Solid Compositions Comprising Solubilized Bradykinin B2 Receptor Antagonists - Patent application

Abstract

The present invention relates to a solid dispersion for oral administration comprising a bradykinin B2 receptor antagonist having a chemical structure according to formula (1), such as (S)-. / V-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1-1 / f-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, or a salt or solvate thereof, wherein R is deuterium or hydrogen. The solid dispersion comprises a BK B2 receptor antagonist that is amorphous and homogeneously dispersed in a pharma- ceutically acceptable polymer. Additionally provided are methods for preparing the solid dispersion and uses, including therapeutic uses. [Formula 1] TIFF2025512818000014.tif87116

Description

[Technical field]

[0001] The present invention relates to pharmaceutical compositions comprising bradykinin (BK) B2 receptor antagonists having a chemical structure according to formula (1), methods for preparing such compositions, and their use as medicaments in the treatment of subjects who may benefit from bradykinin B2 receptor antagonists. [Background technology]

[0002] Bradykinin (BK) is a peptide hormone involved in inflammatory processes through activation of endothelial cells, causing vasodilation, increased vascular permeability, production of nitric oxide, and mobilization of arachidonic acid. BK also stimulates sensory nerve endings, causing burning sensations. Thus, all of the classical parameters of inflammation (e.g., redness, heat, swelling, and pain) can result from BK formation. BK is a short-lived component of the kallikrein-kinin system. The concentration of circulating BK is maintained at low levels under normal physiological conditions and can rapidly increase in pathological situations by enzymatic degradation of circulating glycoprotein precursors called kininogens. The two most potent kininogen-metabolizing enzymes are the trypsin-like serine proteases plasma kallikrein and tissue kallikrein. Precursors of these enzymes are normally present in all tissues and are ready to be activated by physiological or pathophysiological processes. The BK B2 receptor is constitutively expressed in most cell and tissue types and mediates most of the known effects of BK when produced in plasma or tissues. Numerous in vivo studies have demonstrated that agents that block the BK B2 receptor provide therapeutic benefit in pathological conditions such as asthma, allergic rhinitis, pancreatitis, osteoarthritis, traumatic brain injury, Alzheimer's disease, and angioedema.

[0003] A number of peptide and non-peptide antagonists of the BK B2 receptor have been described in the prior art. Quinoline derivatives having activity as BK B2 receptor antagonists have been disclosed, for example, in WO 2014 / 159637, WO 2010 / 031589, WO 2008 / 116620, WO 2006 / 40004, WO 03 / 103671, WO 03 / 87090, WO 00 / 23439, WO 00 / 50418, WO 99 / 64039, WO 97 / 41104, WO 97 / 28153, WO 97 / 07115, WO 96 / 13485, EP 0 795 547, EP 0 796 848, EP 0 867 432, and EP 1 213 289. However, these compounds exhibited several deficiencies that hinder their usefulness as drugs, including poor metabolic stability, poor bioavailability, formation of glutathione adducts and bioactivation (toxicity) as disclosed in WO 2014 / 159637.

[0004] More recently, compounds of formula (1) have been proposed as novel biologically active and well-tolerated BK B2 receptor antagonists (see, for example, WO 2019 / 101906). These compounds exhibit attractive pharmacological properties but also rather challenging physical or physicochemical properties, including very poor solubility in physiological media.

[0005] The compound according to formula (1) is also known from A. Lesage et al., Frontiers in Pharmacology, Vol. 11, June 19, 2020, doi:10.3389 / fphar.2020.00916. This publication describes the in vitro pharmacological profile of the compound, but does not disclose any specific dosage forms or formulations incorporating the compound.

[0006] Although various formulation techniques have been proposed for poorly soluble drug substances, it is nevertheless still challenging to develop suitable formulations for many new drug candidates with difficult physical and pharmacokinetic properties, and even today many development programs have not been successful. One commonly known formulation technique is solid dispersions. DT Friesen et al., Molecular Pharmaceutics, Vol. 5, No. 6, December 2008, pp. 1003-1019, doi:10.1021 / mp8000793, describes spray-dried dispersions based on hydroxypropyl methylcellulose acetate. These products are used as extemporaneous oral powder (OPC) formulations or as fill material for gelatin capsules, intended to achieve supersaturated concentrations of drug in gastrointestinal fluids. The literature does not disclose the incorporation of the dispersions into tablets, nor does it relate to dosage forms for sustained drug release.

[0007] There is a need for formulations and pharmaceutical compositions that overcome the difficulties due to the challenging properties of the compound according to formula (1) to enable effective oral delivery in human subjects and achieve significant systemic exposure and bioavailability. There is also a need for formulations or pharmaceutical compositions incorporating the compound of formula (1) that achieve reliable oral absorption. There is a further need to provide formulations or pharmaceutical compositions incorporating the compound of formula (1) that are stable in their performance and can be manufactured by well-established pharmaceutical manufacturing techniques.

[0008] Compounds of formula (1) have very low water solubility. This makes it challenging to develop oral formulations that provide sufficient and reliable absorption rates, sufficient bioavailability and effective plasma levels. The pharmacokinetic profile of BK B2 receptor antagonists of formula (1) makes these compounds highly attractive for both acute and chronic treatment, and therefore there is a need to develop formulations of these drugs that overcome challenges, including poor aqueous solubility, and are viable in both acute and chronic treatment settings. Summary of the Invention [Problem to be solved by the invention]

[0009] The object of the present invention is to address one or more of the above needs.Another object is to overcome the deficiencies, gaps and limitations of the prior art with respect to oral delivery of bradykinin B2 receptor antagonists, such as compounds having a chemical structure according to formula (1).Another object will become apparent based on the following description, examples and claims. [Means for solving the problem]

[0010] In one aspect, the present invention provides a solid dispersion for oral administration comprising a bradykinin B2 receptor antagonist having a chemical structure according to formula (1), or a salt or solvate thereof, The solid dispersion relates to a solid dispersion further characterized as comprising a BK B2 receptor antagonist that is amorphous and homogeneously dispersed in a pharma- ceutically acceptable polymer.

[0011] [ka]

[0012] In the formula, R is deuterium or hydrogen.

[0013] In particular, the BK B2 receptor antagonist can be (S)—N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide.

[0014] The pharma- ceutically acceptable polymer in which the active ingredient is dispersed can be, for example, hydroxypropyl methylcellulose acetate succinate (HPMCAS) or copovidone (PVP / PA).

[0015] In another aspect, the present invention relates to a pharmaceutical composition comprising such a solid dispersion, including a sustained release composition, which may be, for example, in the form of a matrix tablet.

[0016] In another aspect, the present invention relates to methods for preparing solid dispersions, such as methods based on melt extrusion or spray drying.

[0017] In yet another aspect, the present invention relates to the use of solid dispersion or sustained release composition, particularly therapeutic use.In general, solid dispersion and sustained release composition can be used in the treatment of diseases or conditions that respond to bradykinin B2 receptor modulation.For example, they are advantageous in the treatment of angioedema (AE), including hereditary angioedema (HAE), acquired angioedema (AAE), idiopathic non-histaminergic angioedema, allergic angioedema, drug-induced angioedema, and angioedema of unknown origin.HAE can be any type of HAE, including type I, type II, or type III HAE, preferably type I or type II HAE. [Brief description of the drawings]

[0018] [Figure 1] FIG. 1 shows the mean plasma concentration-time profiles of two different extended release matrix tablet formulations (formulations 5.1 and 5.2, herein referred to as XR1 and XR2) containing a solid dispersion formulation of the compound according to formula (1), specifically (S)—N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide (herein referred to as PHA-022121), compared to an immediate release capsule formulation of the same drug in healthy volunteers under fasting conditions. [Diagram 2] FIG. 1 shows the mean plasma concentration-time profile of a sustained release matrix tablet comprising a solid dispersion formulation of the compound according to formula (1) (Formulation 5.1) in healthy volunteers under fed and fasted conditions. [Diagram 3]FIG. 1 shows the mean plasma concentration-time profile of a sustained release matrix tablet comprising a solid dispersion formulation of the compound according to formula (1) (Formulation 5.2) in healthy volunteers under fed and fasted conditions. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] In a first aspect, the present invention provides a solid dispersion for oral administration comprising: (a) a BK B2 receptor antagonist having a chemical structure according to formula (1), or a salt or solvate thereof; and (b) at least one pharma- ceutically acceptable polymer; A solid dispersion is provided in which the BK B2 receptor antagonist is amorphous and homogeneously dispersed in the polymer.

[0020] [ka] In the formula, R is deuterium or hydrogen.

[0021] It has been found, completely unexpectedly, by the inventors that the claimed solid dispersion of the BK B2 receptor antagonist of formula (1) is not only effective in providing a rapid and complete release of this pharmacologically active ingredient into physiological media, which is generally useful for designing immediate release compositions incorporating such solid dispersions, but also can substantially improve the release from sustained release formulations of the compound of formula (1).In particular, the solid dispersion can provide a substantially complete release of the active ingredient and reduce the variability in the release rate caused by external factors, such as the pH and composition of the liquid medium in which the active compound is released from the sustained release composition, whether the liquid medium is, for example, water, gastric fluid, intestinal fluid, or a substitute thereof, such as artificial gastric fluid, fasting simulated intestinal fluid (FaSSIF) or fed simulated intestinal fluid (FeSSIF).In contrast, it has been found that when conventional sustained release formulation techniques are applied to the compound of formula (1), they result in unreliable drug release, unsatisfactory release profiles, and unpredictable absorption rates.

[0022] In this context, a solid dispersion can be understood as a solid material that contains a compound, such as a drug substance, that is preferably homogeneously dispersed in an amorphous polymer matrix. Typically, the dispersed compound is also in an amorphous state, i.e. non-crystalline. For example, the dispersed compound may be molecularly dispersed or dispersed in the form of amorphous domains.

[0023] The solid dispersion provided by the present inventors comprises the BK B2 receptor antagonist in amorphous form. In a generally preferred embodiment, the amorphous form of the BK B2 receptor antagonist is quantitatively predominant. In other words, even if some amount of crystalline BK B2 receptor antagonist is present in the solid dispersion, the amount of amorphous form may be greater or substantially greater than the amount of crystalline form. In another generally preferred embodiment, at least about 90%, or at least 95% or even at least 99% of the BK B2 receptor antagonist contained in the solid dispersion is amorphous. Optionally, all or substantially all of the BK B2 receptor antagonist is amorphous. In this context, the percentage reference is the total molar amount of the BK B2 receptor antagonist in the solid dispersion.

[0024] In formula (1), R may be selected from hydrogen and deuterium. In one preferred embodiment or group of embodiments, R is deuterium, as shown in the following formula:

[0025] [ka]

[0026] This compound, which may also be referred to as (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide (CAS 2340111-58-0), or acetamide, N-[(1S)-1-[3-chloro-5-fluoro-2-[[[2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)-8-quinolinyl]oxy]methyl]phenyl]ethyl-1-d]-2-(difluoromethoxy)-, is a particularly advantageous example of a compound according to formula (1) in the context of the present invention. It should be understood that this preference applies in combination with all other optional features or preferences disclosed herein below, whether or not specifically stated.

[0027] Alternatively, in formula (1), R can be hydrogen, as shown in the following formula:

[0028] [ka]

[0029] The compound may also be referred to as (S)—N-(1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide.

[0030] The compound of formula (1) can exist essentially in non-ionized form or in ionized form, i.e., in the form of a salt. In addition, it can be optionally in the form of a solvate. For example, the compound can be a hydrate, such as (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide monohydrate. In one currently preferred embodiment, the compound of formula (1) is in non-ionized form (i.e., not in the form of a salt) and is defined by R being deuterium.

[0031] In another embodiment, the state of the compound of formula (1) in the solid dispersion is substantially non-ionized, and may be completely non-ionized. Moreover, when the compound of formula (1) is present in the solid dispersion as it is, it does not usually show a solvate. However, for the avoidance of doubt, the compound may be in the form of a solvate when combined with the polymer and any other optional components to form the solid dispersion disclosed and claimed herein. For example, a hydrate, such as a monohydrate, of the compound, optionally in crystalline form, may be used to prepare the composition. However, it is considered that it no longer shows a crystalline material or a hydrate when incorporated into the solid dispersion.

[0032] Within the context of this disclosure, the compound of formula (1) may also be referred to as an active ingredient (biologically or pharmacologically), drug substance, active pharmaceutical ingredient (API), etc. Furthermore, in another preferred embodiment, the compound of formula (1) is the sole drug substance contained in the solid dispersion. This is a generally applicable preference within the context of this disclosure.

