous suspensions also may contain one or more [0122] Compositions of the invention also may be for- coloring agents, one or more flavoring agents, and one 10 mulated as syrups and elixirs. Syrups and elixirs may be or more sweetening agents, such as sucrose or saccha- formulated with sweetening agents, for example, glycer- rin. ol, propylene glycol, sorbitol or sucrose. Such formula- [0118] Compositions of the present invention may be tions also may contain a demulcent, a preservative, and formulated as oily suspensions by suspending the active flavoring and coloring agents. Demulcents are protective ingredient in a vegetable oil, for example arachis oil, olive 15 agents employed primarily to alleviate irritation, particu- oil, sesame oil or coconut oil, or in a mineral oil, such as larly mucous membranes or abraded tissues. A number liquid paraffin. The oily suspensions may contain a thick- of chemical substances possess demulcent properties. ening agent, for example, beeswax, hard paraffin or cetyl These substances include the alginates, mucilages, alcohol. Sweetening agents, such as those set forth gums, dextrins, starches, certain sugars, and polymeric above, and flavoring agents may be added to provide a 20 polyhydric glycols. Others include acacia, agar, benzoin, palatable oral preparation. These compositions may be carbomer, gelatin, glycerin, hydroxyethyl cellulose, hy- preservedby the additionof an antioxidant suchas ascor- droxypropyl cellulose, hydroxypropyl methylcellulose, bic acid. propylene glycol, sodium alginate, tragacanth, hydrogels [0119] Compositions of the present invention may be and the like. formulated in the form of dispersible powders and gran- 25 [0123] For buccal administration, the compositions of ules suitable for preparation of an aqueous suspension the present invention may take the form of tablets or loz- by the addition of water. The active ingredient in such enges formulated in a conventional manner. powders and granules is provided in admixture with a [0124] The compositions of the present invention may dispersing or wetting agent, suspending agent, and one be in the form of a sterile injectable aqueous or oleagi- or more preservatives. Suitable dispersing or wetting30 nous suspension. The term "parenteral" as used herein agents and suspending agents are exemplified by those includes subcutaneous injections, intravenous, intra- already mentioned above. Additional excipients, for ex- muscular, intrasternal injection, or infusion techniques. ample, sweetening, flavoring and coloring agents also Injectable preparations, such as sterile injectable aque- may be present. ous or oleaginous suspensions, may be formulated ac- [0120] Compositions of the invention also may be for- 35 cording to the known art using suitable dispersing or wet- mulated as a beverage or as an additive to a beverage, ting agents and suspending agents. The sterile injectable where the term "beverage" refers to any non-alcoholic preparation may also be a sterile injectable solution or flavored carbonated drink, soda water, non- alcoholic still suspension in a nontoxic parenterally acceptable diluent drinks, diluted fruit or vegetable juices whether sweet- or solvent, for example, as a solution in 1,3-butanediol. ened or unsweetened, seasoned or unseasoned with salt 40 Among the acceptable vehicles and solvents that may or spice, or still or carbonated mineral waters used as a be employed are water, Ringer’s solution, and isotonic drink. The term "additive" as used herein refers to any sodium chloride solution. In addition, sterile, fixed oils are substance the intended use of which results, or may rea- conventionally employed as a solvent or suspending me- sonably be expected to result, directly or indirectly, in its dium. For parenteral application, particularly suitable ve- becoming a component or otherwise affecting the char- 45 hicles consist of solutions, preferably oily or aqueous so- acteristics of any beverage. In some embodiments, the lutions, as well as suspensions, emulsions, or implants. beverage is a flavored carbonated beverage. In some Aqueous suspensions may contain substances which in- embodiments, the beverage is a flavored non-carbonat- crease the viscosity of the suspension and include, for ed beverage. In some embodiments, the beverage is a example, sodium carboxymethyl cellulose, sorbitol natural fruit beverage. The beverage also may contain 50 and/or dextran. Optionally, the suspension may also con- one or more coloring agents, one or more flavoring tain stabilizers. agents, one or more sweetening agents, one or more [0125] The term "topical" refers to administration of an antioxidant agents, and one or more preservatives. inventive composition at, or immediately beneath, the [0121] Compositions of the invention also may be in point of application. The phrase "topically applying" de- the form of oil-in-water emulsions. The oily phase may 55 scribes application onto one or more surfaces(s) includ- be a vegetable oil, for example, olive oil or arachis oil, or ing epithelial surfaces. Topical administration generally a mineral oil, for example a liquid paraffin, or a mixture provides a local rather than a systemic effect.. For the thereof. Suitable emulsifying agents may be naturally-oc- purpose of this application, topical applications shall in-

