Solid composition comprising dissolved bradykinin b2 receptor antagonist

Abstract

The present invention relates to a solid dispersion for oral administration comprising a bradykinin B2 receptor antagonist having the chemical structure of formula (1), or a salt or solvate thereof, where R is deuterium or hydrogen; the present invention relates to a compound represented by formula (I), for example, # imgabs 0 #, for example, (S)-N-(1-deuterated-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. The solid dispersion comprises a BK B2 receptor antagonist in amorphous form and homogeneously dispersed in a pharmaceutically acceptable polymer. Further, methods of preparation and uses of the solid dispersions, including therapeutic uses, are provided.

Description

Technical Field

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

[0002] Bradykinin (BK) is a peptide hormone that participates in the inflammatory process by activating endothelial cells, leading to vasodilation, increased vascular permeability, production of nitric oxide and mobilization of arachidonic acid. BK also stimulates sensory nerve endings, causing burning dysesthesia. Therefore, the classic parameters of inflammation (e.g., redness, fever, swelling and pain) may all be the result of BK formation. BK is a short-lived component of the kallikrein-kinin system. Under normal physiological conditions, the concentration of circulating BK remains at a low level, and under pathological conditions, it may increase rapidly through enzymatic degradation of circulating glycoprotein precursors called kininogens. The two most effective kinin-gen metabolizing enzymes are trypsin-like serine proteases plasma kallikrein and tissue kallikrein. The precursors of these enzymes are usually present in all tissues and are 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] Many 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 are 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 0795547, EP 0796848, EP 0867432 and EP 1213289. However, as disclosed in WO 2014 / 159637, many disadvantages of these compounds, including low metabolic stability, low bioavailability, formation of glutathione adducts and bioactivation (toxicity) hinder their use as drugs.

[0004] Recently, compounds of formula (1) have been proposed as a novel, biologically active and well-tolerated BKB2 receptor antagonist (see, e.g., WO 2019 / 101906). Although these compounds exhibit attractive pharmacological properties, they also exhibit rather challenging physical or physicochemical properties, including very poor solubility in physiological media.

[0005] The compound of formula (1) is also known from A. Lesage et al., Frontiers in Pharmacology, vol. 11, 19 June 2020, doi: 10.3389 / fphar.2020.00916. This document describes the in vitro pharmacological properties of the compound, but does not disclose any specific dosage form or formulation containing the compound.

[0006] Various formulation technologies for poorly soluble drug substances have been proposed, however, it remains challenging to develop suitable formulations for many new candidate drugs with unfavorable physical and pharmacokinetic properties, and many development plans have failed to date. The commonly known formulation technology is solid dispersion. DT Friesen et al., Molecular Pharmaceutics, vol.5, no.6, December 2008, 1003-1019, doi: 10.1021 / mp8000793 describes spray-dried dispersions based on hydroxypropyl methylcellulose acetate. These products are used as fillers for oral powder (OPC) formulations or gelatin capsules and are intended to achieve supersaturated concentrations of the drug in gastrointestinal fluids. The document does not disclose incorporating the dispersion into tablets, nor does it involve extended drug release dosage forms.

[0007] There is a need for formulation designs and pharmaceutical compositions that overcome the difficulties caused by the challenging properties of compounds of formula (1) so that they can be effectively delivered orally and achieve significant systemic exposure and bioavailability in human subjects. There is also a need for formulations or pharmaceutical compositions containing compounds of formula (1) that achieve reliable oral absorption. There is also a need for formulations or pharmaceutical compositions containing compounds of formula (1) that are stable in performance and can be prepared by established pharmaceutical preparation techniques.

[0008] The compounds of formula (1) have very low water solubility. This makes it challenging to develop oral formulations that result in adequate and reliable absorption rates, adequate bioavailability, and effective plasma levels. The pharmacodynamic properties of the BK B2 receptor antagonists of formula (1) make these compounds very attractive for both acute and chronic treatments, so there is a need to overcome challenges including poor water solubility and develop formulations for these drugs that are feasible in both acute and chronic therapies.

[0009] The object of the present invention is to address one or more of the above needs. Another object is to overcome the defects, gaps and limitations of the prior art in the oral delivery of bradykinin B2 receptor antagonists, such as compounds having the chemical structure of formula (1). Other objects will be apparent from the following description, examples and patent claims. Summary of the invention

[0010] In one aspect, the present invention relates to a solid dispersion for oral administration, which comprises a bradykinin B2 receptor antagonist having a chemical structure of formula (1) or a salt or solvate thereof:

[0011]

[0012] wherein R is deuterium or hydrogen; the solid dispersion is further characterized in that it comprises a BK B2 receptor antagonist in an amorphous form and uniformly dispersed in a pharmaceutically acceptable polymer. In particular, the BK B2 receptor antagonist can be (S)-N-(1-deuterated-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.

[0013] The pharmaceutically acceptable polymer in which the active ingredient is dispersed may be, for example, hydroxypropyl methylcellulose acetate succinate (HPMCAS) or copovidone (PVP / PA).

[0014] In another aspect, the present invention relates to a pharmaceutical composition comprising the solid dispersion, including a sustained-release composition. For example, the sustained-release composition may be in the form of a matrix tablet.

[0015] In another aspect, the invention relates to a process for preparing a solid dispersion, for example a process based on melt extrusion or spray drying.

[0016] On the other hand, the present invention relates to the use of solid dispersions or sustained-release compositions, particularly therapeutic uses. Generally, solid dispersions or sustained-release compositions can be used to treat diseases or conditions that respond to bradykinin B2 receptor regulation. For example, they are beneficial for treating angioedema (AE), including hereditary angioedema (HAE), acquired angioedema (AAE), non-histaminergic idiopathic angioedema, allergic angioedema, drug-induced angioedema, or angioedema of unknown cause. HAE can be any type, including type I HAE, type II HAE, or type III HAE, preferably type I HAE or type II HAE. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1Shown are mean plasma concentration-time profiles for two different extended release matrix tablets (Formulations 5.1 and 5.2, referred to herein as XR1 and XR2) comprising a solid dispersion formulation of a compound of formula (1), specifically (S)-N-(1-deuterated-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, referred to herein as PHA-022121, compared to an immediate release capsule formulation of the same drug in healthy volunteers under fasting conditions.

[0018] Figure 2 Shown are the mean plasma concentration-time profiles of a sustained release matrix tablet (Formulation 5.1) comprising a solid dispersion formulation of a compound of formula (1) in healthy volunteers under fed and fasting conditions.

[0019] Figure 3 Shown are the mean plasma concentration-time profiles of a sustained release matrix tablet (Formulation 5.2) comprising a solid dispersion formulation of a compound of formula (1) in healthy volunteers under fed and fasting conditions. DETAILED DESCRIPTION

[0020] 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 of formula (1) or a salt or solvate thereof:

[0021]

[0022] wherein R is deuterium or hydrogen, and (b) at least one pharmaceutically acceptable polymer; wherein the BK B2 receptor antagonist is amorphous and uniformly dispersed in the polymer.

[0023] The inventors have found that the claimed solid dispersions of the BK B2 receptor antagonist of formula (1) not only effectively release such pharmacologically active ingredients quickly and completely into physiological media, which is generally useful for designing immediate release compositions containing the solid dispersions, but they are also able to significantly improve the release of the compound of formula (1) from a sustained release formulation, which is completely unexpected. In particular, the solid dispersion can achieve substantially complete release of the active ingredient and reduce changes in the release rate caused by external factors (e.g., the pH and composition of the liquid medium into which the active compound is released from the sustained release composition, such as whether the liquid medium is water, gastric fluid, intestinal fluid or a substitute thereof, such as simulated gastric fluid, fasting state simulated intestinal fluid (FaSSIF) or fed state simulated intestinal fluid (FeSSIF)). In contrast, it has been found that when applied to compounds of formula (1), conventional sustained release formulation technology results in unreliable drug release, unsatisfactory release characteristics and unpredictable absorption rates.

[0024] In this context, a solid dispersion is understood to be a solid material comprising a compound, such as a drug substance, uniformly dispersed in a preferably amorphous polymer backbone. Typically, the dispersed compound is also amorphous, i.e., non-crystalline. For example, the dispersed compound may be molecularly dispersed, or may be dispersed in the form of non-crystalline domains.

[0025] The solid dispersion provided by the inventors contains a BK B2 receptor antagonist in an amorphous form. In a generally preferred embodiment, the amorphous form of the BK B2 receptor antagonist is dominant in quantity. In other words, even if a certain amount of crystalline BK B2 receptor antagonist is present in the solid dispersion, the amount of the amorphous form is greater, or even much greater, than the amount of the crystalline form. In another generally preferred embodiment, at least about 90%, or even at least 95%, or 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 antagonists are in an amorphous form. In this case, the basis of the percentage is the total molar amount of the BK B2 receptor antagonist in the solid dispersion.

[0026] In formula (1), R can be selected from hydrogen and deuterium. In a preferred embodiment or a group of embodiments, R is deuterium, as shown in the following formula:

[0027]

[0028] This compound, which may also be referred to as (S)-N-(1-deuterated-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 alternatively as 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-(difluoroethoxy)-acetamide, is a particularly preferred example of the compound of formula (1) in the present invention. It should be understood that this preference also applies in combination with all other optional features or preferences disclosed in the following description, whether specifically mentioned or not.

[0029] Alternatively, in formula (1), R may be hydrogen, as shown in the following formula:

[0030]

[0031] This 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.

[0032] The compound of formula (1) can exist in a substantially non-ionized form, or in an ionized form, i.e., in the form of a salt. In addition, it can be alternatively in the form of a solvate. For example, the compound can be a hydrate, such as (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl isophthalic acid H-1,2,4-triazol-5-yl)quinoline-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide monohydrate. In a generally preferred embodiment, the compound of formula (1) is non-ionized (i.e., not in the form of a salt) and R is deuterium.

[0033] In another embodiment, the state of the compound of formula (1) in the solid dispersion is substantially or even completely non-ionized. In addition, the compound of formula (1) does not generally represent a solvate when present in a solid dispersion. However, for the avoidance of doubt, when the compound is combined with a polymer and any other optional ingredients to form a solid dispersion disclosed and claimed herein, the compound may be in the form of a solvate. For example, a hydrate of the compound, such as a monohydrate, optionally in crystalline form, may be used to prepare a composition. However, it is believed that once incorporated into a solid dispersion, it no longer represents a crystalline material or a hydrate.

[0034] In the present invention, the compound of formula (1) may also be referred to as a (biologically or pharmacologically) active ingredient, a drug substance, an active pharmaceutical ingredient (API), etc. In addition, in another preferred embodiment, the compound of formula (1) is the only drug substance contained in the solid dispersion. This is a generally applicable preference in the present invention.

[0035] As described above, the solid dispersion comprises at least one pharmaceutically acceptable polymer in which the BK B2 receptor antagonist is dispersed. The polymer can be selected from polymers suitable for oral administration and capable of containing the BK B2 receptor antagonist in the form of a solid dispersion. In particular, the polymer can be selected from the group consisting of hydrophilic neutral polymers and hydrophilic anionizable polymers. In this case, hydrophilicity means that the polymer exhibits at least some moderate solubility or swelling in an aqueous medium with a pH in the gastrointestinal pH range (i.e., between pH 1 and pH 8). Neutral means that the 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 a portion that is easily deprotonated when dissolved in an aqueous medium, except at acidic pH. Some anionizable pharmaceutically acceptable hydrophilic polymers are sometimes also used as gastric acid resistant or enteric polymers. In addition, the polymer is optionally a non-crosslinked polymer.

