New delayed release compositions for oral administration

Abstract

To provide a pharmaceutical dosage form that is suitable for peroral administration to the gastrointestinal tract.SOLUTION: According to the Invention, there is provided a pharmaceutical composition comprising N-butoxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (C21), or a pharmaceutically-acceptable salt thereof, in which composition the C21 or salt thereof is protected by the presence of a coating comprising an enteric substance. Preferred dosage forms comprise capsules in which C21 or salt thereof is presented in the form of a dry powder mixture or a suspension of particles of C21 in a solvent in which it is insoluble. Such dosage forms have been found to be useful in the treatment of lung diseases, such as idiopathic pulmonary fibrosis, sarcoidosis and respiratory virus-induced tissue damage.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to new pharmaceutical dosage forms, their use as medicaments and in particular their administration for treating, inter alia, pulmonary diseases, such as interstitial lung diseases. [Background technology]

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

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

[0004] The most common 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 collections of inflammatory cells that form lumps (granulomas) and often begins in the lungs (as well as the skin and / or lymph nodes; any organ can be affected.) When sarcoidosis affects the lungs, symptoms include coughing, wheezing, shortness of breath, and / or chest pain.

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

[0007] IPF is a lung disease of unknown cause that affects approximately 5 million people worldwide. There are no treatment options except for lung transplantation, which is rare. The result is a chronic, irreversible, progressive decline in lung function that, in most cases, leads to death within 2-5 years (median survival 2.5-3.5 years). The overall prognosis of IPF is poor, but it is difficult to predict the rate of progression in individual patients. Risk factors for IPF include age, male sex, genetic predisposition, and smoking history. The annual incidence is 5-16 per 100,000, with a prevalence of 13-20 cases per 100,000, 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 treatments that target the immune system, distinguishing it from pulmonary fibrosis (PF), which is associated with systemic disease.

[0008] Patients with IPF usually seek medical assistance because of chronic and progressive exertional dyspnea and cough. Lung imaging classically reveals traction bronchiectasis, thickened interlobar septa, and subpleural honeycombing. When all three findings are present and there is no evidence of systemic connective tissue disease or environmental exposure, the diagnosis of IPF is highly likely. A definite diagnosis is usually made by lung biopsy, which requires a multidisciplinary team of expertise including pulmonologists, radiologists, and pathologists with experience in ILD.

[0009] IPF exhibits a variety of phenotypes with different prognoses, defined as mild, moderate, and severe. Mild cases follow a stable or slowly progressive course and patients may take years to seek medical advice. Accelerated IPF progresses much more rapidly with shorter survival times and affects a subgroup of patients, usually male smokers. Acute exacerbations of IPF are defined as a rapid worsening of the disease and this subpopulation of patients shows a very poor outcome with high mortality in the short term. The cause of IPF is unknown, but the interplay of environmental and genetic factors makes it appear to be a disease that likely results in relentless tissue remodeling by fibroblasts rather than normal repair, with a pathogenesis that is primarily fibrotic rather than inflammatory. Increasing evidence suggests that the disease is initiated by microdamage and apoptosis of alveolar epithelial cells, attracting stem or progenitor cells that activate neighboring epithelial cells and produce factors responsible for the expansion of fibroblast and myofibroblast populations in a tumor-like manner. Fibroblastic foci secrete excessive amounts of extracellular matrix, which destroys the lung parenchyma and ultimately leads to loss of lung function.

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

[0011] Many therapeutic approaches have been tested in preclinical models and clinical trials, including anti-inflammatory, immunomodulatory, cytotoxic, general antifibrotic, antioxidant, anticoagulant, antichemokine, antiangiogenic drugs as well as RAS blockers, endothelin antagonists, and sildenafil, all of which have essentially shown limited or no benefit (Rafii R et al., J. Thorac. Dis. (2013) 5, 48-73).

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

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

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

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

[0016] Therefore, the development of new therapeutic strategies for IPF is important. Therefore, a fundamental challenge for the future is to develop appropriate therapeutic approaches to reverse or halt the progression of the disease.

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

[0018] Angiotensin II type 1 (AT1) receptors are expressed in most organs and are thought to be responsible for most of the pathological effects of Ang II. The safety and efficacy of losartan (an AT1 receptor inhibitor) was recently investigated in a small, uncontrolled, open-label pilot study in IPF (www.clinicaltrials.gov identifier NCT00879879).

[0019] Several studies in adults appear to indicate that activation of angiotensin II type 1 (AT2) receptors has effects opposite to those mediated by AT1 receptors in regulating responses after AngII 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 disorders of the gastrointestinal tract, such as dyspepsia and irritable bowel syndrome, and multiple organ failure (see International Patent Application No. WO 99 / 43339).

[0022] The expected pharmacological effects of AT2 receptor agonism are generally described in de Gasparo M et al. (supra). There is no mention that AT2 receptor agonism may be used to treat IPF.

[0023] International Patent Application No. 2002 / 096883 describes the preparation of imidazolyl, triazolyl, and tetrazolylthiophene sulfonamides and derivatives as AT2 receptor agonists. Among the compounds described in that document (as Example 1), N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (Compound 21, or "C21" as used below) was selected for clinical development from a group of about 20 related analogues as a selective AT2 receptor agonist. C21 is currently in clinical development for the treatment of disorders, including IPF, in which treatment with AT2 receptor agonists is believed to be beneficial (see, for example, International Patent Application WO 2016 / 139475).

[0024] Formulation efforts carried out with C21 and its salts have proven to be very difficult. As a result, C21 has previously been formulated as an aqueous solution, frozen during storage, and then thawed immediately prior to oral administration.

[0025] The applicant has been working with this active ingredient for about 20 years and, until recently, has not been able to obtain a pharma- ceutically acceptable dosage form, one in which the active ingredient is stable when stored at ambient temperature.

[0026] In addition, a significant food effect was observed in a Phase I clinical trial conducted in healthy subjects to evaluate the safety, tolerability, and pharmacokinetics of C21.

[0027] This was unexpected given that unpublished preclinical studies in simulated intestinal fluids in both fasted and fed states appear to be sufficient to allow availability of the active ingredient in the intestine for good absorption at clinical doses. Summary of the Invention

[0028] According to a first aspect of the present invention, there is provided a pharmaceutical dosage form suitable for oral administration to the gastrointestinal tract, the dosage form comprising a pharmaceutical composition comprising C21 or a pharma- ceutically acceptable salt thereof, the C21 or salt thereof of the composition being protected by the presence of a coating comprising an enteric material. Such dosage forms are hereinafter collectively referred to as "the dosage forms of the present invention."

[0029] The dosage forms of the present invention are suitable for oral administration and delivery to the gastrointestinal tract as an intact dosage form, meaning that the dosage forms of the present invention are suitable for swallowing in their entirety and are intact dosage forms for subsequent consumption and / or ingestion in the gastrointestinal tract, and during use are swallowed and then consumed and / or ingested in that tract.

[0030] In the context of the present invention, "enteric" materials are used to coat, enclose and / or encapsulate compositions comprising C21 or a pharma- ceutically acceptable salt thereof to prevent the active ingredient from being released from the composition in the stomach and / or from contacting gastric fluids and / or until the ingredient reaches the small intestine. "Substantially prevent" includes about 20% or less of the active ingredient, such as about 15%, for example about 10%, more specifically about 5% or less, being released in the acidic environment of the stomach.

[0031] Typical enteric coating materials include the following: cellulose acetate, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate tetrahydrophthalate, polyvinyl acetate phthalate, hydroxyethyl ethyl cellulose phthalate, methacrylic acid copolymers, polymethacrylic acid / acrylic acid copolymers, styrene maleic acid copolymers, hydroxypropyl methylcellulose phthalate, acrylic resins, cellulose acetate trimellitate, hydroxypropyl methylcellulose trimellitate, shellac, hydroxyethyl ethyl cellulose phthalate, carboxymethyl cellulose, and hydroxypropyl methylcellulose acetate succinate. Preferred enteric materials include polyvinyl acetate phthalate, especially methacrylic acid copolymers.

[0032] Enteric materials can be used to coat various dosage forms. There are many formulation / administration principles that can be used to prepare the dosage forms of the present invention, which are described in a non-limiting manner below.

[0033] In this regard, C21 and its salts may be presented in any form that can be coated, enclosed, and / or encapsulated with an enteric material to make a final dosage suitable for oral administration to the gastrointestinal tract, and thus provided in the form of a powder, simple mixture, granules, pellets, beads, solutions and / or suspensions. Final dosage forms include pills, tablets, capsules, films, solutions or suspensions (e.g., syrups), powders, cakes, etc.

[0034] When C21 or a salt thereof is provided in multiparticulate form as a powder, granules, pellets, and / or beads, the particles must be individually or collectively coated with an enteric material. This can be done in a variety of ways.

[0035] In this regard, C21 and its salts can be presented in the form of a simple mixture with a carrier system, which is any pharma- ceutically acceptable inert material that can increase the mass of the composition or a component of the composition to provide a suitably processable dosage form.

[0036] Thus, suitable carriers include pharma- ceutically acceptable inorganic salts, such as sodium chloride, calcium phosphate, dicalcium phosphate hydrate, dicalcium phosphate dihydrate, tricalcium phosphate, calcium carbonate, and barium sulfate; polymers, such as microcrystalline cellulose (optionally silicified), cellulose and cross-linked polyvinylpyrrolidone; starches; sugars and sugar alcohols, such as lactose, mannitol, xylitol, isomalt, dextrose; or mixtures of any of the foregoing.

[0037] The carrier material is preferably used in an amount of about 5% to about 90% by weight, based on the total weight of the composition containing C21 or a salt thereof to be coated, with a preferred range being about 10% to about 80% by weight.

[0038] Preferred carrier materials include lactose, xylitol, isomalt, microcrystalline cellulose, and more preferably mannitol. The carrier particles may comprise a physical mixture of any of the foregoing materials and / or may comprise complexes of one or more of these materials.

[0039] The C21 / salt and carrier material mixture can then be filled directly into a capsule followed by application of the enteric material. Alternatively, such a mixture can be granulated into pellets, granules or beads, and these secondary particles can be individually coated with the enteric material or loaded into a suitable capsule before being coated with the enteric material. Alternatively, the powder, pellets, granules or beads can be compressed into a tablet before being coated with the enteric material.

[0040] Granulation can be carried out using well known techniques including dry granulation, wet granulation, melt granulation, thermoplastic pelletization, spray granulation or extrusion / spheronization.

[0041] The powders, granules, pellets or beads containing C21 or a salt thereof may contain, in addition to the carrier material, other commonly used pharmaceutical additives and / or excipients used in the art (e.g., Rowe et al, Handbook of Pharmaceutical Excipients, 8 th ed. (2017) and documents cited therein).

[0042] Other pharma- ceutically acceptable excipients, such as binders, disintegrants, glidants, lubricants, etc., are known to those skilled in the art.

