SOLID SUSTAINED RELEASE COMPOSITIONS COMPRISING BRADYKININ B2 RECEPTOR ANTAGONISTS - Patent application

Abstract

The present invention relates to a pharmaceutical matrix tablet for oral administration comprising a bradykinin B2 receptor antagonist having a chemical structure represented by formula (1), such as (S)-IV-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1-1 / / -1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, or a salt or solvate thereof, wherein R is deuterium or hydrogen. The matrix tablet ensures a sustained release of the bradykinin B2 receptor antagonist, making it particularly suitable for prophylaxis and / or chronic treatment. Therapeutic uses of the matrix tablet are provided. [Formula 1] TIFF2025510860000019.tif127161

Description

[Technical field]

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

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

[0003] A number of peptide and non-peptide antagonists of the BK B2 receptor have been described in the prior art. Quinoline derivatives active as BK B2 receptor antagonists are disclosed, for example, in WO2014 / 159637, WO2010 / 031589, WO2008 / 116620, WO2006 / 40004, WO03 / 103671, WO03 / 87090, WO00 / 23439, WO00 / 50418, WO99 / 64039, WO97 / 41104, WO97 / 28153, WO97 / 07115, WO96 / 13485, EP0795547, EP0796848, EP0867432 and EP1213289. However, these compounds exhibited several deficiencies that hinder their usefulness as drugs, including poor metabolic stability, poor bioavailability, formation of glutathione adducts and bioactivation (toxicity) as disclosed in WO2014 / 159637.

[0004] More recently, compounds of formula (1) have been proposed as novel biologically active and well-tolerated BK B2 receptor antagonists (see, for example, WO2019 / 101906). These compounds exhibit attractive pharmacological properties but also exhibit rather challenging physical or physicochemical properties, including very poor aqueous solubility in physiological media.

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

[0006] In order to provide sustained release of drug substance after oral administration, various dosage form designs and preparation techniques have been proposed, such as tablets or capsules with sustained release coating, tablets or capsules containing pellets with sustained release coating, or matrix tablets. The sustained release coating can be based on water-insoluble polymers, such as ethyl cellulose or certain methacrylate copolymers, which can form a drug-permeable film on the pellets, tablets or capsules. Matrix-forming materials in sustained release formulations include hydrophobic excipients, such as lipids, waxes, or hydrophobic polymers; and hydrophilic gel-forming polymers.

[0007] L.-A. Tziveleka et al., Carbohydrate Polymers, Volume 218, April 29, 2019, Pages 355-370, doi:10.1016 / J.CARBPOL.2019.04.074, describes the use of ulvan, a sulfated polysaccharide found in green algae, in hydrogels for pharmaceutical applications such as matrix tablets.

[0008] Developing suitable sustained release formulations for new drug candidates with difficult physical and pharmacokinetic properties, such as poor solubility, remains challenging, and to this day many development programs are unsuccessful.

[0009] Thus, there is a need for formulations and pharmaceutical compositions that overcome the difficulties due to the challenging properties of the compound of formula (1) to enable effective oral delivery in human subjects and achieve significant systemic exposure and bioavailability. There is also a need for formulations or pharmaceutical compositions incorporating the compound of formula (1) that achieve reliable oral absorption. There is a further need to provide formulations or pharmaceutical compositions incorporating the compound of formula (1) that are stable in their performance and can be manufactured by well-established pharmaceutical manufacturing techniques.

[0010] The compounds of formula (1) have very low water solubility. This makes it extremely challenging to develop oral formulations that provide sufficient and reliable bioavailability rates and amounts and effective plasma levels. The pharmacokinetic profile of the BK B2 receptor antagonists of formula (1) makes these compounds highly attractive for both acute and chronic treatment, and therefore there is a need to develop formulations of these drugs that overcome challenges, including poor water solubility, and are viable in both acute and chronic treatment environments. Summary of the Invention [Problem to be solved by the invention]

[0011] The object of the present invention is to address any one or more of these needs. Another object is to overcome the deficiencies, gaps and limitations of the prior art with respect to oral delivery of bradykinin B2 receptor antagonists, such as compounds having the chemical structure represented by formula (1). Other objects will become apparent based on the following description, examples and claims. [Means for solving the problem]

[0012] In one aspect, the present invention relates to a matrix tablet for oral administration, comprising a bradykinin B2 receptor antagonist having a chemical structure represented by formula (1), or a salt or solvate thereof, and at least one hydrophilic matrix-forming polymer.

[0013] [ka]

[0014] In the formula, R is deuterium or hydrogen.

[0015] As described in more detail below, the matrix tablet is preferably formulated to provide sustained release of the incorporated BK B2 receptor antagonist. The hydrophilic matrix-forming polymer functions to embed the active ingredient and cause its sustained release. For example, the matrix-forming polymer may be compressed into a tablet and, upon contact with water or aqueous medium, swell or gel, and then slowly erode over time, to cause sustained release of the BK B2 receptor antagonist. The hydrophilic matrix-forming polymer may be selected, for example, from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and combinations thereof. The matrix tablet may include one or more tablet fillers, binders, flow agents, and / or other excipients, such as lubricants. Optionally, the matrix tablet may be coated, as described in more detail below.

[0016] In some preferred embodiments, the BK B2 receptor antagonist of formula (1) is very poorly soluble in physiological media, but is incorporated in a physical form, such as a micronized form or a form that is already solubilized, that is specifically adapted to promote the dissolution of the drug substance when contacted with water or an aqueous medium. In some other preferred embodiments, the matrix tablet comprises a solid dispersion of the amorphous BK B2 receptor antagonist in a carrier, the carrier comprising at least one pharma- ceutically acceptable carrier polymer. The carrier polymer can be selected, for example, from HPMC, hydroxypropyl methylcellulose acetate succinate (HPMCAS), copovidone, and combinations thereof, together with other optional excipients. The solid dispersion can be prepared by hot melt extrusion and incorporated into the matrix tablet in the form of a milled extrudate.

[0017] According to another embodiment, the matrix tablet is a sustained release tablet that releases the BK B2 receptor antagonist over a period of 12 to 24 hours as determined by the in vitro dissolution method described in more detail below.

[0018] In another embodiment, the present invention relates to some therapeutic uses of matrix tablets.Generally, it can be used in the treatment of any disease or condition that responds to bradykinin B2 receptor modulation.For example, they are advantageous in the treatment of angioedema, including hereditary angioedema (HAE), acquired angioedema (AAE), idiopathic non-histaminergic angioedema, allergic angioedema, drug-induced angioedema, and angioedema of unknown origin, especially in the chronic stage treatment of AE, especially hereditary angioedema.HAE can be any type of HAE, including type I, type II, or type III HAE, preferably type I or type II HAE. [Brief description of the drawings]

[0019] [Figure 1] FIG. 1 shows the mean plasma concentration-time profiles of two different extended release matrix tablet formulations (Formulations 5.1 and 5.2, herein referred to as XR1 and XR2) containing a solid dispersion formulation of the compound of formula (1), specifically (S)—N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide (herein referred to as PHA-022121), compared to an immediate release capsule formulation of the same drug in healthy volunteers under fasting conditions. [Diagram 2] FIG. 1 shows the mean plasma concentration-time profile of a sustained release matrix tablet comprising a solid dispersion formulation of compound of formula (1) (Formulation 5.1) in healthy volunteers under fed and fasted conditions. [Diagram 3] FIG. 1 shows the mean plasma concentration-time profile of a sustained release matrix tablet comprising a solid dispersion formulation of compound of formula (1) (Formulation 5.2) in healthy volunteers under fed and fasted conditions. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] In a first aspect, the present invention provides a pharmaceutical matrix tablet comprising a bradykinin (BK) B2 receptor antagonist having the chemical structure represented by formula (1), or a stereoisomer, salt or solvate thereof, and at least one hydrophilic matrix-forming polymer. [ka]

[0021] In the formula, R is deuterium or hydrogen.

[0022] The inventors have found that formulating such BK B2 receptor antagonists as matrix tablets is particularly useful for providing reliable and complete drug release, despite the unfavorable physicochemical properties of, for example, the compound of formula (1), which is very poorly soluble in aqueous media. Moreover, it has been found that matrix tablets are highly compatible with these drug substances and can incorporate them in various forms, including amorphous, leading to surprisingly stable and robust products, not only in terms of chemical stability over extended storage at standard conditions, but also in terms of stable biopharmaceutical performance. A further unexpected advantage is that matrix tablets incorporating BK B2 receptor antagonists of formula (1) can be designed to provide sustained release of such active ingredients over extended periods, such as 12 hours or more, and even over periods such as about 18-24 hours, as described in more detail below. Moreover, matrix tablets are easy to manufacture using commonly available pharmaceutical manufacturing equipment and are therefore associated with modest costs.

[0023] As commonly understood in the context of pharmacology, a pharmaceutical matrix tablet is a matrix tablet that contains a pharmaceutical active ingredient or its placebo version and is formulated and processed to be pharma- ceutical acceptable. Thus, in this disclosure, the expressions "matrix tablet" and "pharmaceutical matrix tablet" are used interchangeably.

[0024] Matrix tablets, as generally understood in the field of pharmacology, refer to compositions for oral administration in the form of compressed tablets, which contain an active ingredient uniformly dispersed in one or more suitable excipients, which excipients can form a matrix capable of controlling the release of the active ingredient after compression. The matrix of matrix tablets can be gelling. As used in this disclosure, the term "matrix" is used for such tablets both in their original dry form as produced and provided, which may also be described as a porous matrix, and in the gelling matrix resulting from the contact of such matrix tablets with water.

[0025] Matrix tablets are often designed to provide a sustained release of incorporated active ingredients. In this case, such tablets may also be called sustained release tablets or sustained release matrix tablets, respectively. As used herein, sustained release is understood as a prolonged release of active ingredients after oral administration, or is characterized by a gradual release, particularly over substantially 30 minutes or more, particularly over several hours, in a suitable in vitro model. In this context, sustained release, slow release, extended release and sustained release are used as interchangeable expressions. Sustained release is also in the form of modified release dosage forms, often referred to as controlled release formulations. In one generally preferred embodiment, the matrix tablet disclosed herein is a sustained release matrix tablet.

[0026] In another embodiment, the matrix tablet is also designated as a single unit dosage form, meaning that a single unit of the formulation contains a single dose of the active ingredient, as opposed to multiple unit designs such as sustained release capsules or tablets that incorporate multiple sustained release subunits, e.g., pellets, that disperse upon contact with moisture prior to drug release.

[0027] The release of an active ingredient, also described as drug release in the context of pharmaceutical products for oral administration, refers to the release of the active ingredient in dissolved form, i.e. dissolved in an aqueous dissolution medium, such as gastric fluid, intestinal fluid, or surrogate versions thereof, such as dilute hydrochloric acid, buffers, artificial gastric fluid, artificial intestinal fluid, etc. Thus, for practical purposes, the release profile of an oral pharmaceutical composition can also be described as a dissolution profile, and vice versa.

[0028] In the context of the present invention, with respect to the active ingredient, i.e., the compound of formula (1), R is selected from hydrogen and deuterium. In one preferred embodiment or group of embodiments, R is deuterium, as shown in the following formula:

[0029] [ka]

[0030] This compound, which may also be referred to as (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide (CAS 2340111-58-0), or acetamide, N-[(1S)-1-[3-chloro-5-fluoro-2-[[[2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)-8-quinolinyl]oxy]methyl]phenyl]ethyl-1-d]-2-(difluoromethoxy)-, is a particularly advantageous example of a compound of formula (1) in the context of the present invention. It should be understood that this preference applies in combination with all other optional features or preferences disclosed herein below, whether or not specifically stated.

[0031] Alternatively, in formula (1), R can be hydrogen, as shown below:

[0032] [ka]

[0033] The compound may also be referred to as (S)—N-(1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide.

[0034] In a preferred embodiment, the BK B2 receptor antagonist is a compound of formula (1), a salt or a solvate thereof, preferably a compound of formula (1) or a solvate thereof. That is, the compound of formula (1) can exist essentially in non-ionized form or in ionized form, i.e., in the form of a salt. In addition, it can be optionally in the form of a solvate. For example, the compound can be a hydrate, such as (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide monohydrate. In one generally preferred embodiment, the compound of formula (1) is in non-ionized form (i.e., not in the form of a salt) and is defined by R being deuterium.

[0035] In general, matrix tablets can be formulated based on various types of matrix-forming excipients, such as hydrophilic, inert, lipid, biodegradable and resin matrices. However, as stated, besides the BK B2 receptor antagonist of formula (1), the key component of the matrix tablet according to the embodiment of the present invention is the hydrophilic matrix-forming excipient, more precisely the hydrophilic matrix-forming polymer.

[0036] Such matrix tablets are different from tablets, for example, whose sustained release function is mainly provided by sustained release membranes or coatings. Sustained release matrix tablets can also include coatings, but when applied, these coatings typically have little effect on the drug release profile. For example, so-called non-functional coatings can be applied to matrix tablets, and such coatings are mainly used to improve the appearance of the tablet, facilitate its handling and swallowing, cover the taste, or reduce friability.

[0037] In some preferred embodiments, the matrix tablets described herein are monolayer tablets, optionally coated. Monolayer tablets are distinct from bilayer or multilayer tablets, and consist of a single compressed tablet layer. The manufacture of monolayer tablets is generally more cost-effective than the manufacture of tablets having two or more layers. Monolayer tablets are also smaller and therefore potentially easier to swallow than tablets having an additional layer or layers, which may be used to create a drug release profile. The inventors have found that compounds of formula (1) can be very effectively formulated as monolayer sustained release matrix tablets that exhibit extended drug release even over a relatively long period of time, such as 12 to 24 hours. The optional coating is preferably a film coating. For example, the coating can be a water-soluble pH-independent film coating based on a water-soluble film-forming polymer.

[0038] The formulation techniques for sustained release matrix tablets are generally known to those skilled in the art. Depending on the primary mechanism of drug release, "erodible" matrix tablets can be distinguished from "insoluble" matrix tablets, which release active ingredients from the swollen but intact matrix mainly by diffusion. In practice, a combination of release mechanisms will often be present at the same time, with some drug release occurring by diffusion and some drug released as a result of tablet erosion. As used herein, erosion includes any gradual loss of matrix material, regardless of the mechanism by which this loss occurs.

[0039] One of the main functions of hydrophilic matrix-forming polymers is to form a matrix capable of embedding an active ingredient and providing its sustained release. Typically, such hydrophilic matrix-forming polymers are compressed into tablets and, upon contact with water or an aqueous medium, are capable of swelling or gelling, followed by slow erosion over time, i.e., at least several hours.

[0040] A variety of hydrophilic polymers can be used to create a compressed porous matrix capable of providing extended drug release. According to one embodiment, the hydrophilic matrix-forming polymer can be, for example, one or more of the following polymer excipients: hydroxypropyl cellulose (HPC or hyprolose), hydroxypropyl methylcellulose (HPMC or hypromellose), hydroxypropyl methylcellulose acetate succinate (HPMCAS or hypromellose acetate succinate), alginic acid, bentonite, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carrageenan, cellulose, copovidone, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl starch, methylcellulose, pectin, polyethylene oxide, polymethacrylate, potassium (or calcium or sodium) alginate, povidone, tragacanth, or xanthan gum.

[0041] In one preferred embodiment, the hydrophilic matrix-forming polymer is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and combinations thereof. In one preferred embodiment, the hydrophilic matrix-forming polymer in the matrix tablet is or comprises hydroxypropyl cellulose. In a related embodiment, the matrix tablet comprises a combination of two or more hydrophilic matrix-forming polymers, preferably comprising hydroxypropyl methylcellulose.