13 25 EP 2 589 381 A1 26 clude mouthwashes and gargles. Pat. No. 4,778,054 and is used with Glaxo’s Diskhaler® [0126] Topical administration may also involve the use (U.S. Pat. Nos. 4,627,432; 4,811,731; and 5,035,237). of transdermal administration such as transdermal patch- All of these references are incorporated herein by refer- es or iontophoresis devices which are prepared accord- ence. ing to techniques and procedures well known in the art. 5 [0129] The compositions of the present invention may The terms "transdermal delivery system", transdermal be in the form of suppositories for rectal administration patch" or "patch" refer to an adhesive system placed on ofthe composition. These compositions may be prepared the skin to deliver a time released dose of a drug(s) by by mixing the drug with a suitable nonirritating excipient passage from the dosage form through the skin to be such as cocoa butter and polyethylene glycols which are available for distribution via the systemic circulation.10 solid at ordinary temperatures but liquid at the rectal tem- Transdermal patches are a well-accepted technology perature and will therefore melt in the rectum and release used to deliver a wide variety of pharmaceuticals, includ- the drug. When formulated as a suppository the compo- ing, but not limited to, scopolamine for motion sickness, sitions of the invention may be formulated with traditional nitroglycerin for treatment of angina pectoris, clonidine binders and carriers, such as triglycerides. for hypertension, estradiol for postmenopausal indica- 15 [0130] The therapeutically active agent of the present tions, and nicotine for smoking cessation. invention may be formulated per se or in salt form. The [0127] Patches suitable for use in the present invention term "pharmaceutically acceptable salt" as used herein include, but are not limited to, (1) the matrix patch; (2) refers to those salts which are, within the scope of sound the reservoir patch; (3) the multi-laminate drug-in-adhe- medical judgment, suitable for use in contact with the sivepatch; and (4) the monolithic drug- in-adhesivepatch; 20 tissues of humans and lower animals without undue tox- TRANSDERMAL AND TOPICAL DRUG DELIVERY icity, irritation, allergic response and the like and are com- SYSTEMS, pp. 249-297 (Tapash K. Ghosh et al. eds., mensurate with a reasonable benefit/risk ratio. When 1997), hereby incorporated herein by reference. These used in medicine the salts should be pharmaceutically patches are well known in the art and generally available acceptable, but non-pharmaceutically acceptable salts commercially. 25 may conveniently be used to prepare pharmaceutically [0128] The compositions of the present invention may acceptable salts thereof. Such salts include, but are not be in the form of a dispersible dry powder for pulmonary limited to, those prepared from the following acids: hy- delivery. Dry powder compositions may be prepared by drochloric, hydrobromic, sulfuric, nitric, phosphoric, processes known in the art, such as lyophilization and maleic, acetic, salicylic, p- toluene sulfonic, tartaric, citric, jetmilling, as disclosedin International PatentPublication 30 methane sulfonic, formic, malonic, succinic, naphtha- No. WO 91/16038 and as disclosed in U.S. Pat. No. lene-2-sulfonic, and benzene sulfonic. Also, such salts 6,921,527, the disclosures of which are incorporated by may be prepared as alkaline metal or alkaline earth salts, reference. The composition of the present invention is such as sodium, potassium or calcium salts of the car- placed within a suitable dosage receptacle in an amount boxylic acid group. By "pharmaceutically acceptable salt" sufficient to provide a subject with a unit dosage treat- 35 is meant those salts which are, within the scope of sound ment. The dosage receptacle is one that fits within a suit- medical judgment, suitable for use in contact with the able inhalation device to allow for the aerosolization of tissues of humans and lower animals without undue tox- the dry powder composition by dispersion into a gas icity, irritation, allergic response and the like and are com- stream to form an aerosol and then capturing the aerosol mensurate with a reasonable benefit/risk ratio. Pharma- so produced in a chamber having a mouthpiece attached 40 ceutically acceptable salts are well- known in the art. For for subsequent inhalation by a subject in need of treat- example, P. H. Stahl, et al. describe pharmaceutically ment. Such a dosage receptacle includes any container acceptable salts in detail in "Handbook of Pharmaceuti- enclosing the composition known in the art such as gel- cal Salts: Properties, Selection, and Use" (Wiley VCH, atin or plastic capsules with a removable portion that al- Zurich, Switzerland: 2002). The salts may be prepared lows a stream of gas (e.g., air) to be directed into the 45 in situ during the final isolation and purification of the container to disperse the dry powder composition. Such compounds described within the present invention or containers are exemplified by those shown in U.S. Pat. separately by reacting a free base function with a suitable Nos. 4,227,522; U.S. Pat. No. 4,192,309; and U.S. Pat. organic acid. Representative acid addition salts include, No. 4,105,027. Suitable containers also include those but are not limited to, acetate, adipate, alginate, citrate, used in conjunction with Glaxo’s Ventolin® Rotohaler 50 aspartate, benzoate, benzenesulfonate, bisulfate, bu- brand powder inhaler or Fison’s Spinhaler® brand pow- tyrate, camphorate, camphorsulfonate, digluconate, der inhaler. Another suitable unit-dose container which glycerophosphate, hemisulfate, heptanoate, hexanoate, provides a superior moisture barrier is formed from an fumarate, hydrochloride, hydrobromide, hydroiodide, 2- aluminum foil plastic laminate. The pharmaceutical- hydroxyethansulfonate(isethionate), lactate, maleate, based powder is filled by weight or by volume into the 55 methanesulfonate, nicotinate, 2-naphthalenesulfonate, depression in the formable foil and hermetically sealed oxalate, pamoate, pectinate, persulfate, 3-phenylpropi- with a covering foil- plastic laminate. Such a container for onate, picrate, pivalate, propionate, succinate, tartrate, use with a powder inhalation device is described in U.S. thiocyanate, phosphate, glutamate, bicarbonate, p-tol-

