Use of broxib for the treatment of idiopathic pulmonary fibrosis.

Abstract

According to the present invention, there is provided N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (C21), or a pharma- ceutically acceptable salt thereof, for use in a method of improving (e.g., restoring) function in a patient with idiopathic pulmonary fibrosis, the method comprising orally administering to the patient a therapeutically effective amount of C21 or a salt thereof. The treatment may treat the IPF in a therapeutic manner, including a curative manner.

Description

[Technical field]

[0001] The present invention relates to novel uses of known pharma- ceutical active compounds, in particular to novel curative therapeutic treatments of idiopathic pulmonary fibrosis. [Background technology]

[0002] Interstitial lung diseases (ILDs) are a group of lung diseases that affect the interstitium and are characterized by scarring and / or thickening of the tissue surrounding the alveoli, thereby physically impeding the breathing process.

[0003] ILDs are distinct from obstructive airway diseases (e.g., chronic obstructive airway disease (COPD) and asthma), which are typically characterized by narrowing (obstruction) of the bronchi and / or bronchioles. ILDs can be caused by injury to the lungs, triggering an abnormal healing response, although in some cases the cause of these diseases is unknown. ILDs can be caused by chemicals (silicosis, asbestosis, certain drugs), infections (e.g., pneumonia), or other diseases (e.g., rheumatoid arthritis, systemic sclerosis, myositis, hypersensitivity pneumonitis, or systemic lupus erythematosus (lupus)).

[0004] The most common ILDs are idiopathic pulmonary fibrosis (IPF), progressive fibrosing ILD (also called non-IPF progressive fibrosing ILD), and sarcoidosis, both of which are characterized by fibrosis, chronic inflammation, and reduced lung function.

[0005] In particular, IPF is a chronic lung disease characterized by a progressive and irreversible loss of lung function caused by lung scarring. Symptoms typically include coughing and shortness of breath.

[0006] There are currently no curative treatment options for IPF, except for lung transplantation in rare cases. Thus, the disease typically manifests as a chronic, irreversible, progressive deterioration of lung function followed by death within 2-5 years in most cases (median survival 2.5-3.5 years). The overall prognosis is poor in IPF, but it is difficult to predict the rate of progression in individual patients. Risk factors for IPF include age, male sex, genetic predisposition, and smoking history.

[0007] The annual incidence of IPF is 5-16 per 100,000, and the prevalence is 13-20 cases per 100,000, increasing dramatically with age (King et al., Lancet (2011) 378, 1949-1961; Noble et al., J. Clin. Invest. (2012); 122, 2756-2762). IPF is refractory to therapies that target the immune system, which distinguishes it from pulmonary fibrosis (PF), which is associated with a purely systemic disease.

[0008] Patients with IPF usually seek medical assistance due to chronic and progressive exertional dyspnea and cough. Lung imaging classically reveals traction bronchiectasis, thickened interlobar septa, and subpleural honeycombing. When all three signs are present and there is no evidence of systemic connective tissue disease or environmental exposure, the diagnosis of IPF is highly likely. Definitive diagnosis is usually made by high-resolution computed tomography (HRCT) and / or lung biopsy and requires a multidisciplinary team of expertise including pulmonologists, radiologists, and pathologists with experience in ILDs.

[0009] IPF presents different phenotypes with different prognoses defined as mild, moderate, and severe. Mild cases follow a stable or slowly progressive course, and patients may take years to seek medical advice. Acute exacerbations of IPF are defined as a rapid worsening of the disease, and this subpopulation of patients shows a very poor outcome with a high mortality rate in the short term.

[0010] Although the cause of IPF is unknown, the interplay between environmental and genetic factors makes it appear to be a disorder that likely results in unabated tissue remodeling by fibroblasts rather than normal repair, and the pathogenesis is primarily fibrotic rather than inflammatory. Growing evidence suggests that the disease is initiated through microdamage and apoptosis of alveolar epithelial cells, activating adjacent epithelial cells and attracting stem or progenitor cells that produce factors involved in the expansion of fibroblast and myofibroblast populations in a tumor-like manner. Fibroblast nests secrete excessive amounts of extracellular matrix that destroys the lung parenchyma and ultimately leads to loss of lung function.

[0011] As a restrictive lung disease, diagnosis and monitoring of IPF may involve the use of static spirometry, where the only consideration is the volume of air exhaled, as opposed to dynamic spirometry, which measures the time it takes to exhale a fixed volume of air and is typically used to diagnose obstructive pulmonary diseases such as COPD and asthma.

[0012] The most common and useful static spirometry test for diagnosing IPF and / or monitoring its progression is the forced vital capacity (FVC) test, in which the subject is asked to breathe in as far as they can and breathe out as far as they can. This test is classified as static because there is no time component.

[0013] On the other hand, dynamic tests, i.e., the forced expiratory volume in 1 second (FEV1) test, in which the subject is asked to breathe in as much as possible and then breathe out as much as possible as quickly as possible, are typically used to diagnose obstructive pulmonary disease. The volume the subject breathes out in 1 second is the FEV1. FEV1 is commonly expressed as a percentage of the FVC (FEV1 / FVC×100).

[0014] The mean annual rate of decline in lung function (vital capacity) in IPF has previously been reported to be in the range of 0.13-0.21 liters, although more recent evidence from clinical trials indicates that declines may be considerably greater than this (e.g., up to approximately 0.4 liters per year). Symptoms often precede diagnosis by 1-2 years, and radiographic signs may precede symptoms (Ley et al., Am. J. Respir. Crit. Care Med. (2011); 183, 431-440).

[0015] Many IPF treatment approaches have been tested in preclinical models and clinical trials, including anti-inflammatory, immunomodulatory, cytotoxic, general antifibrotic, antioxidant, anticoagulant, antichemokine, antiangiogenic drugs as well as RAS blockers, endothelin antagonists, and sildenafil, and have essentially been shown to provide limited or no benefit (Rafii R et al., J. Thorac. Dis. (2013) 5, 48-73).

[0016] Besides supplemental oxygen, the only medications currently used to treat IPF are the anti-fibrotic drugs, pirfenidone or nintedanib, which have had limited success in slowing the progression of the disease.

[0017] For example, a review article by Maher and Strek (Respiratory Research, 20, 205 (2019)) states that clinical trials have demonstrated that nintedanib and pirfenidone reduce the decline in lung function in patients with IPF, and more specifically, reduce the rate of decline (as measured by FVC) by approximately 50% over a one-year period.

[0018] Thus, although nintedanib and pirfenidone are believed to reduce the risk of acute deterioration of lung function and improve life expectancy by reducing the rate at which IPF progresses (as reported by Isshiki et al, Respiratory Medicine, 187, 106551 (2021)), and may help protect against acute exacerbations of IPF (AE-IPF, acute respiratory deterioration in the absence of other known causes, with a very low median survival rate), both of these drugs can, at best, only slow the progression of the disease. Moreover, these drugs generally cause significant (mainly gastrointestinal) side effects, which can sometimes shorten treatment (see, e.g., Maher and Strek, supra).

[0019] As mentioned above, lung transplantation is the only intervention that substantially improves survival in patients with IPF, however complications such as infection and graft rejection are highly likely.

[0020] Thus, there is a real clinical need for safer and / or more effective treatments for IPF. The development of new treatment strategies for IPF is of great importance, and a fundamental challenge for the future is to develop appropriate therapeutic approaches to halt or even reverse the progression of the disease.

[0021] The renin-angiotensin system (RAS) is a key regulator of blood pressure homeostasis. The protease renin cleaves its only known substrate (angiotensinogen) to form angiotensin I (Ang I), which then serves as a substrate for angiotensin-converting enzyme (ACE) to form Ang II. The endogenous hormone Ang II is a linear octapeptide (Asp 1 -Arg 2 -Val 3 -Tyr 4 -lle 5 -His 6 -Pro 7 -Phe 8 ) and is an active component of the renin-angiotensin system (RAS).

[0022] Angiotensin II type 1 (AT1) receptors are expressed in most organs and are thought to be responsible for most of the pathological effects of Ang II. The safety and efficacy of losartan (an AT1 receptor inhibitor) was recently investigated in a small uncontrolled, open-label pilot study in IPF (www.clinicaltrials.gov identifier NCT00879879).

[0023] Several studies in adult individuals appear to demonstrate that activation of angiotensin II type 1 (AT2) receptors has an opposing effect to that mediated by AT1 receptors in modulating responses following Ang II stimulation.

[0024] The AT2 receptor has also been shown to be involved in the inhibition of apoptosis and cell proliferation (de Gasparo M et al., Pharmacol. Rev., 2000;52:415-472).

[0025] AT2 receptor agonists have also been shown to be potentially useful in the treatment and / or prevention of disorders of the gastrointestinal tract, such as dyspepsia and irritable bowel syndrome, and multiple organ failure (see International Patent Application No. WO 99 / 43339).

[0026] The expected pharmacological effects of AT2 receptor agonism are generally described in de Gasparo M et al. (see above). There is no mention that AT2 receptor agonism could be used to treat IPF.

[0027] International Patent Application No. 2002 / 096883 describes the preparation of imidazolyl, triazolyl, and tetrazolylthiophene sulfonamides and derivatives as AT2 receptor agonists. Among the compounds described in the document (as Example 1), N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (compound 21, or "C21" as used below) was selected for clinical development from a group of about 20 related analogues as a selective AT2 receptor agonist.

[0028] Mei et al, Pharm. Res., 161 105223 (2020) reported that C21 prevented cigarette smoke-induced emphysema and improved lung function in a model of obstructive pulmonary disease (specifically COPD), which, as discussed above, is very different from restrictive pulmonary diseases such as IPF.

[0029] Despite this, promising findings in preclinical models of IPF (see, e.g., Bruce et al, Br. J. Pharmacol., 172, 2219 (2015) and Rathinasabapathy et al, Front. Physiol., 9, 180 (2018)) (see also International Patent Application No. 2016 / 139475) have led to C21 being clinically developed for use in treating IPF. More recently, C21 has been entered into clinical development as a therapeutic treatment for COVID-19 (see International Patent Application No. 2021 / 191582).

[0030] C21 is currently in ongoing Phase II clinical trials in IPF patients. The targeted efficacy endpoint at the start of this trial was the reduction of lung function decline, as measured by FVC, over time compared to the current standard treatment in IPF (nintedanib and pirfenidone), but as demonstrated hereafter, we have found that C21 not only prevents the progression of lung function decline in IPF patients in a clinical setting, but can actually at least partially restore it. This represents an unexpected and highly significant development in the treatment of this debilitating and ultimately fatal disease. Summary of the Invention

[0031] According to a first aspect of the present invention, there is provided a method of improving pulmonary function in a patient having IPF, comprising orally administering to such a patient a therapeutically effective amount of C21, or a pharma- ceutically acceptable salt thereof, which method of treatment is hereinafter also referred to as the "method of the present invention".