[0042] The inventors have found that these polymers and combinations of polymers are particularly suitable matrix-forming excipients for incorporating the BK B2 receptor antagonists of formula (1).

[0043] Combinations of different grades of HPC and / or HPMC may also be used, in particular combinations of various grades of HPMC. For example, HPMC with a relatively low content of hydroxypropoxy groups (e.g. HPMC type 2208, as classified by most pharmacopoeias; currently available, for example, as "K" type Methocel™ grade) may be combined with an HPMC grade with a medium content of hydroxypropoxy groups and a relatively high content of methoxy groups (e.g. HPMC type 2910; currently available, for example, as "E" type Methocel™ grade), respectively, or HPMC with a relatively low viscosity (e.g. E4M, as classified by commercial providers of Methocel™) may be combined with HPMC with a relatively high viscosity (e.g. Methocel™ K100M). In this context, the viscosity of HPMC or HPC is understood as the typical viscosity of a 2% (w / v) aqueous solution of the polymer, measured at 20°C. The increase in viscosity values ​​is to some extent, but not exclusively, related to the increase in molecular mass of each polymer grade.

[0044] In some embodiments of the matrix tablets described herein, the hydrophilic matrix-forming polymer may comprise or consist of a combination of hydroxypropyl methylcellulose type 2208 and hydroxypropyl methylcellulose type 2910. In some related embodiments, a high viscosity grade of hydroxypropyl methylcellulose type 2910 is used in combination with hydroxypropyl methylcellulose type 2208.

[0045] In this context, it should be noted that there are some highly soluble HPMC grades with very low apparent viscosities that may not be fully qualified as matrix-forming polymers. As used herein, a matrix-forming HPMC polymer is preferably an HPMC grade having an apparent viscosity of at least about 100 cP, determined according to the European Pharmacopoeia using a 2% aqueous solution at 20° C.

[0046] The hydrophilic matrix-forming polymer is typically provided in the form of a powder or granule suitable for incorporation into a pharmaceutical tablet. The amount of hydrophilic matrix-forming polymer in the matrix tablet, or the total amount of hydrophilic matrix-forming polymer in the matrix tablet provided by the present invention when a combination of hydrophilic matrix-forming polymers is used, can be selected, for example, in the range of about 10% to about 80% by weight, based on the weight of the matrix tablet. In some preferred embodiments, the amount is selected in the range of about 15% to about 60% by weight, or about 15% to about 50% by weight, respectively.

[0047] In another preferred embodiment, the hydrophilic matrix-forming polymer is HPMC or a combination of two or more different grades of HPMC, and the total amount of HPMC in the matrix tablet is in the range of about 15% to about 50% by weight, in particular about 20% to about 40% by weight, such as about 20%, 25%, 30%, 35% or 40% by weight, based on the weight of the matrix tablet. The inventors have found that these ranges provide an excellent balance between drug loading and matrix functionality in terms of achieving a sustained release profile resulting in drug release even over an extended period of about 12 to 24 hours, even when the active ingredient is incorporated in a special form, such as a solubilized form, e.g. in the form of a solid dispersion, as described in more detail below.

[0048] In another embodiment, the matrix tablet further comprises one or more excipients to enhance the mechanical stability of the compressed tablet by improving the particle binding behavior during compression. These excipients, in contrast to the matrix-forming polymers, have little or no effect on the release control properties of the matrix tablet. Some of these optional excipients can be chemically related to some of the preferred matrix-forming polymers, but the skilled artisan will understand the main function and effect of the excipients present in the matrix tablet and whether a particular excipient plays a significant role in controlling the release of the active ingredient incorporated in the matrix tablet. For example, some highly water-soluble HPMC grades with low molecular weight or viscosity, such as BonuCel® D 5 H (which has an apparent viscosity of only about 4-6 cP at 20°C in a 2% aqueous solution), appear to act as binders rather than matrix formers contributing to the release control provided by the matrix, at least when used in low amounts, such as 5% by weight relative to the weight of the uncoated matrix. They essentially increase the physical stability of the tablet. Similarly, low amounts of other excipients, such as macrogol (also called polyethylene glycol, e.g., macrogol 6000) or HPMCAS, can be used without interfering with the extended drug release profile achieved by the hydrophilic matrix-forming excipients.

[0049] When present, such matrix-modifying excipients or combinations of matrix-modifying excipients are preferably used at relatively low levels, e.g. not more than about 20% by weight, or not more than about 10% by weight, e.g. about 2-8% by weight, or about 5% by weight, respectively, based on the total weight of the matrix tablet (not including coating).

[0050] According to another preferred embodiment, the matrix tablet further comprises a tablet filler. A tablet filler can be understood as a pharmaceutical excipient that improves the overall processability of a powder or granule mixture in consideration of tablet compression. The functions of a tablet filler can include those of a diluent or extender, a compression aid, and a dry binder (often simply called a binder). A tablet filler is also called a tablet filler-binder. Such an excipient can be a compound or a combination of compounds. Tablet fillers potentially suitable for use in matrix tablets include, but are not limited to, microcrystalline cellulose (MCC), starch, such as corn starch, potato starch, or pregelatinized starch; mannitol, lactose, sorbitol, cellulose, calcium sulfate, calcium phosphate, such as anhydrous calcium hydrogen phosphate or calcium hydrogen phosphate dihydrate; erythritol and calcium carbonate.

[0051] In one preferred embodiment, the tablet filler comprises microcrystalline cellulose and / or calcium phosphate, such as calcium hydrogen phosphate dihydrate. In a related embodiment, the tablet filler may comprise or consist of a combination of microcrystalline cellulose and calcium hydrogen phosphate dihydrate. For example, the two excipients may be combined in a weight ratio of about 1:1. It is believed that such a combination may be particularly useful in matrix tablets, since MCC is insoluble in aqueous environment but swells when contacted with water; calcium phosphate is inactive and insoluble; and the combination of both also contributes to maintaining the matrix structure over time.

[0052] As a tablet filler, sometimes also referred to as a filler-binder, microcrystalline cellulose, alone or in combination with, for example, calcium hydrogen phosphate dihydrate, has also been found to be particularly compatible with some of the preferred hydrophilic matrix formers, such as HPMC, since the microcrystalline cellulose does not interfere with the drug release controlling function of the matrix former, even when the latter is incorporated into the matrix tablet in only relatively small amounts, such as about 20% to 40% by weight, based on the total weight of the matrix tablet. Thus, according to another embodiment, the matrix tablet may comprise about 20% to 40% by weight of HPMC, and a combination of microcrystalline cellulose and calcium hydrogen phosphate dihydrate.

[0053] Microcrystalline cellulose or a portion thereof may also be incorporated in the form of silicified microcrystalline cellulose. When used as a tablet filler, silicified microcrystalline cellulose, which also functions as a flow agent, can simultaneously replace other commonly used flow agents such as colloidal silica, also called colloidal silicon dioxide. In addition, silicified microcrystalline cellulose can impart superior binding properties compared to non-silicified microcrystalline cellulose. When silicified microcrystalline cellulose is incorporated in a matrix tablet, its amount in the matrix tablet may range, for example, from about 15% to about 25% by weight based on the total weight of the matrix tablet, such as from about 20% to 22% by weight based on the total weight of the matrix tablet. The amount of tablet filler in the matrix tablet may range, for example, from about 20% to about 80% by weight based on the total weight of the matrix tablet. In one preferred embodiment, the amount of tablet filler ranges from about 25% to about 65% by weight, or from about 30% to about 50% by weight, respectively. These ranges also apply to the total amount of tablet filler in matrix tablets in which more than one filler is used.

[0054] Regarding the combination of crystalline cellulose and calcium hydrogen phosphate dihydrate, the weight ratio of crystalline cellulose to calcium hydrogen phosphate dihydrate can be, for example, in the range of about 1:9 to 9:1, or about 2:8 to about 8:2. A weight ratio of about 4:6 to 6:4, for example about 5:5, is also preferred. For example, the matrix tablet can contain about 20% to 40% by weight of HPMC and about 30% to 50% by weight of a combination of crystalline cellulose and calcium hydrogen phosphate dihydrate, based on the total weight of the matrix tablet, and the weight ratio of crystalline cellulose to calcium hydrogen phosphate dihydrate is in the range of 4:6 to 6:4.

[0055] According to another preferred embodiment, the matrix tablet further comprises a flow agent and / or a lubricant. Related embodiments, in which the matrix tablet comprises a hydrophilic matrix-forming polymer, a tablet filler, a flow agent and a lubricant, are also preferred.

[0056] A flow agent is an excipient that improves the flow properties of a powder or granule by reducing interparticle friction and cohesion. Potentially suitable flow agents include, but are not limited to, silicon dioxide, especially colloidal silicon dioxide, anhydrous colloidal silica, peptized silica, talc, magnesium trisilicate, or powdered cellulose. In one embodiment, the flow agent is colloidal silicon dioxide. The flow agent can be present in the matrix tablet, for example, in an amount of about 0.1% to about 5% by weight, especially about 0.1% to about 3% by weight, based on the total weight of the matrix tablet. When two or more flow agents are present in the matrix tablet, these amounts refer to the total amount of flow agents. According to another preferred embodiment, the matrix tablet comprises about 0.2% to 2% by weight of colloidal silicon dioxide.

[0057] In the context of pharmaceutical tablet compression, a lubricant can be understood as an excipient that reduces friction between the surface of a powder, granule or tablet on the one hand and the walls of the die and tablet punches of the tablet press on the other hand. Thus, the lubricant reduces the wear and tear of the tablet die and punches. Potentially suitable lubricants include, but are not limited to, magnesium stearate, polyoxyethylene glycol, aluminum stearate, calcium stearate, calcium behenate, castor seed oil, talc, sodium benzoate, glyceryl mono fatty acid, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated cottonseed oil, sodium lauryl sulfate, sodium stearyl fumarate, fumaric acid, and stearic acid. The lubricant can be present, for example, in the matrix tablet in an amount of about 0.1% to about 5% by weight, in particular about 0.1% to about 4% by weight, based on the total weight of the matrix tablet. When two or more lubricants are present in the matrix tablet, these amounts refer to the total amount of lubricant. In another preferred embodiment, the matrix tablet contains about 0.2% to 2% by weight of a lubricant, in particular magnesium stearate.

[0058] Matrix tablets may contain one or more additional excipients, also referred to as inactive ingredients, such as one or more excipients selected from wetting agents such as surfactants, binders, granulating agents, anti-caking agents, flavors, sweeteners, dyes, stabilizers, waxes, antioxidants, preservatives, and pH adjusters.

[0059] As described, the active ingredient, i.e., the BK B2 receptor antagonist represented by formula (1), can thus be incorporated into the matrix tablet, for example in the form of a powder that is provided and mixed with the inactive ingredient, typically also provided in the form of a powder or granules, to form a powder or granule mixture that can be compressed into a tablet. Alternatively, the active ingredient can be incorporated in a physical form, for example, a micronized or solubilized form, that is specifically adapted to promote the dissolution of the drug substance when contacted with water or an aqueous medium. Although such formulation techniques are sometimes proposed for oral immediate release compositions of poorly soluble active ingredients, as the inventors have found, the design of the matrix tablet generally achieves a sustained release of the active ingredient, and the micronized or solubilized form is surprisingly advantageous for the sustained release matrix tablet of the compound of formula (1), since factors such as pH, food, and gastric motility are only small or relatively moderately affected, and the active ingredient is reliably and completely released.

[0060] In view of the above, in one preferred embodiment, the BK B2 receptor antagonist represented by formula (1) is incorporated in a matrix tablet in a micronized form. Micronization, in the broad sense, refers to the reduction of the average particle diameter to the micrometer range, even if there are no precise and generally accepted upper and lower boundaries of such range. In the context of the present invention, a micronized form should be understood as a form of powder having an average particle size (D50) in the range of about 0.1 μm to about 50 μm. In some other preferred embodiments, the BK B2 receptor antagonist is incorporated in the matrix tablet as a powder having an average particle size (D50) in the range of about 0.2 μm to about 40 μm, about 0.5 μm to about 10 μm, respectively. D50 values ​​in the range of about 1 μm to about 10 μm, as measured by laser diffraction, are particularly preferred.

[0061] Even in preferred embodiments, the particle size distribution is narrow, with only a small portion of the particles being substantially smaller or larger than the D50 value. In one embodiment, the ratio of the D90 value to the D10 value of the micronized BK B2 receptor antagonist is about 15 or less, or about 10 or less, respectively. Such a small ratio of the D90 value to the D10 value is believed to favor good distribution of the active agent within the matrix tablet and to aid in achieving the desired drug release characteristics described above. In another embodiment, the D50 ranges from about 3 μm to about 7 μm, the D90 ranges from about 6 μm to about 14 μm, and the D10 ranges from about 0.5 μm to about 2 μm, respectively. As known to those skilled in the art, the D10 value and the D90 value, respectively, refer to percentile values, designating the particle size below which 10% or 90% of all particles are found. When measured by laser diffraction, the percentages are typically volume-weighted percentages.

[0062] The micronized form of the BK B2 receptor antagonist of formula (1) can be produced by commonly known micronization techniques. For example, various milling methods for producing micronized active ingredients are available and can be applied to the compound of formula (1). Optionally, co-milling of the BK B2 receptor antagonist with a hydrophilizing agent and optionally one or more other excipients can be used. Milling or co-milling can be carried out in conventional milling equipment such as ball mill, cross beater mill, air jet mill, pin mill, classifier mill, disk mill, mortar grinder, rotor mill, etc. Among the preferred mills used to micronize the BK B2 receptor antagonist are planetary mill and air jet mill.

[0063] In a preferred embodiment, a crystalline form of the BK B2 receptor antagonist of formula (1) is used to prepare the micronized active ingredient. In particular, crystalline (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide monohydrate can be incorporated into a matrix tablet.

[0064] For the avoidance of doubt, the incorporation of micronized active ingredients with a particular particle size distribution into a compressed tablet may or may not allow the recovery of the active ingredient still with the same particle size distribution as when it was incorporated. Tablet compression methods can change particle size and can make particle size measurement difficult. In the context of the present invention, a matrix tablet incorporating a material with a particular particle size characteristic should be interpreted to include a matrix tablet obtained from a method in which such a material is provided, mixed with the remaining components, and compressed into a matrix tablet, regardless of whether the specified particular particle size characteristic can still be observed in the matrix tablet.

[0065] In some alternative but still preferred embodiments, the BK B2 receptor antagonist is incorporated in a solubilized form into the matrix tablet. For example, the active ingredient can be provided and incorporated in the form of a formulated, prefabricated particle that contains the BK B2 receptor antagonist and one or more excipients.

[0066] As used herein, solubilized form should be understood as a form in which active ingredient is released in aqueous medium with a substantially increased dissolution rate due to the specific physical form of the active ingredient itself, the presence of one or more solubilizing excipients, or both.Solubilization techniques that can be used in pharmaceutical compositions for oral use are generally known to those skilled in the art, even though they are typically proposed for immediate release formulations rather than sustained release formulations, since sustained release formulations essentially require slow drug release and do not inherently require accelerated drug dissolution.Examples of solubilization techniques and solubilized forms that can be used to implement these embodiments of the present invention include, for example, but are not limited to, cyclodextrin inclusion complexes, the use of acids such as tartaric acid, citric acid or fumaric acid to maintain basic active ingredients in a more soluble ionized form, the use of bases such as meglumine to maintain acidic active ingredients in an ionized form; amphiphilic lipid-based nano- or microparticles, drug-micelle-forming surfactant mixtures, self-emulsifying or self-microemulsifying systems, and association with solid dispersions.

