Solid sustained release composition comprising bradykinin b2 receptor antagonist

Abstract

The present invention relates to a pharmaceutical matrix tablet for oral administration comprising a bradykinin B2 receptor antagonist having the chemical structure of formula (1) or a salt or solvate thereof, where R is deuterium or hydrogen; # imgabs 0 #, for example, (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1, 2, 4-triazol-5-yl) quinolin-8-yloxy) methyl) phenyl) ethyl)-2-(difluoromethoxy) acetamide. The matrix tablets reliably provide sustained release of bradykinin B2 receptor antagonists making them particularly suitable for prophylactic and / or chronic treatments. Therapeutic uses of the matrix tablets are provided.

Description

Technical Field

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

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

[0003] Many peptide and non-peptide antagonists of the BK B2 receptor have been described in the prior art. Quinoline derivatives having activity as BK B2 receptor antagonists are disclosed, for example, in WO 2014 / 159637, WO 2010 / 031589, WO 2008 / 116620, WO 2006 / 40004, WO 03 / 103671, WO 03 / 87090, WO 00 / 23439, WO 00 / 50418, WO 99 / 64039, WO 97 / 41104, WO 97 / 28153, WO 97 / 07115, WO 96 / 13485, EP 0795547, EP 0796848, EP 0867432 and EP 1213289. However, as disclosed in WO 2014 / 159637, many disadvantages of these compounds, including low metabolic stability, low bioavailability, formation of glutathione adducts and bioactivation (toxicity) hinder their use as drugs.

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

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

[0006] Various dosage form designs and formulation techniques have been proposed for providing sustained release of drug substances after oral administration, such as tablets or capsules with sustained release coatings, tablets or capsules containing granules with sustained release coatings, or matrix tablets. The sustained release coating can be based on, for example, water-insoluble polymers capable of forming a drug permeable film on the granules, tablets or capsules, such as ethylcellulose or certain methacrylate copolymers. 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, vol. 218, 29 April 2019, pages 355-370, doi: 10.1016 / J.CARBPOL.2019.04.074 describe 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 unfavorable physical and pharmacokinetic properties, such as poor solubility, remains challenging, and many such development programs still fail.

[0009] Therefore, there is a need for formulation designs and pharmaceutical compositions that overcome the difficulties caused by the challenging nature of compounds of formula (1), so that they can be effectively delivered orally and achieve significant systemic exposure and bioavailability in human subjects. There is also a need for formulations or pharmaceutical compositions comprising compounds of formula (1) that achieve reliable oral absorption. There is also a need for formulations or pharmaceutical compositions comprising compounds of formula (1) that are stable in performance and can be prepared by established pharmaceutical preparation techniques.

[0010] The compounds of formula (1) have very low water solubility. This makes it extremely challenging to develop oral formulations that result in adequate and reliable absorption, bioavailability, and effective plasma levels. The pharmacodynamic properties of the BK B2 receptor antagonists of formula (1) make these compounds very attractive for both acute and chronic treatments, so there is a need to overcome challenges including poor water solubility and develop formulations for these drugs that are feasible in both acute and chronic treatments.

[0011] The object of the present invention is to meet any one or more of these needs. Another object is to overcome the defects, gaps and limitations of the prior art in the oral delivery of bradykinin B2 receptor antagonists, such as compounds having the chemical structure of formula (1). Other objects will be apparent from the following description, examples and patent claims. Summary of the invention

[0012] In one aspect, the present invention relates to a pharmaceutical sustained-release matrix tablet for oral administration, comprising a bradykinin B2 receptor antagonist or a salt or solvate thereof having a chemical structure of formula (1):

[0013]

[0014] Wherein R is deuterium or hydrogen; The skeleton tablet is further characterized in that it comprises at least one hydrophilic skeleton-forming polymer. As described in further detail below, the skeleton tablet is preferably formulated to provide a sustained release of the contained BK B2 receptor antagonist. The role of the hydrophilic skeleton-forming polymer is to embed the active ingredient and achieve its sustained release. For example, when the skeleton-forming polymer is pressed into a tablet and contacted with water or an aqueous medium, it may be able to swell or gel, and then slowly erode over time, resulting in a sustained release of the BK B2 receptor antagonist. The hydrophilic skeleton-forming polymer can be, for example, selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) and combinations thereof. The skeleton tablet may contain other excipients, such as one or more tablet fillers, binders, glidants and / or lubricants. Optionally, the skeleton tablet can be coated, as described further below.

[0015] In some preferred embodiments, the BK B2 receptor antagonist of formula (1), which has very poor solubility in physiological media, is incorporated in a physical form particularly suitable for promoting dissolution of the drug substance when in contact with water or aqueous media, for example in a micronized or already dissolved form. In some further preferred embodiments, the matrix tablet comprises a solid dispersion of the BK B2 receptor antagonist in amorphous form in a carrier, wherein the carrier comprises at least one pharmaceutically acceptable carrier polymer. The carrier polymer can be, for example, selected from HPMC, hydroxypropylmethylcellulose acetate succinate (HPMCAS), copovidone and combinations thereof and other optional excipients. The solid dispersion can be prepared by hot melt extrusion and incorporated into the matrix tablet in the form of a ground extrudate.

[0016] 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.

[0017] On the other hand, the present invention relates to certain therapeutic uses of skeleton tablets. Generally, it can be used to treat any disease or condition that responds to bradykinin B2 receptor regulation. For example, they are beneficial for treating angioedema (AE), including hereditary angioedema (HAE), acquired angioedema (AAE), non-histaminergic idiopathic angioedema, allergic angioedema, drug-induced angioedema and angioedema of unknown cause, particularly for the chronic treatment of AE, especially hereditary angioedema. HAE can be any type, including type I HAE, type II HAE or type III HAE, preferably type I HAE or type II HAE. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Shown are the mean plasma concentration-time profiles of two different extended release matrix tablets (Formulations 5.1 and 5.2, referred to herein as XR1 and XR2) comprising a solid dispersion formulation of a compound of formula (1), specifically (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide (referred to herein as PHA-022121), in healthy volunteers under fasting conditions, compared to an immediate release capsule formulation of the same drug.

[0019] Figure 2 Shown are the mean plasma concentration-time profiles of a sustained release matrix tablet (Formulation 5.1) comprising a solid dispersion formulation of a compound of formula (1) in healthy volunteers under fed and fasting conditions.

[0020] Figure 3 Shown are the mean plasma concentration-time profiles of a sustained release matrix tablet (Formulation 5.2) comprising a solid dispersion formulation of a compound of formula (1) in healthy volunteers under fed and fasting conditions. DETAILED DESCRIPTION

[0021] In one aspect, the present invention provides a pharmaceutical matrix tablet comprising a bradykinin (BK) B2 receptor antagonist or a stereoisomer, salt or solvate thereof having a chemical structure of formula (1):

[0022]

[0023] wherein R is deuterium or hydrogen; and at least one hydrophilic backbone-forming polymer.

[0024] The inventors have discovered that, despite the unfavorable physicochemical properties of the compounds of formula (1), such as very poor solubility in aqueous media, the formulation of the BK B2 receptor antagonist as a matrix tablet is particularly useful for providing reliable and complete drug release. In addition, it has been found that the matrix tablet is highly compatible with these drug substances and can be incorporated with the drug substance in various forms (such as amorphous forms), resulting in a surprisingly stable and robust product not only in terms of chemical stability but also in terms of stable biopharmaceutical performance under normal conditions for long-term storage. Another unexpected advantage is that the matrix tablet incorporating the BK B2 receptor antagonist of formula (1) can be designed to provide sustained release of the active ingredient over a long period of time, such as 12 hours or more, even about 18 to 24 hours, as will be described in more detail below. In addition, the matrix tablet is easy to manufacture using commonly used pharmaceutical equipment and is therefore of moderate cost.

[0025] As generally understood in the pharmaceutical context, a pharmaceutical matrix tablet is a matrix tablet comprising an active pharmaceutical ingredient or a placebo thereof, formulated and processed to be acceptable as a pharmaceutical product. Therefore, in the present invention, the expressions "matrix tablet" and "pharmaceutical matrix tablet" are used interchangeably.

[0026] As generally understood in the pharmaceutical field, a matrix tablet describes a composition for oral administration in the form of a compressed tablet containing an active ingredient uniformly dispersed in one or more suitable excipients, which after compression can form a matrix capable of controlling the release of the active ingredient. The matrix of the matrix tablet can be gelled. In the present invention, the expression "framework" is used for tablets manufactured and provided in their original dry form, which can also be called porous framework, and for the gelled framework caused by contact of the matrix tablet with water.

[0027] Matrix tablets are usually designed to provide sustained release of the active ingredient incorporated. In this case, the tablets may also be referred to as sustained release tablets or sustained release matrix tablets, respectively. Sustained release as used herein is understood to be the extended release of the active ingredient after oral administration or in a suitable in vitro model, particularly characterized in that it is released gradually over a period of time significantly longer than 30 minutes, particularly over several hours. In this case, sustained release, slow release, extended release and sustained release are used with interchangeable expressions. Sustained release is also a modified release dosage form, also commonly referred to as a controlled release formulation. In a generally preferred embodiment, the matrix tablet disclosed herein is a sustained release matrix tablet.

[0028] In another embodiment, matrix tablets are also designed as single unit dosage forms, meaning that a single unit of formulation contains a single dose of active ingredient. This is in contrast to multi-unit designs, such as sustained-release capsules or tablets, which contain multiple sustained-release sub-units (e.g., granules) that disperse after contact with moisture before drug release.

[0029] In the case of orally administered pharmaceutical products, the release of the active ingredient, also called drug release, 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 substitutes thereof, such as dilute hydrochloric acid, buffer, simulated gastric fluid, simulated intestinal fluid, etc. Therefore, for practical purposes, the release characteristics of an oral pharmaceutical composition may also be described as dissolution characteristics, and vice versa.

[0030] Regarding the active ingredient in the present invention, i.e., the compound of formula (1), R is selected from hydrogen and deuterium. In a preferred embodiment or a group of embodiments, R is deuterium, as shown in the following formula:

[0031]

[0032] This compound, which may also be referred to as (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide (CAS 2340111-58-0) or alternatively as N-[(1S)-1-[3-chloro-5-fluoro-2-[[[2-methyl-4-(1-methyl-1H-1-2,4-triazol-5-yl]-8-quinolinyl]oxy]methyl]phenyl]ethyl-1-d]-2-(difluoroethoxy)-acetamide, is a particularly preferred example of a compound of formula (1) according to the present invention. It should be understood that this preference also applies in combination with all other optional features or preferences disclosed in the following description, whether specifically mentioned or not.

[0033] Alternatively, in formula (1), R may be hydrogen, as described below:

[0034]

[0035] This compound may also be referred to as (S)-N-(1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide.

[0036] In a preferred embodiment, the BK B2 receptor antagonist is a compound of formula (1), a salt or solvate thereof, preferably a compound of formula (1) or a solvate thereof. That is, the compound of formula (1) may exist in a substantially non-ionized form, or in an ionized form, i.e., in the form of a salt. In addition, it may optionally be in the form of a solvate. For example, the compound may be a hydrate, such as (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide monohydrate. In a generally preferred embodiment, the compound of formula (1) is non-ionized (i.e., not in the form of a salt), and wherein R is deuterium.

[0037] Generally speaking, matrix tablets can be formulated based on various types of matrix-forming excipients such as hydrophilic, inert, lipid, biodegradable and resin matrices. However, as described above, according to one aspect of the present invention, in addition to the BK B2 receptor antagonist of formula (1), the key ingredient of the matrix tablet is a hydrophilic matrix-forming excipient, more specifically a hydrophilic matrix-forming polymer.

[0038] Such matrix tablets differ from tablets in which the sustained release function is achieved primarily by, for example, a sustained release film or coating. Sustained release matrix tablets may also contain a coating, but if used, such coatings generally have little effect on the drug release characteristics. For example, so-called non-functional coatings may be applied to matrix tablets, which coatings are primarily used to improve the appearance of the tablet, facilitate its handling and swallowing, mask the taste or reduce friability.

[0039] In some preferred embodiments, the matrix tablet provided herein is an optionally coated single-layer tablet. A single-layer tablet consists of a single-layer compressed tablet layer, which is different from a double-layer or multi-layer tablet. The manufacture of a single-layer tablet is generally more cost-effective than a two-layer or multi-layer tablet. A single-layer tablet may also be smaller than a tablet having one or more additional layers that are sometimes used to customize the drug release characteristics, and therefore easier to swallow. The inventors have found that the compound of formula (1) can be very effectively formulated into a single-layer sustained-release matrix tablet, showing 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.

[0040] The formulation techniques for sustained release matrix tablets are generally well known to those skilled in the art. "Erosionable" matrix tablets can be distinguished from "insoluble" matrix tablets based on the primary mechanism of drug release, the latter releasing their active ingredient primarily by diffusion out of a swollen but intact matrix. In practice, it is believed that a combination of release mechanisms often exists simultaneously, with some drug release occurring by diffusion and other portions of the drug being released by tablet erosion. As used herein, erosion includes any gradual loss of matrix material, regardless of the mechanism by which such loss occurs.

[0041] One of the main functions of a hydrophilic matrix-forming polymer is to form a matrix capable of encapsulating the active ingredient and achieving its sustained release. Typically, when compressed into tablets and in contact with water or an aqueous medium, such a hydrophilic matrix-forming polymer is capable of swelling or gelling and then slowly eroding over time, i.e., over at least several hours.

[0042] Various hydrophilic polymers can be used to produce a compressed porous skeleton capable of prolonged drug release. According to one embodiment, for example, one or more of the following polymer excipients can be used as hydrophilic skeleton forming polymers: hydroxypropyl cellulose (HPC or hydroxypropyl cellulose), hydroxypropyl methylcellulose (HPMC or hydroxypropyl methylcellulose), hydroxypropyl methylcellulose acetate succinate (HPMCAS or hydroxypropyl methylcellulose acetate succinate), alginic acid, bentonite, carbomer, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, carrageenan, cellulose, copolyvidone, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl starch, methylcellulose, pectin, polyethylene oxide, polymethacrylate, potassium alginate (or calcium or sodium), povidone, tragacanth gum or xanthan gum.

[0043] In a preferred embodiment, the hydrophilic matrix forming polymer is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) and combinations thereof. In a 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 including hydroxypropyl methylcellulose.