[0033] As described, the solid dispersion comprises at least one pharma- ceutically acceptable polymer in which the BK B2 receptor antagonist is dispersed. The polymer may be selected from polymers suitable for oral administration and capable of incorporating the BK B2 receptor antagonist in the form of a solid dispersion. In particular, the polymer may be selected from the group consisting of hydrophilic neutral polymers and hydrophilic anionizable polymers. In this context, hydrophilic means that the polymer exhibits at least some moderate solubility or swelling in aqueous media having pH values ​​of the gastrointestinal tract, i.e., a pH in the range of pH 1 to pH 8. Neutral means that an aqueous solution of the polymer has an approximately neutral effect, at least in the absence of other solutes. Preferably, the neutral polymer is also a non-ionic polymer. Anionizable means that the polymer contains moieties that are easily deprotonated when dissolved in an aqueous medium except at acidic pH. Some of the anionizable pharma- ceutically acceptable hydrophilic polymers may also be used as gastroresistant or enteric polymers. Furthermore, the polymer is optionally a non-crosslinked polymer.

[0034] According to another preferred embodiment, the pharma- ceutical acceptable polymer in which the BK B2 receptor antagonist is dispersed amorphously and homogeneously is a thermoplastic polymer, i.e. a polymer that becomes flexible or moldable at high temperature and becomes solid again when cooled, for example, to room temperature.A thermoplastic polymer can also be understood as a polymer that undergoes a glass transition temperature while maintaining chemical stability when heat is applied.In one embodiment, the polymer is a water-soluble (optionally pH-dependent), neutral (e.g., non-ionic or also non-ionizable) or anionizable polymer, and a thermoplastic polymer.

[0035] Specific pharma- ceutically acceptable polymers that may be selected include hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC or hypromellose), hydroxypropyl methylcellulose acetate succinate (HPMCAS or hypromellose acetate succinate), povidone (PVP), copovidone (PVP / PA), polyethylene glycol (PEG), and polyethylene oxide (PEO). Each of these polymers may be used individually to form a solid dispersion incorporating a BK B2 receptor antagonist. Alternatively, any combination of two or more of these polymers may be used, such as HPC in combination with HPMC, HPMC in combination with HPMCAS, PVP in combination with PVP / PA, or any other combination.

[0036] In one preferred embodiment, the pharma- ceutically acceptable polymer is HPMCAS. HPMCAS, i.e., hydroxypropyl methylcellulose acetate succinate, is an example of a hydrophilic anionizable polymer with pH-dependent solubility, since it is insoluble in water at acidic pH but soluble at neutral or alkaline pH. HPMCAS may be understood as hydroxypropyl methylcellulose esterified with a mixture of acetic acid and succinic acid. In general, HPMCAS contains about 12% to about 28% methoxy groups, about 4% to about 23% hydroxypropyl groups, about 2% to about 16% acetyl groups, and about 4% to about 28% succinoyl groups, calculated on a dry basis. HPMCAS is an exemplary pharma- ceutically acceptable polymer, which is also a thermoplastic polymer, and is further hydrophilic and anionizable. Various grades of HPMCAS have an average particle size in the range of about 5 μm and a viscosity of about 3 mPa. * HPMCAS-LF is available, featuring a viscosity range of s.

[0037] The inventors have found that the BK B2 receptor antagonists according to formula (1) are not only surprisingly compatible with HPMCAS, but also form solid dispersions at a variety of useful weight ratios of drug substance to polymer. It has also been discovered that the respective solid dispersions are highly stable, both chemically and physically, i.e., they exhibit little chemical degradation and only a very low tendency for the drug substance to form crystals over time. Moreover, surprisingly, solid dispersions of the compound of formula (1) and HPMCAS exhibit very useful drug release profiles, despite the pH-dependent solubility of the polymer.

[0038] In some preferred embodiments, the solid dispersions described herein consist essentially of a pharma- ceutically acceptable polymer, particularly HPMCAS, and a BK B2 receptor antagonist according to formula (1), particularly (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide. Various pharmaceutical grades of HPMCAS as described above may be used. In some preferred embodiments of HPMCAS, the content of acetyl groups is about 8% to about 12%, and the content of succinoyl groups is about 7% to about 15%, respectively. These polymer grades are typically insoluble in aqueous media at a pH below about 5.5 to about 6.5, but are soluble at or above such a pH. In some alternative preferred embodiments, the HPMCAS contains about 9% acetyl groups and about 11% succinoyl groups and is soluble in water at a pH of about 6.0 or greater (e.g., currently available commercially as Aqoat® AS-MMP). Additionally, HPMCAS grades having an average particle size in the range of about 200-300 μm are advantageous, although smaller particle sizes may also be used.

[0039] Alternatively, the solid dispersion may contain copovidone (PVP / PA) as a pharma- ceutically acceptable polymer. This polymer has also been found to allow the formation of advantageous solid dispersions containing the compound of formula (1). These solid dispersions are also chemically and physically stable. One of their additional advantages is that they allow high drug loading for the BK B2 receptor antagonist.

[0040] Copovidone, also called copolyvidone, PVP / VA copolymer, or polyvinylpyrrolidone-vinyl acetate copolymer, is obtained by free radical polymerization of vinylpyrrolidone and vinyl acetate in a molar ratio of about 6:4. Typical molecular weights range from about 45,000 to 70,000. Examples of currently commercially available copovidone products include Kollidon VA 64 and Luviskol VA. Grades with different average particle sizes are also available.

[0041] In addition to the above pharma- ceutically acceptable polymers, one or more other polymers may be present in the solid dispersion. In addition, the solid dispersion claimed herein may also include a surfactant. In one embodiment, the surfactant is a non-ionic surfactant, particularly a non-ionic surfactant selected from the group of poloxamers and polysorbates. It is recognized that these surfactants may also be considered as polymers. In other words, they may also function as contributors to the effect of polymeric drug carriers forming solid dispersions containing drug substances. They also function as surfactants because they enhance the wetting of the solid dispersion upon contact with an aqueous medium such as water.

[0042] Poloxamers, also known as polyethylene-propylene glycol copolymers or polyoxyethylene-polyoxypropylene copolymers, are polyol block copolymers, each containing a block of polyoxypropylene sandwiched between two blocks of polyoxyethylene. A variety of grades are available with different molecular weight ranges and different molecular ratios between the polyoxypropylene and polyoxyethylene blocks, such as Poloxamer 124, 188, 237, 338 and 407.

[0043] The inventors have found poloxamer 188 to be particularly useful. It is a solid material having an average molecular weight in the range of about 7,680 to 9,510, with the polyoxypropylene oxide blocks containing on average about 27 repeat units and the polyoxyethylene blocks containing on average about 80 repeat units. Poloxamer 188 in combination with copovidone is particularly advantageous.

[0044] Polysorbates, also called polyoxyethylene sorbitan fatty acid esters, are another group of nonionic surfactants that can be used as excipients in the formulation of solid dispersions disclosed herein.Potentially suitable polysorbates include polysorbate 20, 40, 60, 65 and 80, especially polysorbate 20, also known as polyoxyethylene 20 sorbitan monolaurate, with average molecular weight of 1,128, and polysorbate 80, whose chemical name is polyoxyethylene 20 sorbitan monooleate, with molecular weight of 1,310.A well-known brand product series is Tween.

[0045] Typically, the amount of nonionic surfactant present in the solid dispersion is substantially lower than the amount of non-surfactant polymer, e.g., hydrophilic neutral or anionizable polymer. Furthermore, typically, the amount of nonionic surfactant in the solid dispersion is lower than the amount of active ingredient. In one specific embodiment, the amount of nonionic surfactant in the solid dispersion is in the range of about 0.5% to about 10% by weight, or about 0.5% to about 5% by weight, based on the total weight of the solid dispersion. In another specific embodiment, the weight ratio of nonionic surfactant to polymer, or the weight ratio of nonionic surfactant to polymer combination, when a combination of two or more polymers is present, is in the range of about 1:100 to about 20:100, or about 1:100 to about 10:100, respectively.

[0046] In some embodiments, the solid dispersions described herein consist essentially of a pharma- ceutically acceptable polymer, such as HPMCAS or copolyvidone, a BK B2 receptor antagonist according to formula (1), in particular (S)—N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, and optionally a non-ionic surfactant, such as a poloxamer or polysorbate.

[0047] In one preferred embodiment, the solid dispersion exhibits a BK B2 receptor antagonist content of at least about 10% by weight based on the total weight of the solid dispersion.As mentioned above, it is also a preferred embodiment that the BK B2 receptor antagonist of formula (1) is the sole drug substance in the solid dispersion.Therefore, the range of at least about 10% by weight also exhibits a favorable drug loading of the solid dispersion.

[0048] According to another preferred embodiment, the solid dispersion exhibits a content of the BK B2 receptor antagonist of formula (1) of about 10% by weight based on the total weight of the solid dispersion. More preferred is a solid dispersion in which the content of the BK B2 receptor antagonist of formula (1), in particular (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, is in the range of about 10% to about 50% by weight, or about 15% to about 50% by weight, or about 15% to about 45% by weight based on the total weight of the solid dispersion. Moreover, in related embodiments, the solid dispersion exhibits a drug loading in any of the ranges described above, such as in the range of about 15% to about 50% by weight, and the BK B2 receptor antagonist of formula (1), particularly (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, represents the sole drug substance present in the solid dispersion. It was unexpected that such high drug loadings could be achieved in compounds of formula (1) without significant chemical or physical instability when following the guidance set forth in this disclosure.

[0049] In another preferred embodiment, the solid dispersion comprises about 15% to about 45% by weight, for example about 15% to about 25% by weight, of the BK B2 receptor antagonist of formula (1) and about 55% to about 85% by weight, for example about 75% to 85% by weight, of the polymer HPMCAS, based on the total weight of the solid dispersion. In a related embodiment, there is provided a solid dispersion consisting essentially of about 15% to 25% by weight of the BK B2 receptor antagonist of formula (1) and about 75% to 85% by weight of HPMCAS. For example, the solid dispersion consists essentially of about 20% by weight of a BK B2 receptor antagonist of formula (1), particularly (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, and about 80% by weight of HPMCAS. In another embodiment, the solid dispersion comprises about 25% by weight each of (S)—N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide and about 75% by weight HPMCAS; or about 30% by weight of (S)—N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2 ,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide and about 70% by weight HPMCAS, or about 35% by weight (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide and about 65% by weight HPMCAS.

[0050] The above ranges and corresponding weight ratios of drug substance to polymer HPMCAS have been found by the inventors to result in solid dispersions that exhibit sufficiently high drug loading to allow for effective and convenient administration, high product stability and shelf life, and desirable release profiles.

[0051] According to an alternative preferred embodiment, the solid dispersion comprises about 30% to 50% by weight of the BK B2 receptor antagonist of formula (1), about 50% to 70% by weight of copovidone, and optionally up to about 5% by weight of a poloxamer, such as poloxamer 188, based on the total weight of the solid dispersion. Furthermore, in a related embodiment in which no other components are present in the solid dispersion, a solid dispersion is provided that consists essentially of about 30% to 50% by weight of the BK B2 receptor antagonist of formula (1), about 50% to 70% by weight of copovidone, and optionally up to about 5% by weight of a poloxamer, such as poloxamer 188. For example, the solid dispersion can consist essentially of about 40% by weight of the BK B2 receptor antagonist of formula (1), about 58.5% by weight of copovidone, and about 1.5% by weight of poloxamer 188. These embodiments are advantageous because they allow for particularly high drug loading while at the same time being chemically and physically stable and providing useful drug release profiles.

[0052] The solid dispersion may be provided in a physical form suitable for oral administration or suitable for incorporation into a pharmaceutical dosage form adapted for oral administration, such as a capsule or tablet. When designed to be administered as such, the solid dispersion may be provided as a solid single unit, such as a melt-extruded form that is convenient to handle and swallow. Such product design may be particularly useful when an immediate release profile is desired, such as in the acute treatment of spontaneously occurring symptoms. Although the BK B2 receptor antagonist has very low solubility in physiological media, it is provided in a solubilized format, so that it can be released substantially faster than from conventional solid dosage forms that typically contain the active ingredient in crystalline form.

[0053] Moreover, the inventors have surprisingly discovered that the solid dispersions disclosed herein are not only useful in immediate release formulations, but also in sustained release products that release the BK B2 receptor antagonist over an extended period of time, as described in more detail below. In such products, it is particularly advantageous to provide the solid dispersion in a powder or granular form to facilitate its incorporation into sustained release dosage units, such as capsules or tablets.