14 27 EP 2 589 381 A1 28 uenesulfonate and undecanoate. Also, the basic nitro- of a cystic fibrosis therapeutic agent and a second con- gen-containing groups may be quaternized with such tainer filled with a composition comprising a therapeuti- agents as lower alkyl halides such as methyl, ethyl, pro- cally effective amount of N-acetylcysteine , a pharma- pyl, and butyl chlorides, bromides and iodides; dialkyl ceutically acceptable salt of N- acetylcysteine, or a phar- sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; 5 maceutically acceptable derivative of N-acetylcysteine, long chain halides such as decyl, lauryl, myristyl and and a pharmaceutically acceptable carrier. stearyl chlorides, bromides and iodides; arylalkyl halides [0133] In another embodiment, a pharmaceutical kit for like benzyl and phenethyl bromides and others. Water or preserving or restoring lung function in cystic fibrosis pa- oil-soluble or dispersible products are thereby obtained. tients according to the present invention includes a first Examples of acids which may be employed to form phar- 10 container filled with a pharmaceutically effective amount maceutically acceptable acid addition salts include such of a cystic fibrosis therapeutic agent and a second con- inorganic acids as hydrochloric acid, hydrobromic acid, tainer filled with a composition comprising a therapeuti- sulphuric acid and phosphoric acid and such organic ac- cally effective amount of N-acetylcysteine , a pharma- ids as oxalic acid, maleic acid, succinic acid and citric ceutically acceptable salt of N- acetylcysteine, or a phar- acid. Basic addition salts may be prepared in situ during 15 maceutically acceptable derivative of N-acetylcysteine, the final isolation and purification of compounds de- and a pharmaceutically acceptable carrier. scribed within the invention by reacting a carboxylic acid- [0134] In yet another embodiment, a pharmaceutical containing moiety with a suitable base such as the hy- kit for prolonging the time interval between exacerbations droxide, carbonate or bicarbonate of a pharmaceutically in cystic fibrosis patients according to the present inven- acceptable metal cation or with ammonia or an organic 20 tion includes a first container filled with a pharmaceuti- primary, secondary or tertiary amine. Pharmaceutically cally effective amount of a cystic fibrosis therapeutic acceptable salts include, but are not limited to, cations agent and a second container filled with a composition based on alkali metals or alkaline earth metals such as comprising a therapeutically effective amount of N- lithium, sodium, potassium, calcium, magnesium and acetylcysteine , a pharmaceutically acceptable salt of N- aluminum salts and the like and nontoxic quaternary am- 25 acetylcysteine, or a pharmaceutically acceptable deriv- monia and amine cations including ammonium, tetram- ativeof N- acetylcysteine,and a pharmaceuticallyaccept- ethylammonium, tetraethylammonium, methylamine, able carrier. dimethylamine, trimethylamine, triethylamine, diethyl- [0135] Regular, routine treatment to keep secretions amine, ethylamine and the like. Other representative or- cleared and prevent infection is very important in CF be- ganic amines useful for the formation of base addition 30 cause respiratory complications are the leading cause of salts include ethylenediamine, ethanolamine, dieth- morbidity and mortality in CF patients. Thick mucus anolamine, piperidine, piperazine and the like. Pharma- blocks the bronchial tubes in the lungs leading to inflam- ceutically acceptable salts also may be obtained using mation and recurrent infections. With each infection, standard procedures well known in the art, for example more damage or scarring occurs, causing lung function by reacting a sufficiently basic compound such as an35 to progressively worsen. amine with a suitable acid affording a physiologically ac- [0136] According to one embodiment, the composition ceptable anion. Alkali metal (for example, sodium, po- of the present invention reverses at least one symptom tassium or lithium) or alkaline earth metal (for example of the pulmonary disorder that includes an inflammatory calcium or magnesium) salts of carboxylic acids may also component. Symptoms associated with, for example, be made. Additional compositions of the present inven- 40 cystic fibrosis, include but are not limited to chronic tion may be readily prepared using technology which is coughing, difficulty breathing, pneumonia caused by ab- known in the art such as described in Remington’s Phar- normal mucus in respiratory and gastrointestinal tracts, maceutical Sciences, 18th or 19th editions, published by lung obstruction, infection, poor digestion, poor food ab- the Mack Publishing Company of Easton, Pennsylvania, sorption, etc. which is incorporated herein by reference. 45 [0137] In some embodiments known techniques are [0131] The present invention further provides a phar- used to monitor lung function. Such known techniques maceutical pack or kit comprising one or more containers include, but are not limited to spirometry, plethysmogra- filled with one or more of the ingredients of the pharma- phy, transfer factor, gas washout tests, computational ceutical compositions of the invention. Associated with tomography, and oscillometry. Exemplary endpoints that such container(s) may be a notice in the form prescribed 50 reflect lung function include, but are not limited to, FEV1, by a governmental agency regulating the manufacture, FEF, FVC, etc. use or sale of pharmaceuticals or biological products, [0138] In some embodiments, administration of a phar- which notice reflects approval by the agency of manu- maceutical composition comprising a therapeutically ef- facture, use or sale for human administration. fective amount of N-acetylcysteine, a derivative ofN- ace- [0132] For example, in one embodiment, a pharma- 55 tylcysteine, or a pharmaceutically acceptable salt of N- ceutical kit for treating inflammation in cystic fibrosis pa- acetylcysteine, increases Forced Expiratory Volume in tients according to the present invention includes a first one second (FEV1) value of a treated patient from about container filled with a pharmaceutically effective amount at least 0.1% to about at least 99%, as compared to the

15 29 EP 2 589 381 A1 30

FEV1 value of an untreated control patient. In one em- composition increases the FEV 1 valueof a treated patient bodiment, administration of the pharmaceutical compo- at least 60.0 % as compared to the FEV 1 of an untreated sition increases the FEV1 value of a treated patient at control patient. In one embodiment, administration of the least 0.1% as compared to the FEV 1 value of an untreat- pharmaceutical composition increases the FEV1 of a 5 ed control patient. In one embodiment, administration of treated patient at least 70.0 % as compared to the FEV 1 the pharmaceutical composition increases the FEV 1 val- of an untreated control patient. In one embodiment, ad- ue of a treated patient at least 0.5% as compared to the ministrationof the pharmaceutical composition increases

FEV1 value of an untreated control patient. In one em- the FEV1 value of a treated patient at least 80.0 % as bodiment, administration of the pharmaceutical compo- compared to the FEV1 value of an untreated control pa- 10 sition increases the FEV1 value of a treated patient at tient. In one embodiment, administration of the pharma- least 1.0% as compared to the FEV 1 value of an untreat- ceutical composition increases the FEV 1 value of a treat- ed control patient. In one embodiment, administration of ed patient at least 90.0 % as compared to the FEV 1 value the pharmaceutical composition increases the FEV 1 val- of an untreated control patient. In one embodiment, ad- ue of a treated patient at least 2.0 % as compared to the ministrationof the pharmaceutical composition increases 15 FEV1 value of an untreated control patient. In one em- the FEV1 value of a treated patient at least 99.0 % as bodiment, administration of the pharmaceutical compo- compared to the FEV1 value of an untreated control pa- sition increases the FEV1 value of a treated patient at tient. least 3.0 % as compared to the FEV 1 value of an untreat- [0139] In some embodiments, administration of a phar- ed control patient. In one embodiment, administration of maceutical composition comprising a therapeutically ef- 20 the pharmaceutical composition increases the FEV 1 val- fective amount of N-acetylcysteine, a derivative of N- ace- ue of a treated patient at least 4.0 % as compared to the tylcysteine, or a pharmaceutically acceptable salt of N- FEV1 value of an untreated control patient. In one em- acetylcysteine, increases Forced Expiratory Volume in bodiment, administration of the pharmaceutical compo- one second (FEV 1) value measured in a patient following sition increases the FEV1 value of a treated patient at treatment from about at least 0.1% to about at least 99%, 25 least 5.0 % as compared to the FEV 1 value of an untreat- as compared to a baseline FEV1 value measured in the ed control patient. In one embodiment, administration of patient measured before treatment. In one embodiment, the pharmaceutical composition increases the FEV 1 val- administration of the pharmaceutical composition in- ue of a treated patient at least 10.0 % as compared to creases the FEV1 value measured in a patient following the FEV1 value of an untreated control patient. In one treatment by at least 0.1% as compared to a baseline 30 embodiment, administration of the pharmaceutical com- FEV1 value measured in the patient measured before position increases the FEV 1 value of a treated patient at treatment. In one embodiment, administration of the least 15.0% as compared to the FEV1 value of an un- pharmaceutical composition increases the FEV1 value treated control patient. In one embodiment, administra- measuredin apatient followingtreatment by atleast 0.5% tion of the pharmaceutical composition increases the as compared to a baseline FEV1 value measured in the 35 FEV1 value of a treated patient at least 20.0 % as com- patient measured before treatment. In one embodiment, pared to the FEV 1 of an untreated control patient. In one administration of the pharmaceutical composition in- embodiment, administration of the pharmaceutical com- creases the FEV1 value measured in a patient following position increases the FEV1 of a treated patient at least treatment by at least 1.0 % as compared to a baseline 25.0 % as compared to the FEV1 value of an untreated FEV1 value measured in the patient measured before control patient. In one embodiment, administration of the 40 treatment. In one embodiment, administration of the pharmaceutical composition increases the FEV1 value pharmaceutical composition increases the FEV1 value of a treated patient at least 30.0 % as compared to the measured in a patient following treatment by at least 2.0

