New delayed release composition for peroral 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] The present invention relates to new pharmaceutical dosage forms, their use as medicaments, in particular their administration for treating lung diseases, such as interstitial lung diseases.

Background Art

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

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

[0004] The most common forms of ILD are idiopathic pulmonary fibrosis (IPF) and sarcoidosis, both of which are characterized by chronic inflammation and a decline in lung function.

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

[0006] The treatment of sarcoidosis varies from patient to patient. In most cases, symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is possible, but for patients presenting with lung symptoms, glucocorticoids (e.g., prednisone or prednisolone), antimetabolites, and / or monoclonal anti-tumor necrosis factor antibodies are often used.

[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, a chronic, irreversible, and progressive decline in lung function occurs, and most patients die within 2 to 5 years (median survival 2.5 to 3.5 years). The overall prognosis of IPF is poor, but it is difficult to predict the rate of progression in individual patients. Risk factors for IPF include age, male gender, genetic predisposition, and smoking history. The annual incidence is 5 to 16 per 100,000 population, with a prevalence of 13 to 20 cases per 100,000 population, increasing 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 limited to the lungs and is refractory to immune system-targeted therapies that distinguish it from pulmonary fibrosis (PF) associated with systemic connective tissue diseases.

[0008] Patients with IPF typically seek medical assistance due to chronic and progressive exertional dyspnea and cough. Lung imaging classically reveals traction bronchiectasis, thickened interlobular septa, and subpleural honeycombing. If all three findings are present and there is no evidence of systemic connective tissue disease or environmental exposure, the likelihood of a diagnosis of IPF is very high. A definitive diagnosis is usually made by lung biopsy and requires an interdisciplinary team of experts, including a respiratory physician, radiologist, and pathologist with experience in ILD.

[0009] IPF presents various phenotypes with different prognoses, defined as mild, moderate, and severe. Mild cases follow a stable or slowly progressive course, and patients may take several years to seek medical advice. Accelerated IPF has a shorter survival period, progresses much more rapidly, and affects a subgroup of patients, usually male smokers. Acute exacerbation of IPF is defined as a rapid deterioration of the disease, and patients in this subgroup show very poor outcomes with high short-term mortality. The cause of IPF is unknown, but it appears to be a disease that, due to the interaction of environmental and genetic factors, is likely to cause relentless tissue remodeling by fibroblasts rather than normal repair, and is a pathological process mainly due to fibrosis rather than inflammation. There is increasing evidence suggesting that this disease is initiated by microdamage and apoptosis of alveolar epithelial cells, which activate adjacent epithelial cells and attract stem cells or progenitor cells that produce factors involved in the expansion of fibroblast and myofibroblast populations in a tumor-like manner. Fibroblastic foci secrete excessive amounts of extracellular matrix, which destroys the lung parenchyma and ultimately leads to loss of lung function.

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

[0011] Numerous treatment approaches have been tested in preclinical models and clinical trials, including anti-inflammatory drugs, immunomodulatory drugs, cytotoxic drugs, general antifibrotic drugs, antioxidants, anticoagulants, anti-chemokine drugs, anti-angiogenic drugs, as well as RAS blockers, endothelin antagonists, and sildenafil, etc. All of these have basically shown limited or no benefits (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, thereby repairing 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 challenge for the future is to develop appropriate treatment approaches that 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 -lle 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 the cause of most of the pathological effects of AngII. The safety and efficacy of losartan (an AT1 receptor inhibitor) were recently investigated in a small, uncontrolled, non-blinded pilot trial regarding IPF (www.clinicaltrials.gov identifier NCT00879879).

[0019] Several studies in adults appear to show that the activation of the angiotensin II type 2 (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).

[0022] 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, triazolyl, and tetrazolylthiophenesulfonamides and derivatives as AT2 receptor agonists. Among the compounds described in that document (as Example 1), N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide (Compound 21, or "C21" when used hereinafter) was selected for clinical development from a group of about 20 related analogs as a selective AT2 receptor agonist. C21 is currently in clinical development for the treatment of disorders including IPF, for which treatment with an AT2 receptor agonist is thought to be beneficial (see, for example, International Patent Application, International Publication No. 2016 / 139475).

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

[0025] The applicant has been working on this active ingredient for about 20 years and until recently has not been able to obtain a pharmaceutically acceptable dosage form that is stable when stored at ambient temperature.

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

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

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

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

[0030] In the context of the present invention, an "enteric" substance is used to coat, encapsulate and / or capsule a composition comprising C21 or a pharmaceutically acceptable salt thereof, to prevent the active ingredient from being released from the composition, and / or from contacting gastric juice, and / or until its components reach the small intestine within the stomach. "Substantially prevent" includes that no more than about 20%, for example about 15%, for example about 10%, more specifically no more than about 5% of the active ingredient is released in the acidic environment of the stomach.

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

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

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

[0034] When C21 or its salts are provided in the form of multi-particles as powders, granules, pellets, and / or beads, the particles must be individually or collectively coated with enteric substances. This can be done in various ways.

[0035] In this regard, C21 and its salts can be presented in the form of a simple mixture with a carrier system, and the carrier system is any pharmaceutically acceptable inert material that can increase the mass of the composition or the components of the composition to provide a properly 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 silicated) microcrystalline cellulose, cellulose and cross-linked polyvinylpyrrolidone; starch; sugars and sugar alcohols, such as lactose, mannitol, xylitol, isomalt, dextrose; or mixtures of any of the foregoing.

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

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

[0039] Subsequently, 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 a salt thereof 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 binding formation promoter, which can facilitate the compression of powder masses into coherent compacts. Suitable binders include polyvinylpyrrolidone, gelatin, sodium alginate, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose gum, cellulose derivatives such as microcrystalline cellulose (optionally silicated), and the like. When present, the binder is preferably used in an amount of about 2% to about 50% by weight, based on the total weight of the composition containing C21 or its salt. A preferred range is about 5% to about 30% by weight.

[0044] A disintegrant can be defined as a material that can accelerate the disintegration / dispersion of components of a composition containing C21 or its salt, such as granules or tablets, to a measurable extent. This can be achieved, for example, by a material that can swell and / or expand when placed in contact with an aqueous medium (especially body fluids including those found in the gastrointestinal tract), and thus cause at least a part of the dosage form of the present invention to disintegrate when containing water. Suitable disintegrants include cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose (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), low-substituted hydroxypropyl cellulose, and the like. The disintegrant (which may contain one or more of the above materials) is preferably used in an amount of about 1% (e.g., about 5%) to about 40% by weight, based on the total weight of the composition containing C21 or its salt. A preferred range is about 5% (e.g., about 10%) to about 30% by weight. Preferred disintegrants used include cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, and especially low-substituted hydroxypropyl cellulose.