[0044] The inventors have found that these polymers and polymer combinations are particularly suitable matrix-forming excipients for incorporating the BK B2 receptor antagonists of formula (1).

[0045] 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 hydroxypropoxy content (e.g., HPMC type 2208 in most pharmacopoeias; currently available, for example, as Methocel "K") TMgrades) can be used with HPMC grades with medium hydroxypropoxy content and relatively high methoxy content (e.g., HPMC type 2910; currently, for example, Methocel "E" TM grades) or HPMC with relatively low viscosity (such as Methocel TM E4M as classified by commercial suppliers) and relatively high viscosity HPMC (such as Methocel TM In this case, the viscosity of HPMC or HPC is understood to be the typical viscosity of a 2% (w / v) aqueous solution of the polymer measured at 20° C. Higher viscosity values ​​are to some extent (but not exclusively) related to the higher molecular weight of the corresponding polymer grade.

[0046] In some embodiments of the matrix tablets provided herein, the hydrophilic matrix-forming polymer includes or even consists of a combination of hydroxypropylmethylcellulose type 2208 and hydroxypropylmethylcellulose type 2910. In some related embodiments, a high viscosity grade of hydroxypropylmethylcellulose type 2910 is used in combination with hydroxypropylmethylcellulose type 2208.

[0047] In this context, it should be noted that there are some highly soluble HPMC grades with very low apparent viscosities which may not fully meet the requirements of the matrix-forming polymer. The matrix-forming HPMC polymer used herein is preferably a HPMC grade with an apparent viscosity of at least about 100 cP, as measured according to the European Pharmacopoeia at 20° C. using a 2% aqueous solution.

[0048] Hydrophilic matrix forming polymers are usually provided in the form of powders or particles suitable for inclusion in pharmaceutical tablets. According to one aspect of the present invention, relative to the weight of the matrix tablet, the content of the hydrophilic matrix forming polymer in the matrix tablet, or if a combination of hydrophilic matrix forming polymers is used, the total content of the hydrophilic matrix forming polymer in the matrix tablet provided can be selected to be, for example, about 10 wt % to about 80 wt %. In some preferred embodiments, the content is selected to be about 15 wt % to about 60 wt % or about 15 wt % to about 50 wt %.

[0049] In a further preferred embodiment, the hydrophilic matrix-forming polymer is HPMC or a combination of two or more different grades of HPMC, and the total content of HPMC in the matrix tablet is 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, relative to the weight of the matrix tablet. The inventors have found that these ranges provide an excellent balance between drug loading and achieving a matrix function of providing a sustained release profile of drug release even over a long period of about 12 to 24 hours, even if the active ingredient is incorporated in a special form as described in further detail below (such as a dissolved form, such as a solid dispersion form).

[0050] In a further embodiment, the matrix tablet further comprises one or more excipients to enhance the mechanical stability of the compressed tablet by improving the bonding behavior of the particles during compression. Compared to the matrix-forming polymer, these excipients have little or no effect on the controlled release properties of the matrix tablet. Although some of these optional excipients may be chemically related to some preferred matrix-forming polymers, those skilled in the art will understand the primary functions and roles of the excipients present in the matrix tablet and will know whether a particular excipient plays an important role in controlling the release of the active ingredient contained in the matrix tablet. For example, some low molecular weight or high viscosity HPMC grades, such as D 5H (apparent viscosity of 2% aqueous solution at 20°C is only about 4-6 cP), when used at least in low levels, such as 5% by weight relative to the weight of the uncoated matrix, is considered to act as a binder rather than a matrix forming agent that contributes to the controlled release achieved by the matrix; they mainly increase the physical stability of the tablet. Similarly, small amounts of other excipients, such as polyethylene glycol (also known as polyoxyethylene, such as polyethylene glycol 6000) or HPMCAS, can be used without interfering with the extended drug release characteristics achieved by the hydrophilic matrix forming excipients.

[0051] If present, such matrix modifying excipients or combinations of matrix modifying excipients are preferably used in relatively low amounts, e.g., no more than about 20 wt % or no more than about 10 wt %, e.g., about 2-8 wt % or about 5 wt %, relative to the total weight of the matrix tablet (uncoated).

[0052] According to another preferred embodiment, the matrix tablet further comprises a tablet filler. A tablet filler can be understood as a pharmaceutical excipient that considers the general processability of a tablet compression-enhancing powder or granule mixture. The function of a tablet filler may include a diluent or filler, a compression aid, and a dry binder (usually referred to as a binder). A tablet filler is also referred to as a tablet filler-binder. This excipient can be a compound or a combination of compounds. Possible suitable tablet fillers for matrix tablets include, but are not limited to, microcrystalline cellulose (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 dihydrated calcium hydrogen phosphate), erythritol, and calcium carbonate.

[0053] In a preferred embodiment, the tablet filler comprises microcrystalline cellulose and / or calcium phosphate, such as dibasic calcium phosphate dihydrate. In a related embodiment, the tablet filler comprises a combination of microcrystalline cellulose and dibasic calcium phosphate dihydrate or even consists of them. For example, the two excipients can be combined in a weight ratio of about 1:1. It is believed that this combination may be particularly useful in matrix tablets because MCC is insoluble in aqueous environments but swells upon contact with water; calcium phosphate is inert and insoluble; the combination of the two also helps to maintain the matrix structure over a long period of time.

[0054] It has also been found that microcrystalline cellulose, alone or in combination with, for example, calcium hydrogen phosphate dihydrate, as a tablet filler (sometimes also referred to as filler-binder) is particularly compatible with some preferred hydrophilic matrix formers (such as HPMC), because microcrystalline cellulose does not interfere with the drug release control function of the matrix former, even if the latter is only included in the matrix tablet in a relatively small amount (such as about 20 wt % to 40 wt %) based on the total weight of the matrix tablet. Therefore, according to another embodiment, the matrix tablet may contain about 20 wt % to 40 wt % HPMC and a combination of microcrystalline cellulose and calcium hydrogen phosphate dihydrate.

[0055] Microcrystalline cellulose or a part thereof can also be incorporated in the form of silicified microcrystalline cellulose. If the silicified microcrystalline cellulose that also acts as a glidant is used as a tablet filler, it can simultaneously replace other commonly used glidants, such as colloidal silicon oxide, also referred to as colloidal silicon dioxide. In addition, compared with non-silicified microcrystalline cellulose, silicified microcrystalline cellulose can give excellent bonding properties. If silicified microcrystalline cellulose is incorporated into a skeleton tablet, then based on the skeleton tablet gross weight, its content in the skeleton tablet can be, for example, about 15 wt % to about 25 wt %, for example, based on about 20 wt % to 22 wt % of the skeleton tablet gross weight. Based on the skeleton tablet gross weight, the content of tablet filler in the skeleton tablet can be, for example, about 20 wt % to about 80 wt %. In a preferred embodiment, the content of tablet filler is about 25 wt % to about 65 wt %, or about 30 wt % to about 50 wt %. These scopes are also applicable to the total content of tablet filler in the skeleton tablet using more than one filler.

[0056] Regarding the combination of microcrystalline cellulose and dibasic calcium phosphate dihydrate, the weight ratio of microcrystalline cellulose and dibasic calcium phosphate dihydrate can be, for example, about 1:9 to 9:1 or about 2:8 to about 8:2. Also preferred is a weight ratio of about 4:6 to 6:4, such as about 5:5. For example, the matrix tablet can contain about 20 wt % to 40 wt % of HPMC and about 30 wt % to 50 wt % of the combination of microcrystalline cellulose and dibasic calcium phosphate dihydrate, relative to the total weight of the matrix tablet, wherein the weight ratio of microcrystalline cellulose to dibasic calcium phosphate dihydrate is 4:6 to 6:4.

[0057] According to a further preferred embodiment, the matrix tablet further comprises a glidant and / or a lubricant. Also preferred are related embodiments wherein the matrix tablet comprises a hydrophilic matrix forming polymer, a tablet filler, a glidant and a lubricant.

[0058] Glidants are excipients that improve the flow properties of powders or granules by reducing inter-particle friction and cohesion. Possibly suitable glidants include, but are not limited to, silicon dioxide, particularly colloidal silicon dioxide, anhydrous colloidal silicon dioxide, peptized silicon dioxide, talc, magnesium trisilicate, or powdered cellulose. In one embodiment, the glidant is colloidal silicon dioxide. For example, the content of the glidant in the skeleton tablet can be about 0.1% by weight to about 5% by weight, particularly about 0.1% by weight to about 3% by weight, relative to the total weight of the skeleton tablet. If two or more glidants are present in the skeleton tablet, these contents refer to the total content of the glidant. According to another preferred embodiment, the skeleton tablet comprises about 0.2% by weight to 2% by weight of colloidal silicon dioxide.

[0059] In the case of drug tablet compression, lubricant can be understood as a kind of excipient, which reduces the friction between powder, granule or tablet surface on the one hand and tablet press die wall and tablet punch on the other hand.Therefore, lubricant can reduce the wear of tablet die and punch.Possibly suitable lubricant includes but is not limited to magnesium stearate, polyoxyethylene glycol, aluminum stearate, calcium stearate, calcium behenate, castor oil, talcum, sodium benzoate, monoglyceride, glyceryl monostearate, glyceryl dibehenate, palmitic acid-stearate glyceride, hydrogenated cottonseed oil, sodium lauryl sulfate, sodium stearyl fumarate, fumaric acid and stearic acid.For example, relative to the skeleton tablet gross weight, the content of lubricant in skeleton tablet can be about 0.1 wt % to about 5 wt %, particularly about 0.1 wt % to about 4 wt %.If there are two or more lubricants in skeleton tablet, these contents refer to the total content of lubricant.In another preferred embodiment, skeleton tablet comprises about 0.2 wt % to 2 wt % lubricant, particularly magnesium stearate.

[0060] The matrix tablet may comprise one or more further excipients, also referred to as inactive ingredients, for example 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.

[0061] As described above, the active ingredient, i.e., the BK B2 receptor antagonist of formula (1), can be incorporated into a matrix tablet, for example, provided in powder form and mixed with an inactive ingredient, which is also usually provided in powder or granular form, to form a powder or granular mixture that can be compressed into a tablet. Alternatively, the active ingredient can be incorporated in a physical form that is particularly suitable for promoting drug dissolution when in contact with water or an aqueous medium, for example, in a micronized or dissolved form. Such formulation techniques are sometimes proposed for oral immediate release compositions of poorly soluble active ingredients, but as the inventors have discovered, they are also surprisingly advantageous for sustained release matrix tablets of compounds of formula (1), the design of which usually achieves sustained release of the active ingredient, while the micronized or dissolved form ensures that the active ingredient is released reliably and completely, with little or relatively moderate effects on factors such as pH, food and gastric motility.

[0062] Therefore, in a preferred embodiment, the BK B2 receptor antagonist of formula (1) is incorporated into the matrix tablet in micronized form. Micronization generally refers to reducing the average particle size to the micrometer range, even though there are no precise, generally accepted upper and lower limits of this range. In the present invention, micronized form is understood to be a powder form with an average particle size (D50) of about 0.1 μm to about 50 μm. In some further preferred embodiments, the BK B2 receptor antagonist is incorporated into the matrix tablet in the form of a powder, the average particle size (D50) of the powder being about 0.2 μm to about 40 μm, about 0.5 μm to about 10 μm. Particularly preferred are D50 values ​​of about 1 μm to about 10 μm measured by laser diffraction.

[0063] In another preferred embodiment, the particle size distribution is narrow, with only a small portion of particles being significantly smaller or larger than the D50 value. In one embodiment, the ratio of the D90 value to the D10 value of the micronized BKB2 receptor antagonist is no greater than about 15 or no greater than about 10. This small ratio of the D90 value to the D10 value appears to be beneficial for good distribution of the active agent in the matrix tablet and helps achieve the desired drug release characteristics described above. In a further embodiment, the D50 is from about 3 μm to about 7 μm, the D90 is from about 6 μm to about 14 μm, and the D10 is from about 0.5 μm to about 2 μm. As is well known to those skilled in the art, the D10 and D90 values ​​refer to the corresponding percentiles and refer to the particle size at which 10% or 90% of all particles are below. If measured by laser diffraction, the percentages are usually volume-weighted percentages.

[0064] The micronized form of the BK B2 receptor antagonist of formula (1) can be prepared by commonly known micronization techniques. For example, various grinding methods for preparing micronized active ingredients can be used and can be applied to compounds of formula (1). Optionally, the BK B2 receptor antagonist is co-ground with a hydrophilic agent and optionally one or more other excipients. Grinding or co-grinding can be carried out in conventional grinding equipment, such as a ball mill, a cross-stirred mill, an air jet mill, a pin mill, a graded mill, a disc mill, a mortar mill, a rotor mill. Preferred grinders for micronizing the BK B2 receptor antagonist include planetary mills and air jet mills.

[0065] In a preferred embodiment, the micronized active ingredient is prepared using a crystalline form of the BK B2 receptor antagonist of formula (1). In particular, the crystalline monohydrate of (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide can be incorporated into the matrix tablet.

[0066] For the avoidance of doubt, incorporation of a micronized active ingredient having a specific particle size distribution in a compressed tablet may or may not allow recovery of the active ingredient having the same particle size distribution as when incorporated. The tablet compression process may alter the particle size and may also make particle size measurement difficult. In the present invention, matrix tablets incorporating materials having specific particle size characteristics should be interpreted as including matrix tablets obtained from a process of providing such material, mixing with other ingredients and compressing into a matrix tablet, regardless of whether the specified specific particle size characteristics are still observed in the matrix tablet.

[0067] In some alternative but also preferred embodiments, the BK B2 receptor antagonist is incorporated into the matrix tablet in dissolved form. For example, the active ingredient may be provided and incorporated in the form of a formulated and preformed granulate comprising the BK B2 receptor antagonist and one or more excipients.

[0068] As used herein, dissolved form is understood to be a form in which the active ingredient is released from it into an aqueous medium at a significantly increased dissolution rate due to the specific physical form of the active ingredient itself, the presence of one or more solubilizing excipients, or both. Dissolution techniques that can be used for oral pharmaceutical compositions are generally well known to those skilled in the art, although they are generally used for regular release formulations rather than sustained release formulations, because the latter essentially require slow drug release rather than primarily requiring accelerated drug dissolution. Examples of dissolution techniques and dissolved forms that can be used to implement these embodiments of the present invention include, but are not limited to, for example, cyclodextrin inclusion compounds, the use of acids such as tartaric acid, citric acid or fumaric acid to keep alkaline active ingredients in ionized and more soluble forms, the use of bases such as meglumine to keep acidic active ingredients in ionized form, nanoparticles or microparticles based on amphiphilic lipids, the combination of drugs with micelle-forming surfactant mixtures, self-emulsifying or self-microemulsifying systems, and solid dispersions.

