Novel delayed-release composition for oral administration

Abstract

To provide a pharmaceutical dosage form of N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (C21), or a pharmaceutically acceptable salt thereof, suitable for peroral administration to the gastrointestinal tract.SOLUTION: According to the invention, there is provided a pharmaceutical composition comprising N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (C21), or a pharmaceutically acceptable salt thereof, in which the C21 or salt thereof is protected by the presence of a coating comprising an enteric substance. Preferred dosage forms comprise capsules in which the C21 or salt thereof is presented in the form of a dry powder mixture or in the form of a suspension of particles of C21 in a solvent in which it is insoluble. Such dosage forms have been found 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] This invention relates to new pharmaceutical dosage forms, their use as pharmaceuticals, and in particular, their administration for the treatment of lung diseases, such as interstitial lung disease. [Background technology]

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

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

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

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

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

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

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

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

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

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

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

[0013] There are drawbacks associated with all of the aforementioned drug treatments for ILD (and IPF), and safer and / or more effective treatments are actually clinically needed.

[0014] Since restoring alveolar epithelium is highly desirable as a treatment effect for IPF, stem cell therapy has also been tested. Some preclinical studies have shown promise in the use of pluripotent stem cells that can differentiate into lung epithelial and endothelial cells and thereby repair lung injury and fibrosis.

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

[0016] Therefore, the development of new treatment strategies for IPF is important. Therefore, a fundamental future challenge is to develop an appropriate treatment approach that can reverse or halt the progression of the disease.

[0017] The renin-angiotensin system (RAS) is an important regulator of blood pressure homeostasis. The protease renin cleaves its only known substrate (angiotensinogen) to form angiotensin I (AngI), which then functions 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 -Ile 5 -His 6 -Pro 7 -Phe 8 ) and is the active ingredient of the renin-angiotensin system (RAS).

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

[0019] Several studies in adults appear to show that activation of the angiotensin II type 1 (AT2) receptor has an effect opposite to that mediated by the AT1 receptor in the regulation of the response 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 gastrointestinal diseases such as dyspepsia and irritable bowel syndrome, and multiple organ failure (see International Patent Application No. 99 / 43339).[[ID=十六]] [[ID=十七]]

[0022] [[ID=十八]] [[ID=十九]] [[ID=二十]]

[0023] [[ID=二十一]] The expected pharmacological effects of AT2 receptor agonism are generally described in de Gasparo M et al. (supra). It has not been mentioned that AT2 receptor agonism may be used in the treatment of IPF.

[0023] International Patent Application No. 2002 / 096883 describes the preparation of imidazolyl, triazollyl, and tetrazolylthiophene sulfonamides and derivatives as AT2 receptor agonists. Of the compounds described in that document (as Example 1), N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (Compound 21, or "C21" as used hereafter) 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, where treatment with an AT2 receptor agonist is considered beneficial (see, for example, International Patent Application, International Publication No. 2016 / 139475).

[0024] The compounding process involving C21 and its salts has proven to be extremely difficult. As a result, C21 was previously compounded as an aqueous solution, frozen during storage, and then thawed immediately before oral administration.

[0025] The applicant has been working on this active ingredient for about 20 years, and until recently, has been unable to obtain a pharmaceutically acceptable dosage form in which the active ingredient remains stable when stored at ambient temperature.

[0026] In addition, a significant effect of food 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 intestinal fluid, simulated in both fasting and feeding conditions, appeared to be sufficient to enable the availability of the active ingredient in the intestine for good absorption at clinical doses. [Overview of the project]

[0028] According to a first aspect of the present invention, a pharmaceutical dosage form suitable for oral administration into the gastrointestinal tract is provided, comprising a pharmaceutical composition comprising C21 or a pharmaceutically acceptable salt thereof, wherein the C21 or salt thereof in the composition is protected by the presence of a coating comprising an enteric-coated substance. Such dosage forms are collectively referred to below as "the dosage forms of the present invention."

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

[0030] In the context of the present invention, “enteric-coated” substances are used to coat, encapsulate, and / or encapsulate compositions containing C21 or a pharmaceutically acceptable salt thereof in order to prevent the active ingredient from being released from the composition in the stomach and / or from coming into contact with gastric juice and / or from reaching the small intestine. “Substantially prevent” includes preventing about 20% or less of the active ingredient from being released in the acidic environment of the stomach, e.g., about 15%, e.g., about 10%, more specifically about 5% or less.

[0031] Typical enteric coating materials include cellulose acetate, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate tetrahydrophthalate, polyvinyl acetate phthalate, hydroxyethyl ethyl cellulose 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, hydroxyethyl ethyl cellulose phthalate, carboxymethylcellulose, and hydroxypropyl methylcellulose acetate succinate. Preferred enteric materials include polyvinyl acetate phthalate, particularly methacrylic acid copolymer.

[0032] Enteric coatings can be used to coat various dosage forms. Many formulation / administration principles can be used to prepare the dosage forms of the present invention, and these are described below in an indefinite sense.

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

[0034] If C21 or its salts are supplied in multi-particle form as powder, granules, pellets, and / or beads, the particles must be coated individually or collectively with an enteric coating. 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, the carrier system being any pharmaceutically acceptable inert material that can increase the mass of the composition or components of the composition to provide a suitablely processable dosage form.

[0036] Therefore, suitable carriers include pharmaceutically 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 (optionally silicified) microcrystalline cellulose, cellulose, and crosslinked polyvinylpyrrolidone; starch; sugars and sugar alcohols, such as lactose, mannitol, xylitol, isomalt, dextrose; or mixtures of any of the above.

[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 its salt to be coated. The preferred range is about 10% to about 80% by weight.

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

[0039] Thereafter, after directly filling the mixture of C21 / salt and the carrier material into capsules, an enteric substance can be applied. Alternatively, such a mixture can be granulated into pellets, granules or beads, and these secondary particles can be individually coated with an enteric substance or loaded into suitable capsules before being coated with an enteric substance. Alternatively, powders, pellets, granules, or beads can be compressed into tablets before being coated with an enteric substance.

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

[0042] Other pharmaceutically acceptable excipients such as binders, disintegrants, glidants, lubricants 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 cohesive molded body. Suitable binders include polyvinylpyrrolidone, gelatin, sodium alginate, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose gum, and cellulose derivatives such as (optionally silicified) microcrystalline cellulose. If 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] A disintegrant (or disintegrating agent) can be defined as a material that can accelerate the disintegration / dispersion of components of a composition containing C21 or a salt thereof, such as granules or tablets, to a measurable degree. This can be achieved, for example, by a material that can swell and / or expand when placed in contact with an aqueous medium (particularly body fluids, including those found in the gastrointestinal tract), and thus disintegrate at least a portion of the dosage forms of the present invention when in contact with water. Suitable disintegrants include cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose (croscarmellose, e.g., Ac-Di-Sol, FMC Corp., USA), carboxymethyl starch, natural starch, pregelatinized starch, corn starch, potato starch, sodium starch glycolate (Primojel®, DMV International BV, Netherlands), and low-substituted hydroxypropylcellulose. The disintegrant (which may comprise one or more of the above materials) is preferably used in an amount of about 1% by weight (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% by weight (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 flow accelerator is a pharmaceutically acceptable material that facilitates the flow of powder by reducing friction and / or aggregation between particles (however, it does not necessarily need to have the ability to reduce and / or prevent adhesion to external materials such as capsule filling machines or hoppers). Therefore, suitable pharmaceutically acceptable flow materials include talc, magnesium carbonate, or calcium silicate, but the flow accelerator is preferably a hydrophilic flow accelerator such as fumed / calcined silica or, more specifically, one or more of 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, and they prevent granules or powder from adhering to the punch die / face and facilitate smooth discharge from the die after compression. Suitable lubricants include stearic acid, sodium stearyl fumarate, colloidal silica anhydrous, talc, or preferably magnesium stearate. When using lubricants, they should be used in very small amounts (for example, 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, fragrances (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, unicion, superoxide dismutase (SOD), glutathione peroxidase, or peroxidase catalase)), preservatives, and buffers.

