Use of blotinid for treatment of idiopathic pulmonary fibrosis

Abstract

According to the present invention there is provided N-butoxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide (C21), or a pharmaceutically acceptable salt thereof, for use in a method of improving (e.g., restoring) function in a patient suffering from idiopathic pulmonary fibrosis, the method comprises orally administering to the patient a therapeutically effective amount of C21 or a salt thereof. The treatment is capable of treating the IPF in a therapeutic (including curative) manner.

Description

Technical Field

[0001] The present invention relates to new uses of known pharmaceutically active compounds, in particular new curative therapeutic treatments for idiopathic pulmonary fibrosis.

[0002] Background and Prior Art

[0003] Interstitial lung disease (ILD) is a group of lung diseases that affect the interstitium and is characterized by the tissue surrounding the alveoli becoming scarred and / or thickened and thus physically inhibiting the breathing process.

[0004] ILD is different from obstructive airway diseases, such as chronic obstructive airway disease (COPD) and asthma, which are typically characterized by narrowing (obstruction) of the bronchi and / or bronchioles. ILD may be caused by damage to the lungs that triggers an abnormal healing response, but in some cases the cause of these diseases is unknown. ILD may be triggered by chemicals (silicosis, asbestosis, certain medications), infections (such as pneumonia), or other diseases (such as rheumatoid arthritis, systemic sclerosis, myositis, hypersensitivity pneumonitis, or systemic lupus erythematosus (lupus)).

[0005] 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 decreased lung function.

[0006] Specifically, IPF is a chronic lung disease characterized by a progressive and irreversible decline in lung function caused by lung scarring. Symptoms typically include coughing and shortness of breath.

[0007] Except lung transplantation in rare cases, there is no curative treatment option for IPF at present. Therefore, this disease usually shows as chronic, irreversible, progressive deterioration of lung function, and then in most cases, death within 2-5 years (median survival period 2.5 to 3.5 years). Although the overall prognosis of IPF is poor, it is difficult to predict the progression rate of individual patients. The risk factors of IPF include age, male, genetic susceptibility and smoking history.

[0008] The annual incidence of IPF is between 5-16 cases per 100,000 people, and the prevalence is between 13-20 cases per 100,000 people, which increases sharply with age (King et al., Lancet (2011) 378, 1949-1961; Noble et al., J. Clin. Invest. (2012) 122, 2756-2762). IPF is resistant to therapies targeting the immune system, which distinguishes it from pulmonary fibrosis (PF) associated with pure systemic diseases.

[0009] Patients with IPF typically present with chronic and progressive exertional dyspnea and cough. Lung imaging studies typically show traction bronchiectasis, interlobular thickening, and subpleural honeycombing. The diagnosis of IPF is likely when all three clinical manifestations are present and there is no evidence of systemic connective tissue disease or environmental exposure. The definitive diagnosis is usually made with high-resolution computed tomography (HRCT) and / or lung biopsy and requires a multidisciplinary team of professionals, including a pulmonologist, radiologist, and pathologist experienced in ILD.

[0010] IPF presents with different phenotypes with different prognoses, defined as mild, moderate, and severe. Mild cases follow a steady or slowly progressive path, with patients sometimes taking several years to seek medical advice. Acute exacerbations of IPF are defined as rapid worsening of the disease, and patients in this subgroup have a very poor prognosis and high mortality in the short term.

[0011] The etiology of IPF is unknown, but it appears to be a disorder that may result from an interaction between environmental and genetic factors, leading to ongoing fibroblast-driven tissue remodeling rather than normal repair, and a pathogenesis that is primarily driven by fibrosis rather than inflammation. Accumulating evidence suggests that the disease is initiated by alveolar epithelial cell microinjury and apoptosis, activating neighboring epithelial cells and attracting stem or progenitor cells that produce factors that cause fibroblast and myofibroblast populations to expand in a tumor-like manner. Fibroblast foci secrete excess extracellular matrix that destroys the lung parenchyma and ultimately leads to loss of lung function.

[0012] As a restrictive lung disease, the diagnosis and monitoring of IPF may involve the use of static spirometry. Here, the only thing that is considered is the volume of air exhaled, as opposed to dynamic spirometry, which measures the time it takes to exhale a certain volume of air and is often used to diagnose obstructive lung diseases such as COPD and asthma.

[0013] 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 urged to breathe in as hard as they can and then breathe out as hard as they can. This test is classified as a static test because it does not involve a timing element.

[0014] On the other hand, a dynamic test, the forced expiratory volume in 1 second (FEV1) test, is often used to diagnose obstructive lung disease, in which the subject is urged to breathe in as hard as they can and then breathe out as hard as they can, as quickly as they can. The amount of air the subject exhales in 1 second is the FEV1. FEV1 is often expressed as a percentage of FVC (FEV1 / FVC x 100).

[0015] The average 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 recent evidence from clinical trials suggests that the decline may be much greater than this (e.g., up to about 0.4 liters per year). Symptoms typically 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).

[0016] Many IPF treatments have been tested in preclinical models and clinical trials, such as anti-inflammatory, immunomodulatory, cytotoxic, general antifibrotic, antioxidant, anticoagulant, anti-chemokine, antiangiogenic drugs as well as RAS blockers, endothelin antagonists and sildenafil, all of which have essentially been shown to provide limited or no benefit (Rafii R et al., J. Thorac. Dis. (2013) 5, 48-73).

[0017] Aside from oxygen supplementation, the only drugs currently used to treat IPF are the anti-fibrotic drugs, pirfenidone or nintedanib, but these have had only limited success in slowing disease progression.

[0018] For example, a review article by Maher and Strek (Respiratory Research, 20, 205 (2019)) states that clinical trials have shown that nintedanib and pirfenidone reduce lung function decline in patients with IPF, and more specifically, reduce the rate of decline (as measured by FVC) by approximately 50% over a one-year period.

[0019] Therefore, although nintedanib and pirfenidone are thought to reduce the risk of acute deterioration of lung function and increase life expectancy by reducing the speed of IPF progression, and (as reported by Isshiki et al., Respiratory Medicine, 187, 106551 (2021)) they may help prevent acute exacerbations of IPF (AE-IPF; acute respiratory exacerbations in the absence of other known causes, which have a very poor median survival rate), these two drugs can only slow down the progression of the disease at best. In addition, these drugs usually cause significant (mainly gastrointestinal) side effects, which sometimes limit treatment (see, for example, Maher and Strek, supra).

[0020] As mentioned above, lung transplantation is the only intervention that has significantly improved the survival of IPF patients. However, complications such as infection and transplant rejection are not uncommon.

[0021] Therefore, there is a real clinical need for safer and / or more effective treatments for IPF. The development of new treatment strategies for IPF is extremely important, and a fundamental challenge for the future is to develop appropriate treatments to halt or even reverse the progression of the disease.

[0022] The renin-angiotensin system (RAS) is a key regulator of blood pressure homeostasis. Renin is a protease that cleaves its only known substrate (angiotensinogen) to form angiotensin I (Ang I), which in turn 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).

[0023] 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 trial in IPF (www.clinicaltrials.gov identifier NCT00879879).

[0024] Several studies in adult individuals appear to indicate that activation of the angiotensin II type 1 (AT2) receptor has an opposing role to the effects mediated by the AT1 receptor in the regulation of responses following Ang II stimulation.

[0025] 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).

[0026] AT2 receptor agonists have also been shown to have potential utility in the treatment and / or prevention of digestive disorders, such as dyspepsia and irritable bowel syndrome, and multiple organ failure (see International Patent Application WO 99 / 43339).

[0027] The expected pharmacological effects of AT2 receptor agonism are generally described in de Gasparo M et al., supra. There is no mention that agonism of the AT2 receptor may be used to treat IPF.

[0028] International patent application WO 2002 / 096883 describes the preparation of imidazole-based, triazole-based and tetrazolyl thiophene sulfonamides and derivatives as AT2 receptor agonists. The compound described in the document (as Example 1) is N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide (Compound 21 or "C21" as used hereinafter), which was selected from a group of about 20 related analogs for clinical development as a selective AT2 receptor agonist.

[0029] Mei et al., Pharm. Res., 161 105223 (2020) reported that C21 prevented cigarette smoke-induced emphysema and improved lung function in models of obstructive lung disease (particularly COPD), which, as mentioned above, is very different from restrictive lung diseases such as IPF.

[0030] Nevertheless, 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 WO 2016 / 139475) have led to C21 being clinically developed for IPF treatment. Recently, C21 has been put into clinical development as a therapeutic treatment for COVID-19 (see International Patent Application WO 2021 / 191582).

[0031] C21 is currently in a Phase II clinical trial in patients with IPF. Although the target efficacy endpoint at the outset of this study was a reduction in deterioration in lung function as measured by FVC over time compared to the current standard of care for IPF (nintedanib and pirfenidone), as demonstrated below, we found that, remarkably, C21 was not only able to halt the progression of worsening lung function in patients with IPF in a clinical setting, but was actually able to at least partially restore lung function. This represents an unexpected and extremely important development in the treatment of this debilitating and ultimately fatal disease. Summary of the invention

[0032] According to a first aspect of the present invention, a method for improving lung function in a patient with IPF is provided, the method comprising orally administering a therapeutically effective amount of C21 or a pharmaceutically acceptable salt thereof to the patient, the method of treatment being hereinafter referred to as "the method of the present invention".

[0033] The term "IPF" should be understood to include not only prototype IPF (it is well-known progressive fibrosis ILD, characterized by accelerated respiratory failure, frequent disease aggravation and early death), but also includes illness "progressive fibrosis ILD" (PF-ILD), some of which 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)). PF-ILD phenotype is usually caused by disease (e.g. connective tissue disease, such as rheumatoid arthritis, scleroderma, dermatomyositis / polymyositis, related ILD (CTD-ILD), fibrosis hypersensitivity pneumonitis (fHP), pneumoconiosis such as asbestosis, silicosis), sarcoidosis, idiopathic nonspecific interstitial pneumonia (NSIP) and ILD that cannot be classified. Regardless of the disease trigger, PF-ILD has similar risk factors to the prototypical IPF and progresses through similar mechanisms, such as self-maintaining dysregulated cellular repair, fibroblast proliferation, and alveolar dysfunction, and can be targeted together in a similar manner. To avoid unnecessary repetition, the conditions IPF and PF-ILD are collectively referred to as "IPF" below.

