Lipid-Based Compositions for Oral Administration of Bradykinin B2 Receptor Antagonists - Patent application

Abstract

The present invention relates to a pharmaceutical composition for oral administration comprising a bradykinin (BK) B2 receptor antagonist having a chemical structure represented by the following formula 1 or a salt or solvate thereof: Formula (1) is, for example, (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. The composition comprises the BK B2 receptor antagonist in a form dissolved in a liquid vehicle comprising propylene glycol monocaprylate, polyoxyl castor oil, and propylene glycol. Further, therapeutic uses of the composition are provided. [Formula 1] TIFF2024528195000020.tif4680 (wherein R is deuterium or hydrogen.)

Description

[Technical field]

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

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

[0003] A large number of peptidic and non-peptidic 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 WO2014 / 159637, WO2010 / 031589, WO2008 / 116620, WO2006 / 40004, WO03 / 103671, WO03 / 87090, WO00 / 23439, WO00 / 50418, WO99 / 64039, WO97 / 41104, WO97 / 28153, WO97 / 07115, WO96 / 13485, EP0795547, EP0796848, EP0867432 and EP1213289. However, these compounds exhibited a number of deficiencies that hinder their usefulness as drugs, including poor metabolic stability, poor bioavailability, formation of glutathione adducts, and bioactivation (toxicity), as disclosed in WO2014 / 159637.

[0004] Recently, the compound of formula 1 has been proposed as a BK B2 receptor antagonist with novel biological activity and good tolerability (see, for example, WO2019 / 101906). Although this compound exhibits attractive pharmacological properties, it also exhibits rather challenging physical or physicochemical properties, including very low water solubility in physiological media. Thus, there is a need for formulations and pharmaceutical compositions that overcome the problems caused by these challenging compound properties, for example, enabling effective oral delivery and achieving significant systemic exposure and bioavailability in human subjects. There is also a need for formulations or pharmaceutical compositions incorporating the compound of formula 1 to reach a rapid onset of action by rapid oral absorption into the systemic circulation (i.e., being rapidly absorbed after oral administration), for the purpose of providing effective treatment for acute indications or conditions associated with BK, which represents a special challenge for such poorly soluble compounds. There is a further need to provide formulations or pharmaceutical compositions incorporating the compound of formula 1 that are stable in their performance and can be produced by established pharmaceutical manufacturing techniques.

[0005] The compound of formula 1 has very low water solubility, for example, making it extremely difficult to develop an oral formulation that would provide a sufficient rate and extent of bioavailability and effective plasma levels, particularly rapid enough systemic absorption following oral administration, to allow for effective non-invasive treatment of acute indications and conditions associated with BK. Summary of the Invention [Problem to be solved by the invention]

[0006] It is an object of the present invention to address any one or more of these needs. A further object is to overcome the deficiencies, gaps, and limitations of the prior art relating to oral delivery of BK B2 receptor antagonists, e.g., compounds having the chemical structure represented by Formula 1. Further objects will become apparent based on the following description, examples, and claims. [Means for solving the problem]

[0007] In one embodiment, the present invention provides a compound represented by formula 1:

[0008] [ka] wherein R is deuterium or hydrogen; or a stereoisomer, salt, or solvate thereof; further characterized in that the BK receptor antagonist is dissolved in a liquid vehicle comprising propylene glycol monocaprylate, polyoxyl castor oil, and propylene glycol. In particular, the BK B2 receptor antagonist may be (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, the propylene glycol monocaprylate may be type II propylene glycol monocaprylate, and the polyoxyl castor oil may be polyoxyl 40 hydrogenated castor oil.

[0009] In a further aspect, the present invention relates to a capsule, such as a soft capsule or soft gel, comprising such a liquid pharmaceutical composition.

[0010] In a further aspect, the present invention relates to the use of such capsule or liquid pharmaceutical composition according to the present invention, particularly in therapy.Generally, the liquid pharmaceutical composition or capsule described herein can be used in the treatment of disease or condition that responds to bradykinin B2 receptor modulation.For example, they are advantageous in the treatment of edema, such as hereditary angioedema. [Brief description of the drawings]

[0011] [Figure 1] Figure 1 shows individual API concentrations in monkey plasma versus time on linear and semi-log scales. Figures 1A and 1B show API concentrations in plasma of three monkeys administered API in an aqueous carrier containing methylcellulose (1 wt.%). Figures 1C and 1D show API concentrations in plasma of three monkeys administered API in a formulation according to the invention. [Diagram 2]FIG. 2 shows the mean and standard deviation of plasma API concentrations for human subjects administered doses of 1, 2, 4.5, 12, and 22 mg formulated according to the invention. [Diagram 3] FIG. 3 shows the mean and standard deviation of API concentrations in plasma for human subjects administered a 22 mg dose fasting (open circles) or after a high-calorie / high-fat (HCHF) breakfast (closed circles). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The present invention relates to a compound of formula 1:

[0013] [ka] The present invention provides a liquid pharmaceutical composition for oral administration comprising a bradykinin (BK) B2 receptor antagonist having a chemical structure according to the formula: wherein R is deuterium or hydrogen, or a salt or solvate thereof; the composition being further characterized in that the BK B2 receptor antagonist is dissolved in a liquid vehicle comprising propylene glycol monocaprylate, polyoxyl castor oil, and propylene glycol.

[0014] Surprisingly, it has been discovered by the inventors that such compositions substantially facilitate the oral delivery of BK B2 receptor antagonists in that they become incorporated in a dissolved form without being subject to rapid crystallization upon dilution in aqueous media, resulting in unexpectedly rapid absorption of the compound into the bloodstream of a subject, which is particularly notable in view of their physical properties, in particular their large molecular size, the absence of readily ionizable chemical groups, and their poor water solubility.

[0015] In formula 1, R may be selected from hydrogen and deuterium. In one preferred embodiment or group of embodiments, R is deuterium:

[0016] [ka]

[0017] This compound, which may also be referred to as (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide (CAS 2340111-58-0), or acetamide, N-[(1S)-1-[3-chloro-5-fluoro-2-[[[2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)-8-quinolinyl]oxy]methyl]phenyl]ethyl-1-d]-2-(difluoromethoxy)-, is a particularly advantageous example of a compound according to formula 1 in the context of the present invention. It should also be understood that this preference applies in combination with all other optional features or preferences disclosed in this description below, whether or not specifically mentioned.

[0018] Alternatively, in formula 1, R can be hydrogen:

[0019] [ka] It may also be called (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.

[0020] The compound of formula 1 may exist in essentially non-ionized form or in ionized form, i.e., in the form of a salt. It may also be in the form of a solvate, if necessary. For example, the compound may be a hydrate, such as (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide monohydrate.

[0021] In one of the preferred embodiments, the state of the compound in the liquid composition is substantially non-ionized, for example completely non-ionized. Moreover, the compound of formula 1 will not usually be in the form of a salt or a solvate, or in any solid form, when present in the liquid pharmaceutical composition described herein. However, for the avoidance of doubt, the compound may be in the form of a solid, salt and / or solvate, when it is combined with other components to form the composition of the present invention. For example, a hydrate of the compound, such as a monohydrate, in a crystalline form, may be used to prepare the liquid pharmaceutical composition, if necessary. However, when the fully dissolved state, i.e. the compound is converted to the form in which it is present in the liquid pharmaceutical composition, the compound is considered to no longer be in the form of a crystalline material or in the form of a hydrate.

[0022] In one of the preferred embodiments, the BK B2 receptor antagonist of formula 1 is the only active pharmaceutical ingredient (API) in the liquid pharmaceutical composition of the present invention. This should also be understood as a general preference in the context of the present invention. Alternatively, the composition may contain one or more additional active ingredients.

[0023] Pharmaceutical composition in the context of the present invention should be understood as a composition that is technically suitable for administration to a subject, such as a human patient, as a medicine.It is constructed, formulated and processed according to general pharmaceutical standards, such as those defined in official pharmacopoeias or guidelines issued by regulatory authorities, such as FDA and EMA.In one of the preferred embodiments, the composition is adapted for oral administration, which implies that, for example, the excipients used, including their grades and their amounts, are safe and acceptable for oral use, particularly for oral administration to human subjects.

[0024] The term "liquid" as used herein refers to the liquid state of a material under normal conditions, i.e., at room temperature and normal atmospheric pressure. An example of a more precisely defined set of normal conditions is Normal Temperature and Pressure (abbreviated as NTP) as defined by the National Institute of Standards and Technology (NIST) in the United States, using a temperature of 20° C. (293.15 K, 68° F.) and an absolute pressure of 1 atm (14.696 psi, 101.325 kPa).

[0025] A liquid vehicle, as used in the context of the present invention, is a pharma- ceutically acceptable liquid excipient or mixture of excipients in which at least one active pharmaceutical ingredient, such as a compound represented by formula 1, is incorporated. Formally, the API is not considered part of the liquid vehicle, even if dissolved therein. Any suspended solid excipients are also not considered part of the vehicle. Thus, the weight of the liquid vehicle excludes the weight of the API incorporated therein, and the weight of materials suspended therein, if any. The liquid vehicle may also be referred to as a carrier.

[0026] For the avoidance of doubt, it is not necessary to separately prepare a liquid vehicle containing all of its components and then combine with at least one API to form the liquid pharmaceutical composition of the present invention. Rather, it is possible to dissolve at least one API in one of the liquid components of the liquid vehicle and then add the remaining components or combine all components of the liquid pharmaceutical composition simultaneously. Also, for the avoidance of doubt, it is not required that all components of the liquid vehicle be liquid themselves (individually) under normal conditions, provided that they form a liquid phase (i.e., dissolve) when combined.

[0027] The term "pharmaceutical acceptable," as used herein, means approved or approvable by a federal or state regulatory agency or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, and more particularly in humans. In particular, pharmaceutical acceptable means that the pharmacopoeia and other ingredients used in the pharmaceutical compositions and methods described herein are suitable for use in contact with the tissues of humans and lower animals, without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio.

[0028] As mentioned, the liquid pharmaceutical composition comprises the BK B2 receptor antagonist dissolved in a liquid vehicle as defined herein.In this context, the expression "dissolved" refers to the presence of the compound in a dissolved state, i.e., completely dissolved state.This suggests that the compound is molecularly dispersed in the liquid vehicle rather than being incorporated in the form of suspended particles.Therefore, the BK B2 receptor antagonist, which may also be referred to as the active ingredient, API, or drug substance in this context, is present in the liquid pharmaceutical composition in a non-solid form.

[0029] As used herein, the expression "propylene glycol monocaprylate" should be understood in the context of pharmacology rather than in strict chemical nomenclature.In the context of pharmacology, propylene glycol monocaprylate refers to an excipient that meets the commonly recognized compendial monographs related to propylene glycol monocaprylate.This includes, for example, the monographs "propylene glycol monocaprylate type I" and "propylene glycol monocaprylate type II" in the United States Pharmacopeia and National Formulary (USP / NF), such as its version USP-NF2021, and / or related monographs in other pharmacopeias, such as the European Pharmacopoeia (Ph.Eur.).