[0036] According to another preferred embodiment, the pharmaceutically acceptable polymer in which the BKB2 receptor antagonist is amorphous and uniformly dispersed is a thermoplastic polymer, i.e. a polymer that is soft or plastic at high temperatures and becomes solid again once cooled to, for example, room temperature. A thermoplastic polymer can also be understood as a polymer that undergoes a glass transition temperature when heated while maintaining chemical stability. In one embodiment, the polymer is water-soluble (optionally pH-dependent), neutral (e.g. nonionic or even non-ionizable) or anionizable and thermoplastic.

[0037] Specific pharmaceutically acceptable polymers that can 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 can be used alone to form a solid dispersion containing a BK B2 receptor antagonist; alternatively, any combination of two or more of these polymers can be used, such as a combination of HPC and HPMC, a combination of HPMC and HPMCAS, a combination of PVP and PVP / PA, or any other combination.

[0038] In a preferred embodiment, the pharmaceutically acceptable polymer is HPMCAS. HPMCAS or hydroxypropyl methylcellulose acetate succinate is an example of a hydrophilic anionizable polymer that has a pH-dependent solubility, being insoluble in water at acidic pH but soluble in water at neutral or alkaline pH. HPMCAS can be understood as hydroxypropyl methylcellulose esterified with a mixture of acetic acid and succinic acid. Typically, 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% succinyl groups (calculated on a dry basis). HPMCAS is an exemplary pharmaceutically acceptable polymer that is also a thermoplastic polymer, and is hydrophilic and anionizable. Various grades of HPMCAS are available, including HPMCAS-LF, which is characterized by an average particle size of about 5 μm and a viscosity of about 3 mPa*s.

[0039] The inventors have found that the BK B2 receptor antagonist of formula (1) is not only surprisingly compatible with HPMCAS, it forms solid dispersions at various useful drug substance and polymer weight ratios; it is also found that the corresponding solid dispersions are highly stable chemically and physically; that is, they show little chemical degradation over time and the tendency of the drug substance to form crystals is very low. It is also surprising that despite the pH-dependent solubility of the polymer, the solid dispersion of the compound of formula (1) with HPMCAS exhibits very useful drug release characteristics.

[0040] In some preferred embodiments, the solid dispersion provided herein consists essentially of a pharmaceutically acceptable polymer, particularly HPMCAS, and a BK B2 receptor antagonist of formula (1), particularly (S)-N-(1-deuterated-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 can be used. In some preferred embodiments of HPMCAS, the acetyl content is from about 8% to about 12%, and the succinyl content is from about 7% to about 15%. These polymer grades are generally insoluble in aqueous media at pHs below about 5.5 to about 6.5, and are soluble at or above these pHs. In other preferred embodiments, HPMCAS contains about 9% acetyl and about 11% succinyl, is soluble in water at pH about 6.0 and above (currently commercially available, for example, as HPMCAS grades with an average particle size of about 200-300 μm are advantageous, but smaller particle sizes can also be used.

[0041] Alternatively, the solid dispersion may contain copolyvidone (PVP / PA) as a pharmaceutically acceptable polymer. It has been found that this polymer also enables the formation of advantageous solid dispersions containing compounds of formula (1). These solid dispersions are also chemically and physically stable. Another advantage of them is that they enable high drug loading in terms of BK B2 receptor antagonists.

[0042] Copovidone, also known as cross-linked polyvinylpyrrolidone, 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. The typical molecular weight is about 45,000 to 70,000. Examples of currently available commercial copovidone products include Kollidon VA 64 and Luviskol VA. Grades with different average particle sizes are also available.

[0043] In addition to the pharmaceutically acceptable polymers described above, one or more other polymers may be present in the solid dispersion. In addition, the solid dispersion claimed herein may also contain a surfactant. In one embodiment, the surfactant is a nonionic surfactant, particularly a nonionic surfactant selected from the group of poloxamers and polysorbates. It is worth noting that these surfactants may also be considered polymers; in other words, they may also function as polymer drug carriers that form solid dispersions with drug substances. They are also used as surfactants because they enhance the wettability of the solid dispersion once in contact with an aqueous medium such as water.

[0044] Poloxamer, also known as polyethylene-propylene glycol copolymer or polyoxyethylene-polyoxypropylene copolymer, is a polyol block copolymer, each comprising a polyoxypropylene block sandwiched between two polyoxyethylene blocks. Various grades are available with different molecular weight ranges and different molecular ratios of polyoxypropylene and polyoxyethylene blocks, such as poloxamer 124, 188, 237, 338 and 407.

[0045] The inventors have found that poloxamer 188 is particularly useful. It is a solid material with an average molecular weight of about 7680 to 9510, wherein the polyoxypropylene block contains an average of about 27 repeating units and the polyoxyethylene block contains an average of about 80 repeating units. It is particularly advantageous to combine poloxamer 188 with copovidone.

[0046] Polysorbates, also known as polyoxyethylene sorbitan fatty acid esters, are another group of nonionic surfactants that can be used as excipients in the solid dispersion formulations disclosed herein. Examples of potentially suitable polysorbates include polysorbate 20, 40, 60, 65, and 80, particularly polysorbate 20, also known as polyoxyethylene 20 sorbitan monolaurate, with an average molecular weight of 1128, and polysorbate 80, with a chemical name of polyoxyethylene 20 sorbitan monooleate, with a molecular weight of 1310. A well-known brand product line is Tween.

[0047] Typically, the content of nonionic surfactant in the solid dispersion (if present) is much lower than the content of polymer (e.g., hydrophilic neutral or anionizable polymer that does not represent a surfactant). In addition, the content of nonionic surfactant in the solid dispersion is typically lower than the content of active ingredient. In a specific embodiment, the content of nonionic surfactant in the solid dispersion is from about 0.5 wt % to about 10 wt % or from about 0.5 wt % to about 5 wt % 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 the combination of polymers if there are two or more polymers is from about 1:100 to about 20:100 or from about 1:100 to about 10:100.

[0048] In some embodiments, the solid dispersion provided herein consists essentially of a pharmaceutically acceptable polymer (e.g., HPMCAS or copovidone), a BKB2 receptor antagonist of formula (1) (particularly (S)-N-(1-deuterated-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 nonionic surfactant (e.g., poloxamer or polysorbate).

[0049] In a preferred embodiment, the BK B2 receptor antagonist content of the solid dispersion is at least about 10% by weight based on the total weight of the solid dispersion. As described above, this is also a preferred embodiment in which the BK B2 receptor antagonist of formula (1) is the only drug substance in the solid dispersion. Therefore, the range of at least about 10% by weight also represents a preferred drug loading of the solid dispersion.

[0050] According to another preferred embodiment, the content of the BKB2 receptor antagonist of formula (1) in the solid dispersion is about 10% by weight relative to the total weight of the solid dispersion. It is further preferred that the content of the BKB2 receptor antagonist of formula (1) in the solid dispersion, in particular (S)-N-(1-deuterated-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 about 10% by weight to about 50% by weight, or about 15% by weight to about 50% by weight, or about 15% by weight to about 45% by weight, based on the total weight of the solid dispersion. Likewise, in a related embodiment, the drug content of the solid dispersion is within any of the above ranges, e.g., from about 15 wt % to about 50 wt %, wherein the BKB2 receptor antagonist of formula (1), particularly (S)-N-(1-deuterated-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. Surprisingly, such high drug loading can be achieved for compounds of formula (1) without significant chemical or physical instability when following the guidance provided herein.

[0051] In another preferred embodiment, the solid dispersion comprises about 15 wt % to about 45 wt %, such as about 15 wt % to 25 wt %, of the BK B2 receptor antagonist of formula (1) and about 55 wt % to 85 wt %, such as about 75 wt % to 85 wt % of the polymer HPMCAS, based on the total weight of the solid dispersion. A related embodiment provides a solid dispersion consisting essentially of about 15 wt % to 25 wt % of the BK B2 receptor antagonist of formula (1) and about 75 wt % to 85 wt % of HPMCAS. For example, the solid dispersion can consist essentially of about 20 weight % of a BKB2 receptor antagonist of formula (1), particularly (S)-N-(1-deuterated-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 weight % of HPMCAS. In other embodiments, the solid dispersion consists essentially of about 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 about 75 wt % HPMCAS; or about 30 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. -1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide and about 70 wt % of HPMCAS, or about 35 wt % 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 wt % of HPMCAS.

[0052] The inventors have discovered that the above ranges and corresponding weight ratios of drug substance to polymer HPMCAS produce solid dispersions exhibiting sufficiently high drug loading to allow for effective and convenient dosing, high product stability and shelf life, and desirable release characteristics.

[0053] According to an alternative preferred embodiment, the solid dispersion comprises about 30% to 50% by weight of the BKB2 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. Similarly, in a related embodiment in which no other ingredients are present in the solid dispersion, a solid dispersion is provided that consists essentially of about 30% to 50% by weight of the BKB2 receptor antagonist of formula (1), about 50% to 70% by weight of copovidone, and optionally up to about 5% by weight of a poloxamer (e.g., poloxamer 188). For example, the solid dispersion may consist essentially of about 40% by weight of the BKB2 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 in that they allow for exceptionally high drug loadings while being chemically and physically stable and providing useful drug release characteristics.

[0054] The solid dispersion can be provided in a physical form suitable for oral administration, or in a physical form suitable for incorporation into a pharmaceutical dosage form adapted for oral administration (such as a capsule or tablet). If the solid dispersion is designed to be administered in this way, it can be provided as a solid single unit, such as a melt-extruded form that is convenient for handling and swallowing. If a constant release characteristic is required, such as in the acute treatment of spontaneous symptoms, this product design may be particularly useful. Since the BK B2 receptor antagonist, which is poorly soluble in physiological media, is provided in a dissolved form, it is released much faster than from a traditional solid dosage form that usually contains an active ingredient in a crystalline form.

[0055] In addition, the inventors surprisingly found that the solid dispersions disclosed herein are not only useful for immediate release formulations, but also for sustained release products that release BK B2 receptor antagonists over a long period of time, as will be discussed in more detail below. For such products, it is particularly advantageous to provide the solid dispersion in powder or granular form to facilitate its incorporation into sustained release dosage units, such as capsules or tablets.

[0056] Therefore, in a preferred embodiment, the inventors provide a solid dispersion in the form of a powder or granules. Both powders and granules provide solid dispersions in the form of multi-granules, i.e., multi-particles. In this case, the expressions "powder" and "granules" are simply understood to refer to approximate particle sizes, wherein powders refer to relatively fine multi-particle materials and granules refer to coarser materials, regardless of the manufacturing method by which these materials are obtained. In other words, the expression "granules" should not be narrowly interpreted as requiring the use of a specific granulation method to produce the corresponding particles.

[0057] In another aspect, the present invention provides a method for preparing the above-mentioned solid dispersion. In some embodiments related to this aspect, the method for preparing the solid dispersion includes the step of hot melt extruding a powder or granular mixture containing a BK B2 receptor antagonist and a pharmaceutically acceptable polymer. In some other embodiments, the method includes the step of spray drying an organic solution of a BK B2 receptor antagonist and a pharmaceutically acceptable polymer, or the step of spraying an organic solution of an active ingredient and a pharmaceutically acceptable polymer onto particles of a pharmaceutically inactive material under conditions that cause evaporation of the organic solvent. Similarly, in this case, the BK B2 receptor antagonist is a compound of formula (1), particularly a preferred form as described above; and the polymer is at least one pharmaceutically acceptable polymer in which the BK B2 receptor antagonist is uniformly dispersed.