[0043] A binder can be defined as a material that can act as a bond-forming promoter, which can facilitate the compression of a powder mass into a coherent compact. Suitable binders include polyvinylpyrrolidone, gelatin, sodium alginate, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose gum, cellulose derivatives such as microcrystalline cellulose (optionally silicified), and the like. When present, the binder is preferably used in an amount of about 2% to about 50% by weight, based on the total weight of the composition containing C21 or a salt thereof. A preferred range is about 5% to about 30% by weight.

[0044] Disintegrants (disintegrants or disintegrating agents) can be defined as materials that can measurably accelerate the disintegration / dispersion of the components of the composition containing C21 or its salts, such as granules or tablets. This can be achieved, for example, by materials that can swell and / or expand when placed in contact with an aqueous medium (particularly body fluids, including those found in the gastrointestinal tract), thus disintegrating at least a portion of the dosage form of the present invention when water is present. Suitable disintegrants include cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose (croscarmellose, e.g., Ac-Di-Sol, FMC Corp., USA), carboxymethyl starch, native starch, pregelatinized starch, corn starch, potato starch, sodium starch glycolate (Primojel®, DMV International BV, Netherlands), low-substituted hydroxypropyl cellulose, and the like. The disintegrant (which may include one or more of the above materials) is preferably used in an amount of about 1% (e.g., about 5%) to about 40% by weight based on the total weight of the composition containing C21 or a salt thereof. A preferred range is about 5% (e.g., about 10%) to about 30% by weight. Preferred disintegrants used include cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, sodium starch glycolate, and especially low-substituted hydroxypropylcellulose.

[0045] A glidant is a pharma- ceutically acceptable material that promotes powder flow by reducing interparticle friction and / or cohesion (but does not necessarily have to have the ability to reduce and / or prevent adhesion to external materials such as capsule fillers or hoppers).Suitable pharma-ceutically acceptable flow materials thus include talc, magnesium carbonate or calcium silicate, although it is preferred that the glidant is a hydrophilic glidant such as fumed / sintered silica or more specifically one or more of the various forms of silica including silica gel, silica aerogel and / or colloidal silica.

[0046] Lubricants are typically used when the final dosage form to be swallowed is in the form of a tablet, suitable lubricants to prevent granules or powders from sticking to the punch die / face and to facilitate smooth exit from the die after compression include stearic acid, sodium stearyl fumarate, anhydrous colloidal silica, talc, or preferably magnesium stearate. When lubricants are used, they should be used in very small amounts (e.g., up to about 3% by weight, preferably up to 2% by weight, based on the total weight of the composition containing C21 or a salt thereof).

[0047] Other excipients that can be used in oral dosage forms include surfactants, humectants, flavorings (e.g., lemon, menthol, or peppermint powder), sweeteners (e.g., neohesperidin, sucralose, or acesulfame potassium), dyes, antioxidants (which may or may not be naturally occurring (e.g., butylated hydroxytoluene (BHT), vitamin C, vitamin E, beta-carotene, uric acid, unicorn, superoxide dismutase (SOD), glutathione peroxidase, or peroxidase catalase)), preservatives, and buffers.

[0048] These and other pharma- ceutically acceptable excipients mentioned herein may be commercially available or are otherwise described in the literature, including, for example, for all of this type of excipients, those described in, for example, Rowe et al., supra and Remington The Science and Practice of Pharmacy, 21st ed., Lippincott Williams and Wilkins, Philadelphia (2006) and documents referenced therein, the relevant disclosures of all of which are incorporated herein by reference. Alternatively, suitable oral preparations can be accomplished non-inventively by those of skill in the art using routine techniques.

[0049] The granules, pellets or beads can be further processed after formation. For example, the dried granules can be crushed, ground or milled using appropriate milling techniques to produce smaller sized particulate matter, which can also be sieved to separate the desired size fraction. The wet granules can be screened to break up granule agglomerates and remove fine material. In either case, unused undersized (fines) and oversized material can be reprocessed to avoid waste.

[0050] However, if the powder mixture, granules, tablets or capsules are made prior to coating with the enteric material, preparation of the composition to be coated will ensure that the C21 or a pharma- ceutically acceptable salt thereof is evenly dispersed throughout the carrier material (and / or other excipients used).

[0051] In the case of a simple mixture, this involves mixing for a period of time to provide a uniformly distributed active ingredient, for example as described below, which may vary depending on the equipment used.

[0052] The terms "homogeneous" and "homogeneously distributed" in the context of the present invention mean that there is a substantially uniform inclusion of C21 or a salt thereof throughout the carrier material (and / or other excipients used). In other words, when multiple (e.g., at least two, more preferably about six, e.g., about 10 to up to about 30, or more as needed) samples are taken from a mixture containing an active ingredient and a carrier blend, the measured content of active ingredient present among such samples results in a standard deviation (i.e., coefficient of variation and / or relative standard deviation) from the average amount of less than about 8%, e.g., less than about 6%, e.g., less than about 5%, in particular less than about 2%.

[0053] Preferred mixing devices include standard mixing devices such as tumblers, shaker mixers (e.g., Turbula), convection, hopper, and fluidizing blenders. Preferred blenders include V-blenders.

[0054] Tablets may be formed by the process of compression / compaction. Direct compression / compaction may be accomplished using techniques such as those described in, for example, Pharmaceutical Dosage Forms: Tablets. Volume 1, 3rd Edition, Augsburger et al (eds.), CRC Press (2008) and documents cited therein. Suitable compression equipment includes standard tablet presses such as the Kilian SP300 or Korsch EK0.

[0055] The composition comprising C21 or a salt thereof is preferably contained within a capsule suitable for such oral administration.

[0056] Suitable pharma- ceutically acceptable capsules include soft- or hard-shell capsules made from gelatin, cellulose polymers, such as hydroxypropyl methylcellulose (HPMC or hypromellose), hypromellose acetate succinate (HPMCAS), starch polymers, pullulan, or other suitable materials, e.g., by standard capsule filling processes.

[0057] Where the dosage form of the present invention comprises a solid formulation comprising a mixture of C21 or a salt thereof together with a carrier material (e.g., in the form of a powder, granules, etc.), in a preferred embodiment of the present invention, the capsule is preferably a hard-shelled two-piece capsule, such as a capsule made from gelatin, or more preferably HPMC, and supplied as closed halves that can be separated and filled with particulate matter and then reassembled. Such capsules can be of any size (e.g., 00-5), although preferred capsule sizes are size 2, size 1, or, more preferably, size 0.

[0058] In this and other preferred embodiments of the present invention, C21 or a salt thereof is presented in the form of particles, which may be amorphous or crystalline, or a mixture of the two. Preferred particles are of a size that does not lead to separation, either during the capsule filling process or during storage in the formation of the composition to be filled into the capsule.

[0059] In this regard, C21 or a salt thereof may be provided in the form of a plurality of primary (i.e., non-agglomerated) particles, typically having an average diameter on a weight and / or volume basis of about 1,000 μm or less, e.g., 500 μm, including about 250 μm, preferably about 100 μm or less, including about 50 μm or less, e.g., about 20 μm, or about 10 μm or less. Although there is no lower limit to the particle size that can be used according to the present invention, for ease of manufacture, it is preferred that the primary particles of C21 or a salt thereof have an average diameter on a weight and / or volume basis of less than 1 μm, e.g., about 2 μm, about 3 μm.

[0060] As used herein, the term "weight-based average diameter" is understood by those skilled in the art to include the average particle size being characterized and defined from a particle size distribution by weight, i.e., a distribution in which the existing fraction (relative amount) in each size class is defined as the weight fraction obtained, for example, by sieving (e.g., wet sieving). The term "volume-based average diameter" is similar in meaning to the weight-based average diameter, but is understood by those skilled in the art to include the average particle size being characterized and defined from a particle size distribution by volume, i.e., a distribution in which the existing fraction (relative amount) in each size class is defined as the volume fraction measured, for example, by laser diffraction. Particle size can also be measured by standard equipment, such as dry particle size measurement techniques, including dry dispersion techniques, available from manufacturers such as Sympatec GMbH (Clausthal-Zellerfeld, Germany). Other instruments well known in the art can be used to measure particle size, for example, instruments sold by Malvern Instruments, Ltd (Worcestershire, UK), Shimadzu (Kyoto, Japan) and Elzone, Micromeritics (USA; electrical sensing zone method).

[0061] By particles having an average diameter on a weight and / or volume basis within the above limits, we include the average diameter of the particles during preparation according to the invention and before mixing with the relevant excipients and / or before loading into a capsule. It will be understood that some aggregation of primary particles to form secondary particles may occur during handling and / or processing of the active ingredient. However, this should be minimized.

[0062] C21 or a salt thereof also has a mass median diameter (D 50 ; log-normal mass median diameter), mean particle size by mass and / or diameter that contains 50% of the mass of the cumulative PSD) and / or geometric standard deviation (formula D 84.1 3 / D 50 Or D 50 / D 15.78 GSD or σ measured at g where D84.13 and D. 15.78 are the diameters that contain 84.13% and 15.78% of the mass, respectively, and D 50 The particles may be provided in the form of particles having a relatively narrow particle size distribution (PSD) as measured by standard techniques and art-recognized parameters, including PSD, as described above. Such parameters may be measured and calculated in-process using any suitable sampling method and particle size measurement technique, as described above.

[0063] In this regard, it is preferred that C21 or a salt thereof has a PSD that is a GSD of less than about 4, such as less than about 3.

[0064] Primary particles of C21 or a salt thereof can be prepared by any suitable technique, such as precipitation, cutting (e.g., by dissolution in a supercritical fluid under pressure followed by rapid expansion), spray drying, or, where appropriate, can be micronized by techniques known in the art, such as grinding, dry milling, jet milling, wet milling and / or crushing.

[0065] The particles may also be sieved to separate into desired size fractions and / or screened to break up agglomerates and / or remove fine material. In either case, unused undersized (fines) and oversized material can be reprocessed to avoid waste. Alternatively, the particles may be separated to the appropriate particle size using cyclone separation, by air classifiers, sedimentation, force field fractionation, and / or elutriation.

[0066] While the C21 or a salt thereof can be selected and / or provided with the aforementioned weight or volume based average diameter, particle size, PSD and / or GSD using one or more of the techniques described above, one of the primary advantages of formulating a composition to be loaded into a capsule to form the dosage form of the present invention is that the C21 or a salt thereof does not require the particle processing techniques described above prior to blending with the associated excipients.

[0067] In this regard, as mentioned above, C21 and its salts have been found to be very difficult to work with. Part of the problem is the heretofore unreported extreme sensitivity of C21 and its salts to the combined presence of light and water.

[0068] In addition, and in particular as described 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-like crystals that are sticky and tend to aggregate. This means that dry mixing with certain standard pharma- ceutically acceptable ingredients is very difficult, and it is not easy to produce blends that have a pharma- ceutically acceptable content uniformity of the active ingredient and / or that uniformity in capsules.

[0069] Moreover, micronizing the primary particles of the active ingredient also does not provide a solution to these problems, as would be expected by a person skilled in the art, and also gives rise to additional problems related to localized heating and static electricity.