[0030] Generally speaking, a material or excipient designated as propylene glycol monocaprylate contains a mixture of several chemical species. It may be described as a mixture of mono- and diesters of propylene glycol of fatty acids, mainly composed of caprylic acid. The content of mono- and diesters may vary between types of propylene glycol monocaprylate: according to USP-NF, an excipient designated as propylene glycol monocaprylate type I contains 55.0 to 80.0 percent monoesters and 20 to 45 percent diesters, while a material designated as propylene glycol monocaprylate type II contains at least 90.0 percent monoesters and no more than 10.0 percent diesters. With respect to the fatty acid residues in either type I or type II, at least 90.0 percent of the fatty acid esters are caprylate (or octanoate), and no more than 3.0 percent are caprate (or decanoate), laurate (or dodecanoate), and myristate (or tetradecanoate), respectively - for each of these residues individually. Neither Type I nor Type II propylene glycol monocaprylate contains more than 1.0 percent palmitate (or hexadecanoate). Non-limiting examples of currently available commercial grades of propylene glycol monocaprylate Type I include Capryol® PGMC (Gattefosse) and Capmul® PG-8-70 NF (Abitec), while commercial versions of Type II propylene glycol monocaprylate include Capmul® PG-8 NF (Abitec), and Capryol® 90 (Gattefosse).

[0031] In one of the preferred embodiments, the propylene glycol monocaprylate contained in the liquid vehicle contained in the liquid pharmaceutical composition of the present invention is propylene glycol monocaprylate type II, for example, propylene glycol monocaprylate type II (USP / NF).In another preferred embodiment, propylene glycol monocaprylate type II is the only type of propylene glycol monocaprylate incorporated in the liquid vehicle.Alternatively, a mixture of propylene glycol monocaprylates may also be used.

[0032] In a further embodiment, propylene glycol monocaprylate exhibiting a hydrophilic-lipophilic balance (HLB value) in the range of about 5 to 6 is selected.

[0033] Similarly, the term "polyoxyl castor oil" should be interpreted in the technical context of the present invention to mean an excipient or material that meets the normally accepted pharmaceutical standards for any polyoxyl castor oil established in the appropriate compendium, e.g., in the respective monographs of the above-mentioned pharmacopoeias. The term therefore refers to pharmaceutical grade polyoxyethylene castor oil derivatives. Polyoxyl castor oil is a mixture of different chemical species, typically produced by reacting ethylene oxide with castor oil or hydrogenated castor oil.

[0034] One type of polyoxyl castor oil is a material conforming to the monograph "Polyoxyl 40 hydrogenated castor oil" (USP, latest edition), which corresponds substantially to the monograph "Macrogol glycerol hydroxystearate" (European Pharmacopoeia, latest edition), also called PEG-40 hydrogenated castor oil. Polyoxyl 40 hydrogenated castor oil typically exists as a white to yellowish semi-solid paste at room temperature and liquefies above about 30°C. The main component of this excipient is glycerol polyethylene glycol hydroxystearate, which further comprises fatty acid glycerol polyglycol esters, polyethylene glycol, and glycerol ethoxylate. According to the European Pharmacopoeia, it mainly comprises the reaction product of trihydroxystearyl glycerol ethoxylated with 7 to 60 molecules of ethylene oxide (nominal value), with small amounts of macrogol hydroxystearate and the corresponding free glycol. Examples of commercially available grades of polyoxyl 40 hydrogenated castor oil include Kolliphor® RH40 (BASF), formerly sold under the name Cremophor® RH40, and Croduret (Croda).

[0035] Another type of polyoxyl castor oil conforms to the monograph "Polyoxyl 35 castor oil" (USP, latest edition), which corresponds to the monograph "Macrogol glycerol ricinoleate" (European Pharmacopoeia, latest edition), and is also called PEG-35 castor oil. It contains mainly ricinoleyl glycerol ethoxylated with 30-50 molecules of ethylene oxide (nominal value), with small amounts of macrogol ricinoleate and the corresponding free glycol. It is obtained from the reaction of castor oil with ethylene oxide. An example of a commercial grade of polyoxyl 35 castor oil is Kolliphor® EL (BASF), previously sold as Cremophor® EL.

[0036] In one of the preferred embodiments, the polyoxyl castor oil contained in the liquid vehicle of the liquid pharmaceutical composition of the present invention is polyoxyl 40 hydrogenated castor oil, such as polyoxyl 40 hydrogenated castor oil (USP / NF). In another preferred embodiment, polyoxyl 40 hydrogenated castor oil is the only type of polyoxyl castor oil incorporated in the liquid vehicle. Alternatively, additional types of polyoxyl castor oils may be present.

[0037] According to a further preferred embodiment, the polyoxyl castor oil contained in the liquid vehicle is polyoxyl 40 hydrogenated castor oil, the propylene glycol monocaprylate is type II propylene glycol monocaprylate, and there is no other type of polyoxyl castor oil or propylene glycol monocaprylate.In other words, the liquid pharmaceutical composition may comprise a compound of formula 1 dissolved in a liquid vehicle that comprises polyoxyl 40 hydrogenated castor oil, type II propylene glycol monocaprylate, and propylene glycol as defined herein, but does not comprise other propylene glycol monocaprylate or polyoxyl castor oil.

[0038] According to a further preferred embodiment, the liquid vehicle, and therefore also the pharmaceutical composition of the present invention, may further comprise water. Water may be intentionally added as part of the components of the liquid vehicle, or may become part of the liquid vehicle as a result of the water content of the raw materials or intermediate products used for the preparation of the liquid pharmaceutical composition or its further processing, for example by encapsulation in soft gelatin capsules. For example, if the compound of formula 1 used to prepare the liquid pharmaceutical composition is provided in the form of a crystalline hydrate, the water of crystallization of the hydrate will become part of the liquid vehicle. Furthermore, when the liquid pharmaceutical composition is combined with a wet gelatin mass that is typically used in the preparation of soft gelatin capsules, some of the water of the gelatin mass may migrate to the liquid pharmaceutical composition and form part of the liquid vehicle.

[0039] In a further preferred embodiment of the liquid pharmaceutical composition of the present invention, the bradykinin B2 receptor antagonist is a compound according to Formula 1, wherein R is deuterium, and is dissolved in a liquid vehicle comprising polyoxyl 40 hydrogenated castor oil, Type II propylene glycol monocaprylate, propylene glycol, and water.

[0040] Generally, the liquid vehicle may contain one or more additional excipients if necessary.In one embodiment, it may contain additional solvents and / or additional surfactants.In this context, additional solvent means not only propylene glycol but also any solvent that is present in any case according to the present invention.Preferably, the solvent is an organic solvent, such as a water-miscible organic solvent, such as a pharma-ceutically acceptable water-miscible organic solvent, such as glycerol or ethanol.In one embodiment, the liquid vehicle contains ethanol.

[0041] In one embodiment, additional surfactants, such as additional pharma- ceutically acceptable surfactants, may be used. In this context, "additional surfactants" refers to surfactants in addition to propylene glycol monocaprylate and polyoxyl castor oil, either of which may be considered as surfactants, even though some other functional labels may also be used for these excipients. In a preferred embodiment, the liquid vehicle may contain caprylocaproyl polyoxyl-8 glyceride, also called caprylocaproyl macrogol-8 glyceride, as additional surfactant. An example of a commercially available excipient that represents caprylocaproyl polyoxyl-8 glyceride is the product Labrasol® ALF (Gattefosse).

[0042] In addition, one or more additional excipients may be optionally incorporated into the liquid pharmaceutical composition as part of the liquid vehicle (e.g., when one or more liquid excipients are incorporated) and may be selected from stabilizers, antioxidants, preservatives, pH modifiers, taste modifiers, colorants, and viscosity modifiers. Mixtures or combinations of two or more of the foregoing additional excipients may also be used.

[0043] In one embodiment, the liquid pharmaceutical composition is adapted for multiple doses, e.g., the liquid is presented in a multiple dose container, and is further characterized by comprising at least one taste modifier and not comprising any preservative.In fact, one of the advantages of the present invention is that even when presented as a multiple dose liquid formulation, it does not require the addition of a preservative.In this context, the term "preservative" should be understood as referring to an excipient whose sole or primary function is to perform a safe and persistent antimicrobial function.Examples of preservatives are antimicrobial preservatives, such as benzoic acid and its salts, sorbic acid and its salts, methylparaben, propylparaben, etc.

[0044] As mentioned, the inventors have surprisingly found that the liquid pharmaceutical composition described herein exhibits excellent performance both in vitro and in vivo. It substantially facilitates the oral delivery of BK B2 receptor antagonists in that they become incorporated in a completely dissolved (non-solid) form without being subject to rapid crystallization when diluted with aqueous media, such as water, acidified water, or artificial gastric fluid. Without wishing to be bound by theory, the inventors believe that the liquid pharmaceutical composition described herein behaves as or corresponds to a so-called self-emulsifying or self-microemulsifying drug delivery system (SEDDS or SMEDDS, respectively). These may be described as isotropic liquid mixtures that spontaneously form oil-in-water (o / w) emulsions or oil-in-water (o / w) microemulsions when diluted with aqueous media, typically without even the need for mechanical stirring. In the context of the present invention, SEDDS should be understood as a broad expression that encompasses SMEDDS. SMEDDS is characterized by a small average droplet size, sometimes less than 800 nm, even in the range of 100 nm. In one of the preferred embodiments, the liquid pharmaceutical composition is in the form of a SMEDDS. This is a general preference, and should be understood as being applicable in combination with all other preferences described herein.

[0045] Although SEDDS has been suggested as a potential formulation strategy for poorly soluble drug substances, not many drug products have actually been successfully developed as SEDDS and received market approval. Many SEDDS formulations fail in that they do not achieve sufficient drug loading (so that a single dose of the drug cannot be accommodated in, for example, one or two soft gelatin capsules) or do not incorporate the active ingredient in such a way that it remains dissolved in the (micro)emulsion formed upon dilution with water or gastric juice. In fact, even when the active ingredient is sufficiently soluble in the liquid carrier, problems frequently arise with the active ingredient rapidly precipitating, which is one of the reasons why SEDDS formulation strategies are often not successful in practice. Moreover, drug substances dissolved in SEDDS very often exhibit poor stability, leading to short shelf lives due to rapid chemical degradation, which is unattractive or even unfeasible from a marketing and supply chain perspective.