[0034] As described below, we have found that, unlike existing anti-fibrotic drug-based IPF treatments (i.e., nintedanib and pirfenidone as described above), C21 not only arrests disease progression, but actually improves lung function compared to "baseline" lung function levels (i.e., levels measured before treatment begins), and is therefore able to treat or even reverse the disease and / or its symptoms itself in a therapeutic (e.g., curative and / or restorative) manner, as opposed to a simple disease-modifying manner.

[0035] Technicians will understand that the term "disease delaying" includes only the medical care forms for the illness that slows down or stops the progression of the disease. This treatment may or may not alleviate the symptoms of the disease (in IPF, existing treatments based on antifibrotic drugs, nintedanib and pirfenidone, usually do not alleviate symptoms), but, in any case, disease delaying treatment will not reverse potential illness or its overall progress. According to the present invention, the term "non-disease delaying" means not only or only for slowing down the progress of IPF, and as shown below, potentially reverses the treatment of IPF.

[0036] In this regard, C21 has a disease-modifying effect as it is able to alter the course and / or pathology of IPF.

[0037] By "improving lung function" (in any type of "therapeutic" manner), we mean that C21 is not only able to have a beneficial effect when compared to placebo and / or otherwise untreated patients, or even compared to the established drug-based IPF therapies described above, but that after several weeks of treatment, it is able to show a clear and statistically significant clinical improvement and / or restoration of lung function, as measured by, for example, lung function tests (such as those described herein), when compared to equivalent baseline lung function test measurements performed in the same patients before starting treatment with C21 or a salt thereof.

[0038] Therefore, the present invention further provides a method for restoring lung function in a patient with IPF, comprising orally administering a therapeutically effective amount of C21 or a pharmaceutically acceptable salt thereof to the patient. The method of treatment is hereinafter also referred to as "the method of the present invention".

[0039] Recovery of a patient's lung function may include any improvement compared to baseline and, thus, providing at least partial recovery of lung function as measured by such lung function test, compared to an equivalent test prior to initiation of treatment. By "at least partially recovered", we mean any situation from complete recovery (i.e., values ​​within the normal range for an otherwise healthy (non-IPF) patient) to an improvement in lung function of at least about 1%, for example at least about 2%, at least about 3% or at least about 4%, such as at least about 5%, for example 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%, for example at least about 17.5% or at least about 20%, including at least about 22.5%, for example 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, compared to lung function as measured by relevant lung function tests before the start of said treatment (e.g. in conjunction with the first day of treatment, and up to about one month, such as within about seven to about ten days) from the start of treatment.

[0040] Thus, essentially, C21 and its salts are able to restore lung function by providing a curative therapeutic treatment of IPF, and therefore restore the patient's general health and well-being. Based on the clinical results, we have good reason to believe that C21 may even be able to provide at least a partial cure for the disease itself.

[0041] By providing "at least a partial cure" for IPF (which may be used interchangeably with "curative treatment" or "curative therapeutic treatment" of IPF), we mean that lung function can be restored by the methods of the present invention to a stable level (i.e., lung function tests, such as FVC, show no decrease compared to the baseline level measured at the beginning of treatment), or to a level that is improved relative to such baseline level, partially or to a level that is generally considered "normal" by a physician, in which case the patient shows fewer or even no obvious persistent symptoms of IPF.

[0042] Given that the observed improvements were established in the absence of co-therapy with the established anti-fibrotic IPF therapies described above (i.e., nintedanib and pirfenidone), C21 or its salts may be used as first-line / stand-alone treatment for IPF in the absence of such other drugs.

[0043] For the avoidance of doubt, the improvements in lung function in patients reported below may be the result of improved breathing (i.e. efficiency of gas exchange at the cellular level) or, more likely given the rate of improvement observed, a physical improvement in the extent to which the lungs are able to inflate air (i.e. improved breathing through an increase / recovery of lung volume and / or vital capacity, i.e. the amount of air that can be inhaled / expired), or may be due to other factors, or any combination of these factors.

[0044] Improvements in lung function may also be measured directly or indirectly in a number of different ways, for example quantitatively, such as by (e.g. radiological) imaging of the lungs (e.g. by high-resolution computed tomography), by measuring the patient's activity by physical measures, such as the same number of steps before fatigue (on a horizontal surface or on an upward incline, such as uphill or up a flight of stairs), or otherwise the patient's average number of steps per day, week, or month, and measures of manageability of symptoms, including feelings of breathlessness, reduction in coughing, blood oxygen levels, or other quantitative markers; or qualitatively, such as by measuring qualitative markers of stress and / or anxiety, quality of life, or more generally, how the patient "feels,"

[0045] Therefore, the present invention further provides a method for improving the lung capacity (or vital capacity) of a patient with IPF, which comprises orally administering a therapeutically effective amount of C21 or a pharmaceutically acceptable salt thereof to the patient. The treatment method is hereinafter also referred to as "the method of the present invention".

[0046] Thus, the method of the invention may alternatively be described as the use of C21 or a pharmaceutically acceptable salt thereof in the therapeutic (and / or curative) treatment of IPF as indicated by one or more of the following in an IPF patient:

[0047] Improved breathing

[0048] ● Improved / restored lungs / lung ventilation;

[0049] ● Improved / restored ventilated lungs / lung function; and / or

[0050] Increased / restored vital capacity (defined as the maximum amount of air that can be expelled from the lungs after taking the deepest possible breath),

[0051] and / or as indicated by the use of C21 or a salt thereof in a method for preventing (or completely eliminating) AE-IPF as defined above.

[0052] The methods of the present invention may also provide one or more of the improvements mentioned 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).

[0053] AEs, adverse drug reactions (ADRs), and SAEs are defined by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH, Guideline E2A (ICH 1994)).

[0054] The term "AE" includes any adverse medical event that occurs in a subject to whom an investigational drug (IMP, in this case C21 or a salt thereof) has been administered, and may or may not be causally related to the IMP. Thus, an AE can be any unfavorable and / or unexpected sign (e.g., significant abnormal laboratory results, symptoms), or disease temporally associated with the use of an IMP, whether or not considered to be related to the IMP.

[0055] An ADR is any adverse and unintended reaction to an IMP associated with any dose of the IMP.

[0056] SAE is any adverse medical event at any dose:

[0057] ● Causes death;

[0058] ● Life-threatening (i.e., events that place the subject at risk of death at the time of the event, as opposed to events that would hypothetically have resulted in death if the condition were more severe);

[0059] ●Need hospitalization or prolongation of existing hospitalization;

[0060] ● Causes lasting or severe disability or incapacity;

[0061] ● is a congenital anomaly or birth defect; and / or

[0062] ● Judged to be medically important (i.e., events that may not be immediately life-threatening or result in death or hospitalization, but that may endanger the subject or may require intervention to prevent one of the other outcomes listed above).

[0063] In this regard, C21 and its salts are capable of treating IPF according to the methods of the present invention in such a manner that any AEs, SAEs or other side effects that may result from its use in treating the patient are outweighed by the positive effects of treating the disease itself, based on the patient's consideration and / or based on the medical opinion of his / her physician.

[0064] In the method of the present invention, C21 and its salts can be administered in the form of any formulation suitable for oral administration and delivery to the gastrointestinal tract as a complete dosage form. This means that the final dosage form containing the C21-containing formulation should be suitable for swallowing as a whole, the complete dosage form is used for subsequent consumption and / or ingestion in the gastrointestinal tract, and is swallowed during use, and then consumed and / or ingested in the gastrointestinal tract.

[0065] Therefore, C21 and its salt can be provided in the form of powder, simple mixture, granule, pellet, bead, solution and / or suspension. The final dosage form includes pill, tablet, capsule, film, solution or suspension (such as syrup), powder, cake, etc.

[0066] Thus, C21 and its salts may be present in the form of a simple mixture with a carrier system, which is any pharmaceutically acceptable inert material capable of increasing the mass of the composition or components of the composition to provide a suitably handleable dosage form.

[0067] Thus, suitable carriers include pharmaceutically 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 (optionally silicified) microcrystalline cellulose, cellulose and cross-linked polyvinyl pyrrolidone; starch; sugars and sugar alcohols such as lactose, mannitol, xylitol, isomalt, dextran; or mixtures of any of the foregoing.

[0068] The carrier material is preferably used in an amount between about 5% and about 90% by weight, based on the total weight of the composition comprising C21 or a salt thereof. The preferred range is about 10% to about 80% by weight.

[0069] 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 above materials and / or may comprise a composite material of one or more of these materials.

[0070] The mixture of C21 / salt and carrier material can then be filled directly into capsules. Alternatively, this mixture can be granulated into pellets, granules or beads and then loaded into suitable capsules. Alternatively, the powder, pellets, granules or beads can be compressed into tablets.

[0071] Granulation can be carried out using well-known techniques including dry granulation, wet granulation, melt granulation, thermoplastic pelletizing, spray granulation or extrusion / spheronization.

[0072] In addition to the carrier material, the powder, granules, pellets or beads containing C21 or its salt may also contain other commonly used pharmaceutical additives and / or excipients used in the art (see, for example, Rowe et al., Handbook of Pharmaceutical Excipients, 8th Edition (2017) and documents cited therein).

[0073] Other pharmaceutically acceptable excipients are known to those skilled in the art, such as binders, disintegrants, glidants, lubricants and the like.

[0074] Binder can be defined as the material that can serve as bonding to form reinforcing agent, and it can promote powder mass to be pressed into viscous compact.Suitable binder includes polyvinyl pyrrolidone, gelatin, sodium alginate, cellulose derivatives, such as low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose gum, (optionally silicified) microcrystalline cellulose etc.If present, based on the gross weight of the composition comprising C21 or its salt, binder is preferably used with the amount between about 2% and about 50% by weight.Preferred range is about 5% to about 30% by weight.

[0075] Disintegrants or disintegrants can be defined as materials that can accelerate the disintegration / dispersion of components of a composition (such as a granule or tablet) comprising C21 or a salt thereof to a measurable degree. This can be achieved, for example, by a material that can swell and / or expand when in contact with an aqueous medium (particularly body fluids, including those found in the gastrointestinal tract), thereby causing at least a portion of a dosage form comprising a formulation comprising C21 or a salt thereof to disintegrate when so wetted. Suitable disintegrants include cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose (cross-linked carboxymethyl cellulose, e.g., Ac-Di-Sol, FMC Corp., USA), carboxymethyl starch, native starch, pregelatinized starch, corn starch, potato starch, sodium starch glycolate ( DMV International BV, Netherlands), low-substituted hydroxypropyl cellulose, etc. Based on the total weight of the composition containing C21 or its salt, the disintegrant (which may include one or more of the above materials) is preferably used in an amount between about 1% (e.g., about 5%) and about 40% by weight. The preferred range is about 5% (e.g., about 10%) to about 30% by weight. Preferred disintegrants include cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, and in particular low-substituted hydroxypropyl cellulose.