[0048] These, and other pharmaceutically acceptable excipients referred to herein, are either commercially available or otherwise documented in the literature, including, for example, those described in Rowe et al., supra and Remington, The Science and Practice of Pharmacy, 21st ed., Lippincott Williams and Wilkins, Philadelphia (2006) and the documents referenced therein, the relevant disclosures of all such documents are incorporated herein by reference. Alternatively, suitable oral preparations can be achieved non-inventively by those skilled in the art using routine techniques.

[0049] Granules, pellets, or beads can be further processed after formation. For example, dry granules can be crushed, ground, or pulverized using appropriate grinding techniques to produce smaller particulate matter, which can then be sieved to separate fractions of the desired size. Wet granules can be screened to break up granular aggregates and remove fine material. In any case, unused smaller (fine) and larger materials can be reprocessed to avoid waste.

[0050] However, powder mixtures, granules, tablets, or capsules are prepared before coating with an enteric coating, and the preparation of the composition to be coated ensures that C21 or its pharmaceutically acceptable salts are uniformly dispersed throughout the carrier material (and / or other excipients used).

[0051] For simple mixtures, this includes mixing for a period of time to provide a uniformly dispersed active ingredient, as described below, for example. This may vary depending on the equipment used.

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

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

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

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

[0056] Appropriate pharmaceutically acceptable capsules include soft-shell 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, for example, by a standard capsule filling process.

[0057] If the dosage form of the present invention includes a solid formulation comprising a mixture of C21 or a salt thereof together with a carrier material (e.g., in the form of powder, granules, etc.), according to a preferred embodiment of the present invention, the capsule is preferably a hard-shell two-piece capsule, supplied as a closed half, made from, for example, gelatin, or more preferably HPMC, which can be separated, filled with particulate matter, and then reassembled. Such capsules may be of any size (e.g., 00-5), but 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, 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 the formation of the composition to be filled into the capsules during storage.

[0059] In this regard, C21 or its salts can typically be provided in the form of multiple primary (i.e., non-aggregated) particles having an average diameter on a weight and / or volume basis of about 1,000 μm or less, for example, 500 μm including about 250 μm, preferably about 100 μm or less including about 50 μm or less, for example, about 20 μm, or about 10 μm or less. There is no lower limit to the particle size that can be used according to the present invention, but for ease of production, the primary particles of C21 or its salts preferably have an average diameter on a weight and / or volume basis of less than 1 μm, for example, about 2 μm, about 3 μm.

[0060] Where 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 weight-based particle size distribution, i.e., a distribution defined as the weight fractions (relative amounts) of existing fractions in each size class, for example, by sieving (e.g., wet sieving). The term “volume-based average diameter” is similar in meaning to 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 volume-based particle size distribution, i.e., a distribution defined as the volume fractions (relative amounts) of existing fractions in each size class, for example, by laser diffraction. Particle size can also be measured with standard instruments such as dry particle size measurement techniques, including dry dispersion techniques available from manufacturers such as Sympatec GMbH (Clausthal-Zellerfeld, Germany). For example, particle size can be measured using other instruments well-known in this field, such as those sold by Malvern Instruments, Ltd (Worcestershire, UK), Shimadzu (Kyoto, Japan), and Elzone, Micromeritics (USA; electrical sensing zone method).

[0061] The average diameter of the particles, having a weight and / or volume-based average diameter within the above limits, includes the average diameter of the particles during preparation according to the present invention, before mixing with the associated excipients, and / or before loading into capsules. 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 kept to a minimum.

[0062] C21 or its salts also have a mass median (D 50 (Logarithmic normal mass median diameter), average particle size by mass and / or diameter containing 50% of the cumulative PSD mass) and / or geometric standard deviation (Equation D 84.1 3 / D 50 or D 50 / D 15.78 GSD or σ measured by g And here D84.13 and D 15.78 These are the diameters that contain 84.13% and 15.78% of the mass, respectively, 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 parameters accepted in the art, including (as described above). Such parameters can be measured and calculated in-process using any suitable sampling method and particle size measurement technique as described above.

[0063] In this regard, C21 or its salts preferably have a PSD that is less than about 4, such as less than about 3, which is a GSD of less than about 4.

[0064] Primary particles of C21 or its salts can be prepared by appropriate techniques such as precipitation, cleavage (e.g., by dissolution in a supercritical fluid under pressure followed by rapid expansion), and spray drying, or, where appropriate, can be pulverized by techniques well known in the art such as grinding, dry grinding, jet grinding, wet grinding and / or crushing.

[0065] The particles may also be sieved to separate them into fractions of the desired size, and / or screened to break down aggregates and / or remove fine matter. In any case, unused smaller (fine) and larger materials can be reprocessed to avoid waste. Alternatively, the particles may be separated to the appropriate particle size using cyclone separation by air classification, sedimentation, force field fractionation, and / or elutriation.

[0066] C21 or its salts can be selected and / or provided with the aforementioned average diameter, particle size, PSD and / or GSD based on weight or volume using one or more of the above techniques, but one of the main advantages of formulating the composition to be loaded into capsules to form the dosage form of the present invention is that C21 or its salts do not require the above particle processing techniques before being blended with the relevant excipients.

[0067] In this regard, as mentioned above, C21 and its salts have been found to be extremely difficult to handle. Part of the problem is the previously unreported extreme sensitivity of C21 and its salts to the presence of light and water in combination.

[0068] Furthermore, particularly, and 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. Moreover, C21 and its salts form as needle-shaped crystals that are sticky and tend to aggregate. This means that dry mixing with certain standard pharmaceutically acceptable ingredients is extremely difficult, and it is not easy to produce a pharmaceutically acceptable homogeneity of the active ingredient and / or a blend that has that homogeneity within the capsule.

[0069] Furthermore, atomizing the primary particles of the active ingredient does not provide a solution to these problems, as those skilled in the art would have anticipated, and also introduces additional problems related to localized heating and static electricity.

[0070] However, the present inventors have made it possible to avoid the aforementioned problems and provide a composition for filling capsules by blending C21 or a pharmaceutically acceptable salt thereof with a pre-mixed blend of particle carriers having a weight-based and / or volume-based average diameter and / or structural (particle) density similar to that of the weight-based and / or volume-based average diameter and / or structural (particle) density of the solid particles of C21 or a pharmaceutically acceptable salt thereof, and a flow enhancer, thereby ensuring uniform and even distribution of C21 or its salt, and not only ensuring dose uniformity of the active ingredient between such filled capsules, but also enabling physical and chemical stability during and after manufacturing, under normal storage conditions, and during use.

[0071] Accordingly, in this first preferred embodiment of the present invention, the excipient mixed with C21 particles or a pharmaceutically acceptable salt thereof comprises 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 that of C21 or a pharmaceutically acceptable salt thereof, respectively, and a flow enhancer. Such a composition is then loaded into a capsule suitable for oral administration and coated with an enteric-coated substance.

[0072] In the context of this embodiment of the present invention, the terms “uniform” and “uniformly distributed” are defined as described above.

[0073] In this preferred embodiment of the present invention, suitable carrier particle materials may include water-soluble, pharmaceutically acceptable substances, including carbohydrates such as sorbitol, xylitol, and sugar alcohols, particularly mannitol. The carrier particles may also include physical mixtures of any of these materials, and / or composites of one or more of these materials.