[0054] Therefore, in one of the preferred embodiments, the solid dispersion provided by the present inventors is in the form of powder or granule. Both powder and granule provide the solid dispersion as multiple particles, i.e. in a multiparticulate format. In this context, the terms "powder" and "granule" should be understood as merely referring to the approximate particle size, with powder referring to a relatively fine multiparticulate material and granule referring to a coarse material, regardless of the manufacturing method by which these materials are obtained. In other words, the term "granule" should not be interpreted narrowly to require that a specific granulation method is used to generate each particle.

[0055] In another aspect, the present invention provides a method for preparing the solid dispersion described above. In some embodiments related to this aspect, the method for preparing the solid dispersion comprises hot melt extrusion of a powder or granule mixture comprising a BK B2 receptor antagonist and a pharma- ceutically acceptable polymer. In some other embodiments, the method comprises spray drying an organic solution of a BK B2 receptor antagonist and a pharma- ceutically acceptable polymer, or spraying an organic solution of an active ingredient and a pharma- ceutical acceptable polymer onto particles of a pharma- ceutical inert material under conditions that cause the evaporation of the organic solvent. In this context, furthermore, the BK B2 receptor antagonist is a compound according to formula (1), in particular a compound according to formula (1) in the preferred form disclosed above, and the polymer is at least one pharma- ceutical acceptable polymer, in which the BK B2 receptor antagonist is homogeneously dispersed.

[0056] Hot melt extrusion is a technique generally known in the pharmaceutical field. It is also generally known that in principle the technique can be used to produce melt extrudates. This includes the equipment that can potentially be used for hot melt extrusion and some of the common process parameters such as temperature and screw rotation speed if a screw extruder is used. Based on the technical guidance related to the composition of the solid dispersion described herein and taking into account the examples below, a person skilled in the art can easily prepare a melt extruded solid dispersion containing an active ingredient according to formula (1).

[0057] Hot melt extrusion converts a powder or granular mixture containing the BK B2 receptor antagonist of formula (1) and at least one pharma- ceutical acceptable polymer into an extrudate that represents a solid dispersion since the active ingredient is homogeneously and amorphously dispersed in the polymer. Hot melt extrusion involves heating, softening or melting, mixing or homogenizing, and extruding the mixture. It may also be described as a process in which the blended composition is heated and / or compressed to a molten (or softened) state, followed by extrusion through an orifice, forming the extruded product (extrudate) into its final shape and solidifying upon cooling. The blended composition may be conveyed through one or more heated zones. This is typically accomplished by a screw mechanism. The screw or set of screws may be rotated by a variable speed motor inside a cylindrical barrel, but there is only a small gap between the outer diameter of the screw and the inner diameter of the barrel. In this configuration, high shear occurs at the barrel walls and between the screw flights, which thoroughly mixes and deagglomerates the components of the powder or granular blend as they are transported through the extruder. Extrudate refers to the composition formed by hot melt extrusion.

[0058] In one embodiment, the hot melt extrusion step comprises the following substeps: (i) adding the optionally crystalline BK B2 receptor antagonist of formula (1) (or, for example, a hydrate thereof) and a pharma- ceutically acceptable polymer to a hot melt extrusion device; (ii) melting the BK B2 receptor antagonist and the polymer at a temperature close to or above the melting point of the BK B2 receptor antagonist and substantially below its decomposition temperature; (iii) mixing the BK B2 receptor antagonist and the polymer to form a homogenous blend; (iv) extruding the homogenous blend to form a solid dispersion shaped as an extrudate. Steps (ii) and (iii) may be performed simultaneously, or step (iii) may begin as soon as the optionally crystalline BK B2 receptor antagonist of formula (1) and the polymer begin to melt. Additionally, the BK B2 receptor antagonist starting material in step (i) may be crystalline and subsequently converted to amorphous during the hot melt extrusion process.

[0059] In one preferred embodiment, the hot melt extrusion step is carried out with a powder or granular mixture comprising about 15% to about 45% by weight, e.g., about 15% to 25% by weight, of a BK B2 receptor antagonist and about 55% to about 85% by weight, e.g., about 75% to about 85% by weight, of HPMCAS, based on the total weight of the powder or granular mixture. In a related embodiment, a powder or granular mixture consisting essentially of about 15% to 45% by weight, or about 15% to 25% by weight, for example about 20% by weight, of a BK B2 receptor antagonist, in particular (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, and about 55% to 85% by weight, or about 75% to 85% by weight, for example about 80% by weight, of HPMCAS, is subjected to hot melt extrusion to obtain a molten extrudate exhibiting a solid dispersion. In another embodiment, the powder subjected to hot melt extrusion is composed of about 25% by weight each of (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide and about 75% by weight HPMCAS; or about 30% by weight of (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H- or consisting essentially of about 35% by weight of (S)—N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide and about 65% by weight of HPMCAS.

[0060] In another preferred embodiment, the hot melt extrusion step is carried out with a powder or granular mixture comprising about 30% to 50% by weight of the BK B2 receptor antagonist, about 50% to 70% by weight of copovidone, and optionally up to 5% by weight of poloxamer, particularly poloxamer 188, based on the total weight of the powder or granular mixture. In a related embodiment, the powder or granular mixture consists of about 30% to 50% by weight (such as about 40%) of the BK B2 receptor antagonist, about 50% to 70% by weight (such as about 58.5%) of copovidone, and optionally up to 5% by weight (such as about 1 to 2%) of poloxamer, particularly poloxamer 188. For the avoidance of doubt, in these and the previous embodiments, the weight percentages are based on the weight of the powder or granular mixture subjected to the hot melt extrusion step.

[0061] The extrusion temperature, in some preferred embodiments, is determined based on the glass transition temperature (T g ) or the highest T when more than one carrier polymer is used. g The carrier polymer T g In a related preferred embodiment, the extrusion temperature is selected to be above the melting temperature of the active ingredient as well. For example, extrusion at a temperature at least about 20° C. above the melting point of the API promotes solubilization of the drug substance in the carrier polymer. In another preferred embodiment, extrusion is performed at a temperature above the T g The extrusion temperature is preferably at least about 20° C. higher than the extrusion temperature of the extruder. In practice, the extruder may have several temperature zones that may be set at different temperatures. In this context, the extrusion temperature is to be understood as the temperature of the extruder zone having the highest temperature.

[0062] As mentioned, the solid dispersions disclosed herein can also be prepared using a method comprising a step of spray drying an organic solution of the BK B2 receptor antagonist and a polymer, i.e. at least one pharma- ceutically acceptable polymer, in which the BK B2 receptor antagonist according to formula (1) is amorphously and homogeneously dispersed. Prior to the actual spray drying step, an organic solution of the BK B2 receptor antagonist according to formula (1) and the polymer (and any other components of the solid dispersion that may be optionally incorporated) in an organic solvent that is pharma- ceutically suitable for the spray drying process and capable of completely dissolving both the active ingredient and the polymer must be prepared. This can be done by any conventional method of adding a granular or powdery solid to an organic solvent under conditions conducive to dissolution of the solid (e.g. stirring or elevated temperature).

[0063] Organic solvents that may be used in this context include, for example, methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, ethyl acetate, and mixtures thereof. Optionally, the solvent or solvent mixture can contain limited amounts of water.

[0064] The spray drying step itself can be described as atomization under conditions that allow evaporation of the organic solvent. For example, atomization can be performed by a nozzle or on a rotating disk. Another drying step, such as fluidized bed drying, vacuum drying, tray drying, microwave drying, drum drying or double cone vacuum drying, can be used subsequently to reduce residual solvent to a pharma-ceutically acceptable level. In general, spray drying refers to contacting a highly dispersed liquid suspension or solution with a sufficient volume of air to cause evaporation and drying of the droplets. Optionally, the BK B2 receptor antagonist according to formula (1) and the polymer are injected into a warm filtered air or inert gas flow to evaporate the solvent. The dried product particles can be conveyed to an accumulator, such as a cyclone-type particle collector.

[0065] Typically, the spray drying step is carried out at a temperature (i.e., inlet temperature) ranging from about 40°C to 150°C, or about 50°C to 150°C, depending on the organic solvent used. In some embodiments, the inlet temperature is about 80°C to 120°C. The outlet temperature of the spray drying is typically lower, for example about 40°C to 100°C or 40°C to 75°C. For example, fluidized bed drying (such as about room temperature to about 100°C), vacuum drying (such as about room temperature to about 200°C), for example about room temperature to about 65°C, for example about 45°C.

[0066] Besides methods that rely on hot melt extrusion or spray drying, several other techniques or methods can also be used to prepare the solid dispersions disclosed herein, including, for example, low temperature processing techniques, freeze drying, fluidized bed coating, microwave irradiation, co-precipitation, electrostatic spinning, supercritical anti-solvent precipitation, spray congealing, spray coating of carrier particles, melt agglomeration, etc.

[0067] As mentioned above, the solid dispersion disclosed herein can be provided in the form of a powder or granules. Both powders and granules provide the solid dispersion as multiple particles, i.e. in a multiparticulate format. Such powders or granules can be obtained directly by the technique applied to prepare the solid dispersion. For example, when spray drying or a method including a spray drying step is used to prepare the solid dispersion, the direct product obtained from such a method is already in the form of a powder or granules. Optionally, a subsequent step of adjusting the particle size (distribution) of the product, such as sieving, milling, or agglomeration, can be performed. When a method including a hot melt extrusion step is used, the product obtained directly from the extrusion step is typically not in the form of a powder or granules, but in the form of larger units or elongated cylindrical rods, which can then be cut or pelletized into smaller units. The tools for cutting or pelletizing the extrudate can be incorporated as downstream modules of the extrusion device. If another reduction is required, taking into account the desired particle size, a separate subsequent milling step can be used, optionally followed by a classification step, such as sieving.

[0068] In another preferred embodiment, the solid dispersion is in the form of a powder or granules and is prepared by a method comprising the above-mentioned hot melt extrusion step and a milling step in which the extrudate is converted into a powder or granule, optionally including an intermediate step of cutting or pelleting the extrudate prior to milling. Milling can be carried out using any pharma- ceutically suitable equipment, such as hammer mills, centrifugal impact mills, jet mills, ball mills, cone mills, vibratory and rotary sieve mills, to name just a few. Optionally, milling is carried out at controlled temperature and / or under cooling and feeding. The milling process itself can include screening or classification of the milled particles, depending on the milling method and the type of equipment used. Alternatively, a separate screening or classification step can be carried out after milling. Milling of the extrudate can be carried out, optionally including a subsequent screening step, to achieve an average particle size in the range of about 50 μm to 800 μm, or another preferred range of about 100 μm to 700 μm, respectively. In this context, the average particle size typically means the D50 value of the powder or granules as measured by laser diffraction. Alternatively, if the particle size distribution is characterized by sieve analysis, the more relevant parameter is the mass median sieve diameter, which according to some preferred embodiments is also in the range of about 50 μm to 800 μm, or about 100 μm to 700 μm, or about 150 μm to 500 μm.

[0069] Another aspect of the present invention relates to the use of the above solid dispersion, especially when provided in the form of powder or granule.In general, the solid dispersion can be used to prepare any type of pharmaceutical composition, for example by incorporating the solid dispersion into a pharmaceutical dosage form together with optional pharmaceutical excipients.In some preferred embodiments, the solid dispersion is used in oral dosage forms, especially solid single-unit oral dosage forms, such as tablets, capsules (such as two-piece hard capsules), oral films, oral granules (such as single-unit sachets or stick packs), etc.

[0070] Pharmaceutical composition, in the context of the present invention, should be understood as a composition that is technically suitable for administration as a medicine to a subject, such as a human patient. Its composition, formulation and processing are carried out according to common pharmaceutical standards, as may be defined in official pharmacopoeias or guidelines issued by regulatory agencies, such as FDA, PMDA and EMA. In one preferred embodiment, the composition is adapted for oral administration. This implies that, for example, the excipients used, including their grades and their amounts, are safe and acceptable for oral use, particularly for oral administration to human subjects.

