Novel dry powder composition for oral administration

Abstract

This invention provides a pharmaceutical dosage form suitable for oral administration into the gastrointestinal tract of N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide (C21) for the treatment of lung diseases such as interstitial pneumonia. [Solution] The dosage form of the present invention comprises a pharmaceutical composition in the form of a particulate mixture, the particulate mixture comprising solid particles of C21 or a pharmaceutically acceptable salt thereof, mixed with a blend of a flow enhancer and carrier particles having a weight and / or volume-based average diameter and / or structure / particle density similar to that of the weight and / or volume-based average diameter and / or structure / particle density of the C21 solid particles, the composition being contained within a capsule suitable for such oral administration. Preferred carrier particles have a weight and / or volume-based average diameter of less than about 100 μm. Preferred carrier particle materials include mannitol.

Description

[Technical Field]

[0001] The present invention relates to new pharmaceutical dosage forms, their use as pharmaceuticals, and in particular, their administration for the treatment of lung diseases, such as interstitial lung disease. [Background technology]

[0002] Interstitial lung disease (ILD) is a group of lung diseases that affect the interstitium, characterized by scarring and / or thickening of the tissue surrounding the alveoli, which inhibits the respiratory process.

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

[0004] The most common intrapulmonary diseases (ILDs) are idiopathic pulmonary fibrosis (IPF) and sarcoidosis, both of which are characterized by chronic inflammation and decreased lung function.

[0005] Sarcoidosis is a disease of unknown cause characterized by clusters of inflammatory cells that form lumps (granulomas), often beginning in the lungs (as well as the skin and / or lymph nodes, but any organ can be affected). When sarcoidosis affects the lungs, symptoms include cough, wheezing, shortness of breath, and / or chest pain.

[0006] Treatment for sarcoidosis varies from patient to patient. In most cases, symptomatic treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) is possible, but patients with pulmonary symptoms often receive glucocorticoids (e.g., prednisone or prednisolone), antimetabolites, and / or monoclonal antitumor necrosis factor antibodies.

[0007] IPF is a lung disease of unknown cause, affecting approximately 5 million people worldwide. Although rare, there are no treatment options other than lung transplantation. As a result, it leads to chronic, irreversible, and progressive decline in lung function, and in most cases, death occurs within 2 to 5 years (median survival time 2.5 to 3.5 years). The overall prognosis for IPF is poor, but it is difficult to predict the rate of progression in individual patients. Risk factors for IPF include age, sex (male or female), genetic predisposition, and smoking history. The annual incidence is 5 to 16 cases per 100,000 people, with a prevalence of 13 to 20 cases per 100,000 people, which increases dramatically with age (King Jr TE et al., Lancet (2011); 378, 1949-1961; Noble PW et al., J. Clin. Invest. (2012) 122, 2756-2762). IPF is confined to the lungs and is refractory to immune system-targeted therapies, differentiating it from pulmonary fibrosis (PF) associated with systemic diseases.

[0008] Patients with IPF typically seek medical help for chronic and progressive exertional dyspnea and cough. Lung imaging classically reveals traction bronchiectasis, thickened interlobar septum, and subpleural honeycomb lung. If all three findings are present and there is no evidence of systemic connective tissue disease or environmental exposure, the likelihood of diagnosing IPF is very high. A definitive diagnosis is usually made by lung biopsy and requires an interdisciplinary team of experts, including pulmonologists, radiologists, and pathologists with experience in ILD.

[0009] IPF presents with a variety of phenotypes and varying prognoses, defined as mild, moderate, and severe. Mild cases follow a stable or slowly progressive path, and patients may take several years to seek medical advice. Accelerated IPF progresses much more rapidly, with shorter survival times, and affects a subgroup of patients, typically male smokers. Acute exacerbations of IPF are defined as a rapid deterioration of the disease, and patients in this subgroup exhibit very poor outcomes with high mortality in the short term. The cause of IPF is unknown, but it appears to be a disease likely caused by the interaction of environmental and genetic factors, leading to unrelenting tissue remodeling by fibroblasts rather than normal repair, and is pathogenesis primarily fibrotic rather than inflammatory. There is growing evidence suggesting that the disease is initiated by microinjury and apoptosis of alveolar epithelial cells, attracting stem cells or progenitor cells that activate adjacent epithelial cells and produce factors involved in the expansion of fibroblast and myofibroblast populations in a tumor-like manner. Lesions of fibroblasts secrete excessive amounts of extracellular matrix, which destroys the lung parenchyma and ultimately leads to loss of lung function.

[0010] The average annual decline in lung function (vital capacity) is in the range of 0.13 to 0.21 liters. Symptoms precede diagnosis by 1 to 2 years, and X-ray signs may precede symptoms ((Ley B et al., Am.J.Respir.Crit.Care Med.(2011);183,431-440).

[0011] Many therapeutic approaches, including anti-inflammatory drugs, immunomodulators, cytotoxic drugs, common antifibrotic drugs, antioxidants, anticoagulants, antichemokines, anti-angiogenic drugs, as well as RAS blockers, endothelin antagonists, and sildenafil, have been tested in preclinical models and clinical trials, and have generally shown to provide limited or no benefit ((Rafii R et al., J. Thorac. Dis. (2013); 5, 48-73).

[0012] Current treatments for IPF include oxygen supplementation. Medications used include pirfenidone or nintedanib, but these have only shown limited success in slowing disease progression. Furthermore, both of these drugs commonly cause side effects (primarily gastrointestinal).

[0013] All of the aforementioned drug treatments for ILD (and IPF) have drawbacks, and there is a real clinical need for safer and / or more effective treatments.

[0014] Because restoring alveolar epithelium is highly desirable as a therapeutic effect for IPF, stem cell therapy is also being investigated. Several preclinical studies have shown promise in the use of pluripotent stem cells that can differentiate into lung epithelial and endothelial cells, thereby repairing lung damage and fibrosis.

[0015] Currently, lung transplantation is the only intervention that significantly improves the survival rate of IPF patients. However, complications such as infection and graft rejection are not uncommon.

[0016] Therefore, the development of new treatment strategies for IPF is crucial. Thus, the fundamental challenge for the future is to develop appropriate therapeutic approaches that can reverse or halt disease progression.

[0017] The renin-angiotensin system (RAS) is a crucial regulator of blood pressure homeostasis. Renin, a protease, cleaves its only known substrate (angiotensinogen) to form angiotensin I (AngI), which then acts as a substrate for angiotensin-converting enzyme (ACE) to form AngII. The endogenous hormone AngII is converted into a linear octapeptide (Asp). 1 -Arg 2 -Val 3 -Tyr 4 -lle 5 -His 6 -Pro 7 -Phe 8 It is an active ingredient in the renin-angiotensin system (RAS).

[0018] The angiotensin II type 1 (AT1) receptor is expressed in most organs and is thought to be the cause of most of the pathological effects of AngII. The safety and efficacy of losartan (an AT1 receptor inhibitor) were recently investigated in a small, non-blinded pilot trial regarding IPF (www.clinicaltrials.gov identifier NCT00879879).

[0019] Some studies in adults appear to show that the activation of the angiotensin II (AT2) type 1 receptor has an effect opposite to that mediated by the AT1 receptor in the regulation of the response after angiotensin II receptor stimulation.

[0020] 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).

[0021] AT2 receptor agonists have also been shown to be potentially useful in the treatment and / or prevention of gastrointestinal diseases such as dyspepsia and irritable bowel syndrome, as well as multiple organ failure (see International Patent Application No. 99 / 43339).

[0022] The expected pharmacological effects of AT2 receptor agonism are generally described in de Gasparo M et al. (cited above). It is not mentioned that AT2 receptor agonism can be used in the treatment of IPF.

[0023] International Patent Application No. 2002 / 096883 describes the preparation of imidazolyl, triazolyl, and tetrazolyl thiophene sulfonamides and derivatives as AT2 receptor agonists. Among the compounds described in that document (as Example 1), N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide (Compound 21, or "C21" as used hereinafter) was selected for clinical development from a group of about 20 related analogs as a selective AT2 receptor agonist. C21 is currently in clinical development for the treatment of AT2 receptor-related diseases where treatment with an AT2 receptor agonist is considered beneficial, including IPF (see, for example, International Patent Application No. 2016 / 139475).

[0024] The formulation work carried out on C21 and its salts has proven to be very difficult. Part of the problem is the previously unreported extreme sensitivity of C21 and its salts to the combined presence of light and water. Furthermore, attempts to provide a stable solid-state formulation have resulted in blends with conventional excipients that are chemically unstable, even in the dry state. This information has not been generally publicly available until now.

[0025] As a result, C21 has previously been formulated as an aqueous solution, which is frozen during storage and then thawed immediately prior to oral administration. Protecting C21 in this way from photo-catalyzed aqueous degradation presents logistical problems, given the transportation of pharmaceuticals around the world. Even if not a requirement for a commercially viable product, a more stable, pharmaceutically acceptable composition is highly desirable.

[0026] The applicant has studied this active ingredient for nearly 20 years, but until recently, a pharmaceutically acceptable dosage form in which the active ingredient is stable when stored at ambient temperature could not be obtained in a reproducible manner.

[0027] In attempting to prepare such improved oral capsule-based dosage forms, the applicant found that the above problems could be solved by dry blending with specific combinations of excipients in a specific manner, as described below. [Overview of the project]

[0028] According to a first aspect of the present invention, a pharmaceutical dosage form suitable for oral administration to the gastrointestinal tract is provided, wherein the dosage form comprises a pharmaceutical composition in the form of a particulate mixture, the particulate mixture comprising solid particles of C21 or a pharmaceutically acceptable salt thereof mixed with a blend of carrier particles having an average diameter and / or structural (particle) density on a weight and / or volume basis, similar to the weight and / or volume basis diameter and / or structural (particle) density of each of the solid particles of C21 or a pharmaceutically acceptable salt thereof, and a flow enhancer, the composition being contained within a capsule suitable for such oral administration. Such dosage forms are collectively referred to below as "the dosage forms of the present invention."

[0029] The dosage forms of the present invention are suitable for oral administration and delivery as a complete dosage form into the gastrointestinal tract. This means that the dosage forms of the present invention are suitable for swallowing as a whole and are a complete dosage form for subsequent consumption and / or ingestion in the gastrointestinal tract, and are swallowed during use and subsequently consumed and / or ingested in the gastrointestinal tract.

[0030] Appropriate pharmaceutically acceptable capsules include, for example, soft-shell or hard-shell capsules that can be made by standard capsule filling processes from gelatin, cellulose polymers such as hydroxypropyl methylcellulose (HPMC or hypromellose), hypromellose acetate succinate (HPMCAS), starch polymers, pullulan, or other suitable materials.

