Lipid-based composition for oral administration of bradykinin B2 receptor antagonists

Abstract

The present invention relates to a pharmaceutical composition for oral administration, comprising a bradykinin (BK) B2 receptor antagonist having a chemical structure according to Formula 1, or a salt or solvate thereof, wherein R is deuterium or; #imgabs0# For example, (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide. The composition comprises a BK B2 receptor antagonist dissolved in a liquid carrier, and the liquid carrier comprises propylene glycol monocaprylate, polyoxyethylene castor oil and propylene glycol. In addition, therapeutic uses of the composition are provided.

Description

Technical Field

[0001] The present invention relates to pharmaceutical compositions comprising bradykinin B2 receptor antagonists having a chemical structure according to Formula 1, methods of preparing such compositions, and their use as pharmaceuticals to treat subjects who may benefit from bradykinin B2 receptor antagonists. Background Art

[0002] Bradykinin (BK) is a peptide hormone that participates in the inflammatory process by activating endothelial cells, leading to vasodilation, increased vascular permeability, production of nitric oxide, and mobilization of arachidonic acid. BK also stimulates sensory nerve endings, causing burning dysesthesia. Therefore, the classic parameters of inflammation (e.g., redness, fever, swelling, and pain) may all be caused by BK formation. BK is a short-lived component of the kallikrein-kinin system. Under normal physiological conditions, the concentration of circulating BK remains low, but in pathological conditions, it may increase rapidly through enzymatic degradation of circulating glycoprotein precursors called kininogens. The two most effective 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 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 shown that drugs that block the BK B2 receptor provide therapeutic benefits in pathological conditions such as asthma, allergic rhinitis, pancreatitis, osteoarthritis, traumatic brain injury, Alzheimer's disease, and angioedema.

[0003] Many peptide and non-peptide antagonists of the BK B2 receptor have been described in the prior art. Quinoline derivatives having BK B2 receptor antagonist activity are disclosed, for example, in WO 2014 / 159637, WO 2010 / 031589, WO 2008 / 116620, WO 2006 / 40004, WO 03 / 103671, WO 03 / 87090, WO 00 / 23439, WO 00 / 50418, WO 99 / 64039, WO 97 / 41104, WO 97 / 28153, WO 97 / 07115, WO 96 / 13485, EP 0 795 547, EP 0 796 848, EP 0 867432, and EP 1 213 289. However, as disclosed in WO 2014 / 159637, a number of drawbacks of these compounds hinder their use as pharmaceuticals, including low metabolic stability, low bioavailability, formation of glutathione adducts, and bioactivation (toxicity).

[0004] Recently, compounds of Formula 1 have been proposed as a novel, bioactive and well-tolerated BK B2 receptor antagonist (see, for example, WO 2019 / 101906). Although these compounds exhibit attractive pharmacological properties, they also exhibit quite challenging physical or physicochemical properties, including very poor water solubility in physiological media. Therefore, there is a need to overcome the difficult formulation designs and pharmaceutical compositions caused by the properties of these challenging compounds, such as those that can be effectively delivered orally and achieve significant systemic exposure and bioavailability in human subjects. There is also a need for formulations or pharmaceutical compositions comprising compounds of Formula 1, for example, by rapid oral absorption (i.e., rapid absorption after oral administration) into the systemic circulation to achieve rapid effectiveness, with the aim of providing effective treatment for acute symptoms or conditions associated with BK, which is a particular challenge for such poorly soluble compounds. There is also a need to provide formulations or pharmaceutical compositions comprising compounds of Formula 1 that have stable performance and can be prepared by established drug preparation techniques.

[0005] The very low aqueous solubility of the compound of Formula 1, for example, makes it extremely challenging to develop an oral formulation that results in sufficient bioavailability and utilization and effective plasma levels, and particularly rapid enough systemic absorption after oral administration to allow for effective non-invasive treatment of acute symptoms and conditions associated with BK.

[0006] It is an object of the present invention to satisfy any one or more of these needs. Another object is to overcome the deficiencies, gaps, and limitations of the prior art in the oral delivery of BK B2 receptor antagonists, such as compounds having a chemical structure according to Formula 1. Other objects will become apparent from the following description, examples, and patent claims. Summary of the Invention

[0007] In one aspect, the present invention relates to a liquid pharmaceutical composition for oral administration comprising a bradykinin (BK) B2 receptor antagonist having a chemical structure according to Formula 1, or a stereoisomer, salt, or solvate thereof:

[0008]

[0009] wherein R is deuterium or hydrogen; and the composition is further characterized in that the BK B2 receptor antagonist is dissolved in a liquid carrier comprising propylene glycol monocaprylate, polyoxyethylene castor oil, and propylene glycol. Specifically, the BK B2 receptor antagonist may be (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide, the propylene glycol monocaprylate may be Type II propylene glycol monocaprylate, and the polyoxyethylene castor oil may be polyoxyethylene 40 hydrogenated castor oil.

[0010] In another aspect, the present invention relates to a capsule, such as a soft capsule or soft gel, containing such a liquid pharmaceutical composition.

[0011] In another aspect, the present invention relates to the use of such capsules or liquid pharmaceutical compositions according to the present invention, in particular for use in therapy. Generally, the liquid pharmaceutical compositions or capsules described herein can be used to treat diseases or conditions responsive to bradykinin B2 receptor modulation. For example, they are useful in treating edema, such as hereditary angioedema. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 shows the relationship between the concentration of each API in monkey plasma and time on both linear and semi-logarithmic scales. Figure 1A and 1B Shown are the API concentrations in plasma of three monkeys following administration of the API in an aqueous vehicle containing methylcellulose (1 wt %). Figure 1C and 1D Shown are the API concentrations in plasma of 3 monkeys after administration of the API in a formulation according to the invention.

[0013] Figure 2 Shown are the means and standard deviations of the concentrations of API in the plasma of human subjects administered 1, 2, 4.5, 12 and 22 mg doses formulated according to the present invention.

[0014] Figure 3 Shown are the means and standard deviations of the API concentrations in plasma of human subjects administered a 22 mg dose in the fasting state (open circles) or after a high calorie / high fat (HCHF) breakfast (closed circles). DETAILED DESCRIPTION

[0015] The present invention provides a liquid pharmaceutical composition for oral administration, comprising a bradykinin (BK) B2 receptor antagonist having a chemical structure according to Formula 1, or a salt or solvate thereof:

[0016]

[0017] wherein R is deuterium or hydrogen; the composition is further characterized in that the BK B2 receptor antagonist is dissolved in a liquid carrier comprising propylene glycol monocaprylate, polyoxyethylene castor oil and propylene glycol.

[0018] The inventors have surprisingly discovered that this composition significantly enhances the oral delivery of BK B2 receptor antagonists because it allows for incorporation in a dissolved form that is not susceptible to rapid crystallization upon dilution with an aqueous medium and results in unexpectedly rapid absorption of the compound into the subject's bloodstream, which is particularly noteworthy given its physical properties, particularly its large molecular size, the absence of readily ionizable chemical groups, and its low water solubility.

[0019] In Formula 1, R can be selected from hydrogen and deuterium. In a preferred embodiment or a group of embodiments, R is deuterium:

[0020]

[0021] 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 alternatively as N-[(1S)-1-[3-chloro-5-fluoro-2-[[[2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl]-8-quinolinyl]oxy]methyl]phenyl]ethyl-1-d]-2-(difluoroethoxy)-acetamide, is a particularly advantageous example of a compound according to formula 1 of the present invention. It should be understood that this preference also applies in combination with all other optional features or preferences disclosed in the following description, whether specifically mentioned or not.

[0022] Alternatively, in Formula 1, R may be hydrogen:

[0023]

[0024] It may also be referred to as (S)-N-(1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide.

[0025] The compound of Formula 1 can exist in a substantially non-ionized form, or in an ionized form, i.e., in the form of a salt. In addition, it can optionally be in the form of a solvate. For example, the compound can be a hydrate, such as (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide monohydrate.

[0026] In a preferred embodiment, the state of the compound in the liquid composition is substantially non-ionized, for example, completely non-ionized. In addition, the compound of Formula 1 present in the liquid pharmaceutical composition described herein is generally not in the form of a salt or solvate, or any solid form. However, for the avoidance of doubt, when the compound is combined with other components to form the composition of the present invention, the compound can be in solid form, or in the form of a salt and / or solvate. For example, a hydrate of the compound, such as a monohydrate, is optionally in a crystalline form and can be used to prepare a liquid pharmaceutical composition. However, it is believed that once converted into a completely dissolved state, that is, the compound is present in the form of a liquid pharmaceutical composition, the compound is no longer in the form of a crystalline material or a hydrate.

[0027] In a preferred embodiment, 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 present invention. Alternatively, the composition may contain one or more other active ingredients.

[0028] In the present invention, pharmaceutical composition is understood to be a composition that is technically suitable for use as a drug to a subject (e.g., a human patient). Its formation, formulation, and processing conform to general pharmaceutical standards, as may be defined in the official pharmacopoeias or guidelines issued by regulatory agencies such as the FDA and EMA. In a preferred embodiment, the composition is suitable for oral administration, which means, for example, that the excipient used, including its grade and dosage, is safe and acceptable for oral use, particularly for oral administration to a human subject.

[0029] As used herein, the term "liquid" refers to the liquid state of a material under normal conditions, i.e., at room temperature and standard atmospheric pressure. An example of a more precisely defined set of normal conditions is the normal temperature and pressure (NTP) defined by the National Institute of Standards and Technology (NIST), which uses a temperature of 20°C (293.15K, 68°F) and an absolute pressure of 1 atm (14.696 psi, 101.325 kPa).

[0030] The liquid carrier used in the present invention is a pharmaceutically acceptable liquid excipient or excipient mixture containing at least one active pharmaceutical ingredient, such as a compound according to Formula 1. Formally speaking, the API is not considered part of the liquid carrier even if it is dissolved therein. Nor are any suspended solid excipients considered part of the carrier. Therefore, the weight of the liquid carrier does not include the weight of the API contained therein and the weight of the materials suspended therein (if any). The liquid carrier may also be referred to as a carrier.

[0031] For the avoidance of doubt, it is not necessary to provide a liquid carrier containing all of its components separately and then combine it with at least one API to form the liquid pharmaceutical composition of the present invention. Rather, it is also possible to dissolve at least one API in one liquid component of the liquid carrier and subsequently add the remaining components, or to combine all of the components of the liquid pharmaceutical composition simultaneously. Furthermore, for the avoidance of doubt, it is not required that all of the components of the liquid carrier themselves (individually) be liquids under normal conditions, as long as they form a liquid phase (i.e., dissolve) when combined.

[0032] As used herein, the term "pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or state government, or by an equivalent agency in a country outside the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and particularly humans. In particular, pharmaceutically acceptable means that the pharmaceutically active compounds 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 excessive toxicity, irritation, allergic response, or the like, commensurate with a reasonable benefit / risk ratio.