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

[0075] "Similar particle size distribution and / or structural (particle) density" means that the average diameter and / or particle density on a weight and / or volume basis of the carrier particles are within approximately ±75% of the relevant dimensions of the C21 or its salt used, for example, approximately ±40%, approximately ±30%, or approximately ±20%, including approximately ±10%, including approximately ±50%, etc.

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

[0077] The inventors have found that separation of the blend can be avoided by using carrier particles having a size similar to and / or within the above range as those of the active ingredient.

[0078] Therefore, in order to prepare a composition to be filled into capsules for making a dosage form according to this aspect of the present invention, carrier particles of the required size are pre-blended with a suitable flow promoter, preferably 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 / calcined silica, before being mixed with the active ingredient. Thus, preferred forms of silica include stable aqueous dispersions (sols) of amorphous silica particles having an average diameter on a weight basis 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., about 10 nm to about 15 nm).

[0079] Therefore, it is preferable to mix the flow accelerator and the carrier particles together to form an interaction (or ordering) mixture of carrier particles that are mostly coated with smaller particles of the flow accelerator material, and then mix this mixture with the active ingredient particles.

[0080] Furthermore, the inventors have found that by adding the aforementioned flow promoter to the carrier particles before mixing with the active ingredient to initially form the excipient blend, the flow properties of the excipient blend are improved, allowing for better mixing with C21 or its pharmaceutically acceptable salts, and further reducing the possibility of blend separation.

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

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

[0083] All preferred features relating in any way to this aspect of the present invention, as referred herein to in relation to other aspects of the present invention, are equally applicable.

[0084] The term "essentially derived from" is understood to mean that the scope of this (and only) aspect of the Invention is limited to the aforementioned essential features, along with other features that do not substantially affect the basic and novel features of this aspect of the Invention.

[0085] In this regard, although not an essential feature of this preferred embodiment of the present invention, a lubricant (such as sodium stearyl fumarate, or preferably magnesium stearate) is added to the blend before filling the capsules to prevent the blend from adhering to the equipment (such as the capsule filling machine and hopper). This is a preferred feature that does not substantially affect the basic and novel properties of this embodiment of the present invention.

[0086] The composition to be filled into capsules "essentially" consisting of a particulate mixture containing solid particles of C21 or a pharmaceutically acceptable salt thereof, mixed with the carrier particles and flow promoter blend defined above, means that it contains at least about 95%, such as at least about 97% by weight of the total of those particular components.

[0087] In this first preferred embodiment of the present invention, it is also preferable that the dry mixed blend passes through a sieve at some point during the blending process to break down any aggregates formed during the blending process, as described below, for example. A suitable sieve has a pore size that is as small as (or to that extent) the particle size of the largest constituent of the blend. Thus, suitable sieve sizes are 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 embodiment 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 pharmaceutically acceptable salt thereof, wherein C21 or a pharmaceutically acceptable salt thereof is suspended on a pharmaceutically acceptable hydrophobic lipid-based carrier in which C21 or a pharmaceutically acceptable salt thereof is essentially insoluble, and the composition is loaded into a capsule coated with an enteric-coated substance, suitable for such oral administration.

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

[0090] According to this preferred embodiment of the present invention, the capsule is preferably a soft-shell, one-piece capsule, such as a soft gelatin capsule, which is filled with a suspension of lipid-based C21 or a salt thereof and then sealed as a whole, for example, with droplets of gelatin solution. Gelatin can be obtained from any source (e.g., pig and bovine sources), but 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, amorphous solution of sorbitol, glucose, fructose and glucose syrup, more preferably glycerin / glycerol, sorbitol and / or proprietary plasticizers such as Anidrisorbs (proprietary mixtures of sorbitol, sorbitan, maltitol and mannitol, including Anidrisorb 85 / 70 (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, elliptical, tubular, etc.) and any size (e.g., 3 to 24 rectangles, 1 to 20 circles, 2 to 20 ellipses, 5 to 120 tubes, 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 pharmaceutically acceptable salt thereof is essentially insoluble in a lipid-based carrier under normal storage conditions. "Essentially insoluble" means that C21 or a salt thereof has solubility in the carrier of about 0.015 mg or less of C21 or a salt thereof per gram of carrier.

[0094] Thus, due to the dual properties of the hydrophobic carrier and its lack of tendency to dissolve C21 or its salts, the active ingredient is not exposed to an amount of water that could catalyze its decomposition, as described above.

[0095] Surprisingly, it has been found that there are relatively few lipid-based carrier materials that satisfy these requirements and can therefore stabilize C21 or its salts at ambient temperature in the dosage form of the present invention.

[0096] As mentioned above, hydrophobic lipid-based carrier materials, in which C21 or a salt thereof must be insoluble, may contain nonpolar oils or fats that are essentially miscible with water. Lipid-based carriers are preferably composed mainly 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] Therefore, lipids may contain saturated or unsaturated chain fatty acids, the chains of which may range from 1 carbon atom to a maximum of 30 carbon atoms (including a maximum of 26 carbon atoms), or a maximum of 22 carbon atoms (including 8, 10, 12, 14, 16, 18, or 20 carbon atoms).

[0098] Saturated fatty acids that may be mentioned include acetic acid (2), propionic acid (3), butyric acid (4), varreic 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), and stearyl acid. This includes nic 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), carboceric acid (27), montanic acid (28), nonacosylic acid (29), and melisic acid (30), where the numbers in parentheses indicate the number of carbon atoms in the fatty acid molecule.

[0099] Unsaturated fatty acids that may be mentioned include 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), laurorinolic acid (12:2), myristobasenoic 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), and 11,14,17-eicosatrienoic acid. (20:3), eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5), heneicosapentaenoic acid (21:5), crupanodonic acid (22:5), docosahexaenoic acid (22:6), 9,12,15,18,21-tetracosapentaenoic acid (24:5), hernic acid (24:6) and 6,9,12,15,18,21-tetracosahexaenoic acid (24:6); ω-5 unsaturated fatty acids, e.g., myristoleic acid (14:1), palmitovaccenic acid (16:1), α-eleostearic acid (18:3), β-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, e.g., tetradecenoic acid (14:1), 12-octadecenoic acid (18:1), linoleic acid (18:2), linoleidic 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 Acids (20:3), arachidonic acid (20:4), docosadienoic acid (22:2), adrenoic acid (22:4), osbondic acid (22:5), tetracosatetraenoic acid (24:4), and tetracosapentaenoic acid (24:5); ω-7 unsaturated fatty acids, e.g., 5-dodecenoic acid (12:1), 7-tetradecenoic acid (14:1), palmitolic acid (16:1), vaccenic acid (18:1), rumenic acid (18:2), pauric acid (20:1), 7,10,13-eicosatrienoic acid (20:3), 15-docosenoic acid (22:1), and 17-tetracosenoic acid (24:1);This includes ω-9 unsaturated fatty acids, such as hypogetic acid (16:1), oleic acid (18:1), elaidic acid (trans-18:1), gondic acid (20:1), 8,11-eicosadienoic acid (20:2), erucic acid (22:1), nervonic acid (24:1), meadic acid (20:3), and xymenic 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), petroseric acid (18:1), and eicosenoic acid (20:1), where the numbers in parentheses represent 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 primarily contain triglycerides, which are mixtures of glycerides with different fatty acid chain lengths.

[0104] Naturally occurring, pharmaceutically acceptable oils classified in this category include sunflower oil, soybean oil, corn oil, grape seed oil, rapeseed oil, sesame oil, almond oil, apricot kernel oil, cottonseed oil, coconut kernel oil, castor oil, olive oil, palm oil, and coconut oil (for their respective compositions, see, for example, 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 this preferred embodiment of the present invention, the naturally occurring oils should be pharmaceutical grade and, therefore preferably, be purified after extraction from their natural source(s). This 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 support systems can be prepared using techniques well known in the art, such as separation, transesterification, lipolysis, and transesterification (glycerolysis).