[0069] In some of these systems, the drug substance is present in an amorphous rather than a crystalline form. Although amorphous active ingredients are not used directly due to challenges in processability and stability, the amorphous form dissolves much faster than the crystalline form of the same compound of similar particle size. The inventors have found that the amorphous form of the BK B2 receptor antagonist can indeed be advantageously used in a matrix tablet. Therefore, another preferred embodiment provides a matrix tablet comprising a BK B2 receptor antagonist in a predominantly amorphous form, preferably an amorphous form. Amorphous form refers to 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 an amorphous form does not exclude the presence of any crystallinity. For example, the particles may include an active ingredient in a partially amorphous form as well as a partially crystalline form. In some preferred embodiments, the matrix tablet contains only an amorphous form of the BK B2 receptor antagonist.

[0070] According to some further preferred embodiments, the matrix tablet comprises a solid dispersion of an amorphous BKB2 receptor antagonist in a carrier, wherein the carrier comprises at least one pharmaceutically acceptable carrier polymer. The inventors have found that the solid dispersion of the BKB2 receptor antagonist of formula (1) not only effectively provides a rapid and complete release of such pharmacologically active ingredients into a physiological medium, which is generally used to design a regular release composition comprising the solid dispersion, but also that they can significantly improve the release of the compound of formula (1) from a sustained release formulation, which is completely unexpected. In particular, the solid dispersion can achieve substantially complete release of the active ingredient and reduce changes in the release rate caused by external factors (e.g., pH and composition of the liquid medium into which the active compound is released from the sustained release composition, e.g., the liquid medium is water, gastric fluid, intestinal fluid or a substitute thereof, such as simulated gastric fluid, fasting state simulated intestinal fluid (FaSSIF) or fed state simulated intestinal fluid (FeSSIF)). In contrast, it has been found that when applied to compounds of formula (1), conventional sustained release formulation technology results in unreliable drug release, unsatisfactory release characteristics and unpredictable absorption rate.

[0071] In this context, a solid dispersion is understood to be a solid material comprising a compound, such as a drug substance, uniformly dispersed in a preferably amorphous polymer backbone. Typically, the dispersed compound is also in an amorphous state, i.e., non-crystalline. For example, the dispersed compound may be molecularly dispersed or dispersed in the form of non-crystalline domains.

[0072] In a generally preferred embodiment, the amorphous form of the BK B2 receptor antagonist is predominant in the solid dispersion in terms of quantity. In other words, even if a certain amount of crystalline BK B2 receptor antagonist is present in the solid dispersion, the amount of amorphous form is greater, or even much greater, than the amount of crystalline form. In another generally preferred embodiment, at least about 90%, or even at least 95%, or at least 99% of the BK B2 receptor antagonist contained in the solid dispersion is amorphous. It is also preferred that all or substantially all of the BK B2 receptor antagonist is in amorphous form. In this case, the basis of the percentage is the total molar amount of the BK B2 receptor antagonist in the solid dispersion.

[0073] In another embodiment, the state of the compound of formula (1) in the solid dispersion is substantially or even completely non-ionized. In addition, the compound of formula (1) present in the solid dispersion is generally not a solvate. However, for the avoidance of doubt, when the compound is combined with a carrier polymer and any other optional ingredients to form a solid dispersion disclosed herein, the compound may be in the form of a solvate. For example, a hydrate of the compound, such as a monohydrate, optionally in crystalline form, can be used to prepare a composition. However, it is believed that once incorporated into the solid dispersion, it is no longer a crystalline material or hydrate. In addition, in another preferred embodiment, the compound of formula (1) is the only drug substance contained in the solid dispersion. This is a generally applicable preference in the present invention.

[0074] As described above, the solid dispersion comprises a carrier comprising at least one pharmaceutically acceptable carrier polymer in which the BKB2 receptor antagonist is dispersed. In this case, the carrier generally refers to an excipient or excipient combination in which the active ingredient is dispersed. The carrier may consist 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, and the like.

[0075] The carrier polymer may be selected from polymers suitable for oral administration and capable of incorporating the BKB2 receptor antagonist in the form of a solid dispersion. In this case, the polymer in which the active ingredient is embedded or dispersed to form a solid dispersion is sometimes referred to herein as a carrier polymer, which indicates its carrier function in the solid dispersion rather than its chemical nature. For the avoidance of doubt, polymers that may be suitable for use as hydrophilic matrix-forming polymers in matrix tablets, such as HPMC, may also be useful candidates for use as carrier polymers for solid dispersions.

[0076] The carrier polymer can be, for example, selected from the group consisting of hydrophilic neutral polymers and anionizable polymers. In this case, hydrophilicity refers to the polymer exhibiting at least some moderate solubility or swelling in an aqueous medium with a pH in the gastrointestinal pH range (i.e., between pH 1 and pH 8). Neutral refers to an aqueous solution of the polymer having an approximately neutral effect, at least in the absence of other solutes. Preferably, the neutral polymer is also a nonionic polymer. Anionizable refers to a polymer containing a portion that is easily deprotonated when dissolved in an aqueous medium except an acidic pH. Anionizable pharmaceutically acceptable hydrophilic polymers are sometimes also used as gastric acid resistant or enteric polymers. In addition, the polymer is optionally a non-crosslinked polymer.

[0077] According to another preferred embodiment, the pharmaceutically acceptable polymer in which the BKB2 receptor antagonist is amorphous and uniformly dispersed is a thermoplastic polymer, i.e. a polymer that is soft or moldable at high temperatures and becomes solid again once cooled to, for example, room temperature. A thermoplastic polymer can also be understood as a polymer that undergoes a glass transition temperature (Tg) when heated while maintaining chemical stability. In one embodiment, the polymer is water-soluble (optionally pH-dependent), neutral (e.g. nonionic or even non-ionizable) or anionizable and thermoplastic.

[0078] 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 alone to form a solid dispersion containing a BKB2 receptor antagonist; alternatively, any combination of two or more of these polymers can be used, such as a combination of HPC and HPMC, a combination of HPMC and HPMCAS, a combination of PVP and PVP / PA, or any other combination. In some preferred embodiments, the carrier polymer is selected from HPMC, HPMCAS, copovidone and a combination thereof.

[0079] In a preferred embodiment, the pharmaceutically acceptable carrier polymer contained in the solid dispersion is HPMCAS. HPMCAS, or hydroxypropylmethylcellulose acetate succinate, is an example of a hydrophilic anionizable polymer whose solubility depends on pH, being insoluble in water at acidic pH but soluble in water at neutral or alkaline pH. HPMCAS can be understood as hydroxypropylmethylcellulose esterified with a mixture of acetic acid and succinic acid. Typically, HPMCAS contains about 12% to about 28% methoxy groups, about 4% to about 23% hydroxypropyl groups, about 2% to about 16% acetyl groups, and about 4% to about 28% succinyl groups (calculated on a dry basis). HPMCAS is an exemplary pharmaceutically acceptable carrier polymer, is also a thermoplastic polymer, and is hydrophilic and anionizable. Various grades of HPMCAS are available, including HPMCAS-LF, which is characterized by an average particle size of about 5 μm and a viscosity of about 3 mPa*s.

[0080] The present inventors have found that the BK B2 receptor antagonist of formula (1) is not only surprisingly compatible with HPMCAS, as it forms solid dispersions at various useful weight ratios of drug substance and polymer; it is also found that the corresponding solid dispersions are highly stable both chemically and physically; i.e., there is little chemical degradation over time and the tendency of the drug substance to form crystals is very low. It is also surprising that, despite the pH-dependent solubility of the polymer, the solid dispersion of the compound of formula (1) with HPMCAS exhibits very useful drug release characteristics.

[0081] Alternatively, the solid dispersion may comprise copolyvidone (PVP / PA). It has been found that this carrier polymer is also capable of forming advantageous solid dispersions comprising compounds of formula (1). These solid dispersions are also chemically and physically stable. Another advantage of them is that they are capable of achieving high drug loading in terms of BK B2 receptor antagonists.

[0082] Copovidone, also known as crospovidone, PVP / VA copolymer or polyvinyl pyrrolidone-vinyl acetate copolymer, is obtained by free radical polymerization of vinyl pyrrolidone and vinyl acetate in a molar ratio of about 6:4. Typical molecular weights are about 45,000 to 70,000. Examples of currently available commercial copovidone products include Kollidon VA 64 and Luviskol VA. Grades with different average particle sizes are also available.

[0083] In addition to the above-mentioned carrier polymers, one or more other polymers may also be present in the solid dispersion. In addition, the solid dispersion claimed herein may also contain a surfactant. In one embodiment, the surfactant is a nonionic surfactant, in particular a nonionic surfactant selected from poloxamers and polysorbates. It is worth noting that these surfactants can also be regarded as polymers; in other words, they can also act as polymer drug carriers that form solid dispersions with drug substances. They are also used as surfactants because they enhance the wettability of the solid dispersion when in contact with an aqueous medium such as water.

[0084] Poloxamer, also known as polyethylene-propylene glycol copolymer or polyoxyethylene-polyoxypropylene copolymer, is a multi-block copolymer, each copolymer comprising a polyoxypropylene block sandwiched between two polyoxyethylene blocks. Various grades are available with different molecular weight ranges and different molecular ratios of polyoxypropylene and polyoxyethylene blocks, such as poloxamer 124, 188, 237, 338 and 407.

[0085] The inventors have found that poloxamer 188 is particularly useful. It is a solid material with an average molecular weight of about 7680 to 9510, wherein the polyoxypropylene block contains an average of about 27 repeating units and the polyoxyethylene block contains an average of about 80 repeating units. Particularly advantageous is the combination of poloxamer 188 and copovidone.

[0086] Polysorbates, also known as polyoxyethylene sorbitan fatty acid esters, are another group of nonionic surfactants that can be used as excipients in the solid dispersion formulations disclosed herein. Examples of potentially suitable polysorbates include polysorbate 20, 40, 60, 65, and 80, particularly polysorbate 20, also known as polyoxyethylene 20 sorbitan monolaurate, with an average molecular weight of 1128, and polysorbate 80, with a chemical name of polyoxyethylene 20 sorbitan monooleate, with a molecular weight of 1310. A well-known brand product line is Tween.

[0087] Typically, the content of nonionic surfactant in the solid dispersion (if present) is much lower than the content of the carrier polymer (e.g., hydrophilic neutral or anionizable polymer that does not represent a surfactant). In addition, the content of nonionic surfactant in the solid dispersion is typically lower than the content of the active ingredient. In a specific embodiment, the content of nonionic surfactant in the solid dispersion is from about 0.5 wt % to about 10 wt %, or from about 0.5 wt % to about 5 wt %, relative to the total weight of the solid dispersion. In another specific embodiment, the weight ratio of nonionic surfactant to polymer or the weight ratio of the polymer combination if there is a combination of two or more polymers is from about 1:100 to about 20:100, or from about 1:100 to about 10:100.

[0088] In a preferred embodiment, the content of the BK B2 receptor antagonist in the solid dispersion is at least about 10% by weight based on the total weight of the solid dispersion. As described above, this is also a preferred embodiment in which the BK B2 receptor antagonist of formula (1) is the only drug substance in the solid dispersion. Therefore, the range of at least about 10% by weight also represents the preferred drug loading of the solid dispersion.

[0089] According to further preferred embodiments, the content of the BKB2 receptor antagonist of formula (1) of the solid dispersion is about 10% to about 50%, about 15% to about 50%, or about 15% to about 45% by weight, based on the total weight of the solid dispersion. Similarly, in a related embodiment, the drug content of the solid dispersion is about 10% to about 50%, about 15% to about 50%, or about 15% to about 45%, wherein the BKB2 receptor antagonist of formula (1) represents the only drug substance present in the solid dispersion. Unexpectedly, when following the guidance provided in the present invention, such high drug loading can be achieved for the compound of formula (1) without significant chemical or physical instability.

[0090] In another preferred embodiment, the solid dispersion comprises a BKB2 receptor antagonist of formula (1) and about 55% to about 85% by weight, for example, about 75% to 85% by weight, of the polymer HPMCAS, based on the total weight of the solid dispersion. A related embodiment provides a solid dispersion that consists essentially of about 15% to 45% by weight, for example, about 15% to 25% by weight, of the BKB2 receptor antagonist of formula (1) and about 55% to about 85% by weight, for example, about 75% to 85% by weight, of HPMCAS. For example, the solid dispersion may consist essentially of about 20% by weight of the BKB2 receptor antagonist of formula (1) and about 80% by weight of HPMCAS. The inventors have found that the solid dispersion obtained by the above range and the corresponding weight ratio of the drug substance to the carrier polymer HPMCAS has a sufficiently high drug loading to allow effective and convenient administration, high product stability and shelf life, and ideal release characteristics.

[0091] In another alternative preferred embodiment, the solid dispersion comprises about 30% to 50% by weight of the BKB2 receptor antagonist of formula (1), about 50% to 70% by weight of copovidone, and optionally up to about 5% by weight of a poloxamer, such as poloxamer 188, based on the total weight of the solid dispersion. Similarly, in a related embodiment in which no other ingredients are present in the solid dispersion, a solid dispersion is provided that consists essentially of about 30% to 50% by weight of the BKB2 receptor antagonist of formula (1), about 50% to 70% by weight of copovidone, and optionally up to about 5% by weight of a poloxamer (e.g., poloxamer 188). For example, the solid dispersion may consist essentially of about 40% by weight of the BKB2 receptor antagonist of formula (1), about 58.5% by weight of copovidone, and about 1.5% by weight of poloxamer 188. These embodiments are advantageous because they allow for particularly high drug loadings while being chemically and physically stable and providing useful drug release characteristics.

[0092] As described above, the inventors surprisingly found that the solid dispersions disclosed herein are particularly useful in formulations that release BKB2 receptor antagonists over an extended period of time, such as matrix tablets in some preferred embodiments thereof. In order to facilitate the incorporation of the solid dispersion into the matrix tablet, according to some preferred embodiments, the solid dispersion is provided in the form of a powder or granules. Both powders and granules provide the solid dispersion in the form of multi-granules, i.e., multi-particles. In this case, the expressions "powder" and "granules" should be simply understood to refer to approximate particle sizes, wherein powders refer to relatively fine multi-granular materials and granules refer to relatively coarse materials, regardless of the manufacturing method of obtaining these materials. In other words, the expression "granules" should not be narrowly interpreted as requiring the use of a specific granulation method to produce the corresponding particles.