[0076] A glidant is a pharmaceutically acceptable material that facilitates powder flow by reducing inter-particle friction and / or cohesion (but does not necessarily have the ability to reduce and / or prevent adhesion to external materials such as a capsule filling machine or hopper). Thus, suitable pharmaceutically acceptable glidant materials include talc, magnesium carbonate or calcium silicate, although preferably the glidant is a hydrophilic glidant such as one or more of various forms of silicon dioxide, including fumed / pyrogenic silicon dioxide, or more specifically silicon dioxide gel, silicon dioxide aerogel and / or colloidal silicon dioxide.

[0077] When the final dosage form to be swallowed is in tablet form, a lubricant is generally used to prevent the granules or powder from adhering to the stamping die / face and to facilitate smooth ejection from the die after compression. Suitable lubricants include stearic acid, sodium stearyl fumarate, anhydrous colloidal silicon dioxide, 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, and preferably up to 2% based on the total weight of the composition comprising C21 or its salt).

[0078] Other excipients that can be used in oral dosage forms include surfactants, wetting agents, flavoring agents (e.g., lemon, menthol, or mint powder), sweeteners (e.g., neohesperidin, sucralose, or acesulfamide potassium), dyes, antioxidants (which may be naturally occurring or otherwise present (e.g., butylated hydroxytoluene (BHT), vitamin C, vitamin E, β-carotene, uric acid, uniquion, superoxide dismutase (SOD), glutathione peroxidase, or peroxidase catalase)), preservatives, and buffers.

[0079] These and other pharmaceutically acceptable excipients mentioned herein may be commercially available or otherwise described in the literature, for example, for all these types of excipients, including those described in, for example, Rowe et al., supra and Remington The Science and Practice of Pharmacy, 21st edition, Lippincott Williams and Wilkins, Philadelphia (2006) and the documents cited therein, the relevant disclosures in all these documents are incorporated herein by reference. In addition, the preparation of suitable oral formulations can be achieved non-inventively by a skilled person using conventional techniques.

[0080] Granules, pellets or beads can be further processed after they are formed. For example, dry particles can be broken, ground or milled to produce smaller sized granular materials using suitable grinding techniques, or they can be sieved to separate the required size fractions. Wet granules can be screened to break up agglomerates of granules and remove fine material. In either case, unused undersized (thin) and oversized materials can be reprocessed to avoid waste.

[0081] However, when preparing a powder mixture, granules, tablets or capsules, the composition should be prepared so that C21 or a pharmaceutically acceptable salt thereof is evenly distributed throughout the carrier material (and / or other excipients used).

[0082] For simple mixtures this involves mixing for a period of time to provide a uniform distribution of the active ingredient, for example as described below. This may vary depending on the equipment used.

[0083] In the context of the present invention, the terms "homogeneous" and "uniformly distributed" mean that there is a substantially uniform content of C21 or a salt thereof throughout the carrier material (and / or other excipients used). In other words, if a plurality of (e.g., at least 2, more preferably about 6, such as about 10 up to about 30 or more, if necessary) samples are taken from a mixture comprising an active ingredient and a carrier blend, the measured content of the active ingredient present between these samples produces a standard deviation (i.e., coefficient of variation and / or relative standard deviation) from the average amount of less than about 8%, such as less than about 6%, for example less than about 5%, in particular less than about 2%.

[0084] Preferred mixing equipment includes standard mixing equipment such as tumblers, shaker mixers (eg Turbula), convection mixers, hopper mixers and fluidizing mixers. Preferred mixers include V-type mixers.

[0085] Tablets can be formed by a compression / compacting process. Direct compression / compacting can be achieved using techniques such as those described in Pharmaceutical Dosage Forms: Tablets. Vol. 1, 3rd ed., Augsburger et al. (eds.), CRC Press (2008) and references cited therein. Suitable compacting equipment includes a standard tablet press, such as a Kilian SP300 or a Korsch EKO.

[0086] The composition comprising C21 or a salt thereof may be contained within a capsule suitable for such oral administration.

[0087] Suitable pharmaceutically acceptable capsules include soft or hard shell capsules which may be made from gelatin, cellulosic polymers such as hydroxypropylmethylcellulose (HPMC or hypromellose), hypromellose acetate succinate (HPMCAS), starch polymers, pullulan or other suitable materials, for example by standard capsule filling techniques.

[0088] According to a preferred aspect of the present invention, when the dosage form comprises a solid preparation, the solid preparation comprises a mixture of C21 or a salt thereof and a carrier material (e.g., in the form of a powder, granules, etc.), and the capsule is preferably a hard shell two-piece capsule, such as a capsule made of gelatin or more preferably HPMC, and is provided in the form of two closed halves, which can be separated and filled with granular material and then reassembled. Such capsules can be of any size (e.g., 00 to 5), but the preferred capsule size is size 2, size 1, or more preferably size 0.

[0089] In this and other preferred embodiments of the present invention, C21 or its salt is present in the form of particles, which may be amorphous or crystalline or a mixture of the two. Preferred particles have a size that does not cause segregation during the formation of the composition to be filled into the capsule during the capsule filling process or during storage.

[0090] In this regard, C21 or its salt can be provided in the form of a plurality of primary (i.e., non-agglomerated) particles, which generally have an average diameter of no more than 1,000 μm, such as about 500 μm, including about 250 μm, preferably no more than about 100 μm, including no more than about 50 μm, such as about 20 μm, or no more than about 10 μm, such as an average diameter based on weight and / or volume. Although there is no lower limit to the particle size that can be adopted according to this aspect of the present invention, for ease of manufacture, we prefer that the primary particles of C21 or its salt have an average diameter based on weight and / or volume of no less than about 1 μm, such as about 2 μm, including about 3 μm.

[0091] As used herein, the term "mean diameter based on weight" will be understood by the skilled person to include that the average particle size is characterized and defined by a particle size distribution by weight, i.e., a distribution in which the existing fraction (relative amount) in each size class is defined as the weight fraction, as obtained by, for example, sieving (e.g., wet sieving). The term "mean diameter based on volume" is similar in its meaning to the mean diameter based on weight, but will be understood by the skilled person to include that the average particle size is characterized and defined by a particle size distribution by volume, i.e., a distribution in which the existing fraction (relative amount) in each size class is defined as the volume fraction, as measured by, for example, 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). Particle size may be measured using other instruments known in the art, such as those sold by, for example, Malvern Instruments, Ltd. (Worcestershire, UK), Shimadzu (Kyoto, Japan), and (Elzone, Micromeritics (USA; inductive zone method).

[0092] The above-mentioned particle size measurement methods generally assume that the particles are substantially spherical. In the case where the shape of the particles is very different from a sphere, the average diameter may also include the average Feret's diameter of the particles as measured, for example, by microscopy. In the case of needle-shaped particles, the average diameter may be expressed as the average length of the longest Feret's diameter of the needles (i.e., the average "length" of the needles).

[0093] For particles with an average diameter (such as an average diameter based on weight and / or volume) within the above limits, we include the average diameter of the particles as prepared and before mixing with the relevant excipients according to the present invention and / or before encapsulation. It will be appreciated that during the handling and / or processing of the active ingredient, some aggregation of primary particles to form secondary particles may occur. Nevertheless, this should be minimized.

[0094] C21 or its salt can also be provided in the form of particles having a relatively narrow particle size distribution (PSD), as measured by standard techniques and parameters accepted in the art, including mass median diameter (D 50 ; lognormal mass median diameter), mass average particle size and / or cumulative PSD containing 50% of the mass diameter) and / or geometric standard deviation (as determined by formula D 84.13 / D 50 or D 50 / D 15.78 GSD or σ of the measurement g , where D84.13 and D 15.78 are the diameters that contain 84.13% and 15.78% of the mass, respectively, and D 50 As defined above). Such parameters may be measured and calculated in-process using any suitable sampling method and particle size measurement technique as described above.

[0095] 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.

[0096] Primary particles of C21 or its salt can be prepared by appropriate techniques, such as precipitation, cutting (for example by dissolution in a supercritical fluid under pressure, followed by rapid expansion), spray drying, or, if appropriate, micronization by techniques well known to those skilled in the art, such as grinding, dry milling, jet milling, wet milling and / or pulverizing.

[0097] The particles may also be sieved to separate into desired size fractions, and / or screened to break up agglomerates and / or remove fine material. In either case, unused undersized (fine) and oversized material may be reprocessed to avoid waste. Alternatively, the particles may be separated into appropriate particle sizes using cyclonic separation, by air classifiers, sedimentation, force field classification, and / or elutriation.

[0098] Although one or more of the above-mentioned techniques may be used to select and / or provide C21 or a salt thereof having the above-mentioned average diameter, particle size, PSD and / or GSD based on weight or volume, one of the major benefits 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 above-mentioned particle processing techniques prior to blending with the relevant excipients.

[0099] In this regard, and as mentioned above, we have found that C21 and its salts are extremely difficult materials to process. Part of the problem lies in the extreme sensitivity of C21 and its salts to the combined presence of light and water.

[0100] In addition, particularly and as described below, compatibility studies have revealed that certain standard excipients cause significant chemical instability of active ingredients when co-mixed with C21 and its salts. In addition, C21 and its salts (particularly its sodium salt) form viscous needle-shaped crystals with a tendency to agglomerate. This means that dry mixing with certain standard pharmaceutically acceptable ingredients is very difficult, and it is not simple to produce a blend with pharmaceutically acceptable active ingredient content uniformity and / or the same dosage uniformity in the capsule.

[0101] Furthermore, it has been found that micronizing primary particles of the active ingredient (eg in the form of a sodium salt) also does not provide a solution to these problems, as one skilled in the art might have expected, and also causes other problems related to localized heating and static electricity.

[0102] However, we have found that by blending C21 or a pharmaceutically acceptable salt thereof with a premixed blend of carrier particles and a glidant having an average diameter (such as an average diameter based on weight and / or volume and / or a structural (particle) density that is similar to the average diameter based on weight and / or volume, and / or a structural (particle) density of solid particles of C21 or a pharmaceutically acceptable salt thereof), the above problems can be avoided and a composition for loading into capsules can be provided, wherein C21 or a salt thereof is not only uniformly and equally distributed in the capsules, ensuring uniformity of dosage of the active ingredient between capsules after such loading, but also is physically and chemically stable during and after manufacturing, under normal storage conditions, and during use.