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

[0109] Whatever form the hydrophobic lipid-based carrier system may take, the main component of the carrier system preferably contains at least about 85% triacylglycerol, more preferably at least about 90% triacylglycerol, and particularly at least about 95% triacylglycerol.

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

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

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

[0113] As described herein, particles having an average diameter on a weight and / or volume basis within the aforementioned limits include the average diameter of the particles at the time of preparation and before suspension on a lipid-based carrier, when so suspended and / or before loading into capsules. Thus, primary particles of C21 / its salt can be prepared as described above.

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

[0115] C21 or its salts can be selected and / or provided using one or more of the above techniques to provide a stable suspension in which C21 / salt particles are uniformly distributed within the suspension, but the C21 / salt is thoroughly mixed with a lipid-based carrier system to ensure that the active ingredient particles are uniformly distributed within the carrier before filling. This is especially true for bulk suspensions used as part of a capsule filling process, in which case it is important not only that the mixture is uniform at the start, but that this uniformity is maintained during the filling process to ensure uniformity of doses within the production batch.

[0116] The terms “uniform” and “uniformly distributed” mean that there is a substantially uniform content of C21 or its salts throughout the lipid-based carrier material, and are defined as described above.

[0117] If the lipid-based carrier system is in the form of fat (i.e., solid or semi-solid at or around normal manufacturing and / or product storage temperatures), those skilled in the art will understand that it is necessary to melt the fat by raising the temperature before mixing.

[0118] Furthermore, in order to ensure that such suspensions provide a stable, uniform, and even distribution of the active ingredients within the carrier, the lipid-based carrier system (and in particular, those in the form of liquid oil at or around normal manufacturing and / or product storage temperatures) may further include, as necessary, a thickener to avoid particle aggregation and / or sedimentation, such as microcrystalline cellulose and sodium carboxymethylcellulose, as well as a blend of mono, di, and triglycerides with PEG esters of unsaturated fats such as Gelucire 43 / 01, hydrogenated vegetable oil, beeswax, and paraffin wax.

[0119] By presenting C21 or a salt thereof in the form of a suspension of particles according to this embodiment of the present invention, we have found that the dosage form of the present invention can not only deliver a consistent and / or uniform dose of the active ingredient, but also ensure that the active ingredient remains physically and chemically stable during and / or after manufacture, under normal storage conditions, and / or during use.

[0120] As used herein, C21, or a pharmaceutically acceptable salt thereof, may be prepared and stored in the form of a composition that can be directly filled into capsules to prepare the dosage forms of the present invention, and furthermore, once prepared, the dosage forms of the present invention may be stored under normal storage conditions with slight changes over time in the physicochemical properties of the dosage form, the composition mixture contained herein, and / or most importantly, the active ingredient.

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

[0122] "Chemical stability" means that a composition containing a C21 / salt on a suitable carrier, and the dosage form of the present invention, can be stored under normal storage conditions with minimal chemical degradation or disintegration of the dosage form and / or the suspension contained therein, particularly the active ingredient (with or without suitable pharmaceutical packaging).

[0123] "Physical stability" means that a suspension containing C21 / salt on a suitable carrier, and the dosage forms of the present invention, can be stored under normal storage conditions (with or without suitable pharmaceutical packaging) with minimal physical transformations of the dosage forms and / or compositions contained therein, particularly the active ingredients, including dissolution, solvation, solid-phase transition, aggregation, separation or fission, or sedimentation, or changes in properties and / or integrity.

[0124] Examples of “normal storage conditions” include a temperature of -80 to +50°C (preferably 0 to 40°C, more preferably ambient temperature, e.g., 15 to 30°C), a pressure of 0.1 to 2 bar (preferably atmospheric pressure), a relative humidity of 5 to 95% (preferably 10 to 60%), and / or prolonged exposure (i.e., 6 months or more) to 460 lux of UV / visible light.

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

[0126] Whether the pharmaceutical composition is in the form of a dry powder mixture, a lipid-based suspension, or other form, and / or whether it is contained within a capsule as described above or in other ways, it is preferable that they be manufactured and / or stored in an essentially water-free state.

[0127] "Essentially water-free" means that both the particles C21 or its salt and the excipients to which they are mixed are prepared and / or provided separately in an essentially dry manner, appropriate precautions are taken to ensure they are also kept in an essentially dry environment, and that they are mixed together to form a dry mixture.

[0128] "Essentially dry" or "essentially water-free" means that a composition comprising C21 / salt and related excipients contains, in whole, about 5% or less including about 2% or less, about 1% or less including about 0.5% or less, for example, about 0.1% or less of water.

[0129] Further treatment of a composition comprising C21 or a salt thereof and related excipients into the dosage forms of the present invention as described above may also be carried out in a manner that keeps it in such an essentially water-free state.

[0130] In this regard, pharmaceutically acceptable capsule materials may contain residual amounts of water, but the intrusion of water from the capsule material into the composition (whether in solid (e.g., powder mixture) or liquid (e.g., lipid suspension) form) must be minimized, thereby protecting the sensitive C21 or its salts from contact with water and preventing decomposition in the presence of light.

[0131] Nevertheless, it is preferable (though not necessarily required) to package the dosage form of the present invention in a manner that keeps the dosage form itself dry and protects it from light. This may include airtight packaging or the use of hygroscopic materials.

[0132] A further aspect of the present invention provides a process for producing a dosage form of the present invention, the process comprising coating a composition containing C21 or a pharmaceutically acceptable salt thereof with an enteric coating.

[0133] Pharmaceutically acceptable salts of C21 include acid addition salts. Such salts can be formed by conventional means, for example, by the reaction of 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 the removal of the solvent or medium using standard techniques (e.g., by vacuum, freeze-drying, or filtration). Salts may also be prepared by exchanging the counterions of the active ingredient in the form of a salt with other counterions, for example, using a suitable ion exchange resin. Preferred salts of C21 include alkaline earth salts such as HCl salts, magnesium and calcium salts, and alkali metal salts such as potassium salts or preferably sodium salts.

[0134] The amount of C21 or its salt in the dosage form of the present invention may depend on and / or be selected accordingly to the severity of the condition, or the expected severity of such condition, and the patient being treated, but can be determined by those skilled in the art. The method of administration may also be determined by the timing and frequency of administration, as well as the severity of the condition.

[0135] An appropriate lower daily dose of C21 in adult patients (with an average weight of, for example, 70 kg) may be approximately 10 mg, for example, approximately 20 mg, or for example, approximately 25 mg per day. An appropriate upper limit for the daily dose range of C21 may include approximately 900 mg, such as 600 mg including approximately 400 mg, and approximately 200 mg, such as approximately 100 mg, and approximately 50 mg.

[0136] All of the above doses are calculated as free C21. The dose can be divided into several individual doses per day. The dose may be given once to six times a day, for example four times, preferably three times a day, and more preferably twice a day.

[0137] In any case, a practicing physician or other person skilled in the art can routinely determine the most appropriate actual dosage for each individual patient, depending on the severity of the condition and the route of administration. The above dosages are examples of average cases, and naturally, there may be individual cases where higher or lower dosage ranges are appropriate, and such cases fall within the scope of the present invention.

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

[0139] The dosage form of the present invention is useful under conditions in which AT2 receptors are expressed and their stimulation is desired 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 and musculoskeletal disorders.

[0141] The dosage form of the present invention is particularly suitable for the treatment and / or prevention of sarcoidosis or fibrosis, more specifically ILDs such as PF, especially IPF, as well as conditions that can induce ILDs, such as systemic sclerosis, rheumatoid arthritis, myositis, or systemic lupus erythematosus, or conditions associated with ILDs, such as pulmonary hypertension and / or pulmonary arterial hypertension.