[0070] However, the present inventors have found that by blending C21 or a pharma- ceutically acceptable salt thereof with a premixed blend of particulate carriers having a weight-based and / or volume-based average diameter and / or structural (particle) density similar to the weight-based and / or volume-based average diameter and / or structural (particle) density of the solid particles of C21 or a pharma- ceutically acceptable salt thereof, and a glidant, it is possible to avoid the above-mentioned problems and provide a composition for filling capsules in which C21 or a salt thereof is evenly and uniformly distributed, thus ensuring dose uniformity of the active ingredient among capsules after such filling, as well as allowing the composition to be physically and chemically stable during and after manufacture, under normal storage conditions, and during use.

[0071] Thus, in this first preferred embodiment of the invention, the excipients mixed with the particles of C21 or a pharma- ceutically acceptable salt thereof comprise a blend of at least one type of carrier particles having a weight-based and / or volume-based average diameter and / or structural (particle) density similar to the weight-based and / or volume-based average diameter and / or structural (particle) density, respectively, of C21 or a pharma- ceutically acceptable salt thereof, and a glidant. Such a composition is then loaded into a capsule suitable for oral administration and coated with an enteric material.

[0072] The terms "uniform" and "uniformly distributed" in the context of this aspect of the invention are defined as above.

[0073] In this preferred aspect of the invention, suitable carrier particle materials may include pharma- ceutically acceptable substances that are soluble in water, including carbohydrates such as sugar alcohols such as sorbitol, xylitol, and especially mannitol, and the carrier particles may also comprise physical mixtures of any of these materials and / or complexes of one or more of these materials.

[0074] The carrier particles have a similar particle size distribution and / or structural (particle) density as the active ingredient particles used in the composition that is loaded into the capsule to make the dosage form of the present invention.

[0075] By "similar particle size distribution and / or structural (particle) density" is meant that the weight and / or volume based average diameter and / or particle density of the carrier particles is within about ±75%, such as about ±50%, including about ±10%, including, for example, about ±40%, for example, about ±30%, or about ±20%, of the relevant dimension of the C21 or salt thereof used.

[0076] In this regard, preferred carrier particle sizes include weight- and / or volume-based average diameters that are less than about 100 μm, such as less than about 80 μm, such as less than about 70 μm, for example, from about 20 μm to about 60 μm (e.g., about 25 μm, or more preferably about 50 μm).

[0077] The inventors have found that by using carrier particles having a size similar to that of the active ingredient and / or within the ranges set out above, segregation of the blend is avoided.

[0078] Thus, to produce a composition to be filled into a capsule for making a dosage form according to this aspect of the invention, carrier particles of the required size are pre-blended with a suitable glidant, preferably a proprietary silica manufactured under the trade name Syloid® (see https: / / grace.com / pharma-and-biotech / en-us / Documents / Syloid / M309c), colloidal silica, and / or fumed / pyrogenic silica, prior to mixing with the active ingredient. Preferred forms of silica thus include stable aqueous dispersions (sols) of amorphous silica particles having an average diameter on a weight and / or volume basis of about 1 nm to about 100 nm (e.g., up to about 50 nm, e.g., up to about 20 nm, e.g., from about 10 nm to about 15 nm).

[0079] It is therefore preferred to mix the glidant and carrier particles together to form an interacting (or ordered) mixture of carrier particles largely coated with smaller particles of glidant material, and then mix this mixture with the active ingredient particles.

[0080] The inventors have also found that by first forming an excipient blend by adding the aforementioned glidants to the carrier particles prior to mixing with the active ingredient, the flow properties of the excipient blend are improved, which then blends better with C21 or a pharma- ceutically acceptable salt thereof, further reducing the likelihood of blend segregation.

[0081] In this aspect of the invention, the dosage form may also contain other excipients well known to those skilled in the art for oral delivery of active ingredients, such as those mentioned above.

[0082] However, in view of the extreme sensitivity of C21 and its salts to other chemicals, it is preferred that such other excipients are not included in the dosage form according to this aspect of the invention.In this regard, there is provided a dosage form of the invention consisting essentially of a pharmaceutical composition in the form of a particulate mixture comprising solid particles of C21 or a pharma- ceutically acceptable salt thereof mixed with carrier particles having a weight- and / or volume-based average diameter and / or structural (particle) density similar to that of the solid particles of C21, and a blend of glidants, the composition being suitable for oral administration and contained within a capsule coated with an enteric material.

[0083] All preferred features relating in any way to this aspect of the invention mentioned herein for other aspects of the invention are equally applicable.

[0084] The term "consisting essentially of" is understood to mean that the scope of this (and only this) aspect of the invention is limited to the specific essential features listed above, together with other features that do not materially affect the basic and novel characteristic(s) of this aspect of the invention.

[0085] In this regard, although not an essential feature of this preferred embodiment of the invention, a lubricant (such as sodium stearyl fumarate, or preferably magnesium stearate) is added to the blend prior to filling into capsules to prevent the blend from sticking to equipment (such as capsule filling machines and hoppers), but this is a preferred feature that does not materially affect the basic and novel characteristics of this embodiment of the invention.

[0086] A composition filled into a capsule that "consists essentially of" a particulate mixture comprising solid particles of C21 or a pharma- ceutically acceptable salt thereof mixed with a blend of carrier particles and a glidant as defined above alternatively means that it comprises at least about 95%, such as at least about 97% by weight of the sum of those particular ingredients.

[0087] In this first preferred embodiment of the invention, it is also preferred that the dry mixed blend is passed through a sieve at some point during the blending process to break up any agglomerates formed during the blending process, for example as described below. A suitable sieve is one that has a pore size as small (or as small as) the particle size of the largest component of the blend. Thus, a suitable sieve size is from about 50 μm, e.g., 75 μm, 100 μm, e.g., 150 μm, 200 μm or 250 μm (e.g., about 300 μm) to about 1,000 μm, e.g., about 400 μm (e.g., about 500 μm) to about 900 μm (e.g., about 800 μm).

[0088] According to a second preferred aspect of the present invention, a dosage form of the present invention is provided in which the pharmaceutical composition is presented in the form of a heterogeneous mixture comprising solid particles of C21 or a pharma- ceutically acceptable salt thereof, the C21 or a pharma- ceutically acceptable salt thereof being suspended in a pharma- ceutically acceptable hydrophobic lipid-based carrier in which the C21 or a salt thereof is essentially insoluble, the composition being suitable for such oral administration and loaded into a capsule coated with an enteric material.

[0089] The lipid-based carrier system in which the solid particles of C21 or a salt thereof are suspended can be in a solid form at room temperature (fats) or, more preferably, in a liquid form at room temperature (oils). Nevertheless, the particles of C21 or a salt thereof can be suspended in either form of lipid carrier.

[0090] According to this preferred aspect of the invention, the capsule is preferably a soft shell monolithic capsule, e.g., a soft gelatin capsule, which is filled with a lipid-based suspension of C21 or a salt thereof and then sealed as a monolith, e.g., with a drop of gelatin solution. Gelatin can be obtained from any source (e.g., porcine and bovine sources), although it should be noted that there are vegan alternatives to soft gelatin capsules.

[0091] The soft gelatin capsule shell may contain one or more plasticizers, such as xylitol, sorbitol, polyglycerol, non-crystallizing solutions of sorbitol, glucose, fructose and glucose syrup, more preferably glycerin / glycerol, sorbitol and / or proprietary plasticizers such as Anidrisorbs (a proprietary mixture of sorbitol, sorbitan, maltitol and mannitol, including Anidrisorb 85 / 70 (a liquid sorbitol-mannitol hydrolyzed starch plasticizer), Roquette Freres). The soft gelatin capsule shell may optionally contain one or more flavoring agents, coloring agents, and / or opacifying agents (such as titanium dioxide).

[0092] Such capsules can be of any shape (e.g., rectangular, circular, oval, tubular, etc.) and any size (e.g., 3-24 rectangular, 1-20 circular, 2-20 oval, 5-120 tubular, etc.) Preferred capsule sizes hold a volume of about 0.3 to about 1.0 mL.

[0093] An essential feature of this preferred embodiment of the present invention is that C21 or a pharma- ceutically acceptable salt thereof is essentially insoluble in the lipid-based carrier under normal storage conditions, including that C21 or a salt thereof has a solubility in the carrier of about 0.015 mg of C21 or a salt thereof per gram of carrier or less.

[0094] Thus, due to the dual nature of the hydrophobic carrier and its lack of tendency to dissolve C21 or its salts, the active ingredient is not exposed to amounts of water that may catalyze its decomposition as discussed above.

[0095] Surprisingly, it has been found that there are relatively few lipid-based carrier materials that meet these requirements and are therefore capable of stabilizing C21 or a salt thereof at ambient temperatures in the dosage forms of the present invention.

[0096] The hydrophobic lipid-based carrier material, in which C21 or its salts must be insoluble as described above, may comprise a non-polar oil or fat that is essentially immiscible with water. The lipid-based carrier is preferably composed primarily of triacylglycerols (also known as "triglycerides"), which are esters formed by the reaction of all three hydroxyl groups of the glycerol moiety with fatty acids (carboxylic acids).

[0097] Thus, lipids can contain saturated or unsaturated chain fatty acids, and the chains can range from 1 carbon atom up to 30 carbon atoms (including up to 26 carbon atoms), up to 22 carbon atoms (including 8, 10, 12, 14, 16, 18 or 20 carbons), etc.

[0098] Among the saturated fatty acids that may be mentioned are acetic acid (2), propionic acid (3), butyric acid (4), valeric acid (5), caproic acid (6), enanthic acid (7), caprylic acid (8), pelargonic acid (9), capric acid (10), undecylic acid (11), lauric acid (12), tridecylic acid (13), myristic acid (14), pentadecylic acid (15), palmitic acid (16), margaric acid (17), stearyl acid (18), glyceryl acid (19), glyceryl acid (20), glyceryl acid (21), glyceryl acid (22), glyceryl acid (23), glyceryl acid (24), glyceryl acid (25), glyceryl acid (26), glyceryl acid (27), glyceryl acid (28), glyceryl acid (29), glyceryl acid (30), glyceryl acid (31), glyceryl acid (32), glyceryl acid (33), glyceryl acid (34), glyceryl acid (35), glyceryl acid (36), glyceryl acid (37), glyceryl acid (38), glyceryl acid (39), glyceryl acid (40), glyceryl acid (41), glyceryl acid (42), glyceryl acid (43), glyceryl acid (44), glyceryl acid (45), glyceryl acid (46), glyceryl acid (47), glyceryl acid (48), glyceryl acid (49), glyceryl acid (50), glyceryl acid (51), glyceryl acid (52), glyceryl acid (53), glyceryl acid (54), glyceryl acid (55), glyceryl acid (56), glyceryl acid (57), glyceryl acid (58), glyceryl acid (59), The fatty acids include glyceric acid (18), nonadecylic acid (19), arachidic acid (20), heneicosylic acid (21), behenic acid (22), tricosylic acid (23), lignoceric acid (24), pentacosylic acid (25), cerotic acid (26), carboseric acid (27), montanic acid (28), nonacosylic acid (29), and melissic acid (30), where the number in parentheses is the number of carbon atoms in the fatty acid molecule.