[0033] As previously described, the liquid pharmaceutical composition comprises a BK B2 receptor antagonist dissolved in a liquid carrier as defined herein. In this context, the term "dissolved" refers to a dissolved state, i.e., the compound is present in a completely dissolved state. This means that the compound is molecularly dispersed in the liquid carrier, rather than being contained in the form of suspended particles within the liquid carrier. Therefore, the BK B2 receptor antagonist, which may also be referred to herein as an active ingredient, API, or drug substance, is present in a non-solid form in the liquid pharmaceutical composition.

[0034] The expression "propylene glycol monocaprylate" as used herein is to be understood in a pharmaceutical context rather than in a strict chemical nomenclature. In the pharmaceutical context, propylene glycol monocaprylate refers to an excipient that complies with the generally accepted concise monographs on propylene glycol monocaprylate. For example, this includes the monographs "Propylene glycol monocaprylate Type I" and "Propylene glycol monocaprylate Type II" of the United States Pharmacopoeia and National Formulary (USP / NF), for example in its edition USP-NF 2021, and / or relevant monographs of other pharmacopoeias, such as the European Pharmacopoeia.

[0035] Generally speaking, the material or excipient referred to as propylene glycol monocaprylate contains a mixture of several chemical substances. It can be described as a mixture of propylene glycol monoesters and diesters of fatty acids, primarily consisting of caprylic acid. The monoester and diester content may vary depending on the type of propylene glycol monocaprylate: according to the USP-NF, excipients representing Type I propylene glycol monocaprylate contain 55.0% to 80.0% monoester and 20 to 45% diester, while materials representing Type II propylene glycol monocaprylate contain at least 90.0% monoester and no more than 10.0% diester. With respect to the fatty acid residues in Type I or Type II, at least 90.0% of the fatty acid esters are caprylate (or octanoate), and no more than 3.0% (of each of these residues individually) are caprate (decanoate), laurate (or dodecanoate), and myristate (or myristate), respectively. Type I and Type II propylene glycol monocaprylates contain no more than 1.0% palmitate (or hexadecanoate). Non-limiting examples of currently available commercial grades of Type I propylene glycol monocaprylate include PGMC (Gattefossé) and PG-8-70NF (Abitec), commercially available versions of Type II propylene glycol monocaprylate include PG-8NF (Abitec) and 90(Gattefossé).

[0036] In a preferred embodiment, the liquid pharmaceutical composition of the present invention comprises a liquid carrier comprising propylene glycol monocaprylate that is Type II propylene glycol monocaprylate, such as Type II propylene glycol monocaprylate (USP / NF). In another preferred embodiment, Type II propylene glycol monocaprylate is the only type of propylene glycol monocaprylate contained in the liquid carrier. Alternatively, a mixture of propylene glycol monocaprylates may also be used.

[0037] In another embodiment, propylene glycol monocaprylate is selected to exhibit a hydrophilic-lipophilic balance (HLB value) in the range of about 5 to 6.

[0038] Similarly, in the context of the present invention, the term "polyoxyethylene castor oil" should be interpreted as referring to an excipient or material that meets the generally accepted pharmaceutical standards for any polyoxyethylene castor oil as specified in the corresponding monograph of the relevant pharmacopoeia (such as the pharmacopoeia mentioned above). Therefore, the term refers to pharmaceutical grade polyoxyethylene castor oil derivatives. Polyoxyethylene castor oil is a mixture of different chemical substances and is generally prepared by reacting ethylene oxide with castor oil or hydrogenated castor oil.

[0039] One type of polyoxyethylene castor oil is the material that conforms to the monograph "Polyoxyl 40 Hydrogenated Castor Oil" (USP, current edition), which essentially corresponds to the monograph "Polyoxyl glyceryl hydroxystearate" (European Pharmacopoeia, current edition), also known as PEG-40 Hydrogenated Castor Oil. Polyoxyl 40 Hydrogenated Castor Oil is typically a white to yellow semisolid paste at room temperature that liquefies above about 30°C. The main component of this excipient is glyceryl polyethylene glycol hydroxystearate, which also contains fatty acid glyceryl polyethylene glycol esters, polyethylene glycol, and polyoxyethyl glyceryl ethers. According to the European Pharmacopoeia, it primarily contains the reaction product of trihydroxystearyl glycerol ethoxylated with 7 to 60 molecules of ethylene oxide (nominal), a small amount of polyethylene glycol hydroxystearate, and the corresponding free glycol. Examples of commercially available grades of polyoxyl 40 hydrogenated castor oil include RH40 (BASF), previously known as RH40 is sold, as well as Croduret (Croda).

[0040] Another type of polyoxyl castor oil conforms to the monograph "Polyoxyl 35 Castor Oil" (USP, current edition), which corresponds to the monograph "Polyoxyl glyceryl ricinoleate" (European Pharmacopoeia, current edition), also known as PEG-35 castor oil. It contains primarily ricinoleic acid glyceryl ethoxylated with 30-50 molecules of ethylene oxide (nominal value), along with smaller amounts of polyoxyl ricinoleate and the corresponding free glycol. It results from the reaction of castor oil with ethylene oxide. Examples of commercially available grades of polyoxyl 35 castor oil include EL (BASF), which was previously EL sales.

[0041] In a preferred embodiment, the polyoxyethylene castor oil contained in the liquid carrier of the liquid pharmaceutical composition of the present invention is polyoxyethylene 40 hydrogenated castor oil, such as polyoxyethylene 40 hydrogenated castor oil (USP / NF). In another preferred embodiment, polyoxyethylene 40 hydrogenated castor oil is the only type of polyoxyethylene castor oil contained in the liquid carrier. Alternatively, another type of polyoxyethylene castor oil may also be present.

[0042] According to another preferred embodiment, the polyoxyethylene castor oil contained in the liquid carrier is polyoxyethylene 40 hydrogenated castor oil, the propylene glycol monocaprylate is Type II propylene glycol monocaprylate, and no other types of polyoxyethylene castor oil or propylene glycol monocaprylate are present. In other words, the liquid pharmaceutical composition may comprise a compound of Formula 1 dissolved in a liquid carrier comprising polyoxyethylene 40 hydrogenated castor oil, Type II propylene glycol monocaprylate, and propylene glycol as defined herein, without comprising other propylene glycol monocaprylates or polyoxyethylene castor oil.

[0043] According to another preferred embodiment, liquid carrier, and therefore the pharmaceutical composition of the present invention, can further include water.Water can be intentionally added as a part for liquid carrier ingredients, or may be due to the water content of the raw material or intermediate product for the preparation of liquid pharmaceutical composition or its further processing (such as being encapsulated in gelatin soft capsules), water becomes a part for liquid carrier. For example, if the compound of Formula 1 for the preparation of liquid pharmaceutical composition is provided in the form of crystalline hydrate, the crystal water of hydrate will become a part for liquid carrier. In addition, if liquid pharmaceutical composition is combined with the wet gelatin material for the preparation of gelatin soft capsules, some water of gelatin material can migrate to the liquid pharmaceutical composition and form a part for liquid carrier.

[0044] In another 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 carrier comprising polyoxyethylene 40 hydrogenated castor oil, type II propylene glycol monocaprylate, propylene glycol and water.

[0045] Typically, the liquid carrier may optionally include one or more other excipients. In one embodiment, it may include other solvents and / or other surfactants. In this case, other solvents refer to solvents other than propylene glycol, which 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 pharmaceutically acceptable water-miscible organic solvent, such as glycerol or ethanol. In one embodiment, the liquid carrier comprises ethanol.

[0046] In one embodiment, other surfactants, such as other pharmaceutically acceptable surfactants, may be used. In this context, "other surfactants" refers to surfactants other than propylene glycol monocaprylate and polyoxyethylene castor oil (either of which may be considered surfactants, even though these excipients may also use other functional labels). In a preferred embodiment, the liquid carrier may contain caprylocaproyl polyoxy-8 glyceride as the other surfactant, also known as caprylocaproyl macrogol-8 glyceride. An example of a commercially available excipient representing caprylocaproyl polyoxy-8 glyceride is the product ALF (Gattefossé).

[0047] In addition, one or more other excipients may be included in the liquid pharmaceutical composition, optionally as part of a liquid carrier (e.g., where one or more liquid excipients are included), and may be selected from stabilizers, antioxidants, preservatives, pH regulators, flavorings, colorants, and viscosity modifiers. Mixtures or combinations of two or more of the above-mentioned other excipients may also be used.

[0048] In one embodiment, the liquid pharmaceutical composition is suitable for multiple administration, such as a liquid present in a multi-dose container, and is further characterized in that it contains at least one flavoring agent and does not contain any preservatives. In fact, one advantage of the present invention is that, even when present in the form of a multi-dose liquid formulation, no preservatives need to be added. In this context, the term "preservative" should be understood to refer to an excipient whose sole or primary function is to provide safety and permanent antimicrobial function. Examples of preservatives include antimicrobial preservatives, such as benzoic acid and its salts, sorbic acid and its salts, methylparaben, propylparaben, and the like.

[0049] As described above, the inventors have surprisingly discovered that the liquid pharmaceutical composition described herein exhibits remarkable performance both in vitro and in vivo. It significantly enhances the oral delivery of the BKB2 receptor antagonist by allowing it to be contained in a fully dissolved (non-solid) form, without being susceptible to rapid crystallization upon dilution with an aqueous medium (e.g., water, acidified water, or simulated gastric fluid). Without wishing to be bound by theory, the inventors believe that the liquid pharmaceutical composition described herein exhibits or represents a so-called self-emulsifying or self-microemulsifying drug delivery system (SEDDS or SMEDDS, respectively). These systems can be described as isotropic liquid mixtures that, when diluted with an aqueous medium, typically do not even require mechanical stirring, and they spontaneously form oil-in-water (o / w) emulsions or microemulsions. In the present invention, SEDDS should be understood as a broader term that includes SMEDDS. SMEDDS are characterized by a small average droplet size of <800 nm, sometimes even in the 100 nm range. In a preferred embodiment, the liquid pharmaceutical composition is in the form of SMEDDS. This is generally preferred and should be understood to also apply to all other preferred combinations described herein.

[0050] Although SEDDS have been suggested as a potential formulation strategy for poorly soluble drugs, few drug products have actually been successfully developed and approved as SEDDS. Many SEDDS formulations fail because they fail to achieve sufficient drug loading (such that a single dose of drug cannot be accommodated in, for example, one or two gelatin softgel capsules) or because the active ingredient contained in them cannot remain soluble in the (micro)emulsion formed after dilution with water or gastric fluid. In fact, even when the active ingredient has sufficient solubility in the liquid carrier, a common problem is the rapid precipitation of the active ingredient, which is one of the reasons why SEDDS formulation strategies are often unsuccessful in practice. In addition, drugs dissolved in SEDDS often exhibit poor stability and rapid chemical degradation, resulting in a short shelf life, which is unattractive or even unfeasible from a market and supply chain perspective.