[0031] However, it is preferable that the capsule is a hard-shell two-piece capsule, for example, made from gelatin or more preferably HPMC, and supplied as a closed half that can be separated, filled with particulate matter, and then reassembled. Such capsules can be of any size (e.g., 00 to 5), but preferred capsule sizes are size 2, size 1, or more preferably size 0.

[0032] As described above, it is even more preferable that the pharmaceutical composition of the dosage form of the present invention contained within the capsule is manufactured and / or stored in a manner that keeps it essentially water-free.

[0033] "Essentially water-free" means that both the particles of C21 or its salt, and the particles of the essential excipients to which they are mixed, are prepared and / or supplied in a manner in which they are essentially dry, and appropriate precautions are taken to ensure that they are mixed together in an environment in which they are also kept essentially dry to form a dry mixture.

[0034] "Essentially dry" or "essentially water-free" means that the composition containing C21 / salt and essential excipients contains, in whole, about 5% or less (including about 2% or less), and about 1% or less (including about 0.5% or less), such as about 0.1% or less water.

[0035] A composition of the dosage form of the present invention, comprising C21 or a salt thereof and the essential excipients defined above, once prepared, can then be filled into capsules. Given the fact that it is preferable that such compositions be prepared in an essentially water-free state, such filling is also preferably carried out in a manner that it is maintained in that state.

[0036] In this regard, while pharmaceutically acceptable capsule materials may contain residual amounts of water, the penetration of water from the capsule material into the composition should be minimized to protect highly sensitive C21 or its salts from contact with water and therefore from degradation in the presence of light.

[0037] However, it is preferable (though not necessarily required) to package the dosage form of the present invention in a manner that keeps the dosage form itself dry and protects it from light. This may include airtight packaging or the use of hygroscopic materials.

[0038] C21 or a salt thereof is presented in the form of particles, which may be amorphous, crystalline, or a mixture of the two. Preferred particles are of a size that does not result in separation, either during the formation of the composition to be filled into the capsule during the capsule filling process or during storage.

[0039] In this regard, C21 or its salts can be provided in multiple forms of particles, typically with a primary (i.e., non-aggregated) average diameter by weight and / or volume of about 1,000 μm or less, 500 μm (including about 250 μm), preferably about 100 μm or less, about 50 μm or less, for example, about 20 μm, or about 10 μm or less. There is no lower limit to the particle size that can be used according to the present invention, but for ease of production, the primary particles of C21 or its salts are preferably about 1 μm or more, with an average diameter by weight and / or volume including, for example, about 2 μm and about 3 μm.

[0040] As used herein, the term "weight-based mean diameter" is understood by those skilled in the art to include that the average particle size is characterized and defined from a particle size distribution by weight, i.e., the existing fraction (relative amount) in each size class, as a weight fraction obtained, for example, by sieving (e.g., wet sieving). The term "volume-based mean diameter" is similar in meaning to the weight-based mean diameter, but the average particle size is characterized and defined from a particle size distribution by volume, i.e., the existing fraction (relative amount) in each size class, as a volume fraction measured, for example, by laser diffraction. The particle size can be measured with standard devices such as dry particle size measurement techniques including dry dispersion techniques available from manufacturers such as Sympatec GmbH (Clausthal-Zellerfeld, Germany). For example, the particle size can be measured using other devices well known in the art, such as those sold by Malvern Instruments, Ltd. (Worcestershire, UK), Shimadzu (Kyoto, Japan), and (Elzone, Micromeritics (USA, electrical sensing zone method)).

[0041] Particles having a weight- and / or volume-based mean diameter within the above limitations include the average diameter of the particles when prepared and before mixing with the essential excipients according to the invention and / or before filling into capsules. It will be understood that some aggregation of the primary particles to form secondary particles can occur during handling and / or processing of the active ingredient. Nevertheless, this should be minimized.

[0042] C21 or a salt thereof also includes a mass median diameter (D 50 ; logarithmic normal mass median diameter), measured by standard techniques and parameters recognized in the art, and including the average particle size by mass and / or the diameter at which 50% of the mass in the cumulative PSD) and / or geometric standard deviation (formula D 84.13 / D 50 or D50 / D 15.78 GSD or σ measured by g Here D 84.13 and D 15.78 These are the diameters that contain 84.13% and 15.78% of the mass, respectively, D 50 As mentioned above, particles can be provided in the form of particles having a relatively narrow particle size distribution (PSD). Such parameters can be measured and calculated in-process using any suitable sampling method and particle sizing technique as described above.

[0043] In this regard, C21 or its salts are preferably PSDs with a GSD of less than 4, such as less than 3.

[0044] Primary particles of C21 or its salts can be prepared by appropriate techniques such as precipitation, cleavage (e.g., by dissolution in a supercritical fluid under pressure followed by rapid expansion), and spray drying, or, where appropriate, can be pulverized by techniques well known to those skilled in the art, such as grinding, dry grinding, jet grinding, wet grinding and / or crushing.

[0045] The particles may also be sieved to separate them into fractions of a desired size, and / or to break down aggregates, and / or to remove fine matter. In any case, unused smaller (fine) and larger materials may be reprocessed to avoid waste. Alternatively, the particles may be separated to the appropriate particle size using cyclone separation by air classification, sedimentation, force field fractionation, and / or elutriation.

[0046] While C21 or a salt thereof may be selected and / or provided with the aforementioned average diameter, particle size, PSD and / or GSD based on weight or volume using one or more of the above techniques, one of the main advantages of formulating a composition to be filled into capsules to form the dosage form of the present invention is that C21 or a salt thereof does not require the above particle processing techniques before being blended with essential excipients.

[0047] As previously mentioned, we found that C21 and its salts are very difficult materials to handle. In particular, and as will be explained below, compatibility studies have revealed that certain standard excipients, when co-mixed with C21 and its salts, cause significant chemical instability of the active ingredient. Furthermore, C21 and its salts form as needle-shaped crystals that are sticky and tend to aggregate. This means that dry mixing with other standard pharmaceutically acceptable ingredients is very difficult, and it is not easy to produce blends with uniform pharmaceutically acceptable content of the active ingredient and / or uniformity of the same dose within a capsule.

[0048] Furthermore, as described below, pulverizing the primary particles of the active ingredient also proved to be ineffective, as those skilled in the art might have anticipated, and it was found to introduce additional problems related to localized heating and static electricity.

[0049] However, we have found that by blending C21 or a pharmaceutically acceptable salt thereof with a pre-mixed blend of (a) carrier particles having an average diameter on a weight and / or volume basis that is approximately the same size as the C21 / salt particles, and (b) a flow enhancer, it is possible to avoid the aforementioned problems and provide a composition for filling capsules that not only ensures the homogeneous and uniform distribution of C21 or its salt, and the dose homogeneity of the active ingredient between such filled capsules, but is also physically and chemically stable during and / or after manufacturing, under normal storage conditions, and / or during use.

[0050] In the context of this invention, the terms “homogeneous” and “homogeneously 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 multiple samples (e.g., at least 2, more preferably about 6, e.g., about 10 to as needed about 30 or more) are taken from a mixture containing the active ingredient and carrier blend, the measured content of the active ingredient present among such samples will result in a standard deviation (i.e., coefficient of variation and / or relative standard deviation) from the average amount of less than about 8%, e.g., less than about 6%, e.g., less than about 5%, particularly less than about 4%, e.g., less than about 3%, and preferably less than about 2%.

[0051] Accordingly, according to the present invention, C21 or a pharmaceutically acceptable salt thereof may be prepared and stored in the form of a composition that can be directly filled into capsules to produce the dosage forms of the present invention, and furthermore, once prepared, the dosage forms of the present invention may be stored over time under normal storage conditions, with only slight changes in the physicochemical properties of the composition mixture contained therein, and / or most importantly, the active ingredient.

[0052] Therefore, “a slight change in physicochemical properties” means that, before and after being filled into capsules (i.e., in the form of the dosage form of the present invention), the composition containing the C21 / salt mixed with the essential excipients as described above possesses both physical and chemical stability.

[0053] "Chemical stability" means that the dry mixture composition comprising the C21 / salt and essential excipients of the present invention, as well as the dosage forms of the present invention, can be stored under normal storage conditions (with or without appropriate pharmaceutical packaging) with only slight chemical degradation or decomposition of the dosage forms, the dry mixture contained herein, and especially the active ingredients.

[0054] "Physical stability" means that the dry mixture composition comprising the C21 / salt and essential excipients of the present invention, and the dosage form of the present invention, can be stored under normal storage conditions with changes in properties and / or integrity, including slight physical transformations such as aggregation, separation or segregation, and / or solid-phase transitions, of the dosage form of the present invention, the dry mixture contained therein, and in particular the active ingredient (with or without appropriate pharmaceutical packaging).

[0055] Examples of “normal storage conditions” include a temperature of -80 to +50°C (preferably 0 to 40°C, more preferably ambient temperature, e.g., 15 to 30°C), a pressure of 0.1 to 2 bar (preferably atmospheric pressure), a relative humidity of 5 to 95% (preferably 10 to 60%), and / or prolonged exposure (i.e., more than 6 months) to 460 lux of UV / visible light.

[0056] Under such conditions, C21, its salts, and / or dry mixed compositions containing them may be found to be physically and / or chemically converted as defined above to less than about 15%, more preferably less than about 10%, and especially less than about 5%. Those skilled in the art will understand that the above upper and lower limits of temperature and pressure represent extremes of normal storage conditions, and that certain combinations of these extremes are not experienced during normal storage (e.g., 50°C and 0.1 bar pressure).

[0057] Essential excipients to be mixed with C21 particles or a pharmaceutically acceptable salt thereof include a blend of carrier particles having an average diameter on a weight and / or volume basis approximately the same as that of the C21 / salt particles, and a flow enhancer.

[0058] Suitable carrier particle materials may include carbohydrates, such as sugars like lactose, and water-soluble pharmaceutically acceptable substances such as sugar alcohols like mannitol, sorbitol, and xylitol, or pharmaceutically acceptable inorganic salts such as sodium chloride. Alternatively, the carrier particles may include water-insoluble or sparingly soluble pharmaceutically acceptable substances such as microcrystalline cellulose, dicalcium phosphate dihydrate, tricalcium phosphate, calcium carbonate, and barium sulfate, starch, and pregelatinized starch. Preferred carrier particle materials include carbohydrates containing sorbitol, xylitol, and, in particular, sugar alcohols such as mannitol. The carrier particles may include physical mixtures of any of these materials and / or composites of one or more of these materials.

[0059] The carrier particles have a particle size distribution and / or structural (particle) density similar to that of the active ingredient particles used in the composition that is filled into capsules to produce the dosage form of the present invention.