[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 (and thus, for example, an antithrombotic effect) and / or can reduce vasoconstriction and / or bronchoconstriction in a therapeutic manner.

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

[0144] Therefore, the dosage forms of the present invention are expected to be useful in treating diseases that may be characterized as described above, such as those affecting the gastrointestinal tract, cardiovascular system, airway, kidneys, immune system, eyes, female reproductive (ovulation) system, and central nervous system (CNS).

[0145] Gastrointestinal disorders that may be mentioned include esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, indigestion (including non-ulcerative indigestion), gastroesophageal reflux, irritant bowel syndrome (IBS), inflammatory bowel disease (IBD), liver disorders (such as hepatitis), gallbladder disease, multiple organ failure (MOF), and sepsis. Other gastrointestinal disorders that may be mentioned include xerostomia, gastritis, gastroparesis, hyperacidity, biliary tract disorders, coelicia, Crohn's disease, ulcerative colitis, diarrhea, constipation, colitis, loss of appetite, vomiting, nausea, dyspepsia, and Sjögren's syndrome.

[0146] Airway disorders that may be mentioned include inflammatory diseases such as asthma, obstructive pulmonary diseases (such as chronic obstructive pulmonary disease), non-infectious pneumonia, pulmonary hypertension, and adult dyspnea syndrome.

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

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

[0149] Disorders of the female reproductive system that may be mentioned include ovulation disorders and endometriosis.

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

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

[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, benign prostatic hyperplasia, autoimmune diseases (e.g., arthritis such as rheumatoid arthritis, or systemic lupus erythematosus), psoriasis, obesity, nerve cell regeneration, ulcer healing, suppression of adipose tissue hyperplasia, stem cell differentiation and proliferation, fibrous diseases, cancer (e.g., of or within the gastrointestinal tract (including the esophagus or stomach), prostate, breast, liver, kidney, and 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 form of the present invention is also useful in the treatment of stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cancer treatment-related cardiotoxicity, peripheral neuropathy, and especially systemic sclerosis.

[0154] Furthermore, the dosage forms of the present invention may be useful in treating respiratory virus-induced tissue injury, which may include damage and / or dysfunction of the relevant tissues. The relevant tissues include the tissues of the airways (such as mucous membranes), particularly the tissues of the lungs. Therefore, the relevant tissues include the respiratory epithelium, which moistens the airways and protects them from the invasion of pathogens such as viruses.

[0155] Respiratory viruses that can be mentioned in this regard include influenza viruses such as influenza A virus (e.g., H1N1 and H3N2 viruses), influenza B virus, or influenza C virus, and more specifically, severe acute respiratory syndrome (SARS) coronaviruses such as SARS coronavirus (SARS-CoV), in particular the 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) and has many genetic variants.

[0156] "Treatment of tissue damage" means that C21 and its salts not only have a beneficial effect on airway tissue damage caused by the aforementioned viruses, but also have the potential to prevent and / or mitigate damage caused by the viruses in other ways within the airways, such as when the viruses invade epithelial cells within the airways.

[0157] Therefore, C21 and its salts may prevent or inhibit tissue damage induced by such viruses and / or the development of disease caused by symptoms of such damage or disease.

[0158] In this regard, C21 and its salts may treat and / or prevent the progression of diseases caused or induced by respiratory viruses (i.e., influenza, and acute lung injury (ALI) as acute lung injury, acute respiratory distress syndrome (ARDS), particularly SARS, more specifically COVID-19) and their sequelae. C21 and its salts may also treat and / or prevent injuries caused or induced by such viruses, including the treatment and / or prevention of symptoms of such respiratory diseases, including cough, dyspnea, tachypnea (e.g., as evidenced by the need for supplemental / supplementary oxygen (which may be administered via a face mask or nasal cannula (high flow or otherwise)) and / or mechanical ventilation / extracorporeal membrane oxygenation), respiratory failure, and / or direct (viral pneumonia) and / or indirect pneumonia (bacterial pneumonia resulting from secondary bacterial infection common in influenza), and subsequent fibrosis resulting from inflammation of the lungs and other organs (e.g., heart and kidneys). Furthermore, C21 and its salts may prevent or inhibit the progression of morbidity and / or mortality induced by respiratory viruses, and C21 may treat and / or prevent the development 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 symptoms of one or more viscera 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 symptoms such as acute respiratory distress syndrome (ARDS), (SARS), multi-organ inflammation, and injuries and / or dysfunctions that may be caused by internal or external trauma (e.g., injury) or infection.

[0160] Therefore, such symptoms may result from sepsis or septic shock caused by viral, bacterial, or fungal infections. Furthermore, acute lung injury, ARDS, and SARS in particular can be caused by viruses such as coronaviruses, including SARS-CoV-2, which can cause damage to internal tissues and / or dysfunction of associated internal tissues (e.g., mucous membranes) and / or cells containing them (e.g., respiratory epithelium). Damage to such tissues can then lead to severe fibrosis. For example, SARS disease, caused by SARS-CoV-2 (coronavirus disease 2019 or COVID-19), is known to often cause fibrosis.

[0161] However, the dosage forms of the present invention are also particularly useful for the treatment and / or prevention of sarcoidosis or fibrosis, more specifically pulmonary fibrosis, ILP in particular, and ILDs such as IPF, as well as conditions that can induce ILDs, such as systemic sclerosis, rheumatoid arthritis, myositis, or systemic lupus erythematosus, or conditions associated with ILDs, such as pulmonary hypertension and / or pulmonary arterial hypertension.

[0162] It will be understood by those skilled in the art that the term "ILD" includes any pulmonary condition characterized by an abnormal healing response, including chronic inflammation, decreased lung function, and / or scarring, regardless of the cause, such as sarcoidosis and PF, and in particular IPF. 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, the dosage forms of the present invention are further provided for use in conditions that lead to and / or cause ILD, such as PF or IPF, including systemic sclerosis.

[0163] In the treatment of pulmonary pulmonary effusion (PF), including intracellular pulmonary effusion (IPF), the dosage forms of the present invention may have an anti-fibrotic effect, accompanied by a reduction in fibrosis and prevention of further deposition of extracellular matrix. The dosage forms of the present invention may affect pulmonary scarring / wound healing and have an anti-apoptotic effect, thereby preventing apoptosis of alveolar endothelial cells, which are initiating factors in the development of PF. The dosage forms of the present invention may also have an antiproliferative effect, and therefore may reduce cancer-like proliferation of fibroblasts and myofibroblasts in PF. The dosage forms of the present invention may also improve vascular remodeling in PF, thereby alleviating secondary pulmonary hypertension. Finally, the dosage forms of the present invention may exhibit anti-inflammatory and anti-cytokine effects.

[0164] A further aspect of the present invention provides a method for treating any of the aforementioned conditions, including respiratory viral injury, more specifically, PF, and in particular ILD including IPF, the method comprising administering a therapeutically effective amount of the dosage form of the present invention to an individual suffering from or susceptible to such a condition.

[0165] According to yet another aspect of the present invention, a method for treating respiratory virus-induced tissue injury in a subject is provided, the method comprising administering a therapeutically effective amount of the dosage form of the present invention to a subject in need of the treatment, in particular, ● The damaged tissue is lung tissue, including respiratory epithelium. ● Damage includes damage and / or dysfunction of the mucous membrane tissue of the airways caused by respiratory viruses. ● Treatment includes treating the disease caused by or resulting from the virus, and / or preventing its progression. ● 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 the disease caused by or resulting from the associated virus. ● Symptoms of injury or disease include cough, shortness of breath, tachypnea (as indicated by the need for supplemental oxygen and / or mechanical ventilation), respiratory failure, pneumonia, one or more fibroses 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 represented both as therapeutic, symptomatic, and / or diagnostic treatment (e.g., during a thorough diagnosis when the condition has stopped) and as prophylactic treatment (including the prevention and / or suppression of the decline and / or worsening of the condition) for any of the above symptoms.