[0045] A flow promoter is a pharmaceutically acceptable material that promotes the flow of a powder by reducing friction and / or aggregation between particles (however, it is not necessarily required to have the ability to reduce and / or prevent adhesion to external materials such as capsule filling machines or hoppers). Thus, suitable pharmaceutically acceptable fluidity materials include talc, magnesium carbonate or calcium silicate, but the flow promoter is preferably a hydrophilic flow promoter such as one or more of various forms of silica including fumed / calcined silica or more specifically silica gel, silica aerogel and / or colloidal silica.

[0046] Lubricants are usually used when the final dosage form to be swallowed is in the form of tablets. Suitable lubricants that prevent granules or powders from adhering to the punch die / face and promote smooth discharge from the die after compression include stearic acid, sodium stearyl fumarate, anhydrous colloidal silica, talc, or preferably magnesium stearate. When using a lubricant, it should be used in very small amounts (e.g., up to about 3% by weight, preferably up to 2% by weight, based on the total weight of the composition containing C21 or its salt).

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

[0048] These, and other pharmaceutically acceptable excipients referred to herein, may be commercially available or, if not, are described in the literature, for example, for all excipients of this type, for example, as 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 cited therein, and the relevant disclosures of all these 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, dried granules can be crushed, ground or milled using appropriate comminution techniques to produce particulate matter of a smaller size, and this can be sieved to separate fractions of the desired size. Wet granules can be screened to break up aggregates of the granules and remove fines. In either case, unused smaller and larger materials can be reprocessed to avoid waste.

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

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

[0052] The terms "homogeneous" and "homogeneously dispersed" in the context of the present invention mean that there is a substantially uniform content of C21 or its salts throughout the carrier material (and / or other excipients used). In other words, when a plurality of (e.g., at least 2, more preferably about 6, e.g., about 10 to a maximum of about 30, or more if necessary) samples are taken from a mixture containing the active ingredient and the carrier blend, the measured content of the active ingredient present between such samples results in a standard deviation (i.e., coefficient of variation and / or relative standard deviation) from the average amount of less than about 8%, e.g., less than about 6%, e.g., less than about 5%, particularly less than about 2%.

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

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

[0055] The composition containing C21 or its salts is preferably contained within capsules suitable for such oral administration.

[0056] Suitable 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 standard capsule filling processes.

[0057] When the dosage form of the present invention includes a solid formulation comprising a mixture of C21 or a salt thereof with a carrier material (for example, in the form of a powder, granule, etc.), according to a preferred embodiment of the present invention, the capsule is preferably a hard shell two-piece capsule, for example made of gelatin, or more preferably HPMC, and is supplied as a closed half that can be separated and filled with particulate matter and then reassembled. Such capsules can be of any size (for example, 00 - 5), but the preferred capsule size is 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 can be amorphous or crystalline, or a mixture of the two. Preferred particles are of a size that does not lead to separation either during the capsule filling process or during the formation of the composition filled into the capsule during storage.

[0059] In this regard, C21 or a salt thereof can be provided in the form of a plurality of primary (i.e., non-aggregated) particles having an average diameter based on weight and / or volume of usually about 1,000 μm or less, for example, about 500 μm including about 250 μm, preferably about 100 μm or less including about 50 μm, 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 manufacture, the primary particles of C21 or a salt thereof preferably have an average diameter based on weight and / or volume of less than 1 μm, for example about 2 μm, about 3 μm.

[0060] As used herein, the term "weight-based average diameter" is understood by those skilled in the art to include that the average particle size is characterized and defined from a particle size distribution by weight, i.e., the existing fraction (relative amount) in each size class is defined as the weight fraction obtained, for example, by sieving (e.g., wet sieving). The term "volume-based average diameter" is similar in meaning to the weight-based average diameter, but the average particle size is characterized and defined from a particle size distribution by volume, i.e., the existing fraction (relative amount) in each size class is defined as the volume fraction measured, for example, by laser diffraction. The particle size can also be measured with standard equipment 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 well-known equipment in this field, such as equipment sold by Malvern Instruments, Ltd (Worcestershire, UK), Shimadzu (Kyoto, Japan) and Elzone, Micromeritics (USA; electrical sensing zone method).

[0061] Includes the average diameter of the particles according to the invention, before preparation according to the invention and before mixing with the relevant excipients and / or before filling into capsules, of particles having a weight and / or volume-based average diameter within the above limitations. It will be understood that some aggregation of the primary particles to form secondary particles may occur during handling and / or processing of the active ingredient. However, this needs to be minimized.

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

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

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

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

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

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

[0068] Furthermore, and in particular, as described hereinafter, compatibility studies have revealed that when certain standard excipients are co-mixed with C21 and its salts, they cause significant chemical instability of the active ingredient. Furthermore, C21 and its salts are formed as sticky, needle-shaped crystals that tend to agglomerate. This means that dry mixing with certain standard pharmaceutically acceptable ingredients is very difficult and it is not easy to produce a pharmaceutically acceptable content uniformity of the active ingredient and / or a blend having such uniformity within the capsule.

[0069] Furthermore, micronizing the primary particles of the active ingredient also does not provide a solution to these problems, as expected by those skilled in the art, and causes additional problems related to local heating and static electricity.

[0070] However, the inventors have found that by blending C21 or its pharmaceutically acceptable salt with a pre-mixed blend of a particulate carrier having a weight-based and / or volume-based average diameter and / or a structural (particle) density similar to the weight-based and / or volume-based average diameter and / or structural (particle) density of the solid particles of C21 or its pharmaceutically acceptable salt, and a flow promoting agent, the aforementioned problems can be avoided, ensuring that C21 or its salt is uniformly and evenly distributed, not only ensuring dose uniformity of the active ingredient between such filled capsules, but also making it possible to provide a composition for filling capsules. It is made possible to be physically and chemically stable during and after manufacture, under normal storage conditions, and during use.

[0071] Accordingly, in this first preferred embodiment of the present invention, the excipient mixed with the particles of C21 or a pharmaceutically acceptable salt thereof comprises at least one type of carrier particle having a weight-based and / or volume-based average diameter, and / or structural (particle) density similar to the weight and / or volume-based average diameter, and / or structural (particle) density of C21 or a pharmaceutically acceptable salt thereof, respectively, and a blend of a flow promoter. Next, such a composition is suitable for oral administration and is loaded into capsules coated with enteric substances.

[0072] The terms "uniform" and "uniformly dispersed" in the context of this embodiment of the present invention are defined as described above.

[0073] In this preferred embodiment of the present invention, suitable carrier particle materials may include pharmaceutically acceptable substances soluble in water, including carbohydrates such as sugar alcohols such as sorbitol, xylitol, especially mannitol. Further, the carrier particles may include a physical mixture of any of these materials and / or may include one or more complexes of these materials.