[0103] Thus, in this regard, the method of the present invention comprises administering a dosage form comprising an excipient mixed with particles of C21 or a pharmaceutically acceptable salt thereof, the particles comprising a blend of at least one type of carrier particles (e.g., carrier particles having an average diameter, such as an average diameter based on weight and / or volume, and / or a structural (particle) density that is similar to the average diameter based on weight and / or volume, and / or a structural (particle) density of solid particles of C21 or a pharmaceutically acceptable salt thereof, respectively) and a glidant.

[0104] In this context, the terms "homogeneous" and "evenly distributed" are as defined above.

[0105] In this preferred aspect of the invention, suitable carrier particle materials may comprise water-soluble pharmaceutically acceptable substances, including carbohydrates, such as sugar alcohols, such as sorbitol, xylitol, and in particular mannitol. Likewise, carrier particles may comprise a physical mixture of any of these materials and / or may comprise a composite material of one or more of these materials.

[0106] The carrier particles may have a similar particle size distribution and / or structural (particle) density as the active ingredient particles used in the composition to be filled into a capsule to prepare such a dosage form.

[0107] By "similar particle size distribution and / or structural (particle) density", we mean that the average diameter of the carrier particles, such as the average diameter based on weight and / or volume, and / or the particle density is within about ±75%, such as about ±50%, including about ±40%, for example about ±30%, or about ±20%, including about ±10% of the relevant size of the C21 or its salt employed. In the case of the sodium salt of C21 formed as needle-shaped particles, the relevant size is the length (and / or longest Feret diameter) of those needle-shaped particles.

[0108] In this regard, preferred carrier particle sizes include average diameters based on weight and / or volume that are less than about 100 μm, including less than about 80 μm, such as less than about 70 μm, for example between about 20 μm and about 60 μm (e.g., about 25 μm, or more preferably about 50 μm).

[0109] We have found that by using carrier particles having a size similar to the active ingredient and / or a size within the above ranges, blend segregation can be avoided.

[0110] In order to prepare the composition to be filled into a capsule to prepare a dosage form according to this aspect of the invention, the carrier particles of the desired size may also be mixed with a suitable glidant material, preferably under the registered trademark GLUTAMATE®, prior to mixing with the active ingredient. (See https: / / grace.com / pharma-and-biotech / en-us / Documents / Syloid / M309c). Thus, a preferred form of silica includes a stable aqueous dispersion (sol) of amorphous silica particles having an average diameter based on weight and / or volume of between about 1 nm and about 100 nm (e.g., up to about 50 nm, such as up to about 20 nm, such as between about 10 nm and about 15 nm).

[0111] 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 the glidant material, and this blend is then mixed with the active ingredient particles.

[0112] We have also found that by adding the above-mentioned glidant to the carrier particles to first form an excipient blend prior to mixing with the active ingredient, this improves the flowability of the excipient blend and thereby leads to better subsequent mixing with C21 or a pharmaceutically acceptable salt thereof, further reducing the likelihood of blend segregation.

[0113] In this aspect of the invention, the dosage form may also include other excipients well known to those skilled in the art for oral delivery of active ingredients, such as those mentioned above.

[0114] However, in view of 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 regard, the dosage form can consist essentially of a pharmaceutical composition in the form of a particle mixture, the particle mixture comprising solid particles of C21 or a pharmaceutically acceptable salt thereof, mixed with a blend of carrier particles (e.g., having an average diameter, such as an average diameter based on weight and / or volume, and / or a structural (particle) density, which is similar to the average diameter of the solid particles of C21 or its salt, such as an average diameter based on weight and / or volume, and / or a structural (particle) density) and a glidant, which composition can be contained in a capsule suitable for such oral administration.

[0115] All preferred features mentioned herein for other aspects of the invention that are in any way related to this aspect of the invention apply equally.

[0116] The term “consisting essentially of will be understood to mean that the scope of this (and only this) aspect of the invention is limited to the basic features specified above, and such other features that do not materially affect the basic and novel characteristics of this aspect of the invention.

[0117] In this regard, although not an essential feature of this aspect of the invention, it is 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 equipment (e.g., capsule filling machines and hoppers). This is a preferred feature that does not materially affect the basic and novel features of this aspect of the invention.

[0118] A composition "essentially consisting of" a granular mixture comprising solid particles of C21 or a pharmaceutically acceptable salt thereof, mixed with a blend of carrier particles and a glidant as defined above, to be filled into a capsule may alternatively mean that the composition contains a total of at least about 95%, such as at least about 97%, by weight of those specified ingredients.

[0119] In this aspect of the invention, it is also preferred that the dry blended blend is passed through a sieve at a point during the mixing process to break up agglomerates formed during the blending process, such as described below. A suitable sieve is one having an aperture as small as (or approximately) the particle size of the largest component of the blend. Thus, a suitable sieve size is about 50 μm, such as 75 μm, including 100 μm, such as 150 μm, 200 μm or 250 μm (e.g., about 300 μm) to about 1,000 μm, such as about 400 μm (e.g., about 500 μm) to about 900 μm (e.g., about 800 μm).

[0120] The dosage form can also be in the form of a heterogeneous mixture comprising solid particles of C21 or a pharmaceutically acceptable salt thereof suspended in a pharmaceutically acceptable hydrophobic lipid-based carrier, wherein C21 or a pharmaceutically acceptable salt thereof is substantially insoluble in the carrier, and the composition is loaded into a capsule suitable for oral administration.

[0121] The lipid-based carrier system in which the solid particles of C21 or its salt are suspended can be in solid form (fat) at room temperature, or more preferably can be in liquid form (oil) at room temperature. However, the particles of C21 or its salt can be suspended in either form of lipid carrier.

[0122] According to this aspect, we prefer that the capsule is a soft shelled monolithic capsule, such as a soft gelatin capsule, wherein the monolithic gelatin capsule is filled with a lipid-based suspension of C21 or a salt thereof and then sealed as a monolith, such as with a drop of gelatin solution. Gelatin can be obtained from any source (such as porcine and bovine sources), but it should be noted that there are vegan alternatives to soft gelatin capsules.

[0123] The soft gelatin capsule shell may contain one or more plasticizers such as xylitol, sorbitol, polyglycerol, non-crystallizing solutions of sorbitol, glucose, fructose and glucose syrup, more preferably glycerol / glycerol, sorbitol and / or proprietary plasticizers such as Anidrisorbs (a proprietary mixture of sorbitol, sorbitan, maltitol and mannitol, Roquette Freres, including Anidrisorb 85 / 70 (liquid sorbitol-mannitol-hydrolyzed starch plasticizer). The soft gelatin capsule shell optionally contains one or more flavoring agents, colorants and / or opacifiers (such as titanium dioxide).

[0124] Such capsules can be of any shape (e.g., rectangular, round, oval, tubular, etc.) and any size (e.g., 3 to 24 rectangular, 1 to 20 round, 2 to 20 oval, 5 to 120 tubular, etc.). Preferred capsule sizes will hold a volume between about 0.3 and about 1.0 mL.

[0125] In this particular aspect of the invention, it is important that C21 or a pharmaceutically acceptable salt thereof is substantially insoluble in the lipid-based carrier under normal storage conditions. By "substantially insoluble", we include that the solubility of C21 or a salt thereof in the carrier does not exceed about 0.015 mg of C21 or a salt thereof per gram of carrier.

[0126] In this way, due to the dual nature of the carrier's hydrophobicity and lack of tendency to solubilize C21 or its salts, the active ingredient is not exposed to amounts of water that might catalyze its degradation as described above.

[0127] 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 its salts in such dosage forms at ambient temperature.

[0128] The hydrophobic lipid-based carrier material in which C21 or its salt as defined above must be insoluble may comprise a substantially water-immiscible non-polar oil or fat. Preferably, the lipid-based carrier consists primarily of triacylglycerols (also known as "triglycerides"), which are esters formed by the reaction of all three hydroxyl groups of the glycerol moiety with fatty acids (carboxylic acids).

[0129] Thus, the lipids may contain saturated or unsaturated chain fatty acids, which chains may range from 1 carbon atom up to 30 carbon atoms, including up to 26 carbon atoms, such as up to 22 carbon atoms, including 8, 10, 12, 14, 16, 18 or 20 carbon atoms, etc.

[0130] Saturated fatty acids that may be mentioned include acetic acid (2), propionic acid (3), butyric acid (4), valeric acid (5), caproic acid (6), heptanoic acid (7), octanoic acid (8), nonanoic acid (9), decanoic acid (10), undecanoic acid (11), lauric acid (12), tridecanoic acid (13), myristic acid (14), pentadecanoic acid (15), palmitic acid (16), heptadecanoic acid (17), stearic acid (18), nonadecanoic acid (19), arachidic acid (20), heneicosanoic acid (21), behenic acid (22), tricosanoic acid (23), tetracosanoic acid (24), pentacosanoic acid (25), cerotic acid (26), heptadecanoic acid (27), montanic acid (28), nonacosanoic acid (29) and melissic acid (30), wherein the number in brackets is the number of carbon atoms in the fatty acid molecule.