[0046] Also, in the case of the BK B2 receptor antagonist according to formula 1, the inventors have found that many liquid vehicle compositions expected to have self-emulsifying or self-microemulsifying properties are not compatible with this active ingredient in that they exhibit rapid drug precipitation or liquid phase separation when the compound of formula 1 is incorporated.However, the inventors have unexpectedly found one particular combination of excipients, namely, propylene glycol monocaprylate, polyoxyl castor oil, and propylene glycol, which, as demonstrated in the examples, does not cause the compound to precipitate or separate liquid phases within a few hours after dilution with acidified water at room temperature immediately after production.More importantly and particularly noteworthy, the inventors have found that this liquid vehicle provides excellent stability and allows for sufficient drug loading.No precipitation or liquid phase separation of the BK B2 receptor antagonist was observed after storage at high temperature, e.g., 40°C, for 6 months, as also shown by the examples.

[0047] In addition to the preferred embodiments related to the further components of the liquid vehicle or liquid pharmaceutical composition of the present invention as described above, the inventors have also found that certain amounts of each excipient in the liquid vehicle appear to be particularly advantageous. In particular, the inventors have found that a relatively large amount of propylene glycol monocaprylate, for example about 40 wt.% or more, based on the weight of the liquid vehicle, is advantageous, which amount significantly exceeds the amount used in some known SMEDDS formulations of other drug substances. For example, in a further preferred embodiment, the amount of propylene glycol monocaprylate in the liquid vehicle is about 40-60 wt.%, for example about 45-55 wt.%, for example about 48-52 wt.%, based on the weight of the liquid vehicle. When more than one type of propylene glycol monocaprylate is used, the amount of about 40-60 wt.% should be understood to refer to the total amount of all propylene glycol monocaprylate in the liquid vehicle. In a related embodiment, the liquid vehicle comprises about 40-60 wt.%, such as about 45-55 wt.%, for example about 48-52 wt.%, of propylene glycol monocaprylate Type II.

[0048] In a further preferred embodiment, the amount of polyoxyl castor oil in the liquid composition is about 30-50 wt.%, for example, about 35-45 wt.%, for example, about 38-42 wt.%, based on the weight of the liquid vehicle. Again, the range refers to the total amount of polyoxyl castor oil in the liquid vehicle when more than one type of polyoxyl castor oil is present in the vehicle. Furthermore, it is also a preferred embodiment when the entire 30-50 wt.% of polyoxyl castor oil represents polyoxyl 40 hydrogenated castor oil. In one embodiment, the liquid composition comprises about 40-60 wt.%, such as about 45-55 wt.%, for example about 48-52 wt.%, of propylene glycol monocaprylate (preferably of Type II) and 30-50 wt.%, for example about 35-45 wt.%, for example about 38-42 wt.%, of polyoxyl castor oil (preferably polyoxyl 40 hydrogenated castor oil).

[0049] With regard to the amount of propylene glycol in the liquid vehicle, it has been found that a relatively small amount, such as up to about 15 wt.%, preferably in the range of about 2.5-15 wt.%, based on the total weight of the liquid vehicle, is advantageous, and again amounts of propylene glycol in the range of about 2.5-11 wt.%, such as about 3.5-11 wt.%, or such as about 4.5-10 wt.%, based on the total weight of the liquid vehicle, are preferred.

[0050] In a preferred embodiment, the liquid vehicle contains propylene glycol monocaprylate (preferably of type II), polyoxyl castor oil (preferably polyoxyl 40 hydrogenated castor oil), and propylene glycol in the amounts described above, with the balance optionally containing additional water. For example, the liquid vehicle may contain about 40-60 wt.% propylene glycol monocaprylate (preferably of type II), 30-50 wt.% polyoxyl castor oil (preferably polyoxyl 40 hydrogenated castor oil), and 2.5-15 wt.% propylene glycol.

[0051] The liquid pharmaceutical composition described herein may also contain water. Water may be present in an amount of up to 5 wt.%. For example, water may be a component of the liquid vehicle, and the liquid vehicle may contain water in an amount of up to 5 wt.%. In this context, it is noted that when the liquid pharmaceutical composition is intended for encapsulation in, for example, a soft gelatin capsule as described further below, the content of certain components, including propylene glycol and / or water, may vary over time during storage, in part because some of the encapsulated propylene glycol and / or water may migrate into the capsule shell. For example, a liquid pharmaceutical composition may be manufactured to exhibit a propylene glycol content of, for example, about 10 wt.%, but after encapsulation in a soft gelatin capsule and storage for months or years, the content of propylene glycol in the liquid fill of the soft gelatin capsule may be small, for example, about 8 or 9 wt.%, due to migration. Conversely, if the capsule wall is formulated to contain, for example, propylene glycol, the amount of migrated propylene glycol may increase the propylene glycol content of the capsule wall after storage.

[0052] In a further preferred embodiment of the liquid pharmaceutical composition, based on the total weight of propylene glycol monocaprylate, polyoxyl castor oil and propylene glycol in the liquid vehicle, the content of propylene glycol monocaprylate (preferably type II) is about 50wt.%, the content of polyoxyl castor oil (preferably polyoxyl 40 hydrogenated castor oil) is about 40wt.%, and the content of propylene glycol is about 10wt.%. As used herein, the term "about" refers to small variations that can be expected, for example, to offset small differences between various grades of excipients, and it should be noted that some may be mixtures of different chemical species themselves (for example, in the case of propylene glycol monocaprylate or polyoxyl castor oil) or contain variable amounts of certain impurities, such as water (for example, in the case of propylene glycol). For example, a relative deviation of up to 10% (e.g., 50±5 wt.%), e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, or 9%, would normally be considered a composition having substantially the same functionality.

[0053] According to another preferred embodiment of the liquid pharmaceutical composition, the liquid vehicle consists essentially of propylene glycol monocaprylate, polyoxyl castor oil, propylene glycol, and about 10 wt.% of the following other liquid components, based on the total weight of all liquid components in the liquid vehicle: As mentioned above, the liquid vehicle may contain further liquid components, such as liquid surfactants, water, or organic solvents, such as ethanol, if necessary, and according to this particular embodiment, the total amount of these is limited to about 10 wt.% based on the weight of the liquid vehicle.

[0054] The content of the BK B2 receptor antagonist of formula 1 in the liquid pharmaceutical composition should be selected taking into consideration the type of subject to be treated (e.g., pediatric human patient, adult human patient), the therapeutic indication, and the presentation of the composition (i.e., whether it is presented as a liquid for oral administration, such as, for example, soft gelatin capsules). Preferably, the relative amount of the compound ranges from about 1 mg to about 160 mg per gram of liquid composition. In this context, the amount of the BK B2 receptor antagonist of formula 1, when given as a weight, should be taken to refer to the amount of the non-ionized, non-solvated form of the active ingredient, or in other words, the amount of the pharmacologically active portion of the compound, which is also published as a dose. For example, when a hydrate form of the compound is used to prepare the liquid pharmaceutical composition, the weight of the active ingredient excludes the water of hydration (which will be part of the liquid vehicle as explained above). In certain embodiments, the amount of the compound of formula 1 is at least about 5 mg per gram of liquid composition, which corresponds to about 0.5 wt.%. In another particular embodiment, said amount is at least about 10 mg per gram of liquid composition, corresponding to about 1 wt.%.

[0055] In a further preferred embodiment, the liquid pharmaceutical composition exhibits a content of BK B2 receptor antagonist in the range of about 5 mg to about 100 mg per gram of the liquid pharmaceutical composition, for example, in the range of about 20 mg to about 70 mg per gram. In a preferred embodiment, the content is in the range of about 5 mg to about 65 mg per gram, for example, in the range of about 5 mg to about 50 mg per gram. It is a particular advantage of the liquid pharmaceutical composition of the present invention that the liquid vehicle identified by the inventors and described herein can accommodate such a relatively large amount of active ingredient. In a further preferred embodiment, the content of BK B2 receptor antagonist is in the range of about 10 mg to about 65 mg per gram, for example, in the range of about 20 mg to about 65 mg per gram. In a particular embodiment, the content is about 20, 25, 30, 40 or 50 mg per gram, corresponding to about 2, 2.5, 3, 4 or 5 wt.%, respectively.

[0056] As with all amounts of BK B2 receptor antagonists discussed above, it should be understood that these preferences also apply specifically to BK B2 receptor antagonists represented by Formula 1, where R is deuterium.

[0057] Further preferred liquid pharmaceutical compositions comprise: (a) about 0.5 to 6.5 wt. %, e.g., 5 wt. %, of a compound represented by Formula 1, wherein R is deuterium, or a stereoisomer, salt, or solvate thereof, based on the total weight of the liquid pharmaceutical composition; (b) about 93.5 to 99.5 wt. %, based on the total weight of the liquid pharmaceutical composition, of a liquid vehicle consisting essentially of: (i) about 50 parts (by weight) of propylene glycol monocaprylate, e.g., Type II propylene glycol monocaprylate; (ii) about 40 parts (by weight) of a polyoxyl castor oil, e.g., 40 hydrogenated castor oil; (iii) about 5 to 10 parts (by weight) of propylene glycol; and (iv) up to about 5 parts (by weight) of water; and optionally (c) the remainder being one or more further excipients dissolved or dispersed in the liquid vehicle. In a further specific embodiment, the liquid pharmaceutical composition comprises about 5 wt.% of a compound of formula 1 and no additional excipients dissolved or dispersed in the liquid vehicle.

[0058] The liquid pharmaceutical composition of the present invention can be used as such, i.e. as a medicament formulated and presented as a liquid for oral administration, or can be processed, for example, by incorporating it into a solid single unit dosage form, for example, a capsule.For presentation as a liquid dosage form, it can be filled into a suitable primary packaging unit or container, for example, to contain either a single dose or multiple doses of active ingredient.As used herein, a primary packaging unit is, for example, a packaging means or a combination of packaging means that holds the drug formulation that will be in direct contact with it.An example of a combination of packaging means that together form a primary packaging unit is a bottle with a screw-on lid.

[0059] The single dose may be contained in, for example, a glass or plastic bottle, vial, or ampoule. Alternatively, a sachet or stick pack may be used. As a primary packaging unit for holding multiple doses of the liquid composition, a glass or plastic bottle is suitable. To facilitate the removal of a measured amount of the composition, a dosing or dispensing aid may be used, which may be part of the primary packaging unit or separate. According to one such embodiment, the present invention provides a primary packaging unit comprising a liquid composition as described above and a dosing or dispensing aid. In a further embodiment, the dosing or dispensing aid is a dosing pump. If necessary, the dosing pump can be directly connected to the primary packaging means; for example, the primary packaging container may be a glass or plastic bottle with a lid that can be twisted off and replaced with a screw-on dosing pump.

[0060] In a further preferred embodiment, the liquid pharmaceutical composition is presented as a single dose unit in the form of a capsule filled with the liquid pharmaceutical composition.Therefore, a further aspect of the present invention is the capsule for oral administration that comprises the liquid pharmaceutical composition as described above.Optionally, the capsule can be a hard capsule, particularly a hard gelatin capsule.