[0067] In some of these systems, the drug substance exists in amorphous rather than crystalline form. Using an amorphous active ingredient is never straightforward due to processability and stability challenges, but the amorphous form can dissolve much more rapidly than a crystalline form of the same compound with a similar particle size. The inventors have found that the amorphous form of the BK B2 receptor antagonist can indeed be used advantageously in matrix tablets. Therefore, another preferred embodiment provides that the matrix tablet contains the BK B2 receptor antagonist primarily in amorphous form, preferably in amorphous form. Amorphous means any non-crystalline form, such as a form in which the compound is molecularly dispersed or in which the compound forms amorphous domains in a carrier. For the avoidance of doubt, the presence of amorphous does not exclude the presence of any crystalline form. For example, the particles can contain the active ingredient in part amorphous and part crystalline form. In some preferred embodiments, the matrix tablet contains the BK B2 receptor antagonist solely in amorphous form.

[0068] According to some other preferred embodiments, the matrix tablet comprises a solid dispersion of an amorphous BK B2 receptor antagonist in a carrier, the carrier comprising at least one pharma- ceutically acceptable carrier polymer.It has been found, completely unexpectedly, by the inventors that the solid dispersion of the BK B2 receptor antagonist of formula (1) is not only effective in providing a rapid and complete release of this pharmacologically active ingredient into physiological medium, which is generally useful for designing an immediate release composition incorporating such a solid dispersion, but also can substantially improve the release from sustained release formulations of the compound of formula (1).In particular, the solid dispersion can provide a substantially complete release of the active ingredient, and reduce the variability of the release rate caused by external factors, such as the pH and composition of the liquid medium in which the active compound is released from the sustained release composition, whether the liquid medium is, for example, water, gastric fluid, intestinal fluid, or a substitute thereof, such as artificial gastric fluid, fasting simulated intestinal fluid (FaSSIF) or fed simulated intestinal fluid (FeSSIF). In contrast, it has been found that conventional sustained release formulation techniques, when applied to compounds of formula (1), result in unreliable drug release, unsatisfactory release profiles, and unpredictable absorption rates.

[0069] In this context, a solid dispersion can be understood as a solid material that contains a compound, such as a drug substance, that is preferably homogeneously dispersed in an amorphous polymer matrix. Typically, the dispersed compound is also in an amorphous state, i.e. non-crystalline. For example, the dispersed compound may be molecularly dispersed or dispersed in the form of amorphous domains.

[0070] In a generally preferred embodiment, the amorphous form of the BK B2 receptor antagonist is quantitatively predominant in the solid dispersion.In other words, even if some amount of crystalline BK B2 receptor antagonist is present in the solid dispersion, the amount of amorphous form may be greater or substantially greater than the amount of crystalline form.In another generally preferred embodiment, at least about 90%, or at least 95% or even at least 99% of the BK B2 receptor antagonist contained in the solid dispersion is amorphous.Moreover, preferably, all or substantially all of the BK B2 receptor antagonist is amorphous.In this context, the percentage standard is the total molar amount of the BK B2 receptor antagonist in the solid dispersion.

[0071] In another embodiment, the state of the compound of formula (1) in the solid dispersion is substantially non-ionized, and may be completely non-ionized. Moreover, when the compound of formula (1) is present in the solid dispersion as it is, it does not usually show a solvate. However, for the avoidance of doubt, the compound may be in the form of a solvate when combined with the carrier polymer and any other components to form the solid dispersion disclosed herein. For example, a hydrate, such as a monohydrate, of the compound, optionally in crystalline form, may be used to prepare the composition. However, it is considered that it no longer shows crystalline material or hydrate when incorporated into the solid dispersion. Furthermore, in one of the other preferred embodiments, the compound of formula (1) is the sole drug substance contained in the solid dispersion. This is a preference that is generally applicable within the context of this disclosure.

[0072] As described, the solid dispersion comprises a carrier comprising at least one pharma- ceutically acceptable carrier polymer in which the BK B2 receptor antagonist is dispersed.In this context, carrier typically means an excipient or combination of excipients in which the active ingredient is dispersed.The carrier may be composed of a polymer or a combination of polymers.In other cases, the carrier may comprise one or more other excipients, such as one or more stabilizers, plasticizers, non-polymeric surfactants, etc.

[0073] Carrier polymer can be selected from polymers that are suitable for oral administration and can incorporate BK B2 receptor antagonist in the form of solid dispersion.In this context, the polymer in which active ingredient is embedded or dispersed to form solid dispersion may be referred to as carrier polymer herein, indicating its carrier function in solid dispersion, not its chemical nature.For the avoidance of doubt, polymers such as HPMC that are potentially suitable for use as hydrophilic matrix-forming polymer in matrix tablets may also be useful candidates for use as carrier polymer for solid dispersion.

[0074] The carrier polymer may, for example, be selected from the group consisting of hydrophilic neutral and anionizable polymers. In this context, hydrophilic means that the polymer exhibits at least some moderate solubility or swelling in aqueous media having pH values ​​of the gastrointestinal tract, i.e., a pH in the range of pH 1 to pH 8. Neutral means that an aqueous solution of the polymer has an approximately neutral effect, at least in the absence of other solutes. Preferably, the neutral polymer is also a non-ionic polymer. Anionizable means that the polymer contains moieties that are easily deprotonated when dissolved in an aqueous medium, except at acidic pH. Anionizable pharma- ceutically acceptable hydrophilic polymers may also be used as gastroresistant or enteric polymers. Furthermore, the polymer is optionally a non-crosslinked polymer.

[0075] According to another preferred embodiment, the pharma- ceutical acceptable polymer in which the BK B2 receptor antagonist is dispersed amorphously and homogeneously is a thermoplastic polymer, i.e. a polymer that becomes flexible or moldable at high temperature and becomes solid again when cooled, for example, to room temperature.A thermoplastic polymer can also be understood as a polymer that undergoes a glass transition temperature (Tg) while maintaining chemical stability when heat is applied.In one embodiment, the polymer is a water-soluble (optionally pH-dependent), neutral (e.g., non-ionic or also non-ionizable) or anionizable polymer, and a thermoplastic polymer.

[0076] Specific carrier polymers that can be selected include hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), povidone (PVP), copovidone (PVP / PA), polyethylene glycol (PEG), and polyethylene oxide (PEO). Each of these polymers can be used individually to form a solid dispersion incorporating BK B2 receptor antagonist. Alternatively, any combination of two or more of these polymers can be used, such as HPC in combination with HPMC, HPMC in combination with HPMCAS, PVP in combination with PVP / PA, or any other combination. In some preferred embodiments, the carrier polymer is selected from HPMC, HPMCAS, copovidone, and combinations thereof.

[0077] In one preferred embodiment, the pharma- ceutically acceptable carrier polymer included in the solid dispersion is HPMCAS. HPMCAS, i.e., hydroxypropyl methylcellulose acetate succinate, is an example of a hydrophilic anionizable polymer with pH-dependent solubility, since it is insoluble in water at acidic pH but soluble at neutral or alkaline pH. HPMCAS can be understood as hydroxypropyl methylcellulose esterified with a mixture of acetic acid and succinic acid. In general, HPMCAS contains about 12% to about 28% methoxy groups, about 4% to about 23% hydroxypropyl groups, about 2% to about 16% acetyl groups, and about 4% to about 28% succinoyl groups, calculated on a dry basis. HPMCAS is an exemplary pharma- ceutically acceptable carrier polymer, which is also a thermoplastic polymer, and is further hydrophilic and anionizable. Various grades of HPMCAS have an average particle size in the range of about 5 μm and a viscosity of about 3 mPa. * HPMCAS-LF is available, featuring a viscosity range of s.

[0078] The inventors have found that the BK B2 receptor antagonists of formula (1) are not only surprisingly compatible with HPMCAS, but also form solid dispersions at a variety of useful weight ratios of drug substance to polymer. The respective solid dispersions have also been found to be highly stable, both chemically and physically, i.e., they exhibit little chemical degradation and only a very low tendency for the drug substance to form crystals over time. Furthermore, surprisingly, solid dispersions of the compound of formula (1) and HPMCAS exhibit very useful drug release profiles, despite the pH-dependent solubility of the polymer.

[0079] Alternatively, the solid dispersion can contain copovidone (PVP / PA). It has been found that this carrier polymer also allows the formation of advantageous solid dispersions containing the compound of formula (1). These solid dispersions are also chemically and physically stable. One of their additional advantages is that they allow high drug loading for BK B2 receptor antagonists.

[0080] Copovidone, also called copolyvidone, PVP / VA copolymer, or polyvinylpyrrolidone-vinyl acetate copolymer, is obtained by free radical polymerization of vinylpyrrolidone and vinyl acetate in a molar ratio of about 6:4. Typical molecular weights range from about 45,000 to 70,000. Examples of currently commercially available copovidone products include Kollidon VA 64 and Luviskol VA. Grades with different average particle sizes are also available.

[0081] In addition to the above carrier polymer, one or more other polymers can be present in the solid dispersion. Furthermore, the solid dispersion claimed herein can also include a surfactant. In one embodiment, the surfactant is a non-ionic surfactant, particularly a non-ionic surfactant selected from the group of poloxamers and polysorbates. It is recognized that these surfactants can also be considered as polymers. In other words, they can also function as contributors to the effect of polymeric drug carriers forming solid dispersions with drug substances. They also function as surfactants because they enhance the wetting of the solid dispersion upon contact with an aqueous medium such as water.

[0082] Poloxamers, also known as polyethylene-propylene glycol copolymers or polyoxyethylene-polyoxypropylene copolymers, are polyol block copolymers, each containing a block of polyoxypropylene sandwiched between two blocks of polyoxyethylene. A variety of grades are available with different molecular weight ranges and different molecular ratios between the polyoxypropylene and polyoxyethylene blocks, such as Poloxamer 124, 188, 237, 338 and 407.

[0083] The inventors have found poloxamer 188 to be particularly useful. It is a solid material having an average molecular weight in the range of about 7,680 to 9,510, with the polyoxypropylene oxide blocks containing on average about 27 repeat units and the polyoxyethylene blocks containing on average about 80 repeat units. Poloxamer 188 in combination with copovidone is particularly advantageous.

[0084] Polysorbates, also called polyoxyethylene sorbitan fatty acid esters, are another group of nonionic surfactants that can be used as excipients in the formulation of solid dispersions disclosed herein.Potentially suitable polysorbates include polysorbate 20, 40, 60, 65 and 80, especially polysorbate 20, also known as polyoxyethylene 20 sorbitan monolaurate, with average molecular weight of 1,128, and polysorbate 80, whose chemical name is polyoxyethylene 20 sorbitan monooleate, with molecular weight of 1,310.A well-known brand product series is Tween.

[0085] Typically, the amount of nonionic surfactant present in the solid dispersion is substantially lower than the amount of non-surfactant carrier polymer, e.g., hydrophilic neutral or anionizable polymer. Furthermore, typically, the amount of nonionic surfactant in the solid dispersion is lower than the amount of active ingredient. In one specific embodiment, the amount of nonionic surfactant in the solid dispersion is in the range of about 0.5% to about 10% by weight, or about 0.5% to about 5% by weight, based on the total weight of the solid dispersion. In another specific embodiment, the weight ratio of nonionic surfactant to polymer, or the weight ratio of nonionic surfactant to polymer combination, when a combination of two or more polymers is present, is in the range of about 1:100 to about 20:100, or about 1:100 to about 10:100, respectively.

[0086] In one preferred embodiment, the solid dispersion exhibits a BK B2 receptor antagonist content of at least about 10% by weight based on the total weight of the solid dispersion.As mentioned above, it is also a preferred embodiment that the BK B2 receptor antagonist of formula (1) is the sole drug substance in the solid dispersion.Therefore, the range of at least about 10% by weight also exhibits a favorable drug loading of the solid dispersion.

[0087] According to another preferred embodiment, the solid dispersion exhibits a BK B2 receptor antagonist of formula (1) content in the range of about 10% to about 50% by weight, about 15% to about 50% by weight, or about 15% to about 45% by weight based on the total weight of the solid dispersion. In further related embodiments, the solid dispersion exhibits a drug content in the range of about 10% to about 50% by weight, about 15% to about 50% by weight, or about 15% to about 45% by weight, and the BK B2 receptor antagonist of formula (1) represents the sole drug substance present in the solid dispersion. It was unexpected that such high drug loadings could be achieved in compounds of formula (1) without significant chemical or physical instability when following the guidance set forth in this disclosure.

[0088] In another preferred embodiment, the solid dispersion comprises the BK B2 receptor antagonist of formula (1) and about 55% to about 85% by weight, e.g., about 75% to 85% by weight, of the polymer HPMCAS, based on the total weight of the solid dispersion. In a related embodiment, a solid dispersion is provided that consists essentially of about 15% to 45% by weight, e.g., about 15% to 25% by weight, of the BK B2 receptor antagonist of formula (1) and about 55% to about 85% by weight, e.g., about 75% to 85% by weight, of HPMCAS. For example, the solid dispersion may consist essentially of about 20% by weight of the BK B2 receptor antagonist of formula (1) and about 80% by weight of HPMCAS. The above ranges and corresponding weight ratios of drug substance to carrier polymer HPMCAS have been found by the inventors to result in solid dispersions that exhibit sufficiently high drug loading to allow for effective and convenient administration, high product stability and shelf life, and a desirable release profile.

[0089] According to an alternative preferred embodiment, the solid dispersion comprises about 30% to 50% by weight of the BK B2 receptor antagonist of formula (1), about 50% to 70% by weight of copovidone, and optionally up to about 5% by weight of a poloxamer, such as poloxamer 188, based on the total weight of the solid dispersion. Furthermore, in a related embodiment in which no other components are present in the solid dispersion, a solid dispersion is provided that consists essentially of about 30% to 50% by weight of the BK B2 receptor antagonist of formula (1), about 50% to 70% by weight of copovidone, and optionally up to about 5% by weight of a poloxamer, such as poloxamer 188. For example, the solid dispersion can consist essentially of about 40% by weight of the BK B2 receptor antagonist of formula (1), about 58.5% by weight of copovidone, and about 1.5% by weight of poloxamer 188. These embodiments are advantageous because they allow for particularly high drug loading while at the same time being chemically and physically stable and providing useful drug release profiles.

[0090] As mentioned, the inventors have surprisingly found that the solid dispersions disclosed herein are particularly useful in formulations that release BK B2 receptor antagonists over an extended period of time, such as matrix tablets in some of their preferred embodiments. To facilitate the incorporation of the solid dispersions into matrix tablets, according to some preferred embodiments, the solid dispersions are provided in the form of powders or granules. Both powders and granules provide the solid dispersions in a multiparticulate, i.e., multiparticulate, format. In this context, the terms "powder" and "granules" should be understood as merely referring to approximate particle sizes, with powders referring to relatively fine multiparticulate materials and granules referring to relatively coarse materials, regardless of the manufacturing method by which these materials are obtained. In other words, the term "granules" should not be interpreted narrowly to require that a specific granulation method was used to generate the respective particles.

[0091] The solid dispersion for matrix tablets can be prepared by various methods generally known to those skilled in the art. For example, the method for preparing the solid dispersion can include a step of hot-melt extrusion of a powder or granule mixture containing BK B2 receptor antagonist and carrier polymer and optionally other excipients. Alternatively, the method can include a step of spray-drying an organic solution of BK B2 receptor antagonist and carrier polymer and optionally other excipients, or a step of spraying an organic solution of active ingredient and polymer onto particles of pharma-ceutical inert material under conditions that cause evaporation of organic solvent. In this context, furthermore, the BK B2 receptor antagonist is a compound represented by formula (1), in particular the compound represented by formula (1) in the preferred form disclosed above, and the carrier polymer is at least one pharma-ceutically acceptable carrier polymer, in which the BK B2 receptor antagonist is homogeneously dispersed.