[0060] "Similar particle size distribution and / or structural (particle) density" means that the average diameter on a weight and / or volume basis of the carrier particles, and / or particle density, are within approximately ±75% of the relevant dimensions of the C21 or its salt used, e.g., approximately ±50% (including approximately ±40%), e.g., approximately ±30%, or approximately ±20% (including approximately ±10%).

[0061] In this regard, preferred carrier particle sizes include an average diameter on a weight and / or volume basis of less than about 100 μm (including less than about 80 μm), for example less than about 70 μm (including about 20 μm to about 60 μm) (for example about 25 μm or more preferably about 50 μm).

[0062] We found that blend segregation can be avoided by using carrier particles of a similar size to the active ingredient and / or within the size range described above.

[0063] To prepare the dry mixed composition to be filled into capsules for the dosage form of the present invention, carrier particles of the required size are pre-blended with a suitable flow material before being mixed with the active ingredient. The flow accelerator is a pharmaceutically acceptable material that facilitates the flow of the powder by reducing friction and / or aggregation between particles (but does not necessarily have the ability to reduce and / or prevent adhesion to external materials such as capsule filling machines or hoppers). Therefore, suitable pharmaceutically acceptable flow materials include talc, magnesium carbonate, or calcium silicate, but the flow accelerator is preferably a hydrophilic flow accelerator such as silica gel, silica aerogel, or more specifically, one or more of various forms of silica, including silica gel, silica aerogel, or proprietary silica manufactured under the registered trademark "Syloid®" (see https: / / grace.com / pharma-and-biotech / en-us / Documents / Syloid / M309c), colloidal silica, and / or fumed / pyrogenic silica. Therefore, preferred forms of silica include stable aqueous dispersions (sols) of amorphous silica particles having an average diameter by weight and / or volume of about 1 nm to about 100 nm (e.g., up to about 50 nm, e.g., up to about 20 nm, e.g., about 10 nm to about 15 nm).

[0064] Therefore, it is preferable to mix the flow accelerator and carrier particles together to form an interaction (or ordering) mixture of carrier particles, which are mostly coated with smaller particles of the flow accelerator material, and then mix this blend with the active ingredient particles.

[0065] We also found that by adding the aforementioned flow enhancer to the carrier particles to form the excipient blend first, before mixing with the active ingredient, the flow properties of the excipient blend are improved, leading to better mixing with C21 or its pharmaceutically acceptable salts and further reducing the possibility of blend segregation.

[0066] The dosage forms of the present invention may include other excipients known to those skilled in the art for oral delivery of the active ingredient. Therefore, as needed, other excipients may be included, such as naturally occurring or non-natural dyes, antioxidants (e.g., butylated hydroxytoluene (BHT), vitamin C, vitamin E, β-carotene, uric acid, unicion, superoxide dismutase (SOD), glutathione peroxidase or peroxidase catalase), preservatives, and disintegrants (e.g., Rowe et al., Handbook of Pharmaceutical Excipients, 8). th (Including those described in ed. (2017)) can be added to the powder blend according to the present invention.

[0067] However, given the extreme sensitivity of C21 and its salts to other chemicals, it is preferable that such other excipients are not included in the dosage forms of the present invention. In this regard, the present invention provides a dosage form that essentially consists of a pharmaceutical composition in the form of a particulate mixture, wherein the particulate mixture comprises solid particles of C21 or a pharmaceutically acceptable salt thereof mixed with a blend of carrier particles having a weight and / or volume-based average diameter and / or structural (particle) density similar to the weight and / or volume-based average diameter and / or structural (particle) density of the solid particles of C21 or a pharmaceutically acceptable salt thereof (as defined above), and a flow enhancer, and the composition is contained within a capsule suitable for such oral administration. All preferred features referred herein to other aspects of the present invention that relate in any way to this aspect of the present invention are equally applicable.

[0068] The term "essentially consisting of" is understood to mean that the scope of this (and only) aspect of the Invention is limited to the aforementioned essential features, along with other features that do not substantially affect the fundamental and novel characteristics of this aspect of the Invention.

[0069] In this regard, although not an essential feature of the present invention, it may be preferable to add a lubricant (e.g., sodium stearyl fumarate, preferably magnesium stearate) to the blend before filling it into capsules to prevent it from adhering to equipment (e.g., capsule filling machines and hoppers). This is a preferred feature that does not substantially affect the basic and novel properties of this aspect of the present invention.

[0070] Alternatively, a composition filled into capsules, essentially consisting of a particle mixture containing solid C21 particles, or a pharmaceutically acceptable salt thereof mixed with a blend of carrier particles and a flow enhancer, may mean that the composition contains at least about 95% (e.g., at least about 97% by weight of the sum of those particular components).

[0071] Furthermore, the dosage forms of the present invention may also be modified to impart or to impart immediate or modified release of the active ingredient.

[0072] The excipients described above may be commercially available, or otherwise, they may be described in the literature, e.g., Remington The Science and Practice of Pharmacy, 21st ed., Lippincott Williams and Wilkins, Philadelphia (2006), and the documents cited therein, all of which relating to the disclosures of these documents are incorporated herein by reference in their entirety. Otherwise, the preparation of a suitable formulation can be achieved without ingenuity by a person skilled in the art using routine techniques.

[0073] Preferred mixing devices include standard mixing devices such as tumblers, shaker mixers (e.g., Turbula), convection mixers, hoppers, and fluidizing blenders. Preferred blenders include V-blenders.

[0074] A further aspect of the present invention provides a method for producing the dosage form of the present invention, the method comprising: (a) mixing the carrier particles and flow enhancer as defined above; (b) mixing the blend from step (a) with C21 particles or a pharmaceutically acceptable salt thereof; and (c) filling the mixture from step (b) into a capsule suitable for oral administration.

[0075] The dry mixed blend is preferably passed through a sieve at some point during the blending process to break down any aggregates that form during the blending process, as described below, for example. A suitable sieve has a pore size that is as small as (or around) the particle size of the largest component of the blend. Thus, suitable sieve sizes are approximately 50 μm, e.g., 75 μm, including 100 μm, e.g., 150 μm, 200 μm, or 250 μm (e.g., approximately 300 μm) to approximately 1,000 μm, e.g., approximately 400 μm (e.g., approximately 500 μm) to approximately 900 μm (e.g., approximately 800 μm).

[0076] pharmaceutically acceptable salts of C21 include acid addition salts. Such salts can be formed by conventional means, for example, by reacting C21 in the form of a free acid (hereinafter, "free C21") with one equivalent or more of a suitable acid or base, optionally in a solvent or in a culture medium in which the salt is insoluble, and then removing the solvent or culture medium using standard techniques (e.g., by lyophilization or filtration in a vacuum). Salts can also be prepared by exchanging the counterions of the active ingredient in the form of a salt with other counterions, for example, using a suitable ion exchange resin. Preferred salts of C21 include HCl salts, alkaline earth salts such as magnesium and calcium salts, and alkali metal salts such as potassium salts or, preferably, sodium salts.

[0077] The amount of C21 or its salt in the dosage form of the present invention may depend on and / or be selected based on the severity of the condition, or the expected severity of such condition, and the patient being treated, but can be determined by those skilled in the art. The mode of administration may also be determined by the timing and frequency of administration, as well as the severity of the condition.

[0078] An appropriate lower daily dose of C21 in adult patients (average body weight, e.g., 70 kg) may be about 10 mg per day, e.g., about 20 mg, e.g., about 25 mg. An appropriate upper limit for the daily dose range of C21 may be up to about 900 mg, e.g., about 600 mg (including about 400 mg) and about 200 mg, e.g., about 100 mg (including about 50 mg).

[0079] All of the above doses are calculated as free C21. The dose may be divided into several individual doses per day. The dose may be given once to six times a day, for example, four times a day, preferably three times a day, and more preferably twice a day.

[0080] In any case, general practitioners or other persons skilled in the art can routinely determine the most appropriate actual dosage for each individual patient, depending on the severity of the condition and the route of administration. The above dosages are examples of average cases, and naturally, there may be individual cases where higher or lower dosage ranges are appropriate, and such cases are within the scope of the present invention.

[0081] The dose administered to the patient must be sufficient to produce an appropriate response in the patient over a reasonable time frame (as described herein) within the context of the present invention. Those skilled in the art will recognize that the precise dose and composition, as well as the selection of the most appropriate delivery regimen, are also influenced, among other things, by the pharmacological properties of the formulation, the nature, stage and / or severity of the condition being treated, the physical and mental state of the recipient, as well as the age, condition, weight, sex and response of the patient being treated, the stage / severity of the disease, and genetic differences among patients.

[0082] The dosage form of the present invention is useful under conditions in which AT2 receptors are expressed and their stimulation is desired or required.

[0083] In this regard, the dosage forms of the present invention are indicated for the treatment of conditions characterized by vasoconstriction, fibrosis, inflammation, increased cell proliferation and / or differentiation, increased cardiac contractility, increased cardiovascular hypertrophy, and / or increased fluid and electrolyte retention, as well as skin and musculoskeletal disorders.

[0084] The dosage form of the present invention is particularly indicated for the treatment and / or prevention of ILDs such as sarcoidosis or fibrosis, more specifically PF, especially IPF, as well as conditions that can induce ILDs, such as systemic sclerosis, rheumatoid arthritis, myositis, or systemic lupus erythematosus, or conditions associated with ILDs, such as pulmonary hypertension and / or pulmonary arterial hypertension.

[0085] The dosage forms of the present invention may also exhibit thromboxane receptor activity. In this regard, the dosage forms of the present invention may have inhibitory effects on platelet activation and / or aggregation (and thus, for example, antithrombotic effects), and / or may reduce vasoconstriction and / or bronchoconstriction in a therapeutic manner.

[0086] The dosage forms of the present invention are further adapted for the treatment of stress-related disorders and / or for the improvement of microcirculation and / or mucosal protective mechanisms.

[0087] Therefore, the dosage forms of the present invention are expected to be useful in treating diseases that may be characterized as described above, such as those affecting the gastrointestinal tract, cardiovascular system, respiratory tract, kidneys, immune system, eyes, female reproductive (ovulatory) system, and central nervous system (CNS).

[0088] Gastrointestinal disorders that may be mentioned include esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, indigestion (including non-ulcerative indigestion), gastroesophageal reflux, irritant bowel syndrome (IBS), inflammatory bowel disease (IBD), liver disorders (such as hepatitis), gallbladder disease, multiple organ failure (MOF), and sepsis. Other gastrointestinal disorders that may be mentioned include xerostomia, gastritis, gastroparesis, hyperacidity, biliary tract disorders, coelicia, Crohn's disease, ulcerative colitis, diarrhea, constipation, colitis, loss of appetite, vomiting, nausea, dyspepsia, and Sjögren's syndrome.

[0089] Airway disorders that may be mentioned include inflammatory diseases such as asthma, obstructive pulmonary diseases (such as chronic obstructive pulmonary disease), non-infectious pneumonia, pulmonary hypertension, and adult dyspnea syndrome.