[0032] The term "IPF" will be understood to include not only prototypic IPF, the well-known progressive fibrosing ILD characterized by accelerated respiratory failure, frequent disease progression, and earlier death, but also a condition termed "progressive fibrosing ILD" (PF-ILD), in which some individuals develop a progressive phenotype similar to IPF (see, e.g., Flaherty et al, N. Engl. J. Med., 381, 1718 (2019) and Wells, Lancet, 9, 437 (2021)). The PF-ILD phenotype is often due to disease (e.g., connective tissue diseases such as rheumatoid arthritis, scleroderma, dermatomyositis / polymyositis, related ILD (CTD-ILD), fibrotic hypersensitivity pneumonitis (fHP), pneumoconiosis such as asbestosis, silicosis), sarcoidosis, idiopathic nonspecific interstitial pneumonia (NSIP), and unclassified ILD. Regardless of the disease trigger, PF-ILD has similar risk factors, progresses through similar mechanisms as prototypical IPF, such as self-sustaining dysregulated cellular repair, fibroblast proliferation, and alveolar dysfunction, and together can be targeted in a similar manner. To avoid unnecessary overlap, the IPF and PF-ILD conditions are hereinafter referred to together as "IPF."

[0033] As described herein below, we have found that, unlike existing anti-fibrotic drug-based treatments for IPF (i.e., nintedanib and pirfenidone, as described above), C21 not only halts disease progression, but actually improves lung function compared to "baseline" lung function levels (i.e., levels measured before treatment begins), and thus can treat or even reverse the disease and / or its symptoms itself in a therapeutic (e.g., curative and / or reparative) manner, as opposed to simply delaying the disease.

[0034] Those skilled in the art will understand that the term "disease retardation" includes forms of medical treatment of a condition that only serves to slow or stop the progression of the disease. Such treatments may or may not alleviate symptoms of the disease (in IPF, existing antifibrotic drug-based treatments, nintedanib and pirfenidone, generally do not alleviate symptoms), but in any event, disease retardation treatments do not reverse the underlying condition or its overall progression. According to the present invention, the term "non-disease retardation" refers to treatments that not only retard the progression of IPF, but also potentially reverse it, as shown herein below.

[0035] In this regard, C21 is disease modifying in that it can alter the course and / or pathology of IPF.

[0036] By "improving lung function" (in any kind of "therapeutic" manner) it is meant that C21 can not only have a beneficial effect when compared to placebo and / or otherwise untreated patients, or even when compared to the established drug-based IPF therapies described above, but can also show a clear and statistically significant clinical improvement and / or modification of lung function, as measured, for example, by lung function tests, such as those described herein, after several weeks of treatment, when compared to comparable baseline lung function test measurements taken in the same patient prior to the start of treatment with C21 or a salt thereof.

[0037] Thus, there is further provided a method of restoring lung function in a patient having IPF, comprising orally administering to such a patient a therapeutically effective amount of C21, or a pharma- ceutically acceptable salt thereof, which method of treatment is hereinafter also referred to as the "method of the invention."

[0038] Restoration of pulmonary function in a patient may include any improvement compared to baseline, thus providing at least partial restoration of pulmonary function as measured by such pulmonary function tests compared to comparable testing prior to the initiation of treatment. "At least partial restoration" refers to a complete recovery (i.e., a reduction in pulmonary function from a value that is within the normal range for an otherwise healthy (non-IPF) patient to at least about 1%, e.g., at least about 2%, at least about 3%, or at least about 4%, e.g., at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 12%, at least about 14%, at least about 16%, at least about 24%, or at least about 36 weeks, including or even longer than about 12 weeks, including or even longer than about 16 weeks, including or even longer than about 24 weeks, including or even longer than about 36 weeks, from the initiation of treatment, as compared to pulmonary function as measured by the relevant pulmonary function test prior to the initiation of treatment (e.g., up to about one month, e.g., about 7 to about 10 days, in conjunction with the first day of treatment). By "improvement" is meant up to about 5%, e.g., at least about 6%, including at least about 8% or at least about 10%, including at least about 12% or at least about 13%, including at least about 15%, e.g., at least about 17.5% or at least about 20%, including at least about 22.5%, e.g., at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or even at least about 80% or more improvement in lung function.

[0039] Thus, in essence, C21 and its salts can provide a curative therapeutic treatment for IPF, thereby restoring lung function and therefore the general health and well-being of the patient. Based on the clinical results, we have good reason to believe that C21 may in some cases provide at least a partial cure for the disease itself.

[0040] By providing an "at least partial cure" for IPF (which may be used interchangeably with "curative treatment" or "curative therapeutic treatment" for IPF), we mean that lung function may be restored by the methods of the present invention to a stabilized level (i.e., pulmonary function tests, such as FVC, show no decline from baseline levels measured at the start of treatment), or to an improved level relative to such baseline level, partially or at most, to a level generally considered "normal" by physicians, where the patient exhibits less noticeable ongoing IPF symptoms, or even no IPF symptoms.

[0041] Given the observed improvements established in the absence of combination therapy with the aforementioned established antifibrotic IPF therapies (i.e., nintedanib and pirfenidone), C21 or a salt thereof may be used as a first-line / sole treatment for IPF in the absence of such other drugs.

[0042] For the avoidance of doubt, the improvements in lung function in patients reported hereinafter may be the result of improved respiration (i.e., efficiency of gas exchange at a cellular level) or, given the rate of improvement observed, likely may be the result of an improvement in the extent of the lungs' ability to expand with air in a physical sense (i.e., improved respiration through an increase / restoration of lung volume and / or vital capacity, i.e., the amount of air that can be inhaled / exhaled), or may be due to other factors, or any combination of these.

[0043] Improvement in lung function may also be measured directly or indirectly in a number of different ways, for example quantitatively, for example by (e.g., radiological) imaging of the lungs (e.g., by high resolution computed tomography), by measuring patient mobility by physical measurements such as the number of steps before fatigue (horizontal or upward incline, e.g., uphill or stair climbing) or otherwise the patient's average number of steps per day, week, or month, and by measuring manageable symptoms including dyspnea, fewer coughing episodes, blood oxygen levels, or other quantitative markers, or qualitatively, for example by measuring stress and / or anxiety, quality of life, or more generally qualitative markers of how the patient "feels".

[0044] Thus, there is further provided a method of improving lung (vital) capacity in a patient having IPF, comprising orally administering to such a patient a therapeutically effective amount of C21, or a pharma- ceutically acceptable salt thereof, which method of treatment is hereinafter also referred to as the "method of the invention."

[0045] Thus, the method of the present invention may alternatively be described as the use of C21 or a pharma- ceutically acceptable salt thereof in the therapeutic (and / or curative) treatment of IPF, as manifested by one or more of the following: Improved breathing, Improved / Restored Lungs / Lung Ventilation, Improved / Restored Ventilatory Lung / Lung Function, and / or Increased / Restored Vital Capacity (defined as the maximum volume of air that can be expelled from the lungs after taking the deepest possible breath), By the use of C21 or a salt thereof in IPF patients and / or in a method for preventing (or completely eliminating) AE-IPF as defined above.

[0046] The methods of the invention may also provide one or more of the improvements described herein above in the complete and / or substantial absence of significant side effects or other drug safety issues, including adverse drug reactions and / or C21-related adverse events (AEs), particularly serious AEs (SAEs).

[0047] AEs, adverse drug reactions (ADRs) and SAEs are defined by the International Conference on Harmonisation (ICH, guideline E2A (ICH 1994)).

[0048] The term "AE" includes any untoward medical occurrence in a subject administered an investigational drug product (IMP, in this case C21 or a salt thereof) that may or may not have a causal relationship to the IMP. Thus, an AE can be any untoward and / or unintended manifestation (e.g., significant abnormal laboratory findings, symptoms) or disease temporally related to the use of the IMP, whether or not considered related to the IMP.

[0049] An ADR is any adverse, unintended response to an IMP associated with any dose of an IMP.

[0050] An SAE is any adverse medical occurrence, at any dose, that: Brings death, is life-threatening (i.e., the event put the subject at risk of death at the time of the event, not an event that could hypothetically have caused death if it had been more severe); - hospitalization or extension of existing hospitalization is required; · causing permanent or serious disability or incapacity; have a birth abnormality or birth defect; and / or · Is judged to be medically significant (i.e., an event that may not be immediately life-threatening or result in death or hospitalization, but may endanger the subject or require intervention to prevent one of the other outcomes listed above).

[0051] In this regard, C21 and its salts are capable of treating IPF in accordance with the methods of the present invention in a manner such that, in the patient's consideration and / or in the physician's medical opinion, any AEs, SAEs, or other side effects that may result from using it to treat that patient are outweighed by the positive effects resulting from treating the disease itself.

[0052] In the methods of the present invention, C21 and its salts can be administered to the gastrointestinal tract as a complete dosage form in any formulation suitable for oral administration and delivery, meaning that the final dosage form containing the C21-containing formulation should be suitable for swallowing as a whole, and the complete dosage form for subsequent consumption and / or ingestion in the gastrointestinal tract and during use is swallowed and then consumed and / or ingested in the tract.

[0053] Thus, C21 and its salts may be provided in the form of a powder, simple mixture, granules, pellets, beads, solutions, and / or suspensions. Final dosage forms include pills, tablets, capsules, films, solutions or suspensions (e.g., syrups), powders, cakes, etc.

[0054] Thus, C21 and its salts may be presented in the form of a carrier system, i.e., a simple mixture with any pharma- ceutically acceptable inert material capable of increasing the mass of the composition, or a component of the composition, to provide a suitably handleable dosage form.

[0055] Thus, suitable carriers include pharma- ceutically acceptable inorganic salts, such as sodium chloride, calcium phosphate, dicalcium phosphate hydrate, dicalcium phosphate dehydrate, tricalcium phosphate, calcium carbonate, and barium sulfate; polymers, such as microcrystalline cellulose (optionally silicified), cellulose, and cross-linked polyvinylpyrrolidone; starches; sugars and sugar alcohols, such as lactose, mannitol, xylitol, isomalt, dextrose; or mixtures of any of the foregoing.

[0056] The carrier material is preferably used in an amount of about 5% to about 90% by weight, based on the total weight of the composition containing C21 or a salt thereof, with a preferred range being about 10% to about 80% by weight.

[0057] Preferred carrier materials include lactose, xylitol, isomalt, microcrystalline cellulose, and more preferably, mannitol. The carrier composition may comprise a physical mixture of any of the foregoing materials and / or may comprise a complex of one or more of these materials.

[0058] The mixture of C21 / salt and carrier material can then be filled directly into a capsule. Alternatively, such a mixture can be granulated into pellets, granules, or beads and then loaded into a suitable capsule. Alternatively, the powder, pellets, granules, or beads can be compressed into a tablet.

[0059] Granulation may be carried out using well known techniques, including dry granulation, wet granulation, melt granulation, thermoplastic pelletization, spray granulation, or extrusion / spheronization.

[0060] In addition to the carrier material, the powders, granules, pellets, or beads containing C21 or a salt thereof may also contain other commonly used pharmaceutical additives and / or excipients used in the art (e.g., Rowe et al, Handbook of Pharmaceutical Excipients, 8 th ed. (2017) and documents cited therein).

[0061] Other pharma- ceutically acceptable excipients, such as binders, disintegrants, glidants, lubricants, etc., are known to those skilled in the art.