[0092] Hot melt extrusion is a technique generally known in the pharmaceutical field. It is also generally known that in principle the technique can be used to produce melt extrudates. This includes the equipment that can potentially be used for hot melt extrusion and some of the common process parameters such as temperature and screw rotation speed if a screw extruder is used. Based on the technical guidance related to the composition of the solid dispersion described herein and taking into account the examples below, a person skilled in the art can easily prepare a melt extruded solid dispersion containing an active ingredient represented by formula (1).

[0093] Hot melt extrusion can be used to convert a powder or granular mixture containing the BK B2 receptor antagonist of formula (1) and at least one pharma- ceutical acceptable carrier polymer into an extrudate that exhibits a solid dispersion, since the active ingredient is homogeneously and amorphously dispersed in the carrier polymer and optionally other excipients. Hot melt extrusion involves heating, softening or melting, mixing or homogenizing, and extruding the mixture. It may also be described as a process in which the blended composition is heated and / or compressed to a molten (or softened) state, followed by extrusion through an orifice, forming the extruded product (extrudate) into its final shape and solidifying upon cooling. The blended composition can be conveyed through one or more heated zones. This is typically accomplished by a screw mechanism. The screw or set of screws can be rotated by a variable speed motor inside a cylindrical barrel, but there is only a small gap between the outer diameter of the screw and the inner diameter of the barrel. In this configuration, high shear occurs at the barrel walls and between the screw flights, which thoroughly mixes and deagglomerates the components of the powder or granular blend as they are transported through the extruder. Extrudate refers to the composition formed by hot melt extrusion.

[0094] In one embodiment, the hot melt extrusion step comprises the following substeps: (i) adding the optionally crystalline BK B2 receptor antagonist of formula (1) (or, for example, its hydrate) and the carrier polymer (and optionally other excipients) to a hot melt extrusion device; (ii) melting the BK B2 receptor antagonist and the polymer at a temperature close to or above the melting point of the BK B2 receptor antagonist and substantially below its decomposition temperature; (iii) mixing the BK B2 receptor antagonist and the carrier polymer to form a homogeneous blend; (iv) extruding the homogeneous blend to form a solid dispersion shaped as an extrudate. Steps (ii) and (iii) may be performed simultaneously, or step (iii) may begin as soon as the optionally crystalline BK B2 receptor antagonist of formula (1) and the carrier polymer begin to melt. Additionally, the BK B2 receptor antagonist starting material in step (i) may be crystalline and subsequently converted to amorphous during the hot melt extrusion process.

[0095] In one preferred embodiment, the process comprising a hot melt extrusion step is carried out using a powder or granular mixture comprising about 15% to about 45% by weight, or such as about 15% to about 25% by weight, of the BK B2 receptor antagonist and about 55% to about 85% by weight, or such as about 75% to about 85% by weight, of HPMCAS, based on the total weight of the powder or granular mixture. In a related embodiment, a powder or granular mixture consisting essentially of about 15% to about 45% by weight, or about 15% to about 25% by weight, or such as about 20% by weight, of the BK B2 receptor antagonist and about 55% to about 85% by weight, or such as about 75% to about 85% by weight, or such as about 80% by weight, of HPMCAS, is subjected to hot melt extrusion so as to obtain a melt extrudate exhibiting a solid dispersion.

[0096] In another preferred embodiment, the hot melt extrusion step is carried out with a powder or granular mixture comprising about 30% to 50% by weight of the BK B2 receptor antagonist, about 50% to 70% by weight of copovidone, and optionally up to 5% by weight of poloxamer, particularly poloxamer 188, based on the total weight of the powder or granular mixture. In a related embodiment, the powder or granular mixture consists of about 30% to 50% by weight (such as about 40%) of the BK B2 receptor antagonist, about 50% to 70% by weight (such as about 58.5%) of copovidone, and optionally up to 5% by weight (such as about 1 to 2%) of poloxamer, particularly poloxamer 188. For the avoidance of doubt, in these and the previous embodiments, the weight percentages are based on the weight of the powder or granular mixture subjected to the hot melt extrusion step.

[0097] The extrusion temperature, in some preferred embodiments, is determined based on the glass transition temperature (T g ) or the highest T when more than one carrier polymer is used. g The carrier polymer T g In a related preferred embodiment, the extrusion temperature is selected to be above the melting temperature of the active ingredient as well. For example, extrusion at a temperature at least about 20° C. above the melting point of the API promotes solubilization of the drug substance in the carrier polymer. In another preferred embodiment, extrusion is performed at a temperature above the T g The extrusion temperature is preferably at least about 20° C. higher than the extrusion temperature of the extruder. In practice, the extruder may have several temperature zones that may be set at different temperatures. In this context, the extrusion temperature is to be understood as the temperature of the extruder zone having the highest temperature.

[0098] As mentioned, the solid dispersion disclosed herein can also be prepared using a method that includes a step of spray drying an organic solution of the BK B2 receptor antagonist and carrier polymer (and optionally other excipients), i.e. at least one pharma- ceutically acceptable carrier polymer in which the BK B2 receptor antagonist of formula (1) is amorphously and homogeneously dispersed. Prior to the actual spray drying step, an organic solution of the BK B2 receptor antagonist of formula (1) and carrier polymer (and any other components of the solid dispersion that may be optionally incorporated) in an organic solvent that is pharma- ceutically suitable for the spray drying process and capable of completely dissolving both the active ingredient and the carrier polymer must be prepared. This can be done by any conventional method of adding a granular or powdery solid to an organic solvent under conditions that lead to the dissolution of the solid (e.g., stirring or elevated temperature).

[0099] Organic solvents that may be used in this context include, for example, methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, ethyl acetate, and mixtures thereof. Optionally, the solvent or solvent mixture can contain limited amounts of water.

[0100] The spray drying step itself can be described as atomization under conditions that allow evaporation of the organic solvent. For example, atomization can be performed by a nozzle or on a rotating disk. Another drying step, such as fluidized bed drying, vacuum drying, tray drying, microwave drying, drum drying or double cone vacuum drying, can be used subsequently to reduce residual solvent to a pharma-ceutically acceptable level. In general, spray drying refers to contacting a highly dispersed liquid suspension or solution with a sufficient volume of air to cause evaporation and drying of the droplets. Optionally, an organic solution of the BK B2 receptor antagonist represented by formula (1) and the carrier polymer (and any other excipients to be incorporated into the carrier or in the case of a solid dispersion) is injected into a warm filtered air or inert gas flow to evaporate the solvent. The dried product particles can be conveyed to an accumulator, such as a cyclone-type particle collector.

[0101] Typically, the spray drying step is carried out at a temperature (i.e., inlet temperature) ranging from about 40°C to 150°C, or about 50°C to 150°C, depending on the organic solvent used. In some embodiments, the inlet temperature is about 80°C to 120°C. The outlet temperature of the spray drying is typically lower, for example about 40°C to 100°C or 40°C to 75°C. For example, fluidized bed drying (such as about room temperature to about 100°C), vacuum drying (such as about room temperature to about 200°C), for example about room temperature to about 65°C, for example about 45°C.

[0102] Besides the methods that rely on hot melt extrusion or spray drying, several other techniques or methods can also be used to prepare the solid dispersions incorporated into the matrix tablets disclosed herein. These methods include, for example, low temperature processing techniques, freeze drying, fluidized bed coating, microwave irradiation, co-precipitation, electrostatic spinning, supercritical anti-solvent precipitation, spray congealing, spray coating of carrier particles, melt agglomeration, etc.

[0103] As mentioned above, the solid dispersion for matrix tablets disclosed herein can be provided in the form of powder or granules. Both powder and granules provide the solid dispersion as multiple particles, i.e. in a multiparticulate format. Such powder or granules can be obtained directly by the technique applied to prepare the solid dispersion. For example, when spray drying or a method including a spray drying step is used to prepare the solid dispersion, the direct product obtained from such a method is already in the form of a powder or granules. Optionally, a subsequent step of adjusting the particle size (distribution) of the product, such as sieving, milling, or agglomeration, can be carried out. When a method including a hot melt extrusion step is used, the product obtained directly from the extrusion step is typically not in the form of a powder or granules, but in the form of larger units or elongated pieces, such as cylindrical rods, which can then be cut or pelletized into smaller units. The tools for cutting or pelletizing the extrudate can be incorporated as a downstream module of the extrusion device. If another grinding is required, taking into account the desired particle size, a separate subsequent milling step can be used, optionally followed by a classification step, such as sieving.

[0104] In another preferred embodiment, the solid dispersion is in the form of a powder or granules and is prepared by a method comprising the above-mentioned hot melt extrusion step and a milling step in which the extrudate is converted into a powder or granule, optionally including an intermediate step of cutting or pelleting the extrudate prior to milling. Milling can be carried out using any pharma- ceutically suitable equipment, such as a hammer mill, centrifugal impact mill, jet mill, ball mill, cone mill, or vibratory and rotary sieve mill, to name just a few. Optionally, milling is carried out at a controlled temperature or under cooling. The milling process itself can include screening or classifying the milled particles, depending on the milling method and the type of equipment used. Alternatively, a separate screening or classifying step can be carried out after milling. Milling of the extrudate can be carried out, optionally including a subsequent screening step, to achieve an average particle size in the range of about 50 μm to 800 μm, or another preferred range of about 100 μm to 700 μm, respectively. In this context, the average particle size typically means the D50 value of the powder or granules as measured by laser diffraction. Alternatively, if the particle size distribution is characterized by sieve analysis, the more relevant parameter is the mass median sieve diameter, which according to some preferred embodiments is also in the range of about 50 μm to 800 μm, or about 100 μm to 700 μm, or about 150 μm to 500 μm.

[0105] In another preferred embodiment, the solid dispersion is incorporated into the matrix tablet in the form of particles with a mean particle size D50 of 250 μm or less. In this context, the respective mean particle size D50 should be understood as characterizing the particle size distribution of the solid dispersion particles before compression, i.e. before the formation of the matrix tablet. As the skilled person will understand, the mean particle size D50 can be affected by compression, and it can also be difficult to isolate the solid dispersion particles again after compression to determine their particle size distribution.

[0106] In some alternative preferred embodiments, the mean particle size D50 of the solid dispersion when incorporated into a matrix tablet is in the range of 125-250 μm, or in the range of about 63-125 μm, respectively, as determined by gravimetric sieve analysis. Solid dispersion particles having a mean particle size D50 substantially below 100 μm, for example even about 50±25 μm or 10±5 μm, respectively, preferably as determined by laser diffraction, are also useful.

[0107] In some preferred embodiments, the solid dispersion incorporated into the matrix tablet contains at least about 10% by weight of the BK B2 receptor antagonist based on the total weight of the solid dispersion. Other preferred amounts of the BK B2 receptor antagonist, particularly (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, range from about 10% to about 50% by weight, from about 15% to about 45% by weight, or from about 20% to about 40% by weight, based on the total weight of the solid dispersion, respectively.

[0108] More preferred is a solid dispersion particle containing about 15% to about 25% by weight of a BK B2 receptor antagonist, for example about 20% by weight of (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide amorphously dispersed in 80% by weight of hypromellose acetate succinate. In another preferred embodiment, about 25% by weight of (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide is amorphously dispersed in 75% by weight of hypromellose acetate succinate; or about 30% by weight of (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide is amorphously dispersed in 75% by weight of hypromellose acetate succinate. solid dispersion particles comprising about 35% by weight of (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide amorphously dispersed in 70% by weight of hypromellose acetate succinate; or about 35% by weight of (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide amorphously dispersed in 65% by weight of hypromellose acetate succinate are incorporated into a matrix tablet.

[0109] As described, the inventors have found that the incorporation of solid dispersions into matrix tablets, particularly sustained release matrix tablets, is unexpectedly advantageous, even though the solid dispersions themselves have drug solubilizing properties and would not be expected to be useful in providing slow drug release over an extended period of time. However, solid dispersions have been found to be highly compatible with the sustained release matrix tablet formulation techniques disclosed herein above, since slow drug release can be achieved, for example, over a period of about 8 to 24 hours, with the solid dispersion providing a more reliable release profile. Furthermore, the use of solid dispersions in sustained release formulations has been found to be associated with low or moderate food effects, contrary to what would normally be expected for sustained release compositions of BK B2 receptor antagonists of formula (1) given their solubility and intrinsic release behavior. In a preferred embodiment, the matrix tablet comprises about 10% to about 60% by weight of the solid dispersion, based on the total weight of the matrix tablet. In another preferred embodiment, the content of the solid dispersion in the matrix tablet is in the range of about 15% to about 50% by weight, particularly in the range of about 15% to about 40% by weight. In another preferred embodiment, the content of the solid dispersion in the matrix tablet is in the range of about 20% to about 40% by weight, such as about 20%, about 25%, about 30%, about 35%, or about 40% by weight, respectively. Furthermore, the percentages are based on the total weight of the matrix tablet, not including any optional coating.

[0110] In some other preferred embodiments, the matrix tablet is formulated to contain the solid dispersion in an amount that is somewhat similar to the amount of the hydrophilic matrix-forming polymer.For example, the weight ratio of the solid dispersion to the hydrophilic matrix-forming polymer can be in the range of 2:1 to 1:2.When more than one hydrophilic matrix-forming polymer is used, the preferred range of 2:1 to 1:2 applies to the weight ratio of the solid dispersion to the total weight of the hydrophilic matrix-forming polymer in the matrix tablet.

[0111] As mentioned, the matrix tablet may incorporate the solid dispersion in the form of a powder or granules, such as in the form of a milled extrudate as described above. In this context, besides the solid dispersion, the matrix tablet preferably comprises other excipients that may be necessary or useful for tablet compression but also for forming the matrix in which the solid dispersion powder or granules are embedded. The incorporation of the powder or granules into the compressed tablet may change certain properties of the solid dispersion described above. For example, when a powder or granule is incorporated into a compressed tablet, the flowability that typically characterizes a powder or granule may no longer be present. Furthermore, even if the particles representing a solid dispersion can be extracted from the matrix tablet with some technical difficulties, the parameters related to the particle size may no longer be the same as they were before the solid dispersion was incorporated into the tablet. In this regard, the embodiments related to the matrix tablet comprising a solid dispersion having optional or preferred characteristics described in the context of the solid dispersion should also be understood as covering matrix tablets that may be obtained from a powder or granule mixture incorporating such a solid dispersion by compressing these mixtures.

[0112] In one of the preferred embodiments, the BK B2 receptor antagonist of formula (1) is the only active ingredient in the matrix tablet. This should also be understood as a general preference in the context of the present invention. Alternatively, the pharmaceutical composition can contain one or more other active ingredients. The other or additional active ingredient or pharmaceutical active ingredient is preferably an active agent or pharmaceutical active ingredient that has utility in the prevention or treatment of one or more conditions that respond to BK B2 receptor modulation, including conditions selected from the group including skin disorders; eye diseases; ear diseases; oral, pharyngeal and respiratory diseases; gastrointestinal diseases; liver, gallbladder and pancreatic diseases; urinary tract and kidney diseases; male and female reproductive organ diseases; hormonal system diseases; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic system diseases; central nervous system disorders; brain disorders; musculoskeletal diseases; allergic disorders; pain; infections; inflammatory disorders; injuries; immune disorders; cancer; genetic diseases; and edema. For example, at least one compound or pharma- ceutically acceptable salt of the present invention may be advantageously included in a combination preparation that includes an antibiotic, antifungal, or antiviral agent, an antihistamine, a nonsteroidal anti-inflammatory drug, a disease-modifying antirheumatic drug, a cytostatic drug, a drug having smooth muscle modulating activity, an antibody, or a mixture of the above as another or additional active agent or medicament active ingredient.