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

[0168] In the treatment of certain conditions such as respiratory virus-induced tissue injury, C21 or a pharmaceutically acceptable salt thereof is preferably administered to adult patients, more specifically those over about 20 years of age, for example, over 30 years of age including over 40 years of age, more preferably over 50 years of age, especially over 60 years of age, especially over 70 years of age, and more specifically over 80 years of age; and / or patients having one or more of the following underlying conditions (whether such patients are located 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 diseases such as heart failure, atrial fibrillation, or hypertension (e.g., heart disease) ● Chronic kidney disease ● Chronic liver diseases such as hepatitis ● Chronic neurological conditions such as Parkinson's disease, motor neuron disease, multiple sclerosis, learning disabilities, or cerebral palsy. ● Diabetes ● Problems with the patient's spleen - for example, sickle cell disease, or if the spleen has been removed. ● A weakened immune system due to conditions such as HIV and AIDS, or as a result of drugs such as steroid tablets or chemotherapy. ● Obesity (e.g., Body Mass Index (BMI) of 40 or higher) ● Pregnancy

[0169] In this regard, according to some further aspects of the present invention, a method for treating and / or preventing one or more of the following conditions is provided. ● What is known as "long COVID," "chronic COVID syndrome" (CCS), and / or "long-haul COVID," for example, post-acute sequelae (PASC) of SARS-CoV-2 infection. ● 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 embolus formation in the heart, lungs and / or brain, for example.

[0170] All of these may be directly or indirectly induced by respiratory viruses (such as SARS-CoV-2), and this method involves administering C21 or a pharmaceutically acceptable salt thereof to subjects in need of such treatment and / or prophylaxis.

[0171] For example, in connection with the acute treatment of respiratory virus-induced tissue injury, doses of C21 or a salt thereof may be administered 1 to 4 times a day (e.g., 1 to 3 times) for a maximum of 3 months (e.g., 2 months), 1 month including, for example, a maximum of 3 weeks, or a maximum of 1 week including, for example, 4 or 3 days. Such treatment periods may be repeated as needed.

[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 its salts should be continued and / or required, in addition to and / or instead of the acute administration regimen described above.

[0173] In the treatment of patients with viral infections, relevant active ingredients that may be used in combination therapy with C21 include standard treatments that vary depending on the viral infection, such as antibody therapies (e.g., LY-CoV555 / LY-CoV016 (bamranivimab and etesevimab)), LY-CoV555 (bamranivimab, Eli Lilly), REGN-COV2 (casiribimab and imdevimab), REGN3048-3051, TZLS-501, SNG001 (Synarigen), eculizumab (Soliris; Alexion Pharmaceuticals), ravulizumab (Ultomiris; Alexion Pharmaceuticals), lenzilumab, leronlimab, tocilizumab (Actemra; Roche), and sarilumab (Kevzara; Regeneron). Pharma, and Octagram (Octapharma), antiviral drugs (e.g., oseltamivir, remdesivir, favipiravir, mornupiravir, 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 This includes therapies such as anti-inflammatory drugs (e.g., NSAIDs like ibuprofen, ketorolac, and naproxen, chloroquine, hydroxychloroquine, interferons (e.g., interferon beta (interferon beta-1a), tocilizumab (Actemra), lenalidomide, pomalidomide, and thalidomide)), analgesics (e.g., paracetamol or opioids), antitussives (e.g., dextromethorphan), vaccinations (e.g., INO-4800 by Inovio Pharmaceuticals and Beijing Advaccine Biotechnology, where possible), and passive antibody therapy using 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] Relevant active ingredients that may be used in combination therapy with C21 in the treatment of ILDs such as IPF include, for example, antifibrotics (e.g., nintedanib, especially pirfenidone); vitamins (e.g., vitamins B, C, and D); mucolytics (e.g., acetylcysteine ​​and ambroxol); corticosteroids such as cortisone and prednisone; anti-inflammatory agents such as cyclophosphamide; other immunosuppressants such as azathioprine and mycophenolate tomofetil; 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; immunosuppressants such as methotrexate, azathioprine, leflunomide, mycophenolate / mycophenolate-mofetil, and cyclophosphamide; aminoquinolines; monoclonal antitumor 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] To avoid misunderstanding, the term "corticosteroids" above includes both naturally occurring and synthetic corticosteroids.

[0176] Naturally occurring corticosteroids that may be mentioned include cortisol (hydrocortisone), aldosterone, corticosterone, cortisone, pregnenolone, progesterone, as well as naturally occurring precursors and intermediates in corticosteroid biosynthesis, and 11-deoxycortisol, 21-deoxycortisol, 11-dehydrocorticosterone, 11-deoxycorticosterone, 18-hydroxy-11-deoxycorticosterone, 18-hydroxy This includes other naturally occurring corticosteroid derivatives such as cyclocorticosterone, 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] Synthetic corticosteroids that may be mentioned include cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate, hydrocortisone valveate, thixocortol and thixocortol pivalate, prednisolone, methylprednisolone, cloprednol, difluprednate, fludrocortisone, fluocinolone, fluperolon, fluprednisolone, prednisone, chloroprednisone, cloprednol, and difluprednate. Hydrocortisone types (Group A) such as fludrocortisone, fluotinolone, fluperolon, fluperednisolone, loteprednol, prednicarbate, and triamcinolone; acetonides and related substances (Group B) such as amcinonides, budesonide, desonide, fluocinolonecetonide, fluocinonide, halcinonide, triamcinolone acetonide, ciclesonide, deflazacort, formocortal, fludroxicortide, flunisolide, and fluocinolone acetonide; beclomethasone, betamethasone Betamethasone dipropionate and betamethasone valveate, dexamethasone, flucortolone, halomethasone, mometasone and mometasone furoate, alclomethasone and alclomethasone dipropionate, clobetasol and clobetasol propionate, clobetasol and clobetasol butyrate, clocortolone, desoxymethasone, diflorasone, difluocortolone, fluchlorolone, flumethasone, fluocortin, flupredniden and flupredniden acetate, fluticasone, fluticasone (β)methasone type (group C) drugs such as sozonfloate, fluticasone propionate, meprednisone, paramethasone, prednilidene, rimexolone, and urobetasol; progesterone type drugs such as flugestone, fluorometholone, medrizone, and prevediolone acetate; and progesterone derivatives (progestins) such as chlormadinone acetate, cyproterone acetate, medrogenestone, medroxyprogesterone acetate, megestrol acetate, and segesterone acetate;This also includes other corticosteroids such as cortibazole 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] Furthermore, relevant active ingredients that may be used in combination therapy with C21 (for example, to treat respiratory viral infections) include H2 receptor blockers, anticoagulants, antiplatelet agents, as well as statins, antibacterial agents, and anti-allergic / anti-asthmatic 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, sertoparin, dalteparin, tinzaparin); direct-acting oral anticoagulants (e.g., dabigatran, argatroban, rivaroxaban, apixaban, edoxaban, betrixaban, dalexaban, otamixaban, retaxaban, eribaxaban, hirudin, repirudin, and bivalirudin); coumarin vitamin K antagonists (e.g., coumarin, asenocoumarol, fencrocumone, atromentin, and phenindione) and factor Xa synthesis pentasaccharide inhibitors (e.g., fondaparinux, hydraparinux, and hydraviotaparinux). Antiplatelet agents that may be mentioned include irreversible cyclooxygenase inhibitors (e.g., aspirin and triflusal); adenosine diphosphate receptor inhibitors (e.g., cangrelol, clopidogrel, prasugrel, ticagrelor and ticlopidine); phosphodiesterase inhibitors (e.g., cilostazol); protease-activated receptor 1 antagonists (e.g., borapaxal); glycoprotein IIB / IIIA inhibitors (e.g., absiximab, eptifivatide and tyrofiban); adenosine reuptake inhibitors (e.g., dipyridamole); and thromboxane inhibitors (e.g., tertroban, ramatroban, seratrodast and picotamide). Statins that may be mentioned include atorvastatin, simvastatin and rosuvastatin. Antimicrobial agents that may be mentioned include azithromycin, ceftriaxone, cefuroxime, doxycycline, fluconazole, piperacillin, tazobactam, and teicoplanin. Antiallergic / antiasthmatic drugs that may be mentioned include chlorpheniramine, levocetirizine, and montelukast.