[0051] Furthermore, in the case of the BK B2 receptor antagonist according to Formula 1, the inventors discovered that many liquid carrier compositions expected to have self-emulsifying or self-microemulsifying properties are incompatible with the active ingredient, as they exhibit rapid drug precipitation or liquid phase separation when containing the compound of Formula 1. However, the inventors unexpectedly discovered a specific excipient combination, namely propylene glycol monocaprylate, polyoxyethylene castor oil, and propylene glycol, which, as shown in the examples, did not cause compound precipitation or liquid phase separation within several hours after dilution with acidified water at room temperature immediately after preparation. More importantly and particularly noteworthy, the inventors discovered that this liquid carrier provided excellent stability and allowed for sufficient drug loading. As also shown in the examples, no BK B2 receptor antagonist precipitation or liquid phase separation was observed after storage at high temperature (e.g., 40°C) for 6 months.

[0052] In addition to the preferred embodiments of other ingredients of the liquid carrier of the present invention or liquid pharmaceutical composition as described above, the inventors have also found that some content of the corresponding excipient in the liquid carrier seems particularly advantageous. In particular, the inventors have found that the relatively high content of propylene glycol monocaprylate is advantageous, such as about 40 % by weight or higher relative to the weight of the liquid carrier, which is significantly higher than the content in some known SMEDDS preparations of other drugs. For example, in another preferred embodiment, based on the weight of the liquid carrier, the content of propylene glycol monocaprylate in the liquid carrier is about 40-60 % by weight, such as about 45-55 % by weight, such as about 48-52 % by weight. When using more than one type of propylene glycol monocaprylate, the content of about 40-60 % by weight should be understood to refer to the total content of all propylene glycol monocaprylates in the liquid carrier. In a related embodiment, the liquid carrier comprises about 40-60 % by weight, such as about 45-55 % by weight, such as about 48-52 % by weight of Type II propylene glycol monocaprylate.

[0053] In another preferred embodiment, based on the weight of the liquid carrier, the content of polyoxyethylene castor oil in the liquid composition is about 30-50 weight %, for example, about 35-45 weight %, for example, about 38-42 weight %. Similarly, when more than one type of polyoxyethylene castor oil is present in the carrier, this range refers to the total content of the polyoxyethylene castor oil in the liquid carrier. In addition, if all 30-50 weight % of the polyoxyethylene castor oil is polyoxyethylene 40 hydrogenated castor oil, this is also a preferred embodiment. In one embodiment, the liquid composition comprises about 40-60 weight %, for example, about 45-55 weight %, for example, about 48-52 weight % of propylene glycol monocaprylate (preferably Type II) and 30-50 weight %, for example, about 35-45 weight %, for example, about 38-42 weight % of polyoxyethylene castor oil (preferably polyoxyethylene 40 hydrogenated castor oil).

[0054] Regarding the content of propylene glycol in the liquid carrier, it has been found that a relatively low content is advantageous, for example, about 15 wt% or less, preferably about 2.5-15 wt% based on the total weight of the liquid carrier is advantageous. In addition, it is preferred that the propylene glycol content is in the range of about 2.5-11 wt%, such as about 3.5-11 wt%, such as about 4.5-10 wt%, based on the total weight of the liquid carrier.

[0055] In a preferred embodiment, the liquid carrier comprises the aforementioned amounts of propylene glycol monocaprylate (preferably Type II), polyoxyethylene castor oil (preferably polyoxyethylene 40 hydrogenated castor oil), propylene glycol, and optionally the remainder is water. For example, the liquid carrier may comprise approximately 40-60% by weight of propylene glycol monocaprylate (preferably Type II), 30-50% by weight of polyoxyethylene castor oil (preferably polyoxyethylene 40 hydrogenated castor oil), and 2.5-15% by weight of propylene glycol.

[0056] Liquid pharmaceutical composition as herein described can also include water.The content of water can be up to 5 wt %.For example, water can be a component of liquid carrier, and for example liquid carrier can include water of content up to 5 wt %.In the present invention, it should be noted that, when liquid pharmaceutical composition is used for capsule, for example, in the gelatin soft capsule described further below, the content of some components including propylene glycol and / or water may change over time during storage, in part because some encapsulated propylene glycol and / or water may migrate into the capsule shell.For example, liquid pharmaceutical composition can be prepared as, for example, a propylene glycol content of about 10 wt %, but after being encapsulated in gelatin soft capsule and stored for several months or years, due to migration, the content of propylene glycol in the liquid filler of gelatin soft capsule may be lower, for example, about 8 wt % or 9 wt %.Vice versa, capsule wall is prepared as, for example, including propylene glycol, and the migration amount of propylene glycol after storage may increase the content of propylene glycol in capsule wall.

[0057] In another preferred embodiment of the liquid pharmaceutical composition, based on the combined weight of propylene glycol monocaprylate, polyoxyethylene castor oil, and propylene glycol in the liquid carrier, the amount of propylene glycol monocaprylate (preferably Type II) is about 50% by weight, the amount of polyoxyethylene castor oil (preferably polyoxyethylene 40 hydrogenated castor oil) is about 40% by weight, and the amount of propylene glycol is about 10% by weight. As used herein, the term "about" indicates that slight variations are possible, such as to compensate for minor differences between different grades of excipients, keeping in mind that some of them are mixtures of different chemical substances (e.g., in the case of propylene glycol monocaprylate or polyoxyethylene castor oil) or may contain varying amounts of certain impurities, such as water (e.g., in the case of propylene glycol). For example, relative deviations of up to 10% (e.g., within 50 ± 5% by weight), such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, or 9%, are generally considered to be compositions having substantially the same function.

[0058] According to another preferred embodiment of the liquid pharmaceutical composition, the liquid carrier consists essentially of propylene glycol monocaprylate, polyoxyethylene castor oil, propylene glycol, and no more than about 10% by weight of other liquid ingredients, based on the combined weight of all liquid ingredients in the liquid carrier. As described above, the liquid carrier may contain other liquid ingredients, such as, for example, an optional liquid surfactant, water, or an organic solvent, such as ethanol, and according to this particular embodiment, the total content of these ingredients is limited to about 10% by weight relative to the weight of the liquid carrier.

[0059] Regarding the amount of the BK B2 receptor antagonist of Formula 1 in the liquid pharmaceutical composition, this should be selected based on the type of subject to be treated (e.g., pediatric human patients, adult human patients), the therapeutic indication, and the form of the composition (i.e., whether it is a liquid for oral administration, a gelatin soft capsule, etc.). Preferably, the relative amount of the compound is in the range of about 1 mg to about 160 mg per gram of liquid composition. In the present invention, when expressed by weight, the amount of the BK B2 receptor antagonist of Formula 1 should be interpreted as referring 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, also referred to as the dose. For example, if a hydrated form of the compound is used to prepare the liquid pharmaceutical composition, the weight of the active ingredient does not include the water of hydration (as described above, the water of hydration is part of the liquid carrier). In a specific embodiment, the amount of the compound of Formula 1 is at least about 5 mg per gram of liquid composition, corresponding to about 0.5% by weight. In another specific embodiment, the amount is at least about 10 mg per gram of liquid composition, corresponding to about 1% by weight.

[0060] In another preferred embodiment, the liquid pharmaceutical composition contains a BκB2 receptor antagonist in an amount ranging from about 5 mg to about 100 mg, for example, from about 20 mg to about 70 mg, per gram of liquid pharmaceutical composition. In a preferred embodiment, the amount ranges from about 5 mg / g to about 65 mg / g, for example, from about 5 mg / g to about 50 mg / g. A particular advantage of the liquid pharmaceutical compositions of the present invention is that the liquid carriers identified and described herein by the inventors are capable of accommodating such relatively large amounts of the active ingredient. In further preferred embodiments, the amount ranges from about 10 mg / g to about 65 mg / g, for example, from about 20 mg / g to about 65 mg / g. In specific embodiments, the amount is about 20, 25, 30, 40, or 50 mg / g, corresponding to about 2, 2.5, 3, 4, or 5% by weight, respectively.

[0061] With respect to all the amounts discussed above for the BK B2 receptor antagonist, it will be understood that these preferences also particularly apply to the BK B2 receptor antagonist according to Formula 1 wherein R is deuterium.

[0062] Another preferred liquid pharmaceutical composition may consist essentially of:

[0063] (a) based on the total weight of the liquid pharmaceutical composition, about 0.5 to 6.5 weight %, for example 5 weight % of a compound according to Formula 1 or a stereoisomer, salt or solvate thereof, wherein R is deuterium; (b) based on the total weight of the liquid pharmaceutical composition, about 93.5 to 99.5 weight % of a liquid carrier; wherein the liquid carrier is essentially composed of: (i) about 50 parts by weight of propylene glycol monocaprylate, for example Type II propylene glycol monocaprylate; (ii) about 40 parts by weight of polyoxyethylene castor oil, for example 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 is one or more other excipients dissolved or dispersed in the liquid carrier. In another specific embodiment, the liquid pharmaceutical composition comprises about 5 weight % of the compound of Formula 1 and does not contain other excipients dissolved or dispersed in the liquid carrier.

[0064] The liquid pharmaceutical composition of the present invention can be used as a medicament formulated and provided as a liquid for oral administration, or can be further processed, for example, by including it in a solid unit dosage form (such as a capsule). When provided as a liquid dosage form, it can be packed into a suitable primary packaging unit or container, for example, containing a single dose or multiple doses of the active ingredient. As used herein, a primary packaging unit is a packaging device or combination of packaging devices that holds a pharmaceutical formulation (e.g., in direct contact with the pharmaceutical formulation). An example of a combination of packaging devices that together form a primary packaging unit is a bottle with a screw-on cap.

[0065] The single dose can be contained in, for example, a glass or plastic bottle, vial or ampoule. Alternatively, sachets or strip packs can also be used. As primary packaging units for containing multiple doses of the liquid composition, glass or plastic bottles are suitable. In order to facilitate the removal of measured amounts of the composition, a dosing or dispensing aid can be used, which can be part of the primary packaging unit or independent. 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 another embodiment, the dosing or dispensing aid is a metering pump. Optionally, the metering pump is directly connectable to the primary packaging device; for example, the primary packaging container can be a glass or plastic bottle equipped with a lid that can be unscrewed and replaced by a screw-on metering pump.

[0066] In another preferred embodiment, the liquid pharmaceutical composition is provided in a single-dose unit in the form of a capsule filled with the liquid pharmaceutical composition. Therefore, another aspect of the present invention is a capsule for oral administration comprising the liquid pharmaceutical composition as described above. Optionally, the capsule can be a hard capsule, in particular a gelatin hard capsule.

[0067] In a preferred embodiment, the capsule is a soft capsule, also known as a gelatin soft capsule or soft gel. More specifically, the soft capsule preferably comprises a capsule wall comprising gelatin, water, and at least one plasticizer. In the present invention, the capsule wall refers to the shell of the capsule that surrounds or encapsulates the liquid fill material, which in the present case is a liquid pharmaceutical composition disclosed herein. Similarly, in the case of gelatin soft capsules, a "plasticizer" is a pharmaceutical excipient used to make the capsule wall more elastic and flexible and minimize its brittleness and risk of rupture. To a certain extent, water also has a plasticizing effect on the gelatin capsule wall material; however, in the present invention, the term "plasticizer" should be understood to exclude water.