[0061] In one of the preferred embodiments, the capsule is a soft capsule, also called a soft gelatin capsule or soft gel. More specifically, the soft capsule preferably comprises a capsule wall comprising gelatin, water, and at least one plasticizer. In this context, capsule wall means the shell of the capsule that surrounds or encapsulates the liquid fill material, which in this case is the liquid pharmaceutical composition disclosed herein. Also, in the context of soft gelatin capsules, "plasticizer" is a pharmaceutical excipient used to make the capsule wall more elastic and flexible, minimizing its brittleness and the risk of cracking. To some extent, water also has a plasticizing effect on gelatin capsule wall material; however, in the context of the present invention, the term "plasticizer" should be understood as excluding water.

[0062] The main component of soft gelatin capsule walls is typically gelatin itself. Gelatin is a generic name for a mixture of purified protein fractions obtained by either partial acid hydrolysis (type A gelatin) or partial alkaline hydrolysis (type B gelatin) of animal collagen obtained from bovine and porcine bones, bovine skins (hide), porcine hides, and fish skins. Gelatin may also be a mixture of both types. The protein fractions consist almost entirely of amino acids linked together by amide bonds to form distinct linear polymers with molecular weights of 20,000 to 200,000.

[0063] The mechanical strength of a gelatin material may be characterized by its Bloom number, also called Bloom value, determined by the Bloom test, which represents the weight in grams that a standardized plunger needs to press 4 mm into the surface of a gelatin gel sample without breaking it. Typically, gelatin gel samples are prepared as 6.67% gelatin solutions, which solidify at about 10° C. for a few hours. Generally, a higher Bloom number indicates a gelatin material with a higher average molecular weight, and vice versa. When a mixture of different types of gelatin is used, the Bloom value should be interpreted - in the context of the present invention - as relating to the mixture.

[0064] The inventors have found that in principle both types of gelatin, i.e. type A and type B, may be used to make soft capsules according to the present invention. Furthermore, gelatins of different gel strengths may also be used as long as they are appropriately plasticized. In one embodiment, the gelatin of the capsule wall has a Bloom value ranging from about 100 to about 250. In another preferred embodiment, the Bloom value (or Bloom number) of the gelatin ranges from about 130 to about 220, and in further embodiments, the Bloom value is about 150±20 or about 200±20, respectively. In some further specific embodiments, the gelatin is type A gelatin with a Bloom value of about 195 or type B gelatin with a Bloom value of about 150, respectively.

[0065] With regard to the plasticizer, this may be selected from, for example, glycerol, propylene glycol, polyethylene glycol, sorbitol, sorbitan, maltitol, corn syrup, citric acid esters such as triethyl citrate, or any combination thereof. In one preferred embodiment, the soft gelatin capsule comprises a capsule wall comprising gelatin, water, and at least one plasticizer selected from propylene glycol, glycerol, sorbitol, sorbitan, a sorbitol-based plasticizer mixture, or any combination thereof.

[0066] When sorbitan is used, it is preferred to also use sorbitol. For example, a mixture of sorbitol and sorbitan (currently sold, for example, by ISP under the name Sorbitol Special®) may be used. A mixture of sorbitol and one or more further excipients for modifying the plasticizing properties is also called a sorbitol-based plasticizer mixture, and typically has the advantage of also containing sorbitol in a substantially non-crystalline form. In this context, the expression "non-crystalline sorbitol" may also be used to encompass a sorbitol-based plasticizer mixture, for example a sorbitol-sorbitan combination, for example Sorbitol Special®, in which the addition of sorbitan and / or another additive prevents sorbitol from crystallizing. A further preferred sorbitol-based plasticizer mixture is Polysorb® 85 / 70 / 00, available from Roquette, and described as a liquid of partially dehydrated sorbitol. More precisely, the product is a mixture of sorbitol (20-40%), 1,4-anhydrous-D-glucitol (20-30%), and hydrogenated corn syrup (20-25%). Such products are also described in the USP monograph "Sorbitol sorbitan solution" (previously "anhydrous liquid sorbitol"), or in the Ph.Eur. monograph "Sorbitol, liquid, partially dehydrated".

[0067] In a further preferred embodiment, the capsule wall is plasticized with at least glycerol. A capsule wall composition comprising glycerol and at least one further plasticizer is also preferred. In one preferred embodiment, the second plasticizer is selected from amorphous sorbitol (or sorbitol-sorbitan or partially dehydrated liquid sorbitol) and propylene glycol.

[0068] The amount of plasticizer, or if more than one plasticizer is used, the total amount of plasticizer in the capsule wall composition before encapsulation and drying the capsule (i.e. the amount in the wet gel composition used in the encapsulation process) should preferably be selected in the range of about 15-35 wt.% based on the total weight of the wet capsule wall composition. As before, in the context of the present invention, water is excluded from the amount of plasticizer. In another preferred embodiment, the amount of plasticizer in the capsule wall composition is in the range of about 15-30 wt.%, in particular in the range of about 18-28 wt.%.

[0069] The amount of plasticizer may also be expressed as a ratio of the amount of (total) gelatin in the capsule wall to the amount of (total) plasticizer. The advantage of referring to this ratio is that it is relatively independent of water content; it may change over time due to the possibility of plasticizer migrating from the capsule wall to the capsule fill, or vice versa, but it is not dramatically different between the wet gelatin mass and the dry soft gelatin capsule wall after manufacture. In some preferred embodiments, the ratio is selected in the range of about 1.0 to 3.0, or about 1.3 to 2.8, or about 1.3 to 2.5, respectively.

[0070] When the soft capsule wall contains a second plasticizer in addition to glycerol, it is preferably propylene glycol or sorbitol (including sorbitol-sorbitan mixtures or partially dehydrated liquid sorbitol), and the weight ratio of glycerol to the second plasticizer may be selected as generally known in the art. For example, the ratio may be in the range of about 0.1 to 10, or in the range of about 0.2 to 5. In one of the preferred embodiments, the ratio is in the range of about 0.5 to 2.

[0071] It has been found by the inventors that liquid compositions can be successfully encapsulated and capsule brittleness and film formation can be largely avoided if certain priorities regarding the composition of the soft gelatin capsule wall are observed.

[0072] The amount of water in the soft capsule wall, or in the initial wet gel mass applied to prepare the capsule, may be selected in a typical range as needed to ensure processability. For example, the wet gelatin mass may have an initial water content of about 20-60 wt.%. In some embodiments, the water content is selected in the range of about 25-45 wt.%. It should be noted that the water content should be calculated to include water introduced by other excipients, for example, glycerol (e.g., when 85% glycerol is used) or sorbitol-sorbitan solutions. The weight ratio of (total) gelatin to (total) water may also be selected as commonly used in soft gel manufacture, i.e., in the range of about 0.5-2.

[0073] Optionally, the capsule wall may contain one or more additional components, such as one or more excipients selected from colorants, pigments, opacifiers, flavors, and lubricants. Typically, these excipients may be incorporated in relatively small amounts to perform their respective functions. For example, titanium dioxide may be used as an opacifier, typically in an amount of up to 3 wt.%. Similarly, if a colored capsule is desired, a colorant, such as one or more iron oxides, may be added, typically in a similarly small amount, such as up to about 5 wt.%. The capsule wall may also contain small amounts of processing aids, such as lubricants. An example of a potentially suitable lubricant is neutral fatty oil (liquid triglyceride). Optionally, a surfactant, such as lecithin, may be added to the oil.

[0074] According to a further aspect, the present invention relates to the use of the liquid pharmaceutical composition, also as described herein, for producing capsules, in particular soft capsules as described above. From a process perspective, the present invention provides a method for preparing soft capsules using the liquid pharmaceutical composition as described herein. The method comprises the steps of: (a) providing a liquid composition as described herein; (b) providing a wet capsule wall material comprising gelatin, water, a first plasticizer which is glycerol, and a second plasticizer selected from sorbitol and propylene glycol; (c) encapsulating the liquid composition within a moist encapsulant, e.g., to form a capsule; (d) drying the capsules formed in step (c); and optionally (e) storing the dried capsules; It can be characterized by:

[0075] With regard to process parameters, the method may be carried out using standard equipment and settings. With regard to the liquid pharmaceutical composition provided in step (a), it is emphasized that the same optional features and preferences apply as described in the context of that aspect of the invention. For example, in step (a): - about 0.5 to 6.5 wt.% - for example 5 wt.% - of a compound of formula 1, where R is deuterium, or a stereoisomer, salt, or solvate thereof, based on the total weight of the liquid composition; - about 93.5 to 99.5 wt. % of a liquid vehicle, based on the total weight of the liquid composition, comprising: (i) about 50 parts (by weight) of propylene glycol monocaprylate, e.g., propylene glycol monocaprylate Type II; (ii) about 40 parts (by weight) of castor oil, e.g., 40 hydrogenated castor oil; (iii) about 5 to 10 parts (by weight) propylene glycol; and optionally (iv) up to about 5 parts (by weight) water; said vehicle consisting essentially of; And as necessary the remainder being one or more further excipients dissolved or dispersed in the liquid vehicle. It is also one of the preferred embodiments of the method for preparing a soft capsule, in which a liquid composition consisting essentially of is provided.

[0076] In a further preferred embodiment, the present invention provides a soft capsule obtainable by a method characterized by steps (a) to (e).Taking into account the changes that a soft capsule may undergo during its shelf life, due for example to migration of plasticizers from the capsule wall to the fill liquid, or migration of ingredients from the liquid fill to the capsule wall, and thus both the liquid fill and the capsule wall changing in quantitative composition over time, it seems entirely appropriate to define a soft capsule in terms of its manufacturing process and its starting (or intermediate) materials.

[0077] According to a further aspect of the present invention, the liquid pharmaceutical composition or capsules containing such compositions may be used in the acute or chronic treatment of subjects suffering from any disease or condition that responds to bradykinin B2 receptor modulation.Examples of diseases or conditions that respond to BK B2 receptor modulation include diseases or conditions such as skin disorders; 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 diseases; hormonal diseases; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic system diseases; central nervous system disorders; brain disorders; musculoskeletal diseases; allergic disorders; pain; infectious diseases; inflammatory disorders; injury; immunological disorders; cancer; genetic diseases; and edema.In other words, one aspect of the present invention relates to a method of treating a subject suffering from any disease or condition that responds to bradykinin B2 receptor modulation, comprising administering a composition or capsule as described above. Similarly, the invention provides the use of a composition or capsule as described herein in the manufacture of a medicament for treating any disease or condition responsive to bradykinin B2 receptor modulation, for example for the acute or chronic treatment of a disease or condition responsive to BK B2 receptor modulation.

[0078] As used herein, the terms "treatment", "treating" and the like should be construed to include any type of preventive or therapeutic treatment. It therefore encompasses the prevention, management, or treatment of disease or its recurrence or any symptoms associated with such disease or condition. Furthermore, in the context of the present invention, "acute" includes any non-chronic administration regimen, such as a single administration of an effective single dose of the composition or capsule described herein, as well as sporadic or regular dosing regimens over a relatively short period of time, such as up to 4 weeks, or up to 2 weeks. In one of the preferred embodiments, the liquid composition or capsule provided by the present invention is used to acutely treat a disease or condition that responds to bradykinin B2 receptor modulation.