[0071] One of the unique properties of solid dispersions found by the present inventors is that they can be advantageously used for oral immediate release compositions and oral sustained release compositions. Incorporated into an immediate release composition, solid dispersions allow the BK B2 receptor antagonist of formula (1), which is a poorly soluble compound, to dissolve rapidly, which otherwise (i.e., when provided in crystalline form) dissolves very slowly and incompletely in commonly used dissolution test models after oral administration of a dose unit of a conventional immediate release composition containing the BK B2 receptor antagonist in crystalline form, for example in the form of a crystalline monohydrate, leading to poor, irregular or variable absorption by the body from the gastrointestinal tract. Thus, when solid dispersions are used in immediate release compositions, they are useful for increasing the oral bioavailability amount of this active ingredient, reducing the variability of bioavailability or plasma level profile bioavailability, and achieving more rapid absorption, thus accelerating the onset of action, compared to conventional formulations containing the drug in crystalline form.

[0072] In this context, an immediate release composition or formulation is one that contains a majority of its active ingredients in the form prescribed by the United States Pharmacopeia (USP), General Chapter <711> ("Dissolution") in accepted in vitro dissolution models, including the model disclosed in. More specifically, immediate release compositions can be described as compositions that meet the criteria, particularly dissolution acceptability criteria, well established by major regulatory agencies, such as those set forth in the applicable FDA Guidances, generally known to those of skill in the art.

[0073] The immediate release oral dosage form using solid dispersion can be designed as immediate release tablet, for example. Tablet formulations that disintegrate quickly when contacted with water are generally known to those skilled in the art. By incorporating BK B2 receptor antagonist as active ingredient in the form of solid dispersion, it is ensured that the tablet not only disintegrates quickly, but also releases the active ingredient in dissolved form quickly, completely and reliably. Similarly, the solid dispersion can be incorporated into capsules such as hard gelatin capsules or other two-piece capsules together with other excipients that may be required or useful as an option.

[0074] Furthermore, the solid dispersions can be used in granule formulations, which can be used, for example, as so-called sprinkle-on formulations, because these granules are typically administered by sprinkling on semi-solid foods, such as applesauce, and ingesting them. In particular, this is a dosage form design suitable for pediatric use. Optionally, the solid dispersions can be provided as coated granules for this purpose, where the coating is typically a non-functional coating, designed primarily to improve product properties not related to drug release, such as the appearance or swallowability of the granules.

[0075] In general, immediate release formulations comprising solid dispersions are highly useful for acute treatment of acute or chronic conditions, such as situations where symptoms appear or the severity of symptoms increases, or as on-demand medicines. "Acute treatment" or "on-demand treatment" involves the immediate halting of progression after the onset of symptoms in order to alleviate, relieve or reduce the severity and / or duration of at least one of the symptoms and / or prevent additional symptoms.

[0076] Another preferred embodiment relates to the use of the above solid dispersion in the preparation of a pharmaceutical composition for sustained release of a BK B2 receptor antagonist. The inventors have found that the incorporation of a solid dispersion into such a sustained release composition is unexpectedly advantageous, despite the fact that the solid dispersion itself has drug solubilization properties that would not be expected to be useful for providing slow drug release over an extended period of time. However, it has been found that the solid dispersion is remarkably compatible with sustained release formulation techniques such as matrix tablets, allowing the creation of sustained release profiles over extended periods of time, for example, about 8 to 24 hours. Furthermore, the solid dispersion helps achieve a reliable release profile when used in a sustained release formulation. Furthermore, it has been found that the use of a solid dispersion sustained release formulation is associated with a low or moderate impact of food on total exposure (e.g., as indicated by AUC) for the sustained release composition of the BK B2 receptor antagonist of formula (1), contrary to what would normally be expected given its solubility and intrinsic release behavior.

[0077] As used in this context, a sustained release composition is any pharmaceutical composition or formulation adapted for oral administration that exhibits sustained release of the active ingredient. Sustained release may also be referred to as slow release, extended release, controlled release, or extended release, to name just a few alternative terms, but without limitation.

[0078] In view of the above, in another aspect, the present invention relates to a pharmaceutical sustained release composition comprising the solid dispersion disclosed herein above.Furthermore, the preferences and optional features described for solid dispersion are also applicable to this aspect.For example, in one preferred embodiment, the solid dispersion contained in the pharmaceutical sustained release composition comprises a BK B2 receptor antagonist of formula (1), where R is deuterium. As another example of a preferred embodiment of the pharmaceutical sustained release composition, the composition may be a solid dispersion according to any one of the preferred embodiments disclosed above, for example a solid dispersion comprising about 15% by weight to about 45% by weight, for example about 15% by weight to about 25% by weight of a BK B2 receptor antagonist of formula (1), in particular (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, and about 55% by weight to about 85% by weight, for example about 75% by weight to about 85% by weight of HPMCAS, or about 30% by weight to about 50% by weight of a BK B2 receptor antagonist of formula (1), in particular (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, inclusive. The solid dispersion comprises a B2 receptor antagonist, about 50% to about 70% by weight of copovidone, and optionally up to about 5% by weight of a poloxamer.

[0079] With regard to the type of dosage form used for the sustained release composition, the inventors have found that tablets and capsules are particularly advantageous. In one preferred embodiment, the sustained release composition is in the form of a matrix tablet. In the context of oral sustained release products, a matrix tablet is a pharmaceutical tablet in which the active ingredient (as such or in the form of formulated particles or granules) is incorporated in an excipient matrix adapted to provide a slow release. Such matrix tablets are different from tablets, for example, whose sustained release function is mainly provided by a sustained release coating. A sustained release matrix tablet can also include a coating, but typically this coating has little effect on the drug release profile. For example, so-called non-functional coatings can be applied to matrix tablets, and such coatings are mainly used to improve the appearance of the tablet, facilitate its handling and swallowing, cover the taste, or reduce friability.

[0080] The formulation techniques for sustained release matrix tablets are generally known to those skilled in the art. Depending on the primary mechanism of drug release, erodible matrix tablets can be distinguished from "insoluble" matrix tablets, which release active ingredients from the swollen but intact matrix mainly by diffusion. In practice, a combination of release mechanisms will likely be present at the same time, with some drug release occurring by diffusion and some drug released as a result of tablet erosion. As used herein, erosion includes any gradual loss of matrix material, regardless of the mechanism by which this loss occurs.

[0081] In a preferred embodiment, the matrix tablet comprises about 10% to about 60% by weight of the solid dispersion, based on the total weight of the matrix tablet. In another preferred embodiment, the content of the solid dispersion in the matrix tablet is in the range of about 15% to about 50% by weight, in particular in the range of about 20% to about 40% by weight, such as about 20%, about 25%, about 30%, about 35%, or about 40% by weight, respectively.

[0082] As described, the matrix tablet can incorporate the solid dispersion in the form of a powder or granule, such as in the form of a milled extrudate described above. The inventors have surprisingly found that a relatively high amount of the solid dispersion described herein can be incorporated into a tablet prepared by direct compression, i.e., in the absence of an intermediate granulation step that is often required to incorporate low compressibility materials into tablets. This was particularly unexpected for solid dispersions prepared by hot melt extrusion, which often leads to particles with low compressibility, followed by pelleting and milling. Thus, in some alternative preferred embodiments, the matrix tablet comprises about 15% to about 50% by weight, or about 20% to about 40% by weight, of the solid dispersion in the form of a milled extrudate.

[0083] Besides the solid dispersion, the matrix tablet preferably contains other excipients that may be necessary or useful for tablet compression but also for forming the matrix in which the solid dispersion powder or granules are embedded. The incorporation of the powder or granules into the compressed tablet may change certain properties of said solid dispersion. For example, when a powder or granule is incorporated into a compressed tablet, the flowability that typically characterizes a powder or granule may no longer be present. Moreover, even if the particles representing a solid dispersion can be extracted from the matrix tablet with some technical difficulties, the parameters related to the particle size may no longer be the same as they were before the solid dispersion was incorporated into the tablet. In this regard, the embodiments related to matrix tablets containing a solid dispersion with optional or preferred characteristics described in the context of a solid dispersion should also be understood as covering matrix tablets that may be obtained from a powder or granule mixture incorporating such a solid dispersion by compressing these mixtures.

[0084] As noted, matrix tablets comprise a solid dispersion and preferably also comprise one or more additional excipients, e.g., to impart compressibility and / or enable the formation of a matrix with sustained release properties.

[0085] In some preferred embodiments, the matrix tablet comprises a tablet filler. A tablet filler can be understood as a pharmaceutical excipient that improves the overall processability of a powder or granule mixture in consideration of tablet compression. The functions of a tablet filler can include those of a diluent or extender, a compression aid, and a dry binder (often simply referred to as a binder). A tablet filler is also referred to as a tablet filler-binder. Such an excipient can be a compound or a combination of compounds. Potentially suitable tablet fillers to be used in matrix tablets include, but are not limited to, microcrystalline cellulose, starch, such as corn starch, potato starch or pregelatinized starch; mannitol, lactose, sorbitol, cellulose, calcium sulfate, calcium phosphate, such as anhydrous calcium hydrogen phosphate, erythritol, and calcium carbonate. In one preferred embodiment, the tablet filler comprises microcrystalline cellulose. In a related embodiment, the tablet filler consists of microcrystalline cellulose or a combination of microcrystalline cellulose and dicalcium phosphate, such as a combination of microcrystalline cellulose and dicalcium phosphate in a weight ratio of about 1:1.

[0086] In another preferred embodiment, the tablet further comprises at least one excipient that is useful for forming a matrix that can embed the solid dispersion powder or granule and provide sustained release of active agent.Such excipients can be called matrix-forming excipients.In another embodiment, this excipient is a matrix-forming polymer, particularly a hydrophilic matrix-forming polymer.Such hydrophilic matrix-forming polymers can swell or gel when compressed into a tablet and contact with water or aqueous medium, and then slowly erode over time, i.e., at least several hours. Examples of potentially suitable hydrophilic matrix-forming polymers that can be used to formulate matrix tablets include, but are not limited to, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), alginic acid, bentonite, carbomer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, carrageenan, cellulose, copovidone, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl methylcellulose acetate succinate, methylcellulose, pectin, polyethylene oxide, polymethacrylate, potassium (or calcium or sodium) alginate, povidone, tragacanth, or xanthan gum.In one preferred embodiment, the hydrophilic matrix-forming polymer in the matrix tablet is or comprises hydroxypropyl methylcellulose, or a combination of two or more grades of HPMC.In a related embodiment, the matrix tablet comprises a combination of two or more hydrophilic matrix-forming polymers, preferably a combination including hydroxypropyl methylcellulose.

[0087] According to another preferred embodiment, the matrix tablet comprises a flow agent and / or a lubricant. A related embodiment is also preferred, in which the matrix tablet comprises a hydrophilic matrix-forming polymer, a tablet filler, a flow agent and a lubricant.

[0088] Glidant is an excipient that improves the flow properties of powder or granules by reducing interparticle friction and cohesion.Potentially suitable glidants include, but are not limited to, silicon dioxide, especially colloidal silicon dioxide, anhydrous colloidal silica, peptized silica, talc, magnesium trisilicate, or powdered cellulose.In one embodiment, the glidant is colloidal silicon dioxide.

[0089] In the context of pharmaceutical tablet compression, lubricants can be understood as excipients that reduce friction between the surface of powder, granules or tablets on the one hand and the walls of the die and tablet punches of the tablet press on the other hand. Thus, lubricants reduce the wear and tear of the tablet die and punches. Potentially suitable lubricants include, but are not limited to, magnesium stearate, polyoxyethylene glycol, aluminum stearate, calcium stearate, calcium behenate, castor seed oil, talc, sodium benzoate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated cottonseed oil, sodium lauryl sulfate, sodium stearyl fumarate, fumaric acid, and stearic acid.

[0090] In an alternative embodiment, when the solid dispersion is provided in the form of a powder or granule, it can be used to make sustained release pellets or granules. For example, the particles (powder or granules) of the solid dispersion can be coated with an excipient or mixture of excipients capable of causing sustained release of the BK B2 receptor antagonist of formula (1). The excipient can be applied to the solid dispersion by dry powder layering, granulation or agglomeration, or wet coating, such as aqueous or organic film coating. A related embodiment is directed to sustained release pellets or granules that include the solid dispersion embedded in or coated with an excipient or mixture of excipients that cause sustained release. Potentially suitable excipients and coating or agglomeration techniques are generally known to those skilled in the art.

[0091] Furthermore, such sustained release pellets or granules incorporating the solid dispersion containing the BK B2 receptor antagonist according to formula (1) can be advantageously used to make tablets, such as fast disintegrating tablets that release the sustained release pellets or granules upon disintegration; or to fill hard capsules, also known as two-piece capsules, such as hard gelatin capsules for on-demand treatment, or similar capsules made of non-gelatin materials.Thus, in some embodiments, the pharmaceutical sustained release composition comprising the solid dispersion is a tablet or hard capsule containing sustained release pellets or granules.