[0093] 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 may include the step of hot melt extruding a powder or granular mixture containing a BK B2 receptor antagonist and a carrier polymer and optionally other excipients. Alternatively, the method may include the step of spray drying an organic solution of the BK B2 receptor antagonist and a carrier polymer and optionally other excipients, or spraying an organic solution of the active ingredient and the polymer onto particles of a pharmaceutically inactive material under conditions that cause the organic solvent to evaporate. Again, in this case, the BK B2 receptor antagonist is a compound of formula (1), particularly a preferred form as described above; and the carrier polymer is at least one pharmaceutically acceptable carrier polymer in which the BK B2 receptor antagonist is uniformly dispersed.

[0094] Hot melt extrusion is a well-known technology in the pharmaceutical field. As is well known, this technology can be used to produce melt extrudates in principle. This includes equipment that may be used for hot melt extrusion and some common process parameters, such as temperature and screw speed (when using a screw extruder). According to the technical guidance on the composition of solid dispersions provided herein, and taking into account the working examples described below, those skilled in the art will be able to prepare melt-extruded solid dispersions of active ingredients comprising formula (1) without difficulty.

[0095] Hot melt extrusion can be used to convert a powder or granular mixture comprising a BK B2 receptor antagonist of formula (1) and at least one pharmaceutically acceptable carrier polymer into an extrudate, which represents a solid dispersion in which the active ingredient is uniformly and amorphously dispersed in the carrier polymer and optionally other excipients. Hot melt extrusion includes heating, softening or melting, mixing or homogenizing, and extruding the mixture. It can also be described as a process whereby the blended composition is heated and / or pressed to a molten (or softened) state, then forced through an orifice, and the product (extrudate) extruded at the orifice forms its final shape, wherein it solidifies when it cools. The blended composition can be conveyed through one or more heating zones, which is usually achieved by a screw mechanism. The screw or screw assembly can be rotated by a variable speed motor in a cylindrical barrel, wherein there is only a small gap between the outer diameter of the screw and the inner diameter of the barrel. In this configuration, high shear forces are generated at the barrel wall and between the screw threads, and the components of the powder or granular blend are fully mixed and depolymerized by the shear forces when conveyed through the extruder. Extrudate refers to a composition formed by hot melt extrusion.

[0096] In one embodiment, the hot melt extrusion step comprises the following sub-steps: (i) adding the optionally crystalline BK B2 receptor antagonist of formula (1) (or, for example, a hydrate thereof) and a carrier polymer (and optionally other excipients) to a hot melt extrusion apparatus; (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 well 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 formed into an extrudate. Steps (ii) and (iii) may be performed simultaneously, or step (iii) may be started once the optionally crystalline BK B2 receptor antagonist of formula (1) and the carrier polymer begin to melt. Similarly, the BK B2 receptor antagonist starting material in step (i) may be crystalline and subsequently converted to an amorphous form during the hot melt extrusion process.

[0097] In a preferred embodiment, the method comprising a hot melt extrusion step is carried out using a powder or granular mixture comprising about 15 wt % to about 45 wt % or, for example, about 15 wt % to 25 wt % of the BK B2 receptor antagonist and about 55 wt % to about 85 wt % of HPMCAS or, for example, about 75 wt % to about 85 wt % 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 wt % to about 45 wt % or about 15 wt % to 25 wt %, for example, about 20 wt % of the BK B2 receptor antagonist and about 55 wt % to about 85 wt % or about 75 wt % to 85 wt %, for example, about 80 wt % of HPMCAS is hot melt extruded to obtain a melt extrudate representing a solid dispersion.

[0098] In another preferred embodiment, the hot melt extrusion step is carried out using a powder or granular mixture, which comprises about 30% to 50% by weight of a BK B2 receptor antagonist, about 50% to 70% by weight of copovidone, and optionally up to 5% by weight of a poloxamer, particularly poloxamer 188, based on the total weight of the powder or granular mixture. In a related embodiment, the powder or granular mixture consists of about 30% to 50% by weight (e.g., about 40% by weight) of a BK B2 receptor antagonist, about 50% to 70% by weight (e.g., about 58.5% by weight) of copovidone, and optionally up to 5% by weight (e.g., about 1-2% by weight) of a poloxamer, particularly poloxamer 188. For the avoidance of doubt, in these and previous embodiments, the weight percentages are based on the weight of the powder or granular mixture subjected to the hot melt extrusion step.

[0099] In some preferred embodiments, the extrusion temperature is selected to be higher than the glass transition temperature (T g ), or higher than T if more than one carrier polymer is used g The highest carrier polymer T g In a related preferred embodiment, the extrusion temperature is also selected to be above the melting temperature of the active ingredient. For example, extrusion at a temperature at least about 20°C above the melting point of the API will promote dissolution of the drug substance in the carrier polymer. In other preferred embodiments, extrusion is performed at a temperature at least about 20°C above the T of the polymer. g The extrusion temperature is preferably at least about 20° C. higher. In practice, the extruder may have several temperature zones set at different temperatures; in this case, the extrusion temperature is understood to be the temperature of the extruder zone having the highest temperature.

[0100] As previously mentioned, the solid dispersions disclosed herein can also be prepared using a process comprising the step of spray drying an organic solution of a BK B2 receptor antagonist and a carrier polymer (and optionally other excipients), i.e., at least one pharmaceutically acceptable carrier polymer in which the BK B2 receptor antagonist of formula (1) is amorphous and uniformly dispersed. Prior to the actual spray drying step, an organic solution of the BK B2 receptor antagonist of formula (1) and the carrier polymer (and optionally any other components of the solid dispersion that may be incorporated) in an organic solvent that is pharmaceutically suitable for the spray drying process and that is capable of completely dissolving the active ingredient and the carrier polymer must be prepared, which can be achieved by any conventional method of adding a granular or powdered solid to an organic solvent under conditions that result in the dissolution of the solid (e.g., stirring or elevated temperature).

[0101] Organic solvents which may be used in this context include, for example, methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, ethyl acetate and any mixtures thereof. Optionally, the solvent or solvent mixture may contain limited amounts of water.

[0102] The spray drying step itself can be described as atomization under conditions that allow the organic solvent to evaporate. For example, atomization can be performed by a nozzle or a rotating disk. A further drying step, such as fluidized bed drying, vacuum drying, tray drying, microwave drying, drum drying or double cone vacuum drying can then be used to reduce the residual solvent to a pharmaceutically acceptable level. Generally, spray drying refers to contacting a highly dispersed liquid suspension or solution with a sufficient volume of air and causing the droplets to evaporate and dry. Alternatively, an organic solution of the BKB2 receptor antagonist of formula (1) and a carrier polymer (and any other excipients incorporated into the carrier or solid dispersion, if any) is injected into a warm filtered air or inert gas stream to evaporate the solvent. The dried product particles can be transported to a collector, such as a cyclonic particle collector.

[0103] Typically, the spray drying step is carried out at a temperature (i.e., inlet temperature) of about 40°C to 150°C or at about 50°C to 150°C, depending on the organic solvent used. In some embodiments, the inlet temperature is about 80°C to 120°C. The outlet temperature of spray drying is generally low, for example, about 40°C to 100°C or 40°C to 75°C, for example, fluidized bed drying (e.g., from about room temperature to about 100°C), vacuum drying (e.g., from about room temperature to about 200°C), for example, from about room temperature to about 65°C, for example, about 45°C.

[0104] In addition to methods that rely on hot melt extrusion or spray drying, several other techniques or methods can be used to prepare the solid dispersions disclosed herein for incorporation into matrix tablets. These methods include, for example, low temperature processing techniques, freeze drying, fluidized bed coating, microwave irradiation, coprecipitation, electrostatic spinning, supercritical antisolvent precipitation, spray congealing, carrier particle spraying, melt agglomeration, etc.

[0105] As previously mentioned, the solid dispersion of the matrix tablet disclosed herein can be provided in the form of powder or particles. Powders and particles are both provided in the form of multi-particles, i.e., multi-particles. Solid dispersions can be obtained directly from the technology applied to prepare solid dispersions. For example, if spray drying or a method involving a spray drying step is used to prepare solid dispersions, the direct product obtained by this method is already in the form of powder or particles. Alternatively, subsequent steps such as screening, grinding or agglomeration can be performed to adjust the particle size (distribution) of the product. If a method including a hot melt extrusion step is used, the product obtained directly from the extrusion step is generally not a powder or particle, but a larger unit or elongated block such as a cylindrical rod, which can then be cut or granulated into smaller units. The tool for cutting or granulating the extrudate can be added as a downstream module of the extrusion device. If it is considered that the required particle size needs to be further reduced, an independent subsequent grinding step can be used, and then a classification step, such as screening, can be optionally performed.

[0106] In another preferred embodiment, the solid dispersion is in the form of a powder or granules and is prepared by a method comprising a hot melt extrusion step and a grinding step as described above, wherein the extrudate is converted into a powder or granules, optionally with an intermediate step of extrudate cutting or granulation before grinding. Grinding can be performed using any pharmaceutically suitable equipment, such as a hammer mill, a centrifugal impact grinder, a jet mill, a ball mill, a cone grinder, or an oscillating and rotating screen grinder, which are just a few examples. Optionally, grinding is performed at a controlled temperature or under cooling. Depending on the type of grinding method and the equipment used, the grinding process itself may include sieving or grading the ground particles. Alternatively, a separate sieving or grading step may be performed after grinding. Grinding of the extrudate may be performed, optionally including a subsequent sieving step, so as to achieve an average particle size of, for example, about 50 μm to 800 μm or further preferably about 100 μm to 700 μm. In this case, the average particle size generally refers to the D50 value of the powder or granules measured by laser diffraction. Alternatively, if the particle size distribution is characterized by sieve analysis, a more relevant parameter is the mass median sieve size, which according to some preferred embodiments is about 50 to 800 μm or about 100 to 700 μm or about 150 to 500 μm.

[0107] In a further preferred embodiment, the solid dispersion is incorporated into the matrix tablet in the form of particles having an average particle size D50 of no more than 250 μm. In this case, the corresponding average particle size D50 is understood to characterize the particle size distribution of the solid dispersion particles before compression, i.e. before the matrix tablet is formed. It is understood by those skilled in the art that the average particle size D50 may be affected by compression and that it may also be difficult to separate the solid dispersion particles again after compression in order to determine their particle size distribution.

[0108] In some further preferred embodiments, when the solid dispersion is incorporated into a matrix tablet, it has an average particle size D50 of 125 to 250 μm or about 63 to 125 μm as determined by gravimetric sieve analysis. Also useful are solid dispersion particles having an average particle size D50 substantially below 100 μm, such as about 50 ± 25 μm or even 10 ± 5 μm, preferably as determined by laser diffraction.

[0109] In some preferred embodiments, the solid dispersion incorporated into the matrix tablet comprises at least about 10% by weight of a BK B2 receptor antagonist relative to the total weight of the solid dispersion. Other preferred amounts of a BK B2 receptor antagonist, particularly (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, relative to the total weight of the solid dispersion, are about 10% to about 50%, about 15% to about 45%, or about 20% to about 40%. Further preferred is the incorporation of solid dispersion particles comprising from about 15 wt % to about 25 wt % of a BKB2 receptor antagonist, for example about 20 wt % of (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide amorphously dispersed in 80 wt % of hypromellose acetate succinate. In a further preferred embodiment, the solid dispersion is incorporated into a matrix tablet and comprises about 25 wt % of (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide amorphously dispersed in 75 wt % of hypromellose acetate succinate; or about 30 wt % of (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide amorphously dispersed in 70 wt % of hypromellose acetate succinate. -(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, or about 35 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 weight % of hydroxypropyl methylcellulose acetate succinate.

[0110] As described above, the inventors have found that, despite the fact that solid dispersions themselves have drug solubilizing properties, it is not expected that they will provide slow drug release for a long time, but the incorporation of solid dispersions into matrix tablets, in particular sustained-release matrix tablets, is unexpectedly advantageous. However, it was found that solid dispersions are very compatible with the formulation technology for sustained-release matrix tablets disclosed above, and slow drug release can be achieved even within, for example, about 8 to 24 hours, and solid dispersions achieve more reliable release characteristics. In addition, it was found that the use of solid dispersions in sustained-release formulations is associated with low or moderate food effects, which is contrary to the usual expectations of sustained-release compositions of BK B2 receptor antagonists of formula (1) in view of their solubility and intrinsic release behavior. In a preferred embodiment, the matrix tablet contains about 10% to about 60% by weight of the solid dispersion, based on the total weight of the matrix tablet. In a further preferred embodiment, the content of the solid dispersion in the matrix tablet is about 15% to about 50% by weight, in particular about 15% to about 40% by weight. In a further preferred embodiment, the content of the solid dispersion in the matrix tablet is from about 20% to about 40% by weight, such as about 20%, about 25%, about 30%, about 35% or about 40% by weight. Again, the percentages are based on the total weight of the matrix tablet without the optional coating.

[0111] In some further preferred embodiments, the matrix tablet is formulated to include a solid dispersion in an amount that is approximately the same as the amount of the hydrophilic matrix-forming polymer. For example, the weight ratio of the solid dispersion to the hydrophilic matrix-forming polymer may be 2:1 to 1:2. If 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.

[0112] As mentioned above, the matrix tablet can include a solid dispersion in the form of powder or particles, for example, in the form of grinding extrudates as described above. In this case, in addition to the solid dispersion, the matrix tablet preferably includes other excipients, for example, may be necessary or useful for tablet compression, but is also used to form a matrix in which solid dispersion powder or particles are embedded. Powder or particles are incorporated into compressed tablets and may change some characteristics of solid dispersions as described above. For example, once powder or particles are incorporated into compressed tablets, the flowability of powder or particles may no longer exist. In addition, even if the particles representing the solid dispersion can be extracted from the matrix tablet (certain technical difficulty is arranged), the parameters related to particle size may no longer be the same as before the solid dispersion is incorporated into the tablet. In this regard, the embodiment related to the matrix tablet comprising the optional or preferred features of the solid dispersion with solid dispersion is understood to also encompass the matrix tablet obtainable from the powder or particle mixture incorporating this solid dispersion by pressing these mixtures.