[0079] The following diseases or conditions may be considered as being responsive or at least potentially responsive to bradykinin B2 receptor modulation:

[0080] Disorders such as, but not limited to, skin aging, skin rashes including pressure sores, pressure ulcers, irritated sensitive paresthesia skin, erythema, rash, skin edema, psoriasis, eczema, Netherton syndrome, lichen, furuncles, abscesses, cellulitis, erysipelas, folliculitis and impetigo, bacterial, viral, fungal and parasite induced skin infections including lice, scabies and herpes simplex, acne, rashes, dermatitis including atopic dermatitis, allergic contact dermatitis, neurodermatitis, radiation damage, sunburn, psoriasis, eczema ... Skin disorders including burning, pruritus, itching, cholestatic pruritus, chronic pruritus, chronic prurigo, prurigo nodularis, urticaria, chronic spontaneous urticaria, chronic inducible urticaria, cold urticaria, cryopyrin-associated periodic syndromes (CAPS), familial cold autoinflammatory syndrome (FCAS), FXII-associated cold autoinflammatory syndrome (FACA), psoriasis, mycoses, tissue ulcers, epidermolysis bullosa, wounds including abnormal wound healing, burns, frostbite, inflammatory skin tumors caused by toxins, viromas, alopecia, hair squama, corns, warts, and whitlow.

[0081] Non-limiting examples of the treatment include inflammatory disorders such as scleritis, conjunctivitis, conjunctival edema, iritis, iridocyclitis, uveitis, chorioretinitis, and disorders such as retinal and choroidal circulatory disorders, bacterial eye infections, non-specific conjunctivitis and eye inflammation, retinopathy of prematurity, proliferative vitreoretinopathy, macular degeneration (including age-related macular degeneration, both wet and dry forms), corneal graft rejection, corneal injury, corneal scarring, corneal collapse, and the like. Eye diseases including corneal diseases including corneal ulcers, corneal opacities, keratoconus, glaucoma (preferably open angle glaucoma), myopia, ocular glaucoma, ocular hypertension, ocular vascular damage, neovascularization, ocular fibrosis (e.g., anterior subcapsular fibrosis, posterior subcapsular opacities, posterior capsular opacities, corneal opacities after laser surgery, subconjunctival scarring after glaucoma surgery), proliferative vitreoretinopathy (PVR), styes, as well as bacterial eye infections including eyelash loss.

[0082] Disorders such as ear diseases, including but not limited to Meniere's disease, otitis media, otitis externa, and acute hearing loss.

[0083] Disorders such as, but not limited to, aphthae and stomatitis, periodontitis, epiglottitis, pharyngitis, laryngotracheitis, tonsillitis, common cold, inflammation of the oral mucosa and gums including sore throat, seasonal or perennial allergic rhinitis, rhinorrhea, sinusitis of all types of etiology or pathogenesis, or purulent or non-purulent sinusitis, acute and chronic sinusitis, and ethmoid, frontal, maxillary or sphenoid sinusitis, rhinitis involving phlegm, e.g., aluminum pneumoconiosis of all types or originating from them, including, in particular, byssinosis, anthraxosis, asbestosis, lithiasis, siderosis, silicosis, tobacco disease, bronchitis, cough, tracheitis, congestion, pneumonia, eosinophilic pulmonary infiltrates, chronic eosinophilic pneumonia, idiopathic pulmonary fibrosis, and other fibrotic lung diseases, e.g., treatment-related fibrotic lung disease associated with radiation, methotrexate, chemotherapy, amiodarone, or nitrofurantoin, sarcoidosis, acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), coronaviruses Disease 2019 (COVID-19), bronchoconstriction, asthma of any type, etiology, or pathogenesis, or atopic asthma, non-atopic asthma, allergic and non-allergic asthma, extrinsic asthma caused by environmental factors, intrinsic asthma caused by pathophysiological perturbations, bronchial asthma, IgE-mediated asthma, intrinsic asthma and intrinsic asthma of unknown or unexplained cause, true asthma, emphysematous asthma, exercise-induced asthma, occupational asthma, infection caused by bacterial, fungal, protozoan, or viral infections Asthma which is a member selected from the group consisting of primary asthma, early asthma, wheezy infant syndrome, bronchial hyperresponsiveness, chronic obstructive pulmonary disease (COPD), COPD characterized by irreversible progressive airway obstruction, acute respiratory distress syndrome (ARDS), and exacerbation of airway hyperresponsiveness resulting from other drug therapies, dyspnea, hyperoxic alveolar damage, emphysema, pleurisy, tuberculosis, exposure to high altitude i.e. acute mountain sickness, preferably high altitude pulmonary edema (HAPE), resistant cough, bronchial hyporesponsiveness.

[0084] Disorders including gastrointestinal disorders including, but not limited to, esophagitis, gastritis, gastric irritability, gastric and duodenal ulcers, ileus, colonic irritability, Crohn's disease and ulcerative colitis, inflammatory bowel disease including proctitis, hypertensive gastric and colonic disease, enteritis, peritonitis, appendicitis, proctitis, gastrointestinal bleeding, collateral circulation or congestion caused by portal hypertension, post-gastrectomy dumping syndrome, digestive discomfort, diarrhea, hemorrhoids, parasitic diseases, abdominal colic and colic of any part of the gastrointestinal system.

[0085] Diseases of the liver, gallbladder, and pancreas, including, but not limited to, disorders such as hepatitis, cirrhosis, liver fibrosis (e.g., caused by viruses (HBV / HCV) infections, toxins (alcohol), fatty liver, cholestasis, hypoxia), portal hypertension, renal-hepatic syndrome, hepatogenic edema, non-malignant ascites, cholangitis, cholecystitis, acute and chronic pancreatitis, and biliary colic.

[0086] Urinary tract and kidney diseases including, but not limited to, urinary tract infections, e.g., acute and chronic cystitis, interstitial cystitis, overactive 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, diuresis, proteinuria, natriuresis, calciuresis, water balance disorders, electrolyte balance disorders, acid-base balance disorders, and renal colic, renal fibrosis, chronic renal allograft dysfunction, contrast-induced nephropathy.

[0087] Diseases of the male and female reproductive tract, 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.

[0088] Hormonal disorders including, but not limited to, menstrual disorders and pain, menopause, vomiting, premature uterine contractions, premature labour, endometriosis, endometritis, fibroids, pre-eclampsia.

[0089] Disorders, including but not limited to, diabetes including non-insulin dependent diabetes mellitus, diabetic retinopathy, diabetic macular edema, diabetic nephropathy, and diabetic neuropathy, insulin resistance, and diabetic ulcers, diseases of protein and purine metabolism, such as gout, and disorders of lipid metabolism, metabolic disorders including hypoglycemia.

[0090] Arterial circulatory disorders including, but not limited to, vascular permeability, vasodilation, hyperemia, peripheral circulatory disorders, cardiac volume overload, aortic aneurysms, abdominal aortic aneurysms, cerebral aortic aneurysms, hypertension, dialysis-induced hypotension and hypotension associated with sepsis, restenosis after percutaneous transmural coronary angioplasty, atherosclerosis including atherosclerotic plaque rupture, hemangiomas, angiofibromas, venous disorders such as thrombosis, varicose veins, phlebitis, thrombophlebitis, venous thrombosis, heart disease, congestive heart failure, hepatic arterial heart disease, carcinoid syndrome, angina pectoris, arrhythmias, endocardial Cardiovascular diseases, including disorders involving systemic inflammatory response syndrome (SIRS), including inflammatory heart disease including myocarditis, pericarditis and constrictive pericarditis, myocarditis, myocarditis, myocardial infarction, post-myocardial infarction syndrome, left ventricular dilation, post-ischemic reperfusion injury, sepsis, allergic, post-traumatic and hemodynamic shock, shock and collapse including amniotic fluid embolism, SIRS caused by cardiopulmonary bypass during surgery, sepsis during cardiopulmonary bypass surgery, and internal and external complications, including but not limited to adverse hemodynamic effects following protamine sulfate reversal of heparin.

[0091] Disorders such as blood disorders including, but not limited to, coagulation, disseminated intravascular coagulopathy, hemorrhage, bleeding diathesis, hypercholesterolemia and hyperlipidemia, hypovolemic shock, paroxysmal nocturnal hemoglobinuria.

[0092] Lymphatic system disorders, including but not limited to splenomegaly, lymphangitis, lymphadenitis, and hyperplastic pharyngeal tonsils.

[0093] Disorders, such as, 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, acute and chronic neurodegenerative disorders including multiple sclerosis, aging, Alzheimer's disease, and Parkinson's disease, multiple sclerosis, myalgic encephalomyelitis / chronic fatigue syndrome, neuritis, and peripheral neuropathies, central nervous system disorders including depression, anorexia, anxiety and schizophrenia, sleep disorders.

[0094] Disorders such as, but not limited to, nootropic or cognitive enhancement, brain disorders including cerebral amyloid angiopathy, stroke, head and brain trauma, traumatic brain injury, brain tumors, thermal brain injury, cerebral ischemia, cerebral hemorrhage, post-traumatic and post-ischemic cerebral edema, generalized cerebral edema, acute mountain sickness, preferably high altitude cerebral edema (HACE), cytotoxic cerebral edema, vasogenic cerebral edema, post-operative cerebral edema, cerebral edema associated with metabolic disease, increased permeability of the blood-brain barrier or blood-brain tumor barrier.

[0095] Musculoskeletal disorders including, but not limited to, disorders such as inflammatory musculoskeletal disorders, after joint trauma, after relatively long periods of immobilization of a joint after meniscus or patellar injury or ligament injury, arthrosis, osteoarthritis, osteoarthritis, or chondroporosis, acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, spondyloarthritis, septic arthritis, psoriatic arthritis, chronic polyarthritis, rheumatoid arthritis of all types, etiologies, or pathogenesis, including rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, low back pain, spondylitis, spondyloarthritis, ankylosing spondylitis, osteomyelitis, sprains, tenosynovitis, inflammation-induced bone resorption, fractures, etc., osteoporosis, musculoskeletal pain and stiffness, spinal disc syndrome.

[0096] Allergy disorders including, but not limited to, disorders such as general allergic reactions, food allergies, anaphylactic shock, allergic contact hypersensitivity, allergic skin reactions, allergic asthma, vernal conjunctivitis, and seasonal or perennial allergic rhinitis.