[0062] Binders may be defined as materials that can act as bond formation enhancers, which may facilitate the compression of powder mass into a coherent compact. Suitable binders include polyvinylpyrrolidone, gelatin, sodium alginate, cellulose derivatives such as low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose gum, microcrystalline cellulose (optionally silicified), and the like. When present, binders are preferably used in an amount of about 2% to about 50% by weight, based on the total weight of the composition containing C21 or a salt thereof. A preferred range is about 5% to about 30% by weight.

[0063] Disintegrants (or disintegrating agents) can be defined as materials that can measurably accelerate the disintegration / dispersion of the components of the composition containing C21 or its salt, such as granules or tablets. This can be achieved, for example, by materials that can swell and / or expand when placed in contact with an aqueous medium (particularly body fluids, including those found in the gastrointestinal tract), thus disintegrating at least a portion of the dosage form containing the formulation containing C21 or its salt when so wetted. Suitable disintegrants include cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose (croscarmellose, e.g., Ac-Di-Sol, FMC Corp., USA), carboxymethyl starch, native starch, pregelatinized starch, corn starch, potato starch, sodium starch glycolate (Primojel®, DMV International BV, Netherlands), low-substituted hydroxypropyl cellulose, and the like. The disintegrant (which may include one or more of the above materials) is preferably used in an amount of about 1% by weight (e.g., about 5% by weight) to about 40% by weight, based on the total weight of the composition containing C21 or a salt thereof. A preferred range is about 5% by weight (e.g., about 10% by weight) to about 30% by weight. Preferred disintegrants used include cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, sodium starch glycolate, and especially low-substituted hydroxypropylcellulose.

[0064] A glidant is a pharma- ceutically acceptable material that promotes powder flow by reducing interparticle friction and / or cohesion (but does not necessarily have the ability to reduce and / or prevent adhesion to external materials, such as capsule fillers or hoppers). Thus, suitable pharma- ceutically acceptable glidant materials include talc, magnesium carbonate, or calcium silicate, although it is preferred that the glidant is a hydrophilic glidant, such as fumed / pyrogenic silica, or one or more of the various forms of silica, including, more particularly, silica gel, silica aerogel, and / or colloidal silica.

[0065] Lubricants are typically used when the final dosage form to be swallowed is in the form of a tablet, to prevent granules or powder from adhering to the punch die / face and to facilitate smooth exit from the die after compression. Suitable lubricants include stearic acid, sodium stearyl fumarate, anhydrous colloidal silica, talc, or, preferably, magnesium stearate). When a lubricant is used, it should be used in very small amounts (e.g., up to about 3% by weight, preferably up to 2% by weight, based on the total weight of the composition containing C21 or its salt).

[0066] Other excipients that may be used in oral dosage forms include surfactants, humectants, flavorings (e.g., lemon, menthol, or peppermint powder), sweeteners (e.g., neohesperidin, sucralose, or acesulfame potassium), dyes, antioxidants (naturally occurring or not (e.g., butylated hydroxytoluene (BHT), vitamin C, vitamin E, beta-carotene, uric acid, unicorn, superoxide dismutase (SOD), glutathione peroxidase, or peroxidase catalase)), preservatives, and buffers.

[0067] These and other pharma- ceutically acceptable excipients mentioned herein may be commercially available or are otherwise described in the literature, including, for example, all of these types of excipients described in Rowe et al., supra, and Remington The Science and Practice of Pharmacy, 21st ed., Lippincott Williams and Wilkins, Philadelphia (2006), and documents cited therein, the relevant disclosures of all of which are incorporated herein by reference. Otherwise, preparation of suitable formulations can be accomplished without inventive effort by those skilled in the art using routine techniques.

[0068] Granules, pellets, or beads may be further processed after their formation. For example, dry granules may be crushed, ground, or milled using suitable grinding techniques to produce smaller sized particulate material, which may also be sieved to separate the desired size fraction. Wet granules may be sieved to break up granular agglomerates and remove fine materials. In either case, unused undersized (fines) and oversized materials may be reprocessed to avoid waste.

[0069] However, whether a powder mix, granules, tablets, or capsules are made, preparation of the composition should ensure that the C21 or a pharma- ceutically acceptable salt thereof is distributed homogeneously throughout the carrier material (and / or other excipients used).

[0070] For simple mixtures, this involves mixing for a period of time that provides a homogeneously distributed active ingredient, for example as described hereinafter, which may vary according to the equipment used.

[0071] The terms "homogeneous" and "homogeneously distributed" in the context of the present invention mean that there is a substantially uniform content of C21 or its salt throughout the carrier material (and / or other excipients used). In other words, when multiple (e.g., at least 2, more preferably about 6, e.g., about 10, and optionally up to about 30 or more) samples are taken from a mixture containing an active ingredient and a carrier blend, the measured content of the active ingredient present among such samples results in a standard deviation (i.e., coefficient of variation and / or relative standard deviation) from the average amount of less than about 8%, e.g., less than about 6%, e.g., less than about 5%, particularly less than about 2%.

[0072] Preferred mixing equipment includes standard mixing equipment such as tumblers, shaker mixers (e.g., Turbula), convection, hopper, and fluidization blenders. Preferred blenders include V blenders.

[0073] Tablets can be formed by the process of compression / compaction. Direct compression is described, for example, in Pharmaceutical Dosage Forms: Tablets. Volume 1, 3 rd This may be achieved using techniques such as those described in The Journal of Applied Physics, Vol. 13, No. 1, 2006, pp. 1171-1175, 2006. Edition, Augsburger et al (eds.), CRC Press (2008) and documents cited therein. Suitable compression equipment includes standard tablet presses, such as the Kilian SP300 or Korsch EK0.

[0074] A composition comprising C21 or a salt thereof may be contained within a capsule suitable for such oral administration.

[0075] Suitable pharma- ceutically acceptable capsules include soft- or hard-shell capsules, which may be made, for example, by standard capsule-filling processes from gelatin, cellulose polymers, such as hydroxypropyl methylcellulose (HPMC or hypromellose), hypromellose acetate succinate (HPMCAS), starch polymers, pullulan, or other suitable materials.

[0076] When the dosage form comprises a solid formulation comprising a mixture of C21 or a salt thereof with a carrier material (e.g., in the form of a powder, granules, etc.), according to a preferred embodiment of the present invention, the capsule is preferably a hard shell, two-piece capsule, such as a capsule made of gelatin or, more preferably, HPMC, and supplied as closed halves that can be separated, filled with particulate matter, and subsequently reconstituted. Such capsules can be of any size (e.g., 00 to 5), but preferred capsule sizes are size 2, size 1, or, more preferably, size 0.

[0077] In this and other preferred embodiments of the present invention, C21 or a salt thereof is presented in the form of particles, which may be amorphous or crystalline or a mixture of the two. Preferred particles are of a size that does not result in segregation, either during the formation of the composition to be filled into the capsule during the capsule filling process or upon storage.

[0078] In this regard, C21 or a salt thereof may typically be provided in the form of a plurality of primary (i.e., non-agglomerated) particles having an average diameter, e.g., weight-based and / or volume-based average diameter, of about 1,000 μm or less, e.g., about 500 μm, about 250 μm, preferably about 100 μm or less, about 50 μm or less, e.g., about 20 μm, or about 10 μm or less. Although there is no lower limit to the particle size that may be used in accordance with this aspect of the invention, for ease of manufacture, it is preferred that the primary particles of C21 or a salt thereof have an average diameter of about 1 μm or more, e.g., about 2 μm, about 3 μm, on a weight and / or volume basis.

[0079] As used herein, the term "weight-based average diameter" is understood by those skilled in the art to include the average particle size being characterized and defined from the particle size distribution by weight, i.e., the existing fraction (relative amount) in each size class is defined as the weight fraction obtained, for example, by sieving (e.g., wet sieving). The term "volume-based average diameter" is similar in meaning to the weight-based average diameter, but is understood by those skilled in the art to include the average particle size being characterized and defined from the particle size distribution by volume, i.e., the existing fraction (relative amount) in each size class is defined as the volume fraction measured, for example, by laser diffraction. Particle size can also be measured by standard equipment, such as dry particle size measurement techniques, including dry dispersion techniques available from manufacturers such as Sympatec GMbH (Clausthal-Zellerfeld, Germany). Other instruments known in the art may be used to measure particle size, such as, for example, instruments sold by Malvern Instruments, Ltd. (Worcestershire, UK), Shimadzu (Kyoto, Japan), and Elzone, Micromeritics (USA, electrical sensing zone method).

[0080] The above particle size measurement methods generally assume that particles are essentially spherical.For particles with shapes very different from spheres, the average diameter can also include the average Feret diameter of the particles, for example, measured by microscopy.For needle-like particles, the average diameter can be expressed as the average length of the longest Feret diameter of the needles (i.e., the average "length" of the needles).

[0081] Particles having an average diameter, such as the average diameter on a weight and / or volume basis, within the above limits includes the average diameter of the particles as they are prepared and before they are mixed with the relevant excipients according to the present invention and / or before they are loaded into a capsule. It will be understood that some aggregation of primary particles to form secondary particles may occur during handling and / or processing of the active ingredient. However, this should be minimized.

[0082] C21 or a salt thereof also has a mass median diameter (D 50 , log-normal mass median diameter), the average particle size by mass, and / or the diameter at which 50% of the mass in the cumulative PSD is contained, and / or the geometric standard deviation (equation D 84.13 / D 50 Or D 50 / D 15.78 GSD or σ measured by g , in the formula, D 84.13 and D. 15.78 are the diameters at which 84.13% and 15.78% of the mass are contained, respectively, and D 50 The particles may be provided in the form of particles having a relatively narrow particle size distribution (PSD) as measured by standard techniques and art-recognized parameters, including PSD (as previously defined herein). Such parameters may be measured and calculated in-process using any suitable sampling method and particle size measurement technique as previously described herein.

[0083] In this regard, it is preferred that C21 or a salt thereof has a PSD with a GSD of less than about 4, such as less than about 3.

[0084] Primary particles of C21 or a salt thereof may be prepared by any suitable technique, such as precipitation, cutting (e.g. by dissolution in a supercritical fluid under pressure followed by rapid expansion), spray drying, or, where appropriate, may be micronized by techniques well known to those skilled in the art, such as grinding, dry grinding, jet grinding, wet grinding and / or crushing.

[0085] The particles may also be sieved to separate into desired size fractions and / or to break up agglomerates and / or to remove fine material. In either case, unused undersized (fines) and oversized material may be reprocessed to avoid waste. Alternatively, the particles may be separated to the appropriate particle size using cyclone separation, by air classifiers, sedimentation, force field fractionation and / or elutriation.

[0086] While the C21 or a salt thereof can be selected and / or provided with the aforementioned weight or volume based average diameter, particle size, PSD, and / or GSD using one or more of the techniques described above, one of the primary advantages of formulating a composition to be loaded into a capsule to form a dosage form for administration is that the C21 or a salt thereof does not require the particle processing techniques described above prior to blending with the associated excipients.

[0087] In this regard, as discussed earlier in this specification, we have found that C21 and its salts are extremely difficult materials to work with. Part of the problem is the extreme sensitivity of C21 and its salts to the combined presence of light and water.