[0090] Kidney diseases that may be mentioned include renal failure, diabetic nephropathy, nephritis, and renal hypertension.

[0091] Eye conditions that may be mentioned include diabetic retinopathy, retinopathy of prematurity, and retinal microangiopathy.

[0092] Disorders of the female reproductive system that may be mentioned include ovulation disorders and endometriosis.

[0093] Cardiovascular diseases that may be mentioned include hypertension, cardiac hypertrophy, heart failure (including heart failure with maintained ejection fraction), atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial lesions, post-balloon stenosis, angiogenesis, diabetic complications, microvascular dysfunction, angina, cardiac arrhythmias, intermittent claudication, pre-eclampsia, myocardial infarction, reinfarction, ischemic lesions, erectile dysfunction, and neoendimal hyperplasia.

[0094] Disorders of the CNS that may be mentioned include cognitive impairment, impaired food intake (hunger / satiety) and thirst, stroke, cerebral hemorrhage, cerebral embolism and cerebral infarction, multiple sclerosis (MS), Alzheimer's disease and Parkinson's disease.

[0095] The dosage forms of the present invention may also be useful in regulating growth metabolism and proliferation, for example, in the treatment of aging, hypertrophic diseases, benign prostatic hyperplasia, autoimmune diseases (e.g., arthritis such as rheumatoid arthritis, or systemic lupus erythematosus), psoriasis, obesity, nerve cell regeneration, ulcer healing, suppression of adipose tissue hyperplasia, stem cell differentiation and proliferation, fibrous diseases, cancer (e.g., of or within the gastrointestinal tract (including the esophagus or stomach), prostate, breast, liver, kidney, as well as lymphoma, lung cancer, ovarian cancer, pancreatic cancer, hematological malignancies, etc.), apoptosis, tumors (in general) and hypertrophy, diabetes, neurological lesions and organ rejection.

[0096] The dosage form of the present invention is also useful in the treatment of stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cancer treatment-related cardiotoxicity, peripheral neuropathy, and especially systemic sclerosis.

[0097] Furthermore, the dosage forms of the present invention may be useful in treating tissue damage induced by respiratory viruses, which may include injury and / or dysfunction of the relevant tissues. The relevant tissues include the (mucosal) tissues of the airways, particularly the tissues of the lungs. Thus, the relevant tissues include the respiratory epithelium, which moistens the airways and protects them from the invasion of pathogens such as viruses.

[0098] Respiratory viruses that can be mentioned in this regard include influenza viruses, such as influenza A viruses (e.g., H1N1 and H3N2 viruses), influenza B viruses, or influenza C viruses), more specifically coronaviruses, including severe acute respiratory syndrome (SARS) coronaviruses such as SARS coronavirus (SARS-CoV), and in particular the novel SARS coronavirus 2 (SARS-CoV-2, formerly known as "2019-nCoV" or "novel coronavirus 2019"), which causes coronavirus disease 2019 (COVID-19) and has many genetic variants.

[0099] "Treatment of tissue damage" means not only that C21 and its salts have a beneficial effect on tissue damage of the airways caused by such viruses, but also that they may prevent and / or reduce damage that would otherwise be caused by the virus in the airways, for example, when the virus invades epithelial cells in the airways.

[0100] Therefore, C21 and its salts may neutralize or prevent tissue damage induced by such viruses and / or the development of disease caused by symptoms of such damage or disease.

[0101] In this regard, C21 and its salts may treat and / or halt the progression of diseases caused or induced by respiratory viruses (i.e., diseases such as influenza, as well as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), particularly SARS, and more specifically COVID-19) and their complications. C21 and its salts may also treat and / or prevent damage caused or induced by such viruses, including the treatment and / or prevention of symptoms of such respiratory diseases, including cough, dyspnea, respiratory distress (e.g., signs of the need for supplemental / supplementary oxygen (which may be administered via a face mask or nasal cannula (high flow or otherwise)), and / or mechanical ventilation / extracorporeal oxygen supply), respiratory failure, and / or pneumonia which may develop directly (viral pneumonia) and / or indirectly (bacterial pneumonia resulting from a secondary bacterial infection common in influenza), as well as subsequent fibrosis resulting from inflammation of the lungs and other organs (such as the heart and kidneys). Furthermore, C21 and its salts may prevent or inhibit the progression of respiratory virus-induced illness and / or death, and C21 may treat and / or prevent the onset of any of the chronic conditions identified above.

[0102] Furthermore, the dosage forms of the present invention may also be useful in the treatment or prevention of any fibrotic condition of one or more viscera characterized by excessive accumulation of fibrous connective tissue, and / or in the treatment or prevention of fibrosis and any associated morbidity and death. Such fibrosis may be associated with acute inflammatory conditions such as acute respiratory distress syndrome (ARDS), SARS, and multi-organ inflammation, as well as injuries and / or dysfunctions that may be caused by internal or external trauma (e.g., injury) or infection.

[0103] Therefore, such conditions can result from sepsis or septic shock caused by viral, bacterial, or fungal infections. Furthermore, acute lung injury, ARDS, and especially SARS, which can be caused by viruses such as coronaviruses including SARS-CoV-2, can result in damage to internal tissues and / or dysfunction of cells constituting related internal (e.g., mucous membrane) tissues and / or airway epithelium, etc. Damage to such tissues can then lead to severe fibrosis. For example, SARS disease, caused by SARS-CoV-2 (coronavirus disease 2019 or COVID-19), is known to often result in fibrosis.

[0104] However, the dosage forms of the present invention are particularly useful for the treatment and / or prevention of ILDs such as sarcoidosis or fibrosis, more specifically pulmonary fibrosis and especially IPF, as well as conditions that can induce ILDs, such as systemic sclerosis, rheumatoid arthritis, myositis or systemic lupus erythematosus, or other conditions associated with ILDs, such as pulmonary hypertension and / or pulmonary arterial hypertension.

[0105] It will be understood by those skilled in the art that the term "ILD" encompasses any pulmonary condition characterized by an abnormal healing response, including chronic inflammation, decreased lung function, and / or scarring, regardless of the cause, such as sarcoidosis and PF, and IPF in particular. The term may also encompass diseases and / or conditions known to lead to and / or cause such pulmonary conditions, such as systemic sclerosis. In this regard, the dosage forms of the present invention are further provided for use in conditions that lead to and / or cause ILD, such as PF or IPF, including systemic sclerosis.

[0106] In the treatment of pulmonary pulmonary effusion (PF), including IPF, the dosage form of the present invention may have an anti-fibrotic effect, accompanied by a reduction in fibrosis and prevention of further deposition of extracellular matrix. The dosage form of the present invention may also affect pulmonary scarring / wound healing and have an anti-apoptotic effect, thereby preventing apoptosis of alveolar endothelial cells, which are an initiating factor in the development of PF. The dosage form of the present invention also has an antiproliferative effect, thereby reducing cancer-like proliferation of fibroblasts and myofibroblasts in PF. The dosage form of the present invention may also improve vascular remodeling in PF, thereby alleviating secondary pulmonary hypertension. Finally, the dosage form of the present invention may exhibit anti-inflammatory and anti-cytokine effects.

[0107] A further aspect of the present invention provides a method for treating any of the above conditions, including respiratory viral injury and, more specifically, intravascular diseases (ILD), including PF, in particular IPF, the method comprising administering a therapeutically effective amount of the dosage form of the present invention to a person suffering from or susceptible to such a condition.

[0108] According to yet another aspect of the present invention, a method for treating respiratory virus-induced tissue injury in a subject is provided, the method comprising administering a therapeutically effective amount of the dosage form of the present invention to a subject in need of such treatment, particularly in the following cases: • The damaged tissue is lung tissue, including respiratory epithelium. • Damage includes injury and / or dysfunction of the mucous membrane tissue of the airways caused by respiratory viruses. Treatment includes treating or preventing the progression of diseases caused by the virus. • The respiratory virus is a coronavirus such as SARS-CoV-2, and the disease is SARS such as COVID-19, or the respiratory virus is an influenza virus, and the disease is influenza. Treatment includes treating symptoms of illness caused by or resulting from the associated virus. • Symptoms of injury or disease include one or more of the following: cough, difficulty breathing, respiratory distress (which may manifest as the need for oxygen supplementation and / or mechanical ventilation), respiratory failure, pneumonia, fibrosis in one or more internal organs including the lungs, heart and / or kidneys, and / or Treatment includes prevention of respiratory virus-induced illness and / or death in one or more of the aforementioned conditions.

[0109] The dosage forms of the present invention are represented both as therapeutic, symptomatic, and / or diagnostic treatment for any of the above conditions (e.g., during diagnostic examination when a condition is suspected), and as prophylactic treatment (including thereby preventing and / or inhibiting the decline and / or worsening of the condition).

[0110] "Patients" include avian and mammalian (especially human) patients. Human patients include both adult and pediatric patients, the latter including patients up to approximately 24 months of age, patients from approximately 2 to approximately 12 years of age, and patients from approximately 12 to approximately 16 years of age. Patients over approximately 16 years of age may be considered adults for the purposes of this invention. These different patient populations may be given different doses of C21 or its salts.

[0111] In the treatment of certain conditions such as respiratory virus-induced tissue injury, C21 or a pharmaceutically acceptable salt thereof is preferably administered to adult patients, more specifically those over approximately 20 years of age, e.g., over approximately 30 years, over approximately 40 years, more preferably over approximately 50 years, particularly over approximately 60 years, particularly over approximately 70 years, more specifically over approximately 80 years; and / or patients having one or more of the following underlying conditions (whether such patients are in one of the above age groups): • Chronic (long-term) respiratory diseases such as pulmonary fibrosis, pulmonary hypertension, pulmonary arterial hypertension, other interstitial lung diseases (ILDs), asthma, chronic obstructive pulmonary disease (COPD), emphysema, or bronchitis. • Chronic cardiovascular (e.g., heart) diseases such as heart failure, atrial fibrillation, or hypertension ·Chronic kidney disease • Chronic liver diseases such as hepatitis Chronic neurological disorders such as Parkinson's disease, motor neuron disease, multiple sclerosis, learning disabilities, or cerebral palsy. ·Diabetes • Problems with the patient's spleen - for example, sickle cell anemia or whether the spleen has been removed. • A weakened immune system as a result of conditions such as HIV and AIDS, or as a consequence of medications or chemotherapy such as steroid tablets. • Obesity (for example, a body mass index (BMI) of 40 or higher) ·pregnancy.