[0131] Unsaturated fatty acids that may be mentioned include crotonic acid (4:1), and ω-3 unsaturated fatty acids such as caprylic acid (8:1), capric acid (10:1), decaenoic acid (10:2), laureic acid (12:1), lauric acid (12:2), myristic acid (14:1), myristic acid (14:2), myristic acid (14:3), palmitic acid (16:3), hexadecadienoic acid (16:3), palmitolenic acid (16:4), α-linolenic acid (18:3), octadecatrienoic acid (18:4), 11,14,17-eicosatrienoic acid (20:3), eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5), heneicosadepentaenoic acid (21:5), dioctadecatrienoic acid (21:6 ...pentaenoic acid (20:4), 11,14,17-eicosatrienoic acid (20:4), 11,14,17-eicosatrienoic acid (20:5), 11,14,17-eicosapentaenoic acid (21:5), 11,14,17-eicosatrienoic acid (20:3), 11,14,17-eicosatrienoic acid (20:4), 11,14,17-eicosapentaenoic acid (20 2-hydroxy-1-hydroxy-2-enoic acid (20:4); ω-6 unsaturated fatty acids such as tetradecenoic acid (14:1), 1-hydroxy-1-hydroxy-2-enoic acid (14:2); 1-hydroxy-1-hydroxy-2-enoic acid (14:3); 1-hydroxy-1-hydroxy-2-enoic acid (14:4); 1-hydroxy-1-hydroxy-2-enoic acid (14:5); 1-hydroxy-1-hydroxy-2-enoic acid (14:6); 1-hydroxy-1-hydroxy-2-enoic acid (14:6); 1-hydroxy-1-hydroxy-2-enoic acid (14:1); 1-hydroxy-1-hydroxy-2-enoic acid (14:3); 1-hydroxy-1-hydroxy-2-enoic acid (14:4); 1-hydroxy-1-hydroxy-2-enoic acid (14:1); 1-hydroxy-1-hydroxy-2-enoic acid (14:1); 1-hydroxy-1-hydroxy-2-enoic acid (14:3); 1-hydroxy-1-hydroxy-2-enoic acid (14:3); 2-octadecenoic acid (18:1), linoleic acid (18:2), trans-linoleic acid (trans-s-18:2), gamma-linolenic acid (18:3), octadecatrienoic acid (18:3), pinoleic acid (18:3), 11,14-eicosadienoic acid (20:2); dihomolinoleic acid (20:2), dihomo-gamma-linolenic acid (20:3), arachidonic acid (20:4), docosadienoic acid (22:2), adrenic acid (22:4), docosapentaenoic acid (22:5), tetracosatetraenoic acid (24:4) and tetracospentaenoic acid (24:5); ω-7 unsaturated fatty acids, such as 5-dodecenoic acid (12:1), 7-tetradecenoic acid (14:1), palmitic acid (16:1), Vaccinic acid (18:1), rumenic acid (18:2), guaranaic acid (20:1), 7,10,13-eicosatrienoic acid (20:3), 15-docosaenoic acid (22:1), and 17-tetracosenoic acid (24:1); ω-9 unsaturated fatty acids, such as arachidonic 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, such as hexadecenoic acid (16:1); ω-11 unsaturated fatty acids, such as gadoleic acid (20:1);and ω-12 unsaturated fatty acids, such as 4-hexadecenoic acid (16:1), petroselinic acid (18:1) and eicosenoic acid (20:1), where the numbers in brackets are the number of carbon atoms and the number of unsaturated (i.e. double) bonds in the fatty acid molecule, respectively. ;

[0132] 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.

[0133] The triglycerides may be naturally occurring oils or fats, may be semi-synthetic or may be synthetic.

[0134] Naturally occurring oils or fats may be obtained from an animal or, more preferably, a plant source, such as seeds, nuts, or fruits.

[0135] Naturally occurring vegetable oils primarily contain triglycerides, which are mixtures of glycerides with different fatty acid chain lengths.

[0136] Naturally occurring pharmaceutically acceptable oils belonging to this class include sunflower oil, soybean oil, corn oil, grape seed oil, rapeseed oil, sesame oil, almond oil, bitter almond oil, cottonseed oil, palm kernel oil, castor oil, olive oil, palm oil and coconut oil (for the composition of each, see, e.g., Occurrence and Characteristics of Oils and Fats in Padley, Gunstone and Harwood (eds.), The Lipid Handbook., Chapman & Hall, London, pp. 47-224, 1994).

[0137] When used in such dosage forms, naturally occurring oils should be of pharmaceutical grade and should therefore preferably be refined after extraction from their natural source. This can be accomplished using techniques well known to those skilled in the art.

[0138] Preferred oils include one or more of sesame oil, corn oil, palm kernel oil, coconut oil or soybean oil.

[0139] Semisynthetic and synthetic lipid-based carrier systems can be prepared using techniques well known to those skilled in the art, such as isolation, transesterification, lipolysis, and transesterification (glycerolysis).

[0140] Thus, semisynthetic and synthetic lipid-based carrier systems include those that are usually in the form of oils and include short-chain (C1 to C5) triglycerides (e.g., triacetin) and medium-chain (C6 to C 12) triglycerides (the major component of naturally occurring palm kernel oil and coconut oil, such as capric triglyceride, more specifically Miglyol 812N); and those that are usually in the form of semi-solid fats, including long chain (C 14 To C 22 ) triglycerides (such as Gelicure 43 / 10).

[0141] Regardless of the form of the hydrophobic lipid-based carrier system employed, it is preferred that the major component of the carrier system comprises at least about 85% triacylglycerols, more preferably at least about 90% triacylglycerols, and especially at least about 95% triacylglycerols.

[0142] Mixtures of any of the above-mentioned naturally occurring, semisynthetic and / or synthetic lipid-based carrier materials may be used.

[0143] In this aspect of the invention, C21 or its salt is present in the form of particles, which may be amorphous or crystalline or a mixture of both.Preferred particles are of a size that does not result in precipitation during suspension formation, encapsulation or storage.

[0144] In this regard, C21 or a salt thereof can be provided for suspension in a lipid-based carrier in the form of a plurality of primary (i.e., non-agglomerated) particles, which generally have an average diameter (as defined above) based on weight and / or volume, in the same ranges and values ​​as those described above for preferred solid dosage forms useful in the methods of the present invention.

[0145] For particles having an average diameter based on weight and / or volume within the above limits, we include the average diameter of the particles when prepared and before suspension in a lipid-based carrier, when so suspended and / or before being loaded into a capsule as described herein. The primary particles of C21 / its salt can thus be prepared as described above.

[0146] It is important to ensure that before the suspension of this aspect of the invention is filled into capsules, it contains C21 or its salt uniformly and equally distributed throughout the suspension to ensure uniformity of dosage of the active ingredient after such filling into capsules. Therefore, C21 and its salts are preferably provided in the form of particles having a relative PSD as defined above.

[0147] Although one or more of the above techniques may be used to select and / or provide C21 or a salt thereof having such a PSD and / or GSD to provide a stable suspension having an even distribution of C21 / salt particles within the suspension, it is important to ensure that the C21 / salt is thoroughly mixed with the lipid-based carrier system to ensure an even distribution of active ingredient particles within the carrier prior to filling. This is particularly true in the case of bulk suspensions used as part of a capsule filling process, where it is important to ensure that the mixture is homogeneous, not only at the start, but also to maintain this homogeneity during the filling process to ensure dosage uniformity within a production batch.

[0148] 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, and are as defined above.

[0149] If the lipid-based carrier system is in the form of a fat (ie solid or semi-solid at or near normal manufacturing temperatures and / or product storage temperatures), the skilled artisan will appreciate that the fat will need to be melted by elevated temperature prior to mixing.

[0150] Furthermore, to ensure that the suspension provides a stable, uniform distribution of the active ingredient within the carrier, lipid-based carrier systems (and particularly those in the form of liquid oils at or near normal manufacturing temperatures and / or product storage temperatures) may further comprise a thickening agent, if necessary, to prevent particle aggregation and / or sedimentation, such as microcrystalline cellulose and sodium carboxymethyl cellulose, and blends of mono-, di- and triglycerides with PEG esters of unsaturated fats, such as Gelucire 43 / 01, hydrogenated vegetable oils, beeswax, paraffin, and the like.

[0151] By providing C21 or a salt thereof in the form of a particle suspension according to this aspect of the invention, we have found that such a dosage form is not only capable of delivering a consistent and / or uniform dose of the active ingredient, but also ensures that the active ingredient remains in a physically and chemically stable form during and / or after manufacture, under normal storage conditions, and / or during use.

[0152] As used herein, C21 or a pharmaceutically acceptable salt thereof can be prepared and stored in the form of a composition that can be directly used to manufacture the dosage form used in the method of the present invention, and further, once prepared, such dosage forms can be stored under normal storage conditions without significant changes in the physicochemical properties of the dosage form, the composition mixture contained therein and / or the most important active ingredient over time.

[0153] Therefore, "insignificant degree of change in physicochemical properties" includes that the composition of C21 / salt contained in a suitable carrier as described above can have both physical stability and chemical stability before and / or after mixing with suitable excipients, encapsulating, compressing into tablets or otherwise.

[0154] By "chemically stable" we include compositions comprising C21 / salts in an appropriate carrier and dosage forms comprising them that can be stored under normal storage conditions (with or without appropriate pharmaceutical packaging) without significant chemical degradation or decomposition of such dosage forms and / or the compositions contained therein, particularly the active ingredients.

[0155] By "physical stability" we include compositions comprising C21 / salts in appropriate carriers and dosage forms comprising them that can be stored under normal storage conditions (with or without appropriate pharmaceutical packaging) without an insignificant degree of physical transformation, such as aggregation, separation or segregation, or sedimentation as described above, or changes in the properties and / or integrity of such dosage forms and / or the compositions contained therein, particularly the active ingredients, including dissolution, solvation, solid-state phase transitions, and the like.

[0156] Examples of "normal storage conditions" include a temperature between minus 80°C and plus 50°C (preferably between 0°C and 40°C, and more preferably ambient temperature, such as between 15°C and 30°C), a pressure between 0.1 bar and 2 bar (preferably atmospheric pressure), a relative humidity between 5% and 95% (preferably 10% to 60%) and / or exposure to UV / visible light at 460 lux for a long time (i.e. greater than or equal to six months).

[0157] Under such conditions, it can be found that the physical and / or chemical conversion of C21, its salts and / or compositions containing them is less than about 15%, more preferably less than about 10%, and especially less than about 5%. The skilled person will understand that the upper and lower limits of temperature and pressure mentioned above represent extreme values ​​of normal storage conditions, and that certain combinations of these extreme values ​​will not be experienced during normal storage (e.g., a temperature of 50° C. and a pressure of 0.1 bar).

[0158] Preferably, pharmaceutical compositions, whether in powder mixture, lipid-based suspension or other form, and / or whether contained in capsules as described above or in other forms, are manufactured and / or stored in a manner that maintains them substantially free of water.

[0159] By "substantially free of water", we include taking appropriate precautions to ensure that the particles C21 or its salt and the excipients mixed therewith are separately prepared and / or provided in a manner in which they are substantially dry, and are also mixed together in an environment in which they remain substantially dry to form a dry mixture.

[0160] By "substantially dry" or "substantially free of water", we include compositions comprising C21 / salt and related excipients as a whole comprising no more than about 5%, including no more than about 2%, such as no more than about 1%, including no more than about 0.5%, such as about 0.1% water or less by weight or volume.

[0161] Further processing of the composition comprising C21 or a salt thereof and associated excipients into the dosage forms described above may also preferably be carried out in such a manner that it remains in this substantially water-free state.

[0162] In this regard, although the pharmaceutically acceptable capsule material may contain residual amounts of water, the entry of water from the capsule material into the composition (whether in solid (e.g., powder mixture) or liquid (e.g., lipid suspension) form) should be minimized to protect the highly sensitive C21 or its salt from contact with water and thereby degradation in the presence of light.

[0163] However, it is preferred (although not necessarily required) to package the dosage form in a manner that keeps the dosage form itself dry and protected from light. This may include sealed packaging, use of deliquescent materials, etc.