[0092] In one of the preferred embodiments, the BK B2 receptor antagonist of formula (1) is the only active ingredient in the pharmaceutical composition. This should also be understood as the general preference of pharmaceutical composition in the context of the present invention. Alternatively, the pharmaceutical composition can contain one or more other active ingredients. The other or additional active ingredient or pharmaceutical active ingredient is preferably an active agent or pharmaceutical active ingredient that has utility in the prevention or treatment of one or more conditions that respond to BK B2 receptor modulation, including conditions selected from the group including skin disorders; eye diseases; ear diseases; oral, pharyngeal and respiratory diseases; gastrointestinal diseases; liver, gallbladder and pancreatic diseases; urinary tract and kidney diseases; male and female reproductive organ diseases; hormonal system diseases; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic system diseases; central nervous system disorders; brain disorders; musculoskeletal diseases; allergic disorders; pain; infections; inflammatory disorders; injuries; immune disorders; cancer; genetic diseases; and edema. For example, at least one compound or pharma- ceutically acceptable salt of the present invention may be advantageously included in a combination preparation that includes an antibiotic, antifungal, or antiviral agent, an antihistamine, a nonsteroidal anti-inflammatory drug, a disease-modifying antirheumatic drug, a cytostatic drug, a drug having smooth muscle modulating activity, an antibody, or a mixture of the above as another or additional active agent or medicament active ingredient.

[0093] The sustained release composition may further be described in terms of the dose strength or amount of the BK B2 receptor antagonist of formula (1) incorporated per dose unit, i.e., per capsule or tablet. In some embodiments, the dose strength is in the range of about 1 mg to about 100 mg, or about 5 mg to about 100 mg, respectively. In other preferred embodiments, the dose strength is in the range of about 10 mg to about 80 mg, for example about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, or 80 mg, respectively. In some other preferred embodiments, the dose strength is in the range of about 20 mg to 50 mg, for example about 20 mg to 40 mg. For pediatric use, lower doses such as about 0.5 mg to about 5 mg may also be useful.

[0094] As already mentioned, the inventors have found that the incorporation of a solid dispersion comprising the BK B2 receptor antagonist of formula (1) into the sustained release composition disclosed herein allows for the tailoring of clinically advantageous sustained release profiles, e.g., with better robustness and reliability, and reduced food effect, particularly on the amount of drug absorbed, compared to conventional formulation techniques. This advantage is particularly evident in sustained release compositions comprising solid dispersions using hydroxypropyl methylcellulose acetate succinate (HPMCAS) as the carrier of the solid dispersion, i.e., as a pharma- ceutically acceptable polymer in which the active ingredient is amorphous and homogeneously dispersed. Without wishing to be bound by any particular theory, these release characteristics may be related to the fact that HPMCAS is a polymer that is insoluble in acidic media (e.g., gastric fluids) and causes slow drug release there when such an acidic environment is present, and the drug substance exhibits at least some appreciable solubility, whereas the compound of formula (1) itself is very poorly soluble, particularly in relatively neutral media (e.g., intestinal fluids), and causes relatively slow drug release in such environments, so that various pH-dependent effects on drug release rates may be partially compensated for. In other words, the design of a sustained release composition that includes a solid dispersion based on HPMCAS can provide controlled drug release even in response to changes in pH. In some preferred embodiments, the sustained release composition disclosed herein is an optionally coated monolayer tablet. Monolayer tablets differ from bilayer or multilayer tablets in that they consist of a single compressed tablet layer. The manufacture of monolayer tablets is generally more cost-effective than the manufacture of tablets with two or more layers. Monolayer tablets are also smaller and therefore may be easier to swallow than tablets with an additional layer or layers that may be used to create a drug release profile.

[0095] The sustained release profile is typically measured in a well-defined in vitro model, also for the purpose of describing the behavior of the composition or formulation in a relevant biological environment, i.e., the behavior of the composition or formulation in a clinical situation after administration of the composition or formulation to a subject. As used herein, sustained release profile refers to the dissolution profile of a sustained release composition. Descriptions of some widely accepted dissolution models for determining the dissolution profile can be found, for example, in the United States Pharmacopeia (USP), General Chapter. <711> ("Dissolution"). To characterize the dissolution profile of the sustained release composition disclosed herein, for example, Apparatus II (paddle apparatus) as described in USP can be used. The rotation speed of the paddle can be set at 100 rpm according to a preferred embodiment. The medium to be used for the dissolution test can consist of, for example, 1,000 mL of USP phosphate buffer (pH 6.8) containing 0.3% (w / v) sodium dodecyl sulfate.

[0096] In some preferred embodiments, the sustained release composition comprising the solid dispersion disclosed herein exhibits release of the BK B2 receptor antagonist of formula (1) over at least about 6 hours, or over at least about 8 hours, for example, over about 8 to 24 hours. In another preferred embodiment, the sustained release composition exhibits release of the BK B2 receptor antagonist of formula (1) over at least about 6 hours, or over at least about 8 hours, for example, over about 8 to 24 hours. <711> The composition releases the BK B2 receptor antagonist over a 12-24 hour period as determined by dissolution testing using the apparatus of chapter II at 37°C and a rotation speed of 100 rpm, 1,000 mL of USP phosphate buffer (pH 6.8) containing 0.3% (w / v) sodium dodecyl sulfate as the dissolution medium, and using a tablet weight (e.g., a Japanese weight) to maintain the tablet in the bottom region of the dissolution vessel. In this context, 12-24 hours of active ingredient release means that the time at which 95% of the active ingredient incorporated in the composition has been released falls within the specified time period. For example, a sustained release composition may be characterized by a dissolution profile that reaches 95% drug dissolution after about 12 hours, or about 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours, respectively.

[0097] The sustained release profile, or dissolution profile, may also be described in terms of the time it takes for about 50% of the incorporated drug to be released, i.e., dissolved. In some preferred embodiments, the sustained release composition reaches 50% dissolution within about 3-10 hours, or within about 4-8 hours, e.g., after about 4, 5, 6, 7, or 8 hours, respectively.

[0098] In some preferred embodiments, the sustained release composition has a dosage strength in the range of about 10 mg to 80 mg as defined above and releases the BK B2 receptor antagonist of formula (1) over a period of about 12 to 24 hours. Also preferred are embodiments in which the sustained release composition is in the form of a matrix tablet comprising a solid dispersion based on or incorporating HPMCAS, the tablet having a dosage strength of about 20 mg to 40 mg and exhibiting release over a period of about 12 to 24 hours.

[0099] According to another aspect of the present invention, the solid dispersion disclosed herein or the sustained release composition comprising such solid dispersion can be used in the treatment of subjects suffering from any disease or condition that responds to bradykinin B2 receptor modulation. Such conditions include conditions selected from the group comprising skin disorders; eye diseases; ear diseases; oral, pharyngeal and respiratory diseases; gastrointestinal diseases; liver, gallbladder and pancreatic diseases; urinary tract and kidney diseases; male and female reproductive organ diseases; hormonal system diseases; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic system diseases; central nervous system disorders; brain disorders; musculoskeletal diseases; allergic disorders; pain; infectious diseases; inflammatory disorders; injury; immune disorders; cancer; genetic diseases; and edema. In other words, one aspect of the present invention relates to a method for treating subjects suffering from any disease or condition that responds to bradykinin B2 receptor modulation, comprising administering the above solid dispersion or sustained release composition. Similarly, the invention provides the use of the solid dispersion or sustained release composition in the manufacture of a medicament for the treatment of any disease or condition responsive to bradykinin B2 receptor modulation.

[0100] As used herein, the terms "treatment", "treat" and the like should be construed to include any type of prophylactic or therapeutic treatment. It therefore includes the prevention, management or treatment of a disease or its recurrence, or any symptoms associated with such a disease or condition. Treatment includes acute and chronic treatment.

[0101] In the context of the present invention, chronic treatment refers to continuous treatment of a disease or condition, including repeated administration of a pharmaceutical agent according to a regular dosing regimen over an extended period of time, such as for at least one month or for at least three months. In some embodiments where the patient's or subject's condition does not improve, the compound of formula (1) is administered chronically, i.e., for an extended period of time, including the entire life of the patient or subject, to ameliorate or otherwise control or limit symptoms associated with the disease or condition in the patient or subject. In another preferred embodiment, the treatment can be prophylactic, i.e., treatment before the onset of symptoms, to prevent, delay or reduce the severity of symptoms. Prophylactic treatment can include both acute and chronic treatment. For example, acute prophylactic treatment can include orally administering a therapeutically effective amount of a compound of formula (1) to a human patient or subject in need thereof at least once, thereby preventing or reducing symptoms. Chronic treatment can include, for example, administration of one, two or three dosage units per day over such a period of time.

[0102] As mentioned above, according to one of the preferred embodiments, a sustained release composition is provided comprising a solid dispersion of a BK B2 receptor antagonist of formula (1) in a polymer carrier, which the inventors have found to provide advantageous sustained release properties. It is believed that these properties also make such sustained release compositions particularly suitable for chronic or long-term treatment. One particular benefit provided by these compositions is that they provide effective and acceptable sustained plasma levels with a regimen of only one or two administrations per day. Thus, in some of the preferred embodiments, the solid dispersion or sustained release composition disclosed herein is used in chronic treatment of subjects suffering from a disease or condition that responds to BK B2 receptor modulation, preferably for at least one month. In another embodiment, the chronic treatment is characterized by administration once or twice per day, preferably for at least three months, or at least one year, respectively. In one embodiment, the chronic treatment is lifelong treatment.

[0103] For the avoidance of doubt, each treatment period does not require that the same dosing regimen is used throughout treatment.For example, when once-a-day administration is insufficient to treat a particular subject, the regimen can be switched to twice-a-day administration.Alternatively, the dose per administration event can be increased during chronic treatment.

[0104] Furthermore, in the context of the present invention, "acute" includes any non-chronic administration regimen, such as a single administration of a composition comprising a solid dispersion or an immediate release composition comprising a solid dispersion as disclosed herein, as well as sporadic or regular administration regimens over a relatively short period of time, such as up to 4 weeks or up to 2 weeks. In some embodiments, the solid dispersions provided herein are used for the acute treatment of a disease or condition responsive to bradykinin B2 receptor modulation.

[0105] The following diseases or conditions may be considered to be responsive, or at least potentially responsive, to bradykinin B2 receptor modulation.

[0106] Skin disorders include, but are not limited to, disorders such as skin aging, skin eruptions including bedsores, bedsore ulcers, sore, sensitive and paresthetized skin, erythema, rash, skin edema, bacterial, viral, fungal and parasitic induced skin infections including psoriasis, eczema, lichen, furuncles, abscesses, cellulitis, erysipelas, folliculitis and impetigo, lice, scabies and cold sores, acne, skin eruptions, atopic dermatitis, allergic contact dermatitis, neurodermatitis, radiation damage, sunburn, pruritus, itching, urticaria, psoriasis, mycosis, tissue ulceration, dermatitis including epidermolysis bullosa, wounds including wound healing disorders, burns, frostbite, venom-induced dermatitis and edema, alopecia, hair scales, corns, warts and whitlow.

[0107] Ocular diseases include, but are not limited to, inflammatory disorders such as scleritis, conjunctivitis, conjunctival edema, iritis, iridocyclitis, uveitis, chorioretinitis, as well as disorders such as retinal and choroidal circulatory disorders, bacterial eye infections, nonspecific conjunctivitis and eye irritation, retinopathy of prematurity, proliferative vitreoretinopathy, macular degeneration (including age-related macular degeneration, both wet and dry), corneal graft rejection, corneal damage, corneal scarring, corneal ulcers, corneal opacities, keratoconus, glaucoma (preferably open-angle glaucoma), myopia, ocular hypertension, ocular vascular damage, neovascularization, ocular fibrosis (e.g., anterior subcapsular fibrosis, posterior subcapsular opacities, posterior capsular opacities, corneal opacities after laser surgery, subconjunctival scarring after glaucoma surgery), proliferative vitreoretinopathy (PVR), bacterial eye infections including styes, and eyelash loss. Eye diseases include, but are not limited to, disorders such as Meniere's disease, inflammation of the middle ear, inflammation of the ear canal, and acute hearing loss.