[0113] Matrix tablets may further be described in terms of the dosage strength or amount of BK B2 receptor antagonist of formula (1) incorporated per dosage unit, i.e., per capsule or tablet. In some embodiments, the dosage strength is in the range of about 1 mg to about 100 mg, or about 5 mg to about 100 mg, respectively. In another preferred embodiment, the dosage strength is in the range of about 10 mg to about 80 mg, for example about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, or 80 mg, respectively. For pediatric use, lower doses such as about 0.5 mg to about 5 mg may also be useful.

[0114] In some preferred embodiments, the matrix tablet comprises: About 15% to 40% by weight of a solid dispersion; about 20% to 40% by weight of a hydrophilic matrix-forming polymer, and Approximately 30% to 50% by weight of filler Includes.

[0115] According to some alternative preferred embodiments, the matrix tablet comprises: About 20% to 40% by weight of a solid dispersion; About 20% to 40% by weight of hydroxypropyl methylcellulose, or a combination of different grades of hydroxypropyl methylcellulose; About 30% to 50% by weight of microcrystalline cellulose, calcium hydrogen phosphate dihydrate, or a combination thereof; up to about 2% by weight of a flow agent, in particular colloidal silicon dioxide, and up to about 2% by weight of a lubricant, especially magnesium stearate Includes.

[0116] For the avoidance of doubt, in this context, all weight percentage values ​​are based on the total weight (100%) of the matrix tablet, not including its optional coating. In other words, the total weight percentage of all ingredients contained in the matrix tablet disclosed herein does not exceed 100%.

[0117] Further, even in these embodiments, the solid dispersion may represent a solid dispersion according to some of the preferences described above, for example, it may consist essentially of about 15% to about 45% by weight, or about 15% to 25% by weight of the BK B2 receptor antagonist of formula (1) and about 55% to about 85% by weight, or about 75% to 85% by weight of HPMCAS, or it may consist essentially of about 30% to 50% by weight of the BK B2 receptor antagonist of formula (1), about 50% to 70% by weight of copovidone, and optionally up to about 5% by weight of a poloxamer, such as poloxamer 188.

[0118] As already mentioned, matrix tablets can further comprise a coating, for example, to improve the appearance or swallowability of the tablet. If a coating is present, it is preferably a film coating, for example, a coating comprising a water-soluble film-forming polymer and a plasticizer. The film coating can also comprise more than one polymer and / or more than one plasticizer (e.g., glycerol). In addition, the film coating can comprise other components that are not intended to modify the release of the drug, such as one or more dyes, pigments (e.g., iron oxide), flavors, sweeteners, diluents (e.g., MCC), and opacifiers (e.g., calcium carbonate or calcium phosphate), which are often used in tablet coatings.

[0119] In some embodiments, the amount of coating applied to the matrix tablet is about 10% by weight or less. In this context, percentages are used based on the weight of the uncoated tablet and the weight of the film coating in the dry state, i.e. after removal of the solvent. In another embodiment, the amount of coating is 2% to 8% by weight based on the weight of the uncoated tablet.

[0120] In another aspect, the present invention provides a method for preparing a matrix tablet, in particular a sustained release matrix tablet comprising the solid dispersion disclosed above, comprising the steps of: (a) providing a solid dispersion in powder or granular form, the solid dispersion comprising a BK B2 receptor antagonist and a carrier comprising at least one pharma- ceutically acceptable carrier polymer, the BK B2 receptor antagonist being amorphous and dispersed in the carrier; (b) combining the solid dispersion with a hydrophilic matrix-forming polymer (or combination of hydrophilic matrix-forming polymers), a filler, and optionally other excipients to form a compressible powder or granular mixture; and (c) compressing the powder or granular mixture to obtain a matrix tablet. Step (a) may comprise one or more substeps directed to the preparation of the solid dispersion, as described above, for example by hot melt extrusion, optionally followed by milling, or spray drying.

[0121] For example, according to one preferred embodiment, the method includes the steps of (a) providing a solid dispersion in powder or granular form, the solid dispersion being a milled extrudate comprising (1) about 15% to about 45% by weight, e.g., about 15% to 25% by weight, of a BK B2 receptor antagonist of formula (1) and about 55% to about 85% by weight, e.g., about 75% to about 85% by weight of HPMCAS, or (ii) about 30% to 50% by weight of a BK B2 receptor antagonist of formula (1) and about 50% to 70% by weight of copovidone, and optionally up to about 5% by weight of a poloxamer, e.g., poloxamer 188, and a carrier comprising or consisting essentially of HPMCAS. The B2 receptor antagonist is amorphous and dispersed in a carrier; (b) combining the solid dispersion with about 20% to 40% by weight of a hydrophilic matrix-forming polymer, which is hypromellose, about 30% to 50% by weight of a tablet filler, which is calcium hydrogen phosphate dihydrate, or a combination thereof, and optionally other excipients, to form a compressible powder or granule mixture; and (c) compressing the powder or granule mixture to obtain a matrix tablet.

[0122] As also illustrated by the examples, the matrix tablets described herein can be prepared without any agglomeration step that improves the flowability or compressibility of the powder or granule mixture from which the tablet is compressed. Thus, in some related embodiments, step (c) of compressing the powder or granule mixture to obtain a matrix tablet is performed without any prior dry or wet agglomeration step. In this particular context, agglomeration refers to any powder granulation process in which small primary powder particles agglomerate to form larger secondary particles. Other preferred embodiments of the preparation method will be understood by those skilled in the art based on the guidance provided in this disclosure, for example, regarding the selection of some preferred versions of BK B2 receptor antagonists, excipients and their amounts in solid dispersions, preparation methods related to solid dispersions, and excipients and their amounts in matrix tablets.

[0123] As already mentioned, the inventors have found that matrix tablets, particularly sustained release matrix tablets, according to any of the preferred embodiments disclosed above allow tailoring of clinically advantageous sustained release profiles of BK B2 receptor antagonists of formula (1), e.g. with good robustness and reliability, and reduced food effect, compared to conventional formulation techniques. This advantage is particularly evident in sustained release matrix tablets containing solid dispersions, using hydroxypropyl methylcellulose acetate succinate (HPMCAS) as the carrier polymer of the solid dispersion, i.e. as a pharma- ceutically acceptable carrier polymer in which the active ingredient is amorphous and homogeneously dispersed. Without wishing to be bound by a particular theory, these release characteristics may be related to the fact that HPMCAS is a polymer that is insoluble in acidic media (e.g., gastric juice), causing a relatively slow drug release in such an acidic environment, while the compound of formula (1) itself is poorly soluble, particularly in relatively neutral media (e.g., intestinal juice), causing a relatively slow drug release in such an environment, so that various pH-dependent effects on the drug release rate may be partially compensated. In other words, the design of a sustained release matrix tablet comprising a solid dispersion incorporating solubilized amorphous drug ensures effective drug release and oral bioavailability when the BK B2 receptor antagonist of formula (1) is formulated as a sustained release dosage form.

[0124] The sustained release profile is typically measured in a well-defined in vitro model to describe the behavior of the composition or formulation in a relevant biological environment, i.e., the behavior of the composition or formulation in a clinical situation after administration of the composition or formulation to a subject. As used herein, sustained release profile refers to the dissolution profile of a sustained release composition. Descriptions of some widely accepted dissolution models for determining the dissolution profile can be found, for example, in the United States Pharmacopeia (e.g., USP), General Chapter 1, 2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020, 2030, 2021, 2022, 2023, 2024, 2025, 2026, 2027, 2028, 2030, 2031, 2032, 2033, 2034, 2035, 2040, 2041, 2042, 2043, 2044, 2045, 2046, 2047, 2048, 2050, 2051, 2052, 2060, 2061, 2062, 2063, 2064, 2065, 2066, 2067, 2070, 2071, 2072, 2073, 2074, 2075, 2076, 2077, 2078, 20 <711> ("Dissolution"). For example, Apparatus II (paddle apparatus) as described in USP can be used to characterize the dissolution profile of the matrix tablets disclosed herein. In addition, it is preferable to use 1,000 mL of USP phosphate buffer (pH 6.8) containing 0.3% (w / v) sodium dodecyl sulfate as the dissolution medium. If the sustained release composition floats in the dissolution medium (e.g., as some sustained release matrix tablets tend to float), weights such as Japanese weights should be used to ensure that the composition remains submerged during dissolution testing. Optionally, alternative test conditions can be used if appropriate, taking into account guidance on dissolution testing issued by prominent regulatory offices such as the US FDA.

[0125] In some preferred embodiments, the matrix tablets, particularly the sustained release matrix tablets, comprising the solid dispersions disclosed above, whether coated or not, exhibit a release of the BK B2 receptor antagonist of formula (1) over at least about 6 hours, or over at least about 8 hours, for example, over about 8 to 24 hours. In another preferred embodiment, the sustained release composition releases the BK B2 receptor antagonist over 12 to 24 hours, as determined by dissolution testing using the preferred methods and conditions described herein above. In this context, 12 to 24 hours during which the active ingredient is released means that the time at which 95% of the active ingredient incorporated in the composition is released falls within the specified time. For example, the sustained release composition may be characterized by a dissolution profile that reaches 95% drug dissolution after about 12 hours, or about 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours, respectively.

[0126] The sustained release profile, or dissolution profile, may also be described in terms of the time it takes for about 50% of the incorporated drug to be released, i.e., dissolved. In some preferred embodiments, the sustained release composition reaches 50% dissolution within about 3-10 hours, or within about 4-8 hours, e.g., after about 4, 5, 6, 7, or 8 hours, respectively.

[0127] In some preferred embodiments, matrix tablets, particularly sustained release matrix tablets, comprising the solid dispersions disclosed above have dosage strengths in the range of about 10 mg to 80 mg, as defined above, and release the BK B2 receptor antagonist of formula (1) over a period of about 12 to 24 hours. Also preferred are embodiments in which the matrix tablet comprises a solid dispersion based on or incorporating HPMCAS, the tablet having a dosage strength of about 20 mg to 40 mg, and exhibiting release over a period of about 12 to 24 hours.

[0128] According to another aspect of the present invention, the matrix tablet disclosed herein, particularly the sustained release matrix tablet comprising solid dispersion, can be used in the treatment of subjects suffering from any disease or condition that responds to bradykinin B2 receptor modulation. Such conditions include conditions selected from the group including skin disorders; eye diseases; ear diseases; oral, pharyngeal and respiratory diseases; gastrointestinal diseases; liver, gallbladder and pancreatic diseases; urinary tract and kidney diseases; diseases of male and female reproductive organs; diseases of the hormonal system; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic system diseases; central nervous system disorders; brain disorders; musculoskeletal diseases; allergic disorders; pain; infections; inflammatory disorders; injuries; immune disorders; cancer; genetic diseases; and edema. In other words, one aspect of the present invention relates to a method for treating subjects suffering from any disease or condition that responds to bradykinin B2 receptor modulation, comprising administering the matrix tablet described above. Similarly, the present invention provides the use of the matrix tablet in the manufacture of a medicament for the treatment of any disease or condition that responds to bradykinin B2 receptor modulation.

[0129] As used herein, the terms "treatment", "treat" and the like should be construed to include any type of prophylactic or therapeutic treatment. It therefore includes the prevention, management or treatment of a disease or its recurrence, or any symptoms associated with such a disease or condition. Treatment includes acute and chronic treatment.

[0130] In the context of the present invention, chronic treatment refers to continuous treatment of a disease or condition, including repeated administration of a pharmaceutical agent according to a regular dosing regimen over an extended period of time, such as for at least one month or for at least three months. In some embodiments where the patient's or subject's condition does not improve, the compound of formula (1) is administered chronically, i.e., for an extended period of time, including the entire life of the patient or subject, to ameliorate or otherwise control or limit symptoms associated with the disease or condition in the patient or subject. For example, chronic treatment can include administration of one, two or three dosage units per day over such a period of time. In one preferred embodiment, the matrix tablets disclosed herein, particularly the extended release matrix tablets comprising solid dispersions, are used for chronic treatment or therapy over an extended period of time, such as for at least one month, of a disease or condition responsive to BK B2 receptor modulation, such as AE. In some preferred embodiments, the treatments disclosed herein, particularly the treatment of angioedema, particularly hereditary angioedema, are prophylactic treatments, i.e., treatments prior to the onset of symptoms, to prevent, delay or reduce the severity of symptoms.

[0131] As mentioned above, according to one of the preferred embodiments, there is provided a matrix tablet, in particular a sustained release matrix tablet according to any of the preferred embodiments disclosed above, such as a sustained release matrix tablet comprising a solid dispersion of a BK B2 receptor antagonist of formula (1), which the inventors have found to provide advantageous sustained release properties.It is believed that these properties also make such sustained release compositions particularly suitable for chronic or long-term treatment.One of the specific benefits provided by these compositions is that they provide effective and acceptable sustained plasma levels using a regimen of only one or two administrations per day.

[0132] For the avoidance of doubt, each treatment period does not require that the same dosing regimen is used throughout treatment.For example, when once-a-day administration is insufficient to treat a particular subject, the regimen can be switched to twice-a-day administration.Alternatively, the dose per administration event can be increased during chronic treatment.

[0133] The following diseases or conditions may be considered to be responsive, or at least potentially responsive, to bradykinin B2 receptor modulation.

[0134] Skin disorders include, but are not limited to, disorders such as skin aging, skin eruptions including bedsores, bedsore ulcers, sore, sensitive and paresthetized skin, erythema, rash, skin edema, bacterial, viral, fungal and parasitic induced skin infections including psoriasis, eczema, lichen, furuncles, abscesses, cellulitis, erysipelas, folliculitis and impetigo, lice, scabies and cold sores, acne, skin eruptions, atopic dermatitis, allergic contact dermatitis, neurodermatitis, radiation damage, sunburn, pruritus, itching, urticaria, psoriasis, mycosis, tissue ulceration, dermatitis including epidermolysis bullosa, wounds including wound healing disorders, burns, frostbite, venom-induced dermatitis and edema, alopecia, hair scales, corns, warts and whitlow.

[0135] Ocular diseases include, but are not limited to, inflammatory disorders such as scleritis, conjunctivitis, conjunctival edema, iritis, iridocyclitis, uveitis, chorioretinitis, as well as disorders such as retinal and choroidal circulatory disorders, bacterial eye infections, nonspecific conjunctivitis and eye irritation, retinopathy of prematurity, proliferative vitreoretinopathy, macular degeneration (including age-related macular degeneration, both wet and dry), corneal graft rejection, corneal damage, corneal scarring, corneal ulcers, corneal opacities, keratoconus, glaucoma (preferably open-angle glaucoma), myopia, ocular hypertension, ocular vascular damage, neovascularization, ocular fibrosis (e.g., anterior subcapsular fibrosis, posterior subcapsular opacities, posterior capsular opacities, corneal opacities after laser surgery, subconjunctival scarring after glaucoma surgery), proliferative vitreoretinopathy (PVR), bacterial eye infections including styes, and eyelash loss. Eye diseases include, but are not limited to, disorders such as Meniere's disease, inflammation of the middle ear, inflammation of the ear canal, and acute hearing loss.