[0068] The main component of the gelatin softgel capsule wall is usually gelatin itself. Gelatin is a general term for a mixture of purified protein fractions obtained by partial acid hydrolysis (type A gelatin) or partial alkaline hydrolysis (type B gelatin) of animal collagen obtained from bovine and porcine bones, cow hides (rawhide), pig hides, and fish skins. Gelatin can also be a mixture of these two types. The protein fraction is composed almost entirely of amino acids linked together by amide bonds to form linear polymers, with molecular weights ranging from 20,000 to 200,000.

[0069] The mechanical strength of a gelatin material can be characterized by the Bloom number, also known as the Bloom value, which is determined by a Bloom test and represents the weight (in grams) required for a standardized plunger to press 4 mm below the surface of a gelatin gel sample without breaking. Typically, a gelatin gel sample is prepared as a 6.67% gelatin solution and cured at approximately 10°C for several hours. Generally, gelatin materials with a higher average molecular weight have a higher Bloom number, and vice versa. If a mixture of different types of gelatin is used, the Bloom value should be interpreted as relating to the mixture in the present invention.

[0070] The inventor has found that, in principle, the gelatin of two types (i.e. Type A and Type B) can be used to prepare soft capsules according to the present invention. In addition, the gelatin of different gel strengths can also be used, as long as they are suitably plasticized. In one embodiment, the Bloom value of the gelatin of capsule wall is in the scope of about 100 to about 250. In another preferred embodiment, the Bloom value (or Bloom number) of gelatin is in the scope of about 130 to about 220, and in another embodiment, the Bloom value is respectively about 150 ± 20 or about 200 ± 20. In other specific embodiments, gelatin is respectively the Type A gelatin with a Bloom value of about 195, or the Type B gelatin with a Bloom value of about 150.

[0071] About plasticizer, can for example be selected from glycerine, propylene glycol, polyethylene glycol, sorbitol, sorbitan, maltitol, corn syrup, citric acid ester (such as triethyl citrate) or these any combination.In a preferred embodiment, the gelatin soft capsule comprises capsule wall, and described capsule wall comprises gelatin, water and at least one plasticizer, and described plasticizer is selected from propylene glycol, glycerine, sorbitol, sorbitan, sorbitol-based plasticizer mixture or their any combination.

[0072] If sorbitol is used, it is preferred to also use sorbitol. For example, a mixture of sorbitol and sorbitan (currently marketed by ISP as Sorbitol Such mixtures of sorbitol with one or more other excipients for adjusting the properties of the plasticizer, also known as sorbitol-based plasticizer mixtures, generally also have the advantage that they contain sorbitol in a substantially non-crystalline form. In this case, the expression "non-crystalline sorbitol" is also intended to include sorbitol-based plasticizer mixtures, for example sorbitol-anhydrosorbitol combinations, such as Sorbitol Wherein sorbitol is made non-crystalline by adding sorbitol and / or other additives. Another preferred sorbitol-based plasticizer mixture is sold by Roquette 85 / 70 / 00, which is described as liquid, partially dehydrated sorbitol. More accurately, the product is a mixture of sorbitol (20-40%), 1,4-anhydro-D-glucitol (20-30%), and hydrogenated corn syrup (20-25%). This product is also described in the USP monograph "Sorbitol, Anhydrous Sorbitol Solutions" (formerly "Anhydrous Liquid Sorbitol") or the European Pharmacopoeia monograph "Partially Dehydrated Liquid Sorbitol."

[0073] In another preferred embodiment, the capsule wall is plasticized at least with glycerol. Also preferred are capsule wall compositions comprising glycerol and at least one other plasticizer. In a preferred embodiment, the second plasticizer is selected from amorphous sorbitol (or sorbitol-anhydrosorbitol or partially dehydrated liquid sorbitol) and propylene glycol.

[0074] Prior to encapsulation and capsule drying, the plasticizer content in the capsule wall composition, or the total plasticizer content if more than one plasticizer is used (i.e., the content in the wet gel composition used for the encapsulation process), should preferably be selected to be in the range of about 15-35% by weight relative to the total weight of the wet capsule wall composition. Again, in the present invention, the plasticizer content does not include water. In another preferred embodiment, the plasticizer content in the capsule wall composition is in the range of about 15-30% by weight, particularly about 18-28% by weight.

[0075] The plasticizer content can also be expressed as the ratio of the (total) gelatin content to the (total) plasticizer content in the capsule wall. The advantage of using this ratio is that it is relatively independent of the water content; after preparation, this ratio does not differ significantly between the wet gelatin material and the dry gelatin softgel capsule wall, although it may change over time due to possible migration of plasticizer from the capsule wall into the capsule fill, or vice versa. In some preferred embodiments, this ratio is selected from the range of about 1.0 to 3.0, or about 1.3 to 2.8, or about 1.3 to 2.5, respectively.

[0076] If the soft capsule wall contains a second plasticizer in addition to glycerol, which is preferably propylene glycol or sorbitol (including a sorbitol-anhydrosorbitol mixture or partially dehydrated liquid sorbitol), the weight ratio of glycerol to the second plasticizer can be selected as generally known in the art. For example, the ratio can be in the range of about 0.1-10 or about 0.2-5. In a preferred embodiment, the ratio is in the range of about 0.5-2.

[0077] The inventors have found that when preferences regarding the composition of the gelatin soft capsule wall are adhered to, liquid compositions can be successfully encapsulated and capsule brittleness and thin skin formation can be largely avoided.

[0078] The content of water in the soft capsule wall, or the content of water to water in the wet gel material that is initially used to prepare capsule can be selected in the typical range required for processability.For example, the initial water content of wet gelatin material is about 20-60 % by weight.In certain embodiments, water content is selected in the scope of about 25-45 % by weight.It should be noted that water content should be calculated as, for example, the water that includes other excipients, for example glycerol (for example, if using 85% glycerol) or sorbitol-anhydrosorbitol solution is introduced.The weight ratio of (total) gelatin and (total) water can also be according to the selection commonly used in the soft gel manufacture, i.e., in the scope of about 0.5-2.

[0079] Optionally, the capsule wall can include one or more other ingredients, such as one or more excipients selected from coloring agents, pigments, sunscreens, flavorings and lubricants. Typically, these excipients can be added with relatively low content so that they can perform their respective functions. For example, titanium dioxide can be used as a sunscreen, typically at a content of 3 weight %. Similarly, if colored capsules are desired, coloring agents such as one or more iron oxides can be added, typically also at low levels, such as at approximately 5 weight %. The capsule wall can also include a small amount of processing aids, such as lubricants. The example of a possible suitable lubricant is a neutral fatty oil (liquid triglyceride). Optionally, a surfactant such as lecithin can be added to the oil.

[0080] According to another aspect, the present invention relates to the use of the liquid pharmaceutical composition described herein for preparing capsules, in particular soft capsules as described above. In terms of methods, the present invention provides a method for preparing soft capsules using the liquid pharmaceutical composition described herein. The method is characterized by the following steps:

[0081] (a) providing a liquid composition as described herein;

[0082] (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;

[0083] (c) encapsulating the liquid composition in a wet capsule material to form a capsule;

[0084] (d) drying the capsules formed in step (c); and optionally

[0085] (e) Storage of dry capsules.

[0086] Regarding process parameters, the method can be performed using standard equipment and settings. Regarding the liquid pharmaceutical composition provided in step (a), it is emphasized that the same optional features and preferences described in this aspect of the invention all apply. For example, this is also one of the preferred embodiments of the method for preparing soft capsules, wherein in step (a), a liquid composition consisting essentially of:

[0087] - about 0.5 to 6.5 wt%, for example 5 wt%, of a compound according to Formula 1, or a stereoisomer, salt or solvate thereof, wherein R is deuterium, based on the total weight of the liquid composition;

[0088] - About 93.5 to 99.5 wt. % of a liquid carrier, based on the total weight of the liquid composition, the liquid carrier consisting essentially of:

[0089] (i) about 50 parts by weight of propylene glycol monocaprylate, such as Type II propylene glycol monocaprylate;

[0090] (ii) about 40 parts by weight of castor oil, such as 40 parts by weight of hydrogenated castor oil;

[0091] (iii) about 5 to 10 parts by weight propylene glycol; and optionally

[0092] (iv) up to about 5 parts by weight water;

[0093] and optionally

[0094] - The remainder is one or more other excipients dissolved or dispersed in the liquid carrier.

[0095] In another preferred embodiment, the present invention provides a soft capsule obtainable by a method characterized by steps (a) to (e). Considering that soft capsules may undergo changes during their shelf life, for example due to migration of plasticizers from the capsule wall into the filling liquid or migration of components from the liquid filling into the capsule wall, thereby changing the quantitative composition of the liquid filling and the capsule wall over time, it seems entirely appropriate to define soft capsules according to their manufacturing process and their starting (or intermediate) materials.

[0096] According to another aspect of the present invention, a liquid pharmaceutical composition or a capsule containing such a composition can be used for the acute or chronic treatment of a subject suffering from any disease or condition responsive to bradykinin B2 receptor modulation. Examples of diseases or conditions responsive to BK B2 receptor modulation include diseases or conditions such as skin diseases; eye diseases; ear diseases; oral, throat and respiratory diseases; gastrointestinal diseases; liver, gallbladder and pancreatic diseases; urinary tract and kidney diseases; male and female reproductive organ diseases; hormonal system diseases; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic diseases; central nervous system diseases; brain diseases; musculoskeletal system diseases; allergic diseases; pain; infectious diseases; inflammatory diseases; injuries; immunological diseases; cancer; 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 responsive to bradykinin B2 receptor modulation, wherein the method comprises administering a composition or capsule as described above. Similarly, the present invention provides use of a composition or capsule described herein in the preparation of a medicament for treating any disease or condition responsive to bradykinin B2 receptor modulation, such as the acute or chronic treatment of a disease or condition responsive to BK B2 receptor modulation.

[0097] The expressions "treatment" and the like used herein should be interpreted as including any type of prophylactic or therapeutic treatment. Therefore, it includes the prevention, management or treatment of the disease or its recurrence or any symptom associated with such disease or condition. In addition, in the present invention, "acute" includes any non-chronic administration regimen, such as an effective single dose single administration of the composition or capsule described herein, and occasional or regular administration regimens within a relatively short period of time (e.g., up to four weeks or up to two weeks). In a preferred embodiment, the liquid composition or capsule provided by the invention is used for the acute treatment of a disease or condition that responds to bradykinin B2 receptor modulation.

[0098] The following diseases or conditions may be considered responsive, or at least potentially responsive, to bradykinin B2 receptor modulation:

[0099] Skin diseases, including but not limited to skin aging, weathering of the skin including pressure sores, bedsores, irritated, sensitive and unsightly skin, erythema, rash, skin edema, psoriasis, eczema, Netherton syndrome, lichen, bacterial, viral, fungal and parasitic skin infections (including boils, abscesses, cellulitis, erysipelas, folliculitis and impetigo), lice, scabies and herpes simplex, acne, rash, dermatitis (including atopic dermatitis, allergic contact dermatitis, neurodermatitis), radiation damage, sunburn, pruritus, scabies, cholestatic pruritus Itch, chronic pruritus, chronic eczema, prurigo nodularis, urticaria, chronic spontaneous urticaria, chronic induced urticaria, cold-induced urticaria, cold pyrin-associated periodic syndrome (CAPS), familial cold autoinflammatory syndrome (FCAS), FXII-associated cold autoinflammatory syndrome (FACA), psoriasis, fungal infections, tissue ulcers, epidermolysis bullosa, wounds (including abnormal wound healing, burns, frostbite, skin inflammation, and venom-induced edema), alopecia, dandruff, corns, warts, and digital abscesses.