[0113] In a preferred embodiment, 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 present invention. Alternatively, the pharmaceutical composition may contain one or more other active ingredients. The other or supplementary active ingredients or active pharmaceutical ingredients are preferably active agents or active pharmaceutical ingredients that have utility in preventing or treating one or more diseases that respond to BK B2 receptor modulation, including diseases selected from the group consisting of: skin diseases; eye diseases; ear diseases; oral, throat 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 diseases; central nervous system diseases; brain diseases; musculoskeletal system diseases; allergic diseases; pain; infectious diseases; inflammatory diseases; injuries; immunological diseases; cancer; hereditary diseases; and edema. For example, at least one compound or pharmaceutically acceptable salt of the present invention may advantageously be included in a combination preparation comprising antibiotics, antifungal or antiviral agents, antihistamines, nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, cytostatic drugs, drugs with smooth muscle activity modulating activity, antibodies or mixtures thereof as additional or supplementary active agents or active pharmaceutical ingredients.

[0114] Matrix tablets can also be described according to the dosage strength or amount of the BK B2 receptor antagonist of formula (1) incorporated per dosage unit, i.e., per capsule or tablet. In some embodiments, the dosage strength is from about 1 mg to about 100 mg or from about 5 mg to about 100 mg. In further preferred embodiments, the dosage strength is from about 10 mg to about 80 mg, for example, about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg or 80 mg. For pediatric use, lower doses, for example from about 0.5 mg to about 5 mg, can also be used.

[0115] In some preferred embodiments, the matrix tablet comprises:

[0116] - about 15% to 40% by weight of a solid dispersion,

[0117] - about 20% to 40% by weight of a hydrophilic backbone-forming polymer, and

[0118] - About 30% to 50% by weight of filler.

[0119] According to some further preferred embodiments, the matrix tablet comprises:

[0120] - about 20% to 40% by weight of a solid dispersion;

[0121] - about 20% to 40% by weight of hydroxypropyl methylcellulose or a combination of different grades of hydroxypropyl methylcellulose;

[0123] - about 30% to 50% by weight of microcrystalline cellulose, calcium hydrogen phosphate dihydrate, or a combination thereof;

[0124] - up to about 2% by weight of a glidant, in particular colloidal silicon dioxide, and

[0125] - Up to about 2% by weight of a lubricant, in particular magnesium stearate.

[0126] For the avoidance of doubt, in this case, all weight percentages are based on the total weight of the matrix tablet without the optional coating (100%). In other words, the total weight % of all ingredients contained in the matrix tablet disclosed herein does not exceed 100%.

[0127] Also in these embodiments, the solid dispersion can represent some of the preferred solid dispersions described above, and, for example, consists 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 can 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.

[0128] As previously mentioned, matrix tablets may also include a coating, for example to improve the appearance or swallowability of the tablet. The coating, if present, is preferably a film coating, for example a coating comprising, for example, a water-soluble film-forming polymer and a plasticizer. The film coating may also include more than one polymer and / or more than one plasticizer (e.g., glycerol). In addition, the film coating may include other ingredients commonly used in tablet coatings that do not alter drug release, 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).

[0129] In some embodiments, the coating content applied to the matrix tablet does not exceed about 10% by weight. In this case, the percentage is based on the weight of the uncoated tablet and is for the weight of the film coating in the dry state (i.e., after solvent removal). In further embodiments, the coating content is 2% to 8% by weight relative to the weight of the uncoated tablet.

[0130] In another aspect, the present invention provides a method for preparing a matrix tablet, in particular a sustained-release matrix tablet, comprising the above-mentioned solid dispersion; the method comprises the following steps: (a) providing a solid dispersion in the form of a powder or granules, the solid dispersion comprising a BKB2 receptor antagonist and a carrier, the carrier comprising at least one pharmaceutically acceptable carrier polymer, wherein the BKB2 receptor antagonist is amorphous and dispersed in the carrier; (b) combining the solid dispersion with a hydrophilic matrix-forming polymer (or a combination of hydrophilic matrix-forming polymers), 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. Step (a) may include one or more sub-steps of preparing the solid dispersion, for example by hot melt extrusion optionally followed by grinding or by spray drying, as described above.

[0131] For example, according to one preferred embodiment, the method comprises the following steps: (a) providing a solid dispersion in powder or granular form, the solid dispersion being a milled extrudate comprising (i) about 15 wt % to about 45 wt %, for example about 15 wt % to 25 wt %, of a BK B2 receptor antagonist of formula (1) and a carrier, the carrier comprising or consisting essentially of about 55 wt % to about 85 wt %, for example about 75 wt % to about 85 wt % HPMCAS, or (ii) about 30 wt % to 50 wt % of a BK B2 receptor antagonist of formula (1) and a carrier, the carrier comprising or consisting essentially of about 50 wt % to 70 wt % of copovidone, and optionally up to about 5 wt % of a poloxamer, for example poloxamer 188, wherein BK 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 microcrystalline cellulose, calcium hydrogen phosphate dihydrate or a combination thereof), 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.

[0132] As also shown in the examples, the matrix tablets provided herein can be prepared without any agglomeration step to improve the flowability or compressibility of the powder or granule mixture from which the tablet is compressed. Therefore, in some related embodiments, the step (c) of compressing the powder or granule mixture to obtain the matrix tablet is carried out without any prior dry or wet agglomeration step. In this particular case, agglomeration refers to any powder granulation process in which small primary powder particles agglomerate to form larger secondary particles. Those skilled in the art will understand other preferred embodiments of the preparation method based on the guidance provided in the present invention on selecting certain preferred items (e.g., BK B2 receptor antagonists, excipients and their contents in solid dispersions, preparation methods related to solid dispersions, and excipients and their contents in matrix tablets).

[0133] As mentioned above, the present inventors have found that compared with conventional formulation techniques, matrix tablets, in particular, sustained-release matrix tablets according to any of the preferred embodiments described above, allow tailoring of clinically advantageous sustained-release properties of the BK B2 receptor antagonist of formula (1), such as good robustness and reliability, and reduced food effect. This advantage is particularly evident for sustained-release matrix tablets comprising a solid dispersion of a pharmaceutically acceptable carrier polymer using hydroxypropylmethylcellulose acetate succinate (HPMCAS) as a solid dispersion, i.e., an active ingredient amorphous and uniformly dispersed therein. Without wishing to be bound by theory, these release properties may be related to the fact that HPMCAS is a polymer that is insoluble in acidic media (such as gastric juice), thereby causing relatively slow drug release in such an acidic environment; while the compound of formula (1) itself is poorly soluble, particularly in relatively neutral media (such as intestinal fluid), thereby causing relatively slow drug release in such an environment, thereby partially compensating for various pH-dependent effects on drug release rate. In other words, when the BK B2 receptor antagonist of formula (1) is formulated into a sustained-release dosage form, the design of a sustained-release matrix tablet comprising a solid dispersion incorporating a dissolved amorphous drug ensures effective drug release and oral bioavailability.

[0134] Sustained release properties are also used to describe the behavior of a composition or formulation in a relevant biological environment, i.e., in a clinical setting after administration of the composition or formulation to a subject, usually measured in a well-defined in vitro model. As used herein, sustained release properties refer to the dissolution characteristics of a sustained release composition. For example, in the United States Pharmacopeia (e.g., USP) chapter <711> ("Dissolution"), descriptions of some widely accepted dissolution models for determining dissolution properties can be found in the USP. To characterize the dissolution properties of the matrix tablets disclosed herein, for example, Apparatus II (Paddle Apparatus) described in the USP can be used. In addition, the dissolution medium used is preferably 1000 mL USP phosphate buffer, pH 6.8, containing 0.3% (w / v) sodium lauryl sulfate. If the sustained release composition floats on the dissolution medium (for example, some sustained release matrix tablets tend to do so), a sinker (e.g., a Japanese sinker) should be used to ensure that the composition remains submerged during the dissolution test. Alternatively, alternative testing conditions may be used, if appropriate, in accordance with dissolution testing guidelines issued by well-known regulatory agencies such as the U.S. FDA.

[0135] In some preferred embodiments, matrix tablets, particularly sustained release matrix tablets, comprising the solid dispersion disclosed herein, whether coated or not, exhibit release of the BK B2 receptor antagonist of formula (1) within at least about 6 hours or at least about 8 hours, for example, within about 8 to 24 hours. In another preferred embodiment, the sustained release composition releases the BK B2 receptor antagonist within 12 to 24 hours, as determined by dissolution testing using the preferred methods and conditions described above. In this case, the 12 to 24 hour period of release of the active ingredient refers to the time point at which 95% of the active ingredient contained in the composition has been released falls within the specified time period. For example, the sustained release composition is characterized by a dissolution profile that achieves 95% drug dissolution after about 12 hours or about 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours.

[0136] The sustained release profile or dissolution profile can also be described in terms of the duration of release (i.e., dissolution) of about 50% of the incorporated drug. In some preferred embodiments, the sustained release composition achieves 50% dissolution within about 3 to 10 hours or within about 4 to 8 hours, for example, after about 4, 5, 6, 7 or 8 hours.

[0137] In some preferred embodiments, matrix tablets, particularly sustained-release matrix tablets, comprising the above solid dispersions have a dosage strength of about 10 mg to 80 mg and release the BK B2 receptor antagonist of formula (1) within about 12 to 24 hours, as described above. Also preferred are embodiments in which the matrix tablet comprises a solid dispersion based on HPMCAS or incorporated with HPMCAS, wherein the dosage strength of the tablet is about 20 mg to 40 mg and exhibits release within about 12 to 24 hours.

[0138] According to another aspect of the present invention, the matrix tablet disclosed herein, particularly the sustained-release matrix tablet comprising a solid dispersion, can be used to treat a subject suffering from any disease or condition responsive to bradykinin B2 receptor modulation. The disease includes a disease selected from the following group: skin diseases; eye diseases; ear diseases; oral, throat and respiratory diseases; gastrointestinal diseases; liver, gallbladder and pancreatic diseases; urinary tract and kidney diseases; male reproductive organs and female reproductive organs diseases; hormonal system diseases; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic diseases; central nervous system diseases; brain diseases; musculoskeletal system diseases; allergic diseases; pain; infectious diseases; inflammatory diseases; injuries; immunological diseases; cancer; genetic diseases; and edema. In other words, one aspect of the present invention relates to a method for treating a subject suffering from any disease or condition responsive to bradykinin B2 receptor modulation, wherein the method comprises administering a matrix tablet as described above. Similarly, the present invention provides the use of a matrix tablet in the preparation of a medicament for treating any disease or condition responsive to bradykinin B2 receptor modulation.

[0139] As used herein, the expression "treatment" should be interpreted to include any type of prophylactic or therapeutic treatment. Thus, it includes the prevention, management or treatment of a disease or its recurrence or any symptoms associated with such a disease or condition. Treatment includes acute and chronic treatment.

[0140] In the present invention, chronic treatment refers to continuous treatment of a disease or condition, including repeated administration according to a conventional dosing regimen over a long period of time, such as at least one month or at least three months. In certain embodiments in which the patient's or subject's condition does not improve, the compound of formula (1) is administered chronically, i.e., for a long period of time (including during the entire life of the patient or subject) to improve or control or limit the symptoms associated with the disease or condition in the patient or subject. For example, chronic treatment may include taking one, two or three dosage units per day during this period. In a preferred embodiment, the matrix tablet disclosed herein, particularly the sustained-release matrix tablet comprising a solid dispersion, is used for chronic treatment of a disease or condition responsive to BK B2 receptor modulation, such as AE, over a long period of time, such as at least one month. In certain preferred embodiments, the treatment disclosed herein, particularly the treatment of angioedema, especially hereditary angioedema, is a preventive treatment, i.e., treatment before the onset of symptoms to prevent, delay or reduce the severity of symptoms.

[0141] As described above and according to a preferred embodiment, a matrix tablet, in particular a sustained release matrix tablet according to any of the preferred embodiments described above, for example a sustained release matrix tablet comprising a solid dispersion of a BK B2 receptor antagonist of formula (1), is provided, which the inventors have found to provide advantageous sustained release properties. It is believed that these properties also make the sustained release composition particularly suitable for chronic or long-term treatment. One of the specific benefits provided by these compositions is that they provide sustained effective and tolerable plasma levels through a regimen of only once or twice a day.

[0142] For the avoidance of doubt, the corresponding duration of treatment does not require that the same dosing regimen be used throughout the treatment. For example, if once-daily dosing is insufficient to treat a particular subject, the regimen may be switched to twice-daily dosing. Alternatively, in chronic treatment, the dose per administration may be increased.

[0143] The following diseases or conditions may be considered responsive or at least potentially responsive to bradykinin B2 receptor modulation:

[0144] Skin diseases, including but not limited to skin aging, skin weathering (including pressure sores, bedsores), irritated, sensitive and unsightly skin, erythema, rash, skin edema, psoriasis, eczema, lichen, skin infections caused by bacteria, viruses, fungi and parasites (including furuncle, abscess, cellulitis, erysipelas, folliculitis and impetigo), lice, scabies and herpes simplex, acne, rash, dermatitis (including atopic dermatitis, allergic contact dermatitis, neurodermatitis), radiation damage, sunburn, itching, scabies, urticaria, psoriasis, fungal diseases, tissue ulcers, epidermolysis bullosa, wounds (including abnormal wound healing, burns, frostbite, skin inflammation and edema caused by venom), hair loss, dandruff, corns, warts and digital abscesses.

[0145] Eye diseases, including but not limited to inflammatory diseases, such as scleritis, conjunctivitis, conjunctival edema, iritis, iridocyclitis, uveitis, chorioretinitis, and diseases, such as retinochoroidal circulation disorders, bacterial eye infections, nonspecific conjunctivitis and eye irritation, retinopathy of prematurity, proliferative vitreoretinopathy, macular degeneration (including age-related macular degeneration, including wet and dry forms), corneal diseases, including corneal transplant rejection, corneal injury, corneal scarring, corneal ulcers, corneal opacities, keratoconus, glaucoma (preferably open-angle glaucoma), myopia, glaucoma, high intraocular pressure, ocular vascular damage, angiogenesis, ocular fibrosis (e.g., anterior subcapsular fibrosis, posterior subcapsular opacity, posterior capsule opacity, corneal opacity after laser surgery, subconjunctival scarring after glaucoma surgery), proliferative vitreoretinopathy (PVR), bacterial eye infections, including styes and eyelash loss.