[0136] Oral cavity, pharyngeal and respiratory diseases include inflammation of the oral mucosa and gums, including aphthae and stomatitis, periodontitis, epiglottitis, pharyngitis, laryngotracheitis, tonsillitis, cold, angina, rhinitis, including seasonal or perennial allergic rhinitis, rhinorrhea, sinusitis of whatever type, etiology or pathogenesis, or purulent or non-purulent sinusitis, acute and chronic sinusitis, and sinusitis which is a member selected from the group consisting of ethmoid, frontal, maxillary or sphenoid sinusitis, expectoration, e.g. pneumoconiosis of any type or origin, including for example aluminosis, anthraxosis, asbestosis, stone lung disease, siderosis, silicosis, tobacco disease, in particular byssinosis, bronchitis, cough, tracheitis, congestion, pneumonia, eosinophilic pulmonary infiltrates, chronic eosinophilic pneumonia, idiopathic pulmonary fibrosis and other fibrotic lung diseases, treatment-related fibrotic lung diseases, for example fibrotic lung diseases associated with radiation, methotrexate, chemotherapy, amiodarone or nitrofurantoin, sarcoidosis, acute respiratory distress syndrome (ARDS), bronchoconstriction, Asthma of any type, etiology or mechanism, or includes atopic asthma, non-atopic asthma, allergic and non-allergic asthma, extrinsic asthma caused by environmental factors, intrinsic asthma caused by pathophysiological disorders, bronchial asthma, IgE-mediated asthma, essential asthma and essential asthma of unknown or unclear origin, true asthma, emphysematous asthma, exercise-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infections, primary asthma, Asthma, which is a member selected from the group consisting of early stage asthma, wheezing infant syndrome, bronchial hyperresponsiveness, chronic obstructive pulmonary disease (COPD), COPD characterized by irreversible progressive airway obstruction, acute respiratory distress syndrome (ARDS) and other disorders resulting from drug treatments such as exacerbation of airway hyperresponsiveness, dyspnea, hyperoxic alveolar injury, emphysema, pleurisy, tuberculosis, exposure to high altitude i.e. acute mountain sickness and preferably high altitude pulmonary edema (HAPE), resistant cough, bronchial hyporesponsiveness.

[0137] Gastrointestinal diseases include, but are not limited to, disorders including esophagitis, gastritis, irritable stomach, gastric and duodenal ulcers, ileus, irritable colon, inflammatory bowel disease including Crohn's disease and ulcerative colitis, enteritis, hypertensive gastric and colonic disease, colitis, peritonitis, appendicitis, proctitis, gastrointestinal bleeding caused by portal hypertension, collateral circulation or hyperemia, post-gastrectomy dumping syndrome, digestive discomfort, diarrhea, hemorrhoids, helminthic diseases, abdominal colic and colic of the gastrointestinal system.

[0138] Liver, gallbladder and pancreatic diseases include, but are not limited to, disorders such as hepatitis, cirrhosis, liver fibrosis (e.g., due to viral (HBV / HCV) infection, toxins (alcohol), fatty liver, cholestasis, hypoxia), portal hypertension, hepatorenal syndrome, hepatic edema, cholangitis, cholecystitis, acute and chronic pancreatitis, and biliary colic.

[0139] Urinary tract and kidney diseases include, but are not limited to, urinary tract infections such as acute and chronic cystitis, interstitial cystitis, overactive bladder, overactive bladder, incontinence including, but not limited to, stress, urge and reflex urinary incontinence, benign prostatic hyperplasia, chronic kidney disease, urethritis, glomerulonephritis, renal glomerular disease, interstitial nephritis, pyelonephritis, inflammatory kidney diseases including polyuria, proteinuria, natriuresis, urinary Ca excretion, water balance disorders, electrolyte balance disorders, acid-base balance disorders and renal colic, renal fibrosis, chronic allograft renal dysfunction, contrast-induced nephropathy.

[0140] Diseases of the male and female reproductive systems include, but are not limited to, sperm motility changes, male infertility, orchitis, prostatitis, prostatic hyperplasia, mastitis, inflammatory pelvic disease, vaginal infection and pain, adnexitis, vaginitis, soft ulcers, syphilis, gonorrhea and ovarian hyperstimulation syndrome.

[0141] Hormonal disorders include, but are not limited to, menstrual disorders and pain, menopause, vomiting, premature uterine contractions, premature labor, endometriosis, endometritis, fibroids, and preeclampsia.

[0142] Metabolic diseases include, but are not limited to, diabetes including non-insulin dependent diabetes mellitus, diabetic retinopathy, diabetic macular edema, diabetic nephropathy and diabetic neuropathy, insulin resistance and diabetic ulcers, diseases of protein and purine metabolism such as gout, and disorders of lipid metabolism, hypoglycemia, and the like.

[0143] Cardiovascular diseases include vascular permeability, vasodilation, peripheral circulatory disorders, arterial circulatory disorders including aortic aneurysm, abdominal aortic aneurysm, and cerebral aortic aneurysm, hypertension and hypotension associated with sepsis, restenosis after percutaneous coronary intervention, atherosclerosis including atherosclerotic plaque rupture, venous disorders such as hemangiomas, angiofibromas, thrombosis, varicose swelling, phlebitis, thrombophlebitis, and venous thrombosis, heart disease, congestive heart failure, coronary heart disease, carcinoid syndrome, angina pectoris, cardiac rhythm disorders, inflammatory heart disease including endocarditis, pericarditis, and constrictive pericarditis, and myocarditis. , myocardial infarction, post-myocardial infarction syndrome, left ventricular dilation, post-ischemic reperfusion injury, shock and collapse, including septic, allergic, post-traumatic and hemodynamic shock, amniotic fluid embolism, systemic inflammatory response syndrome (SIRS), including SIRS caused by cardiopulmonary bypass during surgery, sepsis, and disorders including internal and external complications during cardiopulmonary bypass surgery, including, but not limited to, adverse hemodynamic effects following heparin reversal of protamine sulfate.

[0144] Hematological diseases include, but are not limited to, disorders such as coagulation, disseminated intravascular coagulation, hemorrhage, bleeding diathesis, hypercholesterolemia and hyperlipidemia, hypovolemic shock, paroxysmal nocturnal hemoglobinuria, and the like.

[0145] Lymphatic system disorders include, but are not limited to, splenomegaly, lymphangitis, lymphadenitis, and hypertrophic adenoids.

[0146] Disorders of the central nervous system include, but are not limited to, encephalitis, meningitis, encephalomyelitis, meningoencephalitis, hydrocephalus, amyotrophic lateral sclerosis, spinal cord trauma, spinal cord edema, demyelinating diseases of the nervous system, inflammatory diseases of the central nervous system including multiple sclerosis, aging, acute and chronic neurodegenerative disorders including Alzheimer's disease and Parkinson's disease, neuritis, and peripheral neuropathies, disorders such as depression, anorexia, anxiety and schizophrenia, sleep disorders, and the like.

[0147] Brain disorders include, but are not limited to, disorders such as nootropic or hypercognitive, cerebral amyloid angiopathy, stroke, head and brain trauma, traumatic brain injury, brain tumors, thermal brain injury, cerebral ischemia, cerebral hemorrhage, post-traumatic and post-ischemic cerebral edema, generalized cerebral edema, acute mountain sickness and preferably high altitude cerebral edema (HACE), cytotoxic cerebral edema, vasogenic cerebral edema, post-operative cerebral edema, cerebral edema associated with metabolic disease, increased permeability of the blood-brain barrier or blood-brain tumor barrier.

[0148] Musculoskeletal diseases include disorders such as rheumatoid arthritis of any type, etiology, or pathogenesis, osteoporosis, musculoskeletal pain and stiffness, spinal disc syndrome, and the like, including, but not limited to, inflammatory musculoskeletal disorders, arthropathy, osteoarthropathy, osteoarthritis, chondroporosis following joint trauma or relatively long-term joint immobilization following meniscal or patellar injury or ligament damage, acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, spondyloarthritis, septic arthritis, psoriatic arthritis, chronic polyarthritis, rheumatism, Sjogren's syndrome, low back pain, spondylitis, spondyloarthritis, ankylosing spondylitis, osteomyelitis, sprains, tendonitis, inflammation-induced bone resorption, fractures, and the like.

[0149] Allergic disorders include, but are not limited to, disorders such as general allergic reactions, food allergies, anaphylactic shock, allergic contact sensitivity, allergic skin reactions, allergic asthma, vernal conjunctivitis, and seasonal or perennial allergic rhinitis.

[0150] Pain includes, but is not limited to, central and peripheral mediated pain, vascular pain, visceral pain, inflammation mediated pain, neuralgic pain, referred pain, nociceptive pain, reflex pain, psychogenic pain, acute pain such as caused by acute injury, trauma or surgery to bone, muscle, tissue, soft tissue, organs, pain after insect bites, post-stroke pain syndrome, post-operative pain, pain associated with progressive disease, chronic pain such as caused by neuropathic pain conditions (including but not limited to complex regional pain syndrome, causalgia, Sudeck's disease, reflex sympathetic dystrophy, diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, cancer-related pain, pain associated with rheumatoid arthritis, osteoarthritis, tendonitis, gout, menstruation and angina, fibromyalgia, eye pain, back pain, headache, cluster headache, migraine, inflammatory pain that may be associated with acute or chronic inflammation). Inflammatory pain includes, but is not limited to, neuropathic pain, ischemic pain, arthritis-induced pain, acute or chronic inflammation-induced myalgia, acute or chronic inflammation-induced neuralgia, hyperalgesia.In addition, chemotherapy-induced peripheral neuropathy, hyperalgesia, opioid-induced hyperalgesia and fever are also included.In addition, the compound of the present invention is useful as an analgesic agent for use during general and monitored anesthesia.

[0151] Infectious diseases include, but are not limited to, diseases mediated by bacteria, viruses, fungi, parasites, protozoa, prions, or mycobacteria. In particular, the present invention is useful for the treatment of bacterial infections caused by Streptococcus, Escherichia, Salmonella, Staphylococcus, Klebsiella, Moracella, Haemophilus, and Yersinia. Examples of bacterial infections within the scope of the present invention include, but are not limited to, diseases such as plague, septicemia, typhus, food poisoning, tetanus, scarlet red, whooping cough, and diphtheria. Examples of viral infections within the scope of the present invention include, but are not limited to, diseases such as chickenpox, shingles, AIDS, influenza, smallpox, and childhood diseases such as rubella, mumps, and acute spinal cord anterior hornitis. The present invention is useful for the treatment of protozoan and parasitic infections caused by Schistosoma mansoni, Dermatofagoides farinae, and Plasmodium-induced malaria. Examples of prion infections within the scope of the present invention include, but are not limited to, bovine spongiform encephalopathy (BSE), Creutzfeldt-Jakob disease, and diseases such as kuru, dengue fever, and hemorrhagic fever.

[0152] Inflammatory disorders include, but are not limited to, disorders such as acute phase responses, local and systemic inflammation, and inflammation caused by other diseases of any type, etiology or pathogenesis, and inflammation caused by the inflammatory diseases specified within this application.

[0153] Injury: Within this application, the term "injury" includes, but is not limited to, multiple trauma, head trauma, pulmonary injuries, external, internal and surgical wounds.

[0154] Immune disorders include, but are not limited to, disorders such as hypersensitivity, autoimmune disorders, graft rejection in transplantation, transplant toxicity, granulomatous inflammation / tissue remodeling, myasthenia gravis, immunosuppression, immune complex diseases, antibody overproduction and underproduction, vasculitis, delayed graft function, and lupus.

[0155] Cancers include breast cancer, lung cancer (non-small cell lung cancer and small cell lung cancer), prostate cancer, oral cavity and pharynx (lips, tongue, oral cavity, pharynx), esophagus, stomach, small intestine, large intestine, colon, rectum, gallbladder and biliary tract, pancreas, larynx, lung, bone, osteosarcoma, cancer of connective tissue, Kaposi syndrome, skin cancer including melanoma and skin metastases, epidermoid carcinoma, basal cell carcinoma, cervix, endometrial body, ovaries, testes, bladder, ureters and urethra, kidneys, eyes, brain and central nervous system. These include, but are not limited to, solid tumor cancers including cancers of the nervous system, pseudotumor cerebri, sarcoma, sarcoid, thyroid and other endocrine glands (including but not limited to carcinoid tumors), hematopoietic malignancies including Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia and lymphomas including lymphocytic, granulocytic and monocytic lymphomas, disorders of tumor invasion, metastasis, ascites, tumor proliferation and angiogenesis.

[0156] Genetic diseases include, but are not limited to, disorders such as hereditary angioedema and angioneurotic edema, chondrocalcinosis, Huntington's disease, pancreatic fibrosis, and the like.

[0157] As used herein, edema includes, but is not limited to, generalized edema and edema caused by inflammation, factor XII deficiency-induced edema, drug-induced angioedema including but not limited to other drugs, such as angiotensin-converting enzyme inhibitor-induced angioedema, infection, burns, injuries, trauma, frostbite, surgery, sprains, fractures, exposure to high altitude (e.g., high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE)), genetic, autoimmune and other diseases and disorders, specifically, but not limited to, disorders specified in this application, stress-induced edema (palpable swelling) of the intestine. Known forms of angioedema (AE) include hereditary angioedema (HAE), acquired angioedema (AAE), bradykinin-mediated idiopathic nonhistaminergic angioedema, allergic angioedema, and drug-induced angioedema. The HAE can be any type of HAE, including type I HAE, type II HAE, or type III HAE.

[0158] Capillary leak syndrome includes, but is not limited to, systemic capillary leak syndrome in sepsis, burns, allergies, drug / toxin induced conditions, organ transplants and IL-2 cytokine therapy.

[0159] In another preferred embodiment, the matrix tablet, particularly the sustained release matrix tablet, according to any of the preferred embodiments disclosed herein is used in the treatment of AE, including HAE, AAE, bradykinin-mediated non-histaminergic idiopathic AE, allergic AE, and drug-induced AE. AE is an area of ​​swelling of the skin and the tissues beneath the skin or mucous membrane. Debilitating and often painful swelling can occur in the face, lips, tongue, hands and feet, genitals, gastrointestinal mucosa, genitourinary area, and respiratory tract. It is often associated with urticaria, which is swelling in the upper skin. It is characterized by repeated swelling episodes, with episodes typically lasting from minutes to hours. It is impossible to predict where and when the next episode of angioedema will occur. Patients may have one episode per month, but some have only one episode per week or one or two episodes per year.

[0160] In some preferred embodiments, the matrix tablets according to the preferred embodiments disclosed herein, particularly the sustained release matrix tablets, are used in the treatment of any type of HAE, including type I, type II or type III HAE, preferably type I or type II HAE. HAE is a disorder that manifests as recurrent attacks of severe swelling. The swelling often affects the arms, legs, face, intestines and even the airways. When the intestines are affected, abdominal pain and vomiting can occur. The swelling of the airways can result in bronchial obstruction and difficulty breathing. Acute attacks typically last several days, with HAE patients experiencing attacks about every two weeks.

[0161] Matrix tablets are particularly advantageous in chronic treatment of AE, including hereditary angioedema (HAE) and acquired angioedema (AAE), particularly HAE type I or HAE type II. As described, it is patient-friendly since it only requires once-daily administration or twice-daily administration. Considering that the sustained release profile is not dependent on pH fluctuations and the presence of food, these compositions are suitable for long-term treatment over months or years. In view of the above, one preferred embodiment is directed to the use of matrix tablets, particularly sustained release matrix tablets, according to any of the preferred embodiments disclosed herein for chronic treatment of hereditary angioedema, wherein the chronic treatment is preferably carried out over at least one month. As mentioned above, the chronic treatment can also be carried out over at least three months or at least one year, respectively. Chronic treatment using a dosing regimen including once-daily or twice-daily administration of matrix tablets is further preferred.

[0162] In other words, for the BK B2 receptor antagonists of formula (1), the matrix tablet design described herein allows for an extended release profile that allows for longer dosing intervals, thereby increasing patient friendliness and improving patient adherence to the prescribed dosing regimen, thus improving treatment outcomes.