[0164] In another aspect of the invention, C21 and its salts may be presented in any pharmaceutical dosage form, including those described above, which can be coated, surrounded and / or encapsulated with an enteric material to prepare a final dose suitable for oral administration to the gastrointestinal tract.

[0165] Enteric materials can be used to coat a variety of dosage forms, including the various formulations / administration principles described above in a non-limiting sense. For example, the composition can be encapsulated in a capsule, or compressed into a tablet, which is suitable for oral administration and can be coated with an enteric material.

[0166] In this regard, when C21 or its salt is provided in a multi-particulate form (such as a powder, granules, pellets and / or beads), the particles can be coated with an enteric material individually or collectively. This can be accomplished in a variety of ways, such as by filling such multi-particulates with any relevant excipients, such as a solid carrier material (e.g., carrier particles) or a liquid (e.g., oil-based) carrier material as described above, into a capsule before the enteric material is applied to the outside of the capsule. Alternatively, particles comprising C21 or its salt, including granules or pellets, can be coated with an enteric material alone, optionally together with other excipient materials, before being loaded into an appropriate capsule.

[0167] Similarly, C21 / salts and excipients as described above can be compressed into tablets before coating with enteric materials.

[0168] As defined herein, "enteric" materials can be used to coat, surround and / or encapsulate a composition comprising C21 or a pharmaceutically acceptable salt thereof to substantially prevent the active ingredient from being released from the composition in the stomach, and / or from coming into contact with gastric juices, and / or until the component reaches the small intestine. By "substantially prevent," we include no more than about 20%, such as about 15%, for example about 10%, or more particularly no more than about 5% by weight of the active ingredient being released in the acidic environment of the stomach.

[0169] Typical enteric coating materials include the following: cellulose acetate, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate tetrahydrophthalate, polyvinyl acetate phthalate, hydroxyethyl ethyl cellulose phthalate, methacrylic acid copolymers, polymethacrylic acid / acrylic acid copolymers, styrene maleic acid copolymers, hydroxypropyl methylcellulose phthalate, acrylic resins, cellulose acetate trimellitate, hydroxypropyl methylcellulose trimellitate, shellac, hydroxyethyl ethyl cellulose phthalate, carboxymethyl cellulose and hypromellose acetate succinate. Preferred enteric materials include polyvinyl acetate phthalate, and particularly methacrylic acid copolymers.

[0170] Regardless of whether the dosage form comprising C21 comprises one or more enteric coatings as described above, the dosage forms, uses and methods of treatment described herein may include administration in the substantial absence of food and / or administration to a patient in a fasting state.

[0171] By "administered in the substantial absence of food and / or to a patient in a fasting state", we include instructing the patient to orally administer the dosage form not less than about 1 hour, e.g., not less than about 1.5 hours, including not less than about 1.75 hours, such as not less than about 2 hours, or not less than about 2.25, e.g., not less than about 2.5 hours, such as not less than about 3 hours, about 3.5 hours, about 4 hours, including about 5 hours or about 6 hours after the patient's last meal and / or any food (including snacks) has been consumed. The term may also be understood to include that no food may be consumed within about 15 minutes, such as within about 20 minutes, about 25 minutes, or about 30 minutes, including about 45 minutes, such as within about 60 minutes, about 75 minutes, about 90 minutes, or about 2 hours from or after such food has been consumed.

[0172] Pharmaceutically acceptable salts of C21 include acid addition salts. Such salts can be formed by conventional methods, for example, by reacting C21 in free acid form (hereinafter referred to as "free C21") with one or more equivalents of appropriate acid, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or the medium using standard techniques (e.g., in a vacuum, by freeze drying or by filtering). Salts can also be prepared by exchanging the counterions of the active ingredient in salt form with another counterion, for example, using a suitable ion exchange resin. Preferred C21 salts include HCl salts, alkaline earth metal salts such as magnesium salts and calcium salts, and alkali metal salts, such as potassium salts or preferably sodium salts.

[0173] The amount of C21 or its salt in the dosage form used in the method of the present invention will depend on and / or can be selected according to the severity of the relevant condition (i.e., IPF) or the expectation of such severity and the patient to be treated, but can be determined by a skilled person. The mode of administration can also be determined according to the time and frequency of administration and the severity of the condition.

[0174] The suitable lower daily dose of C21 in adult patients (average body weight, e.g., 70 kg) of the method of the present invention, calculated as the dosage of free C21 in the relevant dosage form, can be about 10 mg per day, such as about 20 mg, for example, about 25 mg. The suitable upper limit of the daily dose range of C21 calculated as the dosage of free C21 in the relevant dosage form can be about up to about 900 mg, such as 600 mg, including about 400 mg. Specifically, the daily dose can be about 300 mg, such as about 250 mg, including about 200 mg, such as about 175 mg or about 150 mg, including about 100 mg, and including about 80 mg, about 75 mg, about 70 mg, about 60 mg, or about 50 mg.

[0175] All the above dosages are calculated as free C21. The dosage can be divided into multiple individual dosages per day. The dosage can be given between one and six times, such as four times a day, preferably three times a day, and more preferably twice a day.

[0176] The above dosages, particularly the above-mentioned higher level dosages, can also be considered as part of the "induction" phase of IPF treatment. In addition, after the practitioner or technician has determined that the induction phase has been successful, such as by causing a significant improvement / recovery of lung function or capacity as defined above, C21 or its salt can be subsequently administered with an appropriate dosage as part of the "maintenance" treatment of the disorder. Based on a daily appropriate maintenance dose can be within the above-mentioned lower range, such as up to about 150 mg, including up to about 100 mg, 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, or even less than this. Alternatively, an appropriate induction or maintenance dose can be administered on a less frequent basis, such as by a sustained-release oral dosage form, which produces a plasma concentration curve equivalent to the above-mentioned once-daily dose.

[0177] In any case, a medical practitioner or other technical staff will be able to routinely determine the actual dosage most suitable for an individual patient based on the severity of the condition and the route of administration. The above dosages are examples of general situations; of course, there may be individual situations where a higher or lower dosage range is required, and this is within the scope of the present invention.

[0178] In the context of the present invention, the dose administered to the patient should be sufficient to affect an appropriate response in the patient (as described above) within a reasonable time frame. 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 affected, among other things, by the pharmacological properties of the formulation, the nature, stage and / or severity of the condition being treated, the physical condition and mental acuity of the recipient, including the age, condition, weight, sex and response of the patient to be treated, and the stage / severity of the disease and genetic differences between patients.

[0179] With regard to the nature, stage, and severity of IPF, it is important to note that there is currently no universally accepted or validated staging system. There is a wealth of data available to assess disease severity in IPF using information obtained from physiological, radiological, and pathological parameters, either alone or in combination. Recently, there has been interest in using serum biomarkers and computed tomography-derived quantitative lung fibrosis measures to stage disease severity in IPF (see Robbie et al., Eur. Respir. Rev. 26, 17005 (2017). However, Lopes et al. (Clinics (Sao Paulo), 66, 1015 (2011) proposed an IPF classification system based on 95% confidence intervals of FVC, which is 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%); very severe (<24.3%). An alternative classification system for IPF based on FVC is as follows: mild (>80%); moderate (50%–80%); and severe (<50%).

[0180] The methods of the invention can be used to treat IPF, as well as conditions that may trigger 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.

[0181] Although the remarkable results described below may be at least partially attributed to the anti-fibrotic effects of C21 (e.g., characterized by reducing fibrosis and / or preventing further deposition of extracellular matrix, reversing these fibrotic phenomena, including lung scarring / wound healing, reduced proliferation of fibroblasts and myofibroblasts, vascular remodeling, etc.), it is worth noting that no corresponding effects are seen with existing anti-fibrotic IPF therapies (such as nintedanib and pirfenidone). Therefore, without being limited by theory, we do not believe that these completely unexpected results can be explained solely by the known anti-fibrotic effects of C21, and therefore, the exact mechanism behind them is currently unclear.

[0182] Although primarily used for therapeutic (including curative and / or restorative) treatment of lung function in IPF patients, C21 and its salts are also useful for palliative and / or diagnostic treatment of IPF (e.g. during diagnostic workup, if the condition is suspected), as well as preventive treatment (by which we include preventing and / or eliminating deterioration and / or exacerbation of the condition).

[0183] "Patient" includes mammalian (especially human) patients. Human patients include adult patients.

[0184] Although, as described above, it is preferred to use C21 as a first-line and / or stand-alone treatment for IPF, relevant active ingredients that can be used in combination therapy with C21 in the treatment of IPF include, for example, anti-fibrotic drugs (e.g., nintedanib and pirfenidone, and AP-01 / inhaled pirfenidone (Avalyn Pharma) and deuterium-substituted analogs of pirfenidone / LYT100 (PureTech); cough suppressants (e.g., benzoates, nalbuphine, or more specifically dextromethorphan or codeine), glucocorticoids (e.g., beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone); PRM-151 / pentaxin-2 (Genentech / Roche); connective tissue growth factor inhibitor penrelumab (FibroGen); galectin-3 inhibitor GB0139 (Galecto); c-Jun N-terminal kinase inhibitor CC-90001 (Celgene / Bristol Myers Squibb); phosphodiesterase 4b inhibitor BI1015550 (Boehringer Ingelheim); lidocaine; 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); inflammatory inhibitors, such as cyclophosphamide; other immunosuppressants, such as azathioprine and mycophenolate mofetil; and antioxidants, such as N-acetylcysteine;In addition to the HSP47 RNAi therapeutic ND-L02-s0201 / BMS-986263 (Nitto Denko / Bristol Meyers Squibb), the Hedgehog cell signaling pathway inhibitor ENV-101 / taladegib (Endeavor Biomedicines), the dual inhibitor of αVβ1 / αVβ6 PLN-74809 (Pliant Therapeutics), the dual inhibitor of NADPH oxidase isoforms NOX4 and NOX1 setanaxib / GKT137831 / GKT831 (Calliditas Therapeutics / Genkyotex), HEC585 (Sunshine LakePharma Co), and the galectin-3 inhibitor GB0139 / TD139 (Galecto Biotech), Src tyrosine kinase inhibitor saracutinib (AstraZeneca), humanized anti-FXIIa monoclonal antibody gadacitumab / CSL312 (CSLBehring), LPA1 receptor antagonists BMS-986278 (Bristol Myers Squibb) and HZN-825 (Horizon Therapeutics), autotaxin inhibitors cudetaxestat / BLD-0409 (Blade Therapeutics) and BBT-877 (Bridge Biotherapeutics), prolyl-tRNA synthetase inhibitor DWN12088 (Daewoong Pharmaceutical Co), monoclonal antibody targeting colony stimulating factor 1 receptor AMB-05X (AmMax Bio), IL-11 receptor blocking antibody LASN01 (Lassen Therapeutics), RNAi therapy to reduce MMP7 ARO-MMP7 (Arrowhead Pharmaceuticals), smad ubiquitin regulatory factor 1 inhibitor LTP001 (Novartis), talukast / MN-001 (MediciNova / Kyorin), ifenprodil / NP-120 (Algernon Pharmaceuticals), RG-6354 / PRM-151 / recombinant human pentraxin-2 (Roche / Promedior), and prostacyclin analog reprostinil (United Therapeutics). ;

[0185] Preferred drug treatments that may be used in combination therapy with C21 in treating IPF include anti-fibrotic drugs (eg, nintedanib and pirfenidone) and IMIDs (eg, lenalidomide, pomalidomide, and especially thalidomide).