[0058] Hot melt extrusion is a well-known technology in the pharmaceutical field. As is well known, this technology can be used to produce melt extrudates in principle. This includes equipment that may be used for hot melt extrusion, as well as some common process parameters, such as temperature and screw speed (when using a screw extruder). According to the technical guidance provided herein on the composition of solid dispersions, and considering the working examples described below, those skilled in the art will be able to prepare melt-extruded solid dispersions of active ingredients comprising formula (1) without difficulty.

[0059] Hot melt extrusion converts a powder or granular mixture of a BK B2 receptor antagonist of formula (1) and at least one pharmaceutically acceptable polymer into an extrudate, which represents a solid dispersion of the active ingredient uniformly and amorphously dispersed in the polymer. Hot melt extrusion involves heating, softening or melting, mixing or homogenizing, and extruding the mixture. It can also be described as a process whereby the blended composition is heated and / or pressed to a molten (or softened) state, then forced through an orifice, where the extruded product (extrudate) forms its final shape, wherein the extruded product solidifies upon cooling. The blended composition can be conveyed through one or more heating zones, which is usually achieved by a screw mechanism. The screw or a set of screws can be rotated by a variable speed motor in a cylindrical barrel, wherein 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 forces are generated at the barrel wall and between the screw threads, and the components of the powder or granular blend are fully mixed and depolymerized by the shear forces when conveyed through the extruder. Extrudate refers to a composition formed by hot melt extrusion.

[0060] In one embodiment, the hot melt extrusion step comprises the following sub-steps: (i) adding the optionally crystalline BKB2 receptor antagonist of formula (1) (or, for example, a hydrate thereof) and a pharmaceutically acceptable polymer to a hot melt extrusion device; (ii) melting the BKB2 receptor antagonist and the polymer at a temperature close to or above the melting point of the BKB2 receptor antagonist and well below its decomposition temperature; (iii) mixing the BKB2 receptor antagonist and the polymer to form a uniform blend; (iv) extruding the uniform blend to form a solid dispersion formed into an extrudate. Steps (ii) and (iii) may be performed simultaneously, or step (iii) may be started as soon as the optionally crystalline BKB2 receptor antagonist of formula (1) and the polymer begin to melt. Similarly, the BKB2 receptor antagonist starting material in step (i) may be crystalline and then converted to an amorphous form during the hot melt extrusion process.

[0061] In a preferred embodiment, the hot melt extrusion step is carried out using a powder or granule mixture comprising about 15 wt % to 45 wt %, such as about 15 wt % to 25 wt %, of the BKB2 receptor antagonist and about 55 wt % to 85 wt %, such as about 75 wt % to 85 wt % of HPMCAS, based on the total weight of the powder or granule. 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 BKB2 receptor antagonist, particularly (S)-N-(1-deuterated-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 hot melt extruded to obtain a melt extrudate representing a solid dispersion. In further embodiments, the powder subjected to hot melt extrusion consists essentially of about 25 wt % (S)—N-(1-deuterated-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 wt % HPMCAS; or consists of about 30 wt % (S)—N-(1-deuterated-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. 70 wt % of HPMCAS, or about 35 wt % of (S)—N-(1-deuterated-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 wt % of HPMCAS.

[0062] In another preferred embodiment, the hot melt extrusion step is carried out with a powder or granule mixture comprising about 30% to 50% by weight of a BK B2 receptor antagonist, about 50% to 70% by weight of copovidone, and optionally up to 5% by weight of a poloxamer (particularly poloxamer 188), based on the total weight of the powder or granule. In a related embodiment, the powder or granule mixture consists of about 30% to 50% by weight (e.g., about 40% by weight) of a BK B2 receptor antagonist, about 50% to 70% by weight (e.g., about 58.5% by weight) of copovidone, and optionally up to 5% by weight (e.g., about 1-2% by weight) of a poloxamer (particularly, especially poloxamer 188). For the avoidance of doubt, in these and previous embodiments, the weight percentages are based on the weight of the powder or granule mixture subjected to the hot melt extrusion step.

[0063] In some preferred embodiments, the extrusion temperature is selected to be higher than the glass transition temperature (T g ), or if more than one carrier polymer is used, above T g The highest carrier polymer T g In a related preferred embodiment, the extrusion temperature is also selected to be above the melting temperature of the active ingredient. For example, extrusion at a temperature at least about 20°C above the melting point of the API will promote dissolution of the drug substance in the carrier polymer. In other preferred embodiments, extrusion is performed at a temperature above the T of the polymer. g The extrusion temperature is preferably at least about 20° C. In practice, the extruder may have several temperature zones set at different temperatures; in this case, the extrusion temperature is understood to be the temperature of the extruder zone having the highest temperature.

[0064] As previously mentioned, the solid dispersions disclosed herein can also be prepared using a method comprising the step of spray drying an organic solution of a BKB2 receptor antagonist and a polymer (i.e., at least one pharmaceutically acceptable polymer in which the BKB2 receptor antagonist of formula (1) is amorphous and uniformly dispersed). Prior to the actual spray drying step, an organic solution of the BKB2 receptor antagonist of formula (1) and the polymer (and any other components of the solid dispersion that may be optionally incorporated) in an organic solvent that is pharmaceutically suitable for the spray drying process and capable of completely dissolving the active ingredient and the polymer must be prepared, which can be achieved by any conventional method of adding a granular or powdered solid to an organic solvent under conditions that result in the dissolution of the solid (e.g., stirring or elevated temperature).

[0065] Organic solvents which may be used in this context include, for example, methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, ethyl acetate and any mixtures thereof. Optionally, the solvent or solvent mixture may contain limited amounts of water.

[0066] The spray drying step itself can be described as atomization under conditions that allow the organic solvent to evaporate. For example, atomization can be performed through a nozzle or on a rotating disk. A further drying step, such as fluidized bed drying, vacuum drying, tray drying, microwave drying, drum drying or double cone vacuum drying, can then be used to reduce the residual solvent to a pharmaceutically acceptable level. Generally, spray drying refers to contacting a highly dispersed liquid suspension or solution with a sufficient volume of air and causing the droplets to evaporate and dry. Optionally, an organic solution of the BKB2 receptor antagonist of formula (1) and a polymer is injected into a warm filtered air or inert gas stream to evaporate the solvent. The dried product particles can be transported to a collector, such as a cyclonic particle collector.

[0067] Typically, the spray drying step is carried out at a temperature (i.e., inlet temperature) of 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 spray drying is generally lower, for example, about 40°C to 100°C, or 40°C to 75°C. For example, fluidized bed drying (e.g., from about room temperature to about 100°C), vacuum drying (e.g., from about room temperature to about 200°C), for example, from about room temperature to about 65°C, for example, about 45°C.

[0068] In addition to 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. These methods include, for example, low temperature processing techniques, freeze drying, fluidized bed coating, microwave irradiation, coprecipitation, electrospinning, supercritical antisolvent precipitation, spray congealing, spraying of carrier particles, melt agglomeration, etc.

[0069] As previously mentioned, the solid dispersion disclosed herein can be provided in the form of powder or granules. Both powder and granules provide solid dispersions in the form of multi-granules, i.e., multi-granules. Such powders or granules can be obtained directly from the technology applied to prepare solid dispersions. For example, if a solid dispersion is prepared using spray drying or a method involving a spray drying step, the direct product obtained by this method is already in the form of powder or granules. Optionally, subsequent steps such as screening, grinding or agglomeration to adjust the particle size (distribution) of the product can be performed. If a method including a hot melt extrusion step is used, the product obtained directly from the extrusion step is generally not a powder or granule, but in the form of a larger unit or an elongated cylindrical rod, which can then be cut or granulated to form a smaller unit. The tool for cutting or granulating the extrudate can be added as a downstream module of the extrusion device. Considering the desired particle size, if further reduction is required, an independent subsequent grinding step can be used, optionally followed by a classification step such as screening.

[0070] In another preferred embodiment, the solid dispersion is in the form of a powder or particles and is prepared by a method comprising a hot melt extrusion step and a grinding step as described above, wherein the extrudate is converted into a powder or particles, and an intermediate step of extrudate cutting or granulation is optionally performed before grinding. Grinding can be performed using any pharmaceutically suitable equipment, such as a hammer mill, a centrifugal impact grinder, a jet mill, a ball mill, a conical grinder, an oscillating and rotating screen grinder, which are just a few examples. Optionally, grinding is performed under controlled temperature and / or cooling and feeding. Depending on the type of grinding method and the equipment used, the grinding process itself may include screening or grading of the ground particles. Alternatively, a separate screening or grading step may be performed after grinding. Grinding of the extrudate may be performed, optionally including a subsequent screening step, so as to achieve an average particle size of, for example, about 50 μm to 800 μm, or further preferably about 100 μm to 700 μm. In this case, the average particle size generally refers to the D50 value of the powder or particles measured by laser diffraction. Alternatively, if the particle size distribution is characterized by sieve analysis, a more relevant parameter is the mass median sieve size, which according to some preferred embodiments is about 50 to 800 μm, or about 100 to 700 μm, or about 150 to 500 μm.

[0071] Another aspect of the invention relates to the use of the above-mentioned solid dispersion, especially if provided in the form of a powder or granules. 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 an optional pharmaceutical excipient. In some preferred embodiments, the solid dispersion is used in an oral dosage form, in particular in a solid single unit oral dosage form, such as a tablet, a capsule (e.g., a two-piece hard gelatin capsule), an oral film, an oral granule (e.g., a single unit sachet or a stick pack), etc.

[0072] In the present invention, pharmaceutical composition is understood to be a composition that is technically suitable for use as a drug to a subject (e.g., a human patient). It is composed, formulated, and processed in accordance with general pharmaceutical standards, such as the standards that may be defined in the official pharmacopoeia or guidelines issued by regulatory agencies such as FDA, PMDA, and EMA. In a preferred embodiment, the composition is suitable for oral administration, which means that the excipients (including their grade and dosage) used, for example, are safe and acceptable for oral use, particularly for oral administration of human subjects.

[0073] The inventors have discovered that one of the unique properties of solid dispersions is that they can be advantageously used in oral immediate release compositions as well as oral sustained release compositions. Incorporated into immediate release compositions, solid dispersions enable rapid dissolution of the BK B2 receptor antagonist of formula (1), which is a poorly soluble compound that (when provided in crystalline form) dissolves very slowly and incompletely in commonly used dissolution test models, and has poor, unstable or variable systemic absorption from the gastrointestinal tract following oral administration of a conventional immediate release composition containing a crystalline form (e.g., crystalline monohydrate form) of the BK B2 receptor antagonist. Thus, when used in an immediate release composition, solid dispersions are used to increase the oral bioavailability of the active ingredient, reduce the variability of bioavailability or plasma level characteristics, and achieve faster absorption, thereby accelerating the onset of action, compared to conventional formulations containing a crystalline form of the drug.