[0108] Oral cavity, pharyngeal and respiratory diseases include inflammation of the oral mucosa and gums, including aphthae and stomatitis, periodontitis, epiglottitis, pharyngitis, laryngotracheitis, tonsillitis, cold, angina, rhinitis, including seasonal or perennial allergic rhinitis, rhinorrhea, sinusitis of whatever type, etiology or pathogenesis, or purulent or non-purulent sinusitis, acute and chronic sinusitis, and sinusitis which is a member selected from the group consisting of ethmoid, frontal, maxillary or sphenoid sinusitis, expectoration, e.g. pneumoconiosis of any type or origin, including for example aluminosis, anthraxosis, asbestosis, stone lung disease, siderosis, silicosis, tobacco disease, in particular byssinosis, bronchitis, cough, tracheitis, congestion, pneumonia, eosinophilic pulmonary infiltrates, chronic eosinophilic pneumonia, idiopathic pulmonary fibrosis and other fibrotic lung diseases, treatment-related fibrotic lung diseases, for example fibrotic lung diseases associated with radiation, methotrexate, chemotherapy, amiodarone or nitrofurantoin, sarcoidosis, acute respiratory distress syndrome (ARDS), bronchoconstriction, Asthma of any type, etiology or mechanism, or includes atopic asthma, non-atopic asthma, allergic and non-allergic asthma, extrinsic asthma caused by environmental factors, intrinsic asthma caused by pathophysiological disorders, bronchial asthma, IgE-mediated asthma, essential asthma and essential asthma of unknown or unclear origin, true asthma, emphysematous asthma, exercise-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infections, primary asthma, Asthma, which is a member selected from the group consisting of early stage asthma, wheezing infant syndrome, bronchial hyperresponsiveness, chronic obstructive pulmonary disease (COPD), COPD characterized by irreversible progressive airway obstruction, acute respiratory distress syndrome (ARDS) and other disorders resulting from drug treatments such as exacerbation of airway hyperresponsiveness, dyspnea, hyperoxic alveolar injury, emphysema, pleurisy, tuberculosis, exposure to high altitude i.e. acute mountain sickness and preferably high altitude pulmonary edema (HAPE), resistant cough, bronchial hyporesponsiveness.

[0109] Gastrointestinal diseases include, but are not limited to, disorders including esophagitis, gastritis, irritable stomach, gastric and duodenal ulcers, ileus, irritable colon, inflammatory bowel disease including Crohn's disease and ulcerative colitis, enteritis, hypertensive gastric and colonic disease, colitis, peritonitis, appendicitis, proctitis, gastrointestinal bleeding caused by portal hypertension, collateral circulation or hyperemia, post-gastrectomy dumping syndrome, digestive discomfort, diarrhea, hemorrhoids, helminthic diseases, abdominal colic and colic of the gastrointestinal system.

[0110] Liver, gallbladder and pancreatic diseases include, but are not limited to, disorders such as hepatitis, cirrhosis, liver fibrosis (e.g., due to viral (HBV / HCV) infection, toxins (alcohol), fatty liver, cholestasis, hypoxia), portal hypertension, hepatorenal syndrome, hepatic edema, cholangitis, cholecystitis, acute and chronic pancreatitis, and biliary colic.

[0111] Urinary tract and kidney diseases include, but are not limited to, urinary tract infections such as acute and chronic cystitis, interstitial cystitis, overactive bladder, overactive bladder, incontinence including, but not limited to, stress, urge and reflex urinary incontinence, benign prostatic hyperplasia, chronic kidney disease, urethritis, glomerulonephritis, renal glomerular disease, interstitial nephritis, pyelonephritis, inflammatory kidney diseases including polyuria, proteinuria, natriuresis, urinary Ca excretion, water balance disorders, electrolyte balance disorders, acid-base balance disorders and renal colic, renal fibrosis, chronic allograft renal dysfunction, contrast-induced nephropathy.

[0112] Diseases of the male and female reproductive systems include, but are not limited to, sperm motility changes, male infertility, orchitis, prostatitis, prostatic hyperplasia, mastitis, inflammatory pelvic disease, vaginal infection and pain, adnexitis, vaginitis, soft ulcers, syphilis, gonorrhea and ovarian hyperstimulation syndrome.

[0113] Hormonal disorders include, but are not limited to, menstrual disorders and pain, menopause, vomiting, premature uterine contractions, premature labor, endometriosis, endometritis, fibroids, and preeclampsia.

[0114] Metabolic diseases include, but are not limited to, diabetes including non-insulin dependent diabetes mellitus, diabetic retinopathy, diabetic macular edema, diabetic nephropathy and diabetic neuropathy, insulin resistance and diabetic ulcers, diseases of protein and purine metabolism such as gout, and disorders of lipid metabolism, hypoglycemia, and the like.

[0115] Cardiovascular diseases include vascular permeability, vasodilation, peripheral circulatory disorders, arterial circulatory disorders including aortic aneurysm, abdominal aortic aneurysm, and cerebral aortic aneurysm, hypertension and hypotension associated with sepsis, restenosis after percutaneous coronary intervention, atherosclerosis including atherosclerotic plaque rupture, venous disorders such as hemangiomas, angiofibromas, thrombosis, varicose swelling, phlebitis, thrombophlebitis, and venous thrombosis, heart disease, congestive heart failure, coronary heart disease, carcinoid syndrome, angina pectoris, cardiac rhythm disorders, inflammatory heart disease including endocarditis, pericarditis, and constrictive pericarditis, and myocarditis. , myocardial infarction, post-myocardial infarction syndrome, left ventricular dilation, post-ischemic reperfusion injury, shock and collapse, including septic, allergic, post-traumatic and hemodynamic shock, amniotic fluid embolism, systemic inflammatory response syndrome (SIRS), including SIRS caused by cardiopulmonary bypass during surgery, sepsis, and disorders including internal and external complications during cardiopulmonary bypass surgery, including, but not limited to, adverse hemodynamic effects following heparin reversal of protamine sulfate.

[0116] Hematological diseases include, but are not limited to, disorders such as coagulation, disseminated intravascular coagulation, hemorrhage, bleeding diathesis, hypercholesterolemia and hyperlipidemia, hypovolemic shock, paroxysmal nocturnal hemoglobinuria, and the like.

[0117] Lymphatic system disorders include, but are not limited to, splenomegaly, lymphangitis, lymphadenitis, and hypertrophic adenoids.

[0118] Disorders of the central nervous system include, but are not limited to, encephalitis, meningitis, encephalomyelitis, meningoencephalitis, hydrocephalus, amyotrophic lateral sclerosis, spinal cord trauma, spinal cord edema, demyelinating diseases of the nervous system, inflammatory diseases of the central nervous system including multiple sclerosis, aging, acute and chronic neurodegenerative disorders including Alzheimer's disease and Parkinson's disease, neuritis, and peripheral neuropathies, disorders such as depression, anorexia, anxiety and schizophrenia, sleep disorders, and the like.

[0119] Brain disorders include, but are not limited to, disorders such as nootropic or hypercognitive, cerebral amyloid angiopathy, stroke, head and brain trauma, traumatic brain injury, brain tumors, thermal brain injury, cerebral ischemia, cerebral hemorrhage, post-traumatic and post-ischemic cerebral edema, generalized cerebral edema, acute mountain sickness and preferably high altitude cerebral edema (HACE), cytotoxic cerebral edema, vasogenic cerebral edema, post-operative cerebral edema, cerebral edema associated with metabolic disease, increased permeability of the blood-brain barrier or blood-brain tumor barrier.

[0120] Musculoskeletal diseases include disorders such as rheumatoid arthritis of any type, etiology, or pathogenesis, osteoporosis, musculoskeletal pain and stiffness, spinal disc syndrome, and the like, including, but not limited to, inflammatory musculoskeletal disorders, arthropathy, osteoarthropathy, osteoarthritis, chondroporosis following joint trauma or relatively long-term joint immobilization following meniscal or patellar injury or ligament damage, acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, spondyloarthritis, septic arthritis, psoriatic arthritis, chronic polyarthritis, rheumatism, Sjogren's syndrome, low back pain, spondylitis, spondyloarthritis, ankylosing spondylitis, osteomyelitis, sprains, tendonitis, inflammation-induced bone resorption, fractures, and the like.

[0121] Allergic disorders include, but are not limited to, disorders such as general allergic reactions, food allergies, anaphylactic shock, allergic contact sensitivity, allergic skin reactions, allergic asthma, vernal conjunctivitis, and seasonal or perennial allergic rhinitis.

[0122] Pain includes, but is not limited to, central and peripheral mediated pain, vascular pain, visceral pain, inflammation mediated pain, neuralgic pain, referred pain, nociceptive pain, reflex pain, psychogenic pain, acute pain such as caused by acute injury, trauma or surgery to bone, muscle, tissue, soft tissue, organs, pain after insect bites, post-stroke pain syndrome, post-operative pain, pain associated with progressive disease, chronic pain such as caused by neuropathic pain conditions (including but not limited to complex regional pain syndrome, causalgia, Sudeck's disease, reflex sympathetic dystrophy, diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, cancer-related pain, pain associated with rheumatoid arthritis, osteoarthritis, tendonitis, gout, menstruation and angina, fibromyalgia, eye pain, back pain, headache, cluster headache, migraine, inflammatory pain that may be associated with acute or chronic inflammation). Inflammatory pain includes, but is not limited to, neuropathic pain, ischemic pain, arthritis-induced pain, acute or chronic inflammation-induced myalgia, acute or chronic inflammation-induced neuralgia, hyperalgesia.In addition, chemotherapy-induced peripheral neuropathy, hyperalgesia, opioid-induced hyperalgesia and fever are also included.In addition, the compound of the present invention is useful as an analgesic agent for use during general and monitored anesthesia.

[0123] Infectious diseases include, but are not limited to, diseases mediated by bacteria, viruses, fungi, parasites, protozoa, prions, or mycobacteria. In particular, the present invention is useful for the treatment of bacterial infections caused by Streptococcus, Escherichia, Salmonella, Staphylococcus, Klebsiella, Moracella, Haemophilus, and Yersinia. Examples of bacterial infections within the scope of the present invention include, but are not limited to, diseases such as plague, septicemia, typhus, food poisoning, tetanus, scarlet red, whooping cough, and diphtheria. Examples of viral infections within the scope of the present invention include, but are not limited to, diseases such as chickenpox, shingles, AIDS, influenza, smallpox, and childhood diseases such as rubella, mumps, and acute spinal cord anterior hornitis. The present invention is useful for the treatment of protozoan and parasitic infections caused by Schistosoma mansoni, Dermatofagoides farinae, and Plasmodium-induced malaria. Examples of prion infections within the scope of the present invention include, but are not limited to, bovine spongiform encephalopathy (BSE), Creutzfeldt-Jakob disease, and diseases such as kuru, dengue fever, and hemorrhagic fever.

[0124] Inflammatory disorders include, but are not limited to, disorders such as acute phase responses, local and systemic inflammation, and inflammation caused by other diseases of any type, etiology or pathogenesis, and inflammation caused by the inflammatory diseases specified within this application.

[0125] Injury: Within this application, the term "injury" includes, but is not limited to, multiple trauma, head trauma, pulmonary injuries, external, internal and surgical wounds.

[0126] Immune disorders include, but are not limited to, disorders such as hypersensitivity, autoimmune disorders, graft rejection in transplantation, transplant toxicity, granulomatous inflammation / tissue remodeling, myasthenia gravis, immunosuppression, immune complex diseases, antibody overproduction and underproduction, vasculitis, delayed graft function, and lupus.

[0127] Cancers include breast cancer, lung cancer (non-small cell lung cancer and small cell lung cancer), prostate cancer, oral cavity and pharynx (lips, tongue, oral cavity, pharynx), esophagus, stomach, small intestine, large intestine, colon, rectum, gallbladder and biliary tract, pancreas, larynx, lung, bone, osteosarcoma, cancer of connective tissue, Kaposi syndrome, skin cancer including melanoma and skin metastases, epidermoid carcinoma, basal cell carcinoma, cervix, endometrial body, ovaries, testes, bladder, ureters and urethra, kidneys, eyes, brain and central nervous system. These include, but are not limited to, solid tumor cancers including cancers of the nervous system, pseudotumor cerebri, sarcoma, sarcoid, thyroid and other endocrine glands (including but not limited to carcinoid tumors), hematopoietic malignancies including Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia and lymphomas including lymphocytic, granulocytic and monocytic lymphomas, disorders of tumor invasion, metastasis, ascites, tumor proliferation and angiogenesis.