[0099] Among the unsaturated fatty acids that may be mentioned are crotonic acid (4:1), as well as omega-3 unsaturated fatty acids, such as octanoic acid (8:1), decanoic acid (10:1), decadienoic acid (10:2), lauroleic acid (12:1), laurolinoleic acid (12:2), myristovacenic acid (14:1), myristolinoleic acid (14:2), myristolinolenic acid (14:3), palmitrinolenic acid (16:3), hexadecatrienoic acid (16:3), palmitidonic acid (16:4), alpha-linolenic acid (18:3), stearidonic acid (18:4), 11,14,17-eicosatrienoic acid. (20:3), eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5), heneicosapentaenoic acid (21:5), clupanodonic acid (22:5), docosahexaenoic acid (22:6), 9,12,15,18,21-tetracosapentaenoic acid (24:5), nisic acid (24:6) and 6,9,12,15,18,21-tetracosahexaenoic acid (24:6); omega-5 unsaturated fatty acids such as myristoleic acid (14:1), palmitovaccenic acid (16:1), alpha-eleostearic acid (18:3), beta-eleostearic acid (trans- 18:3), punic acid (18:3), 7,10,13-octadecatrienoic acid (18:3), 9,12,15-eicosatrienoic acid (20:3) and β-eicosatetraenoic acid (20:4); ω-6 unsaturated fatty acids such as tetradecenoic acid (14:1), 12-octadecenoic acid (18:1), linoleic acid (18:2), linoleic acid (trans-18:2), γ-linolenic acid (18:3), calendic acid (18:3), pinolenic acid (18:3), 11,14-eicosadienoic acid (20:2); dihomo-linoleic acid (20:2), dihomo-γ-linolenic acid (20:3), arachidonic acid (20:4), docosadienoic acid (22:2), adrenic acid (22:4), osbondic acid (22:5), tetracosatetraenoic acid (24:4) and tetracosapentaenoic acid (24:5); omega-7 unsaturated fatty acids such as 5-dodecenoic acid (12:1), 7-tetradecenoic acid (14:1), palmitic acid (16:1), vaccenic acid (18:1), rumenic acid (18:2), paulic acid (20:1), 7,10,13-eicosatrienoic acid (20:3), 15-docosenoic acid (22:1) and 17-tetracosenoic acid (24:1);ω-9 unsaturated fatty acids include hypogeic acid (16:1), oleic acid (18:1), elaidic acid (trans-18:1), gondoic acid (20:1), 8,11-eicosadienoic acid (20:2), erucic acid (22:1), nervonic acid (24:1), meadic acid (20:3) and ximenic acid (26:1); ω-10 unsaturated fatty acids, such as sapienic acid (16:1); ω-11 unsaturated fatty acids, such as gadoleic acid (20:1); and ω-12 unsaturated fatty acids, such as 4-hexadecenoic acid (16:1), petroselinic acid (18:1) and eicosenoic acid (20:1), where the numbers in parentheses are the number of carbon atoms and the number of unsaturated (i.e. double) bonds in the fatty acid molecule, respectively;

[0100] Fatty acids that may be mentioned include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, ricinoleic acid, linoleic acid, linolenic acid, eicosenoic acid, behenic acid and erucic acid.

[0101] Triglycerides can be naturally occurring oils or fats, semi-synthetic, or synthetic.

[0102] Naturally occurring oils or fats can be obtained from animals or, more preferably, from plant sources such as seeds, grains, or fruits.

[0103] Naturally occurring vegetable oils contain primarily triglycerides, which are mixtures of glycerides having different fatty acid chain lengths.

[0104] Naturally occurring pharma- ceutically acceptable oils that fall into this category include sunflower oil, soybean oil, corn oil, grapeseed oil, rapeseed oil, sesame oil, almond oil, apricot kernel oil, cottonseed oil, palm kernel oil, castor oil, olive oil, palm oil, and coconut oil (for the respective compositions, see, e.g., Occurrence and Characteristics of Oils and Fats at pages 47-224 in Padley, Gunstone and Harwood (Eds.), The Lipid Handbook., Chapman & Hall, London, 1994).

[0105] When used in the dosage forms of this preferred embodiment of the invention, the naturally occurring oils should be of pharmaceutical grade and therefore should preferably be purified after extraction from their natural source(s), which can be done using techniques well known to those skilled in the art.

[0106] Preferred oils include one or more of sesame oil, corn oil, palm kernel oil, coconut oil or soybean oil.

[0107] Semi-synthetic and synthetic lipid-based carrier systems can be made using techniques well known in the art, such as separation, interesterification, lipolysis and transesterification (glycerolysis).

[0108] Thus, semi-synthetic and synthetic lipid-based carrier systems include short-chain (C1–C5) triglycerides (e.g., triacetin) and medium-chain (C6–C 12 ) triglycerides (the main components of the naturally occurring oils palm kernel and coconut oil, e.g. capric triglyceride, more specifically Miglyol 812N); long chain (C 14 ~C 22 ) triglycerides (such as Gelicure 43 / 10), often in the form of semi-solid fats.

[0109] Whatever the form of the hydrophobic lipid-based carrier system, it is preferred that the major component of the carrier system comprises at least about 85% triacylglycerol, more preferably at least about 90% triacylglycerol, especially at least about 95% triacylglycerol.

[0110] Mixtures of any of the above naturally occurring, semi-synthetic and / or synthetic lipid-based carrier materials can be used.

[0111] In this preferred embodiment of the invention, C21 or a salt thereof is presented in the form of particles, which may be amorphous or crystalline, or a mixture of the two. Preferred particles are of a size that does not cause settling, either during the formation of the suspension, during the capsule filling process, or during storage.

[0112] In this regard, C21 or a salt thereof may be provided for suspension in a lipid-based carrier in the form of a plurality of primary (i.e. non-aggregated) particles having a weight- and / or volume-based average diameter (as above) in the same ranges and values ​​as described herein for the first preferred embodiment of the present invention.

[0113] As used herein, by particles having an average diameter on a weight and / or volume basis within the aforementioned limits includes the average diameter of the particles as prepared and prior to suspension in a lipid-based carrier, when so suspended and / or prior to loading into a capsule. Thus, primary particles of C21 / salts thereof can be prepared as described above.

[0114] Prior to loading the suspension of this second preferred embodiment of the invention into a capsule, it is important to ensure that the C21 or salts thereof are uniformly and evenly distributed throughout the suspension to ensure dose uniformity of the active ingredient after such loading into the capsule. Accordingly, the C21 and salts thereof are preferably provided in the form of particles having a relative PSD as described above.

[0115] C21 or a salt thereof may be selected and / or provided with such a PSD and / or GSD using one or more of the techniques described above to provide a stable suspension with uniform distribution of C21 / salt particles within the suspension, but the C21 / salt is thoroughly mixed with the lipid-based carrier system to provide a uniform distribution of active ingredient particles within the carrier prior to filling. This is particularly true for bulk suspensions used as part of a capsule filling process, where it is important that the mixture is not only uniform to start with, but that this uniformity is maintained throughout the filling process to ensure dose uniformity within a production batch.

[0116] The terms "uniform" and "uniformly distributed" refer to a substantially uniform content of C21 or a salt thereof throughout the lipid-based carrier material, as defined above.

[0117] If the lipid-based carrier system is in the form of a fat (i.e., solid or semi-solid at or around normal manufacturing and / or product storage temperatures), one skilled in the art will understand that the fat must be melted by raising the temperature prior to mixing.

[0118] Additionally, if desired, lipid-based carrier systems (and particularly those that are in the form of liquid oils at or around normal manufacturing and / or product storage temperatures) may further include thickeners to avoid particle aggregation and / or settling, such as microcrystalline cellulose and sodium carboxymethylcellulose, as well as blends of mono-, di- and triglycerides with PEG esters of unsaturated fats, such as Gelucire 43 / 01, hydrogenated vegetable oils, beeswax, paraffin wax, and the like, to ensure that such suspensions provide a stable, uniform and even distribution of the active ingredient within the carrier.

[0119] It has been found that by presenting C21 or a salt thereof in the form of a suspension of particles according to this aspect of the invention, the dosage form of the invention is not only able to deliver a consistent and / or uniform dose of the active ingredient, but also ensures that the active ingredient remains in a physically and chemically stable form during and / or after manufacture, under normal storage conditions, and / or during use.

[0120] As used herein, C21, or a pharma- ceutically acceptable salt thereof, can be prepared and stored in the form of a composition that can be directly filled into a capsule to prepare the dosage form of the present invention; furthermore, once prepared, the dosage form of the present invention can be stored under normal storage conditions with only minor changes in the physicochemical properties of the dosage form, the composition mixture contained therein, and / or, most importantly, the active ingredient(s) over time.

[0121] Therefore, "slight changes in physicochemical properties" includes that a composition comprising C21 / salt in a suitable carrier as described above has both physical and chemical stability before and after being filled into a capsule, and thus in the form of the dosage form of the present invention.

[0122] "Chemical stability" includes that compositions comprising C21 / salts in a suitable carrier, and dosage forms of the present invention, can be stored (with or without suitable pharmaceutical packaging) under normal storage conditions with only slight chemical degradation or disintegration of the dosage forms of the present invention and / or suspensions contained therein, particularly the active ingredient(s).

[0123] "Physical stability" includes that the suspensions comprising C21 / salts in suitable carriers, and the dosage forms of the present invention, can be stored (with or without suitable pharmaceutical packaging) under normal storage conditions with only minor degrees of physical transformation, such as dissolution, solvation, solid-state phase transitions, as described above, aggregation, separation or fragmentation, or precipitation, or changes in the nature and / or integrity, of the dosage forms of the present invention and / or the compositions contained therein, particularly the active ingredients.

[0124] Examples of "normal storage conditions" include temperatures of minus 80 to plus 50°C (preferably 0 to 40°C, more preferably ambient temperature, e.g. 15 to 30°C), pressures of 0.1 to 2 bar (preferably atmospheric pressure), relative humidity of 5 to 95% (preferably 10 to 60%), and / or exposure to 460 lux UV / visible light for extended periods (i.e., 6 months or more).

[0125] Under such conditions, C21, its salts, and / or compositions containing them may be found to be physically and / or chemically transformed by less than about 15%, more preferably less than about 10%, especially less than about 5%. Those skilled in the art will appreciate that the above upper and lower limits of temperature and pressure represent the extremes of normal storage conditions, and that certain combinations of these extremes will not be experienced during normal storage (e.g., a temperature of 50°C and a pressure of 0.1 bar).

[0126] Pharmaceutical compositions, whether in the form of a dry powder mix, lipid-based suspension or other, and / or contained within a capsule as described above or otherwise, are preferably prepared and / or stored in an essentially water-free state.