[0074] In this context, an immediate release composition or formulation is an oral pharmaceutical composition designed to dissolve in a recognized in vitro dissolution model (including United States Pharmacopeia (USP) chapter 1). <711> ("Dissolution") releases a majority of its active ingredient within 30 minutes in a model disclosed in . More specifically, an extended-release composition can be described as a composition that meets the standards set by major regulatory agencies, particularly dissolution acceptance standards, such as those provided in applicable FDA guidance that are generally familiar to those skilled in the art.

[0075] For example, an immediate release oral dosage form using a solid dispersion can be designed as an immediate release tablet. Those skilled in the art are generally familiar with tablet formulations that rapidly disintegrate when in contact with water. Incorporating a BK B2 receptor antagonist as an active ingredient in the form of a solid dispersion not only ensures that the tablet rapidly disintegrates, but also ensures that it can quickly, completely and reliably release the active ingredient in dissolved form. Similarly, the solid dispersion can optionally be contained in a capsule, such as a hard gelatin capsule or other two-piece capsule, together with other excipients that may be necessary or useful.

[0076] In addition, the solid dispersion can be used in a granule formulation, which can be used, for example, as a so-called sprinkle, since these granules are usually administered by sprinkling on semi-solid food (such as applesauce). In particular, this is a dosage form design suitable for pediatric use. Optionally, the solid dispersion can be provided as a coated granule, wherein the coating is usually a non-functional coating and is primarily designed to improve product properties unrelated to drug release, such as the appearance or swallowability of the granule.

[0077] In general, sustained-release formulations comprising solid dispersions are very useful for acute treatment, or as an on-demand medication for acute or chronic conditions, for example, in the event of the onset of symptoms or an increase in the severity of symptoms. In "acute treatment" or "on-demand treatment", the progression of symptoms must be arrested as soon as they appear, in order to relieve, alleviate or reduce the severity and / or duration of at least one symptom and / or to prevent other symptoms.

[0078] Another preferred embodiment relates to the use of the above-mentioned solid dispersion in the preparation of a pharmaceutical composition for sustained release of a BK B2 receptor antagonist. The inventors have found that, although the solid dispersion itself has drug solubilizing properties, which would not be expected to provide slow drug release over a long period of time, incorporating the solid dispersion into such a sustained release composition is unexpectedly advantageous. However, it was found that the solid dispersion is very compatible with sustained release formulation technologies such as matrix tablets and allows for sustained release characteristics to be produced over a long period of time, such as about 8 to 24 hours. In addition, when used in a sustained release formulation, the solid dispersion helps to achieve reliable release characteristics. In addition, it was found that the use of a solid dispersion sustained release formulation is associated with a low or moderate effect of food on overall exposure (e.g., as shown by AUC), which is contrary to what is generally expected considering the solubility and intrinsic release behavior of the sustained release composition of the BK B2 receptor antagonist of formula (1).

[0079] As used herein, a sustained release composition is any pharmaceutical composition or formulation suitable 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 sustained release, which are just a few alternative expressions, but are not limited to these.

[0080] Therefore, in another aspect, the present invention relates to a pharmaceutical sustained-release composition comprising the solid dispersion disclosed above. Similarly, the preferred items and optional features described for the solid dispersion also apply to this aspect. For example, in a preferred embodiment, the solid dispersion contained in the pharmaceutical sustained-release composition comprises a BK B2 receptor antagonist of formula (1), wherein R is deuterium. As another example of a preferred embodiment of a pharmaceutical sustained-release composition, the composition comprises a solid dispersion according to any of the above preferred embodiments, for example, a solid dispersion comprising about 15 wt % to about 45 wt %, for example, about 15 wt % to about 25 wt %, of a BK B2 receptor antagonist of formula (1) (particularly (S)-N-(1-deuterated-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 wt % to about 85 wt %, for example, about 75 wt % to about 85 wt % of HPMCAS, or a solid dispersion comprising about 30 wt % to about 50 wt % of a BK B2 receptor antagonist, about 50 wt % to 70 wt % of copovidone, and optionally up to about 5 wt % of a poloxamer.

[0081] Regarding the type of dosage form used for sustained-release compositions, the inventors have found that tablets and capsules are particularly advantageous. In a preferred embodiment, the sustained-release composition is in the form of a matrix tablet. When used for oral sustained-release products, a matrix tablet is a pharmaceutical tablet in which the active ingredient (in its original form or in the form of formulated particles or granules) is incorporated into an excipient matrix suitable for providing sustained release. For example, this matrix tablet is different from a tablet that mainly achieves sustained-release function through a sustained-release coating. Sustained-release matrix tablets may also include a coating, but generally this coating has little effect on drug release characteristics. For example, so-called non-functional coatings may be applied to matrix tablets, which are primarily used to improve the appearance of the tablet, facilitate its handling and swallowing, mask the taste, or reduce friability.

[0082] The formulation techniques for sustained release matrix tablets are generally well known to those skilled in the art. "Erosionable matrix tablets" can be distinguished from "insoluble" matrix tablets based on the primary mechanism of drug release, the latter releasing their active ingredient primarily by diffusion out of a swollen but intact matrix. In practice, it is believed that a combination of release mechanisms is often present simultaneously, with some drug being released by diffusion and other portions of the drug being released by tablet erosion. As used herein, erosion includes any gradual loss of matrix material, regardless of the mechanism by which the loss occurs.

[0083] In a preferred embodiment, the matrix tablet comprises about 10 wt % to about 60 wt % of the solid dispersion, based on the total weight of the matrix tablet. In a further preferred embodiment, the content of the solid dispersion in the matrix tablet is about 15 wt % to about 50 wt %, in particular about 20 wt % to about 40 wt %, for example about 20 wt %, about 25 wt %, about 30 wt %, about 35 wt % or about 40 wt %.

[0084] The matrix tablet may comprise a solid dispersion in the form of a powder or granules, for example, a ground extrudate as described above. The inventors have surprisingly found that a relatively high content of the solid dispersion as described herein can be incorporated into a tablet prepared by direct compression, i.e., there is no need to incorporate a poorly compressible material into the intermediate granulation step usually required in the tablet. This is particularly unexpected for a solid dispersion prepared by hot melt extrusion followed by granulation and grinding, which usually results in poorly compressed particles. Therefore, in some further preferred embodiments, the matrix tablet comprises a solid dispersion in the form of a ground extrudate of about 15 % by weight to about 50 % by weight or about 20 % by weight to about 40 % by weight.

[0085] In addition to the solid dispersion, the matrix tablet preferably comprises other excipients, such as may be necessary or useful for tablet compression, but is also used to form a matrix in which solid dispersion powder or particles are embedded. Powder or particles are incorporated into compressed tablets and may change some characteristics of solid dispersions as described above. For example, once powder or particles are incorporated into compressed tablets, the flowability of powder or particles may no longer exist. In addition, even if the particles representing the solid dispersion can be extracted from the matrix tablet (certain technical difficulty is arranged), the particle size related parameters may no longer be the same as before the solid dispersion is incorporated into the tablet. In this regard, the embodiment related to the matrix tablet comprising the optional or preferred features of the solid dispersion with solid dispersion should be understood as also covering the powder or particle mixtures of the solid dispersions incorporated by compression and the matrix tablets obtainable from these mixtures.

[0086] As mentioned above, the matrix tablet comprises a solid dispersion and preferably also one or more further excipients, for example in order to impart compressibility and / or to enable formation of a matrix with sustained release properties.

[0087] In some preferred embodiments, the matrix tablet includes a tablet filler. A tablet filler can be understood as a pharmaceutical excipient that considers the usual processability of a tablet compression-enhancing powder or granular mixture. The functions of a tablet filler may include the functions of a diluent or filler, a compression aid, and a dry binder (usually referred to as a binder). A tablet filler is also referred to as a tablet filler-binder. This excipient can be a compound or a combination of compounds. Possible suitable tablet fillers for 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 a preferred embodiment, a tablet filler includes microcrystalline cellulose. In a related embodiment, a tablet filler is composed of a combination of microcrystalline cellulose or microcrystalline cellulose and calcium hydrogen phosphate, such as a combination of microcrystalline cellulose and calcium hydrogen phosphate in a weight ratio of about 1:1.

[0088] In another preferred embodiment, the tablet further comprises at least one excipient which can be used to form a skeleton capable of embedding the solid dispersion powder or particles and achieving sustained release of the active agent. Such excipients may be referred to as skeleton-forming excipients. In another embodiment, such excipients are skeleton-forming polymers, particularly hydrophilic skeleton-forming polymers. When pressed into tablets and in contact with water or an aqueous medium, such hydrophilic skeleton-forming polymers can swell or gel, and then slowly erode over time, i.e., over 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, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carrageenan, cellulose, copovidone, gelatin, guar gum, hydroxyethylcellulose, hydroxypropyl starch, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose), hydroxypropyl methylcellulose acetate succinate, methylcellulose, pectin, polyethylene oxide, polymethacrylate, potassium alginate (or calcium or sodium), povidone, tragacanth gum, or xanthan gum. In a 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 including hydroxypropyl methylcellulose.

[0089] According to a further preferred embodiment, the matrix tablet comprises a glidant and / or a lubricant. Also preferred are related embodiments wherein the matrix tablet comprises a hydrophilic matrix forming polymer, a tablet filler, a glidant and a lubricant.

[0090] A glidant is an excipient that improves the flow properties of a powder or granules by reducing interparticle friction and cohesion. Possibly suitable glidants include, but are not limited to, silicon dioxide, in particular colloidal silicon dioxide, anhydrous colloidal silicon dioxide, peptized silicon dioxide, talc, magnesium trisilicate or powdered cellulose. In one embodiment, the glidant is colloidal silicon dioxide.

[0091] In the case of pharmaceutical tablet compression, a lubricant can be understood as an excipient that reduces the friction between the powder, granule or tablet surface on the one hand and the tablet press die wall and the tablet punch on the other hand. Therefore, the lubricant reduces the wear of the tablet press die and the punch. Possibly suitable lubricants include, but are not limited to, magnesium stearate, polyoxyethylene glycol, aluminum stearate, calcium stearate, calcium behenate, castor oil, talc, sodium benzoate, monoglycerides, glyceryl monostearate, glyceryl behenate, palmitic acid-stearate glyceride, hydrogenated cottonseed oil, sodium lauryl sulfate, sodium stearyl fumarate, fumaric acid, and stearic acid.

[0092] In another embodiment, if provided in the form of a powder or granules, the solid dispersion can be used to prepare sustained-release granules or particles. For example, the particles of the solid dispersion (powder or granules) can be coated with an excipient or excipient mixture that can provide sustained release of the BKB2 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 relates to sustained-release granules or particles comprising a solid dispersion embedded in or coated with an excipient or excipient mixture that provides sustained release. Those skilled in the art are generally familiar with possible suitable excipients and coating or agglomeration techniques.

[0093] In addition, such sustained-release fine particles or granules incorporating a solid dispersion of a BKB2 receptor antagonist of formula (1) can be advantageously used to prepare tablets, such as rapidly disintegrating tablets that release sustained-release fine particles or granules upon disintegration; or for filling 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. Therefore, in some embodiments, the pharmaceutical sustained-release composition comprising a solid dispersion is a tablet or hard capsule comprising sustained-release fine particles or granules.