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

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

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

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

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

[0079] Thus, it is preferred to mix the glidant and the carrier particles together to form an interactive (or ordered) mixture of carrier particles mostly coated with smaller particles of the glidant material, and then to mix this mixture with the active ingredient particles.

[0080] Also, the inventors have found that by adding the aforementioned glidant to the carrier particles prior to mixing with the active ingredient to first form an excipient blend, the flow properties of the excipient blend are improved and thereafter it mixes better with C21 or a pharmaceutically acceptable salt thereof, further reducing the possibility of blend separation.

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

[0082] However, considering the extreme sensitivity of C21 and its salts to other chemical substances, it is preferred that such other excipients are not included in the dosage forms according to this aspect of the invention. In this regard, a dosage form of the invention is provided which consists essentially of a pharmaceutical composition in the form 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- and / or volume-based average diameter, and / or structure (particle) similar to that of the solid particles of C21, and a weight- and / or volume-based average diameter, and / or structure (particle) density, and a flow promoter, the composition being suitable for oral administration and being contained within a capsule coated with an enteric substance.

[0083] All preferred features mentioned herein with respect to this aspect of the invention which are in any way related to this aspect of the invention are equally applicable.

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

[0085] In this regard, although not an essential feature of this preferred aspect of the 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 equipment (such as capsule filling machines and hoppers). This is a preferred feature which does not substantially affect the basic and novel characteristics of this aspect of the invention.

[0086] A composition filled into a capsule "consisting essentially of" a particulate mixture comprising solid particles of C21 or a pharmaceutically acceptable salt thereof, mixed with a blend of carrier particles and a flow promoter as defined above, is meant to include at least about 95%, such as at least about 97% by weight in total of those specific components.

[0087] In this first preferred embodiment of the present invention, for example, as described below, it is also preferred that the dry mixed blend passes through a sieve at some point during the mixing process in order to break down aggregates formed during the blending process. A suitable sieve has a pore size of a size similar to (or of the order of) the particle size of the largest component of the blend. Thus, suitable sieve sizes are from about 50 μm, for example 75 μm, 100 μm, for example 150 μm, 200 μm or 250 μm (for example, about 300 μm) to about 1,000 μm, for example about 400 μm (for example, about 500 μm) to about 900 μm (for example, about 800 μm).

[0088] According to a second preferred embodiment of the present invention, there is provided a dosage form of the present invention 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 in a pharmaceutically acceptable hydrophobic lipid-based carrier in which C21 or its salt is essentially insoluble, and the composition is suitable for such oral administration and is loaded into a capsule coated with an enteric substance.

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

[0090] According to this preferred embodiment of the present invention, the capsule is preferably a soft-shell single-piece capsule, for example, a soft gelatin capsule. The single-piece gelatin capsule is filled with a lipid-based suspension of C21 or its salt and is then sealed as a single piece, for example, with droplets of a gelatin solution. Gelatin can be obtained from any source (for example, porcine 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, an amorphous solution of sorbitol, glucose, fructose and glucose syrup, more preferably glycerin / glycerol, sorbitol and / or Anidrisorbs (a unique mixture of sorbitol, sorbitan, maltitol and mannitol, Anidrisorb 85 / 70 (a liquid sorbitol-mannitol hydrolyzed starch plasticizer), Roquette Freres), etc. The soft gelatin capsule shell may optionally contain one or more flavoring agents, coloring agents, and / or opacifying agents (such as titanium dioxide).

[0092] Such capsules can be of any shape (e.g., rectangular, circular, oval, tubular, etc.) and of any size (e.g., 3 - 24 for rectangular, 1 - 20 for circular, 2 - 20 for oval, 5 - 120 for tube, 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 invention is that C21 or a pharmaceutically acceptable salt thereof is essentially insoluble in the lipid-based carrier under normal storage conditions. "Essentially insoluble" includes that C21 or its salt has a solubility of about 0.015 mg or less of C21 or its salt per gram of the carrier in the carrier.

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

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

[0096] As described above, the hydrophobic lipid-based carrier material in which C21 or its salt must be insoluble may contain a nonpolar oil or fat that is essentially immiscible with water. The lipid-based carrier preferably consists mainly of triacylglycerol (also known as "triglyceride"), which is an ester formed by the reaction of all three hydroxyl groups of the glycerol moiety with fatty acids (carboxylic acids).

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

[0098] Saturated fatty acids that may be mentioned include acetic acid (2), propionic acid (3), butyric acid (4), valeric acid (5), caproic acid (6), enanthic acid (7), caprylic acid (8), pelargonic acid (9), capric acid (10), undecylic acid (11), lauric acid (12), tridecylic acid (13), myristic acid (14), pentadecylic acid (15), palmitic acid (16), margaric acid (17), stearic 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), carnoceric acid (27), montanic acid (28), nonacosylic acid (29), and melissic acid (30), where the numbers in parentheses are the number of carbon atoms in the fatty acid molecule.

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

[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 may be naturally occurring oils or fats, may be semi-synthetic, or may be 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 mainly contain triglycerides, which are mixtures of glycerides having different fatty acid chain lengths.

[0104] Naturally occurring pharmaceutically acceptable oils falling within this category include sunflower oil, soybean oil, corn oil, grape seed oil, rapeseed oil, sesame oil, almond oil, apricot kernel oil, cottonseed oil, palm kernel oil, castor oil, olive oil, palm oil, and coconut oil (for the respective compositions, see, 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 the dosage forms of this preferred embodiment of the present invention, the naturally occurring oils should be of pharmaceutical grade and, accordingly, should 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 carrier systems can be prepared using techniques well known in the art, such as separation, transesterification, lipolysis and ester exchange reactions (glycerolysis).

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

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

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

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

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

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

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

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

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

[0117] If the lipid-based carrier system is in the form of a fat (i.e., solid or semi-solid at or around the normal manufacturing temperature and / or product storage temperature), 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 a stable, uniform and even distribution of the active ingredient in the carrier in such a suspension, if necessary, the lipid-based carrier system (and in particular those in the form of a liquid oil at or around the normal manufacturing temperature and / or product storage temperature) further includes a thickening agent to avoid aggregation and / or sedimentation of particles such as microcrystalline cellulose and sodium carboxymethylcellulose, and a blend of mono, di and triglycerides with PEG esters of unsaturated fats such as Gelucire 43 / 01, hydrogenated vegetable oil, beeswax, paraffin wax, etc.

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

[0120] As used herein, C21, or a pharmaceutically acceptable salt thereof, can be prepared and stored in the form of a composition that can be directly filled into capsules for preparing the dosage form of the invention. Further, once prepared, the dosage form of the invention can be stored under normal storage conditions with only a slight change in the physicochemical properties of the dosage form, the composition mixture contained therein, and / or most importantly, the active ingredient, over time.