[0128] Genetic diseases include, but are not limited to, disorders such as hereditary angioedema and angioneurotic edema, chondrocalcinosis, Huntington's disease, pancreatic fibrosis, and the like.

[0129] As used herein, edema includes, but is not limited to, generalized edema and edema caused by inflammation, factor XII deficiency-induced edema, drug-induced angioedema including but not limited to other drugs, such as angiotensin-converting enzyme inhibitor-induced angioedema, infection, burns, injuries, trauma, frostbite, surgery, sprains, fractures, exposure to high altitude (e.g., high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE)), genetic, autoimmune and other diseases and disorders, specifically, but not limited to, disorders specified in this application, stress-induced edema (palpable swelling) of the intestine. Known forms of angioedema (AE) include hereditary angioedema (HAE), acquired angioedema (AAE), bradykinin-mediated idiopathic nonhistaminergic angioedema, allergic angioedema, and drug-induced angioedema. The HAE can be any type of HAE, including type I HAE, type II HAE, or type III HAE.

[0130] Capillary leak syndrome includes, but is not limited to, systemic capillary leak syndrome in sepsis, burns, allergies, drug / toxin induced conditions, organ transplants and IL-2 cytokine therapy.

[0131] In another preferred embodiment, the solid dispersion or sustained release composition is used in the treatment of AE, including HAE, AAE, bradykinin-mediated non-histaminergic idiopathic AE, allergic AE, and drug-induced AE. AE is an area of ​​swelling of the skin and the tissues beneath the skin or mucous membrane. Debilitating and often painful swelling can occur in the face, lips, tongue, hands and feet, genitals, gastrointestinal mucosa, genitourinary tract, and respiratory tract. It is often associated with urticaria, which is swelling in the upper skin. It is characterized by repeated swelling episodes, with episodes typically lasting from minutes to hours. It is impossible to predict where and when the next episode of angioedema will occur. Patients may have one episode per month, but some have only one episode per week or one or two episodes per year.

[0132] In some preferred embodiments, the solid dispersion or sustained release composition is used in the treatment of any type of HAE, including type I, type II, or type III HAE, preferably type I or type II HAE. HAE is a disorder that manifests as recurrent attacks of severe swelling. Swelling often affects the arms, legs, face, intestines, and even the airways. When the intestines are affected, abdominal pain and vomiting can occur. Swelling of the airways can result in bronchial obstruction and difficulty breathing. Acute attacks typically last several days, with HAE patients experiencing attacks about every two weeks.

[0133] The sustained release composition is particularly advantageous in the chronic phase treatment of AE such as hereditary angioedema (HAE) and acquired angioedema (AAE), especially HAE type I or HAE type II. As described, it is patient-friendly since it requires only once-daily or twice-daily administration. Given that the sustained release profile is independent of pH fluctuations and the presence of food, these compositions are suitable for long-term treatment over months or years.

[0134] Further aspects, embodiments, optional features and preferences of the present invention will become apparent based on the examples and claims. Further definitions

[0135] For ease of understanding, here are some additional definitions of terms used throughout the specification and claims. The definitions should be used to determine the meaning of each expression unless the context requires a different meaning.

[0136] The terms "a" or "an" do not exclude a plurality; that is, the singular forms "a," "an," and "the" should be understood as including plural referents unless the context clearly indicates or requires otherwise. In other words, all references to singular features or limitations in this disclosure include the corresponding plural features or limitations, and vice versa, unless clearly specified otherwise or clearly indicated by the stated context to the contrary. Thus, the terms "a," "an," and "the" have the same meaning as "at least one" or "one or more," unless otherwise defined. For example, reference to "an ingredient" includes mixtures of ingredients, and the like.

[0137] The terms "about" or "ca." are accepted in the pharmaceutical industry to account for variability inherent in pharmaceuticals, such as manufacturing variations and / or differences in content due to product aging. The terms allow for any variation that, in pharmaceutical practice, may be considered to be bioequivalent in a subject to the stated strength of the claimed product.

[0138] The terms "active agent," "therapeutic agent," "active pharmaceutical ingredient (API)," "active ingredient," "drug," and "bioactive agent" are used interchangeably and refer to a compound or combination of compounds that is pharmacologic active against an undesirable condition.

[0139] The term "composition" refers to any type of composition in which the specified component may be incorporated, optionally with any other components.

[0140] The term "compound" refers to a chemical substance that is a material made up of molecules with essentially the same chemical structure and properties. In small molecule compounds, the molecules are typically identical in terms of their atomic composition and structural arrangement. In macromolecular or polymeric compounds, the molecules of the compound are highly similar, although not necessarily all of them are identical.

[0141] The terms "comprise," "comprises," and "comprising" and similar expressions are to be interpreted in an open and inclusive sense, such as "including, but not limited to."

[0142] The terms "essentially," "about," "approximately," "substantially," and the like, in connection with an attribute or value, include the exact attribute or exact value, and also include any attribute or value that is determined to fall within a normal range or variability typically accepted in the art. For example, "essentially free of water" means that water is not intentionally included in the composition, but does not exclude the presence of residual moisture.

[0143] The term "consisting essentially of" refers to a composition or dosage form to which no other ingredients, other than those listed, have been added. Nevertheless, very small amounts of other materials may potentially be present, such as impurities inherent in the material, or trace amounts of additives added by the excipient provider. Furthermore, for example, when reference is made to "consisting essentially of A, B, C, and optionally D," this means that no other ingredients, other than A, B, C, and D, have been added to the composition or dosage form, and that D is an optional ingredient (i.e., not required) in said composition or dosage form.

[0144] The term "essentially free" refers to compositions that contain less than a functional amount of each component, typically less than 1% by weight, preferably less than 0.1%, or even 0.01%, and 0 weight percent of each component. EXAMPLES

[0145] Certain aspects of the present invention are further illustrated by the following examples, which should not be construed as limiting the scope of the invention.

[0146] The compound of formula (1) was prepared under Good Manufacturing Practice (GMP) regulations, as required, as described in WO 2019 / 101906.

[0147] The studies reported in Examples 6 and 7 were conducted in accordance with applicable regulations and national government rules for conducting animal and clinical trials, including the corresponding protocols, existing guidelines and recommendations on laboratory animal science, current guidelines on Good Clinical Practice (GCP) of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), and rules on subject protection and informed consent documents, as well as transparency requirements. All study protocols, the suitability of the investigators, facilities and methods and materials to be used in obtaining and documenting informed consent documents for study subjects were reviewed and approved by an Institutional Review Board (IRB) or an Independent Ethics Committee (IEC) before the start of the study. In this study, subjects received a final release of the investigational drug, i.e., the compound of formula (I), in accordance with Directive 2003 / 94 / EC annex 13, and the study drug labeling contained information meeting applicable regulatory requirements. Packaging, labeling, and release of the investigational medicinal products were performed under the responsibility of the clinical site pharmacist in accordance with GMP implementation guidelines, International Conference on Harmonization (ICH), Good Clinical Practice (GCP), and applicable local laws / regulations.

[0148] Example 1 Solid dispersions prepared by vacuum melt compression Two solid dispersion compositions were prepared by vacuum melt compression. The first composition, designated HME1, consisted of 40% by weight (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, 58.5% by weight copovidone (Kollidon® VA64), and 1.5% by weight poloxamer 188. The second composition, designated HME2, consisted of 20% by weight of (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide and 80% by weight of hypromellose acetate succinate (AQOAT® AS-MMP).

[0149] The active ingredient, (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, was provided in powder form as the crystalline monohydrate. The measured amounts of active ingredient and carrier were mixed in a shaking mixer (Turbula®) for 4 minutes.

[0150] Subsequently, a measured amount of the powder mixture was transferred to a lab-scale vacuum compression molding apparatus (VCM, Meltprep) equipped with a disc molding tool (Meltprep Disc Tool) and molded into discs at a vacuum of -1.0 bar. For HME1, vacuum compression molding was performed at a temperature of 200°C with a heating time of 5 minutes, a cooling time of 2 minutes, and a cooling air pressure of 2.5 bar. For HME2, vacuum compression molding was performed at a temperature of 180°C with a heating time of 5 minutes, a cooling time of 5 minutes, and a cooling air pressure of 3.0 bar. Transparent yellowish discs were obtained with both compositions.

[0151] The disks were crushed using a mortar and pestle and subjected to separate evaluation. First, the drug content was confirmed to be within 90-110% of the theoretical amount by HPLC assay. Furthermore, the crystalline state of the drug substance was evaluated by differential scanning calorimetry (DSC) and powder X-ray diffraction (XRPD, also called powder X-ray diffraction or PXRD). The DSC thermogram did not show a melting point of the active ingredient (approximately 111 °C), only the Tg of the polymer was observable. The XRPD analysis showed no residual crystallinity. Therefore, it was concluded that the sample showed a solid dispersion containing the active ingredient only in an amorphous and completely dissolved state.

[0152] Example 2 Solid dispersions prepared by spray drying Four solid dispersion compositions, designated SDD1 to SDD4, were prepared by spray drying. Each consisted of 25 wt% (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide and 75 wt% carrier polymer. The carrier polymers were hypromellose acetate succinate (AQOAT® AS-MMP) in SDD1, hypromellose type 2910 USP (Methocel® E3) in SDD2, copovidone (Kollidon® VA64) in SDD3, and povidone K-30 in SDD4.

[0153] For each composition, a measured amount of active ingredient and the respective carrier polymer were dissolved in a mixture of dichloromethane (DCM) and methanol (4:1 (w / w) ratio). Spray drying was then carried out using a laboratory scale spray dryer (Buchi B290) using the parameters listed in Table 1 below.

[0154] [Table 1]

[0155] The spray drying process yielded a powder that was collected and subjected to a second drying step using vacuum drying at 40° C. and −26.5 mmHg vacuum for 20 hours.

[0156] The samples thus obtained were evaluated using modulated differential scanning calorimetry (mDSC), XRPD, and thermogravimetric analysis (thermogravimetric analysis also TGA). Both XRPD and mDSC data confirmed that the four prototypes were amorphous and did not contain any detectable levels of crystalline material. The TGA thermograms showed an inflection in the slope of the weight loss step of the SDD4 prototype, suggesting that a small amount of residual solvent remained in the sample. Overall, it was confirmed that all prototypes were amorphous and exhibited homogeneous solid dispersions with the active ingredient completely dissolved in the carrier polymer.

[0157] Samples of spray-dried solid dispersions SSD1-SSD4 were stored at elevated temperature (40° C.) and re-examined by XRPD after 3 weeks. All samples were found to be amorphous and free of crystalline content.

[0158] Example 3 Solid dispersions prepared by hot-melt extrusion A solid dispersion was prepared by hot melt extrusion using the same composition as HME2 (see Example 1), consisting essentially of 20 wt. % (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide and 80 wt. % hypromellose acetate succinate (AQOAT® AS-MMP). The powder blend containing the crystalline active ingredient and the carrier polymer was screened through a sieve with an aperture width of 500 μm. The blend was then extruded using a twin screw extruder (Leistritz ZSE 12 HP-PH) equipped with a 1.5 mm die. The maximum temperature in the kneading zone was in the range of 145-165°C, except that the die zone was set at 200°C. A slightly brownish transparent extrudate was obtained and pelletized in a pelletizer. The pellets were subsequently milled using a two-phase hammer mill with a first phase screen size of 1,000 μm and a second phase screen size of 400 μm at a milling speed of 6,500 rpm. The particle size distribution was then characterized by laser diffraction (Mastersizer®). The two milled batches had mean particle sizes D50 of 262.3 μm and 249.1 μm, respectively. Sieve analysis found that 66.2% and 61.7% by weight, respectively, of the milled particles were in the sieve fraction between 180 μm and 355 μm.

[0159] Another batch of the same composition (HME2) was prepared using the same hot melt extrusion, pelletizing and milling process as above, except that a hammer mill with a 200 μm sieve size was used in the final milling step, resulting in an average particle size D50 of about 100 μm, i.e. in the range of 63 μm to 125 μm, as determined by sieve analysis.

[0160] Samples of HME2 solid dispersions were stored at accelerated temperature (40° C.) to test their chemical and physical stability. Drug content and impurities were quantified by HPLC. XRPD was used to detect changes in crystalline state, if any. The test results are listed in Table 2 below. They show that the active ingredient is highly chemically stable and remains amorphous in the solid dispersion.