[0094] In a preferred embodiment, the BKB2 receptor antagonist of formula (1) is the only active ingredient in the pharmaceutical composition. This should also be understood as a general preference for the pharmaceutical composition in the present invention. Alternatively, the pharmaceutical composition may contain one or more other active ingredients. Other or supplementary active ingredients or active pharmaceutical ingredients are preferably active agents or active pharmaceutical ingredients that are useful in preventing or treating one or more diseases that respond to BKB2 receptor modulation, including diseases selected from the following groups: skin diseases; eye diseases; ear diseases; oral, throat and respiratory diseases; gastrointestinal diseases; liver, gallbladder and pancreatic diseases; urinary tract and kidney diseases; male reproductive organ diseases and female reproductive organ diseases; hormonal system diseases; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic diseases; central nervous system diseases; brain diseases; musculoskeletal system diseases; allergic diseases; pain; infectious diseases; inflammatory diseases; injuries; immunological diseases; cancer; hereditary diseases; and edema. For example, at least one compound or pharmaceutically acceptable salt of the present invention may advantageously be included in a combined preparation comprising antibiotics, antifungal or antiviral agents, antihistamines, nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, cytostatic drugs, drugs with smooth muscle activity modulating activity, antibodies or mixtures thereof as additional or supplementary active agents or active pharmaceutical ingredients.

[0095] The sustained-release composition can also be described according to the dosage strength or amount of the BKB2 receptor antagonist of formula (1) incorporated per dosage unit, i.e., per capsule or tablet. In some embodiments, the dosage strength is from about 1 mg to about 100 mg or from about 5 mg to about 100 mg. In further preferred embodiments, the dosage strength is from 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. In some further preferred embodiments, the dosage strength is from about 20 mg to 50 mg, for example, from about 20 mg to 40 mg. For pediatric use, lower doses, for example from about 0.5 mg to about 5 mg, can also be used.

[0096] As previously mentioned, the inventors have found that incorporating a solid dispersion of a BK B2 receptor antagonist of formula (1) into a sustained release composition as disclosed herein allows for tailoring clinically advantageous sustained release properties, such as good robustness and reliability, and reduced food effects, particularly in terms of drug absorption, compared to conventional formulation techniques. This advantage is particularly evident for sustained release compositions comprising a solid dispersion of a pharmaceutically acceptable polymer using hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a solid dispersion carrier, i.e., as a solid dispersion in which the active ingredient is amorphous and uniformly dispersed. Without wishing to be bound by theory, these release properties may be related to the fact that HPMCAS is a polymer that is insoluble in acidic media (such as gastric fluid), thereby causing slow drug release (if any) in such acidic environments in which the drug substance exhibits at least some appreciable solubility; whereas the compound of formula (1) itself is particularly poorly soluble in relatively neutral media (such as intestinal fluid), thereby causing relatively slow drug release in such environments, making it possible to partially compensate for various pH-dependent effects on drug release rate. In other words, the design of the sustained-release composition comprising a solid dispersion based on HPMCAS can achieve controlled release of the drug even under pH changes. In some preferred embodiments, the sustained-release composition disclosed herein is a single-layer tablet with an optional coating. Single-layer tablets consist of a single compressed tablet layer, unlike double-layer or multi-layer tablets. The manufacture of single-layer tablets is generally more cost-effective than two-layer or multi-layer tablets. Single-layer tablets can also be smaller than tablets with one or more additional layers that are sometimes used to customize drug release characteristics, and therefore easier to swallow.

[0097] Sustained release properties, also used to describe the behavior of a composition or formulation in a relevant biological environment, i.e., in a clinical setting after administration of the composition or formulation to a subject, are usually measured in a well-defined in vitro model. As used herein, sustained release properties refer to the dissolution characteristics of a sustained release composition. For example, in the United States Pharmacopeia (USP) chapter <711> ("Dissolution"), descriptions of some widely accepted dissolution models for determining dissolution properties can be found. In order to characterize the dissolution properties of the sustained-release compositions disclosed herein, for example, Apparatus II (paddle apparatus) described in the USP can be used. According to a preferred embodiment, the speed of the paddle can be set to 100 rpm. For example, the medium used for the dissolution test can consist of 1000 mL of USP phosphate buffer at pH 6.8 and 0.3% (w / v) of sodium dodecyl sulfate.

[0098] 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 at least about 8 hours, such as from about 8 to 24 hours. In another preferred embodiment, the sustained release composition releases the BK B2 receptor antagonist over 12 to 24 hours, such as by using USP <711> The dissolution test of the composition is determined by using apparatus II of Chapter 1000 mL of USP phosphate buffer at pH 6.8 and 0.3% (w / v) sodium lauryl sulfate as the dissolution medium at 37°C and 100 rpm and using a tablet sinker (such as a Japanese sinker) to hold the tablet in the bottom area of ​​the dissolution vessel. In this case, the 12 to 24 hour period of release of the active ingredient refers to the time point at which 95% of the active ingredient incorporated into the composition has been released falls within the specified time period. For example, a sustained release composition is characterized by a dissolution characteristic 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.

[0099] The sustained release profile or dissolution profile can also be described in terms of the duration until about 50% of the incorporated drug is released (i.e., dissolved). In some preferred embodiments, the sustained release composition reaches 50% dissolution within about 3 to 10 hours or about 4 to 8 hours, for example, after about 4, 5, 6, 7 or 8 hours.

[0100] In some preferred embodiments, as described above, the sustained-release composition has a dosage strength of about 10 mg to 80 mg and releases the BK B2 receptor antagonist of formula (1) over about 12 to 24 hours. It is also preferred that the sustained-release composition is in the form of a matrix tablet comprising a solid dispersion based on or incorporating HPMCAS, wherein the dosage strength of the tablet is about 20 mg to 40 mg and releases over about 12 to 24 hours.

[0101] 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 to treat a subject suffering from any disease or condition responsive to bradykinin B2 receptor modulation. Such diseases include diseases selected from the following groups: skin diseases; eye diseases; ear diseases; oral, throat and respiratory diseases; gastrointestinal diseases; liver, gallbladder and pancreatic diseases; urinary tract and kidney diseases; male reproductive organs and female reproductive organs diseases; hormonal system diseases; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic diseases; central nervous system diseases; brain diseases; musculoskeletal system diseases; allergic diseases; pain; infectious diseases; inflammatory diseases; injuries; immunological diseases; cancer; genetic diseases; and edema. In other words, one aspect of the present invention relates to a method for treating a subject suffering from any disease or condition responsive to bradykinin B2 receptor modulation, wherein the method comprises administering a solid dispersion or sustained-release composition as described above. Similarly, the present invention provides the use of a solid dispersion or sustained-release composition in the preparation of a medicament for treating any disease or condition responsive to bradykinin B2 receptor modulation.

[0102] As used herein, the expression "treatment" should be interpreted to include any type of prophylactic or therapeutic treatment. Thus, it 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.

[0103] In the present invention, chronic treatment refers to the continuous treatment of a disease or condition, including repeated administration according to a conventional dosing regimen for a long time, for example, within at least one month or at least three months. In certain embodiments in which the patient or subject's condition is not improved, the compound of formula (1) is administered for a long time, i.e., for a long time (including during the entire life span of the patient or subject), to improve or control or limit the symptoms associated with the disease or condition in the patient or subject. In a further preferred embodiment, the treatment can be a preventive treatment, i.e., treatment before the onset of symptoms to prevent, delay or alleviate the severity of the symptoms. Preventive treatment can include acute and chronic treatment. For example, acute preventive treatment can include oral administration of at least one therapeutically effective dose of the compound of formula (1) to a human patient or subject in need, thereby preventing or alleviating symptoms. For example, chronic treatment can include administering one, two or three dosage units per day during this period.

[0104] As described above, according to a preferred embodiment, a sustained-release composition is provided, which comprises a solid dispersion of a BKB2 receptor antagonist of formula (1) in a polymer carrier; the inventors have found that it provides favorable sustained-release properties. It is believed that these properties also make such sustained-release compositions particularly suitable for chronic or long-term treatment. One of the specific benefits provided by these compositions is that they provide sustained effective and tolerable plasma levels through a regimen of only once or twice a day. Therefore, in some preferred embodiments, the solid dispersion or sustained-release composition disclosed herein is used for chronic treatment of subjects with diseases or conditions responsive to BKB2 receptor modulation, preferably within at least one month. In a further embodiment, chronic treatment is characterized by administration once or twice a day, preferably over a period of at least three months or at least one year. In one embodiment, chronic treatment is lifelong treatment.

[0105] For the avoidance of doubt, the corresponding duration of treatment does not require that the same dosing regimen be used throughout the treatment. For example, if once-daily dosing is insufficient to treat a particular subject, the regimen may be switched to twice-daily dosing. Alternatively, in chronic treatment, the dose per administration may be increased.

[0106] In addition, in the present invention, "acute" includes any non-chronic dosing regimen, such as a single administration of a composition comprising a solid dispersion disclosed herein or a regular release composition comprising a solid dispersion, and occasional or regular dosing regimens over a relatively short period of time (e.g., up to four weeks or up to two weeks). In some embodiments, the solid dispersion provided by the present invention is used for the acute treatment of a disease or condition that responds to bradykinin B2 receptor modulation.

[0107] The following diseases or conditions can be considered to be responsive or at least potentially responsive to bradykinin B2 receptor modulation:

[0108] Skin diseases, including but not limited to skin aging, skin weathering (including pressure sores), bedsores, irritated, sensitive and unsightly skin, erythema, rash, skin edema, psoriasis, eczema, lichen, skin infections caused by bacteria, viruses, fungi and parasites (including boils, abscesses, cellulitis, erysipelas, folliculitis and impetigo), lice, scabies and herpes simplex, acne, rash, dermatitis (including atopic dermatitis, allergic contact dermatitis, neurodermatitis), radiation damage, sunburn, pruritus, scabies, urticaria, psoriasis, fungal diseases, tissue ulcers, epidermolysis bullosa, wounds (including abnormal wound healing, burns, frostbite, skin inflammation and edema caused by venom), hair loss, dandruff, corns, warts and digital abscesses.

[0109] Eye diseases, including but not limited to inflammatory diseases, such as scleritis, conjunctivitis, conjunctival edema, iritis, iridocyclitis, uveitis, chorioretinitis, and diseases, such as retinochoroidal circulation disorders, bacterial eye infections, nonspecific conjunctivitis and eye irritation, retinopathy of prematurity, proliferative vitreoretinopathy, macular degeneration (including age-related macular degeneration, including wet and dry forms), corneal diseases, including corneal transplant rejection, corneal injury, corneal scarring, corneal ulcers, corneal opacities, keratoconus, glaucoma (preferably open-angle glaucoma), myopia, glaucoma, high intraocular pressure, ocular vascular damage, angiogenesis, ocular fibrosis (e.g., anterior subcapsular fibrosis, posterior subcapsular opacity, posterior capsule opacity, corneal opacity after laser surgery, subconjunctival scarring after glaucoma surgery), proliferative vitreoretinopathy (PVR), bacterial eye infections, including styes and eyelash loss.

[0110] Ear diseases, including but not limited to Meniere's disease, otitis media, external ear inflammation and acute hearing loss.