[0121] Thus, "a slight change in physicochemical properties" includes that the composition containing C21 / salt in a suitable carrier, before and after being filled into capsules, and thus in the form of the dosage form of the invention, has both physical stability and chemical stability.

[0122] "Chemical stability" means that the composition containing C21 / salt in a suitable carrier and the dosage form of the invention can be stored under normal storage conditions with only a slight degree of chemical decomposition or disintegration of the dosage form of the invention and / or the suspension contained therein, especially the active ingredient, (regardless of the presence or absence of suitable pharmaceutical packaging).

[0123] "Physical stability" means that the suspension containing C21 / salt in a suitable carrier and the dosage form of the invention can be stored under normal storage conditions with only a slight degree of physical transformation such as aggregation, separation or splitting, sedimentation, or changes in properties and / or integrity, including dissolution, solvation, solid-phase phase transition, of the dosage form of the invention and / or the composition contained therein, especially the active ingredient, (regardless of the presence or absence of suitable pharmaceutical packaging).

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

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

[0126] Regardless of 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 by other means, it is preferably manufactured and / or stored in an essentially water-free state.

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

[0128] "Essentially dry" or "essentially water-free" means that the composition containing C21 / salt and the related excipients contains water in an amount of about 5% or less, about 2% or less, about 1% or less, for example about 0.1% or less, by weight of the total composition.

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

[0130] In this regard, a pharmaceutically acceptable capsule material may contain a residual amount of water, but the ingress of water from the capsule material into the composition (whether in the form of a solid (e.g., powder mixture) or a liquid (e.g., lipid suspension)) needs to be minimized, thereby protecting the sensitive C21 or its salt from contact with water and preventing degradation in the presence of light.

[0131] Nevertheless, it is preferred (but not necessarily essential) to package the dosage forms of the present invention in a manner that keeps the dosage forms themselves in a dry state and protected from light. This may include sealed packaging, use of deliquescent materials, etc.

[0132] According to a further aspect of the present invention, a process for manufacturing the dosage forms of the present invention is provided, which process comprises coating a composition comprising C21 or a pharmaceutically acceptable salt thereof with an enteric substance.

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

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

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

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

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

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

[0139] The dosage forms of the present invention are useful under conditions where 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 symptoms characterized by vasoconstriction, fibrosis, inflammation, increased cell proliferation and / or differentiation, increased cardiac contractility, increased cardiovascular hypertrophy, and / or increased retention of body fluids and electrolytes, as well as skin diseases and musculoskeletal diseases.

[0141] The dosage forms of the present invention are particularly suitable for the treatment and / or prevention of sarcoidosis or fibrosis, more specifically ILDs such as PF, particularly IPF, and 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 (therefore, for example, an antithrombotic effect), and / or may reduce vasoconstriction and / or bronchoconstriction in a therapeutic manner.

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

[0144] Therefore, the dosage forms of the present invention are expected to be useful in the treatment of diseases that can be characterized as described above, which are, for example, the gastrointestinal tract, cardiovascular system, airways, 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, dyspepsia (including non-ulcer dyspepsia), gastroesophageal reflux, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), liver disorders (such as hepatitis), gallbladder disorders, multiple organ failure (MOF), and sepsis. Other gastrointestinal diseases that may be mentioned include xerostomia, gastritis, gastric hypomotility, hyperacidity, biliary tract diseases, coeliac disease, Crohn's disease, ulcerative colitis, diarrhea, constipation, colitis, anorexia, vomiting, nausea, dyspepsia, and Sjogren's syndrome.

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

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

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

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

[0150] Cardiovascular diseases that may be mentioned include hypertension, cardiac hypertrophy, heart failure (including heart failure with preserved ejection fraction), atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial lesions, restenosis after balloon dilation, angiogenesis, diabetic complications, microvascular dysfunction, angina, cardiac arrhythmia, intermittent claudication, preeclampsia, myocardial infarction, reinfarction, ischemic lesions, erectile dysfunction, and neointimal hyperplasia.

[0151] Diseases of the CNS that may be mentioned include cognitive dysfunction, functional disorders of food intake (hunger / satiety) and thirst in the throat, 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 the regulation of growth metabolism and proliferation, for example, in the treatment of aging, hypertrophic diseases, benign prostatic hyperplasia, autoimmune diseases (such as arthritis such as rheumatoid arthritis, or systemic lupus erythematosus), psoriasis, obesity, regeneration of nerve cells, ulcer healing, suppression of over-formation of adipose tissue, differentiation and proliferation of stem cells, fibrotic diseases, cancer (such as in or of 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, treatment of tumors (generally) and hypertrophy, diabetes, neuropathy and organ rejection.

[0153] The dosage forms of the present invention are also useful in the treatment of stroke, spinal cord injury, sickle cell anemia, muscular dystrophy, cancer treatment-related cardiotoxicity, peripheral neuropathy, and in particular, systemic sclerosis.

[0154] Furthermore, the dosage forms of the present invention may be useful in the treatment of respiratory virus-induced tissue damage, which may include damage and / or dysfunction of the associated tissues. Associated tissues include tissues of the respiratory tract (such as mucosa), particularly lung tissue. Thus, associated tissues include the respiratory epithelium that moistens the respiratory tract and protects against invasion of pathogens such as viruses.

[0155] Respiratory viruses that may 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, more specifically, severe acute respiratory syndrome (SARS) coronaviruses such as SARS coronavirus (SARS-CoV), and in particular, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously known as "2019-nCoV" or "novel coronavirus 2019") is the virus that causes coronavirus disease 2019 (COVID-19), and there are many genetic variants among them.

[0156] "Treatment of tissue damage" means that C21 and its salts not only have a beneficial effect on airway tissue damage caused by the above virus, but also that the related virus may prevent and / or reduce damage caused in another way by that virus in the airway, for example when the virus invades epithelial cells in the airway.

[0157] Thus, C21 and its salts may prevent or preclude the onset of tissue damage induced by such viruses and / or diseases 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, as well as acute lung injury as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), especially SARS, more specifically COVID-19) and their sequelae. C21 and its salts may also treat and / or prevent damage caused or induced by such viruses, including treatment and / or prevention of symptoms of such respiratory diseases, including cough, dyspnea, tachypnea (e.g., the need for supplemental / supplemental oxygen (administered via a face mask or nasal cannula (high flow or otherwise)), and / or the need for mechanical ventilation / extracorporeal membrane oxygenation), respiratory failure, and / or direct (viral pneumonia) and / or indirect pneumonia (bacterial pneumonia resulting from secondary bacterial infections common in influenza), and subsequent fibrosis resulting from inflammation of the lungs and other organs (e.g., the heart and kidneys). Furthermore, C21 and its salts may prevent or preclude the progression of morbidity and / or mortality induced by respiratory viruses, and C21 may treat and / or prevent the onset of any of the chronic symptoms identified above.