[0127] "Essentially free of water" includes that appropriate precautions are taken to ensure that both the particles C21 or a salt thereof and the excipient with which it is mixed are prepared and / or provided separately in an essentially dry manner, and are mixed together to form a dry mixture in an environment in which they are also kept essentially dry.

[0128] "Essentially dry" or "essentially free of water" includes that the composition comprising C21 / salt and related excipients, as a whole, contains less than about 5%, including less than about 2%, less than about 1%, including less than about 0.5%, e.g., less than about 0.1% water.

[0129] Further processing of the composition comprising C21 or a salt thereof and associated excipients into the dosage form of the present invention as described above may also preferably be carried out in such a manner that it remains essentially free of water.

[0130] In this regard, a pharma- ceutically acceptable encapsulant may contain residual amounts of water, but ingress of water from the encapsulant into the composition (whether in solid (e.g., a powder mixture) or liquid (e.g., a lipid suspension) form) should be minimized to protect the sensitive C21 or its salt from contact with water and to prevent degradation in the presence of light.

[0131] Nonetheless, it is preferable (though not essential) to package the dosage forms of the present invention in a manner that keeps the dosage form itself dry and protected from light, which may include hermetic packaging, the use of deliquescent materials, and the like.

[0132] According to a further aspect of the present invention, there is provided a process for producing the dosage form of the present invention, the process comprising coating a composition comprising C21 or a pharma- ceutically acceptable salt thereof with an enteric material.

[0133] Pharmaceutically acceptable salts of C21 include acid addition salts. Such salts can be formed by conventional means, for example, by reacting C21 in the form of a free acid (hereinafter, free C21) with one or more equivalents of a suitable acid, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques (for example, by vacuum, lyophilization, or filtration). Salts can also be prepared by exchanging the counterion of the active ingredient in the form of a salt with another counterion, for example, using a suitable ion exchange resin. Preferred salts of C21 include HCl salt, alkaline earth salts such as magnesium and calcium salts, and alkali metal salts such as potassium salt or preferably sodium salt.

[0134] The amount of C21 or a salt thereof in the dosage form of the present invention will depend on and / or can be selected according to the severity of the condition, or the expected severity of such, and the patient being treated, and can be determined by one of skill in the art. The method of administration can also be determined by the timing and frequency of administration, as well as the severity of the condition.

[0135] A suitable lower daily dose of C21 in an adult patient (average body weight, e.g., 70 kg) may be about 10 mg, e.g., about 20 mg, e.g., about 25 mg per day. Suitable upper limits of the daily dose range of C21 can include up to about 900 mg, such as 600 mg, including about 400 mg, and about 200 mg, such as about 100 mg, and about 50 mg.

[0136] All the above doses are calculated as free C21. The dose can be divided into multiple individual doses per day. The dose can be given 1 to 6 times a day, for example 4 times a day, preferably 3 times a day, more preferably 2 times a day.

[0137] In any event, a medical practitioner or other skilled artisan can routinely determine the actual dosage which will be most suitable for an individual patient, depending on the severity of the condition and the route of administration. The above dosage amounts are exemplary of the average case, and there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

[0138] The dose administered to a patient, in the context of the present invention, must be sufficient to bring about an appropriate patient response over a reasonable time frame (as described herein above). Those skilled in the art recognize that the selection of the exact dose and composition and the most appropriate delivery regimen is also influenced by, among other things, the pharmacological properties of the formulation, the nature, stage, and / or severity of the pathology being treated, the physical and mental state of the recipient, the age, condition, weight, sex, and response, etc., of the patient being treated, as well as the stage / severity of the disease, and genetic differences between patients.

[0139] The dosage forms of the present invention are useful in conditions where AT2 receptors are expressed and their stimulation is desirable or required.

[0140] 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 disorders and musculoskeletal disorders.

[0141] The dosage forms of the present invention are particularly indicated for the treatment and / or prevention of ILDs, such as sarcoidosis or fibrosis, more particularly PF, especially IPF, as well as conditions which may 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.

[0142] 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 an inhibitory effect on platelet activation and / or aggregation (hence, for example, an antithrombotic effect) and / or may reduce vasoconstriction and / or bronchoconstriction in a therapeutic manner.

[0143] The dosage forms of the present invention are further indicated in the treatment of stress-related disorders and / or in improving microcirculatory and / or mucosal protective mechanisms.

[0144] Thus, the dosage forms of the present invention are expected to be useful in the treatment of diseases that can be characterized as above, such as those affecting the gastrointestinal tract, the cardiovascular system, the respiratory tract, the kidneys, the immune system, the eye, the female reproductive (ovulation) system and the central nervous system (CNS).

[0145] Gastrointestinal disorders that may be mentioned include esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, dyspepsia (including non-ulcer dyspepsia), gastroesophageal reflux, irritable 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, coeliosis, Crohn's disease, ulcerative colitis, diarrhea, constipation, colitis, anorexia, vomiting, nausea, dyspepsia and Sjogren's syndrome.

[0146] Disorders of the airways 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 respiratory distress syndrome.

[0147] Renal diseases that may be mentioned include renal failure, diabetic nephropathy, nephritis, and renal hypertension.

[0148] Eye diseases that may be mentioned include diabetic retinopathy, retinopathy of prematurity, and retinal microvascularization.

[0149] Diseases of the female reproductive system that may be mentioned include ovulatory dysfunction and endometriosis.

[0150] Cardiovascular diseases that may be mentioned include hypertension, cardiac hypertrophy, heart failure (including heart failure with preserved ejection fraction), atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial lesions, post-balloon dilation stenosis, angiogenesis, diabetic complications, microvascular dysfunction, angina, cardiac arrhythmias, intermittent cloudicates, pre-eclampsia, myocardial infarction, reinfarction, ischemic lesions, erectile dysfunction and neointimal proliferation.

[0151] Diseases of the CNS that may be mentioned include cognitive dysfunction, dysfunction of food intake (hunger / satiety) and thirst, stroke, cerebral hemorrhage, cerebral embolism and cerebral infarction, multiple sclerosis (MS), Alzheimer's disease and Parkinson's disease.

[0152] 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, prostatic hyperplasia, autoimmune diseases (e.g., arthritis such as rheumatoid arthritis, or systemic lupus erythematosus), psoriasis, obesity, nerve cell regeneration, ulcer healing, inhibition of adipose tissue hyperplasia, stem cell differentiation and proliferation, fibrotic diseases, cancer (e.g., of or in 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.), inhibition of apoptosis, tumors (in general) and hypertrophy, diabetes, neurological lesions, and organ rejection.

[0153] The dosage forms of the present invention are also useful in the treatment of stroke, spinal cord injury, sickle cell disease, muscular dystrophies, cancer therapy-related cardiac toxicity, peripheral neuropathy, and especially systemic sclerosis.

[0154] Furthermore, the dosage form of the present invention may be useful for treating respiratory virus-induced tissue damage, which may include damage and / or dysfunction of associated tissue.Associated tissues include tissues (such as mucous membranes) of the airways, particularly lung tissue.Accordingly, associated tissues include the respiratory epithelium, which moistens the airways and protects them from the invasion of pathogens such as viruses.

[0155] Respiratory viruses that may be mentioned in this respect include influenza viruses, such as influenza A viruses (e.g. H1N1 and H3N2 viruses), influenza B viruses or influenza C viruses, and more specifically severe acute respiratory syndrome (SARS) coronaviruses, such as SARS coronavirus (SARS-CoV), in particular novel SARS coronavirus 2 (SARS-CoV-2, formerly known as "2019-nCoV" or "novel coronavirus 2019"), which is the virus that causes coronavirus disease 2019 (COVID-19), of which there are many genetic variants.

[0156] "Treatment of tissue damage" includes that C21 and its salts not only have a beneficial effect on tissue damage in the airways caused by the above viruses, but may also prevent and / or reduce damage otherwise caused by the relevant virus in the airways, which occurs, for example, when the virus invades epithelial cells in the airways.

[0157] Thus, C21 and its salts may inhibit or prevent such virus-induced tissue damage and / or the onset of disease caused by such damage or disease symptoms.

[0158] In this regard, C21 and its salts may treat and / or arrest the progression of diseases caused or caused by respiratory viruses (i.e., influenza, as well as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), particularly SARS, and more specifically COVID-19) and their sequelae. C21 and its salts may also treat and / or prevent damage caused or caused by such viruses, including the treatment and / or prevention of symptoms of such respiratory diseases, including coughing, dyspnea, shortness of breath (e.g., as manifested by the need for supplemental / supplemental oxygen (which may be administered via face mask or nasal cannula (high flow or otherwise)), and / or the need for mechanical ventilation / extracorporeal membrane oxygenation), respiratory failure, and / or direct (viral pneumonia) and / or indirect pneumonia (bacterial pneumonia resulting from secondary bacterial infection common with influenza), and subsequent fibrosis resulting from inflammation of the lungs and other organs (e.g., heart and kidneys). Additionally, C21 and its salts may prevent or arrest the progression of morbidity and / or mortality induced by respiratory viruses, and C21 may treat and / or arrest the onset of any of the chronic conditions identified above.

[0159] Furthermore, the dosage forms of the present invention may also be useful in the treatment or prevention of fibrotic conditions in one or more internal organs characterized by excessive accumulation of fibrous connective tissue, and / or in the treatment or prevention of fibrosis and the morbidity and mortality that may be associated therewith. Such fibrosis may be associated with acute inflammatory conditions such as acute respiratory distress syndrome (ARDS), (SARS), multi-organ inflammation, and injury and / or failure that may be caused by internal or external trauma (e.g., injury) or infection.

[0160] Thus, such conditions may result from sepsis or septic shock caused by viral, bacterial, or fungal infections. Additionally, acute lung injury, ARDS, and especially SARS, may be caused by viruses such as coronaviruses, of which SARS-CoV-2 is a part, and may cause internal tissue damage and / or dysfunction of associated internal (e.g., mucosal) tissues and / or the cells that contain them (such as the respiratory epithelium). Such tissue damage may then cause severe fibrosis. For example, SARS disease caused by SARS-CoV-2 (coronavirus disease 2019 or COVID-19) is known to often cause fibrosis.

[0161] However, the dosage forms of the present invention are also particularly useful for the treatment and / or prevention of ILDs such as sarcoidosis or fibrosis, more particularly pulmonary fibrosis, in particular IPF, as well as conditions which may 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.

[0162] The term "ILD" will be understood by those skilled in the art to include any pulmonary condition, regardless of cause, such as sarcoidosis, and PF, especially IPF, characterized by chronic inflammation, reduced lung function and / or an abnormal healing response, including scarring. The term may also include diseases and / or conditions known to lead to and / or cause such pulmonary conditions, such as systemic sclerosis. In this regard, there is further provided a dosage form of the present invention for use in conditions that lead to and / or cause ILD, such as PF or IPF, including systemic sclerosis.