[0112] In this regard, according to some further aspects of the present invention, a method for treating and / or preventing one or more of the following conditions is provided. • For example, post-acute sequelae of SARS-CoV-2 infection (PASC), also known as "long-term COVID," "chronic COVID syndrome" (CCS), and / or "long-term COVID." • Acute kidney injury and / or chronic kidney disease, • Respiratory diseases such as pulmonary fibrosis, pulmonary hypertension, pulmonary arterial hypertension, asthma, chronic obstructive pulmonary disease (COPD), emphysema and / or bronchitis, as well as Cardiovascular diseases such as myocardial infarction, heart failure, atrial fibrillation, hypertension, or thrombosis, as well as / or embolisms in the heart, lungs, and / or brain, for example. All of these may be directly or indirectly induced by respiratory viruses (such as SARS-CoV-2), and this method involves administering C21 or a pharmaceutically acceptable salt thereof to subjects in need of such treatment and / or prophylaxis.

[0113] For example, in connection with the acute treatment of respiratory virus-induced tissue injury, doses of C21 or a salt thereof may be administered, for example, once to four times a day (e.g., one to three times) for a maximum of three months (e.g., two months), for a maximum of one month, including a maximum of three weeks, or for a maximum of one week, such as four or three days. Such treatment periods may be repeated as needed.

[0114] If one or more of the aforementioned chronic conditions develop, such as pulmonary and other visceral fibrosis, treatment with C21 or a salt thereof may be continued and / or administered as needed / as requested, in addition to and / or instead of the acute administration regimen described above.

[0115] Relevant active ingredients that may be used in combination therapy with C21 in the treatment of patients with viral infections include a wide range of standard therapies applied to various viral infections, including: Antibody therapies (e.g., LY-CoV555 / LY-CoV016 (bamuranivimab and etesevimab), LY-CoV555 (bamuranivimab, Eli Lilly), REGN-COV2 (casiribimab and imdevimab), REGN3048-3051, TZLS-501, SNG001 (Synairgen), eculizumab (Soliris; Alexion Pharmaceuticals), ravulizumab (Ultomiris; Alexion Pharmaceuticals), lenzilumab, leronlimab, tocilizumab (Actemra; Roche), sarilumab (Kevzara; Regeneron) Pharma, and Octapharma), antiviral drugs (e.g., oseltamivir, remdesivir, faviravir, mornupiravir, simeprevir, daclatasvir, sofosbuvir, ribavirin, umifenovir, lopinavir, ritonavir, lopinavir / ritonavir (Kaletra; AbbVie D) eutschland GmbH Co.KG), teicoplanin, baricitinib (Olumiant; Eli Lilly), ruxolitinib (Jakavi; Novartis), tofacitinib (Xeljanz; Pfizer), TMPRSS2 inhibitors, camostat or camostat mesylate, actembra (Roche), TZLS-501, AT-100 (rhSP-D), MK-7110 (CD24Fc; Merck), OYA1 (OyaGen9), BPI-002 (BeyondSpring), NP-120 (Ifenprodil; Algernon Pharmaceuticals), galidesivir (Biocryst Pharmacy), anti-inflammatory drugs (e.g., NSAIDs, ibuprofen, ketrolac, naproxen, etc.), chloroquine, hydroxychloroquine, interferons (e.g., interferon beta (interferon beta-1a), tocilizumab (Actemra), lenalidomide, pomalidomide, thalidomide), analgesics (e.g., paracetamol or opioids), antifungal agents (e.g., dextromethorphan), vaccines (e.g., Inovio Pharmaceuticals) and Beijing Advaccine Biotechnology's INO-4800 (if available), passive antibody therapy with COVID-19 convalescent plasma (CCP) and / or antibodies derived from the blood of people who have recovered from SARS-CoV or SARS-CoV-2 infection.

[0116] Relevant active ingredients that may be used in combination therapy with C21 in the treatment of ILDs such as IPF include, for example, antifibrotics (e.g., nintedanib, especially pirfenidone), vitamins (e.g., vitamins B, C, and D), mucolytics (e.g., acetylcysteine ​​and ambroxol), corticosteroids such as cortisone and prednisone, anti-inflammatory agents such as cyclophosphamide, other immunosuppressants such as azathioprine and mycophenolate mofetil, and antioxidants such as N-acetylcysteine. Relevant active ingredients that may be used in combination with C21 in the treatment of sarcoidosis include, for example, corticosteroids such as cortisone, prednisone, and prednisolone; antimetabolites; immunosuppressants such as methotrexate, azathioprine, leflunomide, mycophenolate / mycophenolate mofetil, and cyclophosphamide; monoclonal antitumor necrosis factor antibodies such as aminoquinoline, infliximab, and adalimumab; immunomodulatory imides, such as lenalidomide, pomalidomide, and especially thalidomide; the TNF inhibitor etanercept; and analgesics such as ibuprofen and paracetamol, cough suppressants, and / or expectorants.

[0117] To avoid misunderstanding, the term "corticosteroids" above includes both naturally occurring and synthetic corticosteroids.

[0118] Naturally occurring corticosteroids that may be mentioned include cortisol (hydrocortisone), aldosterone, corticosterone, cortisone, pregnenolone, progesterone, as well as naturally occurring precursors and intermediates in corticosteroid biosynthesis, and other naturally occurring derivatives of corticosteroids, such as 11-deoxycortisol, 21-deoxycortisol, 11-dehydrocorticosterone, 11-deoxycorticosterone, and 18-hydrocorticosterone. This product contains xy-11-deoxycorticosterone, 18-hydroxycorticosterone, 21-deoxycortisone, 11β-hydroxypregnenolone, 11β, 17α, 21-trihydroxypregnenolone, 17α, 21-dihydroxypregnenolone, 17α-hydroxypregnenolone, 21-hydroxypregnenolone, 11-ketoprogesterone, 11β-hydroxyprogesterone, 17α-hydroxyprogesterone, and 18-hydroxyprogesterone.

[0119] Synthetic corticosteroids that may be mentioned include: cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteplat, hydrocortisone butyrate, hydrocortisone valerate, thixocortol and thixocortol pivalate, prednisolone, methylprednisolone, prednisone, chloroprednisone, cloprednol, difluprednate, fludrocortisone, fluocinolone, fluperolone, fluprednisolone, loteprednol, prednicarbate and Hydrocortisone-type substances (Group A) such as amcinolone; acetonides and related substances (Group B) such as amcinonides, budesonides, desonides, fluocinolone cetonides, fluocinolone cetonides, halcinonides, triamcinolone acetonides, ciclesonides, deflazacort, formocortal, fludroxycortide, flunisolid and fluocinolone acetonides; beclomethasone, betamethasone, betamethasone dipropionate and betamethasone valerate, dexamethasone, fluocortone, halomethasone, mometasone and mometasone f (Beta)methasone-type drugs such as Roate, alclomethasone and alclomethasone dipropionate, clobetasol and clobetasol propionate, clobetasol and clobetasol butyrate, crocoltrone, desoxymethasone, diflorasone, diflocortrone, flurolon, flumetasone, fluocortin, flupredniden and flupredniden acetate, fluticasone, fluticasone furoate and fluticasone propionate, meprednisone, paramethasone, prednilidene, rimexolone and eurobetasol. Progesterone-type substances (Group C); such as flugestone, fluorometholone, medrisone, and prevediolone acetate; and progesterone derivatives (progestins) such as chlormadinone acetate, cyproterone acetate, medroguestone, medroxyprogesterone acetate, megestrol acetate, and segesterone acetate; and other corticosteroids such as cortibazole and 6-methyl-11β,17β-dihydroxy-17α-(1-propynyl)androsta-1,4,6-trien-3-one.

[0120] Preferred corticosteroids include cortisone, prednisone, prednisolone, methylprednisolone, and, in particular, dexamethasone.

[0121] Furthermore, relevant active ingredients that may be used in combination therapy with C21 (for example, for the treatment of respiratory viral infections) include H2 receptor blockers, anticoagulants, antiplatelet agents, as well as statins, antibacterial agents, and anti-allergic / anti-asthmatic agents.

[0122] H2 receptor blockers that may be mentioned include famotidine. Anticoagulants that may be mentioned include heparin and low molecular weight heparins (e.g., bemiparin, nadroparin, reviparin, enoxaparin, parnaparin, sertoparin, dalteparin, tinzaparin), direct-acting oral anticoagulants (e.g., dabigatran, argatroban, rivaroxaban, apixaban, edoxaban, betrixaban, dalexaban, otamichaban, retaxaban, eribaxaban, hirudin, repirudine, and bivalirudine), coumarin vitamin K antagonists (e.g., coumarin, asenocoumarol, fenprocumone, atromentin, and phenindione), and factor Xa synthesis pentasaccharide inhibitors (e.g., fondaparinux, hydraparinux, and hydraviotaparinux). Antiplatelet agents that may be mentioned include irreversible cyclooxygenase inhibitors (e.g., spirin and triflusal), adenosine diphosphate receptor inhibitors (e.g., cangrelor, clopidogrel, prasugrel, ticagrelor and ticlopidine), phosphodiesterase inhibitors (e.g., cilostazol), protease-activated receptor 1 antagonists (e.g., borapaxal), glycoprotein IIB / IIIA inhibitors (e.g., absiximab, eptifivatide and tirofiban), adenosine reuptake inhibitors (e.g., dipyridamole), and thromboxane inhibitors (e.g., tertroban, ramatroban, seratrodast and picotamide). Statins that may be mentioned include atorvastatin, simvastatin and rosuvastatin. Antimicrobial agents that may be mentioned include azithromycin, ceftriaxone, cefuroxime, doxycycline, fluconazole, piperacillin, tazobactam, and teicoplanin. Antiallergic / antiasthmatic drugs that may be mentioned include chlorpheniramine, levocetirizine, and montelukast.

[0123] Further relevant active ingredients that may be used in combination therapy with C21 (e.g., for the treatment of respiratory viral infections) include other AT2 agonists known in the art, as well as combinations with AT1 receptor antagonists known in the art, and / or combinations with angiotensin-converting enzyme (ACE) inhibitors. Non-limiting but exemplary examples of AT1 receptor antagonists that may be used according to embodiments include azilsartan, candesartan, eprosartan, fimasartan, irbesartan, losartan, milfasartan, olmesartan, pomisartan, platosartan, lipiasartan, suprisartan, tasosartan, telmisartan, valsartan, and / or combinations thereof. Non-limiting but exemplary examples of ACE inhibitors that may be used according to the embodiment include captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, fosinopril, moexipril, cilazapril, spirapril, temocapril, seronapril, derepril, mubertipril, and / or combinations thereof.

[0124] A patient concerned may receive (and / or already receive) one or more of the above-mentioned treatments and / or other therapeutic agents for the relevant condition based on the administration of one or more of such active ingredients, which means receiving one or more prescription doses of these active ingredients referred to herein before, in addition to, and / or after treatment with C21 or a salt thereof.