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

[0160] Accordingly, such conditions can be due to sepsis or septic shock caused by viral, bacterial, or fungal infections. Furthermore, acute lung injury, ARDS, and particularly SARS can be caused by viruses such as coronaviruses including SARS-CoV-2, and can cause damage to internal tissues and / or dysfunction of associated internal (e.g., mucosal) tissues, and / or cells (such as respiratory epithelium) that contain them. Such tissue damage can then lead to severe fibrosis. For example, the 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 in the treatment and / or prevention of sarcoidosis or fibrosis, more specifically idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases (ILDs), and 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] The term "ILD" is understood by those skilled in the art to include any lung condition characterized by an abnormal healing response involving chronic inflammation, decreased lung function and / or scarring, regardless of the cause, such as sarcoidosis and PF, particularly IPF. This term may also include diseases and / or conditions known to lead to and / or cause such lung conditions, such as systemic sclerosis. In this regard, there is further provided a dosage form of the invention for use in conditions leading to and / or causing ILD such as PF or IPF including systemic sclerosis.

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

[0164] According to a further aspect of the invention, there is provided a method of treating respiratory virus-induced damage, more specifically any of the aforementioned conditions including ILD including PF, particularly IPF, the method comprising administering to an individual suffering from or susceptible to such symptoms a therapeutically effective amount of the dosage form of the invention.

[0165] According to yet another aspect of the invention, there is provided a method of treating respiratory virus-induced tissue damage in a subject, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of the dosage form of the invention, particularly ● the tissue being damaged is lung tissue including respiratory epithelium, ● the damage includes damage and / or dysfunction of the mucosal tissue of the airway caused by a respiratory virus, ● Treatment includes the treatment of, and / or prevention of progression of, a disease caused by or resulting from a virus, ● The respiratory virus is a coronavirus such as SARS-CoV-2, the disease is SARS such as COVID-19, or the respiratory virus is an influenza virus and the disease is influenza, ● Treatment includes the treatment of symptoms of a disease caused by or resulting from a relevant virus, ● Symptoms of injury or disease include one or more of cough, dyspnea, tachypnea (manifested by the need for supplemental oxygen and / or mechanical ventilation), respiratory failure, pneumonia, and fibrosis of one or more internal organs including the lung, heart, and / or kidney, 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 form of the present invention is indicated for both therapeutic, symptomatic, and / or diagnostic treatment (e.g., during a detailed diagnosis when the condition has subsided), and prophylactic treatment (which includes the prevention and / or suppression of a decline and / or worsening of the condition) of any of the above symptoms.

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

[0168] In the treatment of certain conditions such as respiratory virus-induced tissue damage, C21 or a pharmaceutically acceptable salt thereof is preferably administered to adult patients, more specifically, patients over about 20 years old, for example, over about 30 years old including over about 40 years old, more preferably over about 50 years old, particularly over about 60 years old, especially over about 70 years old, and more specifically over about 80 years old; and / or patients having one or more of the following underlying medical conditions (regardless of whether such patients are present in one of the above age groups). ● Chronic (long-term) respiratory diseases such as pulmonary fibrosis, pulmonary hypertension, pulmonary arterial hypertension, other ILDs, asthma, chronic obstructive pulmonary disease (COPD), emphysema or bronchitis ● Chronic cardiovascular (e.g., heart) diseases such as heart failure, atrial fibrillation or hypertension ● 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 when the spleen has been removed ● Conditions such as HIV and AIDS, or a weakened immune system as a result of drugs such as steroid tablets or chemotherapy ● Obesity (e.g., body mass index (BMI) of 40 or more) ● Pregnancy

[0169] In this regard, according to some further aspects of the present invention, methods for the treatment and / or prevention of one or more of the following conditions are provided. ● Conditions known as "long COVID", "chronic COVID syndrome" (CCS) and / or "long-haul COVID", such as 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 ● Myocardial infarction, heart failure, atrial fibrillation, hypertension or thrombosis and / or cardiovascular diseases such as embolism in the heart, lungs and / or brain, etc.

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

[0171] (For example) In relation to the acute treatment of respiratory virus-induced tissue damage, the dose of C21 or its salt can be administered 1 to 4 times a day (such as 1 to 3 times), for a maximum of 3 months (such as 2 months), for example, for 1 month including a maximum of 3 weeks, for example, for a maximum of 1 week such as 4 days or 3 days. Such treatment periods can be repeated as necessary.

[0172] If one or more of the aforementioned chronic conditions occur, such as fibrosis of the lungs and other internal organs, in addition to and / or instead of the above acute dosing regimen, treatment with C21 or its salt is carried out continuously and / or as needed / required.

[0173] In the treatment of patients with viral infections, the relevant active ingredients that may be used in combination therapy with C21 include standard treatments variously applied for viral infections, antibody therapies (e.g., LY-CoV555 / LY-CoV016 (bamlanivimab and etesevimab)), LY-CoV555 (bamlanivimab, Eli Lilly), REGN-COV2 (casirivimab and imdevimab), REGN3048 - 3051, TZLS-501, SNG001 (sinagen), eculizumab (Soliris; Alexion Pharmaceuticals), ravulizumab (Ultomiris; Alexion Pharmaceuticals), ranizumab, rilonacept, tocilizumab (Actemra; Roche), sarilumab (Kevzara; Regeneron Pharma), and octagam (Octapharma)), antiviral drugs (e.g., oseltamivir, remdesivir, favipiravir, molnupiravir,simeprevir, daclatasvir, sofosbuvir, ribavirin, umifenovir, lopinavir, ritonavir, lopinavir / ritonavir (Kaletra; AbbVie Deutschland GmbH Co.KG), teicoplanin, baricitinib (Olumiant; Eli Lilly), ruxolitinib (Jakavi; Novartis), tofacitinib (Xeljanz; Pfizer), TMPRSS2 inhibitor, camostat, or camostat mesilate, Actemra (Roche), TZLS-501, AT-100 (rhSP-D), MK-7110 (CD24Fc; Merck)), OYA1 (OyaGen9), BPI-002 (BeyondSpring), NP-120 (ifenprodil, Algernon Pharmaceuticals), galidesivir (Biocryst Pharma), anti-inflammatory agents (e.g., NSAIDs such as ibuprofen, ketorolac, naproxen, chloroquine, hydroxychloroquine, interferon (e.g., interferon beta (interferon beta-1a)), tocilizumab (Actemra), lenalidomide, pomalidomide, and thalidomide), analgesics (e.g., paracetamol or opioids), antitussives (e.g., dextromethorphan), vaccination (e.g., INO-4800 by Inovio Pharmaceuticals and Beijing Advaccine Biotechnology, if possible), COVID-19 convalescent plasma (CCP) and / or passive antibody therapy with antibodies from the blood of people who have recovered from SARS-CoV or SARS-CoV-2 infection.