[0146] Ear diseases, including but not limited to Meniere's disease, otitis media, external ear inflammation and acute hearing loss.

[0147] Oral, pharyngeal and respiratory diseases, including but not limited to inflammation of the oral mucosa and gums, including aphthous ulcers and stomatitis, periodontitis, epiglottitis, pharyngitis, laryngotracheitis, tonsillitis, common cold, sore throat, rhinitis (including seasonal allergic rhinitis or perennial allergic rhinitis), epistaxis, sinusitis of any type, etiology or pathogenesis or selected from purulent or non-purulent sinusitis, acute and chronic sinusitis and ethmoid sinusitis, frontal sinusitis, maxillary sinusitis or sphenoid sinusitis, expectoration, any type or origin Pneumoconiosis of a substance of known origin, including, for example, aluminum pneumoconiosis, coal pneumoconiosis, asbestosis, stone dust lung, siderosis, silicosis, fume contusion, especially byssinosis, bronchitis, cough, tracheitis, congestion, pneumonia, eosinophilic pulmonary infiltration, chronic eosinophilic pneumonia, idiopathic pulmonary fibrosis and other fibrotic lung diseases, treatment-related fibrotic lung diseases (e.g. related to radiation, methotrexate, chemotherapy, amiodarone or nitrofurantoin), sarcoidosis, acute respiratory distress syndrome (ARDS) , bronchoconstriction, asthma of any type, etiology or pathogenesis, or asthma selected from the following: allergic asthma, non-allergic asthma, allergic and non-allergic asthma, extrinsic asthma caused by environmental factors, intrinsic asthma caused by pathophysiological disorders, bronchial asthma, IgE-mediated asthma, idiopathic asthma and idiopathic asthma of unknown or unexplained cause, true asthma, emphysematous asthma, exercise-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoan or viral infection, incipient asthma, infantile wheezing syndrome, bronchial hyperresponsiveness, chronic obstructive pulmonary disease (COPD), COPD characterized by irreversible, progressive airway obstruction, acute respiratory distress syndrome (ARDS) and other drug-induced exacerbation of airway hyperresponsiveness, dyspnea, hyperoxic alveolar damage, emphysema, pleurisy, tuberculosis, exposure to high altitude (i.e. acute mountain sickness, preferably high altitude pulmonary edema (HAPE)), intractable cough, bronchial hyporesponsiveness.

[0148] Gastrointestinal disorders, including but not limited to esophagitis, gastritis, irritable gastric disease, gastric and duodenal ulcers, intestinal obstruction, irritable colon disease, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), enteritis, hypertensive gastric and colonic disease, colitis, peritonitis, appendicitis, proctitis, gastrointestinal bleeding due to portal hypertension, collateral circulation or congestion, dumping syndrome after gastrectomy, digestive discomfort, diarrhea, hemorrhoids, helminthiasis, abdominal cramps and cramps in any part of the gastrointestinal system.

[0149] Liver, gallbladder and pancreatic diseases, including but not limited to hepatitis, cirrhosis, liver fibrosis (e.g. due to viral (HBV / HCV) infection, toxins (alcohol), fatty liver, cholestasis, hypoxia), portal hypertension, hepatorenal syndrome, hepatic edema, cholangitis, cholecystitis, acute and chronic pancreatitis and biliary colic, etc.

[0150] Urinary tract and kidney diseases, including but not limited to urinary tract infections (e.g., acute and chronic cystitis, interstitial cystitis, irritative bladder, overactive bladder, incontinence (including but not limited to stress, urge and reflex incontinence)), benign prostatic hyperplasia, chronic kidney disease, urethritis, inflammatory kidney disease (including glomerulonephritis, renal glomerular disease, interstitial nephritis, pyelonephritis), polyuria, proteinuria, natriuresis, calciuria, water balance disorders, electrolyte balance disorders, acid-base balance disorders and renal colic, renal fibrosis, chronic renal transplant dysfunction, contrast-induced nephropathy.

[0151] Diseases of the male and female reproductive organs, including but not limited to altered sperm motility, male infertility, orchitis, prostatitis, prostatic hyperplasia, mastitis, inflammatory pelvic disease, vaginal infection and pain, adnexitis, vaginitis, soft ulcers, syphilis, gonorrhea and ovarian hyperstimulation syndrome.

[0152] Hormonal system diseases, including but not limited to menstrual disorders and pain, menopausal disorders, vomiting, premature uterine contractions, premature birth, endometriosis, endometritis, fibroids, and preeclampsia.

[0153] Metabolic diseases include, but are not limited to, diseases such as diabetes, including non-insulin-dependent diabetes mellitus, diabetic retinopathy, diabetic macular edema, diabetic nephropathy and diabetic neuropathy, insulin resistance and diabetic ulcers, protein and purine metabolism diseases (e.g., gout and lipid metabolism disorders), and hypoglycemia.

[0154] Cardiovascular disease, including but not limited to vascular permeability, vasodilation, peripheral circulatory disorders, arterial circulatory disorders (including aortic aneurysm, abdominal aortic aneurysm, cerebral aortic aneurysm), hypertension and hypotension associated with sepsis, restenosis after percutaneous transluminal coronary angioplasty, atherosclerosis (including rupture of atherosclerotic plaques), hemangioma, angiofibroma, venous disease (such as thrombosis, varicose veins, phlebitis, thrombophlebitis, venous thrombosis), heart disease, congestive heart failure, coronary heart disease, carcinoid syndrome, angina pectoris, Arrhythmias, inflammatory heart disease (including endocarditis, pericarditis, and constrictive pericarditis), myocarditis, myocardial infarction, post-myocardial infarction syndrome, left ventricular dilatation, post-ischemia-reperfusion injury, shock and collapse (including septic, anaphylactic, post-traumatic, and hemodynamic shock), amniotic fluid embolism, systemic inflammatory response syndrome (SIRS) (including SIRS caused by cardiopulmonary bypass during surgery), sepsis during cardiopulmonary bypass, and internal and external complications (including but not limited to adverse hemodynamic effects after reversal of heparin with protamine sulfate).

[0155] Hematological diseases, including but not limited to coagulation, disseminated intravascular coagulopathy, bleeding, bleeding diathesis, hypercholesterolemia and hyperlipidemia, hypovolemic shock, paroxysmal nocturnal hemoglobinuria, etc.

[0156] Lymphatic disorders, including but not limited to splenomegaly, lymphangitis, lymphadenitis, and adenoid hyperplasia.

[0157] Central nervous system diseases, including but not limited to inflammatory diseases of the central nervous system (including encephalitis, meningitis, encephalomyelitis, meningoencephalitis), hydrocephalus, amyotrophic lateral sclerosis, spinal cord trauma, spinal cord edema, demyelinating diseases of the nervous system, multiple sclerosis, acute and chronic neurodegenerative diseases (including aging, Alzheimer's disease and Parkinson's disease, neuritis and peripheral neuropathy), depression, anorexia, anxiety disorders and schizophrenia, sleep disorders.

[0158] Brain diseases, including but not limited to nootropics or cognitive enhancement, cerebral amyloid angiopathy, stroke, head and brain trauma, traumatic brain injury, brain tumors, brain thermal injury, cerebral ischemia, cerebral hemorrhage, post-traumatic and post-ischemic brain edema, general cerebral edema, acute mountain sickness and preferably high altitude cerebral edema (HACE), cytotoxic cerebral edema, vasogenic cerebral edema, post-surgical cerebral edema, cerebral edema associated with metabolic diseases, increased permeability of the blood-brain barrier or blood-brain tumor barrier.

[0159] Diseases of the musculoskeletal system, including but not limited to inflammatory musculoskeletal diseases, arthrosis, osteoarthrosis, osteoarthritis, chondroporosis after joint trauma or relatively long-term immobilization of the joint after meniscus or patellar injury or ligament tear, rheumatoid arthritis of any type, etiology or pathogenesis (including acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis and infectious arthritis, Lyme's arthritis, proliferative arthritis, spondyloarthritis, septic arthritis, psoriatic arthritis, chronic polyarthritis), rheumatism, Sjögren's syndrome, low back pain, spondylitis, spondyloarthritis, ankylosing spondylitis, osteomyelitis, sprains, tenosynovitis, bone resorption caused by inflammation, fractures, etc., osteoporosis, musculoskeletal pain and sclerosis, intervertebral disc syndrome.

[0160] Allergic diseases, including but not limited to general allergic reactions, food allergies, anaphylactic shock, allergic contact hypersensitivity, allergic skin reactions, allergic asthma, vernal conjunctivitis and seasonal or perennial allergic rhinitis.

[0161] Pain, including but not limited to centrally and peripherally mediated pain, vascular pain, visceral pain, inflammation-mediated pain, neuralgia, referred pain, nociceptive pain, reflex pain, psychosomatic pain, acute pain (e.g., acute pain caused by acute injury to bones, muscles, tissues, soft tissues, organs, trauma or surgery), pain following insect bites, post-stroke pain syndrome, postoperative pain, pain associated with progressive diseases, chronic pain (e.g., caused by neuropathic pain (including but not limited to complex regional pain syndrome, causalgia, morbussudeck, reflex sympathetic dystrophy, diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, cancer-related pain, pain associated with rheumatoid arthritis, osteoarthritis, tenosynovitis, gout, menstrual pain and angina, fibromyalgia, eye pain, back pain, headache, cluster headache, migraine, inflammatory pain that may be associated with acute inflammation or chronic inflammation)). Inflammatory pain includes but is not limited to neuropathic pain, ischemic pain, pain caused by arthritis, muscle pain caused by acute or chronic inflammation, neuralgia caused by chronic or acute inflammation, and hyperalgesia. Also chemotherapy-induced peripheral neuropathy, hyperalgesia, opioid-induced hyperalgesia and fever. In addition, the compounds of the present invention are useful as analgesics used during general anesthesia and monitored anesthesia.

[0162] Infectious diseases include, but are not limited to, diseases mediated by bacterial, viral, fungal, parasitic, protozoan, prion or mycobacterial infections. In particular, the present invention can be used to treat bacterial infections caused by Streptococcus, Escherichia coli, Salmonella, Staphylococcus, Klebsiella, Moraxella, Haemophilus and Yersinia. Examples of bacterial infections within the scope of the present invention include, but are not limited to, plague, septicemia, epidemic typhus, food poisoning, tetanus, scarlet fever, whooping cough, diphtheria and the like. Examples of viral infections within the scope of the present invention include, but are not limited to, diseases such as chickenpox and herpes zoster, AIDS, influenza, smallpox, and childhood diseases such as measles, rubella, mumps, acute myelitis, and the like. The present invention can be used to treat protozoan and parasitic infections caused by Schistosoma mansoni, Dermatofagoides farinae, and malaria induced by Plasmodium. Examples of prion infections within the scope of the present invention include, but are not limited to, diseases such as bovine spongiform encephalopathy (BSE), Creutzfeldt-Jakob disease and kuru, dengue fever, hemorrhagic fever, and the like.

[0163] Inflammatory diseases, including but not limited to acute phase reactions, local and systemic inflammation, and inflammation caused by other diseases regardless of their type, etiology or pathogenesis as well as by the inflammatory diseases defined in this application.

[0164] Injury: In this application, the term "injury" includes, but is not limited to, multiple trauma, head trauma, lung injury, external, internal and surgical wounds.

[0165] Immunological diseases, including but not limited to hyperesthesia, autoimmune diseases, transplant rejection in transplantation, transplant toxicity, granulomatous inflammation, tissue remodeling, myasthenia gravis, immunosuppression, immune complex disease, over- and under-production of antibodies, vasculitis, delayed graft function, lupus, etc.

[0166] Cancer, including but not limited to solid tumor cancers, including breast cancer, lung cancer (non-small cell lung cancer and small cell lung cancer), prostate cancer, oral and pharyngeal (lip, tongue, mouth, pharynx) cancer, esophageal cancer, stomach cancer, small intestine cancer, large intestine cancer, colon cancer, rectal cancer, gallbladder cancer and bile duct cancer, pancreatic cancer, laryngeal cancer, lung cancer, bone cancer, osteosarcoma, connective tissue cancer, skin cancer (including Kaposi's syndrome), melanoma and skin metastases, epidermoid cancer, basal cell carcinoma, cervical cancer, endometrial cancer, ovarian cancer, testicular cancer, bladder cancer, ureter and urethra cancer, kidney cancer, eye cancer, brain and central nervous system cancer, pseudotumor brain, sarcoma, sarcoid tumor, thyroid cancer and other endocrine gland cancer (including but not limited to carcinoid tumor), Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, hematological malignancies, including leukemias, lymphomas, including lymphocytic, granulocytic and monocytic lymphomas, tumor invasion, metastasis, ascites, tumor growth and angiogenesis.

[0167] Genetic diseases, including but not limited to hereditary angioedema and angioneurotic edema, chondrocalcinosis, Huntington's disease, visco-obstructive disease, etc.

[0168] Edema used herein includes, but is not limited to, systemic edema and edema caused by inflammation, edema caused by factor XII deficiency, other drugs such as drug-induced angioedema, including but not limited to angioedema caused by angiotensin converting enzyme inhibitors, infection, burns, injuries, trauma, frostbite, surgery, sprains, fractures, exposure to high altitudes (e.g., high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE)), hereditary, autoimmune and other diseases and disorders, particularly but not limited to those specified in this application, pressure-induced intestinal edema (significant swelling). Known forms of angioedema (AE) include hereditary angioedema (HAE), acquired angioedema (AAE), bradykinin-mediated non-histaminergic idiopathic angioedema, allergic angioedema and drug-induced angioedema. HAE can be of any type, including type I HAE, type II HAE or type III HAE.

[0169] Capillary leak syndrome, including but not limited to systemic capillary leak syndrome in sepsis, burns, allergy, drug / toxin induced disease, organ transplantation and IL-2 cytokine therapy.

[0170] In another preferred embodiment, the matrix tablet, in particular the sustained-release matrix tablet according to any preferred embodiment disclosed herein, is used to treat AE, including HAE, AAE, bradykinin-mediated non-histaminergic idiopathic AE, allergic AE and drug-induced AE. AE is an area of ​​swelling of the skin or submucosal skin and tissues below the skin. Debilitating and often painful swelling may occur on the face, lips, tongue, limbs, genitals, gastrointestinal mucosa, urogenital area and airways. This is often associated with urticaria, which is swelling in the upper skin. It is characterized by recurring swelling, usually within a few minutes to a few hours. It is impossible to predict when and where the next angioedema will occur. Patients may have an attack once a month, but some patients have attacks weekly or only once or twice a year.