[0097] Pain may include, but is not limited to, central and peripheral mediated pain, vascular pain, visceral pain, inflammatory mediated pain, neurogenic pain, referred pain, nociceptive pain, reflex pain, psychogenic pain, such as acute pain caused by acute injury to bone, muscle, tissue, soft tissue, organ, trauma, or surgery, opioid-induced hyperalgesia, pain after insect bites, post-stroke pain syndrome, post-operative pain, progressive disease-related pain, chronic pain, such as pain caused by neuropathic pain states. Pain, including pain associated with rheumatoid arthritis, osteoarthritis, tenosynovitis, gout, menstruation, and angina, fibromyalgia, eye pain, back pain, headache, cluster headache, tension headache, migraine, and inflammatory pain that may be associated with acute or chronic inflammation. Inflammatory pain includes, but is not limited to, neuropathic pain, ischemic pain, arthritis-induced pain, muscle pain induced by acute or chronic inflammation, neuralgia caused by acute or chronic inflammation, and hyperalgesia. Also includes chemotherapy-induced peripheral neuropathy, hyperalgesia, opioid-induced hyperalgesia, and fever. In addition, the compounds of the present invention are useful as analgesics for use during general anesthesia and monitored anesthesia.

[0098] Infectious diseases, including, but not limited to, those mediated by bacterial, viral, fungal, parasitic, protozoan, prion, or mycobacterial infections. In particular, the present invention is useful for treating bacterial infections caused by Streptococcus, Escherichia, Salmonella, Staphylococcus, Klebsiella, Moraxella, Haemophilus, and Yersinia. Bacterial infections contemplated within the scope of the present invention include, but are not limited to, plague, septicemia, typhus, food poisoning, tetanus, scarlet fever, whooping cough, and diphtheria. Examples of viral infections contemplated within the scope of the present invention include, but are not limited to, diseases such as chickenpox and herpes zoster, AIDS, influenza, dengue virus fever, SARS-CoV-2 disease (COVID-19), hantavirus disease, smallpox-like diseases, and childhood diseases such as measles, rubella, mumps, and acute anterior horn disease. The present invention is useful for treating protozoan and parasitic infections caused by Schistosoma mansoni, Dermatofagoides·farinae, Trypanosoma·cruzi, Leishmania, and Plasmodium, which causes malaria. Examples of prion infections contemplated within the scope of the present invention include, but are not limited to, bovine spongiform encephalopathy (BSE), Creutzfeldt-Jakob disease, and diseases such as kuru, dengue fever, and hemorrhagic fever.

[0099] Inflammatory disorders, including but not limited to, disorders such as acute phase responses, local and systemic inflammation, as well as inflammation caused by other diseases of all types, etiologies or pathogenesis, and inflammation caused by inflammatory diseases as specified in this application.

[0100] Injury: Within the scope of this application, the term "injury" includes, but is not limited to, multiple trauma, head and brain trauma, hypertensive tissue injury, pulmonary injury, external, internal and surgical wounds, thermal injuries including, but not limited to, thermal injuries, electrical injuries, chemical burns, cryoinjuries, ionizing radiation and solar burns.

[0101] Disorders, such as, but not limited to, immunological disorders including hypersensitivity, autoimmune disorders, graft rejection in transplantation, transplant toxicity, granulomatous inflammation / tissue remodeling, myasthenia gravis, immunosuppression, immune complex diseases, antibody overproduction and underproduction, vasculitis, delayed graft function, lupus.

[0102] Disorders such as, but not limited to, breast cancer, lung cancer (non-small cell lung cancer and small cell lung cancer), prostate cancer, oral cavity and pharynx (lips, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, colon, rectum, gallbladder and bile duct, pancreas, larynx, lung, bone, osteosarcoma, solid tumor cancer including cancer of connective tissue, Kaposi's syndrome, melanoma and skin metastases, epidermoid carcinoma, basal cell carcinoma, cervix, corpus lining Cancer, including skin cancer, including cancer of the ovaries, testes, bladder, ureters and urethra, kidney, eye, brain and central nervous system, pseudotumor cerebri, sarcoma, sarcoid, thyroid and other endocrine glands (including but not limited to carcinoid tumors), hematopoietic malignancies, including Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, and lymphomas, including lymphocytic, granulocytic and monocytic lymphomas, tumor invasion, metastasis, ascites, tumor proliferation and angiogenesis.

[0103] Disorders, such as genetic diseases, including but not limited to hereditary angioedema and angioneurotic edema, chondrocalcinosis, Huntington's disease, cystic fibrosis.

[0104] As used herein, it refers to general edema, including, but not limited to, angioedema (AE) of any form and / or type, and edema caused by inflammation, factor XII deficiency induced edema, other drugs including, but not limited to, angiotensin converting enzyme inhibitor induced angioedema, drug induced angioedema, thrombolytic therapy induced angioedema, e.g., drug induced angioedema, infection, burns, injuries, trauma, frostbite, surgery, sprains, fractures, exposure to high altitude (e.g., high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE)), genetic, autoimmune, and other diseases and disorders, particularly including, but not limited to, the disorders specified in this application, gastrointestinal stress induced edema (significant swelling).

[0105] Capillary leak syndrome, including but not limited to systemic capillary leak syndrome in sepsis, burns, allergies, drug / toxin induced conditions, organ transplants, and IL-2 cytokine therapy.

[0106] In a preferred embodiment, the liquid pharmaceutical composition or capsule is used in the acute or chronic treatment of angioedema (AE), including hereditary angioedema (HAE), acquired angioedema (AAE), bradykinin-mediated non-histamine idiopathic angioedema, allergic angioedema, or drug-induced angioedema, or bradykinin-mediated angioedema of unknown etiology. Hereditary angioedema (HAE) is a disorder that presents with repeated bouts of severe swelling. The swelling often affects the arms, legs, face, intestinal tract, and also the airways. If the intestinal tract is affected, abdominal pain and vomiting may occur. Swelling of the airways may result in bronchial obstruction and difficulty in breathing. Acute attacks typically last for several days, with HAE patients experiencing attacks about every two weeks. HAE may be of any type, including type I HAE, type II HAE, or type III HAE, preferably type I HAE or type II HAE.

[0107] According to a further preferred embodiment, the liquid pharmaceutical composition or capsule is used in the treatment of anterior segment symptoms or acute attacks of angioedema, for example in subjects suffering from hereditary angioedema.As mentioned above, the liquid pharmaceutical composition according to the present invention shows an excellent release rate of the bradykinin B2 receptor antagonist of formula 1, despite the large molecular size of the compound and its low solubility in physiological fluids.Due to such rapid delivery of the active ingredient to the patient's bloodstream, the composition is particularly advantageous when used in the management of acute attacks or episodes of severe swelling, which require rapid onset of drug action.

[0108] In a further embodiment, the liquid pharmaceutical composition or capsule is used in a treatment that includes orally administering the composition or capsule once or twice a day, respectively, preferably for at least two weeks. The composition provides a rapid drug release, almost like an injection, but its oral administration is more convenient than an injection, making such a regimen particularly advantageous.

[0109] Further aspects, embodiments, optional features and preferences of the present invention will become apparent on the basis of the examples and claims.

[0110] Further definitions For clarity, further definitions are provided for some of the terms used throughout the description and claims. The definitions should be used to define the meaning of each expression, unless a different meaning is required by context.

[0111] The terms "a" or "an" do not exclude a plurality, i.e., the singular forms "a", "an", and "the" should be understood to include the plural referent unless the context clearly indicates or otherwise requires. In other words, all references to singular features or limitations in this disclosure should include the corresponding plural features or limitations, and vice versa, unless otherwise clearly specified or clearly implied to the contrary by the referenced context. Thus, the terms "a", "an", and "the" have the same meaning as "at least one" or "one or more", unless otherwise defined. For example, reference to "an ingredient" includes a mixture of ingredients, and the like.

[0112] The term "about" or "ca." is recognized in the pharmaceutical industry and will account for variations inherent in pharmaceutical products, such as differences in content due to manufacturing variations and / or product degradation over time. The term recognizes that any variation, which in pharmaceutical practice, should be evaluated such that a product is considered bioequivalent in a subject to the recited strength of the claimed product.

[0113] The terms "active agent," "therapeutic agent," "active pharmaceutical ingredient (API)," "active principle," "drug," and "bioactive agent" are used interchangeably and refer to a compound or combination of compounds that have pharmacological activity against an undesirable condition.

[0114] The term "composition" refers to any type of composition in which the specified ingredient may be incorporated, optionally with additional components.

[0115] The term "compound" refers to a chemical substance that is a material made up of molecules having substantially the same chemical structure and properties. For small molecule compounds, the molecules are typically identical in terms of their atomic composition and structural configuration. For macromolecular or polymeric compounds, the molecules of the compound are very similar, but not all of them are necessarily identical.

[0116] The terms "comprise," "comprises," and "comprising," and similar expressions, are to be interpreted in an open, inclusive sense, such as "including, but not limited to."

[0117] The terms "essentially," "about," "approximately," "substantially," and the like, in connection with an attribute or value, include the exact attribute or exact value, and any attribute or value is typically considered to fall within a normal range or variation accepted in the relevant art. For example, "substantially free of water" means that water is not intentionally included in the composition, but does not exclude the presence of residual moisture.

[0118] The term "consisting essentially of" refers to a composition or dosage form to which no further components other than those listed have been added. Nevertheless, small amounts of other materials, such as impurities inherent in the materials, may potentially be present. Furthermore, for example, when referring to "consisting essentially of A, B, C, and optionally D," this means that no further components other than A, B, C, and D have been added to the composition or dosage form, and D is an optional component (i.e., not required) in said composition or dosage form.

[0119] The term "substantially free" refers to a composition that contains less than a functional amount of each component, typically less than 1% by weight, preferably less than 0.1%, or even less than 0.01%, including 0 weight percent of each component. EXAMPLES

[0120] [Example 1] Liquid composition A~H Several liquid compositions based on propylene glycol monocaprylate, polyoxyl castor oil, and propylene glycol (see Tables 1A and IB) were prepared by weighing and mixing each liquid component, and then combining the liquid mixture with a specified amount of active ingredient, such as one that allows the active ingredient (API) to dissolve in the liquid mixture. As the API, (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide monohydrate was used. The amount or content of API is specified as the monohydrate. Thus, the liquid compositions contained the specified amount of API monohydrate. As the propylene glycol monocaprylate, commercial grade type II propylene glycol monocaprylate (Capryol® 90) was used. As the polyoxyl castor oil, a commercial grade polyoxyl 40 hydrogenated castor oil (Kolliphor® RH40) was used.

[0121] [Table 1A]

[0122] [Table 1B]

[0123] As a result, it was observed that these compositions AH incorporated the active ingredient in a completely dissolved form, resulting in clear, milky or hazy solutions and without any solid residue that could indicate undissolved API.

[0124] [Example 2] Dilution of Liquid Compositions A to H with Aqueous Medium Compositions A-H were tested for their ability to maintain the API in its dissolved state when diluted in an aqueous medium. For this purpose, a simple surrogate for gastric juice, i.e. water acidified to pH 3 with a hydrochloric acid solution, was added to samples of the compositions, for example to dilute them 10-fold, i.e. 10 times by weight. The diluted samples were stored at room temperature for 3 hours.