[0125] The pharmaceutically acceptable salts and doses of the other active ingredients listed above are known in the art and are based on Martindale-The Complete Drug Reference, 38. th This includes medical literature such as Edition, Pharmaceutical Press, London (2014) and the documents cited herein, which describe the drug in question, and all relevant disclosures in those documents are incorporated herein by reference.

[0126] The dosage form of the present invention has the advantage that it can be manufactured and stored under normal storage conditions, including maintaining the pharmaceutically acceptable physicochemical stability of the composition contained in the capsule, particularly the active ingredient, without being frozen and / or exposed to light.

[0127] The dosage form of the present invention also provides improved drug filling, enabling the presentation of large / high-dose active compounds, and can also provide efficient delivery of such higher doses in a consistent / uniform manner. This, in turn, improves the efficacy and efficiency of treatment and reduces healthcare costs.

[0128] The uses / methods described herein may, in other respects, be more convenient for physicians and / or patients, more effective, less toxic, have a broader range of activity, be more potent, produce fewer side effects, or have other useful pharmacological properties when used in the treatment of one or more of the above-described conditions, particularly in the treatment of ILD and / or respiratory viral infections, whether in those conditions or other conditions, compared to similar methods (treatments) known in the prior art.

[0129] Whenever the word “approximately” is used herein, it will be understood that in the context of absolute quantities, such as numerical values ​​or amounts, i.e., size (e.g., particle size), dose, weight or concentration of (e.g., active) ingredients, age, temperature or period; or relative quantities, including percentages and standard deviations, such variables are approximations and may therefore vary by ±10%, e.g., ±5%, preferably ±2% (e.g., ±1%) from the actual value identified. In this regard, the term “approximately 10%” means, for example, ±10% for the number 10, i.e., 9% to 11%.

[0130] The present invention is illustrated by the following examples, but is not limited thereto, and Figure 1 shows the instability of the C21 sodium salt in the presence of a number of standard excipients. [Brief explanation of the drawing]

[0131] [Figure 1] This figure shows the instability of the C21 sodium salt in the presence of numerous standard excipients. [Examples]

[0132] Comparative Example 1 Solubility of C21 in water The solubility of free C21 was investigated in many different aqueous vehicles, as summarized in Table 1 below.

[0133] The vehicles (along with their sources) are as follows: sodium chloride (Sigma), ethanol (99.5%, Kemetyl), polyethylene glycol (BASF), phosphate-buffered saline (PBS) pH 7.4 (Sigma), buffer pH 2.00 (citric acid, sodium hydroxide solution, hydrogen chloride), buffer pH 4.00 (citric acid, sodium hydroxide), buffer pH 6.00 (citric acid, sodium hydroxide), buffer pH 8.00 (boric acid, sodium hydroxide, hydrogen chloride), and buffer pH 10.00 (boric acid, sodium hydroxide, hydrogen chloride) (all Merck), and purified water (Elga Option 4 water filter).

[0134] Saturated solutions of free C21 (Syntagon AB, obtained from Sodertalje, Sweden) were prepared twice. Before analysis, the samples were continuously magnetically agitated for 48 hours. For some samples, the added substance was dissolved, and then further added to obtain a saturated solution.

[0135] After 48 hours, the pH was measured, and then 1 mL of the solution was withdrawn. Undissolved substances were removed by centrifugation (1500 rpm, 30 minutes). The supernatant was diluted 10 to 500 times with acetonitrile / H2O in a 30:70 ratio.

[0136] The C21 content was measured by HPLC. [Table 1]

[0137] The solubility of free C21 increases significantly above a pH of approximately 8.5. In a 0.9% NaCl solution, 27.4 mg / mL is obtained at pH 9.7.

[0138] An increase in solubility is also observed in the studied cosolvent systems. However, this change is not as dramatic as that caused by changes in pH.

[0139] The solubility of the sodium salt of C21 was measured by similar experiments and found to be considerably higher than that of free C21.

[0140] In this experiment, C21 sodium salt (Syntagon AB) was added to the vehicles in small amounts at a time. Approximately 20–30 mg of sodium salt readily dissolved in all tested vehicles. To obtain a saturated solution, the salt was added sequentially to the same sample. In this way, higher amounts, such as 40–60 mg / mL, could be dissolved. The solubility in the tested vehicles was probably even higher, but this was not established considering the limited amount of drug compounds available. The results are shown in Table 2 below. [Table 2]

[0141] Comparative Example 2 Sensitivity of C21 aqueous solution to light The stability of free C21 in 0.9% NaCl pH 9.4 was investigated.

[0142] A 1 mg / mL solution of C21 was studied for 4 weeks under four different storage conditions. To minimize bacterial growth during stability testing, the solution was filtered through a 0.22 sterile syringe filter. The samples were analyzed for purity by HPLC.

[0143] The results are summarized in Table 3 below, where the amount of C21 is shown as a percentage of the initial amount of drug. The pH of the solution was also measured and is shown in parentheses in Table 3. [Table 3]

[0144] Free C21 was found to be chemically stable when stored in the dark at 5°C, room temperature (RT), and 40°C for 4 weeks. A slight decrease in pH was observed when the solution was stored above room temperature, but not at low temperatures.

[0145] The peaks in the HPLC chromatogram corresponding to impurities / decomposition products were followed by their respective peak areas. The total impurity peak area was approximately 2.5 area % of the C21 peak area for samples stored at 5°C, RT / dark, and 40°C.

[0146] In samples stored using RT / light, there is a clear increase in the number of impurity peaks, suggesting that the substance chemically decomposes when exposed to light (at least in the presence of water). In particular, under these storage conditions, a peak corresponding to 6.9 minutes appears with a relative retention time of 0.84.

[0147] Precipitation was observed in samples stored in RT / light for 2 and 4 weeks; therefore, samples were filtered (0.45 μm, GHP / Acrodisc) before analysis. The relatively low content of 44% and 13%, respectively, may be due to the precipitation of C21, which can occur at pH less than 8.0. However, it is also clear that the decrease in content is due to the formation of degradation products under these storage conditions. Many other impurity peaks were observed by HPLC, which are likely related to the degradation of C21 under these storage conditions.

[0148] A possible explanation for the decrease in pH of samples stored in RT / light for several weeks is that the decomposition of the substance causes a decrease in pH, which sets a limit on the solubility of C21 itself.

[0149] The stability of the sodium salt of C21 was also investigated under the same storage conditions. The results are summarized in Table 4 below. [Table 4]

[0150] During the analysis of samples over a week, it was discovered that the heating cabinet used to store the samples at 40°C was broken. Taking this into consideration, these samples were subsequently held at room temperature for three days.

[0151] Similar to free C21, the sodium salt is chemically stable after 4 weeks when stored in the dark at all temperatures investigated. For samples stored in RT / light, peaks appear at the same relative retention times as observed for free C21. Many other peaks are also present, which were thought to be related to light-induced degradation.

[0152] Therefore, the conclusion is that photo-induced decomposition occurs in both sodium salts and free C21.

[0153] This highlighted a significant challenge for the development of C21. For any future pharmaceutical product, it is difficult to ensure complete avoidance of ambient temperature (or higher), light, and humidity simultaneously during manufacturing, formulation, packaging, transportation, and storage.

[0154] Subsequently, it was decided to formulate C21 at concentrations of 0.2 and 10 mg / mL as an aqueous sodium salt in the presence of carbonate buffer for oral administration, for further preclinical and clinical development. These frozen formulations were found to be chemically stable for 3 months when refrigerated in polyethylene terephthalate (PET) bottles and for 36 months when stored in a -15°C freezer, with no deterioration observed in pH, appearance, or assays.

[0155] Comparative Example 3 An attempt to create a dry blend Two simple blend capsule formulations containing C21 sodium salt (Syntagon AB, obtained from Sodertalje, Sweden) were prepared by Turbula mixing at 67 rpm for 20 minutes. Ten capsules were filled into each of the simple blends having the compositions shown in Table 5 below. The capsules from each batch were divided into three groups: stored in a freezer, at room temperature, and at 40°C for 6 weeks. [Table 5]

[0156] Three capsules from each batch and their storage conditions were analyzed after 6 weeks. The assay results, homogeneity, and associated impurities are shown in Tables 6 (Batch 1) and 7 (Batch 2) below. [Table 6] [Table 7]

[0157] For each batch, the average assay rate under freezer storage conditions was found to be close to 100%. For both batches, the assay rate decreased in the following order: freezer, RT, 40°C. Furthermore, the total amount of organic impurities increased in the same order for both batches.

[0158] Significant variations were observed in the assay results within each capsule set. In batch 1, the total impurities were 0.24 area % higher when stored at 40°C compared to storage in the freezer. Novel impurity 2 constituted a substantial increase of 0.02–0.15 area %. Known impurity 1 increased by 0.09 area %. Two additional impurity peaks were also formed just below the reporting limit of 0.05 area %.

[0159] In batch 2, the total impurity level was 0.29 area percent higher when stored at 40°C compared to when stored in the freezer. This increase was solely due to an increase in impurity 1.

[0160] Three capsules from each batch, stored at ambient temperature, were analyzed for dissolution. Batch 1 was fully released in 15 minutes, with little variation in the data. In batch 2, two of the three capsules were fully released in 30 minutes, but the results showed considerable variability.

[0161] The degradation of C21 observed in two initial simple blend capsule formulations during stability testing was considered unacceptably high. The chemical stability of the C21 capsule formulation became a primary focus of ongoing development research. It was also concluded that further research may be needed to achieve a homogeneous powder blend.

[0162] Comparative Example 4 Compatibility survey The excipients used in the capsules of Comparative Example 3 described above were evaluated along with several additional ones (see Table 8 below).

[0163] The C21 (sodium salt) used in these experiments was crushed and passed through a 300 μm sieve. Mixtures of each excipient and C21 were prepared by thoroughly mixing them in the amounts specified in Table 8. The ratio of C21 to various fillers (D-mannitol, MCC, lactose monohydrate, and HPMC) was adjusted to give a volume equivalent to the majority of the capsule.

[0164] Three capsules of each type were filled with C21. All preparations were stored at 60°C for 12 days under accelerated stability conditions before analysis. [Table 8]

[0165] The results of the relevant impurity analysis after 12 days at 60°C are shown in Table 9 and Figure 1 below. [Table 9]

[0166] No degradation of C21 was observed in accelerated stability tests for samples No. 1 and 5, nor in the reference sample. In sample No. 3, a very significant degradation of C21 to impurity 1 occurred, and sample No. 8 showed similar degradation. All other mixtures showed decomposition of C21, and in some mixtures, new decomposition products were formed in addition to the known impurity 1.

[0167] In addition to the above-mentioned disintegrants (sodium starch glycolate and croscaramelose sodium), two different types of crospovidone (Kollidon® CL (Type A) and Kollidon® CL-SF (Type B) (both from BASF)) were tested.