[0181] Furthermore, relevant active ingredients that may be used in combination therapy with C21 (for example, 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 angiotensin-converting enzyme (ACE) inhibitors. Non-limiting but exemplary examples of AT1 receptor antagonists that can be used according to embodiments include azilsartan, candesartan, eprosartan, fimasartan, irbesartan, losartan, milfasartan, olmesartan, pomisartan, platosartan, lipiasartan, suprisartan, tasosartan, telmisartan, valsartan, and / or combinations thereof. Non-limiting but exemplary examples of ACE inhibitors that can be used according to the embodiments include captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, fosinopril, moexipril, cilazapril, spirapril, temocapril, seronapril, derepril, muovertipril, and / or combinations thereof.

[0182] Related patients may also receive (and / or already receive) one or more of the above-mentioned treatments and / or other therapeutic agents for the related condition based on the administration of one or more of such active ingredients, thereby meaning that the inventors also receive prescription doses of one or more of these active ingredients referred to herein before, in addition to, and / or after, treatment using C21 or a salt thereof.

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

[0184] The dosage form of the present invention has the advantage of being able to be manufactured and stored under normal storage conditions, including maintaining the pharmaceutically acceptable physicochemical stability of the composition contained with the capsule, particularly the active ingredient, without being frozen and / or exposed to light.

[0185] The dosage form of the present invention also provides an improved drug load, enabling the delivery of large / high-dose active compounds and providing efficient delivery of such higher doses in a consistent / uniform manner. This improves the efficacy and efficiency of treatment and reduces healthcare costs.

[0186] The uses / methods described herein, whether used in these conditions or otherwise, may have advantages over similar methods (treatments) known in the prior art, in other respects, such as being more convenient for physicians and / or patients, more effective, less toxic, having a broader range of activity, being more potent, causing fewer side effects, or having other useful pharmacological properties, particularly in the treatment of one or more of the conditions described herein, especially ILD and / or respiratory viral infections.

[0187] Whenever the word “approximately” is used herein, it is understood that such variables are approximate and may vary by ±10%, e.g., ±5%, preferably ±2% (e.g., ±1%) from the actual value identified.

[0188] The present invention is illustrated by the following examples, but is not limited thereto.

[0189] Examples Example 1 Observation of the effects of diet in the 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 trial design allowed for dose escalation with intensive clinical data and PK monitoring to ensure the safety and well-being of the subjects.

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

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

[0192] Participants received two single doses of 75 mg of C21 at least 3 days apart, in a randomized manner, either in a fasted or fed state. The maximum effect was investigated using a high-fat breakfast as recommended by the Food and Drug Administration (FDA).

[0193] In the dietary influence portion of the study, the ages of the subjects ranged from 22 to 44 years, with a median age of 36.0 years. The majority of the subjects were Caucasian (9 subjects, 90.0%) and male (8 subjects, 80.0%). The mean (SD) BMI for all subjects was 23.96 (2.223) kg / m². 2 That was the case.

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

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

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

[0197] ● Actual sampling times related to drug administration, rather than nominal times, were used in the calculation of all derived pharmacokinetic parameters. ● No attribute was found for the missing data. ● At least C max and AUC( 0-t) If the calculation could be done accurately, all subjects with missing concentration data would have been included in the PK analysis set.

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

[0199] The bioequivalence of PK parameters from an open-label diet-effect arm was determined by constructing a 90% confidence interval around the estimated difference between the test and reference treatments using a mixed-effects model based on naturally log-transformed data. The mixed-effects model was implemented using SAS Proc Mixed, with REML estimation and the Kenward-Roger degrees of freedom algorithm.

[0200] AUC( 0-inf) (If data is allowed), AUC( 0-24 ), and C maxThe study analyzed sequence, duration, and treatment as fixed effects, and included subjects within the sequence as a random effect using a mixed-effects model. Estimates of mean differences (trial-reference) and corresponding 90% confidence intervals were obtained from the model. The estimated mean differences and 90% confidence intervals for the differences were indexed to provide estimates of geometric mean ratios (trial / reference) and 90% confidence intervals for the ratios. C21 in the fasting state was the reference treatment, and C21 in the feeding state was the trial treatment.

[0201] Using comparisons to assess the effect of food (bioequivalence), the effect of food on the rate and extent of C21 absorption under fasting and feeding conditions was evaluated, and estimates of the mean difference and corresponding 90% confidence intervals were presented.

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

[0203] [Table 2-1]

[0204] [Table 2-2]

[0205] [Table 2-3]

[0206] After oral administration of 75 mg C21, when administered under fasting and feeding conditions, the median peak plasma concentration was t max It occurred at 0.67 and 1.26 hours, respectively. Geometric mean C max The levels were 1708 ng / mL with a 75 mg dose during fasting and 263 ng / mL with a 75 mg dose during feeding.

[0207] C max The variability (geometric CV%) was 37% and 22% during fasting and feeding, respectively. Geometric mean AUC (0-12)The glycemic index (AUC) was 1767 h*ng / mL and 767 h*ng / mL for fasting and feeding regimens, respectively, for 75 mg. All AUC parameters were comparable for each treatment, and the geometric CV% of the AUC parameters ranged from 21% to 34% for 75 mg in both fasting and feeding regimens. 1 / 2 The duration was less than 1 hour in both fasting and feeding therapy. Consistent with the measured AUC values, CL / F was approximately twice as high in feeding therapy. z / F was three times higher compared to the value obtained during fasting treatment.

[0208] Table 3 summarizes the statistical analysis of the effects of diet on C21. [Table 3]

[0209] This model is an analysis of variance (ANOVA) model, where the sequence, duration, and treatment period are fixed, and there are random effects on the subjects within the sequence. Statistical analysis of the effect of diet on C21PK parameters (see Table 3 above) shows that when C21 is given with food, C max This indicated a decrease in C. max The geometric mean ratio is 0.16, and the 90% confidence interval is less than 1 (100%), C max The difference is statistically significant. When 75 mg of C21 is administered with food, the AUC (0-24) The number of cases decreased. AUC (0-inf) The geometric mean ratio is 0.45 for both, and the 90% confidence interval is below 1 (100%), indicating that the difference in AUC values ​​is statistically 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) while stirring at 37 ± 3°C. The compound dissolved immediately. After stirring for 15 minutes, 2 M acetic acid solution was added dropwise to obtain pH 4.52. The generation of CO2 was noted. After stirring for 1 hour, the formation of small white particles was observed. After stirring for a further 1.5 hours, 1 M NaOH was added to raise the pH to 6.8. Stirring was continued for another 1.5 hours, but there was no 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) at the same temperature while stirring. The added compound formed a thin slurry, which floated on the top 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 fragments smaller, and it became creamy. Stirring was continued for another 1.5 hours, and there was no significant change in appearance (small creamy 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 instantaneously. After stirring for 20 minutes, 1 M NaOH solution was added dropwise to raise the pH to 4.5. No precipitate was observed after the addition of the NaOH solution. After stirring for 2 hours, 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) while stirring at the same temperature. The added compound formed a thin slurry. It appeared that nothing dissolved. After stirring at the same temperature for 7 hours, there was no significant change in appearance. UPLC analysis showed that no C21 decomposition occurred at the end of the experiment.