[0100] Eye diseases, including but not limited to inflammatory diseases, such as scleritis, conjunctivitis, conjunctival edema, iritis, iridocyclitis, uveitis, chorioretinitis, and diseases, such as retinochoroidal circulation disorders, bacterial eye infections, nonspecific conjunctivitis and eye irritation, retinopathy of prematurity, proliferative vitreoretinopathy, macular degeneration (including age-related macular degeneration, including wet and dry forms), corneal diseases, including corneal transplant rejection, corneal injury, corneal scarring, corneal ulcers, corneal opacities, keratoconus, glaucoma (preferably open-angle glaucoma), myopia, glaucoma, elevated intraocular pressure, ocular vascular damage, angiogenesis, ocular fibrosis (e.g., anterior subcapsular fibrosis, posterior subcapsular opacity, posterior capsular opacity, corneal opacity after laser surgery, subconjunctival scarring after glaucoma surgery), proliferative vitreoretinopathy (PVR), bacterial eye infections, including styes and eyelash loss.

[0101] Ear diseases, including but not limited to Meniere's disease, otitis media, external auditory canal inflammation and acute hearing loss.

[0102] Diseases of the oral cavity, throat and respiratory system, including but not limited to inflammation of the oral mucosa and gums, including aphthous ulcers and stomatitis, periodontitis, epiglottitis, pharyngitis, laryngotracheitis, tonsillitis, common cold, sore throat, rhinitis (including seasonal allergic rhinitis or perennial allergic rhinitis), epistaxis, sinusitis of any type, etiology or pathogenesis or sinusitis selected from purulent or non-purulent sinusitis, acute and chronic sinusitis and ethmoid sinusitis, frontal sinusitis, maxillary sinusitis or sphenoid sinusitis, expectoration, pneumoconiosis of any type or origin, including These include, for example, aluminum pneumoconiosis, antalgic lung disease, asbestosis, lithotripsy, siderosis, silicosis, fume contusion, and in particular byssinosis, bronchitis, cough, tracheitis, congestion, pneumonia, eosinophilic pulmonary infiltrates, chronic eosinophilic pneumonia, idiopathic pulmonary fibrosis and other fibrotic lung diseases, therapy-related fibrotic lung diseases (e.g., related to radiation, methotrexate, chemotherapy, amiodarone or nitrofurantoin), sarcoidosis, acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), , coronavirus disease 2019 (COVID-19 infection), bronchoconstriction, asthma of any type, etiology or pathogenesis, or asthma selected from the following: allergic asthma, non-allergic asthma, allergic and non-allergic asthma, extrinsic asthma caused by environmental factors, intrinsic asthma caused by pathophysiological disorders, bronchial asthma, IgE-mediated asthma, idiopathic asthma and idiopathic asthma of unknown or unexplained cause, true asthma, emphysematous asthma, exercise-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infection, early asthma, infantile wheezing syndrome, bronchial hyperresponsiveness, chronic obstructive pulmonary disease (COPD), COPD characterized by irreversible, progressive airway obstruction, acute respiratory distress syndrome (ARDS) and other drug-induced exacerbation of airway hyperresponsiveness, dyspnea, hyperoxic alveolar damage, emphysema, pleurisy, tuberculosis, exposure to high altitude (i.e. acute mountain sickness, preferably high altitude pulmonary edema (HAPE)), intractable cough, bronchial hyporesponsiveness.

[0103] Gastrointestinal disorders, including but not limited to esophagitis, gastritis, irritable gastric disease, gastric and duodenal ulcers, intestinal obstruction, irritable colon disease, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), enteritis, hypertensive gastrointestinal and colonic disease, colitis, peritonitis, appendicitis, proctitis, gastrointestinal necrosis due to portal hypertension, collateral circulation or congestion, post-gastrectomy dumping syndrome, digestive discomfort, diarrhea, hemorrhoids, helminthiasis, abdominal cramps and cramps in any part of the gastrointestinal system.

[0104] Liver, gallbladder, and pancreatic diseases, including but not limited to hepatitis, cirrhosis, liver fibrosis (e.g., due to viral (HBV / HCV) infection, toxins (alcohol), fatty liver, cholestasis, hypoxia), portal hypertension, hepatorenal syndrome, hepatic edema, non-malignant ascites, cholangitis, cholecystitis, acute and chronic pancreatitis, and biliary colic.

[0105] Urinary tract and kidney diseases, including but not limited to urinary tract infections (e.g., acute and chronic cystitis, interstitial cystitis, irritable bladder, overactive bladder, incontinence (including but not limited to stress, urge, and reflex incontinence)), benign prostatic hyperplasia, chronic kidney disease, urethritis, inflammatory kidney disease (including glomerulonephritis, renal glomerular disease, interstitial nephritis, pyelonephritis), polyuria, proteinuria, natriuresis, calciuria, water balance disorders, electrolyte balance disorders, acid-base balance disorders and renal colic, renal fibrosis, chronic allograft renal insufficiency, contrast-induced nephropathy.

[0106] Diseases of the male and female reproductive organs, including but not limited to changes in sperm motility, male infertility, orchitis, prostatitis, benign prostatic hyperplasia, mastitis, inflammatory pelvic disease, vaginal infections and pain, adnexitis, vaginitis, soft tissue ulcers, syphilis, gonorrhea, and ovarian hyperstimulation syndrome.

[0107] Hormonal system diseases, including but not limited to menstrual disorders and pain, menopausal disorders, vomiting, premature uterine contractions, premature birth, endometriosis, endometritis, fibroids, and preeclampsia.

[0108] Metabolic diseases include, but are not limited to, diabetes mellitus, including non-insulin-dependent diabetes mellitus, diabetic retinopathy, diabetic macular edema, diabetic nephropathy and diabetic neuropathy, insulin resistance and diabetic ulcers, protein and purine metabolism diseases (such as gout and lipid metabolism disorders), and hypoglycemia.

[0109] Cardiovascular disease, including but not limited to vascular permeability, vasodilation, congestion, peripheral circulatory disorders, cardiac volume overload, arterial circulatory disorders (including aortic aneurysm, abdominal aortic aneurysm, cerebral aortic aneurysm), hypertension, dialysis hypotension and sepsis-related hypotension, restenosis after percutaneous transluminal coronary angioplasty, atherosclerosis (including rupture of atherosclerotic plaques), hemangioma, angiofibroma, venous disease (such as thrombosis, varicose veins, phlebitis, thrombophlebitis, venous thrombosis), heart disease, congestive heart failure, coronary artery disease, cancer syndrome, angina pectoris, arrhythmias, inflammatory heart diseases, including endocarditis, pericarditis, and constrictive pericarditis, myocarditis, myocardial infarction, post-myocardial infarction syndrome, left ventricular dilatation, post-ischemia-reperfusion injury, shock and collapse, including septic, anaphylactic, post-traumatic, and hemodynamic shock, amniotic fluid embolism, systemic inflammatory response syndrome (SIRS), including SIRS caused by cardiopulmonary bypass during surgery, sepsis during cardiopulmonary bypass, and internal and external complications (including but not limited to adverse hemodynamic effects of heparin reversal with protamine sulfate).

[0110] Hematologic disorders, including but not limited to coagulation, disseminated intravascular coagulopathy, bleeding, bleeding diathesis, hypercholesterolemia and hyperlipidemia, hypovolemic shock, and paroxysmal nocturnal hemoglobinuria.

[0111] Lymphatic disorders, including but not limited to splenomegaly, lymphangitis, lymphadenitis, and adenoid hyperplasia.

[0112] Central nervous system diseases, including but not limited to inflammatory diseases of the central nervous system, including encephalitis, meningitis, encephalomyelitis, meningoencephalitis, hydrocephalus, amyotrophic lateral sclerosis, spinal cord trauma, spinal cord edema, demyelinating diseases of the nervous system, multiple sclerosis, acute and chronic neurodegenerative diseases, including aging, Alzheimer's disease and Parkinson's disease, multiple sclerosis, myalgic encephalomyelitis / chronic fatigue syndrome, neuritis and peripheral neuropathies, depression, anorexia, anxiety disorders and schizophrenia, sleep disorders.

[0113] Brain diseases, including but not limited to nootropics or cognitive enhancement, cerebral amyloid angiopathy, stroke, head and brain trauma, traumatic brain injury, brain tumor, brain thermal injury, cerebral ischemia, cerebral hemorrhage, post-traumatic and post-ischemic cerebral edema, general cerebral edema, acute mountain sickness and preferably high altitude cerebral edema (HACE), cytotoxic cerebral edema, vasogenic cerebral edema, post-operative cerebral edema, cerebral edema associated with metabolic diseases, increased permeability of the blood-brain barrier or blood-brain tumor barrier.

[0114] Diseases of the musculoskeletal system, including but not limited to inflammatory musculoskeletal diseases, arthropathy, osteoarthropathy, osteoarthritis, chondroporosis after joint trauma or relatively long-term immobilization of a joint after injury to the meniscus or patella or ligament tear, rheumatoid arthritis of any type, etiology or pathogenesis, including acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis and infectious arthritis, Lyme disease, proliferative arthritis, spondyloarthritis, septic arthritis, psoriatic arthritis, chronic polyarthritis, rheumatism, Sjögren's syndrome, systemic lupus erythematosus, low back pain, spondylitis, spondyloarthritis, ankylosing spondylitis, osteomyelitis, sprains, tenosynovitis, bone resorption caused by inflammation, fractures, etc., osteoporosis, musculoskeletal pain and sclerosis, intervertebral disc syndrome.

[0115] Allergic diseases include but are not limited to general allergic reactions, food allergies, anaphylactic shock, allergic contact hypersensitivity, allergic skin reactions, allergic asthma, vernal conjunctivitis and seasonal or perennial allergic rhinitis.

[0116] Pain, including but not limited to centrally and peripherally mediated pain, vascular pain, visceral pain, inflammation-mediated pain, neuralgia, referred pain, nociceptive pain, reflex pain, psychosomatic pain, acute pain, such as acute pain caused by acute injury to bones, muscles, tissues, soft tissues, organs, trauma or surgery, opioid-induced hyperalgesia, pain following insect bites, post-stroke pain syndrome, postoperative pain, pain associated with progressive diseases, chronic pain, such as caused by neuropathic pain (including but not limited to complex regional pain syndrome, causalgia, morbussudeck, reflex sympathetic dystrophy, diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, cancer-related pain, pain associated with rheumatoid arthritis, osteoarthritis, tenosynovitis, gout, menstrual pain and angina, fibromyalgia, eye pain, back pain, headache, cluster headache, tension headache, migraine, inflammatory pain that may be associated with acute inflammation or chronic inflammation). Inflammatory pain includes, but is not limited to, neuropathic pain, ischemic pain, pain caused by arthritis, muscle pain caused by acute or chronic inflammation, neuralgia caused by chronic or acute inflammation, and hyperalgesia. Also included are chemotherapy-induced peripheral neuropathy, hyperalgesia, opioid-induced hyperalgesia, and fever. Furthermore, the compounds of the present invention can be used as analgesics during general anesthesia and monitored anesthesia.