FEV1 value of an untreated control patient. In one em- % as compared to a baseline FEV1 value measured in bodiment, administration of the pharmaceutical compo- the patient measured before treatment. In one embodi- 45 sition increases the FEV1 value of a treated patient at ment, administration of the pharmaceutical composition least 35.0 % as compared to the FEV1 value of an un- increases the FEV 1 value measured in a patient following treated control patient. In one embodiment, administra- treatment by at least 3.0 % as compared to a baseline tion of the pharmaceutical composition increases the FEV1 value measured in the patient measured before FEV1 value of a treated patient at least 40.0 % as com- treatment. In one embodiment, administration of the 50 pared to the FEV1 value of an untreated control patient. pharmaceutical composition increases the FEV1 value In one embodiment, administration of the pharmaceutical measured in a patient following treatment by at least 4.0 compositionincreases the FEV 1value of a treatedpatient % as compared to a baseline FEV1 value measured in at least 45.0 % as compared to the FEV1 value of an the patient measured before treatment. In one embodi- untreated control patient. In one embodiment, adminis- ment, administration of the pharmaceutical composition 55 tration of the pharmaceutical composition increases the increases the FEV 1 value measured in a patient following FEV1 value of a treated patient at least 50.0 % as com- treatment by at least 5.0 % as compared to a baseline pared to the FEV1 value of an untreated control patient. FEV1 value measured in the patient measured before In one embodiment, administration of the pharmaceutical treatment. In one embodiment, administration of the

16 31 EP 2 589 381 A1 32 pharmaceutical composition increases the FEV1 value ment, administration of the pharmaceutical composition measured in a patient following treatment by at least 10.0 increases the FEV 1 value measured in a patient following % as compared to a baseline FEV1 value measured in treatment by at least 99.0 % as compared to a baseline the patient measured before treatment. In one embodi- FEV1 value measured in the patient measured before ment, administration of the pharmaceutical composition 5 treatment. increases the FEV 1 value measured in a patient following [0140] Inanother embodimentof thepresent invention, treatment by at least 15.0 % as compared to a baseline compositions and methods of the present invention may

FEV1 value measured in the patient measured before be used in combination with known therapeutic agents, treatment. In one embodiment, administration of the provided that they are compatible with each other. "Com- 10 pharmaceutical composition increases the FEV1 value patible" as used herein means that the compositions and measured in a patient following treatment by at least 20.0 methods of the present invention are capable of being

% as compared to a baseline FEV1 value measured in combined with existing therapies in a manner such that the patient measured before treatment. In one embodi- there is no interaction that would substantially reduce the ment, administration of the pharmaceutical composition efficacy of either the compositions or methods of the 15 increases the FEV 1 value measured in a patient following present invention or the therapies under ordinary use treatment by at least 25.0 % as compared to a baseline conditions.

FEV1 value measured in the patient measured before [0141] In some embodiments, existing cystic fibrosis treatment. In one embodiment, administration of the therapeutic agents that may be combined with the com- pharmaceutical composition increases the FEV1 value positions and methods of the present invention include, measured in a patient following treatment by at least 30.0 20 but are not limited to, anti-infective agents, bronchodilat- % as compared to a baseline FEV1 value measured in ing agents, and anti-inflammatory agents. the patient measured before treatment. In one embodi- [0142] Lung and airway infections in cystic fibrosis may ment, administration of the pharmaceutical composition be treated with potent anti-infective agents, including an- increases the FEV 1 value measured in a patient following tibiotics, to improve lung function, reduce days spent in treatment by at least 35.0 % as compared to a baseline 25 the hospital and to reduce use of intravenous antibiotics FEV1 value measured in the patient measured before to reduce bacterial levels in the lungs. Inhaled antibiotics treatment. In one embodiment, administration of the also are used to prevent lung infections that may lead to pharmaceutical composition increases the FEV1 value hospitalization. measured in a patient following treatment by at least 40.0 [0143] To minimize certain side effects, bronchodilat- 30 % as compared to a baseline FEV1 value measured in ing agents often are used along with inhaled antibiotics. the patient measured before treatment. In one embodi- Bronchodilating agents are used widely for treating a va- ment, administration of the pharmaceutical composition riety of obstructive lung diseases, including cystic fibro- increases the FEV 1 value measured in a patient following sis. They relax smooth muscle in the small airways of the treatment by at least 45.0 % as compared to a baseline lungs, which dilates the airways and makes breathing 35 FEV1 value measured in the patient measured before easier, particularly when airways are narrowed by inflam- treatment. In one embodiment, administration of the mation. Inhaled bronchodilator medications used in asth- pharmaceutical composition increases the FEV1 value ma, such as albuterol, have improved breathing in some measured in a patient following treatment by at least 50.0 people with cystic fibrosis. When used to treat cystic fi- % as compared to a baseline FEV1 value measured in brosis, bronchodilating agents are usually given through the patient measured before treatment. In one embodi- 40 a nebulizer or with a handheld inhaler. Airway dilatation ment, administration of the pharmaceutical composition before physiotherapy helps the cystic fibrosis patient to increases the FEV 1 value measured in a patient following clear chest secretions. treatment by at least 60.0 % as compared to a baseline [0144] Nonsteroidal anti-inflammatory agents reduce FEV1 value measured in the patient measured before inflammation and pain. Cystic fibrosis patients often have treatment. In one embodiment, administration of the45 persistent lung inflammation which becomes part of the pharmaceutical composition increases the FEV1 value cycle of continued lung damage in these patients. Anti- measured in a patient following treatment by at least 70.0 inflammatory medications, such as ibuprofen, in some