[0088] Furthermore, as described in particular herein below, compatibility tests have revealed that certain standard excipients, when co-mixed with C21 and its salts, cause significant chemical instability of the active ingredient. Furthermore, C21 and its salts (especially its sodium salt) are sticky and form as needle-like crystals with a tendency to aggregate. This means that dry mixing with certain standard pharmaceutically acceptable ingredients is very difficult, and it is not easy to produce a blend with pharmaceutically acceptable content uniformity of the active ingredient and / or the same dose uniformity in capsules.

[0089] Furthermore, it has been found that micronizing the primary particles of the active ingredient (e.g. in the form of a sodium salt) does not provide a solution to these problems, as one skilled in the art might expect, and also gives rise to additional problems associated with localized heating and static electricity.

[0090] However, we have found that by blending C21 or a pharma- ceutically acceptable salt thereof with a premixed blend of carrier particles having an average diameter, such as an average diameter on a weight and / or volume basis, and / or structural (particle) density that is similar to the average diameter on a weight and / or volume basis, and / or structural (particle) density, of solid particles of C21, or a pharma- ceutical acceptable salt thereof, and a glidant, it is possible to avoid the aforementioned problems and provide a composition for loading into capsules in which C21 or a salt thereof is not only homogenously and evenly distributed, but also ensures dose homogeneity of the active ingredient among capsules after such loading, but is also physically and chemically stable during and after manufacture, under normal storage conditions, and during use.

[0091] Thus, in this aspect, the method of the invention includes administration of a dosage form comprising an excipient mixed with particles of C21 or a pharma- ceutically acceptable salt thereof, comprising a blend of at least one type of carrier particles (e.g., carrier particles having an average diameter, such as an average diameter on a weight and / or volume basis, and / or a structural (particle) density that is similar to the average diameter on a weight and / or volume basis, and / or a structural (particle) density, respectively, of solid particles of C21 or a pharma- ceutically acceptable salt thereof), and a glidant.

[0092] The terms "homogeneous" and "homogeneously distributed" in the context of this embodiment are as previously defined herein.

[0093] In this preferred aspect of the invention, suitable carrier particle materials may comprise pharma- ceutically acceptable substances that are soluble in water, including carbohydrates, such as sugar alcohols, e.g., sorbitol, xylitol, and especially mannitol. Again, the carrier particles may comprise physical mixtures of any of these materials and / or may comprise complexes of one or more of these materials.

[0094] The carrier particles may have a similar particle size distribution and / or structural (particle) density as the active ingredient particles used in the composition that is loaded into the capsule to make such a dosage form.

[0095] "Similar particle size distribution and / or structural (particle) density" means that the average diameter, e.g., weight and / or volume average diameter, and / or particle density of the carrier particles are within about ±75%, e.g., about ±50%, about ±40%, e.g., about ±30%, or about ±20%, about ±10%, of the relevant dimension of the C21 or salt thereof used. In the case of C21 sodium salt, which is formed as acicular particles, the relevant dimension is the length (and / or longest Feret diameter) of those acicular particles.

[0096] In this regard, preferred carrier particle sizes are less than about 100 μm, including an average diameter on a weight and / or volume basis of less than about 80 μm, e.g., less than about 70 μm, including, for example, from about 20 μm to about 60 μm (e.g., about 25 μm or, more preferably, about 50 μm).

[0097] We have found that by using carrier particles having a size similar to the active ingredient and / or within the ranges set forth above, blend segregation can be avoided.

[0098] To prepare a composition that is loaded into a capsule to produce a dosage form according to this aspect of the invention, carrier particles of the required size may also be pre-blended with a suitable glidant material, preferably a proprietary silica manufactured under the registered trademark "Syloid®" (see https: / / grace.com / pharma-and-biotech / en-us / Documents / Syloid / M309c), colloidal silica, and / or fumed / pyrogenic silica, prior to mixing with the active ingredient. Thus, preferred forms of silica include stable aqueous dispersions (sols) of amorphous silica particles having an average diameter on a weight and / or volume basis of about 1 nm to about 100 nm (e.g., up to about 50 nm, e.g., up to about 20 nm, e.g., from about 10 nm to about 15 nm).

[0099] The glidant and carrier particles may be mixed together to form an interactive (or ordered) mixture of carrier particles that are largely coated with smaller particles of glidant material, and this blend is then mixed with the active ingredient particles.

[0100] We have also found that by first forming an excipient blend by adding the aforementioned glidants to the carrier particles prior to mixing with the active ingredient, the flow properties of the excipient blend are improved, leading to better mixing with C21 or a pharma- ceutically acceptable salt thereof, further reducing the likelihood of blend segregation.

[0101] In this aspect of the invention, the dosage form may also contain other excipients well known to those skilled in the art for oral delivery of active ingredients, such as those previously described herein.

[0102] However, considering the extreme sensitivity of C21 and its salts to other chemicals, it is preferred that such other excipients are not included in the dosage form according to this aspect of the invention. In this respect, the dosage form may consist essentially of a pharmaceutical composition in the form of a particle mixture comprising C21, or a pharma- ceutically acceptable salt thereof, mixed with a blend of carrier particles (e.g., having an average diameter, e.g., average diameter, e.g., weight and / or volume based average diameter, and / or structural (particle) density similar to the average diameter, e.g., weight and / or volume based average diameter, and / or structural (particle) density, of the solid particles of C21 or its salt), and a glidant, which composition may be contained within a capsule suitable for such oral administration.

[0103] All preferred features mentioned herein for other aspects of the invention which relate in any way to this aspect of the invention are equally applicable.

[0104] It will be understood that the term "consisting essentially of" means that the scope of this (and only this) aspect of the invention is limited to the specific essential features listed above, together with other features that do not materially affect the basic and novel feature(s) of this aspect of the invention.

[0105] In this regard, although not an essential feature of this aspect of the invention, it may be preferred to add a lubricant (such as sodium stearyl fumarate or, preferably, magnesium stearate) to the blend prior to filling into capsules to prevent the blend from sticking to the equipment (e.g., capsule filling machines and hoppers), a preferred feature which does not materially affect the basic and novel characteristics of this aspect of the invention.

[0106] A composition loaded into a capsule "consisting essentially of" a particle mixture including solid particles of C21, or a pharma- ceutically acceptable salt thereof, mixed with a blend of carrier particles and a glidant as defined above can alternatively mean that the composition comprises a total of at least about 95% by weight, e.g., at least about 97% by weight, of those particular components.

[0107] In this aspect of the invention, the dry mixed blend is also preferably passed through a sieve at some point during the blending process, for example, as described later in this specification, to break up any agglomerates formed during the blending process. Suitable sieves are those that have a pore size as small as (or about) the particle size of the largest component of the blend. Thus, suitable sieve sizes are about 50 μm, e.g., 75 μm, including 100 μm, e.g., 150 μm, 200 μm, or 250 μm (e.g., about 300 μm), up to about 1,000 μm, e.g., about 400 μm (e.g., about 500 μm), up to about 900 μm (e.g., about 800 μm).

[0108] The dosage form may also be presented in the form of a heterogeneous mixture comprising solid particles of C21, or a pharma- ceutically acceptable salt thereof, suspended in a pharma- ceutically acceptable, hydrophobic, lipid-based carrier in which C21 or a salt thereof is essentially insoluble, and this composition is loaded into a capsule suitable for such oral administration.

[0109] The lipid-based carrier system in which the solid particles of C21 or a salt thereof are suspended can be in a solid form at room temperature (fats) or, more preferably, in a liquid form at room temperature (oils). Nevertheless, the particles of C21 or a salt thereof can be suspended in either form of lipid carrier.

[0110] According to this embodiment, the capsule is preferably a soft shell, single piece capsule, e.g., a soft gelatin capsule, which is filled with a lipid-based suspension of C21 or a salt thereof and then sealed as a single piece, e.g., with a drop of gelatin solution. Gelatin can be obtained from any source (e.g., porcine and bovine sources), although it should be noted that there are vegan alternatives to soft gelatin capsules.

[0111] The soft gelatin capsule shell may contain one or more plasticizers, such as xylitol, sorbitol, polyglycerol, sorbitol, glucose, fructose, and non-crystallizing solutions of glucose syrup, more preferably glycerin / glycerol, sorbitol, and / or proprietary plasticizers, such as Anidrisorb (a proprietary mixture of sorbitol, sorbitan, maltitol, and mannitol, including Roquette Freres, Anidrisorb 85 / 70 (a liquid sorbitol-mannitol hydrolyzed starch plasticizer)). The soft gelatin capsule shell may optionally contain one or more flavoring agents, coloring agents, and / or opacifying agents, such as titanium dioxide.

[0112] Such capsules can be of any shape (e.g., rectangular, circular, oval, tubular, etc.) and any size (e.g., 3-24 rectangular, 1-20 circular, 2-20 oval, 5-120 tubular, etc.) Preferred capsule sizes hold a volume of about 0.3 to about 1.0 mL.

[0113] In this particular embodiment of the invention, it is essential that C21 or a pharma- ceutically acceptable salt thereof is essentially insoluble in the lipid-based carrier under normal storage conditions. "Essentially insoluble" includes that C21 or a salt thereof has a solubility in the carrier of about 0.015 mg of C21 or a salt thereof per gram of carrier or less.

[0114] Thus, due to the dual properties of the carrier, namely its hydrophobicity and lack of tendency to dissolve C21 or its salts, the active ingredient is not exposed to amounts of water that may catalyze its decomposition, as previously described herein.

[0115] We have surprisingly found that there are relatively few lipid-based carrier materials that meet these requirements and are therefore capable of stabilizing C21 or a salt thereof at ambient temperatures in such dosage forms.

[0116] The hydrophobic lipid-based carrier material, in which C21 or a salt thereof must be insoluble as previously defined herein, may comprise a non-polar oil or fat that is essentially immiscible with water. The lipid-based carrier is preferably composed primarily of triacylglycerol (also known as "triglyceride"), which is an ester formed by the reaction of all three hydroxyl groups of the glycerol moiety with a fatty acid (carboxylic acid).

[0117] Thus, lipids may contain saturated or unsaturated chain fatty acids, and the chains may range from 1 carbon atom up to 30 carbon atoms (including up to 26 carbon atoms), up to 22 carbon atoms (including 8, 10, 12, 14, 16, 18 or 20 carbons), etc.