[0111] Oral, pharyngeal and respiratory diseases, including but not limited to inflammation of the oral mucosa and gums, including aphthous ulcers and stomatitis, periodontitis, epiglottitis, pharyngitis, laryngotracheitis, tonsillitis, common cold, sore throat, rhinitis (including seasonal allergic rhinitis or perennial allergic rhinitis), epistaxis, sinusitis of any type, etiology or pathogenesis or selected from purulent or non-purulent sinusitis, acute and chronic sinusitis and ethmoid sinusitis, frontal sinusitis, maxillary sinusitis or sphenoid sinusitis, expectoration, any type or origin Pneumoconiosis of a substance of known origin, including, for example, aluminum pneumoconiosis, coal pneumoconiosis, asbestosis, stone dust lung, siderosis, silicosis, fume contusion, especially byssinosis, bronchitis, cough, tracheitis, congestion, pneumonia, eosinophilic pulmonary infiltration, chronic eosinophilic pneumonia, idiopathic pulmonary fibrosis and other fibrotic lung diseases, treatment-related fibrotic lung diseases (e.g. related to radiation, methotrexate, chemotherapy, amiodarone or nitrofurantoin), sarcoidosis, acute respiratory distress syndrome (ARDS) , bronchoconstriction, asthma of any type, etiology or pathogenesis, or asthma selected from the following: allergic asthma, non-allergic asthma, allergic and non-allergic asthma, extrinsic asthma caused by environmental factors, intrinsic asthma caused by pathophysiological disorders, bronchial asthma, IgE-mediated asthma, idiopathic asthma and idiopathic asthma of unknown or unexplained cause, true asthma, emphysematous asthma, exercise-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoan or viral infection, incipient asthma, infantile wheezing syndrome, bronchial hyperresponsiveness, chronic obstructive pulmonary disease (COPD), COPD characterized by irreversible, progressive airway obstruction, acute respiratory distress syndrome (ARDS) and other drug-induced exacerbation of airway hyperresponsiveness, dyspnea, hyperoxic alveolar damage, emphysema, pleurisy, tuberculosis, exposure to high altitude (i.e. acute mountain sickness, preferably high altitude pulmonary edema (HAPE)), intractable cough, bronchial hyporesponsiveness.

[0112] Gastrointestinal disorders, including but not limited to esophagitis, gastritis, irritable gastric disease, gastric and duodenal ulcers, intestinal obstruction, irritable colon disease, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), enteritis, hypertensive gastric and colonic disease, colitis, peritonitis, appendicitis, proctitis, gastrointestinal bleeding due to portal hypertension, collateral circulation or congestion, dumping syndrome after gastrectomy, digestive discomfort, diarrhea, hemorrhoids, helminthiasis, abdominal cramps and cramps in any part of the gastrointestinal system.

[0113] Liver, gallbladder and pancreatic diseases, including but not limited to 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, etc.

[0114] Urinary tract and kidney diseases, including but not limited to urinary tract infections (e.g., acute and chronic cystitis, interstitial cystitis, irritative bladder, overactive bladder, incontinence (including but not limited to stress, urge and reflex incontinence)), benign prostatic hyperplasia, chronic kidney disease, urethritis, inflammatory kidney disease (including glomerulonephritis, renal glomerular disease, interstitial nephritis, pyelonephritis), polyuria, proteinuria, natriuresis, calciuria, water balance disorders, electrolyte balance disorders, acid-base balance disorders and renal colic, renal fibrosis, chronic renal transplant dysfunction, contrast-induced nephropathy.

[0115] Diseases of the male and female reproductive organs, including but not limited to altered sperm motility, male infertility, orchitis, prostatitis, prostatic hyperplasia, mastitis, inflammatory pelvic disease, vaginal infection and pain, adnexitis, vaginitis, soft ulcers, syphilis, gonorrhea and ovarian hyperstimulation syndrome.

[0116] Hormonal system diseases, including but not limited to menstrual disorders and pain, menopausal disorders, vomiting, premature uterine contractions, premature birth, endometriosis, endometritis, fibroids, and preeclampsia.

[0117] Metabolic diseases include, but are not limited to, diseases such as diabetes, including non-insulin-dependent diabetes mellitus, diabetic retinopathy, diabetic macular edema, diabetic nephropathy and diabetic neuropathy, insulin resistance and diabetic ulcers, protein and purine metabolism diseases (e.g., gout and lipid metabolism disorders), and hypoglycemia.

[0118] Cardiovascular disease, including but not limited to vascular permeability, vasodilation, peripheral circulatory disorders, arterial circulatory disorders (including aortic aneurysm, abdominal aortic aneurysm, cerebral aortic aneurysm), hypertension and hypotension associated with sepsis, restenosis after percutaneous transluminal coronary angioplasty, atherosclerosis (including rupture of atherosclerotic plaques), hemangioma, angiofibroma, venous disease (such as thrombosis, varicose veins, phlebitis, thrombophlebitis, venous thrombosis), heart disease, congestive heart failure, coronary heart disease, carcinoid syndrome, angina pectoris , arrhythmias, inflammatory heart disease (including endocarditis, pericarditis, and constrictive pericarditis), myocarditis, myocardial infarction, post-myocardial infarction syndrome, left ventricular dilatation, post-ischemia-reperfusion injury, shock and collapse (including septic, anaphylactic, post-traumatic, and hemodynamic shock), amniotic fluid embolism, systemic inflammatory response syndrome (SIRS), including SIRS caused by cardiopulmonary bypass during surgery, sepsis during cardiopulmonary bypass, and internal and external complications (including but not limited to the adverse hemodynamic effects of reversal of heparin with protamine sulfate).

[0119] Hematological diseases, including but not limited to coagulation, disseminated intravascular coagulopathy, bleeding, bleeding diathesis, hypercholesterolemia and hyperlipidemia, hypovolemic shock, paroxysmal nocturnal hemoglobinuria, etc.

[0120] Lymphatic disorders, including but not limited to splenomegaly, lymphangitis, lymphadenitis, and adenoid hyperplasia.

[0121] Central nervous system diseases, including but not limited to inflammatory diseases of the central nervous system (including encephalitis, meningitis, encephalomyelitis, meningoencephalitis), hydrocephalus, amyotrophic lateral sclerosis, spinal cord trauma, spinal cord edema, demyelinating diseases of the nervous system, multiple sclerosis, acute and chronic neurodegenerative diseases (including aging, Alzheimer's disease and Parkinson's disease, neuritis and peripheral neuropathy), depression, anorexia, anxiety disorders and schizophrenia, sleep disorders.

[0122] Brain diseases, including but not limited to nootropics or cognitive enhancement, cerebral amyloid angiopathy, stroke, head and brain trauma, traumatic brain injury, brain tumors, brain thermal injury, cerebral ischemia, cerebral hemorrhage, post-traumatic and post-ischemic brain edema, general cerebral edema, acute mountain sickness and preferably high altitude cerebral edema (HACE), cytotoxic cerebral edema, vasogenic cerebral edema, post-surgical cerebral edema, cerebral edema associated with metabolic diseases, increased permeability of the blood-brain barrier or blood-brain tumor barrier.

[0123] Diseases of the musculoskeletal system, including but not limited to inflammatory musculoskeletal diseases, arthrosis, osteoarthrosis, osteoarthritis, chondroporosis after joint trauma or relatively long-term immobilization of the joint after meniscus or patellar injury or ligament tear, rheumatoid arthritis of any type, etiology or pathogenesis (including acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis and infectious arthritis, Lyme's arthritis, proliferative arthritis, spondyloarthritis, septic arthritis, psoriatic arthritis, chronic polyarthritis), rheumatism, Sjögren's syndrome, low back pain, spondylitis, spondyloarthritis, ankylosing spondylitis, osteomyelitis, sprains, tenosynovitis, bone resorption caused by inflammation, fractures, etc., osteoporosis, musculoskeletal pain and sclerosis, intervertebral disc syndrome.

[0124] Allergic diseases, including but not limited to general allergic reactions, food allergies, anaphylactic shock, allergic contact hypersensitivity, allergic skin reactions, allergic asthma, vernal conjunctivitis and seasonal or perennial allergic rhinitis.

[0125] Pain, including but not limited to centrally and peripherally mediated pain, vascular pain, visceral pain, inflammation-mediated pain, neuralgia, referred pain, nociceptive pain, reflex pain, psychosomatic pain, acute pain (e.g., acute pain caused by acute injury to bones, muscles, tissues, soft tissues, organs, trauma or surgery), pain following insect bites, post-stroke pain syndrome, postoperative pain, pain associated with progressive diseases, chronic pain (e.g., caused by neuropathic pain (including but not limited to complex regional pain syndrome, causalgia, morbussudeck, reflex sympathetic dystrophy, diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, cancer-related pain, pain associated with rheumatoid arthritis, osteoarthritis, tenosynovitis, gout, menstrual pain and angina, fibromyalgia, eye pain, back pain, headache, cluster headache, migraine, inflammatory pain that may be associated with acute inflammation or chronic inflammation)). Inflammatory pain includes but is not limited to neuropathic pain, ischemic pain, pain caused by arthritis, muscle pain caused by acute or chronic inflammation, neuralgia caused by chronic or acute inflammation, and hyperalgesia. Also chemotherapy-induced peripheral neuropathy, hyperalgesia, opioid-induced hyperalgesia and fever. In addition, the compounds of the present invention are useful as analgesics used during general anesthesia and monitored anesthesia.

[0126] Infectious diseases include, but are not limited to, diseases mediated by bacterial, viral, fungal, parasitic, protozoan, prion or mycobacterial infections. In particular, the present invention can be used to treat bacterial infections caused by Streptococcus, Escherichia coli, Salmonella, Staphylococcus, Klebsiella, Moraxella, Haemophilus and Yersinia. Examples of bacterial infections within the scope of the present invention include, but are not limited to, plague, septicemia, epidemic typhus, food poisoning, tetanus, scarlet fever, whooping cough, diphtheria and the like. Examples of viral infections within the scope of the present invention include, but are not limited to, diseases such as chickenpox and herpes zoster, AIDS, influenza, smallpox, and childhood diseases such as measles, rubella, mumps, acute myelitis, and the like. The present invention can be used to treat protozoan and parasitic infections caused by Schistosoma mansoni, Dermatofagoides farinae, and malaria induced by Plasmodium. Examples of prion infections within the scope of the present invention include, but are not limited to, diseases such as bovine spongiform encephalopathy (BSE), Creutzfeldt-Jakob disease and kuru, dengue fever, hemorrhagic fever, and the like.

[0127] Inflammatory diseases, including but not limited to acute phase reactions, local and systemic inflammation, and inflammation caused by other diseases regardless of their type, etiology or pathogenesis as well as by the inflammatory diseases defined in this application.

[0128] Injury: In this application, the term "injury" includes, but is not limited to, multiple trauma, head trauma, lung injury, external, internal and surgical wounds.

[0129] Immunological diseases, including but not limited to hyperesthesia, autoimmune diseases, transplant rejection in transplantation, transplant toxicity, granulomatous inflammation, tissue remodeling, myasthenia gravis, immunosuppression, immune complex disease, over- and under-production of antibodies, vasculitis, delayed graft function, lupus, etc.