[0125] Upon dilution, all compositions A-H formed physically stable emulsions or microemulsions without any separation of the two liquid phases as could be visually observed. Thus, the compositions were found to exhibit SEDDS or SMEDDS as defined herein. Furthermore, the diluted samples showed no signs of drug precipitation. In other words, the compositions were able to stabilize the active ingredient in a completely dissolved form even when diluted with a large excess of water.

[0126] Furthermore, the diluted sample obtained from composition E was stored at room temperature for several more days and was very stable. Even after 5 days, the sample still remained in the form of a milky white microemulsion with almost no precipitation, indicating that this composition was particularly advantageous, e.g., capable of solubilizing the active ingredient to allow for rapid absorption and rapid onset of action.

[0127] [Example 3] Liquid composition performance robustness Because it is known that many initially promising SMEDDS formulations of various drug substances ultimately fail during commercial product development due to inconsistent or poor performance robustness, a representative liquid composition according to the present invention, i.e., composition E of Example 1, was subjected to a series of performance robustness tests.

[0128] Dilution of FaSSIF-V2 During therapeutic administration of the liquid composition (e.g., using a soft capsule), the composition may be initially diluted by gastrointestinal fluid. To simulate this scenario, samples of the composition were mixed with FaSSIF-V2 (Fasting State Artificial Intestinal Fluid V2), a widely recognized biologically relevant surrogate of gastrointestinal fluid, to achieve, for example, dilution ratios of 1 / 10 and 1 / 100, respectively. For comparison, a series of samples were further diluted with water using the same dilution ratios. All diluted samples were impermeable microemulsions (also called nanoemulsions given their submicron droplet size) and kept at 37°C. The emulsion droplet size was measured immediately after dilution and 6 hours after dilution using a Malvern Zetasizer Nano ZS.

[0129] As a result, all diluted samples were found to show submicron emulsions with z-average particle sizes ranging from about 50 to 200 nm. Small differences were observed in that the samples with a dilution ratio of 1 / 10 showed slightly larger droplet sizes than those with a dilution ratio of 1 / 100 (e.g., 197 nm vs. 119 nm for FaSSIF-V2), both initially and after 6 hours. Furthermore, storage over 6 hours led to some increase in droplet size for all dilutions. This effect was slightly accentuated in the case of FaSSIF-V2 compared to water as diluent, and it was surprising to discover that even after 6 hours at 37° C., dilutions with FaSSIF-V2 showed submicron emulsions, thus indicating a good robustness of the formulation in terms of performance, especially considering the fact that FaSSIF-V2 contains not only a buffer system but also the surfactants sodium taurocholate and lecithin. The z-average droplets measured in this series of experiments are summarized in Table 2 below.

[0130] [Table 2]

[0131] Dispersions in various media Three to five drops of Composition E were added individually to 10 mL of each of the following media: water, 0.01 n hydrochloric acid, pH 6.8 phosphate buffer, simulated gastric fluid (SGF), fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF) at 37° C. Samples were visually inspected for signs of drug precipitation immediately after mixing, after inversion, and after storage for 2 to 6 hours. As a result, no signs of precipitation were observed.

[0132] Temperature Cycling Approximately 5 g aliquots of Liquid Composition E were filled into vials and stored under refrigeration (2° C. to 8° C.) for approximately 24 hours. The vials were then visually inspected, particularly for any drug precipitation or phase separation. The vials were then stored at elevated temperature (30° C. to 40° C.) for approximately another 24 hours and inspected again. Cycling between the two temperature conditions was performed for 6 days. At no time point was any change in the formulation, particularly no drug precipitation or phase separation, noted by visual inspection.

[0133] [Example 4] Liquid composition I~N A further series of liquid compositions (see Table 2) based on propylene glycol monocaprylate, polyoxyl castor oil, propylene glycol and further liquid excipients were prepared as described in Example 1. Again, the compound (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide monohydrate was used as API, and the same grades of propylene glycol monocaprylate and polyoxyl castor oil were used. As for the excipient, the commercial grade (Labrasol®) of caprylocaproyl polyoxyl-8 glyceride, also called caprylocaproyl macrogol-8 glyceride, was used.

[0134] [Table 3]

[0135] Upon visual inspection, it was also observed that these compositions I-N could incorporate the active ingredient in a completely dissolved form, obtaining clear, milky, or hazy solutions, without any solid residue that could indicate undissolved API. This example also shows that in addition to propylene glycol monocaprylate, polyoxyl castor oil, and propylene glycol, further excipients can be incorporated, such as further organic solvents (as represented by ethanol) and further surfactants (as represented by caprylocaproyl polyoxyl-8 glyceride).

[0136] [Example 5] Stability of the liquid composition Aliquots of Liquid Composition E were filled into glass vials and stored at different temperature and humidity conditions including 25° C. / 60% relative humidity. Samples were taken and tested for drug content (assay) and chemical impurities as well as physical appearance, water content and emulsifying performance at different time intervals up to 36 months.

[0137] As a result, no significant chemical or physical changes were observed. Even after 36 months, the composition was a clear, slightly brownish solution that exhibited emulsification, but no precipitation or phase separation was observed after dilution with water. Notably, the drug content after 36 months was nearly identical to the initial value (94.1% vs. 94.5% of label claim) and showed only a very slight increase in the total content of impurities (1.65% to 2.00%). These results not only promise a commercially attractive product shelf life, but are also very surprising in view of the fact that liquid SMEDDS formulations containing the active ingredient in amorphous form completely dissolved in a mixture of high-performance excipients are typically prone to more drug degradation than conventional pharmaceutical formulations.

[0138] [Example 6] Dilution of Liquid Compositions I to N with Aqueous Medium Similar to Example 2, compositions I-N were tested for their ability to maintain the API in a dissolved state when diluted in aqueous media. Again, all compositions spontaneously formed emulsions or microemulsions that were physically stable and did not exhibit liquid phase separation. Thus, these compositions were also found to exhibit SEDDS or SMEDDS. The diluted samples did not show any signs of drug precipitation.

[0139] Comparative Example Several other excipients and excipient combinations commonly used to prepare SEDDS or SMEDDS formulations of other active ingredients have been tested with the bradykinin B2 receptor antagonist of formula 1 without success. For example: (a) a 50:50 weight ratio of glyceryl caprylate / caprate (Capmul® MCM) and caprylocaproyl polyoxyl-8 glyceride (Labrasol®); (b) glyceryl caprylate / caprate (Capmul® MCM), caprylocaproyl polyoxyl-8 glyceride (Labrasol®) and ethanol in a weight ratio of 50:40:10; (c) Type II propylene glycol monocaprylate (Capryol® 90) and caprylocaproyl polyoxyl-8 glyceride (Labrasol®) in a weight ratio of 20:80; and (d) Various weight ratios of propylene glycol monocaprylate type II (Capryol® 90), caprylocaproyl polyoxyl-8 glyceride (Labrasol®), and propylene glycol Incorporation 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 monohydrate into a mixture of Not only did dilution with acidic water result in rapid precipitation of the active ingredient, but it also led to liquid-liquid phase separation, i.e., physical disruption of the emulsion or microemulsion system and its conversion into two separate non-dispersed liquid phases.

[0140] Additionally, the same compound of formula 1 can be mixed with other commonly used excipient mixtures: (e) Type II propylene glycol monocaprylate (Capryol® 90) and polyoxyl 40 hydrogenated castor oil (Kolliphor® RH40) in a weight ratio of 40:60; (f) caprylocaproyl polyoxyl-8 glyceride (Labrasol®) and glyceryl caprylate / caprate (Capmul® MCM) in a weight ratio of 95:5; and (g) Polyoxyl 40 hydrogenated castor oil (Kolliphor® RH40); Type II propylene glycol monocaprylate (Capryol® 90) and ethanol in a weight ratio of 70:20:10. When dissolved in water, it did not show liquid-liquid phase separation but did show rapid precipitation of the active ingredient.

[0141] [Example 7] Preparation of soft gelatin capsules Composition E of Example 1 was used as a liquid fill material in the manufacture of soft gelatin capsules using standard encapsulation equipment and techniques.

[0142] Two prototype capsule compositions (Prototypes E1 and E-2) were prepared using the wet gelatin capsule shell compositions shown in Table 4. Commercial grade sorbitol syrup or partially dehydrated liquid sorbitol, Polysorb® 85 / 70 / 00 (Roquette), was used.

[0143] [Table 4]

[0144] Upon visual inspection by an experienced technician, the appearance of the soft capsules was found to be very good for both capsule formulations. There was a smooth surface and a well-formed sealed area. No gelatin stretching, especially no defects, was observed, and therefore the capsule shell composition was found to be suitable for encapsulating liquid composition E.

[0145] The hardness of the capsules was tested and monitored over a period of three months storage at various temperature and humidity conditions (25°C / 60% room temperature; 30°C / 65% room temperature; 40°C / 75% room temperature). Only minor changes were observed to occur, which did not affect the overall properties of the capsules.

[0146] [Example 8] Single-dose pharmacokinetic study in monkeys The pharmacokinetic properties of a liquid composition according to the invention following a single oral dose in cynomolgus monkeys were studied and compared to that of a suspension of the same API in an aqueous carrier containing methylcellulose (1 wt.%). The test formulation was based on composition E of Example 1, except that the concentration of the API was 5 mg / mL in substantially the same liquid vehicle as composition E. The comparative formulation contained the same API at a concentration of 2 mg / mL, formulated as an aqueous drug suspension further containing methylcellulose (1 wt.%).

[0147] Materials and Methods: The study was performed in three animals in two phases separated by at least a 5 day washout: Phase 1:

[0148] [Table 4A]

[0149] Upon completion of phase 1, monkeys were reassigned to phase 2 in the same order.

[0150] Phase 2:

[0151] [Table 4B]

[0152] Pharmacokinetic evaluation was performed using nominal dose levels.

[0153] In vitro pharmacological studies revealed that the API has similar high antagonist potency at the B2 receptor in humans and monkeys, but low antagonist potency at the B2 receptor in dogs, rats and mice; non-human primates were a particularly suitable species for this study.

[0154] Blood samples for pharmacokinetic evaluation were taken from all animals at both stages before dosing and at 0.5, 1, 2, 3, 4, 6, 8 and 24 hours after dosing. All blood samples were taken within intervals strictly shorter than 20% of the nominal sampling time, and theoretical sampling times were considered for pharmacokinetic evaluation.

[0155] Pharmacokinetic parameters were determined from individual plasma concentrations by non-compartmental analysis using Kinetica™ 4.4.1 (Thermo Fisher). Plasma concentrations below the LLOQ (<1.2 ng / mL for the test item) were considered as zero. Individual concentration versus time graphs on linear and semi-log scales were performed using Kinetica™ 4.4.1 (Figures 1A-1D).