[0118] Among the saturated fatty acids that may be mentioned are acetic acid (2), propionic acid (3), butyric acid (4), valeric acid (5), caproic acid (6), enanthic acid (7), caprylic acid (8), pelargonic acid (9), capric acid (10), undecylic acid (11), lauric acid (12), tridecylic acid (13), myristic acid (14), pentadecylic acid (15), palmitic acid (16), margaric acid (17), stearyl acid (18), glyceryl acid (19), glyceryl acid (20), glyceryl acid (21), glyceryl acid (22), glyceryl acid (23), glyceryl acid (24), glyceryl acid (25), glyceryl acid (26), glyceryl acid (27), glyceryl acid (28), glyceryl acid (29), glyceryl acid (30), glyceryl acid (31), glyceryl acid (32), glyceryl acid (33), glyceryl acid (34), glyceryl acid (35), glyceryl acid (36), glyceryl acid (37), glyceryl acid (38), glyceryl acid (39), glyceryl acid (40), glyceryl acid (41), glyceryl acid (42), glyceryl acid (43), glyceryl acid (44), glyceryl acid (45), glyceryl acid (46), glyceryl acid (47), glyceryl acid (48), glyceryl acid (49), glyceryl acid (50), glyceryl acid (51), glyceryl acid (52), glyceryl acid (53), glyceryl acid (54), glyceryl acid (55), glyceryl acid (56), glyceryl acid (57), glyceryl acid (58), glyceryl acid (59), The fatty acids include glyceric acid (18), nonadecylic acid (19), arachidic acid (20), heneicosylic acid (21), behenic acid (22), tricosylic acid (23), lignoceric acid (24), pentacosylic acid (25), cerotic acid (26), carboseric acid (27), montanic acid (28), nonacosylic acid (29), and melissic acid (30), where the number in parentheses is the number of carbon atoms in the fatty acid molecule.

[0119] Among the unsaturated fatty acids that may be mentioned are crotonic acid (4:1), as well as omega-3 unsaturated fatty acids, such as octanoic acid (8:1), decanoic acid (10:1), decadienoic acid (10:2), lauroleic acid (12:1), laurolinoleic acid (12:2), myristobacenic acid (14:1), myristolinoleic acid (14:2), myristolinolenic acid (14:3), palmitrinolenic acid (16:3), hexadecatrienoic acid (16:3), palmitidonic acid (16:4), alpha-linolenic acid (18:3), stearidonic acid (18:4), 11,14,17-eicosatrienoic acid ( 20:3), eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5), heneicosapentaenoic acid (21:5), clupanodonic acid (22:5), docosahexaenoic acid (22:6), 9,12,15,18,21-tetracosapentaenoic acid (24:5), nisic acid (24:6), and 6,9,12,15,18,21-tetracosahexaenoic acid (24:6); ω-5 unsaturated fatty acids, such as myristoleic acid (14:1), palmitovaccenic acid (16:1), α-eleostearic acid (18:3), β-eleostearic acid (trans-1 8:3), punic acid (18:3), 7,10,13-octadecatrienoic acid (18:3), 9,12,15-eicosatrienoic acid (20:3), and β-eicosatetraenoic acid (20:4); ω-6 unsaturated fatty acids, such as tetradecenoic acid (14:1), 12-octadecenoic acid (18:1), linoleic acid (18:2), linoleic acid (trans-18:2), γ-linolenic acid (18:3), calendic acid (18:3), pinolenic acid (18:3), 11,14-eicosadienoic acid (20:2); dihomo-linoleic acid (20:2), dihomo-γ-linolenic acid (20:3), arachidonic acid (20:4), docosadienoic acid (22:2), adrenic acid (22:4), osbondic acid (22:5), tetracosatetraenoic acid (24:4), and tetracosapentaenoic acid (24:5); omega-7 unsaturated fatty acids, such as 5-dodecenoic acid (12:1), 7-tetradecenoic acid (14:1), palmitoleic acid (16:1), vaccenic acid (18:1), rumenic acid (18:2), paulic acid (20:1), 7,10,13-eicosatrienoic acid (20:3), 15-docosenoic acid (22:1), and 17-tetracosenoic acid (24:1);ω-9 unsaturated fatty acids include, for example, hypogeic acid (16:1), oleic acid (18:1), elaidic acid (trans-18:1), gondoic acid (20:1), 8,11-eicosadienoic acid (20:2), erucic acid (22:1), nervonic acid (24:1), meadic acid (20:3), and ximenic acid (26:1); ω-10 unsaturated fatty acids, for example, sapienic acid (16:1); ω-11 unsaturated fatty acids, for example, gadoleic acid (20:1); and ω-12 unsaturated fatty acids, for example, 4-hexadecenoic acid (16:1), petroselinic acid (18:1), and eicosenoic acid (20:1), where the numbers in parentheses are the number of carbon atoms and the number of unsaturated (i.e., double) bonds in the fatty acid molecule, respectively;

[0120] Fatty acids that may be mentioned include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, ricinoleic acid, linoleic acid, linolenic acid, eicosenoic acid, behenic acid and erucic acid.

[0121] Triglycerides can be naturally occurring oils or fats, semi-synthetic, or synthetic.

[0122] Naturally occurring oils or fats can be obtained from animals or, more preferably, from plant sources such as seeds, grains, or fruits.

[0123] Naturally occurring vegetable oils contain primarily triglycerides, which are mixtures of glycerides having different fatty acid chain lengths.

[0124] Naturally occurring pharma- ceutically acceptable oils that fall into this category include sunflower oil, soybean oil, corn oil, grapeseed oil, rapeseed oil, sesame oil, almond oil, apricot kernel oil, cottonseed oil, palm kernel oil, castor oil, olive oil, palm oil, and coconut oil (for the respective compositions see, e.g., Occurrence and Characteristics of Oils and Fats, pp. 47-224 of Padley, Gunstone and Harwood (Eds.), The Lipid Handbook., Chapman & Hall, London, 1994).

[0125] When used in such dosage forms, naturally occurring oils should be of pharmaceutical grade and therefore preferably purified after extraction from their natural source(s), which can be done using techniques well known to those skilled in the art.

[0126] Preferred oils include one or more of sesame oil, corn oil, palm kernel oil, coconut oil, or soybean oil.

[0127] Semi-synthetic and synthetic lipid-based carrier systems can be made using techniques well known in the art, such as separation, interesterification, lipolysis and transesterification (glycerolysis).

[0128] Thus, semi-synthetic and synthetic lipid-based carrier systems typically contain short chain (C 1 ~C 5 ) triglycerides (such as triacetin) and medium chain (C 6 ~C 12 ) triglycerides (the main components of naturally occurring palm kernel oil and coconut oil, e.g., capric triglyceride, more specifically Miglyol 812N), which are in the form of oils; and often long-chain (C 14 ~C 22 ) triglycerides (such as Gelicure 43 / 10), which are in the form of semi-solid fats.

[0129] Whatever the form of hydrophobic lipid-based carrier system used, it is preferred that the major component of the carrier system comprises at least about 85% triacylglycerol, more preferably at least about 90% triacylglycerol, especially at least about 95% triacylglycerol.

[0130] Mixtures of any of the above naturally occurring, semi-synthetic and / or synthetic lipid-based carrier materials can be used.

[0131] In this aspect of the invention, C21 or a salt thereof is presented in the form of particles, which may be amorphous or crystalline or a mixture of the two. Preferred particles are of a size that does not cause settling, either during the formation of the suspension, during the capsule loading process, or during storage.

[0132] In this regard, C21 or a salt thereof may be provided, for suspension in a lipid-based carrier, in the form of a plurality of primary (i.e., non-aggregated) particles having a weight- and / or volume-based average diameter (as previously defined herein) in the same ranges and values ​​as those previously described herein for preferred solid dosage forms that may be used in the methods of the present invention.

[0133] Particles having a weight and / or volume based average diameter within the aforementioned limits include the average diameter of the particles as prepared and prior to suspension in a lipid-based carrier, when so suspended, and / or prior to loading into a capsule as described herein. Thus, primary particles of C21 / salts thereof may be prepared as previously described herein.

[0134] It is important to ensure that the suspension of this aspect of the invention contains C21 or a salt thereof homogeneously and evenly distributed throughout the suspension prior to loading into a capsule, and to ensure dose homogeneity of the active ingredient after such loading into a capsule. Thus, C21 and salts thereof are preferably provided in the form of particles having a relative PSD as previously defined herein.

[0135] C21 or a salt thereof may be selected and / or provided with such a PSD and / or GSD using one or more of the techniques described above to provide a stable suspension with uniform distribution of C21 / salt particles within the suspension, provided that the C21 / salt is thoroughly mixed with the lipid-based carrier system to provide a uniform distribution of the active ingredient particles within the carrier prior to loading. This is particularly true in the case of bulk suspensions used as part of a capsule loading process, where it is important that the mixture is not only uniform to start with, but that this uniformity is maintained throughout the loading process to ensure dose uniformity within a production batch.

[0136] The terms "homogeneous" and "homogeneously distributed" mean that there is a substantially uniform content of C21 or a salt thereof throughout the lipid-based carrier material, as previously defined herein.

[0137] If the lipid-based carrier system is in the form of a fat (i.e., solid or semi-solid at or around normal manufacturing and / or product storage temperatures), one skilled in the art will understand that the fat must be melted by raising the temperature prior to mixing.

[0138] Additionally, if necessary, such suspensions to ensure a stable, homogeneous, even distribution of the active ingredient within the carrier, lipid-based carrier systems (and particularly those that are in the form of liquid oils at or around normal manufacturing and / or product storage temperatures) may further include thickeners to avoid particle aggregation and / or settling, such as microcrystalline cellulose and sodium carboxymethylcellulose, as well as blends of mono-, di-, and triglycerides with PEG esters of unsaturated fats, such as Gelucire 43 / 01, hydrogenated vegetable oils, beeswax, paraffin wax, and the like.

[0139] By presenting C21, or a salt thereof, in the form of a suspension of particles according to this aspect of the invention, we have found that such a dosage form is not only able to deliver a consistent and / or uniform dose of the active ingredient, but also to ensure that the active ingredient remains in a physically and chemically stable form both during and / or after manufacture, under normal storage conditions, and / or during use.

[0140] As used herein, C21, or a pharma- ceutically acceptable salt thereof, may be prepared and stored in the form of a composition that may be used directly in the manufacture of a dosage form for use in the methods of the present invention, and further, once prepared, such a dosage form may be stored under normal storage conditions with only minor changes over time in the physicochemical properties of the dosage form, the composition mixture contained therein, and / or, most importantly, the active ingredient(s).

[0141] Thus, "slight changes in physicochemical properties" includes that a composition comprising C21 / salt in a suitable carrier as described herein above may have both physical and chemical stability before and / or after being mixed with suitable excipients, loaded into a capsule, compressed into a tablet or otherwise.

[0142] "Chemical stability" includes that compositions comprising C21 / salts in suitable carriers, and dosage forms containing them, may be stored (with or without suitable pharmaceutical packaging) under normal storage conditions with only minor degree of chemical degradation or decomposition of such dosage forms and / or compositions, and particularly of the active ingredients contained therein.

[0143] "Physical stability" includes that compositions comprising C21 / salts in suitable carriers, and dosage forms comprising them, may be stored (with or without suitable pharmaceutical packaging) under normal storage conditions with only a small degree of physical transformation, such as aggregation, separation or segregation, or precipitation, or dissolution, solvation, solid-state phase transitions, and the like, as described above, with no change in the properties and / or integrity of such dosage forms and / or compositions, and particularly the active ingredients contained therein.

[0144] Examples of "normal storage conditions" include temperatures of minus 80 to plus 50°C (preferably 0 to 40°C, more preferably ambient temperature, e.g. 15 to 30°C), pressures of 0.1 to 2 bar (preferably atmospheric pressure), relative humidity of 5 to 95% (preferably 10 to 60%), and / or exposure to UV / visible light of 460 lux for extended periods of time (i.e., 6 months or more).