[0130] Cancer, including but not limited to solid tumor cancers, including breast cancer, lung cancer (non-small cell lung cancer and small cell lung cancer), prostate cancer, oral and pharyngeal (lip, tongue, mouth, pharynx) cancer, esophageal cancer, stomach cancer, small intestine cancer, large intestine cancer, colon cancer, rectal cancer, gallbladder cancer and bile duct cancer, pancreatic cancer, laryngeal cancer, lung cancer, bone cancer, osteosarcoma, connective tissue cancer, skin cancer (including Kaposi's syndrome), melanoma and skin metastases, epidermoid cancer, basal cell carcinoma, cervical cancer, endometrial cancer, ovarian cancer, testicular cancer, bladder cancer, ureter and urethra cancer, kidney cancer, eye cancer, brain and central nervous system cancer, pseudotumor brain, sarcoma, sarcoid tumor, thyroid cancer and other endocrine gland cancer (including but not limited to carcinoid tumor), Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, hematological malignancies, including leukemias, lymphomas, including lymphocytic, granulocytic and monocytic lymphomas, tumor invasion, metastasis, ascites, tumor growth and angiogenesis.

[0131] Genetic diseases, including but not limited to hereditary angioedema and angioneurotic edema, chondrocalcinosis, Huntington's disease, visco-obstructive disease, etc.

[0132] Edema used herein includes, but is not limited to, systemic edema and edema caused by inflammation, edema caused by factor XII deficiency, other drugs, such as drug-induced angioedema, including but not limited to angioedema caused by angiotensin converting enzyme inhibitors, infection, burns, injuries, trauma, frostbite, surgery, sprains, fractures, exposure to high altitudes (e.g., high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE)), hereditary, autoimmune and other diseases and disorders, particularly but not limited to those specified in this application, pressure-induced intestinal edema (significant swelling). Known forms of angioedema (AE) include hereditary angioedema (HAE), acquired angioedema (AAE), bradykinin-mediated non-histaminergic idiopathic angioedema, allergic angioedema and drug-induced angioedema. HAE can be of any type, including type I HAE, type II HAE or type III HAE.

[0133] Capillary leak syndrome, including but not limited to systemic capillary leak syndrome in sepsis, burns, allergy, drug / toxin induced disease, organ transplantation and IL-2 cytokine therapy.

[0134] In another preferred embodiment, the solid dispersion or sustained-release composition is used to treat 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 or submucosal skin and tissue layers. Debilitating and often painful swelling may occur on the face, lips, tongue, limbs, genitals, gastrointestinal mucosa, urogenital area and airways. This is usually associated with urticaria, which is swelling in the upper skin. It is characterized by recurrent swelling, which usually occurs within a few minutes to a few hours. It is impossible to predict the location and time of the next angioedema. Patients may have an attack once a month, but there are also patients who have attacks every week or only once or twice a year.

[0135] In some preferred embodiments, the solid dispersion or sustained-release composition is used to treat any type of HAE, including type I HAE, type II HAE or type III HAE, preferably type I HAE or type II HAE. HAE is a disease with recurrent episodes of severe swelling. The swelling usually affects the arms, legs, face, intestines, and airways. If the intestines are affected, abdominal pain and vomiting may occur. Swelling of the airways may cause bronchial obstruction and difficulty breathing. Acute attacks usually last for several days, and the frequency of attacks in HAE patients is about once every two weeks.

[0136] The sustained-release composition is particularly advantageous in the chronic treatment of AE, such as hereditary angioedema (HAE) and acquired angioedema (AAE), especially type I HAE or type II HAE. As mentioned above, it is patient-friendly because it only requires one dose per day, or two doses per day. Given the robustness of the sustained-release properties to pH changes and the presence of food, these compositions are suitable for long-term treatments of months or even years.

[0137] Further aspects, embodiments, optional features and preferences of the invention will become apparent on the basis of the examples and claims.

[0138] Other definitions

[0139] For the sake of clarity, some other definitions of terms used in the specification and claims are given. Unless the context requires a different meaning, these definitions should be used to determine the meaning of the corresponding expressions.

[0140] The term "a" does not exclude the plural, that is, the singular forms "a", "the" should be understood to include plural objects, unless the context clearly indicates or requires otherwise. In other words, the singular features or limitations of the present invention should include the corresponding plural features or limitations, and vice versa, unless otherwise expressly provided or clearly implied by the context. Therefore, unless otherwise defined, the terms "a", "the" and "at least one" or "one or more" have the same meaning. For example, "a component" includes a mixture of various components, etc.

[0141] The term "about" or "approximately" will compensate for variability allowed in the pharmaceutical industry and inherent to pharmaceutical products, such as differences in content due to manufacturing variations and / or time-induced degradation of the product. The term allows for any variation that, in pharmaceutical practice, would allow the product being evaluated to be considered bioequivalent in subjects to the stated strength of the claimed product.

[0142] The terms "active agent", "therapeutic agent", 'active pharmaceutical ingredient (API)', 'active ingredient', 'drug', 'biologically active agent' are used synonymously to refer to a compound or combination of compounds that has pharmaceutical activity against an undesirable disease.

[0143] The term "composition" refers to any type of composition into which the specified ingredient may be incorporated, optionally together with any other ingredients.

[0144] The term "compound" refers to a chemical substance, which is a material composed of molecules that have essentially the same chemical structure and properties. For small molecule compounds, the molecules are generally identical in terms of their atomic composition and structural configuration. For macromolecular or polymeric compounds, the molecules of the compound are highly similar, but not all molecules are necessarily identical.

[0145] The terms "including" and similar expressions should be interpreted in an open and inclusive sense as meaning "including but not limited to".

[0146] The terms "substantially", "about", "approximately", "substantially" and the like in relation to an attribute or value include the precise attribute or precise value, as well as any attribute or value that is generally considered to be within the normal range or variation acceptable in the relevant art. For example, "substantially anhydrous" means that the composition does not contain intentionally added water, but does not exclude the presence of residual moisture.

[0147] The term "consisting essentially of" refers to a composition or dosage form to which no other ingredients have been added other than the listed ingredients. However, there may be very small amounts of other materials, such as impurities inherent to the material, or small amounts of additives added by the excipient supplier. In addition, when it is mentioned, for example, "consisting essentially of A, B, C, and optionally D", it means that no other components are added to the composition or dosage form except A, B, C and D, wherein D is an optional (i.e., non-mandatory) component of the composition or dosage form.

[0148] The term "substantially free" means that the composition contains less than a functional amount of the respective ingredient, typically less than 1 wt%, preferably less than 0.1 wt% or even 0.01 wt%, and includes 0 wt% of the respective ingredient.

[0149] The following examples further illustrate some aspects of the present invention, however they should not be construed as limiting the scope of the present invention.

[0150] Example

[0151] The compound of formula (1) is prepared as described in WO 2019 / 101906, where necessary in compliance with Good Manufacturing Practice (GMP) regulations.

[0152] The studies reported in Examples 6 and 7 were conducted in accordance with the respective protocols, current guidelines and recommendations for laboratory animal science, current Good Clinical Practice (GCP) guidelines of the International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), and applicable regulatory and country-specific governmental rules for the conduct of animal and clinical trials, including rules on the protection of subjects and informed consent, and requirements for transparency. Prior to the start of the study, the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) reviewed and approved all trial protocols, the suitability of the investigators, the facilities and methods, and the materials used to obtain and record informed consent from the trial subjects. For this study, the study drug, i.e., the compound of formula (1), was released to final use by qualified personnel in accordance with Annex XIII of Directive 2003 / 94 / EC; the study drug label contained information in accordance with applicable regulatory requirements. The study drug was packaged, labeled, and released at the clinical site by a pharmacist in accordance with the GMP practice guidelines, the International Conference on Harmonization (ICH), Good Clinical Practice (GCP), and applicable local laws / regulations.

[0153] Example 1: Solid dispersion prepared by vacuum melt pressing

[0154] Two solid dispersion compositions were prepared by vacuum melt pressing. The first composition, designated HME1, consisted of 40 wt% (S)-N-(1-deuterated-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 wt% copolyvidone ( The second composition, designated HME2, consisted of 20 wt % (S)-N-(1-deuterated-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 % hydroxypropyl methylcellulose acetate succinate ( AS-MMP) composition.

[0155] The active ingredient (S)-N-(1-deuterated-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 provided as a crystalline monohydrate in powder form. The actual amount of active ingredient and carrier are mixed in a vibrating mixer. Mix for 4 minutes.

[0156] Subsequently, the measured powder mixture was transferred to a laboratory-scale vacuum press molding device (VCM Meltprep) equipped with a disc molding tool (Meltprep Disc Tool) and formed into discs under a vacuum of -1.0 bar. For HME1, vacuum press molding was carried out at a temperature of 200°C, a heating time of 5 minutes, a cooling time of 2 minutes, and a cooling air pressure of 2.5 bar. For HME2, vacuum press molding was carried out at a temperature of 180°C, a heating time of 5 minutes, a cooling time of 5 minutes, and a cooling air pressure of 3.0 bar. With these two compositions, transparent light yellow discs were obtained.

[0157] The disks were crushed with a mortar and pestle for further evaluation. First, the drug content was confirmed to be within the range of 90% to 110% of the theoretical content by HPLC analysis. In addition, the crystalline state of the drug substance was evaluated by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD, also known as powder X-ray diffraction or PXRD). The DSC thermogram did not show the melting point of the active ingredient (about 111°C), and only the Tg of the polymer could be observed. XRPD analysis showed no residual crystallinity. Therefore, it was concluded that the sample represents a solid dispersion containing only the active ingredient in an amorphous, fully dissolved state.

[0158] Example 2: Solid dispersion prepared by spray drying

[0159] Four solid dispersion compositions were prepared by spray drying, named SDD1 to SDD4, each consisting of 25 wt % of (S)-N-(1-deuterated-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 % of a carrier polymer. The carrier polymer of SDD1 was hypromellose acetate succinate ( AS-MMP), SDD2 is 2910USP type hydroxypropyl methylcellulose ( E3) and SDD3 are copolyvidone ( VA64) and SDD4 is povidone K-30.

[0160] For each composition, measured amounts of active ingredient and corresponding carrier polymer were dissolved in a mixture of dichloromethane (DCM) and methanol (ratio 4:1 (w / w)). Spray drying was then performed using a laboratory scale spray dryer (Büchi B290) using the parameters listed in Table 1 below.

[0161] Table 1

[0162]

[0163] The powder produced by the spray drying process was collected and subjected to a secondary drying step by vacuum drying at 40°C and -26.5 mm Hg for 20 hours.

[0164] The obtained samples were evaluated using modulated differential scanning calorimetry (mDSC), XRPD and thermogravimetric analysis (also known as thermogravimetric analysis, TGA). Both XRPD and mDSC data confirmed that all four samples were amorphous and did not contain any detectable levels of crystalline material. The TGA thermogram showed an inflection point in the slope of the weight loss step for the SDD4 sample, indicating that a small amount of solvent remained in the sample. Overall, all samples were confirmed to represent uniform solid dispersions containing the active ingredient in amorphous form and completely dissolved in the carrier polymer.

[0165] Samples of the spray-dried solid dispersions SSD1 to SSD4 were stored at high temperature (40° C.) and retested by XRPD after three weeks. As a result, all samples were amorphous and contained no crystalline content.