[0163] In the treatment of PF, including IPF, the dosage form of the present invention may have an anti-fibrotic effect, involving the reduction of fibrosis and the prevention of further deposition of extracellular matrix. The dosage form of the present invention may affect lung scarring / wound healing and may also have an anti-apoptotic effect, thereby preventing the apoptosis of alveolar endothelial cells, which is an initiator of the development of PF. The dosage form of the present invention may also have an anti-proliferative effect, thus reducing the cancer-like proliferation of fibroblasts and myofibroblasts in PF. The dosage form of the present invention may also improve vascular remodeling in PF, thereby reducing secondary pulmonary hypertension. Finally, the dosage form of the present invention may exhibit anti-inflammatory and anti-cytokine effects.

[0164] According to a further aspect of the present invention there is provided a method for treating any of the aforementioned conditions including respiratory viral damage, more particularly ILD including PF, particularly IPF, which method comprises administering to an individual suffering from or susceptible to such a condition a therapeutically effective amount of a dosage form of the present invention.

[0165] According to yet another aspect of the present invention there is provided a method for treating respiratory virus induced tissue damage in a subject, the method comprising administering a therapeutically effective amount of a dosage form of the present invention to a subject in need of said treatment, in particular • The tissues that are damaged are lung tissues, including the respiratory epithelium; ● The damage includes damage and / or dysfunction of the mucosal tissue of the airways caused by respiratory viruses; Treatment includes curing and / or preventing the progression of a disease caused or caused by a 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 the symptoms of a disease caused or caused by the relevant virus; Symptoms of injury or disease include one or more of the following: coughing, difficulty breathing, shortness of breath (manifested by the need for supplemental oxygen and / or mechanical ventilation), respiratory failure, pneumonia, fibrosis of one or more internal organs including the lungs, heart and / or kidneys; and / or - Treatment includes the prevention of respiratory virus-induced morbidity and / or mortality in one or more of the aforementioned conditions.

[0166] The dosage forms of the present invention are indicated for both the therapeutic, symptomatic and / or diagnostic treatment, (e.g. during diagnostic work-up when the condition has ceased) and prophylactic treatment (thereby including prevention and / or arrest of the reduction and / or worsening of the condition), of any of the above mentioned conditions.

[0167] "Patient" includes avian and mammalian (especially human) patients. Human patients include both adult and pediatric patients, the latter including patients up to about 24 months of age, patients from about 2 to about 12 years of age, and patients from about 12 to about 16 years of age. Patients over about 16 years of age may be considered adults for purposes of the present invention. These different patient populations may be administered different doses of C21 or a salt thereof.

[0168] In the treatment of certain conditions, such as respiratory virus-induced tissue damage, C21 or a pharma- ceutically acceptable salt thereof is preferably administered to adult patients, more particularly to subjects over about 20 years of age, e.g., over about 30 years of age, including over about 40 years of age, more preferably over about 50 years of age, particularly over about 60 years of age, particularly over about 70 years of age, more particularly over about 80 years of age; and / or to patients having one or more of the following underlying medical conditions (regardless of 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 ILDs, asthma, chronic obstructive pulmonary disease (COPD), emphysema or bronchitis ● Chronic cardiovascular (e.g., heart) disease, such as heart failure, atrial fibrillation, or high blood pressure; ● Chronic kidney disease - Chronic liver disease such as hepatitis ● Chronic neurological conditions such as Parkinson's disease, motor neurone disease, multiple sclerosis, learning disabilities or cerebral palsy ● Diabetes Problems with the patient's spleen - for example, sickle cell disease or if the spleen has been removed A weakened immune system as a result of conditions such as HIV and AIDS, or drugs such as steroid tablets or chemotherapy ● Obesity (e.g., a body mass index (BMI) of 40 or higher) Pregnancy

[0169] In this regard, according to some further aspects of the invention there are provided methods for the treatment and / or prophylaxis of one or more of the following conditions: - Post-acute sequelae of SARS-CoV-2 infection (PASC), such as those known as "long COVID", "chronic COVID syndrome" (CCS) and / or "long-haul 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 or bronchitis; and - Cardiovascular diseases such as myocardial infarction, heart failure, atrial fibrillation, hypertension or thrombosis and / or embolism in, for example, the heart, lungs and / or brain.

[0170] All of these may be induced directly or indirectly by a respiratory virus (such as SARS-CoV-2), and the method includes administering C21 or a pharma- ceutically acceptable salt thereof to a subject in need of such treatment and / or prevention.

[0171] In connection with the acute treatment of (for example) respiratory virus-induced tissue damage, a dose of C21 or a salt thereof can be administered 1-4 (e.g. 1-3) times daily for up to 3 months (e.g. 2 months), such as 1 month including up to 3 weeks, for up to 1 week, such as 4 or 3 days. Such treatment periods can be repeated as necessary.

[0172] If one or more of the aforementioned chronic conditions occur, such as fibrosis of the lungs and other internal organs, treatment with C21 or a salt thereof may be administered continuously and / or on an as-needed basis / required in addition to and / or in place of the acute dosing regimen described above.

[0173] Relevant active ingredients that may be used in combination with C21 in the treatment of patients with viral infections include standard therapies that are applied differently depending on the viral infection, such as antibody therapies (e.g. LY-CoV555 / LY-CoV016 (bamlanivimab and etesevimab)), LY-CoV555 (bamlanivimab, Eli Lilly), REGN-COV2 (casirivimab and imdevimab), REGN3048-3051, TZLS-501, SNG001 (Sinaligen), eculizumab (Soliris; Alexion Pharmaceuticals), ravulizumab (Ultomiris; Alexion Pharmaceuticals), lenzilumab, leronlimab, tocilizumab (Actemra; Roche), sarilumab (Kevzara; Regeneron Pharmaceuticals), and sarilumab (Saligen; Regeneron Pharmaceuticals). Pharma, and Octapharma), antivirals (e.g., oseltamivir, remdesivir, favipiravir, molnupiravir, simeprevir, daclatasvir, sofosbuvir, ribavirin, umifenovir, lopinavir, ritonavir, lopinavir / ritonavir (Kaletra; AbbVie Deutschland 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 Pharma), anti-inflammatories (e.g. NSAIDs such as ibuprofen, ketorolac, naproxen, chloroquine, hydroxychloroquine, interferons (e.g. interferon beta (interferon beta-1a), tocilizumab (Actemra), lenalidomide, pomalidomide and thalidomide), analgesics (e.g. paracetamol or opioids), cough suppressants (e.g. dextromethorphan), vaccinations (e.g. INO-4800 by Inovio Pharmaceuticals and Beijing Advaccine Biotechnology, when available), passive antibody therapy with COVID-19 convalescent plasma (CCP) and / or antibodies from the blood of people who have recovered from SARS-CoV or SARS-CoV-2 infection.

[0174] Related active ingredients that may be used in combination therapy with C21 in the treatment of ILDs such as IPF include, for example, antifibrotic agents (e.g., nintedanib, especially pirfenidone); vitamins (e.g., vitamins B, C, D); mucolytic agents (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. In the treatment of sarcoidosis, relevant active ingredients that may be used in combination therapy with C21 include, for example, corticosteroids such as cortisone, prednisone and prednisolone; antimetabolites; immune system suppressants such as methotrexate, azathioprine, leflunomide, mycophenolate / mycophenolate mofetil, cyclophosphamide; aminoquinolines; monoclonal anti-tumor necrosis factor antibodies such as infliximab and adalimumab; immunomodulatory imides such as lenalidomide, pomalidomide and especially thalidomide; TNF inhibitors, etanercept; and analgesics such as ibuprofen and paracetamol; cough suppressants, and / or expectorants.

[0175] For the avoidance of doubt, reference above to "corticosteroids" includes both naturally occurring and synthetic corticosteroids.

[0176] Naturally occurring corticosteroids that may be mentioned include cortisol (hydrocortisone), aldosterone, corticosterone, cortisone, pregnenolone, progesterone, and naturally occurring precursors and intermediates in corticosteroid biosynthesis, as well as 11-deoxycortisol, 21-deoxycortisol, 11-dehydrocorticosterone, 11-deoxycorticosterone, 18-hydroxy- ... Included are other derivatives of naturally occurring corticosteroids such as corticosterone, 21-deoxycortisone, 11β-hydroxypregnenolone, 11β,17α,21-trihydroxypregnenolone, 17α,21-dihydroxypregnenolone, 17α-hydroxypregnenolone, 21-hydroxypregnenolone, 11-ketoprogesterone, 11β-hydroxyprogesterone, 17α-hydroxyprogesterone, and 18-hydroxyprogesterone.

[0177] Among the synthetic corticosteroids that may be mentioned are cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, tixocortol and tixocortol pivalate, prednisolone, methylprednisolone, cloprednol, difluprednate, fludrocortisone, fluocinolone, fluperolone, fluprednisolone, prednisone, chloroprednisone, cloprednol, difluprednate. , hydrocortisone types (Group A) such as fludrocortisone, fluocinolone, fluperolone, fluperednisolone, loteprednol, prednicarbate and triamcinolone; acetonides and related substances (Group B) such as amcinonide, budesonide, desonide, fluocinolone setonide, fluocinonide, halcinonide, triamcinolone acetonide, ciclesonide, deflazacort, formocortal, fludroxycortide, flunisolide and fluocinolone acetonide; beclomethasone, betamethasone betamethasone dipropionate and betamethasone valerate, dexamethasone, flucortolone, halometasone, mometasone and mometasone furoate, alclometasone and alclometasone dipropionate, clobetasol and clobetasol propionate, clobetasone and clobetasone butyrate, clocortolone, desoximetasone, diflorasone, difluocortolone, fluclorolone, flumethasone, fluocortin, fluprednidene and fluprednidene acetate, fluticasone, fluticasone (β)methasone type (group C) such as fluticasone furoate and fluticasone propionate, meprednisone, paramethasone, prednylidene, rimexolone and urobetasol; progesterone type such as flugestone, fluorometholone, medrysone and prebedilon acetate; and progesterone derivatives (progestins) such as chlormadinone acetate, cyproterone acetate, medrogestone, medroxyprogesterone acetate, megestrol acetate and segesterone acetate;and other corticosteroids such as cortivazol and 6-methyl-11β,17β-dihydroxy-17α-(1-propynyl)androsta-1,4,6-trien-3-one.

[0178] Preferred corticosteroids include cortisone, prednisone, prednisolone, methylprednisolone, and especially dexamethasone.

[0179] Additionally, related active ingredients that may be used in combination therapy with C21 (e.g., to treat respiratory viral infections) include H2 receptor blockers, anticoagulants, antiplatelet agents, as well as statins, antibacterial agents, and antiallergic / antiasthmatic agents.