[0145] Under such conditions, C21, its salts, and / or compositions containing them may be found to be physically and / or chemically transformed by less than about 15%, more preferably less than about 10%, especially less than about 5%. Those skilled in the art will appreciate that the above upper and lower limits of temperature and pressure represent the extremes of normal storage conditions, and that certain combinations of these extremes will not be experienced during normal storage (e.g., a temperature of 50°C and a pressure of 0.1 bar).

[0146] Pharmaceutical compositions, whether in the form of a dry powder mix, lipid-based suspension, or otherwise, and / or contained within a capsule as described above or otherwise, are preferably prepared and / or stored in a manner that keeps them essentially free of water.

[0147] "Essentially free of water" includes that appropriate precautions are taken to ensure that both the particles C21 or a salt thereof and the excipients with which it is mixed are individually prepared and / or provided in a manner in which they are essentially dry, and are mixed together to form a dry mixture in an environment in which they are kept essentially dry.

[0148] "Essentially dry" or "essentially free of water" means that the composition comprising C21 / salt and related excipients as a whole contains less than about 5% by weight or volume water, including less than about 2% by weight or volume, for example less than about 1% by weight or volume, including less than about 0.5% by weight or volume, for example less than about 0.1% by weight or volume.

[0149] Further processing of the composition comprising C21 or a salt thereof and related excipients into the dosage forms described herein above may also preferably be carried out in such a manner that it remains essentially free of water.

[0150] In this regard, a pharma- ceutically acceptable encapsulant may contain residual amounts of water, but should minimize ingress of water from the encapsulant into the composition (whether in solid (e.g., powder mixture) or liquid (e.g., lipid suspension) form) to protect the highly sensitive C21 or salt thereof from contact with water and, therefore, from degradation in the presence of light.

[0151] Nonetheless, it is preferable (though not essential) to package the dosage form in a manner that keeps the dosage form itself dry and protected from light, which may include hermetic packaging, use of deliquescent materials, etc.

[0152] In a further aspect of the present invention, C21 and its salts may be presented in any pharmaceutical dosage form, including those described herein above, which may be coated, surrounded, and / or encapsulated with an enteric material to produce a final dosage suitable for oral administration to the gastrointestinal tract.

[0153] The enteric material can be used to coat a variety of dosage forms, including, but not limited to, many of the formulation / dosage principles previously described herein. For example, the composition can be loaded into a capsule or compressed into a tablet suitable for oral administration and coated with an enteric material.

[0154] In this regard, when C21 or a salt thereof is provided in a multiparticulate form, such as a powder, granules, pellets, and / or beads, the particles can be individually or collectively coated with an enteric material. This can be done in a variety of ways, for example, by filling such multiparticulates into a capsule together with any relevant excipients, such as solid carrier materials (e.g., carrier particles) or liquid (e.g., oil-based) carrier materials described above, prior to application of the enteric material to the exterior of the capsule. Alternatively, particles, including granules or pellets, comprising C21 or a salt thereof, can be individually coated with an enteric material prior to loading into a suitable capsule, optionally together with other excipient materials.

[0155] Similarly, the C21 / salt and excipients described above can be compressed into tablets before being coated with an enteric material.

[0156] As defined herein, an "enteric" material may be used to coat, surround, and / or encapsulate a composition comprising C21 or a pharma- ceutically acceptable salt thereof to substantially prevent an active ingredient from being released from the composition in the stomach and / or from contacting gastric fluids and / or until the ingredient reaches the small intestine. By "substantially prevent," we include about 20% by weight, e.g., about 15% by weight, e.g., about 10% by weight or less, or more specifically, about 5% by weight or less of the active ingredient is released into the acidic environment of the stomach.

[0157] Typical enteric coating materials include the following: cellulose acetate, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate tetrahydrophthalate, polyvinyl acetate phthalate, hydroxyethyl ethylcellulose phthalate, methacrylic acid copolymers, polymethacrylic acid / acrylic acid copolymers, styrol maleic acid copolymers, hydroxypropyl methylcellulose phthalate, acrylic resins, cellulose acetate trimellitate, hydroxypropyl methylcellulose trimellitate, shellac, hydroxyethyl cellulose phthalate, carboxymethylcellulose, and hydroxypropyl methylcellulose acetate succinate. Preferred enteric materials include polyvinyl acetate phthalate and, especially, methacrylic acid copolymers.

[0158] Regardless of whether the dosage form containing C21 includes one or more enteric coatings as described above, the dosage forms, uses, and methods of treatment described herein may include administration to a patient in the substantial absence of food and / or in a fasted state.

[0159] By "administration to a patient in the substantial absence of food and / or in a fasting state" includes being instructed that the patient orally administer the dosage form about 1 hour or more, including about 1.5 hours or more, including about 1.75 hours or more, e.g., about 2 hours or more, or about 2.25 hours or more, such as about 2.5 hours or more, including about 3 hours, about 3.5 hours, about 4 hours or more, about 5 hours or about 6 hours, after consumption of any food, including the patient's last meal and / or snack. The term may also be understood to include that food may not be consumed within about 15 minutes, including about 20 minutes or less, about 25 minutes or less, or about 30 minutes or less, including about 45 minutes or less, e.g., about 60 minutes or less, or about 75 minutes or less, about 90 minutes or less, or about 2 hours or less, of such food consumption.

[0160] Pharmaceutically acceptable salts of C21 include acid addition salts. Such salts can be formed by conventional means, for example, by reacting C21 in the form of a free acid (hereinafter "free C21") with one or more equivalents of a suitable acid or base, optionally in a solvent or medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (for example, in vacuum, by lyophilization, or by filtration). Salts can also be prepared by exchanging the counterion of the active ingredient in the form of a salt with another counterion, for example, using a suitable ion exchange resin. Preferred salts of C21 include HCl salt, alkaline earth salts such as magnesium and calcium salts, and alkali metal salts such as potassium salt, or preferably sodium salt.

[0161] The amount of C21 or a salt thereof in a dosage form for use in the methods of the present invention will depend on and / or may be selected according to the severity of the relevant condition (i.e., IPF) being treated, or the expected severity of such, and the patient, and can be determined by one of skill in the art. The mode of administration can also be determined by the timing and frequency of administration, as well as the severity of the condition.

[0162] A suitable lower daily dose of C21 in an adult patient (average body weight, e.g., 70 kg) for use in the method of the present invention can be about 10 mg, e.g., about 20 mg, e.g., about 25 mg, per day, calculated as the dose of free C21 in the relevant dosage form. A suitable upper limit of the daily dose range of C21 calculated as the dose of free C21 in the relevant dosage form can be up to about 900 mg, e.g., 600 mg, including about 400 mg. In particular, the daily dose can be about 300 mg, e.g., about 250 mg, including about 200 mg, e.g., about 175 mg or about 150 mg, including about 100 mg, including about 80 mg, about 75 mg, about 70 mg, about 60 mg, or about 50 mg.

[0163] All of the above doses are calculated as free C21. The dose can be divided into multiple individual doses per day. The dose can be given 1 to 6 times a day, for example 4 times a day, preferably 3 times a day, more preferably 2 times a day.

[0164] The above doses, especially the higher levels, may also be considered as part of the "induction" phase of the treatment of IPF. Furthermore, after a medical professional or person skilled in the art has determined that the induction phase is successful, e.g., thereby resulting in significant improvement / restoration of lung function or capacity as previously defined herein, C21 or a salt thereof may then be administered at an appropriate dose as part of the "maintenance" treatment of the disorder. A suitable daily maintenance dose may be in the lower ranges above, e.g., up to about 75 mg, up to about 50 mg, up to about 40 mg, up to about 30 mg, or up to about 25 mg, including up to about 150 mg, up to about 100 mg, or even lower. Alternatively, a suitable induction or maintenance dose may be administered less frequently, e.g., by a sustained release oral dosage form that produces a plasma concentration profile equivalent to the once-daily dose above.

[0165] In any event, a medical practitioner or other skilled artisan may routinely determine the actual dosage which will be most suitable for an individual patient, depending on the severity of the condition and the route of administration. The dosages mentioned above are exemplary of the average case, and there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of the present invention.

[0166] The dose administered to a patient, in the context of the present invention, must be sufficient to affect an appropriate response in the patient over a reasonable time frame (as described herein above). Those skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by, among other things, the pharmacological properties of the formulation, the nature, stage and / or severity of the condition being treated, the physical and mental state of the recipient, and the age, condition, weight, sex and response of the patient being treated, the stage / severity of the disease, and genetic differences between patients.

[0167] It should be noted that there is currently no universally accepted or validated staging system related to the nature, stage, and severity of IPF. There is a wealth of data on using information obtained from physiological, radiological, and pathological parameters, alone or in combination, to assess disease severity in IPF. Recently, there has been interest in staging disease severity in IPF using serum biomarkers and quantitative pulmonary fibrosis measurements derived from computed tomography (see, e.g., Robbie et al, Eur. Respir. Rev. 26, 17005 (2017)). However, Lopes et al. (Clinics (Sao Paulo), 66, 1015 (2011) proposed a classification system for IPF based on the 95% confidence interval of FVC as follows: mild (≥92.7%), moderately mild (76.9–92.6%), moderate (64.3–76.8%), moderately severe (47.1–64.2%), severe (24.3–47.0%), and very severe (<24.3%). Alternative classification systems for IPF based on FVC are as follows: mild (>80%), moderate (50–80%), and severe (<50%).

[0168] The methods of the invention may be used to treat IPF and conditions that may induce IPF, such as systemic sclerosis, rheumatoid arthritis, myositis, or systemic lupus erythematosus, or conditions that are otherwise associated with IPF, such as pulmonary hypertension and / or pulmonary arterial hypertension.

[0169] The remarkable results described herein below may be at least partially attributable to the antifibrotic effects of C21 (e.g., reduction of fibrosis and / or prevention of further deposition of extracellular matrix, reversal of these fibrotic phenomena, including lung scarring / wound healing, reduction of fibroblast and myofibroblast proliferation, vascular remodeling, etc.), although it should be noted that no corresponding effects are seen with existing antifibrotic IPF therapies (such as nintedanib and pirfenidone). Thus, without being limited by theory, we do not believe that these completely unexpected results can be explained solely by the known antifibrotic effects of C21, and therefore the exact mechanisms behind them are not currently understood.

[0170] Although primarily indicated in the therapeutic (including curative and / or restorative) treatment of lung function in patients with IPF, C21 and its salts may also be useful in the palliative and / or diagnostic treatment of IPF (e.g., during diagnostic work-up when the condition is suspected), as well as in the prophylactic treatment (thereby including preventing and / or arresting the deterioration and / or worsening of the condition).

[0171] A "patient" includes a mammalian, particularly a human, patient. A human patient includes an adult patient.