% as compared to a baseline FEV1 value measured in patientswith CF help to reducethis inflammation. In some the patient measured before treatment. In one embodi- children, anti- inflammatory medications may significantly ment, administration of the pharmaceutical composition 50 slow the progression of lung disease and improve breath- increases the FEV 1 value measured in a patient following ing. treatment by at least 80.0 % as compared to a baseline [0145] In some embodiments, therapeutic agents,

FEV1 value measured in the patient measured before such as corticosteroids, anticoagulation agents, and pir- treatment. In one embodiment, administration of the fenidone, may be administered to treat the inflammation 55 pharmaceutical composition increases the FEV1 value present in some patients with IPF in combination with the measured in a patient following treatment by at least 90.0 compositions and methods of the present invention. An- % as compared to a baseline FEV1 value measured in timicrobial agents also may be used to treat bacterial the patient measured before treatment. In one embodi- organisms, opportunistic pathogens, and common res-

17 33 EP 2 589 381 A1 34 piratory viruses. materials similar or equivalent to those described herein [0146] In some embodiments, standard doses of ex- can also be used in the practice or testing of the present isting therapeutic agents for chronic and acute exacer- invention, the preferred methods and materials are now bations of asthma may be combined with the composi- described. All publications mentioned herein are incor- tions and methods of the present invention. These in- 5 porated herein by reference to disclose and describe the clude, but are not limited to, antimicrobial agents, bron- methods and/or materials in connection with which the chodilators (e.g., epinephrine, terbutaline, ipratropium publications are cited. (Atrovent®)), inhaled corticosteroids, leukotriene antag- [0153] It must be noted that as used herein and in the onists, β-agonists (e.g., albuterol [e.g., Ventolin ®, Prov- appended claims, the singular forms "a", "and", and "the" entil®], levalbuterol, Metaproterenol Sulfate (Alupent), 10 include plural references unless the context clearly dic- isoprotenerol, chromolyn sodium; aminophylline, and tates otherwise. All technical and scientific terms used theophylline. herein have the same meaning. [0147] In another embodiment of the present invention, [0154] Examples compositions and methods of the present invention may [0155] The following examples are put forth so as to be used in combination with known therapies, provided 15 provide those of ordinary skill in the art with a complete that they are compatible with each other. disclosure and description of how to make and use the [0148] The term "respiratory therapy" as used herein present invention, and are not intended to limit the scope refers to chest physiotherapy, which is used to help clear of what the inventors regard as their invention nor are excess mucus out of the lungs. To perform chest physi- they intended to represent that the experiments below otherapy, a patient is placed in various positions allowing 20 are all or the only experiments performed. Efforts have major segments of the lungs to point downward and then been made to ensure accuracy with respect to numbers clapping firmly over chest and back on part of the lung used (e.g. amounts, temperature, etc.) but some exper- segment to shake the mucus loose. Once loosened, the imental errors and deviations should be accounted for. mucus will fall to the large airways, where it may be Unless indicated otherwise, parts are parts by weight, coughed out. Chest physiotherapy may be time-consum- 25 molecular weight is weight average molecular weight, ing since 3-5 minutes is spent clapping over 10-12 lung temperature is in degrees Centigrade, and pressure is segments. It is also difficult for patients to perform on at or near atmospheric. themselves and usually requires a skilled caregiver. [0156] Example 1. Randomized, Placebo-Control- [0149] The term "rehabilitative therapy" refers to a ther- led, Double-Blind Study of the Effects of Oral N-Ace- apy designed to help patients use their energy more ef- 30 tylcysteine on Redox Changes and Lung Inflamma- ficiently, i.e., in a way that requires less oxygen. Reha- tion in CF Patients bilitative therapy improves shortness of breath and over- [0157] A 24-week (6-month) multi-center large clinical all survival, especially in those with advanced disease. trial was designed with randomization stratified to im- [0150] The publications discussed herein are provided prove balance of baseline characteristics between treat- solely for their disclosure prior to the filing date of the 35 ment groups, and to improve precision between group present application. Nothing herein is to be construed as treatment effects. an admission that the present invention is not entitled to [0158] A 6-month multi-center phase II clinical trial was antedatesuch publication by virtueof prior invention. Fur- performed to evaluate the effect of N-acetylcysteine ther, the dates of publication provided may be different (PharmaNAC®, BioAdvantex Pharma, Mississauga, On- from the actual publication dates which may need to be 40 tario Canada)) 900 mg effervescent tablets taken orally independently confirmed. 3 times a day on airway inflammation in CF patients. 70 [0151] Where a range of values is provided, it is un- subjects were randomized to placebo or study drug. Ran- derstood that each intervening value, to the tenth of the domization was stratified by study site, baseline FEV1, unit of the lower limit unless the context clearly dictates age, gender, chronic azithromycin, inhaled aztreonam otherwise,between the upper and lower limitof that range 45 for inhalation solution (AZLI) or tobramycin inhalation so- and any other stated or intervening value in that stated lution, USP (TOBI®, Novartis) and ibuprofen use. A co- range is encompassed within the invention. The upper hort of 16 subjects served as an initial safety cohort. and lower limits of these smaller ranges which may in- [0159] General objectives of the study included deter- dependently be included in the smaller ranges is also mination of safety, tolerability and efficacy of NAC versus encompassed within the invention, subject to any spe- 50 placebo at 0 week, 6 weeks, 12 week and 24 week time cifically excluded limit in the stated range. Where the stat- points. More specific objectives included evaluation of: ed range includes one or both of the limits, ranges ex- (a) effect of NAC on number of pulmonary and sinus ex- cluding either both of those included limits are also in- acerbations and antibiotic use, (b) effect of NAC on lung cluded in the invention. inflammation; (c) effect of NAC on pulmonary function; [0152] Unless defined otherwise, all technical and sci- 55 (d) effect of NAC on weight; (e) effect of NAC on quality entificterms used hereinhave the samemeaning as com- of life (QOL) and (f) whether NAC causes pulmonary hy- monly understood by one of ordinary skill in the art to pertension if used chronically in high doses. which this invention belongs. Although any method and [0160] Figure 1 shows the enrollment scheme. Of 85