[0166] Example 3: Solid dispersion prepared by hot melt extrusion

[0167] with a mixture consisting essentially of 20% by weight of (S)-N-(1-deuterated-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 hydroxypropyl methylcellulose acetate succinate ( AS-MMP) composed of HME2 (see Example 1) was prepared as a solid dispersion by hot melt extrusion. The powder blend containing the crystalline active ingredient and the carrier polymer was sieved through a sieve with a pore width of 500 μm. The blend was then extruded using a twin-screw extruder (Leistritz ZSE 12HP-PH) equipped with a 1.5 mm die. The maximum temperature in the kneading zone was in the range of 145 to 165°C, but the temperature in the die zone was set to 200°C. A slightly brown transparent extrudate was obtained and granulated with a granulator. Subsequently, the particles were ground in two stages using a hammer mill, with a sieve size of 1000 μm in the first stage and 400 μm in the second stage, and a grinding speed of 6500 rpm. Then, by laser diffraction The particle size distribution was characterized. For both milling batches, the average particle size D50 was 262.3 μm and 249.1 μm, respectively. In the sieve analysis, 66.2 wt.-% and 61.7 wt.-% of the milled particles, respectively, were found to be in the sieve size fraction of 180 μm to 355 μm.

[0168] Another batch of the same composition (HME2) was prepared using the same hot melt extrusion, granulation and grinding process as above, but using a hammer mill with a mesh size of 200 μm in the final grinding step. As a result, the average particle size D50 determined by sieve analysis was about 100 μm, i.e., in the range of 63 μm to 125 μm.

[0169] The samples of HME2 solid dispersion were stored at an increased temperature (40°C) to test its chemical and physical stability. Drug content and impurities were quantified by HPLC. XRPD was used to detect the change (if any) in crystalline state. The results are provided in Table 2 below. They show that the active ingredient in the solid dispersion is highly chemically stable and remains in amorphous form.

[0170] Table 2

[0171]

[0172]

[0173] *100% refers to the theoretical content of API in the sample.

[0174] Example 4: Sustained-release formulation containing a solid dispersion

[0175] According to Example 1, solid dispersion formulation HME1 is prepared by vacuum melt pressing, and solid dispersion HME2 is prepared by hot melt extrusion and subsequent grinding as described in Example 3. In addition, solid dispersions SDD1 and SDD3 are prepared as described in Example 2. Each of the four solid dispersions is then mixed with other excipients and pressed into tablets of 150 mg weight using a laboratory-scale tablet press (Kilian Styl'One Evolution, single punch tablet press simulator). The ingredients of these tablets (4.1 to 4.4) are shown in Table 3. It is noteworthy that other excipients do not include hydrophilic skeleton-forming polymers.

[0176] Table 3

[0177]

[0178] Example 5: Matrix tablet comprising a solid dispersion

[0179] The solid dispersion composition HME2 was prepared as described in Example 3 and incorporated into two matrix tablet formulations (5.1 and 5.2) having the compositions shown in Table 4.

[0180] Table 4

[0181]

[0182]

[0183] As described in detail above, hypromellose in these formulations represents the hydrophilic matrix-forming polymer. Microcrystalline cellulose and dibasic calcium phosphate dihydrate are used as tablet fillers, colloidal silicon dioxide is used primarily as a glidant, and magnesium stearate is used primarily as a lubricant.

[0184] The weighed raw materials were mixed in a drum mixer ( 2F) in several subsequent steps: first, the ground extrudate, filler and hydrophilic matrix-forming polymer are mixed, then the glidant is added and mixed, and finally the lubricant is added and mixed. The resulting powder mixture is pressed into white to off-white oval, biconvex tablets with brown spots (17mm×7.2mm) on a laboratory-scale single-punch pharmaceutical tablet press (KilianStyl'One Evolution) using a main compression force ranging from 15kN to 40kN. It was observed that the ground extrudate is easily compressed in the corresponding powder mixture even without a granulation step. The average thickness of the tablets is about 5.7mm, the average crushing resistance is about 110N to 170N, and the friability is about 0.2wt% to 0.7wt%. Analysis (HPLC-UV) shows that the drug content is within the acceptable range of 90% to 110% of the labeled content. The total impurities are less than 1.0%.

[0185] According to Ph. Eur. 2.9.3 / USP <711> The drug release properties of tablets of samples 5.1 and 5.2 were characterized by dissolution testing using apparatus II (paddle apparatus). The dissolution medium was 1000 mL USP phosphate buffer, pH 6.8, containing 0.3% (w / v) sodium lauryl sulfate. The paddle speed was set to 100 rpm. A Japanese sinker was used to prevent the tablets from floating. Samples were taken out at regular intervals and their API concentrations were analyzed by HPLC, from which the amount of drug dissolved was calculated. The dissolution characteristics are shown in Table 5.

[0186] Table 5

[0187]

[0188] As shown in the test results, the matrix tablet containing the solid dispersion of the BK B2 receptor antagonist of formula (1) can achieve sustained release of the active ingredient over a long period of time, for example, about 12 hours or even longer. Matrix tablet 5.1 exhibited a steeper dissolution curve in vitro than tablet 5.2.

[0189] Example 6: Human PK study

[0190] In a clinical Phase I study, the basic pharmacokinetic properties of matrix tablets 5.1 and 5.2 were evaluated after a single dose and compared with immediate-release capsules under fasting and fed (high-carbohydrate high-fat (HCHF) meal) conditions. The study was designed as a randomized five-period crossover study with 10 healthy volunteers. Table 6 lists the key PK parameters obtained in the study.

[0191] Table 6

[0192]

[0193] The data show that the matrix tablet formulation exhibits sustained release properties in vivo, as indicated by the tmax value. Sample 5.2, which has a longer in vitro release of the active ingredient than sample 5.1 (see Example 5), also results in a delayed tmax in vivo under both fasting and fed conditions. It is very noteworthy that the overall drug exposure of the matrix tablets exhibits a sustained release profile (see AUC inf values), from which it can be concluded that, despite its unfavorable physical properties, the active ingredient is reliably released and absorbed even from more distal regions of the intestine.

[0194] Figures 1 to 3 The mean plasma concentration curves of the corresponding preparations over time are shown: Figure 1 describes the plasma profile after administration in the fasting state, while Figure 2 and Figure 3 The skeleton tablets 5.1 ( Figure 2 ) and matrix tablets 5.2 ( Figure 3 ) Comparison of the mean plasma profile after administration in the fed state vs the fasted state. Subsequent simulation studies confirmed the usefulness of the PK properties of the two tested matrix tablet formulations for continuous treatment using a once-daily or twice-daily dosing regimen. The SMEDDS formulation refers to a regular release soft gelatin capsule containing the active ingredient, which is formulated as a self-microemulsifying drug delivery system (SMEDDS), through which a dose of 20 mg of API is administered as a control.

[0195] Example 7: Monkey PK study

[0196] Tablet formulations 4.1 to 4.4 containing solid dispersions were tested in male cynomolgus monkeys to evaluate their biopharmaceutical performance in vivo. For this reason, they were placed in No. 0 hard gelatin capsules. Before administration, each capsule was pierced 10 times with a needle. For comparison, the liquid self-microemulsifying drug delivery system (SMEDDS) of the same active ingredient (65 mg / mL) contained in the hard gelatin capsule was taken. The actual dosage of active ingredient was 2.6 mg to 2.9 mg per dose.

[0197] The study was designed as a three-phase crossover study. The results showed that the dose-normalized (DN) systemic exposure expressed as DN AUC did not differ among the formulations. In addition to such high oral bioavailability, the maximum plasma concentration Cmax and the time to reach the maximum plasma concentration tmax also indicate the stability of the solid dispersion for immediate release products and acute treatment. At the same time, it is worth noting that Tablet 4.2 containing the solid dispersion HME2 with HPMCAS as the carrier polymer showed a delay in reaching the maximum plasma concentration, i.e., t max The values ​​increased, indicating a delayed release consistent with its pH-dependent aqueous solubility properties. Table 7 lists the key PK parameters obtained in the study.

[0198] Table 7

[0199]

Claims

1. A solid dispersion for oral administration, comprising: (a) a bradykinin (BK) B2 receptor antagonist having a chemical structure of formula (1) or a salt or solvate thereof: wherein R is deuterium or hydrogen, and (b) at least one pharmaceutically acceptable polymer; The BK B2 receptor antagonist is amorphous and uniformly dispersed in the polymer.

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

3. The solid dispersion according to claim 1 or 2, wherein the pharmaceutically 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 selected from HPMCAS and copovidone (PVP / PA).

4. The solid dispersion according to any one of the preceding claims, further comprising a non-ionic surfactant selected from poloxamers and polysorbates.

5. The solid dispersion according to any one of the preceding claims, wherein the content of the BK B2 receptor antagonist is 15 wt% to 50 wt%, based on the total weight of the solid dispersion.

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

7. A solid dispersion according to any one of the preceding claims in the form of a powder or granules.

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

9. The method according to claim 8, wherein the hot melt extrusion step is performed by: (i) a powder or granular mixture comprising from about 15 wt % to about 45 wt % of a BK B2 receptor antagonist and from about 55 wt % to about 85 wt % of HPMCAS based on the total weight of the powder or granular mixture; or (ii) a powder or granular mixture comprising 30 to 50 wt% of a BKB2 receptor antagonist and 50 to 70 wt% of copovidone and optionally up to 5 wt% of a poloxamer, based on the total weight of the powder or granular mixture.

10. Use of the solid dispersion according to any one of claims 1 to 7 in the preparation of a pharmaceutical composition for 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. The sustained release composition according to claim 11, wherein the composition is in the form of a matrix tablet, and wherein the matrix tablet comprises 20 to 40 wt% of the solid dispersion based on the total weight of the tablet.

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

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 for treating a subject suffering from a disease or condition responsive to BK B2 receptor modulation.

15. Use of a solid dispersion or sustained-release composition according to claim 14, wherein the disease or condition responsive to BKB2 receptor modulation is selected from the group consisting of skin diseases; eye diseases; ear diseases; oral, throat and respiratory tract 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 diseases; central nervous system diseases; brain diseases; musculoskeletal system diseases; allergic diseases; pain; infectious diseases; inflammatory diseases; injuries; immunological diseases; cancer; hereditary diseases; and edema.

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

17. Use of a solid dispersion or a sustained release composition 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 orally administering to a subject suffering from a disease or condition responsive to BK B2 receptor modulation: (i) an effective amount of the solid dispersion according to any one of claims 1 to 7; or (ii) an effective amount of the sustained-release composition of any one of claims 11 to 13; Thereby preventing or treating the condition or disease in the subject.

19. The method of claim 18, wherein the disease or condition responsive to BKB2 receptor modulation is selected from the group consisting of skin diseases; eye diseases; ear diseases; oral, throat and respiratory tract diseases; gastrointestinal diseases; liver, gallbladder and pancreas diseases; urinary tract and kidney diseases; male and female reproductive organ diseases; hormonal system diseases; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic diseases; central nervous system diseases; brain diseases; musculoskeletal system diseases; allergic diseases; pain; infectious diseases; inflammatory diseases; injuries; immunological diseases; cancer; genetic diseases; and edema.

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

21. The method according to 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 a long period of time.

22. 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 preparation of a medicament for treating or preventing a disease or condition responsive to BK B2 receptor modulation.

23. The use according to claim 22, wherein the disease or condition responsive to BKB2 receptor modulation is selected from the group consisting of skin diseases; eye diseases; ear diseases; oral, throat and respiratory tract diseases; gastrointestinal diseases; liver, gallbladder and pancreas diseases; urinary tract and kidney diseases; male and female reproductive organ diseases; hormonal system diseases; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic diseases; central nervous system diseases; brain diseases; musculoskeletal system diseases; allergic diseases; pain; infectious diseases; inflammatory diseases; injuries; immunological diseases; cancer; hereditary diseases; and edema.

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

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

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