[0168] A mixture of 130 mg of crospovidone and 200 mg of C21 was prepared and thoroughly mixed for 10 minutes using a Turbula mixer. All of these preparations were analyzed after being stored under accelerated stabilization conditions at 60°C for 12 days with zero time.

[0169] The results of impurity analysis related to the studies performed at 60°C are shown in Table 10 below. No significant degradation of C21 was observed in any of the mixtures. Impurity peaks 6 and 7, observed using Kollidon CL, were present initially. [Table 10]

[0170] Compatibility tests show that C21 is stable with CL and CL-SF, which are both types of mannitol and Kollidon, as well as Licaps hard gelatin capsules, but all other tested excipients have various stability issues.

[0171] Comparative Example 5 mixed research Following initial experiments with simple blend capsule formulations, the ability to produce a homogeneous powder mixture of C21 sodium salts was of significant interest (see Comparative Example 3 above).

[0172] Different grades of mannitol than those described in Comparative Examples 3 and 4 above were selected for further study with the aim of determining appropriate mixing parameters and providing a chemically stable and homogeneous powder mixture that can be loaded into capsules.

[0173] C21 sodium salt was used together with seven different types of mannitol from two different manufacturers.

[0174] C21 and mannitol were added to glass flasks and mixed using a Turbula mixer. After a 30-minute mixing time, homogeneity samples were taken from each flask and any associated impurities were analyzed.

[0175] Aliquots of each powder mixture were also exposed to 60°C for 12 days for stability analysis. The nominal C21 content was 7.4% w / w (calculated as free C21) for all but one mannitol mixture, and an additional strength of 14.8% w / w was also tested.

[0176] The results are shown in Table 11 below. [Table 11]

[0177] Acceptable homogeneity was observed only at both intensities of Mannogem EZ spray-dried mannitol (average particle size diameter 150–200 μm).

[0178] However, variability in data points was observed, which was reasonable at 7.4% intensity but much higher at 14.8% intensity. All other mannitol types gave insufficient homogeneity and high or very high variability. In this regard, it was noted that in flasks mixed with Mannogem Granular, Pearlitol 300 DC, and Pearlitol 500 DC, some of the material adhered strongly to the glass wall. Based on the low amount of C21 detected, it is thought that more API was present in that sticky material.

[0179] The results of the accelerated stability test, conducted at 60°C for 12 days, are shown in Table 12 below. [Table 12]

[0180] In all types tested (numbers 8 and 9 above), two new impurities were formed, but C21 was found to be fairly stable for all types of mannitol. An 8-day accelerated stability study at 60°C showed that these two impurities were not mannitol degradation products. In any case, the levels of these impurities were low.

[0181] Two other impurities were detected early in the mixing experiment with Kollidon (see Comparative Example 4 above). These impurities were suspected to be heterogeneously distributed decomposition products of C21.

[0182] The impurities appeared to be moving back and forth, but this behavior cannot be easily explained. Known impurity 1 showed a slight increase.

[0183] Comparative Example 6 Research on scale-up mixing C21 and spray-dried mannitol Mannogem EZ were added to a glass flask and mixed using a Turbula mixer. The nominal C21 content was 7.78% w / w (calculated as free C21).

[0184] After mixing times of 15, 30, 45, 60, and 90 minutes, flasks were sampled for homogeneity analysis. After the last sample was taken at 90 minutes, the remainder of the batch was passed through a 300 μm sieve, placed in a glass flask, and then mixed in a Turbula mixer for 30 minutes before sampling. The results are shown in Table 13 below. [Table 13]

[0185] When using mixing times of 30 minutes or more compared to 15 minutes, the mean value of the C21 assay was close to 100%. However, there was a large degree of variability (3-7% RSD) in the assays at each mixing time up to 90 minutes. Furthermore, paradoxically, homogeneity did not improve as a function of mixing time. Therefore, the good homogeneity observed in spray-dried Mannogem EZ during screening of different types of mannitol (see Comparative Example 5 above) could not be repeated.

[0186] Final sieving and mixing yielded a homogeneous mixture with a 0.7% RSD, although the C21 assay showed a significant decrease to 102–89%. This decrease is most likely due to the particle size distribution of C21, which contains a greater proportion of aggregates in the 100–400 μm size range.

[0187] Comparative Example 7 Mixing after micronization Next, before continuing the mixing experiments with mannitol, it was decided to attempt to pulverize C21.

[0188] Aliquots of C21 were sent to Jetpharma (Balerna, Switzerland) for pulverization using a jet mill to break down aggregates with a particle size of 100-400 μm, in order to prepare a homogeneous mixture with mannitol.

[0189] It was found that the chemical purity of C21 did not change significantly during pulverization, but the particle size distribution of the crystals in the material became narrower.

[0190] Optical microscopy of jet-pulverized C21 revealed that the crystals were rod-shaped, ranging in length from a few micrometers to a maximum of 50 micrometers. The crystals attracted each other, forming loose clusters.

[0191] Micronized C21 and mannitol, along with spray-dried Mannogem EZ, were mixed in the same manner as described in Comparative Example 6 above. In this case as well, the average RSD of the C21 assay approached 100% when a mixing time of 45 minutes or more was used, but there was considerable variability in the assays at each mixing time (4-10% RSD).

[0192] Furthermore, in this case as well, although a homogeneous mixture with 0.7% RSD was obtained by the final sieving and mixing, the C21 assay was significantly reduced from 103% to 88%. This reduction is of the same magnitude as the loss observed in Comparative Example 6 above for unmicronized C21.

[0193] Comparative Example 8 Mixing using a flow accelerator During the mixing experiment, it was observed that some of the powder mixture adhered strongly to the walls of the glass flask.

[0194] Therefore, regardless of how uniform the particle size was before mixing, the results strongly indicated that C21 tends to form aggregates.

[0195] We attempted to solve this problem by adding colloidal silica. Both non-micronized and micronized C21 (see Comparative Example 7 above) were used and mixed with mannitol (Mannogem EZ spray-dried) and Aerosil200 colloidal silica.

[0196] C21 was pre-mixed with colloidal silica (Aerosil® 200Pharma, Evonik Industries) in a glass flask using a Turbula mixer for 10 minutes, after which mannitol was added while continuing to mix. The same mixing and sampling procedure as above was used.

[0197] During mixing, clumps were observed, and their number decreased with increasing mixing time. Mannitol itself contained easily disintegrating clumps from the beginning. After a 30-minute mixing time, a single clump with a mass of 36 mg (consisting of approximately 1 / 10 of the amount in the capsule) was isolated and analyzed.

[0198] The C21 content in that mass was only 24% of the nominal content, which suggests that mannitol may need to be sieved before being mixed with C21.

[0199] Homogeneity analysis showed that the mean value of the C21 assay was initially very high (205%), but decreased to approximately 100% after mixing times of 30 minutes or more. While variability steadily decreased with increasing mixing time, it was only about 6% (i.e., far from acceptable).

[0200] Final sieving and mixing yielded a fairly homogeneous mixture (1.6% RSD), although the C21 assay was significantly reduced from 103% to 75%. This reduction was even greater than that observed in Comparative Examples 5 and 6 above (i.e., without colloidal silica), which was quite surprising.

[0201] Similar results were observed with pulverized C21. Again, C21 tended to aggregate together. Homogeneity increased after 30 minutes of mixing and then decreased with longer mixing times. The assay was unexpectedly low (90%). Variability steadily decreased with increasing mixing time, but only by 11% at most (i.e., far from acceptable).

[0202] Final sieving and mixing yielded a fairly homogeneous mixture (1.2% RSD), but the C21 assay rate decreased significantly from 90% to 81%. The tendency for the assay rate to drop below 100% after 60 minutes indicated a serious mixing problem.

[0203] It was found that only after thorough mixing and subsequent final sieving and mixing could it be possible to produce something resembling a homogeneous mixture.

[0204] Comparative Example 9 Change of container An attempt to determine whether the properties of the mixing container had any influence on the results. C21 and mannitol (Mannogem EZ spray-dried) were sieved through a 300 μm sieve to remove clumps. The components were added to a polyethylene (PE-HD) jar and mixed as described above.

[0205] Again, during mixing, it was observed that several lumps formed, and the walls and lids were coated with a layer of powder.

[0206] The mean value of assay C21 was initially 103%, but decreased by 60 minutes. While variability was high, it decreased with increasing mixing time.

[0207] Final sieving and mixing yielded a homogeneous mixture (0.9% RSD), but again, the C21 assay was significantly reduced (approximately 16%), suggesting that plastic jars tended to adsorb C21 more readily than glass. Indeed, the walls of the jars, including the lids, were found to be covered with a layer of powder.

[0208] Therefore, in summary, it was found that C21 sodium salts cause unexpected chemical instability when mixed in a dry state with many conventional excipients. Furthermore, because they have needle-like particles, are sticky, and tend to aggregate, they cannot be easily mixed with conventional excipients to obtain a powder mixture with acceptable uniformity of content.

[0209] Furthermore, when the equipment was used for automated weighing with an endless screw, the API adhered to the screw and did not fall out of the vial.

[0210] Example 10 Dosage Form I of the present invention The excipient mixture was prepared using a composition containing mannitol (Pearlitol® 25C (average particle size diameter 25 μm; Roquette; 247.75 g) and colloidal silicon dioxide (Aerosil Evonik; 0.25 g).

[0211] Approximately half of the weighed mannitol was placed in a 3L V-shell in a V-blender (Dott Bonapace, Limbiate, Italy), followed by the addition of all the colloidal silicon dioxide. Next, the remaining mannitol was added to the V-shell, and the blending was performed at 30 rpm for 10 minutes.

[0212] Next, the excipient blend was sieved through an 800 μm sieve and then blended for a further 20 minutes at 30 rpm.

[0213] Next, the weight of a 500 mL graduated cylinder was measured, and 100 mL of each additive blend was poured into the cylinder. 50 g of C21 sodium salt (Ardena (formerly Syntagon AB), synthesized in Sodertalje, Sweden) was weighed and transferred to the graduated cylinder. Bulk volume (V bulk ) was read.

[0214] Next, an additional 370 mL of the additive blend was added (up to the cylinder). The resulting mixture was lightly tapped 10 times, and then another 350 mL of the excipient blend was added to compensate for the volume reduction, followed by 5 more light taps (the final volume was 340 mL). The total mass of the loaded cylinder was weighed, and the bulk density of the mixture (dbulk) was determined to be 0.4 g / mL.

[0215] Next, the contents of the graduated cylinder were transferred to a 3L V-shell V-blender, blended at 30 rpm for 10 minutes, then sieved through a 500 μm sieve, and finally blended at 30 rpm for 40 minutes.