18 35 EP 2 589 381 A1 36 subjects screenedfor eligibility, 70 wereenrolled and ran- neutrophil recruitment, lung function, pulmonary and si- domized into NAC and placebo groups of 36 and 34 sub- nus exacerbations, and on weight of CF subjects was jects respectively. Of the NAC group, 33 subjects fol- measured by: change in the sputum neutrophil count, lowed up at week 12, 30 subjects followed up at week change in IL-8 in sputum and plasma, change in GSH in 24, 1 subject withdrew from the study and 1 subject5 whole blood, incidence of pulmonary exacerbations, showed adverse event and hence was removed from the number of and time to first pulmonary exacerbation, in- study. Of the placebo group, 32 subjects followed up at cidence and number of antibiotics for any reason, and week 12, 32 subjects followed up at week 24, one subject change in FEV 1. Patient-reported outcomes (PRO) were withdrew from the study and one subject was removed measured by the CFQ-R and CFRD instruments. for adverse event. 10 [0167] No difference was detected in airways inflam- [0161] The inclusion criteria to include candidate sub- mation, measured by HNE (Figure 5), number of pulmo- jects in the study included the following: (a) 7 years of nary or sinus exacerbations, or new antibiotic prescrip- age or older who are able to tolerate sputum induction tions. But, NAC recipients maintained lung function over and perform reproducible spirometry; (b) stable mild to the 6-month period, while placebo recipients experi- 15 moderate lung disease; (c) no use of acute antibiotics in enced significant loss of function as determined by FEV 1, the previous 4 weeks; and (d) no use of anti-oxidants in FVC, and FEF. Without being limited by theory, NAC may any form at least 6 weeks prior to and for the duration of exert anti- inflammatory and/or anti- oxidant effects via ac- the study, although usual doses of vitamin E and vitamin tion in alternate pathways important in chronic inflamma- C were allowed. The exclusion criteria to exclude candi- tion, such as RANTES (Regulated upon Activation, Nor- date subjects from the study included: (a) use of a non- 20 mal T-cell Expressed, and Secreted), IL-1β / IL-1RA, IL- steroidalanti- inflammatory drug in the previous one week 17, and TGF-β. to assure sputum neutrophil count and elastase at base- [0168] Example 3: Effect of long-term treatment line; (b) initiation of chronic dosing with azithromycin, ibu- with NAC profen, TOBI®, inhaled ("IH") Azhetreonam or Colistin [0169] Effect of long-term treatment with NAC in pro- within previous six weeks; (c) liver disease; (d) active 25 moting the development of pulmonary hypertension (PH) allergic bronchopulmonary aspergillosis ("ABPA") in the in subjects with cystic fibrosis is examined. A panel of previous six months; and (e) acetaminophen use in the clinical and molecular studies, performed at 6-week in- previous three days. tervals, is assessed. This panel included level of NAC in [0162] Figure 2 shows the baseline characteristics of blood, bFGF and VEGF in plasma and urine, and in the subjects enrolled in NAC-treated and placebo-treated 30 initial safety cohort, levels of S-nitrosylated NAC, HIF- groups. Figure 3 shows baseline characteristics of pul- 1α, and ECHO and diffusing capacity of the lung for car- monary function in NAC-treated and placebo-treated bon monoxide (DLCO). groups. No adverse events and no pulmonary hyperten- [0170] Example 4. Use of NAC to treat Acute Exac- sion were shown in the first 16 subject safety cohort erbations of IPF study. 35 [0171] A patient showing the symptoms of an acute [0163] The primary efficacy endpoint in this study were exacerbation of IPF (including, but not limited to, idio- sputum elastase activity as measured by ELISA assay pathic acute respiratory deterioration) may be treated reflecting lung inflammation. Secondary efficacy end- with a composition comprising an acute exacerbation-re- point were: (i) FEV1 (liters and % Pred), reflecting lung ducing amount of either the purified L- enantiomer or the function; (ii) sputum Human Neurophil Elastase (HNE) 40 racemate mixture composed of equal proportions of the activity,reflecting lunginflammation, thecurrent best pre- D- and L-isomers of NAC administered either serially or dictor of CF lung disease; (iii) sputum IL- 8levels reflecting co-administered two, three or four times a day up to the lung inflammation; (iv) whole blood GSH, reflecting redox highest tolerable dose, given that there will be individual imbalance; (v) effect of new use of antibiotics; (vi) Cystic variability in the ability to tolerate NAC. This dosage of Fibrosis Questionnaire Revised (CFQ- R) respiratory do- 45 NAC is sufficient to decrease key aspects of an acute main scores; and (vii) Cystic Fibrosis Respiratory Symp- exacerbation of IPF in such patients. tom Diary (CFRSD) scores. [0172] Example 5. Use of NAC to treat Acute Exac- [0164] Figure 4 shows primary and secondary out- erbations of Asthma comes of NAC treatment over placebo-treated group. [0173] A child or adult showing the symptoms of an 50 The NAC recipients maintained baseline FEV 1, while the acute exacerbation of asthma (including, but not limited placebo cohort displayed a 4% decrease in FEV1 (150 to, a sudden increase in breathlessness over the preced- ml) over the 6-month trial period. (P=0.02) (Figure 6). ing 48 hours and presence of one of the following signs: [0165] Example 2: Effect of NAC on chronic airway tachypnea (respiratory rate of>18), use of accessory inflammation muscles or respiration, audible wheezing, prolonged ex- [0166] The effect of NAC on chronic airway inflamma- 55 piration with rhonchi on auscultation or a silent chest) tion was measured by examining the change in the log 10 may be treated with a composition comprising at least of neutrophil elastase activity measured in sputum from one standard asthma therapeutic agent and an acute ex- enrollment to the end of the trial. The effect of NAC on acerbation-reducing amount of either the purified L-