[0171] In some preferred embodiments, the matrix tablet, in particular the sustained-release matrix tablet according to any preferred embodiment disclosed herein, is used to treat any type of HAE, including type I HAE, type II HAE or type III HAE, preferably type I HAE or type II HAE. HAE is a disease with recurrent episodes of severe swelling. The swelling usually affects the arms, legs, face, intestines, and airways. If the intestines are affected, abdominal pain and vomiting may occur. Swelling of the airways may lead to bronchial obstruction and difficulty breathing. Acute attacks usually last for several days, and the frequency of attacks in HAE patients is about once every two weeks.

[0172] Matrix tablets are particularly advantageous in the chronic treatment of AE, including hereditary angioedema (HAE) and acquired angioedema (AAE), particularly type I HAE or type II HAE. As previously mentioned, it is patient-friendly because it only requires one dose per day or only two doses per day. In view of the robustness of the sustained-release properties to pH changes and the presence of food, these compositions are suitable for long-term treatment for months or even years. Therefore, one of the preferred embodiments relates to the use of a matrix tablet, particularly a sustained-release matrix tablet according to any preferred embodiment disclosed herein, for the chronic treatment of hereditary angioedema, wherein the chronic treatment is preferably carried out within at least one month. As previously mentioned, chronic treatment can also be carried out within at least 3 months or at least one year. Further preferred is the chronic treatment using a dosing regimen comprising administering the matrix tablet once a day or twice a day.

[0173] In other words, for the BK B2 receptor antagonist of formula (1), the matrix tablet design described herein enables a prolonged release profile that allows for a longer dosing interval, which improves patient friendliness and enables patients to better comply with the prescribed dosing regimen, thereby improving treatment outcomes.

[0174] Likewise, for the avoidance of doubt, the corresponding duration of treatment does not require that the same dosing regimen be used throughout the treatment. For example, if once-daily dosing is insufficient to treat a particular subject, the regimen may be switched to twice-daily dosing. Alternatively, in chronic treatment, the dose of the BKB2 receptor antagonist administered per dose may be increased.

[0175] Further aspects, embodiments, optional features and preferences of the invention will be apparent on the basis of the examples and claims.

[0176] Other definitions

[0177] For the sake of clarity, some other definitions of terms used in the specification and claims are given. These definitions should be used to determine the meaning of the corresponding expressions unless the context requires a different meaning.

[0178] The term "a" does not exclude the plural, that is, the singular forms "a", "the" should be understood to include plural objects, unless the context clearly indicates or requires otherwise. In other words, the singular features or limitations of the present invention should include the corresponding plural features or limitations, and vice versa, unless otherwise expressly provided or clearly implied by the context. Therefore, unless otherwise defined, the terms "a", "the" and "at least one" or "one or more" have the same meaning. For example, "a component" includes a mixture of various components, etc.

[0179] The term "about" or "approximately" will compensate for the variability allowed in the pharmaceutical industry and inherent in pharmaceutical products, such as differences in content due to manufacturing variations and / or time-induced degradation of the product. The term allows for any variation that, in pharmaceutical practice, would allow the product evaluated to be considered bioequivalent in a subject to the stated strength of the product.

[0180] The terms "active agent", "therapeutic agent", 'active pharmaceutical ingredient (API)', 'active ingredient', 'drug', 'biologically active agent' are synonymous and refer to a compound or combination of compounds that has pharmaceutical activity against an undesirable disease.

[0181] The term "composition" refers to any type of composition, wherein the specified ingredient may be added, optionally together with any other ingredients.

[0182] In the present invention, "pharmaceutical composition" is understood to be a composition that is technically suitable for use as a drug to a subject (e.g., a human patient). Its ingredients, formulation, and processing meet general pharmaceutical standards, such as those that may be defined in official pharmacopoeias or guidelines issued by regulatory agencies such as FDA, PMDA, and EMA. In a preferred embodiment, the composition is suitable for oral administration, which means that, for example, the excipients used, including their grade and dosage, are safe and acceptable for oral use, particularly for oral administration to human subjects.

[0183] As used herein, "sustained release composition" refers to any pharmaceutical composition or formulation suitable for oral administration that exhibits sustained release of the active ingredient. Sustained release may also be referred to as slow release, controlled release or sustained release, which are just a few alternative expressions, but are not limited to these.

[0184] The term "compound" refers to a chemical substance, which is a material composed of molecules with essentially the same chemical structure and properties. For small molecule compounds, the molecules are generally identical in terms of their atomic composition and structural configuration. For macromolecular or polymeric compounds, the molecules of the compound are highly similar, but not all molecules are necessarily identical.

[0185] The terms "including" and similar expressions should be interpreted in an open and inclusive sense as meaning "including but not limited to".

[0186] The terms "substantially", "about", "approximately", "substantially" and the like in relation to an attribute or value include the precise attribute or precise value, as well as any attribute or value that is generally considered to be within the normal range or variation acceptable in the relevant art. For example, "substantially anhydrous" means that the composition does not contain intentionally added water, but does not exclude the presence of residual moisture.

[0187] The term "consisting essentially of" refers to a composition or dosage form to which no other ingredients have been added other than the listed ingredients. However, there may be very small amounts of other materials, such as impurities inherent to the material, or small amounts of additives added by the excipient supplier. In addition, when it is mentioned, for example, "consisting essentially of A, B, C, and optionally D", it means that no other components have been added to the composition or dosage form except A, B, C and D, wherein D is an optional (i.e., non-mandatory) component of the composition or dosage form.

[0188] The term "substantially free" refers to compositions containing less than a functional amount of the respective ingredient, typically less than 1 wt%, preferably less than 0.1 wt% or even 0.01 wt%, and including 0 wt% of the respective ingredient.

[0189] The following examples further illustrate some aspects of the present invention but should not be construed as limiting the scope of the present invention.

[0190] Example

[0191] The compound of formula (1) is prepared as described in WO 2019 / 101906, where necessary in compliance with Good Manufacturing Practice (GMP) regulations.

[0192] The study reported in Example 6 was conducted in accordance with the corresponding protocol, the current Good Clinical Practice (GCP) guidelines of the International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), and applicable regulatory and country-specific government rules for conducting clinical trials, including rules on the protection of subjects and informed consent, and transparency requirements. Prior to the start of the study, the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) reviewed and approved all trial protocols, the suitability of the investigators, the facilities and methods, and the materials used to obtain and record informed consent from the trial subjects. For this study, the final release of the study drug, i.e., the compound of formula (1), was performed by qualified personnel in accordance with Annex XIII of Directive 2003 / 94 / EC; the study drug label contained information in accordance with applicable regulatory requirements. The study drug was packaged, labeled, and released at the clinical site by a pharmacist in accordance with the GMP practice guidelines, the International Conference on Harmonization (ICH), Good Clinical Practice (GCP), and applicable local laws / regulations.

[0193] Example 1: Solid dispersion prepared by vacuum melt pressing

[0194] Two solid dispersion compositions were prepared by vacuum melt pressing. The first composition, designated HME1, consisted of 40 wt% (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, 58.5 wt% copolyvidone ( The second composition, designated HME2, consisted of 20 wt % (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide and 80 wt % hydroxypropyl methylcellulose acetate succinate ( AS-MMP) composition.

[0195] The active ingredient (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide is provided as a crystalline monohydrate in powder form. The actual amount of active ingredient and carrier are mixed in a vibrating mixer. Mix for 4 minutes.

[0196] Subsequently, the measured powder mixture was transferred to a laboratory-scale vacuum press molding device (VCM Meltprep) equipped with a disc molding tool (Meltprep Disc Tool) and molded into discs under a vacuum of -1.0 bar. For HME1, vacuum press molding was carried out at a temperature of 200°C, a heating time of 5 minutes, a cooling time of 2 minutes, and a cooling air pressure of 2.5 bar. For HME2, vacuum press molding was carried out at a temperature of 180°C, a heating time of 5 minutes, a cooling time of 5 minutes, and a cooling air pressure of 3.0 bar. With these two compositions, transparent light yellow discs were obtained.

[0197] The disks were crushed with a mortar and pestle for further evaluation. First, the drug content was confirmed to be in the range of 90% to 110% of the theoretical amount by HPLC analysis. In addition, the crystalline state of the drug substance was evaluated by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD, also known as powder X-ray diffraction or PXRD). The DSC thermogram did not show the melting point of the active ingredient (about 111°C), and only the Tg of the polymer could be observed. XRPD analysis showed no residual crystallinity. Therefore, it can be concluded that these samples represent solid dispersions containing only the active ingredient in an amorphous, completely dissolved state.

[0198] Example 2: Solid dispersion prepared by spray drying

[0199] Four solid dispersion compositions, designated as SDD1 to SDD4, were prepared by spray drying, each consisting of 25 wt % of (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide and 25 wt % of a carrier polymer. The carrier polymer of SDD1 was hypromellose acetate succinate ( AS-MMP), SDD2 is 2910USP type hydroxypropyl methylcellulose ( E3) and SDD3 are copolyvidone ( The one for SDD4 is povidone K-30.

[0200] For each composition, measured amounts of active ingredient and corresponding carrier polymer were dissolved in a mixture of dichloromethane (DCM) and methanol (ratio 4:1 (w / w)) and then spray dried using a laboratory scale spray dryer (Büchi B290) using the parameters listed in Table 1 below.

[0201] Table 1

[0202]

[0203] The powder produced by the spray drying process was collected and subjected to a secondary drying step, vacuum drying at 40°C and -26.5 mm Hg for 20 hours.

[0204] The obtained samples were evaluated using modulated differential scanning calorimetry (mDSC), XRPD and thermogravimetric analysis (also known as thermogravimetric analysis, TGA). Both XRPD and mDSC data confirmed that all four samples were amorphous and did not contain any detectable crystalline material. The TGA thermogram showed an inflection point in the slope of the weight loss step of the SDD4 sample, indicating that a small amount of residual solvent was left in the sample. Overall, all samples were confirmed to represent uniform solid dispersions containing active ingredients in amorphous form and completely dissolved in the carrier polymer.

[0205] Samples of the spray-dried solid dispersions SSD1 to SSD4 were stored at high temperature (40° C.) and retested by XRPD after three weeks. As a result, all samples were amorphous and contained no crystalline components.

[0206] Example 3: Solid dispersion prepared by hot melt extrusion

[0207] The method comprises a mixture consisting essentially of 20% by weight of (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide and 80% by weight of hydroxypropyl methylcellulose acetate succinate ( AS-MMP) composed of HME2 (see Example 1) was used to prepare a solid dispersion by hot melt extrusion. The powder blend containing the crystallized active ingredient and the carrier polymer was sieved through a sieve with a pore width of 500 μm. The blend was then extruded using a twin-screw extruder (Leistritz ZSE12HP-PH) equipped with a 1.5 mm die. The maximum temperature in the kneading zone was 145 to 165°C, but the temperature in the die zone was set to 200°C. A slightly brown transparent extrudate was obtained and granulated with a granulator. Subsequently, the particles were ground in two stages using a hammer mill, with a sieve size of 1000 μm in the first stage and 400 μm in the second stage, and a grinding speed of 6500 rpm. Then, by laser diffraction The particle size distribution was characterized. For both milling batches, the average particle size D50 was 262.3 μm and 249.1 μm, respectively. In the sieve analysis, 66.2 wt.-% and 61.7 wt.-% of the milled particles, respectively, were found to be in the particle size fraction of 180 μm to 355 μm.

[0208] HME2 solid dispersion samples were stored at high temperature (40°C) to test their chemical and physical stability. Drug content and impurities were quantified by HPLC. Changes in crystalline state (if any) were detected by XRPD. The test results are provided in Table 2 below. They show that the active ingredient in the solid dispersion has high chemical stability and remains in amorphous form.

[0209] Table 2

[0210]

[0211] *100% refers to the theoretical content of API in the sample.

[0212] Example 4: Matrix tablet containing micronized active ingredient

[0213] About 2.9 kg of crystalline (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide monohydrate was micronized in a jet mill using nitrogen as process gas at a gas feed pressure of about 30 psi in the milling chamber and about 60 psi in the venturi injector. A micronized powder was obtained, the particle size distribution of which was 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.

[0214] In the next step, five different types of sustained release matrix tablets incorporating micronized API were prepared. The composition of these tablets is provided in Table 3 below. The corresponding powder mixtures were compressed to give tablets on a laboratory scale single punch pharmaceutical tablet press (Kilian Styl'One Evolution) using a pre-compression force of 0.8 to 2.3 kN and a main compression force of 13 to 25 kN. In all cases, tablets with an average crushing resistance of more than 100 N were obtained.

[0215] Table 3

[0216]

[0217]

[0218] In vitro dissolution testing revealed that all tablet formulations exhibited sustained release of the active ingredient, with drug release lasting for more than 12 hours.

[0219] Example 5: Matrix tablet comprising a solid dispersion

[0220] The solid dispersion composition HME2 was prepared as described in Example 3 and incorporated into two matrix tablet formulations (5.1 and 5.2) having the compositions shown in Table 4.

[0221] Table 4

[0222]

[0223] As described in detail above, hypromellose in these formulations represents the hydrophilic matrix-forming polymer. Microcrystalline cellulose and dibasic calcium phosphate dihydrate are used as tablet fillers, colloidal silicon dioxide is used primarily as a glidant, and magnesium stearate is used primarily as a lubricant.

[0224] The weighed raw materials are mixed in a drum mixer ( 2F) is mixed in several subsequent steps: first, the ground extrudate, filler and hydrophilic matrix-forming polymer are mixed, then the glidant is added and mixed, and finally the lubricant is added and mixed. The resulting powder mixture is compressed into white to off-white oval, biconvex brown-speckled tablets (17 mm××7.2 mm) on a laboratory-scale single-punch pharmaceutical tablet press (Kilian Styl'OneEvolution) using a main compression force of 15 kN to 40 kN. The average thickness of the tablets is about 5.7 mm, the average crushing resistance is about 110 N to 170 N, and the friability is about 0.2 wt % to 0.7 wt %. Determination (HPLC-UV) shows that the drug content is within the acceptable range of 90% to 110% of the labeled content. Total impurities are less than 1%.