[0174] In the treatment of ILD such as IPF, related active ingredients that can be used in combination therapy with C21 include, for example, antifibrotics (e.g., nintedanib, especially pirfenidone); vitamins (e.g., vitamin B, C, D); mucolytics (e.g., acetylcysteine and ambroxol); corticosteroids such as cortisone and prednisone; anti-inflammatory agents such as cyclophosphamide; other immunosuppressants such as azathioprine and mycophenolate mofetil; and antioxidants such as N-acetylcysteine. In the treatment of sarcoidosis, related active ingredients that can be used in combination therapy with C21 include, for example, corticosteroids such as cortisone, prednisone and prednisolone; antimetabolites; immunosuppressants for the immune system such as methotrexate, azathioprine, leflunomide, mycophenolic acid / mycophenolate mofetil, cyclophosphamide; aminoquinolines; monoclonal antitumor necrosis factor antibodies such as infliximab and adalimumab; immunomodulatory imide drugs 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 above "corticosteroids" include both naturally occurring corticosteroids and synthetic corticosteroids.

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

[0177] Synthetic corticosteroids that may be mentioned include hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, tixocortol and tixocortol pivalate, prednisolone, methylprednisolone, cloprednol, difluprednate, fludrocortisone, fluocinolone, flupredolone, prednisone, chloroprednisone, cloprednol, difluprednate, fludrocortisone, fluocinolone, flupredolone, fluprednisolone, loteprednol, prednicarbate, and triamcinolone, etc. (hydrocortisone type, Group A); acetonide and related substances such as amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinide, halcinonide, triamcinolone acetonide, ciclesonide, deflazacort, formocortal, fludroxycortide, flunisolide, and fluocinolone acetonide, etc. (Group B); betamethasone type such as beclomethasone, betamethasone, betamethasone dipropionate, and betamethasone valerate, dexamethasone, flucortolone, halometasone, mometasone, and mometasone furoate, alclometasone and alclometasone dipropionate, clobetasol and clobetasol propionate, clobetasone and clobetasone butyrate, clocortolone, desoxymethasone, diflorasone, diflucortolone, flucortolone, flumethasone, flucortine, flupredniden and flupredniden acetate, fluticasone, fluticasone furoate, and fluticasone propionate, meprednisone, paramethasone, prednylidene, rimexolone, and ubrocortazole, etc. (Group C); progesterone type such as flugestone, fluorometholone, medrysone, and prebediolone acetate, etc.; and progesterone derivatives (progestins) such as chlormadinone acetate, cyproterone acetate, medrogestone, medroxyprogesterone acetate, megestrol acetate, and segesterone acetate, etc.Also included are other corticosteroids such as cortivazol and 6-methyl-11β,17β-dihydroxy-17α-(1-propynyl)androsta-1,4,6-trien-3-one.;

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

[0179] Furthermore, related active ingredients that can be used in combination therapy with C21 (e.g., for treating respiratory viral infections) include H2 receptor antagonists, anticoagulants, antiplatelet agents, as well as statins, antibacterial agents, and anti-allergy / anti-asthma drugs.

[0180] Possible H2 receptor antagonists include famotidine. Possible anticoagulants include heparin and low molecular weight heparins (e.g., bemiparin, nadroparin, reviparin, enoxaparin, parnaparin, certoparin, dalteparin, tinzaparin); direct-acting oral anticoagulants (e.g., dabigatran, argatroban, rivaroxaban, apixaban, edoxaban, betrixaban, darexaban, otamixaban, letaxaban, eliquixaban, hirudin, lepirudin, and bivalirudin); coumarin-type vitamin K antagonists (e.g., coumarin, acenocoumarol, phenprocoumon, atromentin, and phenindione) and synthetic pentasaccharide inhibitors of factor Xa (e.g., fondaparinux, idraparinux, and idrabiotaparinux). Possible antiplatelet agents 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., vorapaxar); glycoprotein IIb / IIIa inhibitors (e.g., abciximab, eptifibatide, and tirofiban); adenosine reuptake inhibitors (e.g., dipyridamole); and thromboxane inhibitors (e.g., terutroban, ramatroban, seratrodast, and picotamide). Possible statins include atorvastatin, simvastatin, and rosuvastatin. Possible antibacterial agents include azithromycin, ceftriaxone, cefuroxime, doxycycline, fluconazole, piperacillin, tazobactam, and teicoplanin. Possible anti-allergy / anti-asthma agents include chlorpheniramine, levocetirizine, and montelukast.

[0181] Furthermore, related active ingredients that can be used in combination therapy with C21 (e.g., for treating respiratory viral infections) include other AT2 agonists known in the art, as well as combinations with AT1 receptor antagonists known in the art and / or combinations with inhibitors of angiotensin-converting enzyme (ACE). Non-limiting but exemplary examples of AT1 receptor antagonists that can be used according to embodiments include azilsartan, candesartan, eprosartan, fimasartan, irbesartan, losartan, milfasartan, olmesartan, pomisartan, pratosartan, ripasartan, saprisartan, tasosartan, telmisartan, valsartan and / or combinations thereof. Non-limiting but exemplary examples of ACE inhibitors that can be used according to embodiments include captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril,trandolapril, fosinopril, moexipril, cilazapril, spirapril, temocapril, ceronapril, delapril, moveltipril, and / or combinations thereof.

[0182] Related patients can also receive (and / or already be receiving) one or more of the above treatments and / or any of the other therapeutic agents for the related condition based on administration of one or more of such active ingredients, whereby the inventors mean receiving one or more of the prescription dosages of these active ingredients referred to herein before, in addition to, and / or after treatment with C21 or a salt thereof.

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

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

[0185] The dosage form of the present invention can also provide improved drug loading, enable the presentation of large amounts / doses of the active compound, and can provide the efficient delivery of such higher doses in a consistent / uniform manner. Thereby, the effectiveness and efficiency of treatment are improved, and medical costs are reduced.

[0186] The uses / methods described herein, whether used in these conditions or in other ways, in other respects, compared to similar methods (treatments) known in the prior art, in one or more of the previously described conditions, particularly in the treatment of ILD and / or respiratory viral infections, these may be more convenient, more effective, less toxic, have a broader range of activities, be more potent, cause fewer side effects, or have other useful pharmacological properties for physicians and / or patients.

[0187] Whenever the term "about" is used herein, for example, in the context of an absolute quantity such as an amount, i.e., size (e.g., particle size), dose, weight or concentration of a (valid) ingredient, age, temperature or period, or a relative quantity including percentage, standard deviation, such variables are approximate and can vary by ±10%, for example ±5%, preferably ±2% (e.g., ±1%) from the actual numerical value specified. In this regard, the term "about 10%" means, for example, ± about 10% for the number 10, i.e., between 9% and 11%.