[0117] Infectious diseases include, but are not limited to, diseases mediated by bacterial, viral, fungal, parasitic, protozoal, prion, or mycobacterial infections. In particular, the present invention can be used to treat bacterial infections caused by Streptococcus, Escherichia coli, Salmonella, Staphylococcus, Klebsiella, Moraxella, Haemophilus, and Yersinia. Examples of bacterial infections within the scope of the present invention include, but are not limited to, plague, septicemia, epidemic typhus, food poisoning, tetanus, scarlet fever, pertussis, diphtheria, and the like. Examples of viral infections within the scope of the present invention include, but are not limited to, diseases such as chickenpox and herpes zoster, AIDS, influenza, dengue fever, SARS-CoV-2 disease (new coronavirus infection), Hantavirus disease, smallpox, and childhood diseases such as measles, rubella, mumps, acute myelitis, and the like. The present invention can be used to treat protozoan and parasitic infections caused by Schistosoma mansoni, Dermatofagoides farinae, Trypanosoma cruzi, Leishmania, and malaria induced by Plasmodium. Examples of prion infections within the scope of the present invention include, but are not limited to, diseases such as bovine spongiform encephalopathy (BSE), Creutzfeldt-Jakob disease and kuru, dengue fever, hemorrhagic fever, and the like.

[0118] Inflammatory diseases include, but are not limited to, acute phase reactions, local and systemic inflammation, and inflammation caused by other diseases regardless of their type, etiology, or pathogenesis, as well as inflammation caused by the inflammatory diseases defined in this application.

[0119] Injury: As used herein, the term "injury" includes, but is not limited to, multiple trauma, head and brain trauma, hypertensive tissue injury, lung injury, external, internal and surgical trauma, burns, including but not limited to thermal injury, electrical injury, chemical burns, cryogenic injury, ionizing radiation and sun burns.

[0120] Immunological diseases, including but not limited to hyperesthesia, autoimmune diseases, transplant rejection in transplantation, transplant toxicity, granulomatous inflammation, tissue remodeling, myasthenia gravis, immunosuppression, immune complex disease, excessive and insufficient antibody production, vasculitis, delayed graft function, lupus, and the like.

[0121] Cancers, including but not limited to solid tumor cancers, including breast cancer, lung cancer (non-small cell lung cancer and small cell lung cancer), prostate cancer, oral and pharyngeal cancer (lip, tongue, mouth, pharynx), esophageal cancer, stomach cancer, small intestine cancer, large intestine cancer, colon cancer, rectal cancer, gallbladder cancer and bile duct cancer, pancreatic cancer, laryngeal cancer, lung cancer, bone cancer, osteosarcoma, connective tissue cancer, skin cancer (including Kaposi's syndrome), melanoma and skin metastases, epidermoid carcinoma, basal cell carcinoma, cervical cancer, endometrial cancer, ovarian cancer, testicular cancer, bladder cancer, ureter and urethra cancer, kidney cancer, eye cancer, brain and central nervous system cancer, pseudotumors of the brain, sarcomas, sarcomas, thyroid cancer and other endocrine gland cancers (including but not limited to carcinoid tumors), Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, hematological malignancies, including leukemias, lymphomas, including lymphocytic, granulocytic and monocytic lymphomas, tumor invasion, metastasis, ascites, tumor growth and angiogenesis.

[0122] Genetic diseases, including but not limited to hereditary angioedema and angioneurotic edema, chondrocalcinosis, Huntington's disease, and visco-obstructive neuropathy.

[0123] Edema as used herein includes, but is not limited to, generalized edema, including any form and / or type of angioedema (AE), as well as edema caused by inflammation, edema caused by Factor XII deficiency, other medications, such as drug-induced angioedema, including but not limited to angioedema caused by angiotensin-converting enzyme inhibitors, drug-induced angioedema, thrombolytic therapy-induced angioedema, infection, burns, injury, 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 conditions, in particular but not limited to those specified in this application, pressure-induced intestinal edema (significant swelling).

[0124] Capillary leak syndromes, including but not limited to systemic capillary leak syndrome in sepsis, burns, allergy, drug / toxin-induced illness, organ transplantation, and IL-2 cytokine therapy.

[0125] In a preferred embodiment, the liquid pharmaceutical composition or capsule is used for the acute or chronic treatment of angioedema (AE), including hereditary angioedema (HAE), acquired angioedema (AAE), bradykinin-mediated non-histaminergic idiopathic angioedema, allergic angioedema or drug-induced angioedema or bradykinin-mediated angioedema of unknown cause. Hereditary angioedema (HAE) is a disease that manifests in recurrent attacks of severe swelling. The swelling usually affects the arms, legs, face, intestines, and airways. If the intestines are affected, abdominal pain and vomiting may occur. Swelling of the airways may cause bronchial obstruction and difficulty breathing. Acute attacks usually last for several days, and the frequency of attacks in HAE patients is about every two weeks. HAE can be of any type, including type I HAE, type II HAE, or type III HAE, preferably type I HAE or type II HAE.

[0126] According to another preferred embodiment, the liquid pharmaceutical composition or capsule is used to treat the prodrome or acute attack of angioedema in a subject suffering from, for example, hereditary angioedema. As previously described, the liquid pharmaceutical composition according to the present invention exhibits a significant release rate of the bradykinin B2 receptor antagonist of Formula 1, despite the compound's large molecular size and poor solubility in physiological fluids. Because the active ingredient is delivered so rapidly to the patient's bloodstream, the composition is particularly advantageous when used to treat acute attacks or severe swelling episodes requiring a rapid drug action.

[0127] In another embodiment, the liquid pharmaceutical composition or capsule is used in a treatment comprising oral administration of the corresponding composition or capsule once or twice daily, preferably over a period of at least two weeks. Although the composition provides rapid drug release almost like an injection, oral administration is much more convenient than injection, which makes this regimen particularly advantageous.

[0128] Other aspects, embodiments, optional features and preferences of the invention will be apparent from the examples and claims.

[0129] Other definitions

[0130] For the sake of clarity, some other definitions of terms used in the specification and claims are given. Unless the context requires a different meaning, these definitions should be used to determine the meaning of the corresponding expressions.

[0131] The terms "a" and "an" do not exclude plural referents, i.e., the singular forms "a" and "the" are to be understood as including plural referents unless the context clearly indicates or requires otherwise. In other words, any singular feature or limitation of the present disclosure shall include the corresponding plural feature or limitation, and vice versa, unless otherwise expressly provided or clearly implied by the context. Therefore, unless otherwise defined, the terms "a", "the", and "at least one" or "one or more" have the same meaning. For example, "an ingredient" includes a mixture of ingredients, etc.

[0132] The term "about" or "approximately" is intended to compensate for the variability allowed in the pharmaceutical industry and inherent in pharmaceutical products, such as differences in content due to manufacturing variations and / or degradation of the product over time. The term allows for any variation that, in pharmaceutical practice, would allow the evaluated product to be considered bioequivalent in subjects to the stated strength of the product.

[0133] The terms "active agent," "therapeutic agent," 'active pharmaceutical ingredient (API)', 'active ingredient', 'drug', 'bioactive agent' are used synonymously to refer to a compound or combination of compounds that has pharmaceutical activity against an undesirable disease.

[0134] The term "composition" refers to any type of composition which may comprise the specified ingredient, optionally together with any other ingredients.

[0135] The term "compound" refers to a chemical substance, which is a material composed of molecules with essentially the same chemical structure and properties. For small molecule compounds, the molecules are generally identical in terms of their atomic composition and structural configuration. For macromolecular or polymeric compounds, the molecules of a compound are highly similar, but not all molecules are necessarily identical.

[0136] The term "including" and similar expressions should be interpreted in an open and inclusive sense as meaning "including but not limited to".

[0137] The terms "substantially," "about," "approximately," "substantially," and the like, with respect to an attribute or value, include the precise attribute or value, as well as any attribute or value that is generally considered to fall within the normal range or variation that is acceptable in the relevant art. For example, "substantially anhydrous" means that the composition does not contain intentionally added water, but does not exclude the presence of residual moisture.

[0138] The term "consisting essentially of" refers to a composition or dosage form to which no ingredients other than the listed ingredients have been added. However, very small amounts of other materials, such as impurities inherent to the materials, may be present. Furthermore, when reference is made, for example, to "consisting essentially of A, B, C, and optionally D," it means that no other components other than A, B, C, and D have been added to the composition or dosage form, where D is an optional (i.e., non-mandatory) component of the composition or dosage form.

[0139] The term "substantially free" refers to a composition containing less than a functional amount of the respective ingredient, typically less than 1 wt%, preferably less than 0.1 wt% or even 0.01 wt%, and including zero wt% of the respective ingredient.

[0140] Example

[0141] Example 1: Liquid Compositions AH

[0142] Several liquid compositions based on propylene glycol monocaprylate, polyoxyethylene castor oil, and propylene glycol (see Tables 1A and 1B) were prepared by weighing and mixing the corresponding liquid ingredients and then mixing the liquid mixture with the active ingredient in a specified amount so that the active ingredient (API) was dissolved in the liquid mixture. As for the API, the compound (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide monohydrate was used. The amount or content of the API was specified as monohydrate. Therefore, the liquid composition contained the specified amount of API monohydrate. As for propylene glycol monocaprylate, a commercial grade of Type II propylene glycol monocaprylate ( 90). As for polyoxyethylene castor oil, commercial grade polyoxyethylene 40 hydrogenated castor oil ( RH40).

[0143] Table 1A

[0144]

[0145] Table 1B

[0146]

[0147] As a result, it was observed that these compositions AH contained the active ingredient in completely dissolved form, resulting in clear, milky or turbid solutions without any solid residues that could indicate undissolved API.

[0148] Example 2: Dilution of liquid compositions AH in aqueous media

[0149] Compositions A and H were tested for their ability to maintain the API in a dissolved state when diluted with an aqueous medium. To this end, a simple surrogate for gastric fluid, water acidified to pH 3 with hydrochloric acid solution, was added to samples of the compositions and diluted 10-fold, i.e., to 10-fold by weight. The diluted samples were stored at room temperature for 3 hours.

[0150] Upon dilution, all compositions A to H formed physically stable emulsions or microemulsions, as observed by the naked eye, without any separation of the two liquid phases. 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 fully dissolved form even when diluted with a significant excess of water.

[0151] Furthermore, the diluted sample obtained from composition E was stored for several more days at room temperature and was very stable: even after 5 days, the sample was still in the form of a milky white microemulsion with almost no precipitation, indicating that this composition is particularly advantageous and enables the active ingredient to be solubilized, thus enabling rapid absorption and rapid action.