[0163] Moreover, for the avoidance of doubt, each treatment period does not require that the same dosing regimen is used throughout treatment.For example, when once-a-day dosing becomes insufficient to treat a particular subject, the regimen can be switched to twice-a-day dosing.Alternatively, the dose of BK B2 receptor antagonist per dosing event can be increased within chronic treatment.

[0164] Further aspects, embodiments, optional features and preferences of the present invention will become apparent based on the examples and claims. Further definitions

[0165] For ease of understanding, here are some additional definitions of terms used throughout the specification and claims. The definitions should be used to determine the meaning of each expression unless the context requires a different meaning.

[0166] The terms "a" or "an" do not exclude a plurality; that is, the singular forms "a," "an," and "the" should be understood as including plural referents unless the context clearly indicates or requires otherwise. In other words, all references to singular features or limitations in this disclosure include the corresponding plural features or limitations, and vice versa, unless clearly specified otherwise or clearly indicated by the stated context to the contrary. Thus, the terms "a," "an," and "the" have the same meaning as "at least one" or "one or more," unless otherwise defined. For example, reference to "an ingredient" includes mixtures of ingredients, and the like.

[0167] The terms "about" or "ca." are accepted in the pharmaceutical industry to account for variability inherent in pharmaceuticals, such as manufacturing variations and / or differences in content due to product aging. The terms allow for any variation that, in pharmaceutical practice, may be considered to be bioequivalent in a subject to the stated strength of the claimed product.

[0168] The terms "active agent," "therapeutic agent," "active pharmaceutical ingredient (API)," "active ingredient," "drug," and "bioactive agent" are used interchangeably and refer to a compound or combination of compounds that is pharmacologic active against an undesirable condition.

[0169] The term "composition" refers to any type of composition in which the specified component may be incorporated, optionally with any other components.

[0170] "Pharmaceutical composition" in the context of the present invention should be understood as a composition that is technically suitable for administration to a subject, such as a human patient, as a pharmaceutical product. Its composition, formulation and processing are carried out according to common pharmaceutical standards, as may be defined in official pharmacopoeias or guidelines issued by regulatory agencies such as FDA, PMDA and EMA. In one preferred embodiment, the composition is adapted for oral administration. This implies that, for example, the excipients used, including their grades and their amounts, are safe and acceptable for oral use, particularly for oral administration to human subjects.

[0171] As used herein, a "controlled release composition" is any pharmaceutical composition or formulation adapted for oral administration that exhibits sustained release of an active ingredient. Controlled release may also be referred to as slow release, controlled release, or sustained release, to name just a few alternative terms, but without limitation.

[0172] The term "compound" refers to a chemical substance that is a material made up of molecules with essentially the same chemical structure and properties. In small molecule compounds, the molecules are typically identical in terms of their atomic composition and structural arrangement. In macromolecular or polymeric compounds, the molecules of the compound are highly similar, although not necessarily all of them are identical.

[0173] The terms "comprise," "comprises," and "comprising" and similar expressions are to be interpreted in an open and inclusive sense, such as "including, but not limited to."

[0174] The terms "essentially," "about," "approximately," "substantially," and the like, in connection with an attribute or value, include the exact attribute or exact value, and also include any attribute or value that is determined to fall within a normal range or variability typically accepted in the art. For example, "essentially free of water" means that water is not intentionally included in the composition, but does not exclude the presence of residual moisture.

[0175] The term "consisting essentially of" refers to a composition or dosage form to which no other ingredients, other than those listed, have been added. Nevertheless, very small amounts of other materials may potentially be present, such as impurities inherent in the material, or trace amounts of additives added by the excipient provider. Furthermore, for example, when reference is made to "consisting essentially of A, B, C, and optionally D," this means that no other ingredients, other than A, B, C, and D, have been added to the composition or dosage form, and that D is an optional ingredient (i.e., not required) in said composition or dosage form.

[0176] The term "essentially free" refers to compositions that contain less than a functional amount of each component, typically less than 1% by weight, preferably less than 0.1%, or even 0.01%, and 0 weight percent of each component. EXAMPLES

[0177] Certain aspects of the present invention are further illustrated by the following examples, which should not be construed as limiting the scope of the invention.

[0178] The compound of formula (1) was prepared under Good Manufacturing Practice (GMP) regulations, as required, as described in WO2019 / 101906.

[0179] The study reported in Example 6 was conducted in accordance with applicable regulations and national governmental regulations for conducting clinical trials, including the corresponding protocol, the current guidelines on Good Clinical Practice (GCP) of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), and regulations on subject protection and informed consent documents, and transparency requirements. All study protocols, the suitability of the investigators, facilities and methods and materials to be used in obtaining and documenting informed consent of study subjects were reviewed and approved by an Institutional Review Board (IRB) or an Independent Ethics Committee (IEC) before the start of the study. In this study, subjects received a final release of the investigational drug, i.e., the compound of formula (I), in accordance with Directive 2003 / 94 / EC annex 13, and the study drug labeling contained information meeting applicable regulatory requirements. Packaging, labeling, and release of the investigational medicinal products were performed under the responsibility of the clinical site pharmacist in accordance with GMP implementation guidelines, International Conference on Harmonization (ICH), Good Clinical Practice (GCP), and applicable local laws / regulations.

[0180] Example 1 Solid dispersions prepared by vacuum melt compression Two solid dispersion compositions were prepared by vacuum melt compression. The first composition, designated HME1, consisted of 40% by weight (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, 58.5% by weight copovidone (Kollidon® VA64), and 1.5% by weight poloxamer 188. The second composition, designated HME2, consisted of 20% by weight of (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide and 80% by weight of hypromellose acetate succinate (AQOAT® AS-MMP).

[0181] The active ingredient, (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, was provided in powder form as the crystalline monohydrate. The measured amounts of active ingredient and carrier were mixed in a shaking mixer (Turbula®) for 4 minutes.

[0182] Subsequently, a measured amount of the powder mixture was transferred to a lab-scale vacuum compression molding apparatus (VCM, Meltprep) equipped with a disc molding tool (Meltprep Disc Tool) and molded into discs at a vacuum of -1.0 bar. For HME1, vacuum compression molding was performed at a temperature of 200°C with a heating time of 5 minutes, a cooling time of 2 minutes, and a cooling air pressure of 2.5 bar. For HME2, vacuum compression molding was performed at a temperature of 180°C with a heating time of 5 minutes, a cooling time of 5 minutes, and a cooling air pressure of 3.0 bar. Transparent yellowish discs were obtained with both compositions.

[0183] The disks were crushed using a mortar and pestle and subjected to separate evaluation. First, the drug content was confirmed to be within 90-110% of the theoretical amount by HPLC assay. Furthermore, the crystalline state of the drug substance was evaluated by differential scanning calorimetry (DSC) and powder X-ray diffraction (XRPD, also called powder X-ray diffraction or PXRD). The DSC thermogram did not show a melting point of the active ingredient (approximately 111 °C), only the Tg of the polymer was observable. The XRPD analysis showed no residual crystallinity. Therefore, it was concluded that the sample showed a solid dispersion containing the active ingredient only in an amorphous and completely dissolved state.

[0184] Example 2 Solid dispersions prepared by spray drying Four solid dispersion compositions, designated SDD1 to SDD4, were prepared by spray drying. Each consisted of 25 wt% (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide and 25 wt% carrier polymer. The carrier polymers were hypromellose acetate succinate (AQOAT® AS-MMP) in SDD1, hypromellose type 2910 USP (Methocel™ E3) in SDD2, copovidone (Kollidon® VA64) in SDD3, and povidone K-30 in SDD4.

[0185] For each composition, a measured amount of active ingredient and the respective carrier polymer were dissolved in a mixture of dichloromethane (DCM) and methanol (4:1 (w / w) ratio). Spray drying was then carried out using a laboratory scale spray dryer (Buchi B290) using the parameters listed in Table 1 below.

[0186] [Table 1]

[0187] The spray drying process yielded a powder that was collected and subjected to a second drying step using vacuum drying at 40° C. and −26.5 mmHg vacuum for 20 hours.

[0188] The samples thus obtained were evaluated using modulated differential scanning calorimetry (mDSC), XRPD, and thermogravimetric analysis (thermogravimetric analysis also TGA). Both XRPD and mDSC data confirmed that the four prototypes were amorphous and did not contain any detectable levels of crystalline material. The TGA thermograms showed an inflection in the slope of the weight loss step of the SDD4 prototype, suggesting that a small amount of residual solvent remained in the sample. Overall, it was confirmed that all prototypes were amorphous and exhibited homogeneous solid dispersions with the active ingredient completely dissolved in the carrier polymer. Samples of spray-dried solid dispersions SSD1-SSD4 were stored at elevated temperature (40° C.) and re-examined by XRPD after 3 weeks. All samples were found to be amorphous and free of crystalline content.

[0189] Example 3 Solid dispersions prepared by hot-melt extrusion A solid dispersion was prepared by hot melt extrusion using the same composition as HME2 (see Example 1), consisting essentially of 20 wt. % (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide and 80 wt. % hypromellose acetate succinate (AQOAT® AS-MMP). The powder blend containing the crystalline active ingredient and the carrier polymer was screened through a sieve with an aperture width of 500 μm. The blend was then extruded using a twin screw extruder (Leistritz ZSE 12 HP-PH) equipped with a 1.5 mm die. The maximum temperature in the kneading zone was in the range of 145-165°C, except that the die zone was set at 200°C. A slightly brownish transparent extrudate was obtained and pelletized in a pelletizer. The pellets were subsequently milled using a two-phase hammer mill with a first phase screen size of 1,000 μm and a second phase screen size of 400 μm at a milling speed of 6,500 rpm. The particle size distribution was then characterized by laser diffraction (Mastersizer®). The two milled batches had mean particle sizes D50 of 262.3 μm and 249.1 μm, respectively. Sieve analysis found that 66.2% and 61.7% by weight, respectively, of the milled particles were in the sieve fraction between 180 μm and 355 μm.

[0190] Samples of HME2 solid dispersions were stored at accelerated temperature (40° C.) to test their chemical and physical stability. Drug content and impurities were quantified by HPLC. XRPD was used to detect changes in crystalline state, if any. The test results are listed in Table 2 below. They show that the active ingredient is highly chemically stable and remains amorphous in the solid dispersion.

[0191] [Table 2]

[0192] Example 4 Matrix tablets containing micronized active ingredient Approximately 2.9 kg of crystalline (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide monohydrate was micronized in a jet mill using nitrogen as the process gas with a gas supply pressure of about 30 psi to the milling chamber and about 60 psi to the Venturi injector. A micronized powder was obtained having a particle size distribution characterized by a D50 of 5.66 μm, a D90 of 11.70 μm, and a D10 of 1.40 μm as measured by laser diffraction. The specific surface area of ​​the powder was 2.19 m 2 / g.

[0193] In the next step, five different types of sustained release matrix tablets incorporating micronized API were prepared. The compositions of these tablets are listed in Table 3 below. Tablets were compressed from each powder blend using a pre-compression force of 0.8-2.3 kN and a main compression force of 13-25 kN in a laboratory scale single-arm pharmaceutical tablet press (Kilian Styl'One Evolution). In all cases, tablets with an average crush resistance higher than 100 N were obtained.

[0194] [Table 3]

[0195] By in vitro dissolution testing, all tablet formulations were found to exhibit sustained release of the active ingredient with the period of drug release extending over a period of more than 12 hours.

[0196] Example 5 Matrix tablets containing solid dispersions Solid dispersion composition HME2 was prepared as described in Example 3 and incorporated into two matrix tablet formulations (5.1 and 5.2), the compositions of which are listed in Table 4.

[0197] [Table 4]

[0198] As explained in the detailed description above, hypromellose in these formulations represents the hydrophilic matrix-forming polymer, microcrystalline cellulose and calcium hydrogen phosphate dihydrate function as tablet fillers, colloidal silicon dioxide functions primarily as a flow agent, and magnesium stearate functions primarily as a lubricant.

[0199] Weighed amounts of raw materials were mixed in a tumble blender (Turbula® 2F) in subsequent steps. First, the milled extrudate, filler and hydrophilic matrix-forming polymer were mixed, then the flow agent was added and mixed, and finally the lubricant was added and mixed. The resulting powder mixture was compressed into brownish speckled white to off-white oval biconvex tablets (17 mm x 7.2 mm) in a laboratory-scale single-unit pharmaceutical tablet press (Kilian Styl'One Evolution) using a main compression force ranging from 15 kN to 40 kN. The tablets had an average thickness of about 5.7 mm, an average crush resistance of about 110 N to 170 N, and a friability of about 0.2% to 0.7% by weight. Assay (HPLC-UV) showed that the drug content was within the acceptable limits of 90% to 110% of the labeled amount. Total impurities were less than 1%.

[0200] The drug release profile of the prototype 5.1 and 5.2 tablets was determined using Apparatus II (Paddle Apparatus) according to Ph.Eur.2.9.3 / USP <711> The tablets were characterized by dissolution testing according to the USP phosphate buffer (pH 6.8) containing 0.3% (w / v) sodium dodecyl sulfate. The paddle rotation speed was set at 100 rpm. Japanese weights were used to prevent floating of the tablets. Samples were periodically withdrawn and analyzed for their API concentration by HPLC, from which the amount of dissolved drug was calculated. The dissolution profile is given in Table 5.

[0201] [Table 5]

[0202] As the test results show, matrix tablets incorporating a solid dispersion of the BK B2 receptor antagonist of formula (1) can provide sustained release of the active ingredient over an extended period of time, for example, about 12 hours or even longer. Matrix tablet 5.1 exhibits a steeper dissolution profile in vitro than tablet 5.2.

[0203] Example 6 Human PK studies The basic pharmacokinetic profiles after single dose administration of matrix tablets version 5.1 and 5.2 were evaluated and compared against the immediate release capsules, both under fasted and fed (HCHF diet) conditions, in a Phase 1 clinical trial. The study was designed as a randomized, five-period crossover study involving 10 healthy volunteers. Table 6 lists the key PK parameters observed in the study.

[0204] [Table 6]

[0205] The data reveal that the matrix tablet formulations exhibit sustained release properties in vivo, as shown, for example, by the tmax values. Prototype 5.2 releases the active ingredient over a longer period in vitro compared to prototype 5.1 (see Example 5), but also has a slower tmax in vivo under both fasted and fed conditions. Quite remarkably, the matrix tablet exhibits total drug exposure (see AUC values) as an immediate release formulation, which allows one to conclude that the active ingredient is reliably released and absorbed even from more distal regions of the intestine, despite its unfavourable physical properties.

[0206] Figures 1-3 show profiles of mean plasma concentrations over time achieved by each formulation. Figure 1 shows the plasma profile after administration in the fasted state, while Figures 2 and 3 show the plasma profile after administration in the fed vs. fasted state for matrix tablet 5.1 (Figure 2) and matrix tablet 5.2 (Figure 3), respectively. Subsequent simulation studies confirmed that the PK profile of both matrix tablet formulations tested was useful for continuous treatment using once-daily or twice-daily dosing regimens. The SMEDDS formulation refers to an immediate release soft gelatin capsule containing the active ingredient formulated as a self-microemulsifying drug delivery system (SMEDDS) as a control, whereby 20 mg of API was administered per dose.