[0186] Based on the administration of one or more of such active ingredients, the relevant patient may also (and / or may already be) receiving one or more of any of the above-mentioned treatments and / or other therapeutic agents for the relevant condition, by which we mean receiving one or more of those active ingredients mentioned herein in a prescribed dose before, in addition to and / or after treatment with C21 or a salt thereof.

[0187] Pharmaceutically acceptable salts and dosages of the above-mentioned other active ingredients include those known in the art and described in the medical literature for the drugs in question, such as Martindale - The Complete Drug Reference, 38th edition, Pharmaceutical Press, London (2014) and documents cited therein, the relevant disclosures of all of which are incorporated herein by reference.

[0188] According to two other aspects of the present invention, there are provided:

[0189] C21 or a pharmaceutically acceptable salt thereof, for use in any of the methods of the invention; and

[0190] ● Use of C21 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in any method of the present invention, which improves / restores the lung function of a patient suffering from IPF as described above, the treatment comprising orally administering a therapeutically effective amount of said C21 or a salt thereof to the patient in any manner as described above.

[0191] The uses / methods described herein may additionally have the following advantages: in the treatment of IPF, they may be more convenient for physicians and / or patients, more effective, less toxic, have a broader spectrum of activity, be more potent, produce fewer side effects, or it may have other more useful pharmacological properties, whether for use in this condition or in other situations, compared to similar methods (treatments) known in the prior art.

[0192] Wherever the word "about" is used herein, for example in the context of a number or amount, i.e., an absolute amount, such as the size (e.g., particle size, PSD or GSD), volume, dose, weight or concentration of a (e.g., active) ingredient, age, temperature, sample size or time period; or a relative amount, including percentages, standard deviations and variation measurements, such as an improvement in FVC measurement or an improvement in lung function measured in a different manner, or a physical / chemical transformation or API release level, it should be understood that these variables are approximate and, therefore, may differ from the actual number specified by ±10%, e.g., ±5%, and preferably ±2% (e.g., ±1%). In this regard, the term "about 10%" means, for example, ±10% with respect to the number 10, i.e., between 9% and 11%.

[0193] The present invention is illustrated by the following examples, but is in no way limited to the present invention, wherein Figure 1 Shown are mean changes in FVC over time (weeks) in IPF patients treated with 100 mg of C21 orally twice daily compared to the expected decline in FVC in an untreated IPF population.

[0194] Examples

[0195] Example 1

[0196] Dosage form

[0197] By weighing 21.4 g of colloidal silicon dioxide ( Evonik) into a weighing pan to prepare the excipient blend. Then weigh 2033.8 g of mannitol (Pearlitol 50C, Roquette) and pour about half of this amount into a 25 L V-shell of a V-blender (Multiblender, Pharmatech, UK). Then add the weighed amount of colloidal silicon dioxide to the V-shell, followed by the remaining mannitol. The resulting mixture is blended at 30 rpm for 10 minutes.

[0198] The excipient blend was then sieved through a 800 μm sieve and then further mixed at 30 rpm for 20 minutes.

[0199] Half of the resulting excipient blend was weighed and added back 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 at 30 rpm for 10 minutes.

[0200] The resulting blend was then sieved through an 800 μm sieve and subsequently blended at 30 rpm for 20 minutes.

[0201] After preparing the blend, the blend homogeneity was determined by weighing approximately 270 mg of the blend sample into a 100 mL volumetric flask, adding 40 mL of MilliQ water and sonicating for 20 minutes, adding 40 mL of methanol and sonicating for another 20 minutes. After equilibration to room temperature, 1.0 mL of the sample solution was added to a 10 mL volumetric flask. It was then diluted to the desired volume with methanol and mixed.

[0202] The sample was filtered through a 0.45 μm PTFE membrane syringe filter and the first 3 mL of filtrate was discarded. The amount of C21 sodium salt was determined by UHPLC. The resulting solution should contain 0.1 mg / mL of C21 Na salt (for a nominal sample concentration of 100%). The results are shown in Table 1 below.

[0203] Table 1

[0204] sample Determination (%, lc) 1 100.3 2 102.1 3 104.1 4 100.9 5 98.7 6 99.3 average value 100.9 RSD 1.9

[0205] Thereafter, 26.1 g of magnesium stearate (Ligamed MF-2-V, Peter Greven, Germany) was sieved through a 800 μm sieve and added to the blend, followed by final blending for 15 minutes at 15 rpm. The final composition is listed in Table 2 below.

[0206] Table 2

[0207]

[0208] Approximately 6,700 capsules were encapsulated using a MG Compact (MG2, Bologna, Italy) with doser size 0, where the following settings were applied: chamber - 11 mm; compression - 0 mm; powder layer: 30.0 mm.

[0209] A tolerance limit of 5% was applied to the net fill weight of the capsules for weight classification and was found to be 18.6%.After encapsulation, the capsules were manually primary packed in 100 mL high density polyethylene (HDPE) cans with child resistant tamper-evident caps containing desiccant (56 capsules / can).

[0210] Such capsules may also be enteric coated.

[0211] The above process was subsequently scaled up so that a total of 2000 cans were produced and labeled for use in the clinical trial described in Example 2 below.

[0212] Example 2

[0213] Clinical trial evaluating the safety and efficacy of C21 in patients with IPF

[0214] We report below the results obtained from an ongoing phase II, multicenter, open-label, single-group trial investigating the safety, efficacy, and pharmacokinetics of C21 in subjects with IPF.

[0215] The research is being conducted at multiple sites in India, Russia, Ukraine and the United Kingdom (UK).

[0216] The primary objective of the study is to investigate the safety of oral administration of C21 200mg daily dose (100mg twice daily) in subjects with IPF. Secondary objectives are to evaluate the effect of the same daily dose of C21 on lung function decline and the pharmacokinetics of C21. Exploratory objectives include studying a series of laboratory parameters as potential biomarkers of inflammation and fibrosis.

[0217] The primary endpoint of the trial was the nature and frequency of adverse events occurring during the trial.

[0218] Secondary endpoints included changes from baseline in:

[0219] ● FVC (defined as the maximum amount of air that can be forced to expire from the lungs after a complete inhalation) at Weeks 12, 24, and 36; ● C21 plasma concentrations and derived PK parameters assessed in subgroups of subjects.

[0220] Blood samples have been stored for possible future analysis of biomarkers reflecting inflammation and lung damage.

[0221] Initially, the aim was to conduct the trial in 60 patients who had not received prior antifibrotic therapy for IPF, but as the trial 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 (refer to Exclusion Criterion 18 listed below).

[0222] Prior to enrollment in the trial, IPF patients have been (and will continue to be) assessed for eligibility during the Screening Visit (Visit 1) and Baseline Visit (Visit 2). During the eligibility assessment, patients have been (and will continue to be) checked to see if they meet all inclusion criteria and do not meet any exclusion criteria.

[0223] Eligible patients have been and will be enrolled to receive daily treatment with 200 mg of C21 for up to 36 weeks (100 mg twice daily).

[0224] Inclusion criteria included the following:

[0225] 1) Obtain written informed consent in compliance with ICH GCP R2 and local laws before any trial-related procedures are initiated.

[0226] 2) IPF diagnosed within 5 years before visit 1 according to the ATS / ERS / JRS / ATLAT / Fleischner guidelines.

[0227] 3) Age ≥ 40 years old.

[0228] 4) FVC ≥ 60% predicted at visits 1 and 2 (UK specific: FVC predicted at visits 1 and 2 for subjects previously treated with antifibrotic drugs such as nintedanib and / or pirfenidone or who refused such treatment

[0229] ≥80% or predicted FVC>60% at visits 1 and 2).

[0230] 5) FEV1 / FVC ratio at visit 1 and 2 > 0.7 before bronchodilator.

[0231] 6) Blood oxygen saturation (SpO2) > 85% as measured by pulse oximetry while at rest and breathing ambient air at visit 1.

[0232] 7) High-resolution computed tomography (HRCT) within 36 months before visit 1 with central reading showing a or b, and c:

[0233] a. According to the ATS / ERS / JRS / ALAT or Fleischner guidelines, the pattern is consistent with common interstitial pneumonia (UIP) (Raghu et al., Am J Respir Crit Care Med, 198, e44 (2018); Lynch et al., Lancet Respir Med, 6, 138 (2018)):

[0234] i. UIP; or

[0235] ii. Possible UIP.

[0236] b. Uncertain pattern of UIP based on ATS / ERS / JRS / ALAT or Fleischner guidelines (see above) and historical biopsies consistent with IPF.

[0237] c. The degree of fibrosis > the degree of emphysema.

[0238] 8) Fully vaccinated against COVID-19 before screening (Visit 1). According to local labels, subjects are considered fully vaccinated against COVID-19 ≥14 days after receiving a vaccination dose.

[0239] Initial exclusion criteria included one or more of the following:

[0240] 1) Previous use of anti-fibrotic drugs to treat interstitial lung disease (such as nintedanib or pirfenidone) for more than 6 months.

[0241] 2) Smoking (including e-cigarettes) within 6 months before visit 1.

[0242] 3) Body mass index (BMI) > 35 or < 18.

[0243] 4) IPF exacerbation within 3 months before visit 1 (as defined by Collard et al., Am J Respir Crit Care Med, 194, 265 (2016)), defined as follows:

[0244] ●Acute worsening or development of dyspnea usually lasting < 1 month;

[0245] ●Computed tomography with new bilateral ground-glass opacities and / or consolidation superimposed on a background pattern consistent with the usual pattern of interstitial pneumonia (the qualifier "new" can be deleted if no prior computed tomography is available); or

[0246] ●Deterioration cannot be fully explained by heart failure or fluid overload.