[0152] Example 3: Performance Robustness of Liquid Compositions

[0153] It is well known that many initially promising SMEDDS formulations of various drugs ultimately fail during commercial product development due to inconsistent performance or poor performance robustness. Therefore, a series of performance robustness tests were performed on a representative liquid composition according to the present invention, namely Composition E of Example 1.

[0154] Dilute in FaSSIF-V2

[0155] After the liquid composition is therapeutically administered (e.g., via softgels), it is likely that the composition is initially diluted by gastrointestinal fluid. To simulate this, samples of the composition are mixed with FaSSIF-V2 (Fasting State Simulated Intestinal Fluid V2), for example to obtain dilution ratios of 1 / 10 and 1 / 100, respectively. FaSSIF-V2 is a widely recognized biologically relevant substitute for gastrointestinal fluid. For comparison, another series of samples are diluted with water using the same dilution ratio. The diluted samples, all of which are opaque microemulsions (also known as nanoemulsions due to their submicron droplet size), are maintained at 37°C. The emulsion droplet size is measured using a Malvern Zetasizer Nano ZS immediately after dilution and 6 hours later.

[0156] All diluted samples were found to exhibit submicron emulsions with z-average particle sizes ranging from approximately 50 to 200 nm. Minor differences were observed, with samples diluted at a 1 / 10 ratio exhibiting slightly larger droplet sizes initially and after 6 hours of dilution compared to samples diluted at a 1 / 100 ratio (e.g., 197 nm vs. 119 nm, respectively, for FaSSIF-V2). Furthermore, storage for more than 6 hours resulted in an increase in droplet size for all dilutions. While this effect was slightly more pronounced with FaSSIF-V2 compared to water as the diluent, it was surprising to find that even after 6 hours at 37°C, FaSSIF-V2 dilutions exhibited submicron emulsions, demonstrating the remarkable robustness of the formulation in terms of performance, particularly considering that FaSSIF-V2 not only contains a buffer system but also the surfactants sodium taurocholate and lecithin. The z-average droplet values measured in this series of experiments are summarized in Table 2 below.

[0157] Table 2

[0158]

[0159] Dispersion in different media

[0160] Three to five drops of Composition E were added to 10 mL of the following media at 37°C: water, 0.01N hydrochloric acid, pH 6.8 phosphate buffer, simulated gastric fluid (SGF), fasted simulated intestinal fluid (FaSSIF), and fed simulated intestinal fluid (FeSSIF). The samples were visually inspected for signs of drug precipitation immediately after mixing, after inversion, and after storage for 2 to 6 hours. No signs of precipitation were observed.

[0161] Temperature Cycle

[0162] Approximately 5 g of aliquots of liquid composition E were placed in vials and stored refrigerated (2°C to 8°C) for approximately 24 hours. The vials were then visually inspected, particularly for any drug precipitation or phase separation. Subsequently, the vials were stored at elevated temperature (30°C to 40°C) for approximately 24 hours and inspected again. This cycle between these two temperature conditions was performed for six days. At no time did visual inspection reveal any changes in the formulation, particularly no drug precipitation or phase separation.

[0163] Example 4: Liquid composition IN

[0164] As described in Example 1, another series of liquid compositions based on propylene glycol monocaprylate, polyoxyethylene castor oil, propylene glycol and other liquid excipients were prepared (see Table 2). Similarly, compound (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide monohydrate was used as the API, and the same grades of propylene glycol monocaprylate and polyoxyethylene castor oil were used. For the excipients, commercial grade Caprylocaproyl Polyoxyl-8 Glyceride, also known as Caprylocaproyl Macrogol-8 Glyceride.

[0165] Table 3

[0166]

[0167] Upon visual inspection, it was found that these compositions IN also contained the active ingredient in completely dissolved form, resulting in clear, milky or turbid solutions without any solid residues that could indicate undissolved API. This example also shows that in addition to propylene glycol monocaprylate, polyoxyethylene castor oil and propylene glycol, other excipients such as other organic solvents (represented by ethanol) and other surfactants (represented by caprylocaproyl polyoxy-8 glyceride) can be added.

[0168] Example 5: Stability of liquid compositions

[0169] Aliquots of liquid composition E were filled into glass bottles and stored under different temperature and humidity conditions, including 25°C / 60% relative humidity. Samples were taken and tested at various time intervals up to 36 months, including drug content (assay) and chemical impurities, as well as physical appearance, water content, and emulsification behavior.

[0170] As a result, no significant chemical or physical changes were found. Even after 36 months, the composition was a transparent, light brown emulsified solution, but there was no precipitation or phase separation after dilution with water. Notably, the drug content after 36 months was almost the same as the initial value (94.1% vs. 94.5% declared on the label), and the total impurity content increased only slightly (from 1.65% to 2.00%). These results not only ensure a commercially attractive product shelf life, but are also very surprising considering the fact that liquid SMEDDS formulations containing fully dissolved, amorphous active ingredients in a mixture of highly functional excipients are generally more susceptible to drug degradation than traditional pharmaceutical formulations.

[0171] Example 6: Dilution of liquid composition IN in aqueous medium

[0172] Similar to Example 2, Compositions IN were tested for their ability to maintain the API in solution upon dilution with aqueous media. Again, all compositions spontaneously formed physically stable emulsions or microemulsions without phase separation. Consequently, these compositions were also found to exhibit SEDDS or SMEDDS. The diluted samples showed no signs of drug precipitation.

[0173] Comparative Example

[0174] Several other excipients and excipient combinations commonly used in preparing SEDDS or SMEDDS formulations of other active ingredients were tested with the bradykinin B2 receptor antagonist according to Formula 1, but without success. For example, (S)-N-(1-deuterated-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide monohydrate was added to the following mixture:

[0175] (a) Glyceryl Caprylate / Caprate ( MCM) and Caprylocaproyl Polyoxyl-8 Glyceryl The weight ratio is 50:50;

[0176] (b) Glyceryl Caprylate / Caprate ( MCM), Caprylocaproyl Polyoxyl-8 Glyceryl and ethanol in a weight ratio of 50:40:10;

[0177] (c) Type II propylene glycol monocaprylate ( 90) and Caprylocaproyl Polyoxyl-8 Glyceryl A weight ratio of 20:80; and

[0178] (d) Type II propylene glycol monocaprylate at different weight ratios ( 90) Caprylocaproyl Polyoxyl-8 Glyceryl and propylene glycol,

[0179] Not only does it lead to rapid precipitation of the active ingredient upon dilution with acidified water, but it also causes liquid-liquid phase separation, i.e., the physical breakdown of the emulsion or microemulsion system and its conversion into two separate, non-dispersed liquid phases.

[0180] In addition, the same compound of formula 1 was dissolved in other commonly used excipient mixtures:

[0181] (e) Type II propylene glycol monocaprylate ( 90) and polyoxyethylene 40 hydrogenated castor oil ( RH40), weight ratio is 40:60;

[0182] (f) Caprylocaproyl Polyoxyl-8 Glyceryl and Glyceryl Caprylate / Caprate ( MCM), in a weight ratio of 95:5; and

[0183] (g) Polyoxyethylene 40 hydrogenated castor oil ( RH40), Type II propylene glycol monocaprylate ( 90) and ethanol, weight ratio is 70:20:10,

[0184] Although no liquid-liquid phase separation occurred, the active ingredient precipitated rapidly.

[0185] Example 7: Preparation of gelatin soft capsules

[0186] Composition E of Example 1 was used as the liquid fill material to make soft gelatin capsules using standard encapsulation equipment and techniques.

[0187] Two prototype capsule compositions (Prototypes E-1 and E-2) were prepared using the wet gelatin capsule shell compositions shown in Table 4. Commercial grades of sorbitol syrup or partially dehydrated liquid sorbitol were used. 85 / 70 / 00(Roquette).

[0188] Table 4

[0189]

[0190] Visual inspection by experienced technicians revealed that the soft capsules of both capsule formulations had excellent appearance. The surface was smooth, and the seal area was well-formed. No gelatin stretching or specific defects were observed, indicating that the capsule shell composition was suitable for encapsulating Liquid Composition E.

[0191] The capsules were stored for three months at different temperature and humidity conditions (25°C / 60% relative humidity; 30°C / 65% relative humidity; 40°C / 75% relative humidity). The hardness of the capsules was tested and monitored during this period. Only minor changes were observed, which did not affect the overall performance of the capsules.

[0192] Example 8: Single-dose pharmacokinetic study in monkeys

[0193] The pharmacokinetic properties of a liquid composition according to the present invention after a single oral administration to cynomolgus monkeys were studied and compared with the pharmacokinetic properties 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 in a liquid carrier substantially identical to Composition E was 5 mg / mL. The comparative formulation comprised the same API at a concentration of 2 mg / mL, formulated as an aqueous drug suspension further containing methylcellulose (1 wt %).

[0194] Materials and methods:

[0195] The study was conducted in 3 animals in two phases with at least a 5-day washout between phases as follows:

[0196] Phase 1:

[0197]

[0198] Once the first phase was completed, the monkeys were reallocated in the same order in the second phase.

[0199] Phase 2:

[0200]

[0201] Nominal dose levels were used for pharmacokinetic assessments.

[0202] Nonhuman primates are a particularly suitable species for this study because in vitro pharmacology testing showed that the API has similarly high antagonist potency at human and monkey B2 receptors, but low antagonist potency at dog, rat, and mouse B2 receptors.

[0203] Blood samples for pharmacokinetic assessments were collected from all animals during two pre-dose periods and at 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post-dose. All blood samples were collected at intervals that were strictly less than 20% of the nominal sampling time, taking into account the theoretical sampling frequency for pharmacokinetic assessments.

[0204] Using Kinetica TM 4.4.1 (Thermo Fisher Scientific) Pharmacokinetic parameters were determined from individual plasma concentrations using non-compartmental analysis. Plasma concentrations below the LLOQ (i.e., plasma concentrations of the test item < 1.2 ng / mL) were taken as zero. TM 4.4.1 Plot concentration versus time on linear and semi-logarithmic scales ( Figures 1A-1D ).

[0205] Pharmacokinetic parameters, ratios, SD, and CV (or Δ%) are reported to three significant figures for values less than 100 and to the nearest integer for all values greater than or equal to 100, except for time values and n.

[0206] Main pharmacokinetic parameters

[0207] Determine the maximum plasma concentration (Cmax), Cmax sampling time (Tmax), and the last plasma concentration sampling time >LLOQ (Tlast) based on the assay results. Calculate the area under the plasma concentration-time curve (AUClast) from the time of dosing to the last quantifiable concentration using the linear upper / log lower trapezoidal rule. At least three consecutive quantifiable concentrations must be available for AUC calculation.

[0208] Secondary pharmacokinetic parameters

[0209] by Kinetica TM 4.4.1 Calculate the linear regression coefficient (R) for the end of the log-linear phase of the concentration-time curve, where at least three data points are provided in addition to Cmax. The regression coefficient (R) is expressed as an absolute value, and the period is determined as the span of time points used in the linear regression to calculate the end of the log-linear phase. When the absolute value of R is greater than or equal to 0.8 and the period is twice the half-life, the elimination rate constant value (k) from the linear regression can be used for further calculations. Therefore, after a single dose, t1 / 2 is calculated using the equation ln2 / k.