[0180] 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, certoparin, dalteparin, tinzaparin); direct acting oral anticoagulants (e.g. dabigatran, argatroban, rivaroxaban, apixaban, edoxaban, betrixaban, darexaban, otamixaban, retaxaban, erivaxaban, hirudin, lepirudin, and bivalirudin); coumarin type vitamin K antagonists (e.g. coumarin, acenocoumarol, phenclocoumone, atromentin, and phenindione) and synthetic pentasaccharide inhibitors of factor Xa (e.g. fondaparinux, idraparinux, and idrabiotaparinux). Antiplatelet drugs that may be mentioned include irreversible cyclooxygenase inhibitors (e.g., aspirin 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., vorapaxal); glycoprotein IIB / IIIA inhibitors (e.g., abciximab, eptifibatide and tirofiban); adenosine reuptake inhibitors (e.g., dipyridamole); and thromboxane inhibitors (e.g., terutroban, ramatroban, seratrodast and picotamide). Statins that may be mentioned include atorvastatin, simvastatin and rosuvastatin. Antibacterial 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.

[0181] Additionally, related active ingredients that may be used in combination therapy with C21 (e.g., to treat 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 inhibitors of angiotensin-converting enzyme (ACE). Non-limiting but illustrative examples of AT1 receptor antagonists that may be used according to the embodiments include azilsartan, candesartan, eprosartan, fimasartan, irbesartan, losartan, milfasartan, olmesartan, pomisartan, pratosartan, lipiasartan, saprisartan, tasosartan, telmisartan, valsartan, and / or combinations thereof. Non-limiting, but illustrative examples of ACE inhibitors that may be used in accordance with the embodiments include captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, fosinopril, moexipril, cilazapril, spirapril, temocapril, ceronapril, delepril, mouvertipril, and / or combinations thereof.

[0182] The relevant patients may also be receiving (and / or are already receiving) one or more of any of the above treatments and / or other therapeutic agents for the relevant condition based on the administration of one or more of such active ingredients, thereby meaning that the inventors will receive prescribed doses of one or more of these active ingredients mentioned herein before, in addition to, and / or after treatment with C21 or a salt thereof.

[0183] Pharmaceutically acceptable salts and dosages of the other active ingredients listed above include those known in the art and are described in the medical literature for the drugs in question, e.g., Martindale-The Complete Drug Reference, 38th Edition, Pharmaceutical Press, London (2014 and documents cited therein, all of which related applications are incorporated herein by reference.

[0184] The dosage forms of the present invention have the advantage that they can be manufactured and stored under normal storage conditions, including without exposure to freezing and / or light, while maintaining pharma- ceutically acceptable physicochemical stability of the compositions, particularly the active ingredients, contained therein along with the capsule.

[0185] The dosage forms of the present invention may also provide improved drug loading, allowing for the presentation of larger amounts / doses of active compound, and may provide efficient delivery of such higher doses in a consistent / uniform manner, thereby improving efficacy and efficiency of treatment and reducing healthcare costs.

[0186] The uses / methods described herein, whether used for these conditions or otherwise, may have advantages over similar methods (treatments) known in the prior art in that they may be more convenient for the physician and / or patient, more effective, less toxic, have a broader spectrum of activity, be more potent, cause fewer side effects, or have other useful pharmacological properties, in the treatment of one or more of the above-mentioned conditions, particularly ILD and / or respiratory viral infections.

[0187] Whenever the word "about" is used herein, for example in the context of an amount, i.e., absolute amount such as size (e.g., particle size), dosage, weight or concentration of an (active) ingredient, age, temperature or duration, or a relative amount including percentages, standard deviations, it is understood that such variables are approximate and may vary from the actual numerical value specified by ±10%, e.g., ±5%, preferably ±2% (e.g., ±1%). In this regard, the term "about 10%" means, for example, ±about 10% for the number 10, i.e., between 9% and 11%.

[0188] The present invention is illustrated by the following examples without, however, being limited thereby.

[0189] Working Example Example 1 Observing the effects of diet in a clinical setting A Phase I clinical trial was conducted to evaluate the safety, tolerability, and pharmacokinetics of C21 in healthy male and female subjects. The study design allowed for dose escalation with intensive clinical data and PK monitoring to ensure the safety and well-being of subjects.

[0190] The study was designed and conducted according to the CRO's standard operating procedures (SOPs), in accordance with the ethical principles based on the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidance required by major regulatory authorities, and in accordance with the Declaration of Helsinki as amended by the 48th Plenary Assembly in October 1996. C21 was found to be safe and generally well tolerated. No serious adverse events were recorded.

[0191] Additionally, the effect of food on the pharmacokinetics (PK) of C21 was investigated in an open-label study in 10 male and female subjects following a single oral dose of 75 mg.

[0192] Subjects were randomized to receive two single doses of 75 mg of C21 at least three days apart in either a fasted or fed state, with a high-fat breakfast as recommended by the Food and Drug Administration (FDA) to study maximum efficacy.

[0193] For the dietary effects portion of the study, subjects' ages ranged from 22 to 44 years, with a median age of 36.0 years. Most subjects were white (9 (90.0%) subjects) and male (8 (80.0%) subjects). The mean (SD) BMI for the entire study was 23.96 (2.223) kg / m 2 It was.

[0194] C21 sodium salt as a pre-frozen oral solution (containing 2.5 mg / mL of C21 sodium salt, sodium salt dissolved in carbonate aqueous buffer), the composition of which is shown in Table 1 below. [Table 1]

[0195] Plasma concentrations below the lower limit of quantification (LLOQ) were expressed as below the lower limit of quantification (BLQ). Plasma concentrations of C21 were summarized by study part, dose cohort, and nominal time point.

[0196] Pharmacokinetic parameters were calculated by non-compartmental analysis from concentration-time data using Phoenix® WinNonlin® (version 8.0) or later according to the following guidelines.

[0197] • Actual sampling times related to dosing rather than nominal times were used for the calculation of all derived pharmacokinetic parameters. ● There was no imputation of missing data. ● At least C max and AUC( 0-t) All subjects with missing concentration data were included in the PK analysis set if they could be reliably calculated.

[0198] All BLQ values ​​during the pre-dose and absorption phase prior to the first quantifiable concentration were replaced with zero. Single BLQs between two evaluable concentrations were replaced with missing values ​​before calculating PK variables. Consecutive BLQs between evaluable concentrations were replaced with zero values ​​before calculating PK variables. Terminal BLQ values ​​were ignored.

[0199] A mixed-effects model based on natural log-transformed data was used to determine bioequivalence of PK parameters from the open-label food effect arm by constructing 90% confidence intervals around the estimated differences between test and reference treatments. The mixed-effects model was implemented using SAS Proc Mixed, using the REML estimation method and the Kenward-Roger degrees of freedom algorithm.

[0200] Natural log-transformed AUC( 0-inf) (if data permits), AUC( 0-24 ), and C maxwas analysed using a mixed-effects model with sequence, period and treatment as fixed effects and subject within sequence as a random effect. Estimates of the mean difference (trial-reference) and corresponding 90% confidence intervals were obtained from the model. The estimated mean difference and the 90% confidence interval of the difference were exponentiated to provide an estimate of the ratio of the geometric means (trial / reference) and the 90% confidence interval of the ratio. C21 in the fasted state is the reference treatment and C21 in the fed state is the test treatment.

[0201] Comparisons assessing the effect of food (bioequivalence) were used to evaluate the effect of food on the rate and extent of absorption of C21 administered under fasted and fed conditions, and estimates of the mean differences and corresponding 90% confidence intervals were presented.

[0202] The pharmacokinetic parameter data for C21 are briefly summarized in Table 2 below (Tables 2-1 to 2-3).

[0203] [Table 2-1]

[0204] [Table 2-2]

[0205] [Table 2-3]

[0206] After oral administration of 75 mg C21, peak plasma concentrations were median t max It occurred in 0.67 and 1.26 hours, respectively. The geometric mean C max was 1708 ng / mL at 75 mg fasting and 263 ng / mL at 75 mg fed.

[0207] C max The variability (geometric CV%) of was 37% and 22% in the fasted and fed states, respectively. (0-12)were 1767 h*ng / mL and 767 h*ng / mL at 75 mg fasted and fed, respectively. All AUC parameters were comparable for each treatment, and the geometric CV% of the AUC parameters ranged from 21% to 34% at 75 mg fasted and fed. Mean t 1 / 2 was less than 1 hour for both fasted and fed treatments. Consistent with the measured AUC values, CL / F was approximately 2-fold higher in the fed treatment, and V z / F was three-fold higher compared with fasting treatment values.

[0208] The statistical analysis of the effect of diet on C21 is summarized in Table 3. [Table 3]

[0209] The model is an analysis of variance (ANOVA) model with fixed effects for sequence, period, and treatment, and a random effect for subject within sequence. Statistical analysis of the effect of food on C21PK parameters (see Table 3 above) showed that C21 was significantly lower when given with food than C21 when given with food. max It was shown that there was a decrease in C max The geometric mean ratio of is 0.16, with a 90% confidence interval below 1 (100%), and C max The difference between the AUC and C21 concentrations was statistically significant. (0-24) is decreased, AUC (0-inf) the geometric mean ratios were both 0.45, with 90% confidence intervals below 1 (100%), indicating that the differences in AUC values ​​were significant.

[0210] Example 2 Dissolution Test (A) 50.7 mg of C21 sodium salt (Ardena, Riga, Latvia) was added to 900 mL of 0.09 M carbonate buffer (pH 8.95) with stirring at a temperature of 37 ± 3 °C. The compound dissolved immediately. After stirring for 15 min, 2 M acetic acid solution was added dropwise to obtain a pH of 4.52. Evolution of CO2 was noted. After stirring for 1 h, the formation of small white particles was observed. After stirring for a further 1.5 h, the pH was raised to 6.8 by adding 1 M NaOH. Stirring was continued for a further 1.5 h without any significant change in appearance (small white particles).

[0211] (B) 51.2 mg of C21 sodium salt was added to 900 mL of acetate buffer (pH 4.4) with stirring at the same temperature. The added compound formed a thin slurry that floated on top of the surface. After stirring for 1 hour, 1 M NaOH solution was added dropwise to raise the pH to 7.2. The slurry became thinner, the pieces became smaller, and it became cream-like. Stirring was continued for another 1.5 hours with no significant change in appearance (small cream-like particles).

[0212] (C) 53.2 mg of C21 sodium salt was added to 900 mL of 0.1 M HCl buffer (pH 1.0) at the same temperature while stirring. The added compound dissolved instantly. After stirring for 20 min, 1 M NaOH solution was added dropwise to raise the pH to 4.5. No precipitation was observed after the addition of NaOH solution. After stirring for 2 h, the formed solution was still clear.

[0213] (D) 51.0 mg of C21 sodium salt was added to 900 mL of 0.1 M citrate buffer (pH 4.42) with stirring at the same temperature. The added compound formed a thin slurry. Nothing seemed to dissolve. After stirring for 7 hours at the same temperature, there was no significant change in appearance. Analysis by UPLC indicated that no decomposition of C21 had occurred at the end of the experiment.

[0214] (E) At the same temperature, 50.8 mg of C21 sodium salt was added to 900 mL of acetate buffer (pH 4.49). The added compound formed a thin slurry floating on the surface. After stirring for 1 hour, 1 M NaOH solution was added dropwise to raise the pH to 6.8. The slurry thinned slightly. Stirring was continued for another hour with no significant change in appearance. UPLC showed that no decomposition of C21 had occurred at the end of the experiment.