[0161] [Table 2]

[0162] Example 4 Immediate release formulations containing solid dispersions Solid dispersion formulation HME1 was prepared by vacuum melt compression according to Example 1, and solid dispersion HME2 was prepared by hot melt extrusion and subsequent milling as described in Example 3. In addition, solid dispersions SDD1 and SDD3 were prepared as described in Example 2. Each of the four solid dispersions was then mixed with additional excipients and compressed into tablets weighing 150 mg using a laboratory-scale tablet press (Kilian Styl'One Evolution, one-punch tablet press simulator). The composition of these tablets (4.1-4.4) is shown in Table 3. It is noted that the additional excipients do not include hydrophilic matrix-forming polymers.

[0163] [Table 3]

[0164] Example 5 Matrix tablets containing solid dispersions Solid dispersion composition HME2 was prepared as described in Example 3 and incorporated into two matrix tablet formulations (5.1 and 5.2), the compositions of which are listed in Table 4.

[0165] [Table 4]

[0166] As explained in the detailed description above, hypromellose in these formulations represents the hydrophilic matrix-forming polymer, microcrystalline cellulose and calcium hydrogen phosphate dihydrate function as tablet fillers, colloidal silicon dioxide functions primarily as a flow agent, and magnesium stearate functions primarily as a lubricant.

[0167] Weighed amounts of raw materials were mixed in a tumble blender (Turbula® 2F) in subsequent steps. First, the milled extrudate, filler and hydrophilic matrix-forming polymer were mixed, then the flow agent was added and mixed, and finally the lubricant was added and mixed. The resulting powder mixture was compressed into brownish speckled white to off-white oval biconvex tablets (17 mm×7.2 mm) in a laboratory-scale single-unit pharmaceutical tablet press (Kilian Styl'One Evolution) using a main compression force ranging from 15 kN to 40 kN. The milled extrudate was observed to be easily compressible within the respective powder mixture even in the absence of a granulation step. The tablets had an average thickness of about 5.7 mm, an average crush resistance of about 110 N to 170 N, and a friability of about 0.2% to 0.7% by weight. Assay (HPLC-UV) showed that the drug content was within the acceptable limits of 90%-110% of the labeled amount. Total impurities were less than 1.0%.

[0168] The drug release profile of the prototype 5.1 and 5.2 tablets was determined using Apparatus II (Paddle Apparatus) according to Ph. Eur. 2.9.3 / USP <711> The tablets were characterized by dissolution testing according to the USP phosphate buffer (pH 6.8) containing 0.3% (w / v) sodium dodecyl sulfate. The paddle rotation speed was set at 100 rpm. Japanese weights were used to prevent floating of the tablets. Samples were periodically withdrawn and analyzed for their API concentration by HPLC, from which the amount of dissolved drug was calculated. The dissolution profile is given in Table 5.

[0169] [Table 5]

[0170] As the test results show, matrix tablets incorporating a solid dispersion of a BK B2 receptor antagonist according to formula (1) can provide sustained release of the active ingredient over an extended period of time, for example over about 12 hours or even longer. Matrix tablet 5.1 exhibits a steeper dissolution profile in vitro than tablet 5.2.

[0171] Example 6 Human PK studies The basic pharmacokinetic profiles after single dose administration of matrix tablets version 5.1 and 5.2 were evaluated and compared against the immediate release capsules, both under fasted and fed (high carbohydrate high fat (HCHF) meal) conditions in a Phase 1 clinical trial. The study was designed as a randomized, five-period crossover study involving 10 healthy volunteers. Table 6 lists the key PK parameters observed in the study.

[0172] [Table 6]

[0173] The data reveal that the matrix tablet formulations exhibit sustained release properties in vivo as shown, for example, by the tmax values. Prototype 5.2 releases the active ingredient over a longer period in vitro compared to prototype 5.1 (see Example 5), but also has a later tmax in vivo under both fasted and fed conditions. Quite significantly, the matrix tablet exhibits a significantly greater total drug exposure (AUC inf values), which allows one to conclude that the active ingredient is reliably released and absorbed even from the more distal regions of the intestine, despite its unfavourable physical properties.

[0174] Figures 1-3 show the time course profiles of the mean plasma concentrations achieved by each formulation. Figure 1 shows the plasma profile after dosing in the fasted state, while Figures 2 and 3 show a comparison of the mean plasma profile after dosing in the fed vs. fasted state for matrix tablet 5.1 (Figure 2) and matrix tablet 5.2 (Figure 3), respectively. Subsequent simulation studies confirmed that the PK profiles of both matrix tablet formulations tested were useful for continuous treatment using once-daily or twice-daily dosing regimens. The SMEDDS formulation refers to an immediate release soft gelatin capsule containing the active ingredient formulated as a self-microemulsifying drug delivery system (SMEDDS) as a control, whereby 20 mg of API was administered per dose.

[0175] Example 7 Monkey PK study Tablet formulations 4.1-4.4 containing solid dispersions were tested to evaluate their biopharmaceutical performance in vivo in male cynomolgus monkeys. For this, they were placed into size 0 hard gelatin capsules. Prior to administration, each capsule was pierced 10 times with a needle. For comparison, a liquid self-microemulsifying drug delivery system (SMEDDS) of the same active ingredient (65 mg / mL) filled into a hard gelatin capsule was administered. The actual administered dose of active ingredient ranged from 2.6 mg to 2.9 mg per administration.

[0176] The study was designed as a three-period crossover study. As a result, the dose-normalized (DN) systemic exposure, expressed as DN AUC, was shown to be no different between the formulations. In addition to such high oral bioavailability, the maximum plasma concentration Cmax and the time to maximum plasma concentration tmax also indicated the suitability of the solid dispersion for immediate release products and acute treatments. At the same time, tablet 4.2, which incorporates the solid dispersion HME2 based on HPMCAS as a carrier polymer, showed a delay in reaching the maximum plasma concentration, i.e., t maxIt is noted that the increase in PK parameters indicates a delayed release consistent with its pH-dependent aqueous solubility profile. Table 7 shows the key PK parameters obtained in the study.

[0177] [Table 7]

Claims

1. A solid dispersion for oral administration, comprising: (a) a bradykinin (BK) B2 receptor antagonist having a chemical structure according to formula (1), or a salt or solvate thereof; (b) at least one pharma- ceutically acceptable polymer; A solid dispersion in which the BK B2 receptor antagonist is amorphous and homogeneously dispersed in the polymer: 【Chemistry 1】 In the formula, R is deuterium or hydrogen.

2. 2. The solid dispersion of claim 1, wherein the BK B2 receptor antagonist is a compound according to formula (1) and R is deuterium.

3. 3. The solid dispersion according to claim 1 or 2, wherein the pharma- ceutically acceptable polymer is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), povidone (PVP), copovidone (PVP / PA), polyethylene glycol (PEG), and polyethylene oxide (PEO), preferably from HPMCAS and copovidone (PVP / PA).

4. 4. The solid dispersion of claim 1, further comprising a non-ionic surfactant selected from the group of poloxamers and polysorbates.

5. 5. The solid dispersion according to claim 1, wherein the content of the BK B2 receptor antagonist is in the range of 15% by weight to 50% by weight, based on the total weight of the solid dispersion.

6. (i) about 15% to about 45% by weight of the BK B2 receptor antagonist of formula (1) and about 55% to about 85% by weight of HPMCAS, based on the total weight of the solid dispersion; or (ii) 30% to 50% by weight of a BK B2 receptor antagonist of formula (1), 50% to 70% by weight of copovidone, and optionally up to 5% by weight of poloxamer, based on the total weight of the solid dispersion.

6. The solid dispersion of claim 5, comprising:

7. 7. The solid dispersion according to claim 1, in the form of a powder or granules.

8. A method for preparing the solid dispersion according to any one of claims 1 to 7, comprising the steps of: (i) a hot melt extrusion step of a powder or granular mixture comprising a BK B2 receptor antagonist and a pharma- ceutically acceptable polymer; or (ii) A method comprising the step of spray drying an organic solution of a BK B2 receptor antagonist and a pharma- ceutically acceptable polymer.

9. The hot melt extrusion step comprises: (i) a powder or granule mixture comprising from about 15% to about 45% by weight of a BK B2 receptor antagonist and from about 55% to about 85% by weight of HPMCAS, based on the total weight of the powder or granule mixture; or (ii) a powder or granule mixture comprising 30% to 50% by weight of a BK B2 receptor antagonist and 50% to 70% by weight of copovidone, based on the total weight of the powder or granule mixture, and optionally up to 5% by weight of a poloxamer. The method of claim 8, wherein the method is carried out using

10. 10. Use of the solid dispersion according to any one of claims 1 to 7 in the preparation of a pharmaceutical composition for the sustained release of a BK B2 receptor antagonist.

11. A pharmaceutical sustained release composition comprising the solid dispersion according to any one of claims 1 to 7.

12. 12. The sustained release composition of claim 11, wherein the composition is in the form of a matrix tablet, the matrix tablet comprising 20% ​​to 40% by weight of the solid dispersion relative to the total weight of the tablet.

13. 13. The sustained release composition of claim 12, wherein the matrix tablet further comprises a hydrophilic matrix-forming polymer and a tablet filler, and optionally a flow agent and / or a lubricant, and the hydrophilic matrix-forming polymer is HPMC, or a combination of two or more grades of HPMC.

14. 14. The solid dispersion of any one of claims 1 to 7 or the sustained release composition of any one of claims 11 to 13 for use in the treatment of a subject suffering from a disease or condition responsive to BK B2 receptor modulation.

15. 15. The solid dispersion or sustained release composition for use according to claim 14, wherein the disease or condition responsive to BK B2 receptor modulation is selected from the group comprising skin disorders; eye diseases; ear diseases; oral, pharyngeal and respiratory diseases; gastrointestinal diseases; liver, gallbladder and pancreatic diseases; urinary tract and kidney diseases; diseases of the male and female reproductive organs; diseases of the hormonal system; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic system diseases; disorders of the central nervous system; brain disorders; musculoskeletal diseases; allergic disorders; pain; infections; inflammatory disorders; injuries; immune disorders; cancer; genetic diseases; and edema.

16. 16. The solid dispersion or sustained release composition for use according to claim 14 or 15, wherein the disease or condition responsive to BK B2 receptor modulation is angioedema, such as hereditary angioedema.

17. 17. The solid dispersion or sustained release composition for use according to any one of claims 14 to 16, wherein the treatment is a chronic treatment.

18. A method of treating or preventing a disease or condition responsive to BK B2 receptor modulation in a subject, comprising administering to a subject having a disease or condition responsive to BK B2 receptor modulation: (i) an effective amount of the solid dispersion of any one of claims 1 to 7; or (ii) an effective amount of the sustained release composition according to any one of claims 11 to 13; orally administering to said subject a compound comprising the steps of:

19. 19. The method of claim 18, wherein the disease or condition responsive to BK B2 receptor modulation is selected from the group including skin disorders; eye diseases; ear diseases; oral, pharyngeal and respiratory diseases; gastrointestinal diseases; liver, gallbladder and pancreatic diseases; urinary tract and kidney diseases; diseases of the male and female reproductive organs; diseases of the hormonal system; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic system diseases; disorders of the central nervous system; brain disorders; musculoskeletal diseases; allergic disorders; pain; infections; inflammatory disorders; injuries; immune disorders; cancer; genetic diseases; and edema.

20. 20. The method of claim 18 or 19, wherein the disease or condition responsive to BK B2 receptor modulation is angioedema.

21. 21. The method of any one of claims 18 to 20, comprising repeated administration of the solid dispersion or sustained release composition according to a regular dosing regimen over an extended period of time.

22. 14. Use of the solid dispersion of any one of claims 1 to 7 or the sustained release composition of any one of claims 11 to 13 in the manufacture of a medicament for treating or preventing a disease or condition responsive to BK B2 receptor modulation.

23. 23. The use of claim 22, wherein the disease or condition responsive to BK B2 receptor modulation is selected from the group including skin disorders; eye diseases; ear diseases; oral, pharyngeal and respiratory diseases; gastrointestinal diseases; liver, gallbladder and pancreatic diseases; urinary tract and kidney diseases; diseases of the male and female reproductive organs; diseases of the hormonal system; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic system diseases; disorders of the central nervous system; brain disorders; musculoskeletal diseases; allergic disorders; pain; infections; inflammatory disorders; injuries; immune disorders; cancer; genetic diseases; and edema.

24. 24. The use according to claim 22 or 23, wherein the disease or condition responsive to BK B2 receptor modulation is angioedema.

25. 25. The use according to any one of claims 22 to 24, wherein the medicament is intended for chronic treatment.

Images