[0210] The extrapolated AUC percentage from Tlast to infinity was calculated by Kinetica™ 4.4.1 using the following equation:

[0211] AUCextra(%)=(Clast / k)×100 / AUCinf

[0212] When this extrapolation is less than 20% and the above two conditions (R and period) are met, the following parameters are given after a single dose:

[0213] AUCinf: The estimated area under the curve from the time of dosing to infinity, calculated using the following equation:

[0214] AUCinf=AUClast+AUCextra

[0215] Dose-effect and comparison of analytes or preparations

[0216] Dose proportionality: This effect was assessed graphically and by calculation of single-dose normalized Cmax and AUClast.

[0217] Comparison of formulations: This effect was assessed by calculating the individual Cmax and AUClast ratios between the comparator and test formulations.

[0218] result

[0219] The pharmacokinetic parameters are listed in Table 5. In addition, Figure 1 shows the relationship between API plasma concentration and time in linear and semi-logarithmic scales. Figure 1A and 1BShown are API plasma concentrations following administration of the API in an aqueous vehicle containing methylcellulose (1 wt%). Figure 1C and 1D The plasma concentrations of API after administration of the API in the composition according to the invention are shown.

[0220] Table 5: Mean pharmacokinetic parameters

[0221]

[0222]

[0223] All animals were exposed to the API.

[0224] Calculated parameters varied widely between animals: 67% of values had a CV or Δ% higher than 30%.

[0225] API plasma concentrations were quantified up to 24 hours after dosing, with the exception of one animal treated with the test formulation for which no compound was detected at 24 hours (Tables 6 and 7). Maximum API plasma concentrations were observed 0.5 to 3 hours after dosing with the control formulation and 1 to 4 hours after dosing with the test formulation (Tables 6 and 7).

[0226] Table 6: Mean pharmacokinetic parameters after administration to monkeys

[0227]

[0228] For the comparator formulation, half-life values could not be reported, and therefore no conclusions regarding clearance could be drawn. For the test formulation, half-life values were relatively similar regardless of dose: values ranged from 2.72 to 4.57 hours (Table 7).

[0229] Table 7: Pharmacokinetic parameters after administration to monkeys

[0230]

[0231] Table 7 (continued)

[0232]

[0233] Formulation Comparison: The systemic exposure of the API for the test formulation was significantly higher than that for the comparator formulation. The mean Cmax and AUClast ratios (ratios of the comparator formulation to the test formulation) were 0.679 and 0.430, respectively (Table 8). In other words, the oral bioavailability of the test formulation was more than double that of the comparator formulation.

[0234] Table 8: Cmax and AUClast Ratios of Comparative / Test Formulations

[0235]

[0236] Mortality. No mortality occurred during the study period.

[0237] Example 9: Oral bioavailability in humans

[0238] The oral bioavailability, pharmacokinetic properties and safety of the liquid composition according to the present invention after a single oral administration were evaluated. This composition is the same as composition E of Example 1.

[0239] Methods: In a first-in-human study in healthy volunteers, the composition was administered as an oral solution in single ascending doses in a double-blind, placebo-controlled manner. Table 9 shows the experimental design of the study.

[0240] Table 9: Experimental design

[0241]

[0242]

[0243] Safety was assessed through physical examination, vital signs, adverse events, safety labs, and electrocardiograms (ECGs) up to 72 hours after dosing. Plasma pharmacokinetic (PK) parameters were assessed up to 72 hours after dosing.

[0244] Pharmacokinetic results:

[0245] Under fasting conditions, the composition was rapidly absorbed and reached peak plasma levels in all subjects within 30 to 60 minutes after administration. Systemic exposure was proportional to dose, with a mean t1 / 2 between doses of 3.5 to 5.6 hours. For all doses, API plasma levels reached therapeutically effective threshold concentrations within 15 minutes (estimated EC50 2.4 ng / mL and EC85 13.8 ng / mL) and were maintained for approximately 12 hours at the 12 and 22 mg doses ( Figure 2 ).

[0246] Administration of a 22 mg dose of HCHF with breakfast resulted in a 32% lower Cmax, a 49% higher AUClast, and a median tmax delay of approximately 2 hours. Plasma levels still reached the expected therapeutically effective level within 15 minutes and were maintained for more than 12 hours ( Figure 3 The observed pharmacokinetic parameters are summarized in Table 10.

[0247] Table 10: Pharmacokinetic parameters in human subjects. max 、C 0.25h 、C 12h , AUC last 、T 1 / 2 、V ZFor Tmax and CL / F, values are mean values with standard deviations shown in parentheses. For Tmax, values are medians with ranges shown in parentheses. * indicates fasting state. § indicates post-HCHF.

[0248]

[0249] These results not only confirm the significant features of the composition already indicated by the results of Example 8, demonstrating that therapeutically relevant plasma levels are reliably achieved, but they also demonstrate that, despite its very low water solubility, the active ingredient is remarkably and rapidly absorbed into the systemic blood circulation. With such pharmacokinetic properties, the composition is clearly useful for the oral treatment of patients suffering from diseases or conditions responsive to bradykinin B2 receptor modulation, even for the treatment of acute attacks or symptoms requiring immediate and effective intervention.

Claims

1. A liquid pharmaceutical composition for oral administration comprising a bradykinin (BK) B2 receptor antagonist having a chemical structure according to Formula 1, or a salt or solvate thereof: (Formula 1) wherein R is deuterium or hydrogen; The BK B2 receptor antagonist or its salt or solvate is dissolved in a liquid carrier comprising propylene glycol monocaprylate, polyoxyethylene castor oil and propylene glycol.

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

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

4. The liquid pharmaceutical composition according to claim 1 or 2, wherein the content of polyoxyethylene castor oil in the liquid carrier is 30-50 wt% based on the weight of the liquid carrier.

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

6. The liquid pharmaceutical composition according to claim 1 or 2, wherein based on the weight of the liquid carrier, the content of propylene glycol monocaprylate in the liquid carrier is 40-60 weight %, the content of polyoxyethylene castor oil in the liquid carrier is 30-50 weight %, and the content of propylene glycol is 2.5-15 weight %.

7. The liquid pharmaceutical composition according to claim 1 or 2, wherein propylene glycol monocaprylate is Type II propylene glycol monocaprylate (USP / NF).

8. The liquid pharmaceutical composition according to claim 6, wherein propylene glycol monocaprylate is Type II propylene glycol monocaprylate (USP / NF).

9. The liquid pharmaceutical composition according to claim 1 or 2, wherein the polyoxyethylene castor oil is polyoxyethylene 40 hydrogenated castor oil (USP / NF).

10. The liquid pharmaceutical composition according to claim 6, wherein the polyoxyethylene castor oil is polyoxyethylene 40 hydrogenated castor oil (USP / NF).

11. The liquid pharmaceutical composition according to claim 1 or 2, wherein based on the total weight of propylene glycol monocaprylate, polyoxyethylene castor oil and propylene glycol in the liquid carrier, the content of propylene glycol monocaprylate is 50 weight %, the content of polyoxyethylene castor oil is 40 weight %, and the content of propylene glycol is 10 weight %.

12. The liquid pharmaceutical composition according to claim 11, wherein propylene glycol monocaprylate is Type II propylene glycol monocaprylate (USP / NF); and / or wherein polyoxylized castor oil is polyoxyl 40 hydrogenated castor oil (USP / NF).

13. The liquid pharmaceutical composition according to claim 1 or 2, wherein the content of the BK B2 receptor antagonist per gram of the liquid pharmaceutical composition is in the range of 5 mg to 100 mg.

14. The liquid pharmaceutical composition according to claim 1 or 2, wherein the content of the BK B2 receptor antagonist per gram of the liquid pharmaceutical composition is in the range of 5 mg to 65 mg.

15. The liquid pharmaceutical composition according to claim 1 or 2, wherein the content of the BK B2 receptor antagonist per gram of the liquid pharmaceutical composition is in the range of 20 mg to 70 mg.

16. The liquid pharmaceutical composition according to claim 1 or 2, consisting of (a) 0.5 to 6.5 wt% of a compound according to Formula 1, or a salt or solvate thereof, wherein R is deuterium, based on the total weight of the liquid pharmaceutical composition; (b) 93.5 to 99.5 wt % of a liquid carrier, based on the total weight of the liquid pharmaceutical composition, the liquid carrier consisting of: (i) 50 parts by weight of propylene glycol monocaprylate; (ii) 40 parts by weight of polyoxyethylene castor oil; (iii) 5 to 10 parts by weight of propylene glycol; and (iv) from 0 to at most 5 parts by weight water.

17. The liquid pharmaceutical composition according to claim 1 or 2, consisting of (a) 0.5 to 6.5 wt% of a compound according to Formula 1, or a salt or solvate thereof, wherein R is deuterium, based on the total weight of the liquid pharmaceutical composition; (b) 93.5 to 99.5 wt % of a liquid carrier, based on the total weight of the liquid pharmaceutical composition, the liquid carrier consisting of: (i) 50 parts by weight of propylene glycol monocaprylate; (ii) 40 parts by weight of polyoxyethylene castor oil; (iii) 5 to 10 parts by weight of propylene glycol; and (iv) from 0 to at most 5 parts by weight water; as well as (c) the remainder is one or more other excipients dissolved or dispersed in the liquid carrier.

18. The liquid pharmaceutical composition according to claim 16, wherein the amount of the compound according to Formula 1 or its salt or solvate is 5 wt%, propylene glycol monocaprylate is Type II propylene glycol monocaprylate (USP / NF), and polyoxyethylene castor oil is 40 hydrogenated castor oil (USP / NF).

19. A capsule for oral administration comprising the liquid pharmaceutical composition according to any one of claims 1 to 18.

20. The capsule of claim 19, wherein the capsule is a soft capsule.

21. The capsule of claim 20, comprising a capsule wall comprising gelatin, water, and at least one plasticizer selected from the group consisting of propylene glycol, glycerin, sorbitol, sorbitan, a sorbitol-based plasticizer mixture, or any combination thereof.

22. A medicament comprising the liquid pharmaceutical composition according to any one of claims 1 to 18 or the capsule according to any one of claims 19 to 21 for the acute or chronic treatment of a subject suffering from a disease or condition responsive to BK B2 receptor modulation, wherein the disease or condition is selected from the group consisting of asthma, allergic rhinitis, pancreatitis, osteoarthritis, traumatic brain injury, Alzheimer's disease and edema.

23. Use of the liquid pharmaceutical composition according to any one of claims 1 to 18 or the capsule according to any one of claims 19 to 21 for the preparation of a medicament for treating or preventing a disease or condition responsive to BK B2 receptor modulation, wherein the disease or condition is selected from the group consisting of asthma, allergic rhinitis, pancreatitis, osteoarthritis, traumatic brain injury, Alzheimer's disease and edema.

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

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

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

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