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

[0215] In summary, these results indicate that the C21 zwitterion formed at intermediate pH is unexpectedly insoluble. This explains the effect of diet observed in Example 1 above.

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

[0217] Next, the excipient blend was sieved through an 800 μm sieve and then blended for a further 20 minutes at 30 rpm.

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

[0219] Next, the resulting blend was sieved through an 800 μm sieve, followed by blending at 30 rpm for 20 minutes.

[0220] After preparing the blend, approximately 270 mg of the blend sample was weighed into a 100 mL volumetric flask, 40 mL of MilliQ water and sonication for 20 minutes were added, and 40 mL of methanol was added. The homogeneity of the blend was determined by sonication for another 20 minutes. After equilibration to room temperature, 1.0 mL of the sample solution was added to a 10 mL volumetric flask. Subsequently, it was diluted to the desired volume with methanol and mixed.

[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 (at 100% nominal sample concentration).

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

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

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

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

[0226] Weight classification was performed by applying a 5% tolerance limit to the net filled weight of the capsules, resulting in a value of 18.6%. After encapsulation, the capsules were manually pre-packaged in 100 mL high-density polyethylene (HDPE) vials with tamper-evident caps containing a desiccant (56 capsules / vial). A total of 97 vials 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 with a 2L drum and a 0.7mm diameter nozzle; ProCepT, Belgium) equipped 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. A propeller stirrer was placed in the center, as close to the bottom of the container as possible, to create a vigorous vortex for homogenization. Before the coating process, the dispersion was passed through a 200 μm sieve.

[0229] To facilitate the smooth movement of capsules within the pan coater and reach the appropriate amount to load into the drum, 560 dummy capsules (size 0) are also added, along with capsules of different colors (dark green) and filling weights (410 mg / capsule of mannitol (Pearlitol 160C)), so that they can be separated later by weighing, sorting, and visual inspection.

[0230] Stepwise coating was performed using samples collected at predetermined times.

[0231] The coating process was carried out by filling a drum with capsules and setting the inlet temperature to 40°C. While the drum was rotating, the capsules were heated to 30°C before spraying 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 them.

[0233] The spray volume was 740 g. The filling content per capsule of the composition was 260.93 mg per capsule. When the weight of an empty capsule was 96.1 mg and the total weight per filled capsule was 357 mg, the total coating / filled capsule weight was 490.66 mg, and the coating amount per capsule was 133.66 mg. This corresponds to the weight of the coating per capsule, which was 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 disk) Two-stage disintegration test on coated capsules (n=6): (a) pH 1.2 (prepared by mixing 0.1N HCl in water, 250 mL of 0.2M NaCl, 425 mL of 0.2M HCl, and 325 mL of purified water); and (b) pH 6.8 using phosphate buffer (prepared 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 1L beaker, and a constant temperature device for heating the fluid to 37°C (±2°C). The basket rack assembly was designed to contain three capsules in three different transparent cylinder tubes placed on a stainless steel screen, allowing the solution to flow into the tubes.

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

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

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

[0239] Next, the basket was transferred to phosphate buffer pH 6.8. According to Ph.Eur, all capsules should disintegrate within 60 minutes according to the specifications.

[0240] Visual inspection revealed that the capsules remained completely intact in an acidic medium (a) and underwent rapid capsule disintegration in a more basic medium (b), thus indicating that the enteric coating of the capsules was successful.

[0241] Example 4 Stability test of the dosage form of the present invention Enteric-coated capsules obtained using the method described in Example 3 above were tested in tests to evaluate their stability in clinical representative packaging under ICH (International Conference 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 results of stability under various storage conditions and time are shown in Table 7 (Purity by Assay and Chromatography) and Table 8 (Disintegration) below. Water content was measured using Karl Fischer titration. Impurity 1 was previously known in C21, while impurities 2 and 3 are novel. LOR represents the limit of the report (i.e., 0.10%, lc). [Table 7] [Table 8]

[0244] All stability breakdown results were consistent with expectations; the enteric-coated capsules did not dissolve in acidic media and dissolved rapidly at pH 6.8. The assay remained stable over a 6-month stability period under both storage conditions.

Claims

1. A tablet for oral administration to the gastrointestinal tract, wherein the tablet comprises compressed granules containing N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof and at least one carrier material, and the tablet comprises an enteric coating used to coat, encapsulate and / or encapsulate the granules to prevent the N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof from being released in the stomach and / or coming into contact with gastric juice.

2. The tablet according to claim 1, wherein the compressed granules comprising N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof are protected by the presence of a coating comprising the enteric coating.

3. The tablet according to claim 1 or claim 2, wherein the enteric-coated substance is selected from the group consisting of cellulose acetate, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate tetrahydrophthalate, polyvinyl acetate phthalate, hydroxyethyl ethyl cellulose 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.

4. The tablet according to any one of claims 1 to 3, wherein the N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof is uniformly dispersed throughout the carrier material.

5. The tablet according to any one of claims 1 to 4, wherein the carrier material is selected from the group consisting of pharmaceutically acceptable inorganic salts, polymers, starches, sugars, sugar alcohols, or mixtures thereof.

6. The tablet according to any one of claims 1 to 5, wherein the carrier material is a sugar or sugar alcohol selected from the group consisting of lactose, mannitol, xylitol, isomalt, dextrose and mixtures thereof.

7. The tablet according to any one of claims 1 to 6, further comprising one or more binders selected from the group consisting of polyvinylpyrrolidone, gelatin, sodium alginate, and cellulose derivatives.

8. A tablet according to any one of claims 1 to 7, further comprising one or more disintegrants selected from the group consisting of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose (croscarmellose), carboxymethyl starch, natural starch, pregelatinized starch, corn starch, potato starch, sodium starch glycolate, and low-substituted hydroxypropylcellulose.

9. The tablet according to any one of claims 1 to 8, further comprising one or more forms of silica selected from the group consisting of fumed / calcined silica, silica gel, silica aerogel, and colloidal silica, and one or more flow promoters selected from the group consisting of talc, magnesium carbonate, and calcium silicate.

10. The tablet according to any one of claims 1 to 9, further comprising one or more lubricants selected from the group consisting of stearic acid, sodium stearyl fumarate, colloidal anhydrous silica, talc, and magnesium stearate.

11. The tablet according to any one of claims 1 to 10, wherein the N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof is provided in the form of particles having an average diameter on a weight and / or volume basis of 50 μm (±10%) or less.

12. A tablet according to any one of claims 1 to 11, which is essentially water-free.

13. The tablet according to claim 12, which contains 5% (±10%) or less of water.

14. The tablet according to claim 13, which contains 2% (±10%) or less of water.

15. The tablet according to any one of claims 1 to 14, wherein the pharmaceutically acceptable salt of N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide is the sodium salt.

16. A process for manufacturing tablets according to any one of claims 1 to 15, wherein the process is: (a) A process of granulating the N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof and the carrier material into granules by dry granulation, wet granulation, melt granulation, thermoplastic pelletization, spray granulation, or extrusion / spheroidization. (b) A step of compressing the granules, (c) A tablet manufacturing process comprising the step of coating the compressed granules with the enteric coating.

17. The tablet manufacturing process according to claim 16, further comprising the step of uniformly dispersing the N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof throughout the carrier material.

18. A tablet according to any one of claims 1 to 15, for use in the treatment of interstitial lung disease.

19. The tablet according to claim 18, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

20. The tablet according to claim 18, wherein the interstitial lung disease is sarcoidosis.

21. The tablet according to any one of claims 18 to 20, wherein the treatment includes the prevention of morbidity and / or mortality in the associated condition.

22. A tablet according to any one of claims 18 to 21, administered by oral route.

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