[0156] Pharmacokinetic parameters, ratios, SD, and CV (or delta %) are reported to three significant figures for numbers less than 100 and to the nearest integer for all numbers ≥ 100 except time values ​​and n.

[0157] Key Pharmacokinetic Parameters The parameters of maximum plasma concentration (Cmax), sampling time of Cmax (Tmax), and sampling time of last plasma concentration above LLOQ (Tlast) were determined by observation. The area under the plasma concentration-time curve from the time of dosing to the last quantifiable concentration was calculated using the linear-ascending / log-descending trapezoidal rule (AUClast). At least three consecutive quantifiable concentrations had to be available for calculation of AUG.

[0158] Secondary Pharmacokinetic Parameters The linear regression coefficient (R) of the log-linear terminal phase of the concentration-time profile was calculated by Kinetica™ 4.4.1, where at least three data points other than Cmax were available. The regression coefficient (R) was expressed as an absolute value, and the period was determined as the range of time points used to calculate the linear regression of the log-linear terminal phase. If the absolute value of R was 0.8 or more and the period was two times the half-life, it could be further calculated using the elimination rate constant (k) of the linear regression, and thus the formula ln2 / k was used to calculate tl / 2 after a single dose.

[0159] The percentage of AUG extrapolated from Tlast to infinity was calculated by Kinetica™ 4.4.1 using the following formula: AUCextra(%)=(Clast / k)×100 / AUCinf

[0160] If this extrapolation is below 20% and the two above mentioned conditions (R and duration) are met, the following parameters are displayed after a single dose: AUCinf: Estimated area under the curve from the time of dosing to infinity calculated using the following formula: AUCinf = AUClast + AUCextra

[0161] Dose Effects and Comparisons of Analytes or Formulations Dose proportionality: This effect was assessed graphically by calculating individual dose-normalized Cmax and AUClast.

[0162] Formulation comparison: This effect was assessed by calculating the individual Cmax and AUClast ratios between the comparator and test formulations.

[0163] result Pharmacokinetic parameters are listed in Table 5. Additionally, Figure 1 shows individual API plasma concentrations versus time on linear and semi-log scales. Figures 1A and IB show API plasma concentrations after administration of API in an aqueous carrier with methylcellulose (1 wt.%). Figures 1C and ID show API plasma concentrations after administration of API in a composition according to the present invention.

[0164] [Table 5]

[0165] Exposure to the API was demonstrated in all animals.

[0166] The calculated parameters were highly variable between animals: 67% of the values ​​had a CV or delta % above 30%.

[0167] API plasma concentrations were quantifiable for up to 24 hours after dosing, except for one animal treated with the test formulation, where no compound was detected at the 24 hour time point (Tables 6 and 7). Maximum API plasma concentrations were observed between 0.5 and 3 hours after dosing with the comparator formulation and between 1 and 4 hours after dosing with the test formulation (Tables 6 and 7).

[0168] [Table 6]

[0169] No half-life values ​​could be reported for the comparator formulations and therefore no conclusions could be drawn regarding elimination. For the test formulations, the half-life values ​​were relatively similar regardless of dose: individual values ​​ranged from 2.72 to 4.57 hours (Table 7).

[0170] [Table 7]

[0171] Comparison of formulations: The systemic exposure of API was much higher for the test formulation than for the comparator formulation. The mean Cmax and AUClast ratios (comparator vs. test formulation) were 0.679 and 0.430, respectively (Table 8). In other words, the degree of oral bioavailability achieved by the test formulation was more than two-fold higher than that of the comparator formulation.

[0172] [Table 8]

[0173] Mortality. No mortality occurred during this study.

[0174] [Example 9] Oral bioavailability in humans The oral bioavailability, pharmacokinetic properties and safety of the liquid composition according to the present invention were evaluated after a single oral administration. The composition was the same as composition E in Example 1.

[0175] Methods: The compositions were administered as oral solutions in a double-blind, placebo-controlled, single ascending dose, first-in-human study in healthy volunteers. Table 9 shows the experimental design of the study.

[0176] [Table 9]

[0177] Safety was assessed through 72 hours post-dose by physical examination, vital signs, adverse events, safety laboratories, and electrocardiogram (ECG). Plasma pharmacokinetic (PK) parameters were assessed through 72 hours post-dose.

[0178] Pharmacokinetic results: The composition was absorbed very rapidly, reaching peak plasma levels within 30 to 60 minutes after dosing in all subjects under fasting conditions. Systemic exposure was dose proportional, with mean t1 / 2 ranging from 3.5 to 5.6 hours across doses. Plasma levels for the API reached therapeutic threshold concentrations (estimated EC50 2.4 ng / mL and EC85 13.8 ng / mL) within 15 minutes for all doses and were maintained for approximately 12 hours at the 12 mg and 22 mg doses (Figure 2).

[0179] Administration of the 22 mg dose with a HCHF breakfast reduced Cmax by 32%, increased AUClast by 49%, and delayed median tmax by approximately 2 hours. Plasma levels still reached levels expected for effective therapeutic effect within 15 minutes and were maintained for over 12 hours (Figure 3). A summary of the observed pharmacokinetic parameters is provided in Table 10.

[0180] [Table 10]

[0181] These results, as already shown by the results of Example 8, confirm the excellent properties of the composition, not only showing that therapeutically relevant plasma levels were reliably achieved, but also that the active ingredient is remarkably rapidly absorbed into the systemic blood circulation, despite its very low water solubility.Within the scope of such pharmacokinetic performance, the composition is clearly useful for the oral treatment of patients suffering from diseases or conditions that respond to bradykinin B2 receptor modulation in general, and even for the treatment of acute episodes or symptoms that require immediate effective intervention.

Claims

1. An oral liquid pharmaceutical composition comprising a bradykinin (BK) B2 receptor antagonist having a chemical structure represented by the following formula 1, or a stereoisomer, salt, or solvate thereof; The liquid pharmaceutical composition, wherein the BK B2 receptor antagonist is dissolved in a liquid vehicle containing propylene glycol monocaprylate, polyoxyl castor oil, and propylene glycol. 【Chemical 1】 (In the formula, R is deuterium or hydrogen.)

2. The liquid pharmaceutical composition according to claim 1, wherein the BK B2 receptor antagonist is a compound represented by formula 1 (wherein R is deuterium), or a salt or solvate thereof.

3. The liquid pharmaceutical composition according to claim 1 or 2, wherein the amount of propylene glycol monocaprylate in the liquid vehicle is about 40 to 60 wt.% based on the weight of the liquid vehicle.

4. The liquid pharmaceutical composition according to claim 1 or 2, wherein the amount of polyoxyl castor oil in the liquid vehicle is about 30 to 50 wt.% based on the weight of the liquid vehicle.

5. The liquid pharmaceutical composition according to claim 1 or 2, wherein the amount of propylene glycol is about 2.5 to 15 wt.% based on the weight of the liquid vehicle.

6. Based on the weight of the liquid vehicle, the amount of propylene glycol monocaprylate in the liquid vehicle is about 40 to 60 wt.%, the amount of polyoxyl castor oil in the liquid vehicle is about 30 to 50 wt.%, and the amount of propylene glycol is about 2.5 to 15 wt.%. The liquid pharmaceutical composition according to claim 1.

7. The liquid pharmaceutical composition according to claim 1 or 6, wherein the propylene glycol monocaprylate is type II propylene glycol monocaprylate (USP / NF).

8. The liquid pharmaceutical composition according to claim 1 or 6, wherein the polyoxyl castor oil is polyoxyl 40 hydrogenated castor oil (USP / NF).

9. Based on the total weight of propylene glycol monocaprylate, polyoxyl castor oil, and propylene glycol in the liquid vehicle, the content of propylene glycol monocaprylate is about 50 wt.%, the content of polyoxyl castor oil is about 40 wt.%, and the content of propylene glycol is about 10 wt.%. The liquid pharmaceutical composition according to claim 1.

10. The liquid pharmaceutical composition according to claim 1 or 6, showing a content of a BK B2 receptor antagonist in the range of about 5 mg to about 100 mg, for example, about 5 mg to about 65 mg per 1 g, or for example, about 20 mg to 70 mg per 1 g.

11. (a) Based on the total weight of the liquid pharmaceutical composition, about 0.5 to 6.5 wt.%, for example 5 wt.%, of a compound represented by Formula 1 (wherein R is deuterium), or a stereoisomer, salt, or solvate thereof; (b) Based on the total weight of the liquid pharmaceutical composition, about 93.5 to 99.5 wt.% of a liquid vehicle, comprising: (i) about 50 parts (by weight) of propylene glycol monocaprylate, for example, Type II propylene glycol monocaprylate (USP / NF); (ii) about 40 parts (by weight) of polyoxyl castor oil, for example, 40 hydrogenated castor oil (USP / NF); (iii) about 5 to 10 parts (by weight) of propylene glycol; and optionally (iv) up to about 5 parts (by weight) of water a liquid vehicle consisting essentially of consisting essentially of, or or (a) Based on the total weight of the liquid pharmaceutical composition, about 0.5 to 6.5 wt.%, for example 5 wt.%, of a compound represented by Formula 1 (wherein R is deuterium), or a stereoisomer, salt, or solvate thereof; (b) Based on the total weight of the liquid pharmaceutical composition, about 93.5 to 99.5 wt.% of a liquid vehicle, comprising: (i) about 50 parts (by weight) of propylene glycol monocaprylate, for example, Type II propylene glycol monocaprylate (USP / NF); (ii) about 40 parts (by weight) of polyoxyl castor oil, for example, 40 hydrogenated castor oil (USP / NF); (iii) about 5 to 10 parts (by weight) of propylene glycol; and optionally (iv) up to about 5 parts (by weight) of water, and (c) the balance being one or more additional excipients dissolved or dispersed in the liquid vehicle The liquid pharmaceutical composition according to claim 1, consisting essentially of.

12. A capsule for oral administration, comprising the liquid pharmaceutical composition according to claim 1.

13. The capsule according to claim 12, which is a soft capsule.

14. Gelatin, water, at least one plasticizer selected from propylene glycol, glycerol, sorbitol, sorbitan, a sorbitol-based plasticizer mixture, or any combination thereof The capsule according to claim 13, comprising a capsule wall containing **Claim 15** The liquid pharmaceutical composition according to claim 1, for use in the acute or chronic treatment of a subject suffering from a disease or condition responsive to a BK B2 receptor modulator. **Claim 16** The liquid pharmaceutical composition according to claim 15, wherein the disease or condition responsive to a BK B2 receptor modulator is edema, hereditary angioedema (HAE) or acquired angioedema (AAE). **Claim 17** The capsule according to any one of claims 12 to 14, for use in the acute or chronic treatment of a subject suffering from a disease or condition responsive to a BK B2 receptor modulator. **Claim 18** The capsule according to claim 17, wherein the disease or condition responsive to a BK B2 receptor modulator is edema, hereditary angioedema (HAE) or acquired angioedema (AAE).

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