19 37 EP 2 589 381 A1 38 enantiomer or the racemate mixture composed of equal 4. The pharmaceutical composition according to claim proportions of the D- and L- isomers of NAC administered 1, wherein the composition is capable of acute or either serially or co- administered two, three or four times chronic administration. a day up to the highest tolerable dose, given that there will be individual variability in the ability to tolerate NAC. 5 5. The pharmaceutical composition according to claim This dosage of NAC is sufficient to decrease key aspects 1, wherein the pharmaceutical composition is a tab- of an acute exacerbation of asthma in such patients. let. [0174] Example 6: Use of NAC to treat acute exac- erbations of TB in HIV patients 6. The pharmaceutical composition according to claim [0175] An HIV patient having latent or active TB who 10 5, wherein the pharmaceutical composition is an ef- is being treated with a formulation comprising a thera- fervescent tablet. peutically effective amount of a multi-drug regimen as normally used to treat HIV and/or TB may be further treat- 7. The pharmaceutical composition according to claim ed with a composition comprising an acute exacerbation 5, wherein each dose of the pharmaceutical compo- reducing amount of either the purified L-enantiomer or 15 sition is individually wrapped to avoid oxidation. the racemate mixture composed of equal proportions of the D- and L- isomers of NAC administered either serially 8. The pharmaceutical composition according to claim or co-administered two, three or four times a day up to 1, wherein the pharmaceutical composition is for oral the highest tolerable dose, given that there will be indi- administration. vidual variability in the ability to tolerate NAC. This dos- 20 age of NAC is sufficient to decrease key aspects of IRIS 9. The pharmaceutical composition according to claim in such patients. 1, wherein the pharmaceutical composition is for pa- [0176] Equivalents rental, intravenous, intratracheal, intramuscular, or [0177] While the described invention has been de- intraperitoneal administration. scribedwith referenceto the specificembodiments there- 25 of, it should be understood by those skilled in the art that 10. The pharmaceutical composition according to claim various changes may be made and equivalents may be 1, wherein the therapeutically effective amount com- substituted without departing from the true spirit and prises at least 200 mg of N-acetylcysteine, the de- scope of the invention. In addition, many modifications rivative of N-acetylcysteine, or the pharmaceutically may be made to adapt a particular situation, material, 30 acceptable salt of N-acetylcysteine but less than composition of matter, process, process step or steps, 20,000 mg of N-acetylcysteine, the derivative of N- to the objective, spirit and scope of the described inven- acetylcysteine, or the pharmaceutically acceptable tion. All such modifications are intended to be within the salt of N-acetylcysteine. scope of the claims appended hereto. 35 11. The pharmaceutical composition according to claim 8, wherein the therapeutically effective amount rang- Claims es from about 900 mg of N-acetylcysteine, the de- rivative of N-acetylcysteine, or the pharmaceutically 1. A pharmaceutical composition comprising a thera- acceptable salt of N-acetylcysteine per day to about peutically effective amount ofN- acetylcysteine, a de- 40 2,700 mg of N-acetylcysteine, the derivative of N- rivative of N-acetylcysteine, or a pharmaceutically acetylcysteine, or the pharmaceutically acceptable acceptable salt ofN-acetylcysteine and a carrier for salt of N-acetylcysteine. use in treating a patient suffering from a pulmonary disorder that comprises an inflammatory compo- 12. The pharmaceutical composition according to claim nent, wherein the therapeutically effective amount is 45 1, wherein the therapeutically effective amount for effective to improve or preserve a lung function in oral administration is about 900 mg of acetyl- N- the patient. cysteine, the derivative ofN-acetylcysteine, or the pharmaceutically acceptable salt of acetyl- N- 2. The pharmaceutical composition according to claim cysteine each time, three times a day. 1, wherein the pulmonary disorder comprising an in- 50 flammatory component is cystic fibrosis, chronic ob- 13. The pharmaceutical composition according to claim structive pulmonary disorder (COPD), idiopathic pul- 1, wherein the improved lung function of the patient monary fibrosis (IPF), or a bacterial infection in the is maintained for at least 6 months following admin- lung. istration of the therapeutically effective amount of N- 55 acetylcysteine, the derivative of N- acetylcysteine, or 3. The pharmaceutical composition according to claim the pharmaceutically acceptable salt of N-acetyl- 1, wherein the pulmonary disorder comprising an in- cysteine. flammatory component is tuberculosis.

20 39 EP 2 589 381 A1 40

14. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition increas- es Forced Expiratory Volume in one second (FEV 1) of the patient compared to the Forced Expiratory Vol- 5 ume in one second (FEV1) of an untreated control patient.

15. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition increas- 10 es Forced Expiratory Volume in one second (FEV 1) of the patient by at least 0.15% over a baseline

Forced Expiratory Volume in one second (FEV 1) val- ue of the patient measured before treatment.

16. The pharmaceutical composition according to claim 15 1, wherein the pharmaceutical composition increas- es time between exacerbations in the patient com- pared to a control.

17. The pharmaceutical composition according to claim 20 1, wherein administration of the pharmaceutical composition reverses at least one symptom associ- ated with the pulmonary disorder.

18. The pharmaceutical composition according to claim 25 1, wherein the pharmaceutical composition further comprises an anti-infective agent, bronchodilating agent, or anti-inflammatory agent.