[0215] Taken together, these results indicate that the zwitterion of C21 formed at intermediate pH is unexpectedly insoluble, explaining the dietary effect seen in Example 1 above.

[0216] Example 3 Dosage forms of the present invention The excipient blend was prepared by weighing 21.4 g of colloidal silicon dioxide (Aerosil®; Evonik) into a weigh boat. Next, 2033.8 g of mannitol (Pearlitol 50C, Roquette) was weighed and approximately half of that amount was poured into the 25L V-shell of a V-blender (Multiblender, Pharmatech, UK). The weighed amount of colloidal silicon dioxide was then added to the V-shell, followed by the remaining mannitol. The resulting mixture was blended for 10 minutes at 30 rpm.

[0217] The excipient blend was then sieved through an 800 μm sieve and then blended for an additional 20 minutes at 30 rpm.

[0218] Half of the resulting excipient blend was weighed and re-added to the V-shell. Next, 528 g of C21 sodium salt (Ardena, Riga, Latvia) was added to the V-shell. Next, the remaining excipient blend was added to the V-shell, followed by blending for 10 minutes at 30 rpm.

[0219] The resulting blend was then sieved through an 800 μm sieve and subsequently blended at 30 rpm for 20 minutes.

[0220] After the blends were prepared, approximately 270 mg of blend sample was weighed into a 100 mL volumetric flask, 40 mL of MilliQ water and sonicated for 20 minutes, and the homogeneity of the blends was determined by adding 40 mL of methanol and sonicating for an additional 20 minutes. After equilibrating to room temperature, 1.0 mL of the sample solution was added to a 10 mL volumetric flask. This was followed by dilution to the desired volume with methanol and mixing.

[0221] 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 C21 Na salt (for a nominal sample concentration of 100%).

[0222] The results are shown in Table 4 below. [Table 4]

[0223] After this, 26.1 g of magnesium stearate (Ligamed MF-2-V, Peter Greven, Germany) was sieved through an 800 μm sieve and added to the blend, followed by final blending for 15 minutes at 15 rpm.

[0224] The final composition is as shown in Table 5 below. [Table 5]

[0225] Approximately 6,700 capsules were encapsulated using a MG Compact (MG2, Bologna, Italy) dosator size 0 with the following settings applied to the chamber-11 mm: compression-0 mm; powder layer: 30.0 mm;

[0226] Weight classification was performed by applying a 5% acceptance limit to the capsule net fill weight, which was found to be 18.6%. After encapsulation, the capsules were primary packaged manually into 100 mL high density polyethylene (HDPE) bottles with child-resistant tamper-resistant caps containing a desiccant (56 capsules / bottle). A total of 97 bottles were produced and labeled for use in clinical trials.

[0227] Approximately 600 of these capsules (obtained according to the procedure described in Example 3 above) were coated using a pan coater (4M8TriX pan coater equipped with a 2 L drum and a 0.7 mm diameter nozzle; ProCepT, Belgium) with an aqueous acrylic enteric coating system (applied as a 20% solution in water).

[0228] 640 g of purified water was weighed into an 800 mL beaker, and 160 g of pre-weighed Acryl-EZE® 93F19225 Clear (Colorcon) was gradually added to the water while mechanically stirring for 20 minutes, with the propeller stirrer placed in the center and as close to the bottom of the container as possible, forming a vigorous vortex to homogenize. Prior to the coating process, the dispersion was passed through a 200 μm sieve.

[0229] To facilitate good capsule movement in the pan coater and to arrive at the right amount to load into the drum, 560 dummy capsules (size 0) are also added along with different capsule colors (dark green) and fill weights (410 mg / capsule of mannitol (Pearlitol 160C) to allow later separation by weighing and visual inspection.

[0230] Stepwise coating was performed with samples taken at given times.

[0231] The coating process was carried out by loading the capsules into a drum and setting the inlet temperature at 40° C. While the drum was rotating, the capsules were heated to 30° C. before being sprayed with the coating solution, at which point the final inlet temperature was set.

[0232] At the end of the coating process, the heating system was turned off and the capsules were allowed to dry by slowly rolling.

[0233] The spray volume was 740 g. The fill content of the composition per capsule is 260.93 mg per capsule. With an empty capsule weight of 96.1 mg and a total weight per filled capsule of 357 mg, the total weight of coating / filled capsule is 490.66 mg, resulting in a coating weight per capsule of 133.66. This corresponds to a coating weight per capsule of 139.08% of the empty capsule and 37.44% of the filled capsule.

[0234] The capsules were submitted to Ph.Eur. (10th edition) standard (2.9.1 Apparatus B; with discs) Two-stage disintegration test on coated capsules (n=6): (a) pH 1.2 (made by mixing 0.1 N HCl in water, 250 mL of 0.2 M NaCl, 425 mL of 0.2 M HCl, and 325 mL of purified water); and (b) pH 6.8 using phosphate buffer (made by mixing 250 mL of 0.2 M potassium hydrogen phosphate, 112 mL of 0.2 M NaOH, and 638 mL of purified water).

[0235] The apparatus consisted of a basket rack assembly, a device for raising and lowering the basket, a 1 L beaker, and a thermostat for heating the fluid at 37 °C (± 2 °C). The basket rack assembly was designed to contain three capsules in three different transparent cylindrical tubes that were placed on a stainless steel screen, allowing the flow of solutions into the tubes.

[0236] In these experiments, a cylindrical transparent plastic disk with five holes was placed on top of the floating capsule and kept inside the tube during the test (without the disk the capsule would float on the surface of the medium).

[0237] According to Ph.Eur., a capsule with a gastro-resistant shell must survive two hours in an acidic medium without showing signs of disintegration or rupture that would allow the contents to escape.

[0238] After 2 hours, the basket rack assembly was gently dried and the coated capsules were visually inspected to identify signs of deformation or rupture.

[0239] The basket was subsequently transferred to a phosphate buffer pH 6.8. According to Ph.Eur, the specifications state that all capsules should disintegrate within 60 minutes.

[0240] Visual inspection showed fully intact capsules in acidic media (a) and rapid capsule disintegration in more basic media (b), thus indicating that the capsules were successfully enteric coated.

[0241] Example 4 Stability testing of the dosage form of the present invention The enteric coated capsules obtained using the method described in Example 3 above were tested in a study to assess their stability in clinical representative packaging at ICH (International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) storage conditions: (i) 25° C. and 60% RH (long-term storage conditions) and (ii) 40° C. and 75% RH (accelerated storage conditions).

[0242] The final composition is as shown in Table 6 below. [Table 6]

[0243] The stability results at various storage conditions and times are shown below in Table 7 (assay and chromatographic purity) and Table 8 (disintegration). Water content was measured using Karl Fischer titration. Impurity 1 was previously known in C21, while impurities 2 and 3 are new. LOR stands for limit of reporting (i.e., 0.10%, lc). [Table 7] [Table 8]

[0244] All stability disintegration results were consistent with expectations, with the enteric-coated capsules not dissolving in acidic media and dissolving rapidly at pH 6.8. The assays were stable over the 6-month stability period at both storage conditions.

Claims

1. A pharmaceutical formulation for oral administration to the gastrointestinal tract for use in the treatment of interstitial lung disease, the pharmaceutical formulation comprising a pharmaceutical composition comprising N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide, or a pharma- ceutically acceptable salt thereof; the composition comprises an enteric material used to coat, enclose and / or encapsulate the composition to prevent the N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or salt thereof from being released in the stomach and / or coming into contact with gastric fluids; said treatment comprising oral administration to the gastrointestinal tract of one or more of said pharmaceutical formulations at a daily dose of between 10 mg±10% and 400 mg±10% of N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or a salt thereof, calculated as free N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide; A pharmaceutical preparation for oral administration to the gastrointestinal tract.

2. The formulation of claim 1 , which is administered from 1 to 3 times daily.

3. 3. The formulation of claim 1 or 2, wherein the daily dose is between 25 mg ± 10% and 200 mg ± 10%.

4. The formulation of any one of claims 1 to 3, wherein the enteric material is selected from the group consisting of cellulose acetate, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate tetrahydrophthalate, polyvinyl acetate phthalate, hydroxyethyl ethylcellulose phthalate, methacrylic acid copolymer, polymethacrylic acid / acrylic acid copolymer, styrene maleic acid copolymer, hydroxypropyl methylcellulose phthalate, acrylic resin, cellulose acetate trimellitate, hydroxypropyl methylcellulose trimellitate, shellac, carboxymethylcellulose and hydroxypropyl methylcellulose acetate succinate.

5. 5. The formulation of claim 4, wherein the enteric material is polyvinyl acetate phthalate or a methacrylic acid copolymer.

6. The formulation of any one of claims 1 to 5, wherein the N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or a salt thereof is uniformly distributed in a pharma- ceutically acceptable carrier material.

7. The formulation of any one of claims 1 to 6, in the form of an enteric coated pill, tablet, capsule, or film.

8. The formulation of claim 7, which is an enteric coated capsule.

9. The formulation of claim 7, which is an enteric coated tablet.

10. 10. The formulation of any one of claims 1 to 9, wherein N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or a salt thereof is provided in the form of a powder, mixture, granules, pellets, beads, solution or suspension.

11. The formulation of claim 10, wherein the form is a powder mixture.

12. The formulation of claim 11, which is an enteric coated capsule, said capsule being a hard shell, two-piece capsule.

13. 13. The formulation of claim 12, wherein the capsule comprises hydroxypropyl methylcellulose.

14. 11. The formulation of claim 10, wherein the composition is in the form of a suspension of particles of N-butyloxycarbonyl-3-(4-imidazol-1-ylmethyl-phenyl)-5-iso-butylthiophene-2-sulfonamide or a salt thereof that is insoluble therein, in a lipid carrier.

15. 15. The formulation of claim 14, wherein the final dosage form is an enteric coated capsule, said capsule being a soft shell monolithic capsule.

16. 16. The formulation of claim 15, wherein the capsule comprises gelatin.

17. 17. A formulation for use according to any one of claims 1 to 16, wherein N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butyl-thiophene-2-sulfonamide or a pharma- ceutically acceptable salt thereof is provided in the form of particles having a mean diameter on a weight and / or volume basis of 50 μm±10% or less.

18. A formulation for use according to any one of claims 1 to 17 which is essentially free of water.

19. A formulation for use according to any one of claims 1 to 18, wherein the pharma- ceutically acceptable salt of N-butyloxycarbonyl-3-(4-imidazol-1-ylmethyl-phenyl)-5-iso-butylthiophene-2-sulfonamide is the sodium salt.

20. The formulation for use according to any one of claims 1 to 19, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

21. The formulation for use according to any one of claims 1 to 19, wherein the interstitial lung disease is sarcoidosis.

22. 22. The formulation for use according to claim 20 or 21, wherein said treatment includes the prevention of morbidity and / or mortality in the associated condition.

23. The formulation for use according to any one of claims 20 to 22, wherein said formulation is administered by oral route.

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