[0172] As mentioned above, it is preferred that C21 is used as a first-line and / or sole treatment for IPF, however, related active ingredients that may be used in combination therapy with C21 in treating IPF include, for example, antifibrotic agents (e.g., nintedanib and pirfenidone, and AP-01 / inhaled pirfenidone (Avalyn Pharma) and deuterium-substituted analogs of pirfenidone dupirfenidone / LYT100 (PureTech); antitussive drugs (e.g., benzonate, nalbuphine, or more specifically, dextromethorphan or codeine), glucocorticoids (e.g., beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone); PRM-151 / Pentraxin-2 (Genentech / Roche); connective tissue growth factor inhibitor pamrevlumab (FibroGen); galectin-3 inhibitor GB0139 (Galecto); c-Jun N-terminal kinase inhibitor CC-90001 (Celgene / Bristol Myers Squibb); phosphodiesterase 4b inhibitor BI1015550 (Boehringer Ingelheim); xylocaine; inhaled nitric oxide; immunomodulatory imide drugs (IMIDs, e.g., lenalidomide, pomalidomide, and especially thalidomide); other immunosuppressants such as azathioprine and mycophenolate mofetil; vitamins (e.g., vitamins B, C, and D); mucolytics (e.g., acetylcysteine ​​and ambroxol); anti-inflammatory agents such as cyclophosphamide; other immunosuppressants such as azathioprine and mycophenolate mofetil; and antioxidants such as N-acetylcysteine;In addition to the HSP47 RNAi treatment ND-L02-s0201 / BMS-986263 (Nitto Denko / Bristol Meyers Squibb), we also investigated the use of the Hedgehog cell signaling pathway inhibitor ENV-101 / taladegib (Endeavor Biomedicines), dual inhibitor of αVβ1 / αVβ6 PLN-74809 (Pliant Therapeutics), dual inhibitor of NADPH oxidase isoforms NOX4 and NOX1 setanaxib / GKT137831 / GKT831 (Calliditas Therapeutics / Genkyotex), HEC585 (Sunshine Lake Pharma Co), Galectin-3 inhibitor GB0139 / TD139 (Galecto Biotech), Src tyrosine kinase inhibitor saracatinib (AstraZeneca), humanized anti-FXIIa monoclonal antibody galadacimab / CSL312 (CSL Behring), LPA1 receptor antagonists BMS-986278 (Bristol Myers Squibb), and HZN-825 (Horizon Therapeutics), autotaxin inhibitors cudetatestat / BLD-0409 (Blade Therapeutics) and BBT-877 (Bridge Biotherapeutics), prolyl-tRNA synthetase inhibitor DWN12088 (Daewoong Pharmaceutical Co), monoclonal antibody AMB-05X targeting colony-stimulating factor 1 receptor (AmMax Bio), IL-11 receptor blocking antibody LASN01 (Lassen Therapeutics), MMP7-reducing RNAi treatment ARO-MMP7 (Arrowhead Pharmaceuticals), smad ubiquitin regulatory factor 1 inhibitor LTP001 (Novartis), tipelukast / MN-001 (MediciNova / Kyorin), ifenprodil / NP-120 (Algernon Pharmaceuticals), RG-6354 / PRM-151 / recombinant human pentraxin-2 (Roche / Promedior), and prostacyclin analog 38 reprostinil (United Therapeutics);

[0173] Preferred pharmaceutical treatments that may be used in combination therapy with C21 in treating IPF include antifibrotic agents (e.g., nintedanib and pirfenidone) and IMIDs (e.g., lenalidomide, pomalidomide, and especially thalidomide).

[0174] The relevant patient may receive (and / or may already be receiving) one or more of any of the treatments and / or other therapeutic agents mentioned above for the relevant condition based on administration of one or more of such active ingredients, which means receiving prescribed doses of one or more of these active ingredients mentioned herein before, in addition to, and / or after treatment with C21 or a salt thereof.

[0175] The pharma- ceutically acceptable salts and dosages of the other active ingredients listed above are known in the art and are described in Martindale-The Complete Drug Reference, 38 th The subject drugs are described in the medical literature, such as The Journal of Clinical Oncology, Vol. 13, No. 1, 2012, pp. 1171-1175, 2012. Edition, Pharmaceutical Press, London (2014, and documents cited therein, the relevant disclosures of all of which are incorporated herein by reference.

[0176] According to two further aspects of the invention, C21, or a pharma- ceutically acceptable salt thereof, for use in any method of the invention; and There is provided the use of C21, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for any of the methods of the invention, Improve / restore pulmonary function in a patient having IPF as described herein above, the treatment comprising orally administering to the patient a therapeutically effective amount of said C21 or a salt thereof in any manner as described herein above.

[0177] The uses / methods described herein may have advantages over similar methods (treatments) otherwise known in the prior art in the treatment of IPF, whether used in that condition or otherwise, in that they may be more convenient for the physician and / or patient, more effective, less toxic, have a broader spectrum of activity, be more potent, cause fewer side effects, or have other useful pharmacological properties.

[0178] Whenever the term "about" is used herein, for example in the context of a number or amount, i.e., absolute amounts such as size (e.g., particle size, PSD or GSD), volume, dose, weight or concentration of (e.g., active) ingredient, age, temperature, sample size, or duration, or relative amounts including percentages, standard deviations, and measurements of variation, such as improvement in FVC measurement or improvement in lung function measured by different methods, or levels of physical / chemical conversion or release of an API, it will be understood that such variables are approximate and may vary by ±10%, e.g., ±5%, preferably ±2% (e.g., ±1%) from the actual number specified as such. In this regard, the term "about 10%" means, for example, ±10% for the number 10, i.e., 9% to 11%. The present invention is illustrated, but in no way limited, by the following examples. [Brief description of the drawings]

[0179] [Figure 1] FIG. 1 shows the mean change in FVC over time (weeks) in IPF patients treated orally with 100 mg C21 twice daily compared to the expected FVC decline in an untreated IPF population. EXAMPLES

[0180] Example 1 Dosage form The excipient blend was prepared by weighing 21.4 g of colloidal silicon dioxide (Aerosil®, Evonik) into a weigh boat. Then, 2033.8 g of mannitol (Pearlitol 50C, Roquette) was weighed and approximately half of that amount was poured into the 25 L V-shell of a V-blender (Multiblender, Pharmatech, UK). The weighed amount of colloidal silicon dioxide was then added to the V-shell, followed by the remaining mannitol. The resulting mixture was blended for 10 minutes at 30 rpm.

[0181] The excipient blend was then sieved through an 800 μm sieve and then blended for an additional 20 minutes at 30 rpm.

[0182] Half of the resulting excipient blend was weighed and re-added to the V-shell. 528 g of C21 sodium salt (Ardena, Riga, Latvia) was then added to the V-shell. The remaining excipient blend was then added to the V-shell followed by blending for 10 minutes at 30 rpm.

[0183] The resulting blend was then sieved through an 800 μm sieve and subsequently blended at 30 rpm for 20 minutes.

[0184] After the blends were prepared, blend uniformity was determined by weighing approximately 270 mg of blend sample into a 100 mL volumetric flask, adding 40 mL of MilliQ water, sonicating for 20 minutes, adding 40 mL of methanol, and sonicating for an additional 20 minutes. After equilibrating to room temperature, 1.0 mL of sample solution was added to a 10 mL volumetric flask. This was followed by dilution to the desired volume with methanol and mixing.

[0185] The sample was filtered through a 0.45 μm PTFE membrane syringe filter and the first 3 mL of the filtrate was discarded. The amount of C21 sodium salt was determined by UHPLC. The resulting solution should contain 0.1 mg / mL of C21Na salt (for 100% of the nominal sample concentration). The results are shown in Table 1 below. [Table 1]

[0186] After this, 26.1 g of magnesium stearate (Ligamed MF-2-V, Peter Greven, Germany) was sieved through an 800 μm sieve and added to the blend, followed by final blending for 15 minutes at 15 rpm. The final composition is shown in Table 2 below. [Table 2]

[0187] Approximately 6,700 capsules were encapsulated using an MG Compact (MG2, Bologna, Italy) with a dosator size 0, applying the following settings: chamber-11 mm, compression-0 mm, powder layer: 30.0 mm.

[0188] Weight sorting was performed by applying a 5% tolerance limit to the net loaded weight of the capsules, which was found to be 18.6%. After encapsulation, the capsules were primary packaged manually into 100 mL high density polyethylene (HDPE) jars with child-resistant tamper-evident caps containing desiccant (56 capsules / jar).

[0189] Such capsules may also be enteric coated.

[0190] The above process was later scaled up to produce a total of 2000 vials and labeled for use in the clinical trial described in Example 2 below.

[0191] Example 2 A clinical trial to evaluate the safety and efficacy of C21 in patients with IPF We report below the results obtained in an ongoing phase II, multicenter, open-label, single-arm study investigating the safety, efficacy, and pharmacokinetics of C21 in subjects with IPF.

[0192] Trials are in the process of being conducted at multiple sites in India, Russia, Ukraine, and the United Kingdom (UK).

[0193] The primary objective of the study was to investigate the safety of C21, 200 mg daily dose (100 mg bid) administered orally to subjects with IPF. Secondary objectives were to evaluate the effect of C21 at the same daily dose on lung function decline and the pharmacokinetics of C21. Exploratory objectives included investigating a range of laboratory parameters as potential biomarkers of inflammation and fibrosis.

[0194] The primary endpoint of the study was the nature and frequency of adverse events occurring over the study period.

[0195] Secondary endpoints include change from baseline in the following: FVC (defined as the maximum amount of air that can be forcefully exhaled from the lungs after a full inhalation) at 12, 24, and 36 weeks. Plasma concentrations and derived PK parameters of C21 assessed in a subset of subjects.

[0196] Blood samples are stored for potential future analysis of biomarkers reflecting inflammation and lung injury.

[0197] It was initially intended to conduct the study in 60 IPF antifibrotic drug naive patients, but as the study progressed, the patient population was expanded to include patients who had discontinued other IPF medications (i.e., the antifibrotic drugs listed above) after less than 6 months of treatment due to intolerance (see exclusion criterion number 18 listed below).

[0198] Patients with IPF were assessed for eligibility during a screening visit (Visit 1) before enrollment in the study and during a baseline visit (Visit 2) (and will continue to be assessed in the future). During the eligibility assessment, it was determined whether patients met all inclusion criteria and did not meet any of the exclusion criteria (and will continue to be assessed in the future).

[0199] Eligible patients have been and will be enrolled to receive daily treatment with 200 mg of C21 (100 mg bid) for up to 36 weeks.

[0200] Selection criteria included: 1) Written informed consent, in accordance with ICH GCP R2 and local law, obtained prior to the initiation of any study-related procedures. 2) Diagnosis of IPF within 5 years prior to Visit 1 according to any of the ATS / ERS / JRS / ATLAT / Fleischner guidelines. 3) Age ≥ 40 years. 4) FVC ≥ 60% predicted at Visits 1 and 2 (UK specific: FVC ≥ 80% predicted at Visits 1 and 2, or FVC > 60% predicted at Visits 1 and 2 for subjects previously treated with antifibrotic drug treatment, e.g., nintedanib and / or pirfenidone, or who refused such treatment). 5) FEV1 / FVC ratio ≥ 0.7 pre-bronchodilator at Visits 1 and 2. 6) Oxygen saturation (SpO2) >85% by pulse oximetry while breathing ambient air at rest at Visit 1. 7) High-resolution computed tomography (HRCT) within 36 months prior to Visit 1 with a central read demonstrating either a or b, and c: a. Pattern consistent with usual interstitial pneumonia (UIP) according to the ATS / ERS / JRS / ALAT or Fleischner guidelines (Raghu et al, Am J Respir Crit Care Med, 198, e44 (2018), Lynch et al, Lancet Respir Med, 6, 138 (2018)): i.UIP, or ii. Potential UIP. b. Indeterminate pattern for UIP according to either the ATS / ERS / JRS / ALAT or Fleischner guidelines (see above) and previous biopsy consistent with IPF. c. Degree of fibrosis > degree of emphysema. 8) Fully vaccinated against COVID-19 prior to screening (Visit 1). Subjects are considered fully vaccinated against COVID-19 ≥ 14 days after receiving the vaccination dose(s) according to local labeling.