[0225] According to Ph. Eur. 2.9.3 / USP <711> The drug release properties of samples 5.1 and 5.2 tablets were characterized by dissolution testing using apparatus II (paddle apparatus). The dissolution medium was 1000 mL USP phosphate buffer, pH 6.8, containing 0.3% (w / v) sodium dodecyl sulfate. The paddle speed was set to 100 rpm. A Japanese sinker was used to prevent the tablets from floating. Samples were taken out at regular intervals and their API concentrations were analyzed by HPLC, from which the amount of drug dissolved was calculated. The dissolution characteristics are shown in Table 5.

[0226] Table 5

[0227]

[0228] As shown in the test results, the matrix tablet containing the solid dispersion of the BK B2 receptor antagonist of formula (1) can achieve sustained release of the active ingredient over a long period of time, for example, about 12 hours or even longer. Matrix tablet 5.1 exhibited a steeper dissolution profile in vitro than tablet 5.2.

[0229] Example 6: Human PK study

[0230] In a clinical Phase I study, the basic pharmacokinetic properties of matrix tablets 5.1 and 5.2 after a single dose were evaluated and compared with immediate-release capsules under fasting and fed (HCHF meal) conditions. The study was designed as a randomized five-period crossover study with 10 healthy volunteers. Table 6 lists the key PK parameters obtained in the study.

[0231] Table 6

[0232]

[0233]

[0234] The data show that the matrix tablet formulation exhibits sustained release properties in vivo, as indicated by the tmax values. Sample 5.2, which releases the active ingredient for a longer time in vitro, also results in a delay in tmax in vivo, both under fasting and fed conditions, compared to sample 5.1 (see Example 5). It is very noteworthy that the overall drug exposure of the matrix tablet behaves like that of a regular release formulation (see AUC values), from which it can be concluded that, despite its unfavorable physical properties, the active ingredient can be reliably released and absorbed even from more distal regions of the intestine.

[0235] Figures 1 to 3 The mean plasma concentration curves of the corresponding preparations over time are shown: Figure 1 describes the plasma profile after administration in the fasting state, while Figure 2 and Figure 3 The skeleton sheet 5.1 ( Figure 2 ) and matrix tablets 5.2 ( Figure 3 ) Plasma profiles after administration in the fed state vs fasted state. Subsequent simulation studies confirmed the usefulness of the PK properties of the two tested matrix tablet formulations for continuous treatment using a once-daily or twice-daily dosing regimen. The SMEDDS formulation refers to a regular release soft gelatin capsule containing the active ingredient, formulated as a self-microemulsifying drug delivery system (SMEDDS), through which a dose of 20 mg of API was administered as a control.

[0236] Example 7: Film-coated matrix tablets

[0237] Tablets of samples 5.1 and 5.2 (see Example 5) were film coated using an aqueous dispersion of a premix containing the following ingredients, the percentages based on the total weight of the film ingredients: hydroxypropylcellulose (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 01Lab) at 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 a spray volume of 350 m / min. 3 / h inlet air volume. Spraying was performed until the weight of the tablet core increased by 5 wt%. In other batches using the same procedure, the tablet coating contained 20 wt% microcrystalline cellulose (MCC) and 5 wt% yellow iron oxide. Except for a slight time lag caused by the coating, the coated tablets had essentially the same sustained-release properties as the uncoated tablet cores, which had no correlation with the overall sustained-release properties.

[0238] Example 8: Matrix tablet containing solid dispersion

[0239] Other batches of solid dispersion composition HME2 were prepared as described in Example 3, except that in some batches, the final stage of grinding the particles used a 200 μm mesh size, which resulted in an average particle size D50 of about 100 μm; for some tablets, the extrudates were jet-milled (rather than using a hammer mill) to an average particle size D50 of about 50 μm and about 10 μm, respectively. The milled extrudates were incorporated into each matrix tablet formulation with a dosage strength of 1 mg to 50 mg. The matrix tablet compositions are shown in Tables 7 to 9.

[0240] In this case, an average particle size D50 of about 200 μm or ˜200 μm is to be understood as a median value of the corresponding particle size distribution determined gravimetrically by sieve analysis between 125 μm and 250 μm. In other words, more than 50% by weight of the ground particles pass through a sieve with an aperture width of 250 μm, while less than 50% by weight of the particles pass through a sieve with an aperture width of 125 μm. Likewise, an average particle size D50 of about 100 μm or ˜100 μm is to be understood as a median value of the particle size distribution determined gravimetrically by sieve analysis between 63 μm and 125 μm, more than 50% by weight of the ground particles pass through a sieve with an aperture width of 125 μm, while less than 50% by weight of the particles pass through a sieve with an aperture width of 63 μm. The average particle size D50 of about 50 μm or ~50 μm should be understood as the average value of D50 measured by laser diffraction (such as Beckman Coulter's particle size analyzer LS13 320XR) is about 50±25 μm, and the average particle size D50 of about 10 μm or ~10 μm should be understood as the average value of D50 measured by laser diffraction is about 10±5 μm.

[0241] These matrix tablet formulations provide, among other things, further examples of sustained release matrices containing compounds of formula (1) composed of a single grade of hypromellose polymer, particularly a high viscosity grade of hypromellose 2208 type polymer (e.g., Methocel TM K100M DC2 or Methocel TM K 100M Premium); or a combination of hypromellose polymers, such as a combination of hypromellose 2208 and hypromellose 2910; for example, a high viscosity grade of hypromellose 2208 and a high viscosity grade or low viscosity grade of hypromellose 2910 (such as Methocel TM E4M) combination.

[0242] Matrix tablet formulations also provide examples of other excipients that can be used to modify the physical properties of the tablet, such as polyethylene glycol, special low viscosity grades of hydroxypropylcellulose or hypromellose, or acid insoluble polymers such as HPMCAS.

[0243] Furthermore, the examples show how a tablet filler (or filler binder) such as MCC and a glidant such as colloidal silicon dioxide can be replaced together by a multifunctional excipient, in this case siliconized MCC.

[0244] Table 7

[0245]

[0246] Table 8

[0247]

[0248] Table 9

[0249]

[0250]

[0251] *Diameter of round tablets

[0252] The in vitro drug release characteristics of several sample formulations were tested using a dissolution test apparatus (also known as a "pressure tester" or "dissolution pressure tester"), as described in G. Garbacz et al., Expert Opin. Drug Deliv. vol. 7, 2010, pages 1251-1261. In short, the device includes a central device with a dissolution container, which contains a spherical probe chamber made of stainless steel wire mesh for fixing the test sample. Each chamber has a bottom that is screwed into the central tubular shaft through a bushing and a nozzle. In the working mode, the central tube is placed on the deck of the device, about 3 mm from the top edge of a series of standard dissolution containers on the symmetry plane. Each probe chamber operates in a separate container. At one end, the central shaft itself is connected to a pressure regulating device, and at the other end, a stepper motor is connected. The pressure wave is generated by the periodic expansion and contraction of the balloon located in the probe chamber. These are controlled by the synchronous switching of the valve, and the pressure can be adjusted by the pressure reducing device. The central axis is driven by a stepper motor that can be programmed to position the probe chamber inside and outside the dissolution vessel, either immersed in the media or in contact with air. The dissolution media (typically 1160 mL) is mixed by a separate paddle stirrer (typically operated at 200 rpm).

[0253] Two different pressure dissolution testing procedures were performed using this apparatus, briefly summarized below as "Method 1" and "Method 2." In both protocols, simulated gastric fluid (SGF) without pepsin, pH 1.8, was used as the dissolution medium for the gastric phase, and modified fasted state simulated intestinal fluid (mFaSSIF), pH 6.8, was used as the dissolution medium for the intestinal transit phase, according to USP.

[0254] Method 1 described in Table 10 is intended to simulate drug administration in the fasted state under relatively low gastrointestinal motility conditions, while Method 2 simulates drug administration in the fasted state under high intestinal motility or enhanced pressure conditions. Method 2 differs from Method 1 in that the colonic phase includes additional agitation and pressure events at 7 hours (two 200 mbar pressure waves at 50 rpm for 30 seconds). In addition, the colonic phase is repeated 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, 17.5, Other agitation events occurred at 18.5, 19.5, 20.5, 21.5, 22.5 and 23.5 hours and other minor pressure events (a 150 mbar pressure surge and 50 rpm for 30 seconds) occurred 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.

[0255] Dissolution medium samples were placed into HPLC vials through PE filters (1 μm pore size) every 60 minutes to 24 hours. Subsequently, the concentration of drug substance was determined by HPLC.

[0256] Table 10

[0257]

[0258]

[0259] The test results are shown in Tables 11 and 12. The results provided in Table 11 were obtained by Method 1, while the results in Table 12 were obtained by Method 2.

[0260] Table 11

[0261]

[0262] Note: Each value represents the average of three tested tablets.

[0263] Table 12

[0264]

[0265]

[0266] Note: Each value represents the average of four or five tablets tested. 7.1a, 7.1b and 7.1c are different batches of the same matrix tablet formulation 7.1.

[0267] The results clearly show that the matrix tablets tested are all suitable as sustained release formulations for oral delivery of the active ingredient, where the desired release occurs over a long period of time, i.e. 12 hours or even up to 24 hours. The comparative results shown in Table 12 further show that the design and composition of the matrix determine the release rate and that the coating has a negligible effect on the overall release characteristics.

Claims

1. A pharmaceutical matrix tablet comprising a bradykinin (BK) B2 receptor antagonist or a stereoisomer, salt or solvate thereof having a chemical structure of formula (1): wherein R is deuterium or hydrogen; and at least one hydrophilic backbone-forming polymer.

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

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

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

5. A pharmaceutical matrix tablet according to any one of the preceding claims, wherein the hydrophilic matrix-forming polymer is selected from the group consisting of 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 alginate (or calcium or sodium), povidone, tragacanth gum or xanthan gum.

6. The pharmaceutical matrix tablet according to claim 5, wherein the hydrophilic matrix-forming polymer is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose and combinations thereof.

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

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

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

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

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

12. A pharmaceutical matrix tablet according to any one of the preceding claims, wherein the BK B2 receptor antagonist is incorporated in dissolved form.

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

14. The pharmaceutical matrix tablet according to claim 12 or 13, comprising a solid dispersion of an amorphous BKB2 receptor antagonist in a carrier, wherein the carrier comprises at least one pharmaceutically acceptable carrier polymer selected from hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, copovidone and combinations thereof.

15. The pharmaceutical matrix tablet according to claim 14, wherein the solid dispersion is incorporated as particles having an average particle size D50 of not more than 250 μm.

16. The pharmaceutical matrix tablet according to claim 14 or 15, wherein the solid dispersion comprises at least 10 wt% of the BK B2 receptor antagonist relative to 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 15 to 40 wt% of the solid dispersion relative to the total weight of the tablet without the 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 2:1 to 1:

2.

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

20. The pharmaceutical matrix tablet according to claim 19, comprising: - 20 to 40% by weight of 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 glidant, in particular colloidal silicon dioxide, and - Up to 2% by weight of lubricants, in particular magnesium stearate.

21. A pharmaceutical matrix tablet according to any one of the preceding claims comprising a coating comprising a water-soluble film-forming polymer and a plasticizer.

22. The pharmaceutical matrix tablet according to claim 21, wherein the content of the coating is 2 wt% to 8 wt% relative to the weight of the uncoated tablet.

23. A pharmaceutical matrix tablet according to any one of the preceding claims, wherein <711> The matrix tablet releases the BK B2 receptor antagonist over at least 8 hours as determined by dissolution testing using Apparatus II at pH 6.8 and a paddle speed of 100 rpm.

24. The pharmaceutical matrix tablet according to claim 23, wherein the matrix tablet releases the BK B2 receptor antagonist within 12 to 24 hours.

25. A method for preparing a matrix tablet according to any one of the preceding claims, comprising the steps of: (a) providing a solid dispersion in the form of a powder or granules, the solid dispersion comprising a BK B2 receptor antagonist and a carrier, the carrier comprising at least one pharmaceutically acceptable carrier polymer, wherein the BK B2 receptor antagonist is amorphous and dispersed in the carrier; (b) mixing the solid dispersion with a hydrophilic matrix-forming polymer, 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.

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

27. Use of a pharmaceutical matrix tablet according to any one of claims 1 to 24 for treating a subject suffering from a disease or condition responsive to BK B2 receptor modulation.

28. Use of a pharmaceutical matrix tablet according to claim 27, wherein the disease or condition responsive to BKB2 receptor modulation is selected from the group consisting of skin diseases; eye diseases; ear diseases; oral, throat and respiratory tract diseases; gastrointestinal diseases; liver, gallbladder and pancreas diseases; urinary tract and kidney diseases; male and female reproductive organ diseases; hormonal system diseases; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic diseases; central nervous system diseases; brain diseases; musculoskeletal system diseases; allergic diseases; pain; infectious diseases; inflammatory diseases; injuries; immunological diseases; cancer; hereditary diseases; and edema.

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

31. A method for treating or preventing a disease or condition responsive to BK B2 receptor modulation in a subject, comprising orally administering to a subject suffering from a disease or condition responsive to BK B2 receptor modulation an effective dose of the pharmaceutical matrix tablet of any one of claims 1 to 24, thereby preventing or treating the condition or disease in the subject.

32. The method of claim 31, wherein the disease or condition responsive to BKB2 receptor modulation is selected from the group consisting of skin diseases; eye diseases; ear diseases; oral, throat and respiratory tract diseases; gastrointestinal diseases; liver, gallbladder and pancreas diseases; urinary tract and kidney diseases; male and female reproductive organ diseases; hormonal system diseases; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic diseases; central nervous system diseases; brain diseases; musculoskeletal system diseases; allergic diseases; pain; infectious diseases; inflammatory diseases; injuries; immunological disorders; cancer; genetic diseases; and edema.

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 the pharmaceutical matrix tablet according to a regular dosing regimen 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 preparation of a medicament for the treatment or prevention of a disease or condition responsive to BK B2 receptor modulation.

36. The use according to claim 35, wherein the disease or condition responsive to BKB2 receptor modulation is selected from the group consisting of skin diseases; eye diseases; ear diseases; oral, throat and respiratory tract diseases; gastrointestinal diseases; liver, gallbladder and pancreas diseases; urinary tract and kidney diseases; male and female reproductive organ diseases; hormonal system diseases; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic diseases; central nervous system diseases; brain diseases; musculoskeletal system diseases; allergic diseases; pain; infectious diseases; inflammatory diseases; injuries; immunological diseases; cancer; hereditary diseases; and edema.

37. 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. Use according to any one of claims 35 to 37, wherein the medicament is for chronic treatment.

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