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

[0189] Examples Example 1 Observation of the Effects of Diet in a Clinical Setting A Phase I clinical trial was conducted to evaluate the safety, tolerability, and pharmacokinetics of C21 in healthy male and female subjects. The study design allowed for a gradual increase in dosage 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 standard operating procedures (SOP) of the CRO. It complies with the ethical principles based on the International Conference on Harmonization of Technical Requirements for 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 World Medical 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 a non-blind manner in 10 male and female subjects with a single oral dose of 75 mg.

[0192] The subjects were administered 75 mg of C21 twice as single doses at least 3-day intervals in a randomized manner, either in a fasting or fed state. A high-fat breakfast recommended by the Food and Drug Administration (FDA) was used to investigate the maximum effect.

[0193] In the diet effect part of the study, the age of the subjects ranged from 22 to 44 years, and the median age was 36.0 years. Most of the subjects were white (9 (90.0%) subjects) and male (8 (80.0%) subjects). The mean (SD) BMI of all subjects was 23.96 (2.223) kg / m 2 was.

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

Table 1

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

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

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

[0198] All BLQ values before dosing and during the absorption phase before the first quantifiable concentration were replaced with zero. Before calculating PK variables, a single BLQ between two evaluable concentrations was replaced with missing. Before calculating PK variables, consecutive BLQs between evaluable concentrations were replaced with zero. Terminal BLQ values were ignored.

[0199] The bioequivalence of PK parameters from the non-blind 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 natural logarithm-transformed data. The mixed effects model was implemented using SAS Proc Mixed with REML estimation method and Kenward-Roger degrees of freedom algorithm.

[0200] Natural logarithm-transformed AUC( 0-inf) (if data were admissible), AUC( 0-24 ), and C maxSequences, periods, and treatments were analyzed as fixed effects, and subjects within sequences were analyzed as random effects using a mixed effects model. Estimates of the mean differences (test - reference) and the corresponding 90% confidence intervals were obtained from the model. The estimated mean differences and 90% confidence intervals for the differences were exponentiated to provide estimates of the geometric mean ratio (test / reference) and the 90% confidence intervals for the ratio. C21 in the fasting state was the reference treatment, and C21 in the fed state was the test treatment.

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

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

[0203]

Table 2 - 1

[0204]

Table 2 - 2

[0205]

Table 2 - 3

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

[0207] C max variability (geometric CV%) was 37% and 22% under fasting and fed conditions, respectively. The geometric mean AUC (0-12)It was 1767 h*ng / mL and 767 h*ng / mL under fasting and fed conditions at 75 mg, respectively. All AUC parameters were comparable for each treatment, and the geometric CV% of the AUC parameters ranged from 21% to 34% at 75 mg under fasting and fed conditions. The mean t 1 / 2 was less than 1 hour for both the fasting treatment and the fed treatment. Consistent with the measured AUC values, CL / F was approximately 2-fold higher in the fed treatment, and V z / F was 3-fold higher compared to the fasting treatment value.

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

Table 3

[0209] This model is an analysis of variance (ANOVA) model with sequence, period, and treatment period fixed, and a random effect for subjects within the sequence. The statistical analysis of the effect of food on the C21 PK parameters (see Table 3 above) showed a decrease in C max when C21 was administered with food. The geometric mean ratio of C max was 0.16, and the 90% confidence interval was below 1 (100%), indicating that the difference in C max was statistically significant. When 75 mg of C21 was administered with food, AUC (0-24) decreased, AUC (0-inf) ; the geometric mean ratios were both 0.45, and the 90% confidence interval was below 1 (100%), indicating that the difference in AUC values was significant.

[0210] Example 2 Dissolution Test (A) 50.7 mg of the C21 sodium salt (Ardena, Riga, Latvia) was added to 900 mL of 0.09 M carbonate buffer (pH 8.95) with stirring at a temperature of 37 ± 3 °C. The compound dissolved immediately. After stirring for 15 minutes, 2 M acetic acid solution was added dropwise to obtain a pH of 4.52. Generation of CO2 was noted. After stirring for 1 hour, formation of small white particles was observed. After further stirring for 1.5 hours, 1 M NaOH was added to raise the pH to 6.8. Stirring was continued for a further 1.5 hours, but there was no significant change in appearance (small white particles).

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

[0212] (C) 53.2 mg of the C21 sodium salt was added to 900 mL of 0.1 M HCl buffer (pH 1.0) with stirring at the same temperature. 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 precipitation was observed after the addition of the NaOH solution. After stirring for 2 hours, the resulting solution was still clear.

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

[0214] (E) 50.8 mg of the C21 sodium 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 1 hour and there was no significant change in appearance. UPLC showed that no degradation of C21 occurred at the end of the experiment.

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

[0216] Example 3 Dosage form of the present 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 that amount was poured into the 25 L V-shell of a V-blender (Multiblender, Pharmatech, UK). Next, 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 at 30 rpm for an additional 20 minutes.

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

[0219] Next, the resulting blend was sieved through an 800 μm sieve and then blended 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 ultrasonic treatment for 20 minutes were added, 40 mL of methanol was added, and the blend uniformity was determined by further ultrasonic treatment for 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 the Na salt of C21 (in the case of 100% nominal sample concentration).

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

Table 4

[0223] Thereafter, 26.1 g of magnesium stearate (Ligamed MF-2-V, Peter Greven, Germany) was sieved through an 800 μm sieve, added to the blend, and subsequently the final blend was carried out at 15 rpm 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), and the dosator was size 0, applying the following settings to chamber - 11 mm. Compression - 0 mm; powder layer: 30.0 mm.

[0226] When weight classification was performed by applying a 5% tolerance limit to the net fill weight of the capsules, it was found to be 18.6%. After encapsulation, the capsules were manually primary packaged (56 capsules / bottle) into 100 mL high-density polyethylene (HDPE) bottles with child-resistant caps containing desiccant. A total of 97 bottles were manufactured 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 (4M8 TriX pan coater with a 2L drum and a 0.7 mm 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 and as close to the bottom of the container as possible to form a vigorous vortex for homogenization. Before the coating process, the dispersion was passed through a 200 μm sieve.

[0229] To facilitate the good movement of the capsules in the pan coater and reach the appropriate amount to load into the drum, different capsule colors (dark green) and fill weights (410 mg / capsule of mannitol (Pearlitol 160C)) were used, and 560 dummy capsules (size 0) were also added so that they could be separated later by weighing and visual inspection.

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

[0231] The coating process was carried out by filling the 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, and at that 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 dried while being slowly rolled.

[0233] The spray liquid 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 weight per coated / filled capsule was 490.66 mg, and the coating amount per capsule was 133.66. This corresponded to the weight of the coating per capsule and was 139.08% of the empty capsule and 37.44% of the filled capsule.