[0201] Initial exclusion criteria included one or more of the following: 1) Previous use of antifibrotic drug treatment for interstitial lung disease (e.g., nintedanib or pirfenidone) for >6 months. 2) smoking (including e-cigarettes) within 6 months prior to Visit 1; 3) Body mass index (BMI) >35 or <18. 4) IPF exacerbation within 3 months prior to Visit 1, as defined by the following (as defined by Collard et al, Am J Respir Crit Care Med, 194, 265 (2016)): Acute worsening or onset of dyspnea, typically lasting <1 month, A computed tomography scan with new bilateral ground-glass opacities and / or consolidations superimposed on a background pattern consistent with the usual interstitial pneumonia pattern (if a previous computed tomography scan is not available, the qualifier "new" can be dropped), or Exacerbations not fully explained by heart failure or fluid overload. 5) Any concurrent serious medical condition with special precautions for cardiac or ophthalmic condition (e.g., contraindication to cataract surgery), or moderate to severe hepatic impairment, which in the opinion of the investigator makes the subject unsuitable for this study. 6) Malignancy within the past 5 years, excluding in situ removal of basal cell carcinoma and grade I cervical intraepithelial neoplasia. 7) Treatment with any of the medications listed below within 4 weeks prior to Visit 1: Strong CYP3A4 inducers (e.g., rifampicin, phenytoin, St. John's wort), Strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole, nefazodone, itraconazole, ritonavir), -Medicines that are substrates of CYP1A2, CYP3A4, or CYP2C9 with a narrow therapeutic range; Experimental drugs, Antifibrotic drug treatment, and Any systemic immunosuppressive therapy other than: - inhaled corticosteroids, which may be used throughout the study provided that the dose is kept stable; Corticosteroids to treat acute exacerbations, or Continuation of a stable daily dose of <15 mg prednisolone or equivalent. 8) Treatment with any of the medications listed below within 2 weeks prior to Visit 1: Proton pump inhibitors (PPIs) taken more than twice a day Histamine H2 receptor antagonist (H2Ras), Sulfasalazine and rosuvastatin, and High doses of breast cancer resistance protein-sensitive substrates (other than sulfasalazine or rosuvastatin). 9) Any of the following findings at Visit 1: o Prolonged QTcF (QT interval with Fridericia correction) (>450 ms), clinically significant cardiac arrhythmias, or any other clinically significant abnormalities on resting ECG as determined by the investigator. o AST or ALT increased >3 times the upper limit of normal (ULN) or bilirubin >1.5 times the ULN, a positive result for Hepatitis B surface antigen (HbsAg), Hepatitis C virus antibody (HCVAb), or Human Immunodeficiency Virus 1+2 Antigen / Antibody (HIV1+2 Ag / Ab), and o Positive serum pregnancy test (minimum sensitivity 25 IU / L or equivalent units of human chorionic gonadotropin [HCG]). 10) Inability to generate pulmonary function data at Visit 1 that meet the minimum standards of the ATS / ERS 2005 guidelines (Miller et al, Eur Respir J, 26, 319 (2005)), as determined by central review. 11) Clinically significant abnormal laboratory values ​​at Visit 1 indicating potential risk for the subject if enrolled in the study as assessed by the principal investigator. 12) Pregnant or breastfeeding women. 13) Women of childbearing potential who are not willing to use contraception. 14) Male subjects who are not willing to use contraception. 15) Subjects who are unwilling to comply with dietary restrictions during the study period. 16) Participation in any other interventional study during the study period. 17) Subjects known or suspected to be unable to comply with this study protocol (e.g., due to alcoholism, drug addiction, or psychiatric disorder). 18) Discontinuation or change of previous antifibrotic treatment (e.g., nintedanib or pirfenidone) due to disease progression.

[0202] After completion of each 12-week treatment period, the Investigator will perform a medical evaluation to determine whether the subject may continue into the next 12-week treatment period. This decision will be based on the following: - no urgent need for other antifibrotic drugs; and Positive risk / benefit balance Failure to pass the medical evaluation will result in the subject being removed from the study.

[0203] Criteria for discontinuing the study were established if any of the following occurred: A decline from baseline of two consecutive FVC values ​​>10% predicted and FVC<60% predicted (UK specific: FVC<80% predicted, or FVC<60% predicted for subjects previously treated with nintedanib and / or pirfenidone or who refused such treatment); - a decline from baseline in FVC values ​​of 5–10% predicted on two consecutive occasions and worsening respiratory symptoms and FVC<60% predicted (UK specific: FVC<80% predicted, or FVC<60% predicted for subjects previously treated with nintedanib and / or pirfenidone or who refused such treatment); ·Not consistently following dietary requirements according to the responsible physician; · The responsible physician determines that it is necessary for medical reasons; ·Failing a medical evaluation after each 12-week treatment period; The subject wishes to discontinue for any reason; or ·pregnancy.

[0204] C21 in the form of the sodium salt is delivered in 50 mg capsules obtained according to Example 1 above.

[0205] The capsules are packaged in plastic container units containing 56 capsules each, with each unit containing either C21 or a matching placebo (same composition except that C21 is replaced by mannitol).

[0206] At the study facility, C21 is stored separately from regular clinic stock in a securely locked area accessible only to authorised study personnel. Labelling of C21 is in the relevant local language (English) in compliance with GMP and local regulatory requirements.

[0207] C21 is being administered twice daily to subjects for 36 weeks as follows: Morning dose: Two 50 mg capsules (100 mg C21 or placebo) taken with a glass of water after at least two hours of fasting; and Afternoon / Evening Dose: Two 50 mg capsules (100 mg C21 or placebo) taken with a glass of water after at least two hours of fasting. Subjects are asked not to eat anything for one hour after taking the study drug.

[0208] Clinical sites in India, Russia, Ukraine and the UK are required to follow the clinical trial protocol. Any deviations from the protocol are recorded as protocol deviations.

[0209] Following analysis of the results reported below and documented protocol deviations, all such data collected from enrolled patients regarding the safety and efficacy of C21 have been confirmed to be valid when considered individually or as part of a cohort.

[0210] result A total of 21 subjects with a diagnosis of IPF (confirmed by high-resolution computed tomography central reading) were included in the ad hoc interim analysis described below, of which 13, 9, and 7 patients had reached 12, 24, and 36 weeks of C21 treatment, respectively.

[0211] Patients were enrolled to receive C21 (100 mg bid) for a total of 36 weeks. Age and sex of treated evaluable subjects were characteristic of patients with IPF.

[0212] As shown in Figure 1 (observational data), after initial stabilization of FVC, mean FVC increased by +250 mL at 24 weeks (solid line with circles), a difference of +371 mL compared to the expected (based on several previously published IPF studies) mean decline of -120 mL at 24 weeks in untreated patients (dashed line).

[0213] At week 36, the mean FVC had increased by +750 mL (solid line with circles), a notable difference of +930 mL compared to the expected mean decline of -180 mL at week 36 in untreated patients (dashed line). Slope values ​​(analysis of the change in FVC scaled to 24 weeks by visit, observed case) were statistically significant at weeks 28 (p=0.012), 32 (p=0.032), and 36 (p=0.016) versus the expected mean in untreated patients. An ad hoc interim analysis was performed later during the course of the study on data from existing patients and patients enrolled later in the study. At the time of analysis, data were available from a total of 45 patients, of which 23, 13, and 10 had reached 12, 24, and 36 weeks of C21 treatment, respectively. Demographics continue to characterize the IPF population.

[0214] Updated results show stabilization of the disease already at week 6 and confirm the increase over time. The mean FVC increased by +210 mL at week 24 (a difference of +330 mL compared to the expected decline in FVC for the untreated population). At week 36, the mean FVC increased by +630 mL, a notable difference of +810 mL compared to the expected decline in FVC.

[0215] There were no associated serious adverse events, no gastrointestinal signals, and an overall safety profile of no concern. Two deaths have occurred in ongoing trials, but neither have been reported to be related to C21.

Claims

1. N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide, or a pharmaceutically acceptable salt thereof, for use in a method for improving lung function in a patient having idiopathic pulmonary fibrosis, wherein the method comprises orally administering a therapeutically effective amount of N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide, or a pharmaceutically acceptable salt thereof, to the patient at least two hours after the intake of a meal, wherein the patient having idiopathic pulmonary fibrosis exhibits a pattern consistent with that of typical interstitial pneumonia.

2. The compound for use according to claim 1, wherein the use comprises a restorative, therapeutic, and / or curative treatment of the idiopathic pulmonary fibrosis.

3. The compound for use according to claim 1 or 2, wherein the use results in at least partial restoration of lung function compared to the corresponding lung function of the patient prior to the administration of N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or a salt thereof.

4. The aforementioned administration of N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or a salt thereof (i) In the absence of combination therapy with antifibrotic drugs; (ii) as monotherapy for idiopathic pulmonary fibrosis in the aforementioned patient; and / or (iii) The compound for use according to claim 1 or 2, which is performed as a first-line treatment for idiopathic pulmonary fibrosis in the patient.

5. The aforementioned improvement in lung function, (i) In the patient, one or more of the following are observed: improved respiration, improved or restored lung ventilation, improved or restored ventilatory pulmonary function, and increased or restored vital capacity; (ii) to prevent acute exacerbations of idiopathic pulmonary fibrosis; and / or (iii) The compound for use according to claim 1 or 2, which occurs in the remarkable absence of drug-related adverse events.

6. The compound for use according to claim 1 or 2, wherein the N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof is provided in a dosage form including tablets or capsules.

7. The compound for use according to claim 6, wherein the dosage form comprises N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof in the form of a powder mixture in which it is homogeneously distributed within the carrier material and / or other excipients used.

8. The aforementioned dosage form includes an enteric coating, optionally The compound for use according to claim 6, wherein the substance used in the enteric coating is polyvinyl phthalate acetate or methacrylic acid copolymer.

9. The compound for use according to claim 6, wherein the dosage form is essentially water-free.

10. The compound for use according to claim 6, wherein the daily dose of N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof is about 50 mg to about 300 mg (calculated as the amount of free N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide in the dosage form).

11. The compound for use according to claim 6, wherein the dosage form is administered two hours after the consumption of food.

12. The patient does not consume food within 60 minutes after such administration of N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide. The compound for use according to claim 11.

13. The compound for use according to claim 1 or 2, wherein the pharmaceutically acceptable salt of N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide is a sodium salt.

14. The compound for use according to claim 1 or 2, wherein the compound is used in combination therapy with an antifibrotic agent.

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