[0207] Example 7 Film-coated matrix tablets Tablets of prototypes 5.1 and 5.2 (see Example 5) were film coated using an aqueous dispersion of a premix containing the following components. The percentages are based on the total weight of the film components: hydroxypropyl cellulose (7.00 wt%), hypromellose (60.00 wt%), MCC (15 wt%), yellow iron oxide (10.00 wt%), and glycerol (8.00 wt%). The coating process was carried out in a perforated pan coater (Manesty XL 01 Lab) with an inlet temperature of 50-55°C and an outlet temperature of 40-45°C, using an atomizing air pressure of 1000 mbar, a spray rate of 10-30 g / min, and an inlet air volume of 350 m. 3 / hour. Spraying was performed until the tablet core weight increased by 5% by weight. In another batch using the same procedure, the tablet coating contained microcrystalline cellulose (MCC) at a level of 20% by weight and yellow iron oxide at a level of 5% by weight. The coated tablets had essentially the same sustained release characteristics as the plain cores, except that the coating introduced a slight lag time that was not significant to the overall sustained release profile.

[0208] [Example 8] Matrix tablets containing solid dispersions Additional batches of solid dispersion composition HME2 were prepared as described in Example 3, except that in some batches, a 200 μm screen size was used for the final phase of milling the pellets, resulting in an average particle size D50 in the range of about 100 μm, and in some tablets, the extrudate was milled by jet milling (rather than using a hammer mill) to an average particle size D50 in the range of about 50 μm and about 10 μm, respectively. The milled extrudate was incorporated into various matrix tablet formulations with dose strengths ranging from 1 mg to 50 mg. The matrix tablet compositions are listed in Tables 7-9.

[0209] In this context, a mean particle size D50 in the range of approximately 200 μm or about 200 μm should be understood as having a median value between 125 μm and 250 μm, with the respective particle size distribution determined gravimetrically by sieve analysis. In other words, more than 50% by weight of the milled particles pass through a screen with an aperture width of 250 μm and less than 50% by weight of the particles pass through a screen width of 125 μm. Similarly, a mean particle size D50 in the range of approximately 100 μm (or ~100 μm) should be understood as having a median value between 63 μm and 125 μm, with reference to the particle size distribution determined gravimetrically by sieve analysis, with more than 50% by weight of the milled particles pass through a screen with an aperture width of 125 μm and less than 50% by weight of the particles pass through a screen width of 63 μm. An average particle size D50 in the range of about 50 μm (or ∼50 μm), as determined by laser diffraction (e.g. with a particle size analyzer LS 13 320 XR by Beckman Coulter), is to be understood as an average D50 in the range of about 50±25 μm, and an average particle size D50 in the range of about 10 μm (or ∼10 μm), as an average D50 in the range of about 10±5 μm, also determined by laser diffraction.

[0210] These matrix tablet formulations provide, inter alia, another example of a sustained release matrix incorporating a compound of formula (1) formed by a single grade of hypromellose polymer, in particular a high viscosity grade hypromellose type 2208 polymer (such as Methocel™ K100M DC2 or Methocel™ K 100M Premium; or a combination of hypromellose polymers, such as a combination of hypromellose type 2208 and hypromellose type 2910; for example, a high viscosity grade of hypromellose type 2208 in combination with a high or low viscosity grade of hypromellose type 2910 (such as Methocel™ E4M).

[0211] Matrix tablet formulations provide further examples of additional excipients that can be used to modify the physical properties of the tablet, such as acid-insoluble polymers such as macrogols, special low viscosity grades of hyprolose or hypromellose, or HPMCAS. Furthermore, the examples show how a tablet filler (or filler-binder) such as MCC and a flow agent such as colloidal silica can be replaced together with a multifunctional excipient, in this case silicified MCC.

[0212] [Table 7]

[0213] [Table 8]

[0214] [Table 9]

[0215] The in vitro drug release profile of several prototype formulations was tested using a dissolution test device (also called "stress tester" or "dissolution stress tester") as described by G. Garbacz et al., Expert Opin. Drug Deliv., Vol. 7, 2010, pp. 1251-1261. In brief, the device comprises a central apparatus with a dissolution vessel in which are housed spherical probe chambers made of stainless steel wire mesh that hold the specimens. Each chamber has a bottom that is screwed by a bush and a nozzle to a central pipe-like shaft. In working mode, the central pipe is placed on the deck of the device, about 3 mm above the upper end of a series of standard dissolution vessels in their symmetrical plane. Each probe chamber operates with a separate vessel. At one end, the central shaft itself is connected to a pressure regulation device, and at the other end, a stepping motor is attached. Pressure waves are generated by the cyclic expansion and contraction of a balloon located inside the probe chamber. These are controlled by synchronous switching of valves, and the pressure can be regulated by a pressure reducing device. The central axis is driven by a stepper motor and can be programmed to position the probe chamber inside and outside the dissolution vessel, either immersed in the medium or in contact with air. The dissolution medium (typically 1160 mL) is mixed by a separate paddle stirrer (typically operated at 200 rpm).

[0216] Two different stress dissolution testing programs were performed using this device, briefly outlined below as "Method 1" and "Method 2." In both protocols, USP-compliant pepsin-free simulated gastric fluid (SGF) pH 1.8 was used as the dissolution medium for the gastric phase, and modified fasting simulated intestinal fluid (mFaSSIF) pH 6.8 was used as the dissolution medium for the intestinal transit phase.

[0217] Method 1, described in Table 10, is intended to simulate drug administration under fasted conditions and relatively low gastrointestinal motility conditions, whereas Method 2 simulates administration under fasted conditions and high intestinal motility or stress-enhanced conditions. Method 2 differs from Method 1 in that the colonic phase includes an additional agitation and stress event at 7 hours (2 pressure waves of 200 mbar, 30 sec rotation at 50 rpm). Further, additional stirring events (rotating at 50 rpm for 30 seconds) were performed at 0.75, 1.25, 1.75, 2.25, 2.75, 3.25, 3.75, 4.25, 4.75, 5.25, 5.75, 6.25, 6.75, 7.25, 7.75, 8.25, 8.75, 9.25, 9.75, 10.25, 10.75, 11.25, 11.75, 12.5, 13.5, 14.5, 15.5, 16.5, These were performed at 17.5, 18.5, 19.5, 20.5, 21.5, 22.5 and 23.5 hours, and additional minor stress events (one pressure wave of 150 mbar + 30 s rotation at 50 rpm) were performed at 1.5, 2.5, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5, 9.5, 10.5, 11.5, 13, 14, 15, 17, 18, 19, 21, 22 and 23 hours.

[0218] Dissolution media samples were collected every 60 min for up to 24 h through PE filters (1 μm pore size) into HPLC vials. Drug substance concentrations were subsequently determined by HPLC.

[0219] [Table 10]

[0220] The test results are presented in Tables 11 and 12. The results set forth in Table 11 were obtained using Method 1, and the results in Table 12 were obtained using Method 2.

[0221] [Table 11]

[0222] [Table 12]

[0223] The results clearly show that all the tested matrix tablets are suitable as sustained release formulations for oral delivery of the active ingredient, with the desired release occurring over an extended period of time, i.e., 12 hours or even up to 24 hours. The comparative results shown in Table 12 further demonstrate that the matrix design and composition determine the release rate, and that the coating has only a negligible effect on the overall release profile.

Claims

1. A pharmaceutical matrix tablet comprising a bradykinin (BK) B2 receptor antagonist having the chemical structure represented by formula (1), or a stereoisomer, salt or solvate thereof, and at least one hydrophilic matrix forming polymer: 【Chemistry 1】 In the formula, R is deuterium or hydrogen.

2. 2. The pharmaceutical matrix tablet of claim 1, wherein the BK B2 receptor antagonist is a compound of formula (1) or a solvate thereof, and R is deuterium.

3. 3. The pharmaceutical matrix tablet according to claim 1 or 2, which consists of an optionally coated monolayer tablet.

4. The pharmaceutical matrix tablet according to any one of claims 1 to 3, wherein the matrix tablet is a sustained release matrix tablet.

5. 5. The pharmaceutical matrix tablet according to any one of claims 1 to 4, wherein the hydrophilic matrix forming polymer is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, alginic acid, bentonite, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carrageenan, cellulose, copovidone, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl starch, methylcellulose, pectin, polyethylene oxide, polymethacrylate, potassium (or calcium or sodium) alginate, povidone, tragacanth, or xanthan gum.

6. 6. The pharmaceutical matrix tablet of claim 5, wherein the hydrophilic matrix forming polymer is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, and combinations thereof.

7. 7. The pharmaceutical matrix tablet of claim 6, wherein the hydrophilic matrix forming polymer comprises or consists of a combination of hydroxypropyl methylcellulose type 2208 and hydroxypropyl methylcellulose type 2910.

8. The pharmaceutical matrix tablet according to claim 7, comprising 20% ​​to 40% by weight of hydroxypropyl methylcellulose or a combination of different grades of hydroxypropyl methylcellulose.

9. The pharmaceutical matrix tablet according to any one of claims 1 to 8, further comprising a tablet filler selected from microcrystalline cellulose and / or calcium hydrogen phosphate dihydrate.

10. 10. The pharmaceutical matrix tablet of claim 9, wherein the microcrystalline cellulose is silicified.

11. A pharmaceutical matrix tablet according to any one of claims 1 to 10, wherein the BK B2 receptor antagonist is incorporated in micronized form.

12. The pharmaceutical matrix tablet according to any one of claims 1 to 11, wherein the BK B2 receptor antagonist is incorporated in a solubilized form.

13. 13. The pharmaceutical matrix tablet according to claim 12, wherein the BK B2 receptor antagonist is incorporated predominantly in amorphous form.

14. 14. The pharmaceutical matrix tablet according to claim 12 or 13, comprising a solid dispersion of an amorphous BK B2 receptor antagonist in a carrier, the carrier comprising at least one pharma- ceutically acceptable carrier polymer selected from hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, copovidone, and combinations thereof.

15. 15. The pharmaceutical matrix tablet according to claim 14, wherein the solid dispersion is incorporated as particles having a mean particle size D50 of 250 μm or less.

16. 16. The pharmaceutical matrix tablet according to claim 14 or 15, wherein the solid dispersion comprises at least 10% by weight of the BK B2 receptor antagonist based on the total weight of the solid dispersion.

17. The pharmaceutical matrix tablet according to any one of claims 14 to 16, wherein the matrix tablet comprises from 15% to 40% by weight of the solid dispersion, based on the total weight of the tablet not including any optional coating.

18. The pharmaceutical matrix tablet according to any one of claims 14 to 17, wherein the weight ratio of the solid dispersion to the hydrophilic matrix forming polymer is in the range of 2:1 to 1:

2.

19. 15% to 40% by weight of a solid dispersion; 20% to 40% by weight of a hydrophilic matrix-forming polymer, and 30% to 50% by weight of filler The pharmaceutical matrix tablet according to any one of claims 14 to 18, comprising:

20. 20% to 40% by weight of a solid dispersion; 20% to 40% by weight of hydroxypropyl methylcellulose or a combination of different grades of hydroxypropyl methylcellulose; 30% to 50% by weight of microcrystalline cellulose, calcium hydrogen phosphate dihydrate, or a combination thereof; up to 2% by weight of a flow agent, in particular colloidal silicon dioxide, and up to 2% by weight of a lubricant, especially magnesium stearate 20. The pharmaceutical matrix tablet of claim 19, comprising:

21. Including coating, The pharmaceutical matrix tablet according to any one of claims 1 to 20, wherein said coating comprises a water-soluble film-forming polymer and a plasticizer.

22. The pharmaceutical matrix tablet according to claim 21, wherein the amount of said coating is from 2% to 8% by weight based on the weight of the core tablet.

23. 23. The pharmaceutical matrix tablet according to any one of claims 1 to 22, wherein the matrix tablet releases the BK B2 receptor antagonist for at least 8 hours as determined by dissolution testing according to United States Pharmacopeia Chapter <711> using Apparatus II at pH 6.8 and a paddle rotation speed of 100 rpm.

24. 24. The pharmaceutical matrix tablet of claim 23, wherein the matrix tablet releases the BK B2 receptor antagonist over a period of 12 to 24 hours.

25. A method for preparing a matrix tablet according to any one of claims 1 to 24, comprising the steps of: (a) providing a solid dispersion in powder or granular form, the solid dispersion comprising a BK B2 receptor antagonist and a carrier comprising at least one pharma- ceutically acceptable carrier polymer, the BK B2 receptor antagonist being amorphous and dispersed in the carrier; (b) combining the solid dispersion with a hydrophilic matrix-forming polymer, a filler, and optionally other excipients to form a compressible powder or granule mixture; and (c) compressing the powder or granule mixture to obtain a matrix tablet. The method includes:

26. 26. The method of claim 25, further characterized in that step (c) of compressing the powder or granule mixture to obtain a matrix tablet is performed without any prior agglomeration step.

27. A pharmaceutical matrix tablet according to any one of claims 1 to 24 for use in the treatment of a subject suffering from a disease or condition responsive to BK B2 receptor modulation.

28. 28. The pharmaceutical matrix tablet for use according to claim 27, wherein the disease or condition responsive to BK B2 receptor modulation is selected from the group comprising skin disorders; eye diseases; ear diseases; oral, pharyngeal and respiratory diseases; gastrointestinal diseases; liver, gallbladder and pancreatic diseases; urinary tract and kidney diseases; diseases of the male and female reproductive organs; diseases of the hormonal system; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic system diseases; disorders of the central nervous system; brain disorders; musculoskeletal diseases; allergic disorders; pain; infections; inflammatory disorders; injuries; immune disorders; cancer; genetic diseases; and edema.

29. 29. The pharmaceutical matrix tablet for use according to claim 27 or 28, wherein the disease or condition responsive to BK B2 receptor modulation is angioedema, such as hereditary angioedema.

30. The pharmaceutical matrix tablet for use according to any one of claims 27 to 29, wherein the treatment is a chronic treatment for at least one month.

31. 25. A method of treating or preventing a disease or condition responsive to BK B2 receptor modulation in a subject, comprising the step of orally administering to a subject having a disease or condition responsive to BK B2 receptor modulation an effective amount of a pharmaceutical matrix tablet according to any one of claims 1 to 24, thereby preventing or treating said condition or disease in said subject.

32. 32. The method of claim 31, wherein the disease or condition responsive to BK B2 receptor modulation is selected from the group comprising skin disorders; eye diseases; ear diseases; oral, pharyngeal and respiratory diseases; gastrointestinal diseases; liver, gallbladder and pancreatic diseases; urinary tract and kidney diseases; diseases of the male and female reproductive organs; diseases of the hormonal system; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic system diseases; disorders of the central nervous system; brain disorders; musculoskeletal diseases; allergic disorders; pain; infections; inflammatory disorders; injury; immune disorders; cancer; genetic diseases; and edema.

33. 33. The method of claim 31 or 32, wherein the disease or condition responsive to BK B2 receptor modulation is angioedema, such as hereditary angioedema.

34. The method according to any one of claims 31 to 33, comprising repeated administration of pharmaceutical matrix tablets according to a regular dosing regime over a long period of time for chronic treatment.

35. Use of a pharmaceutical matrix tablet according to any one of claims 1 to 24 in the manufacture of a medicament for the treatment or prevention of a disease or condition responsive to BK B2 receptor modulation.

36. 36. The use of claim 35, wherein the disease or condition responsive to BK B2 receptor modulation is selected from the group including skin disorders; eye diseases; ear diseases; oral, pharyngeal and respiratory diseases; gastrointestinal diseases; liver, gallbladder and pancreatic diseases; urinary tract and kidney diseases; diseases of the male and female reproductive organs; diseases of the hormonal system; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic system diseases; disorders of the central nervous system; brain disorders; musculoskeletal diseases; allergic disorders; pain; infections; inflammatory disorders; injuries; immune disorders; cancer; genetic diseases; and edema.

37. 37. The use according to claim 35 or 36, wherein the disease or condition responsive to BK B2 receptor modulation is angioedema, such as hereditary angioedema.

38. The use according to any one of claims 35 to 37, wherein the medicament is intended for chronic treatment.

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