[0234] The capsules were submitted to Ph.Eur. (10th edition) standards (2.9.1 Apparatus B; with disk) for a two-stage disintegration test on coated capsules (n = 6): (a) pH 1.2 (prepared by mixing 0.1 N HCl in water, 250 mL of 0.2 M NaCl, 425 mL of 0.2 M HCl, and 325 mL of purified water); and (b) pH 6.8 using phosphate buffer (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] This apparatus consisted of a basket rack assembly, a device for moving the basket up and down, a 1 L beaker, and a thermostat for heating the fluid at 37 °C (±2 °C). The basket rack assembly was designed to contain three capsules in three different transparent cylindrical tubes placed on a stainless-steel screen, allowing the inflow of the solution into the tubes.

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

[0237] According to the Ph.Eur., capsules with a gastric-resistant shell must survive in an acidic medium for 2 hours without showing signs of disintegration or rupture that would allow the contents to escape.

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

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

[0240] Visual inspection showed capsules completely intact in the acidic medium (a) and rapid capsule disintegration in the more basic medium (b), thus indicating that the capsules had successfully achieved enteric coating.

[0241] Example 4 Stability testing of the dosage form of the present invention The enteric-coated capsules obtained using the method described in Example 3 above were tested in a test to evaluate their stability in clinical representative packaging under ICH (International Conference on Harmonization of Technical Requirements for 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 at various storage conditions and times are shown in Table 7 (assay and chromatographic purity) and Table 8 (disintegration) below. The water content was measured using the Karl Fischer titration method. Impurity 1 was previously known as C21, while Impurities 2 and 3 are new. LOR represents the limit of reporting (i.e., 0.10%, l.c.).

Table 7

Table 8

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

Claims

1. A pharmaceutical dosage form suitable for oral administration to the gastrointestinal tract, wherein the dosage form comprises a pharmaceutical composition comprising N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide, or a pharmaceutically acceptable salt thereof, and the N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide or a salt thereof is protected by the presence of a coating containing an enteric substance, a pharmaceutical dosage form suitable for oral administration to the gastrointestinal tract.

2. The dosage form according to claim 1, wherein the enteric substance is polyvinyl acetate phthalate or a methacrylic acid copolymer.

3. The dosage form according to claim 1 or claim 2, wherein the final dosage form comprises an enteric-coated pill, tablet, capsule, or film.

4. The dosage form according to claim 3, wherein the final dosage form is an enteric-coated capsule.

5. The dosage form according to any one of claims 1 to 4, wherein the N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide or a salt thereof is provided in the form of a powder, simple mixture, granule, pellet, bead, solution, or suspension.

6. The dosage form according to claim 5, wherein the form is a simple powder mixture.

7. The dosage form according to claim 6, dependent on claim 4, wherein the capsule is a two-piece hard-shell capsule.

8. The dosage form according to claim 7, wherein the capsule contains hydroxypropylmethylcellulose.

9. The dosage form according to claim 5, wherein the form is a suspension of particles of N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide or a salt thereof that is insoluble therein in a lipid carrier.

10. The dosage form according to claim 9, dependent on claim 4, wherein the capsule is a one-piece soft-shell capsule.

11. The dosage form according to claim 10, wherein the capsule contains gelatin.

12. The pharmaceutical dosage form according to any one of claims 1 to 11, wherein N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutyl-thiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof is provided in the form of particles having an average diameter based on weight and / or volume of about 50 μm or less.

13. The pharmaceutical dosage form according to any one of claims 1 to 12, which is substantially water-free.

14. The pharmaceutical dosage form according to any one of claims 1 to 13, wherein the pharmaceutically acceptable salt of N-butyloxycarbonyl-3-(4-imidazol-1-ylmethyl-phenyl)-5-isobutylthiophene-2-sulfonamide is a sodium salt.

15. The process for manufacturing the pharmaceutical dosage form according to any one of claims 1 to 14, comprising coating a composition containing N-butyloxycarbonyl-3-(4-imidazol-1-ylmethyl-phenyl)-5-isobutylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof with an enteric substance.

16. The process for manufacturing the pharmaceutical dosage form according to any one of claims 4 to 14, comprising filling a capsule with N-butyloxycarbonyl-3-(4-imidazol-1-ylmethyl-phenyl)-5-isobutylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof, wherein the capsule is coated with an enteric substance.

17. The pharmaceutical dosage form obtained by the process defined in claim 15 or claim 16.

18. The pharmaceutical dosage form according to any one of claims 1 to 14 or 17 for use in the treatment of interstitial lung disease.

19. Use of the pharmaceutical dosage form according to any one of claims 1 to 14 or 17 for the manufacture of a medicament for the treatment of interstitial lung disease.

20. A method for treating interstitial lung disease, comprising administering to a patient in need of said treatment the pharmaceutical dosage form according to any one of claims 1 to 14 or 17.

21. The pharmaceutical dosage form for use according to claim 18, the use according to claim 19, or the treatment method according to claim 20, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

22. The pharmaceutical dosage form for use according to claim 18, the use according to claim 19, or the treatment method according to claim 20, wherein the interstitial lung disease is sarcoidosis.

23. The dosage form according to any one of claims 1 to 14 or 17 for use in the treatment of respiratory virus-induced tissue damage.

24. Use of the dosage form according to any one of claims 1 to 14 or 17 for the manufacture of a medicament for the treatment of respiratory virus-induced tissue damage.

25. A method for treating respiratory virus-induced tissue damage, comprising administering to a patient in need of said treatment the dosage form according to any one of claims 1 to 14 or 17.

26. The dosage form for use according to claim 23, the use according to claim 24, or the treatment method defined in claim 25, wherein said damage includes damage and / or dysfunction of the mucosal tissue of the respiratory tract caused by a respiratory virus.

27. The dosage form, use, or treatment method for use according to claim 26, wherein said respiratory virus is a coronavirus or an influenza virus.

28. The dosage form, use, or treatment method for use according to claim 27, wherein said respiratory virus is severe acute respiratory syndrome coronavirus 2.

29. The dosage form, use, or treatment method (where appropriate) for use according to any one of claims 23 to 28 (as appropriate), wherein said treatment includes treatment of the symptoms of the disease caused by or caused by said virus.

30. The dosage form, use, or treatment method for use according to claim 29, wherein said damage or said symptoms of said disease include one or more of cough, dyspnea, tachypnea, respiratory failure, pneumonia, fibrosis in one or more internal organs selected from the lungs, heart, and / or kidneys.

31. The dosage form, use, or treatment method for use according to any one of claims 18 to 30 (as appropriate), wherein said treatment includes prevention of the morbidity and / or mortality in said associated condition.

32. The dosage form, use, or treatment method for use according to any one of claims 18 to 31 (as appropriate), wherein said composition is administered by the oral route.

Images