30

35

40

45

50

55

21 EP 2 589 381 A1

22 EP 2 589 381 A1

23 EP 2 589 381 A1

24 EP 2 589 381 A1

25 EP 2 589 381 A1

26 EP 2 589 381 A1

27 EP 2 589 381 A1

28 EP 2 589 381 A1

29 EP 2 589 381 A1

30 EP 2 589 381 A1

31 EP 2 589 381 A1

32 EP 2 589 381 A1

33 EP 2 589 381 A1

34 EP 2 589 381 A1

35 EP 2 589 381 A1

36 EP 2 589 381 A1

37 EP 2 589 381 A1

38 EP 2 589 381 A1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 42057709 A [0002] • US 4192309 A [0128] • US 50770606 A [0002] • US 4105027 A [0128] • US 71080705 P [0002] • US 4778054 A [0128] • WO 05017094 A [0024] • US 4627432 A [0128] • WO 9116038 A [0128] • US 4811731 A [0128] • US 6921527 B [0128] • US 5035237 A [0128] • US 4227522 A [0128]

Non-patent literature cited in the description

• GUENGERICH, F.P. Chem. Res. Toxicol., 1991, vol. • RANCOURT et al. Am. J. Physiol. Lung Cell Mol. 4, 391-407 [0017] Physiol., 2004, vol. 286 (5), L931-38 [0035] • BECKETT, G.J. ; HAYES, J.D. Adv. Clin. Chem., • ROCHAT et al. J. Cell Physiol., 2004, vol. 201 (1), 1993, vol. 30, 281-380 [0018] 106-16 [0036] • FALANY, CN. Trends Pharmacol. Sci., 1991, vol. 12, • G. STAFANGER et al. Eur. Respir. J., 1988, vol. 1 255-59 [0018] (2), 161-67 [0036] • BOCK, KW. Crit. Rev. Biochem. Mol. Biol., 1991, vol. • RATJEN, F. et al. Eur. J. Pediatr., 1985, vol. 144 (4), 26, 129-50 [0018] 374-78 [0036] • CARLBERG ; MANNERVICK. J. Biol. Chem., 1975, • GOTZ et al. Eur. J. Resp. Dis., 1980, vol. 61 (111), vol. 250, 5475-80 [0021] 122-26 [0036] • GILLISSEN, A. ; NOWAK, A. Respir. Med., 1998, • DUIJVESTIJN, Y.C. ; BRAND, P.L. Acta Paediatr., vol. 92 (609-23), 613 [0024] 1999, vol. 88 (1), 38-41 [0037] • DROST, E.M. ; SKWARSKI, K.N. ; SAULEDA, J. ; • CANTIN. Curr Opin Pulm Med., 2004, vol. 10 (6), SOLER, N. ; ROCA, J. ; AGUSTI, A. ; MACNEE, W. 531-6 [0038] Oxidative Stress and Airway Inflammation in Severe • ZAFARULLAH et al. Cell Mol Life Sci., 2003, vol. 60 Exacerbations of COPD.Thorax, 2005, vol. 60, (1), 6-20 [0038] 293-300 [0028] • ADHIKARI, N. ; BUMS,KEA ; MEADE, MO. The Co- • GILLISSEN ; NOWAK. Respir. Med., 1998, vol. 92 chrane Library. John Wiley & Sons, Ltd, 2008, vol. 1, (609-23), 615 [0029] 1-43 [0040] • SUTHERLAND, E.R. et al. COPD Chronic Obstruc- • REID, D. W. et al. Respirology, 2007, vol. 12 (1), tive Pulmonary Disease, 2006, vol. 3, 195-202 [0029] 63-69 [0041] • DECRAMER, M. Lancet, 2005, vol. 365, 1552-60 • MCGRATH, L.T. et al. Oxidative stress during acute [0029] respiratory exacerbations in cystic fibrosis. Thorax, • GRANDJEAN, E.M. et al. Clinical Therapeutics, 1999, vol. 54, 518-523 [0041] 2000, vol. 22 (2), 209-21 [0029] • DEMEDTS ; MAURITS et al. New England J. Med., • STEY, C. et al. Eur. Resp. J., 2000, vol. 16, 253-62 2005, vol. 353 (21), 2229-42 [0045] [0029] • COLLARD, H.R. et al. Am. J. Respir. Crit. Care med., • CHMIEL et al. Clin Rev Allergy Immunol., 2002, vol. 2007, vol. 176 (7), 636-43 [0046] 3 (1), 5-27 [0033] • KIRKHAM, P. ; RAHMAN, I. Pharmacology & Ther- • HOGG. Physiol Rev., 1987, vol. 67 (4), 1249-95 apeutics, 2006, vol. 111, 476-94 [0047] [0033] [0038] • NADEEM, A. et al. J. Asthma, 2005, vol. 1, 45-50 •WOODal.et J. Am. Coll. Nutr., 2001, vol. 20 (2), [0048] 157-165 [0033] • SACCHETINI, J.C. et al. Nat. Rev. Microbiol., 2008, •GIBSONal.et Am. J. Respir. Crit Care Med., 2003, vol. 6 (1), 41-52 [0052] vol. 168 (8), 918-951 [0034] • BOUGARIT, A. et al. AIDS, 2006, vol. 20, 1-7 [0052] • WALKER et al. Infect Immun., 2005, vol. 73 (6), • SHANKAR, E.M. AIDS Research & Therapy, 2007, 3693-3701 [0034] vol. 4, 29 [0052]

39 EP 2 589 381 A1

• FUNDAMENTAL IMMUNOLOGY. Lippincott-Raven • NOSZAL et al. J. Med. Chem., 2000, vol. 43, Publishers, 1999, 1051-1053 [0082] 2176-2182 [0112] • SKAPER et al. Free Radical Biol. & Med., 1997, vol. • CHASSAING et al. J. Chromatogr. B. Biomed. Sci. 22 (4), 669-678 [0093] Appl., 1999, vol. 735 (2), 219-27 [0113] • PHARMACOLOGICALBASIS OF THERAPEUTICS. • TRANSDERMAL AND TOPICAL DRUG DELIVERY McGraw Hill, 2001 [0102] SYSTEMS. 1997, 249-297 [0127] • THE PHYSICIAN’S DESK REFERENCE. Medical • P. H. STAHL et al. Handbook of Pharmaceutical Economics Company, Inc, 1995 [0102] Salts: Properties, Selection, and Use. Wiley VCH, • DRUG FACTS AND COMPARISONS, FACTS AND 2002 [0130] COMPARISONS. INC, 1993 [0102] • Remington’s Pharmaceutical Sciences. Mack Pub- • SAMSTRAND et al. J. Pharmacol. Exp. Ther., 1999, lishing Company [0130] vol. 288, 1174-84 [0111]

40