[0216] It was found that the blend adhered to the metal walls of the V-shell, forming clumps. Therefore, a further sieving process was performed using an 800 μm sieve, followed by blending at 30 rpm for another 30 minutes.

[0217] After preparing the blend, approximately 270 mg of the blend sample (equivalent to the weight of one capsule) was weighed into a 100 mL volumetric flask, 40 mL of MilliQ water was added, and the mixture was sonicated for 20 minutes. Then, 40 mL of methanol was added, and the mixture was sonicated for another 20 minutes to determine the uniformity of the blend. After equilibration to room temperature, 1.0 mL of the sample solution was added to a 10 mL volumetric flask. This was then diluted with methanol and mixed.

[0218] The sample was filtered through a 0.45 μm PTFE membrane syringe filter, and the first 3 mL of the filtrate was discarded. The amount of C21 sodium salt was determined by UHPLC. The resulting solution should contain 0.1 mg / mL of C21Na salt (for 100% of the nominal sample concentration).

[0219] The results for blend uniformity are shown in Table 14 below. [Table 14]

[0220] Good blend uniformity was observed (i.e., mean assay values, lc, and RSD of less than 2.0% for 95.0–105.0%).

[0221] 460 capsules (i.e., 3 x 120 and 1 x 100; Vcaps® Plus, size 0, white opaque; Capsugel) were loaded into a secondary Artem using a manual Feton® encapsulation device. Weight sorting was performed by applying a 5% tolerance limit to the net loaded weight of the capsules.

[0222] The homogeneity of the contents was determined using the same UHPLC method as described above (except for weighing the capsules, opening them, and transferring the contents and shells to a 100 mL volumetric flask).

[0223] Thirty capsules were evaluated. Evaluations were performed for n=10 (the first 10 capsules were measured) and n=30 capsules. The results are shown in Table 15 below. [Table 15]

[0224] Example 11 Dosage Form II of the present invention The excipient mixture was prepared essentially as described in Example 10 above, except that the final ratio of mannitol to silica in the final blend was 99.17:0.83.

[0225] After preparation, 37.725 g of the excipient blend was weighed and added to a 3 L V-shell in a V-blender. Next, 50 g of C21 sodium salt was added to the V-shell. Then, another 37.725 g of the excipient blend was added to the V-shell, followed by blending at 30 rpm for 10 minutes.

[0226] Next, the resulting blend was sieved twice through an 800 μm sieve, followed by blending at 30 rpm for 40 minutes. Then, this blend was sieved again through an 800 μm sieve, followed by further blending at 30 rpm for 15 minutes.

[0227] Next, the uniformity of the blend was determined essentially according to the procedure described in Example 10 above. After re-diluting the initial sample stock solution of the sample preparation and re-analyzing it to eliminate laboratory (dilution) errors, the precise blend uniformity results are shown in Table 16 below. [Table 16]

[0228] The capsules were loaded and the homogeneity of the contents was determined using the same UHPLC method as described in Example 10 above. The results are shown in Table 17 below. [Table 17]

[0229] Example 12 Composition according to Invention I The excipient blend was prepared by weighing 2.6 g of colloidal silicon dioxide into a weighing boat. Next, 197.4 g of mannitol (Pearlitol® 50C, mannitol from the same supplier with a slightly larger average particle size diameter (50 μm)) was weighed, and approximately half of this amount was poured into a 3 L V-shell of a V-blender. Then, the weighed amount of fluidity enhancer was added to the V-shell, followed by the remaining mannitol. The resulting mixture was blended at 30 rpm for 10 minutes.

[0230] Next, the blend was sieved through an 800 μm sieve, then returned to the blender and blended at 30 rpm for 20 minutes.

[0231] Approximately 75 mL of the additive blend was added to a pre-weighed 500 mL graduated cylinder. 26.4 g of C21 sodium salt was weighed and added to the graduated cylinder, and an additional amount of the blended excipient was added up to 370 mL, followed by 10 light taps. To compensate for the volume reduction, another 350 mL of the excipient blend was added, followed by 5 light taps (the final confirmed volume was 340 mL).

[0232] The total mass of the cylinder and its contents are measured, the net mass of the contents is calculated, then it is transferred to a 3L V-shell and blended at 30 rpm for 10 minutes. The resulting blend is then sieved through a 400 μm sieve and blended again at 30 rpm for 20 minutes.

[0233] Based on the above volume measurements, the new composition for 50 mg of C21 / capsule is shown in Table 18 below. [Table 18]

[0234] Example 13 Composition according to Invention II Using essentially the same blending process as described in Example 12 above, 120 active capsules were prepared from 0.642 g of colloidal silicon dioxide, 61.014 g of mannitol (Pearlitol 50C), and 15.84 g of C21 sodium salt.

[0235] After preparing the excipient blend, half of it is added back into a 3L V-shell, then C21 is added, followed by the remaining excipient blend, then blended at 30 rpm for 10 minutes, sieved through an 800 μm sieve, and finally blended at 30 rpm for another 20 minutes.

[0236] The uniformity of the blend was determined as described in Example 10 above, and the results are shown in Table 19 below. [Table 19]

[0237] The results for blend uniformity were within acceptable limits. 120 capsules were loaded into a secondary Artem using a manual Feton® encapsulation device. Weight classification was performed by applying a 5% tolerance limit to the net loaded weight of the capsules, and the results were found to be within acceptable limits.

[0238] Example 14 Dosage Form III of the Invention (Scale-up) 10,000 capsules were prepared using 21.4 g of colloidal silicon dioxide, 2033.8 g of mannitol (Pearlitol 50C) and 528 g of C21 sodium salt (Ardena, Riga, Latvia) using essentially the same blending process as described in Example 13 above. A larger V blender (Multiblender, Pharmatech, UK) with a 25 L V shell was employed.

[0239] The uniformity of the blend was determined as described in Example 10 above and is shown in Table 20 below.

Table 20

[0240] Thereafter, 26.1 g of magnesium stearate (Ligamed® MF-2-V, Peter Greven, Germany) was sieved through an 800 μm sieve, added to the blend, and subsequently final blended at 15 rpm for 15 minutes.

[0241] The final composition is as shown in Table 21 below.

Table 21

[0242] Approximately 6,700 capsules were encapsulated at dosage size 0 using MG Compact (MG2, Bologna, Italy) applying the following settings. Chamber - 11 mm, Compression - 0 mm, Powder layer 30.0 mm.

[0243] Weight sorting was performed by applying a 5% tolerance limit to the net loaded weight of the capsules, resulting in a yield of 18.6%. After encapsulation, the capsules were manually pre-packaged into 100 mL high-density polyethylene (HDPE) jars with pediatric safety tamper-evident caps containing a desiccant (56 capsules / jar). A total of 97 vials were produced and labeled for use in clinical trials.

[0244] Example 15 Stability study of the dosage form of the present invention The capsules obtained in Example 14 above were tested in a study to evaluate the stability of clinical representative packaging under ICH (International Conference on Harmonisation of Human Use) storage conditions (i) 25°C and 60% RH (long-term storage conditions) and (ii) 40°C and 75% RH (accelerated storage conditions).

[0245] The stability data is shown in Table 22 below. [Table 22]

[0246] No significant changes were observed in the stability results, and all results met the applicable acceptance criteria after storage at 25°C and 60%RH for 12 months and at 40°C and 75%RH for 6 months.

Claims

1. A pharmaceutical preparation for oral administration to the gastrointestinal tract, wherein the preparation comprises a pharmaceutical composition in the form of a particulate mixture, the particulate mixture comprising solid particles of the sodium salt of N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide having an average diameter by weight or volumewise of about 100 μm or less, the solid particles being homogeneously distributed in a blend of carrier particles having an average diameter by weight or volumewise of about ±75% of the relevant dimensions of the solid particles of the sodium salt of N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide, and a flow enhancer. A pharmaceutical formulation comprising the composition contained within a capsule suitable for such oral administration.

2. The formulation according to claim 1, wherein the carrier particles comprise a physical mixture of materials selected from one or more carbohydrates, one or more pharmaceutically acceptable inorganic salts, and / or one or more pharmaceutically acceptable substances that are insoluble or sparingly soluble in water.

3. The formulation according to claim 2, wherein the one or more carbohydrates are selected from the group consisting of sugars and sugar alcohols.

4. The formulation according to claim 3, wherein the one or more sugars include lactose, and / or the one or more sugar alcohols are selected from the group consisting of mannitol, sorbitol, and xylitol.

5. The formulation according to any one of claims 2 to 4, wherein the one or more pharmaceutically acceptable inorganic salts include sodium chloride.

6. The formulation according to any one of claims 2 to 5, wherein the pharmaceutically acceptable substance that is insoluble or sparingly soluble in water is selected from the group consisting of microcrystalline cellulose, anhydrous dicalcium phosphate, dicalcium phosphate dihydrate, tricalcium phosphate, calcium carbonate, barium sulfate, starch, and pregelatinized starch.

7. The formulation according to any one of claims 1 to 6, wherein the capsule is a hard-shell two-piece capsule.

8. The formulation according to claim 7, wherein the capsule is made from hydroxypropyl methylcellulose.

9. The formulation according to any one of claims 1 to 8, wherein the particles of the sodium salt of N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide have an average diameter by weight or volume of about 50 μm or less.

10. The formulation according to claim 9, wherein the particles of the sodium salt of N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide have an average diameter by weight or volume of less than about 20 μm.

11. The formulation according to claim 10, wherein the particles of the sodium salt of N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide have an average diameter by weight or volume of less than about 10 μm.

12. The formulation according to any one of claims 1 to 11, wherein the material of the carrier particles comprises mannitol.

13. The formulation according to any one of claims 1 to 12, wherein smaller particles of the flow-promoting material coat the carrier particles.

14. A formulation according to any one of claims 1 to 13, which is essentially water-free.

15. A formulation as defined in any one of claims 1 to 14, for use in the treatment of interstitial lung disease.

16. Use of a formulation as defined in any one of claims 1 to 14 for the manufacture of a pharmaceutical product for the treatment of interstitial lung disease.

17. A formulation for use as defined in claim 15, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

18. The use as defined in claim 16, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

19. A formulation for use as defined in claim 15, wherein the interstitial lung disease is sarcoidosis.

20. The use as defined in claim 16, wherein the interstitial lung disease is sarcoidosis.

21. A formulation for use as defined in any one of claims 15, 17, or 19, wherein the treatment includes the prevention of morbidity and / or death in the associated condition.

22. Use as defined in any one of claims 16, 18, or 20, wherein the treatment includes the prevention of illness and / or death in the associated condition.

23. A formulation for use as defined in any one of claims 15, 17, 19, or 21, wherein the composition is administered by oral route.

24. The use of the composition as defined in any one of claims 16, 18, 20, or 22, wherein the composition is administered by oral route.

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