[0247] 5) Concurrent serious medical conditions, with particular attention to cardiac or ocular conditions (e.g., contraindications to cataract surgery), or moderate to severe liver impairment, which the investigator considers makes the subject unsuitable for this trial.

[0248] 6) Malignant tumors within the past 5 years, except for excisional basal cell carcinoma in situ and cervical intraepithelial neoplasia grade I.

[0249] 7) Treatment with any of the following medications within 4 weeks prior to visit 1:

[0250] ●Strong CYP3A4 inducers (eg, rifampin, phenytoin, St. John's wort);

[0251] ●Strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole, nefazodone, itraconazole, ritonavir);

[0252] ●Drugs that are substrates of CYP1A2, CYP3A4, or CYP2C9 with a narrow therapeutic range;

[0253] ●Experimental drugs;

[0254] Antifibrotic therapy; and

[0255] Any systemic immunosuppressive therapy except:

[0256] ○ Inhaled corticosteroids, which can be used throughout the trial as long as the dose remains stable;

[0257] ○ Corticosteroids for the treatment of an acute exacerbation; or

[0258] ○Continue with a stable daily dose < 15 mg prednisolone or equivalent.

[0259] 8) Treatment with any of the following medications within 2 weeks prior to visit 1:

[0260] ○ Proton pump inhibitors (PPI) more than once a day;

[0261] ○Histamine H2 receptor antagonist (H2Ras);

[0262] o Sulfasalazine and rosuvastatin; and

[0263] ○ High-dose breast cancer resistance protein-sensitive substrates (except sulfasalazine or rosuvastatin).

[0264] 9) Any of the following findings at Visit 1:

[0265] ○ QTcF prolongation (Fridericia-corrected QT interval) (>450ms), clinically significant arrhythmia, or any other clinically significant abnormality in the resting electrocardiogram (ECG) as judged by the investigator;

[0266] ○ AST or ALT elevation > 3 times the upper limit of normal (ULN), or bilirubin > 1.5 times ULN;

[0267] ○ Positive results for hepatitis B surface antigen (HbsAg), hepatitis C virus antibody (HCVAb), or human immunodeficiency virus 1+2 antigen / antibody (HIV 1+2Ag / Ab); and

[0268] ○ Positive serum pregnancy test (minimum sensitivity 25 IU / L or equivalent units of human chorionic gonadotropin [HCG]).

[0269] 10) Failure to generate a baseline questionnaire that complies with the ATS / ERS 2005 guidelines (Miller et al., Eur Respir J, 26, 319) at visit 1

[0270] (2005)) were used to determine the minimum standard of lung function data, as determined by central review.

[0271] 11) Clinically significant abnormal laboratory values ​​at Visit 1 indicating that the subject would be at potential risk if enrolled in the trial as assessed by the investigator.

[0272] 12) Pregnant or lactating female subjects.

[0273] 13) Female subjects of childbearing potential are unwilling to use contraceptive methods.

[0274] 14) Male subjects are unwilling to use contraceptive methods.

[0275] 15) The subject is unwilling to adhere to the dietary restrictions during the trial.

[0276] 16) Participating in any other interventional trials during the trial period.

[0277] 17) Subjects who are known or suspected to be unable to comply with the trial protocol (e.g. due to alcoholism, drug dependence, or psychological disorders). 18) Subjects who have stopped or changed previous anti-fibrotic drug treatment (e.g., nintedanib or pirfenidone) due to disease progression.

[0278] At the end of each 12-week treatment period, the investigator will conduct a medical evaluation and decide whether the subject can continue into the next 12-week treatment period. This decision is based on:

[0279] ●No immediate need for other antifibrotic drugs; and

[0280] ● Positive risk / reward balance

[0281] Failure to pass the medical evaluation will result in the subject's withdrawal from the trial.

[0282] Establish criteria for exiting the trial if any of the following occurs:

[0283] ●Two consecutive predicted FVC values ​​decreased by >10% from baseline and predicted FVC <60% (UK specific:

[0284] Predicted FVC <80%; or for subjects previously treated with nintedanib and / or pirfenidone or who refused such treatment, predicted FVC <60%);

[0285] ● Two consecutive decreases in predicted FVC values ​​from baseline of 5%-10% and worsening of respiratory symptoms with predicted FVC <60% (UK specific: predicted FVC <80%; or predicted FVC <60% for subjects previously treated with nintedanib and / or pirfenidone or who refused such treatment);

[0286] ●Consistent noncompliance with dietary requirements, according to the researchers;

[0287] ● The researcher believes that it is necessary for medical reasons;

[0288] ●Failure to pass the medical evaluation after each 12-week treatment period;

[0289] ● The subject wishes to withdraw for any reason; or

[0290] ●Pregnancy.

[0291] C21 in sodium salt form has been delivered as 50 mg capsules obtained according to Example 1 above.

[0292] The capsules have been packaged into plastic container units, with 56 capsules in each unit. Each unit contains C21 or a matching placebo (same composition except that C21 has been replaced by mannitol).

[0293] At the trial site, C21 is stored separately from general clinic inventory in a secure locked area accessible only to authorized trial personnel. C21 is labeled in the relevant local language (English) in compliance with GMP and local regulatory requirements.

[0294] Subjects were administered C21 twice daily for 36 weeks as follows:

[0295] Morning dose: two 50 mg capsules (100 mg C21 or placebo) with a glass of water after fasting for at least 2 hours; and

[0296] ●Afternoon / evening dose: Take two 50 mg capsules (100 mg C21 or placebo) with a glass of water after fasting for at least 2 hours.

[0297] Subjects were asked not to eat anything within 1 hour after taking the study drug.

[0298] Clinical centers in India, Russia, Ukraine, and the UK have been asked to follow the clinical trial protocol. Deviations from the protocol are recorded as protocol deviations.

[0299] All such data collected from enrolled patients on the safety and efficacy of C21, whether considered individually or as part of a cohort, have been confirmed to be valid following analysis of the results reported below and documented protocol deviations.

[0300] result

[0301] A total of 21 subjects diagnosed with IPF (as confirmed by high-resolution computed tomography central readout) were included in the interim analysis described below, of which 13, 9, and 7 patients had reached 12, 24, and 36 weeks of C21 treatment, respectively.

[0302] Patients were enrolled and received C21 (100 mg twice daily) for 36 weeks. The age and sex of the treated and evaluable subjects were characterized for patients with IPF.

[0303] like Figure 1As shown in (observed data), after initial stabilization of FVC, mean FVC increased by +250 mL at 24 weeks (solid line with circles), compared with the expected mean decrease of −120 mL (dashed line) over 24 weeks in untreated patients (based on several previously published IPF trials), a difference of +371 mL.

[0304] At week 36, the mean FVC increased by +750 mL (solid line with circles), a striking difference of +930 mL compared to the expected mean decrease of -180 mL over 36 weeks in untreated patients (dashed line). The slope values ​​(analysis of changes in FVC scaled to 24 weeks based on visit, observed cases) at week 28 (p=0.012), week 32 (p=0.032), and week 36 (p=0.016) were statistically significant compared to the expected mean for untreated patients. Later in the study, an interim analysis of data obtained from existing patients and patients enrolled later in the study was performed. At the time of the analysis, data were available from a total of 45 patients, of whom 23, 13, and 10 had reached 12, 24, and 36 weeks of C21 treatment, respectively. Demographics remain characteristic of the IPF population.

[0305] Updated results showed that the disease had stabilized at Week 6 and confirmed increases over time. At Week 24, the mean FVC increased by +210 mL (a difference of +330 mL compared to the expected decrease in FVC in the untreated population). At Week 36, the mean FVC increased by +630 mL, a significant difference of +810 mL compared to the expected decrease in FVC.

[0306] There were no relevant serious adverse events, no gastrointestinal signals, and overall, no safety issues. There have been two deaths in the ongoing trial, neither of which was reported to be related to C21.

Claims

1. N-butoxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof, for use in a method for improving lung function in a patient with idiopathic pulmonary fibrosis, the method comprising orally administering to the patient a therapeutically effective amount of N-butoxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof.

2. The compound for use according to claim 1, wherein said use comprises restorative, therapeutic, curative and / or non-disease-delaying treatment of said idiopathic pulmonary fibrosis.

3. A compound for use according to claim 1 or claim 2, wherein said use results in at least partial restoration of lung function compared to the corresponding lung function of the patient before said administration of N-butoxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide or a salt thereof.

4. The compound for use according to any one of the preceding claims, wherein the administration of N-butoxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide or a salt thereof is performed in the absence of co-therapy with anti-fibrotic drugs.

5. A compound for use according to any one of the preceding claims, wherein the improvement in lung function results in one or more of the following groups in the patient: improved breathing, improved or restored lung ventilation, improved or restored ventilation lung function and increased or restored vital capacity.

6. Compound for use according to any one of the preceding claims, wherein the improvement in lung function results in the prevention of acute exacerbations of idiopathic pulmonary fibrosis.

7. A compound for use according to any one of the preceding claims, wherein the improvement in lung function occurs in the substantial absence of drug-related adverse events.

8. A compound for use according to any one of the preceding claims, wherein the N-butoxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof is provided in a dosage form comprising a tablet or a capsule.

9. A compound for use according to any one of the preceding claims, wherein the dosage form comprises N-butoxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof in the form of a powder mixture, wherein it is homogeneously distributed within the carrier material and / or other excipients used.

10. A compound for use according to any preceding claim, wherein the dosage form comprises an enteric coating.

11. The compound for use according to claim 10, wherein the material used for the enteric coating is polyvinyl acetate phthalate or methacrylic acid copolymer.

12. A compound for use according to any one of the preceding claims, wherein the dosage form is substantially free of water.

13. A compound for use according to any one of the preceding claims, wherein the daily dose of N-butoxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof is between about 50 mg and about 300 mg (calculated as the amount of free N-butoxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide in the dosage form.

14. A compound for use according to any one of the preceding claims, wherein the method comprises administration to a patient in a fasting state.

15. The compound for use according to claim 14, wherein the dosage form is administered 2 hours after consumption of food and / or within about 60 minutes after consumption of such food.

16. A compound for use according to any one of the preceding claims, wherein the pharmaceutically acceptable salt of N-butoxycarbonyl-3-(4-imidazol-1-ylmethyl-phenyl)-5-isobutylthiophene-2-sulfonamide is the sodium salt.

17. Use of N-butoxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in a method of improving lung function in a patient as defined in any one of claims 1 to 16 or as otherwise defined or described herein.

18. A method of improving lung function in a patient as defined in any one of claims 1 to 16 or otherwise as defined or described herein, comprising orally administering to the patient a therapeutically effective amount of N-butoxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof.

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