Thromboxane receptor antagonist preparations

Abstract

The present invention provides a formulation that enhances the bioavailability of a thromboxane receptor antagonist and enables the antagonist to bind to the thromboxane A2 receptor in subjects suffering from disease indications involving the prostanoid thromboxane A2 and incidental thromboxane A2 receptor ligands. The formulation comprises a solid dispersion containing benzenesulfonylurea and a polymer suitable for oral or other delivery routes.

Description

[Technical Field]

[0001] Technical field This disclosure relates to an orally delivered formulation of a thromboxane receptor antagonist. [Background technology]

[0002] background Individuals suffering from imbalances in T-prostanoid thromboxane A2 levels or imbalances in the signaling of its receptor may have disorders that interfere with numerous vital systems in the body, including the cardiovascular, renal, pulmonary, and prostatic systems. More recently, T-prostanoid thromboxane A2, T-prostanoid thromboxane A2 synthase, and T-prostanoid receptors have also been linked to neoplasmic disease states, including bladder, prostate, breast, and lung cancers, in which T-prostanoid thromboxane A2 may promote tumor cell proliferation, migration, invasion, angiogenesis, inflammation, and immunity, among other protumor-promoting effects.

[0003] Despite knowledge of the role of T prostanoid thromboxane A2 and its receptor, many individuals continue to suffer from these imbalances and their devastating effects without receiving appropriate treatment. Traditional therapeutic approaches aim to inhibit the biosynthesis of T prostanoid thromboxane A2. Among these are a class of cyclooxygenase inhibitors, known as nonsteroidal anti-inflammatory drugs (NSAIDs). This includes aspirin, as well as associated cyclooxygenase 1 and / or cyclooxygenase 2 inhibitors. Low-dose aspirin is still widely used to prevent excessive thrombosis in patients at risk of cardiovascular events by inhibiting T prostanoid thromboxane A2 production.

[0004] However, approaches involving the use of low-dose aspirin are not sufficiently effective, and other prostanoids (prostaglandin D2, prostaglandin E2, prostaglandin F) are also used. 2αIt causes associated side effects due to the indiscriminate inhibition of the synthesis of prostaglandin I2 / prostacyclin. Lack of efficacy can also occur because a relatively high percentage of the general population exhibits aspirin resistance, which generally leads to a failure to lower T prostanoid thromboxane A2 levels in response to aspirin treatment. Furthermore, an increased incidence of adverse cardiovascular events may occur in patients receiving cyclooxygenase IB (cyclooxygenase 2 selective inhibitor) treatment.

[0005] As a result, many individuals with T-prostanoid thromboxane A2 imbalance continue to suffer from side effects of treatments that are either ineffective or only partially effective. [Overview of the project] [Means for solving the problem]

[0006] Abstract This disclosure provides a formulation of a thromboxane A2 receptor antagonist drug having a vinylpyrrolidone-vinyl acetate copolymer for oral administration for human use. The drug is protected at the low pH of the stomach and remains intact as a drug:polymer complex, but is ready for dissolution at the higher pH of the intestines for maximum absorption. The present invention provides a formulation that enables the thromboxane receptor antagonist to bind to the prostanoid thromboxane A2 receptor in subjects suffering from prostanoid thromboxane A2 imbalance in order to effectively balance prostanoid thromboxane levels. The formulation comprises a solid dispersion containing the thromboxane receptor antagonist and a pharmaceutically acceptable polymer suitable for oral administration. Once the formulation of the present invention is administered, the cardiovascular, renal, pulmonary, and prostatic systems can be rescued from dysfunction and eventual collapse. Furthermore, the risk and proliferation of bladder, prostate, breast, and lung cancers resulting from T-prostanoid thromboxane A2-related disorders can be prevented.

[0007] The substituted benzenesulfonylurea compounds of the formulations of the present invention bind to thromboxane A2 receptors and can inhibit thrombosis and other events in the cardiovascular, renal, pulmonary, or other systems where thromboxane A2 receptors are expressed, including but not limited to platelets, various types of smooth muscle cells, endothelial cells, monocytes / macrophages, keratinocytes, primary afferent neurons, and certain cells of the immune system.

[0008] Substituted benzenesulfonylurea compounds may have good permeability but insufficient solubility. This can significantly reduce their bioavailability, particularly in oral formulations. Advantageously, the formulations of the present invention provide a significant increase in solubility of drugs containing substituted benzenesulfonylureas, maximizing their absorption and oral bioavailability. As a result, the formulations are protected from the acidic environment of the stomach, which has a pH of approximately 1.6, but disperse in the higher pH environment of the intestines, which has a pH of approximately 6.5 and where maximum absorption is possible. The formulations of the present invention can provide an appropriate oral administration form. The formulations of the present invention can enable drugs containing substituted benzenesulfonylureas with relatively insufficient solubility to have their absorption, oral bioavailability, and exposure maximized, along with increased solubility.

[0009] The formulations of the present invention may be more insoluble in lower pH environments than in higher pH environments. For example, the formulations of the present invention may be substantially insoluble at pH less than 2. The formulations of the present invention may be substantially soluble at pH higher than 5.

[0010] The formulation of the present invention not only inhibits T-prostanoid thromboxane A2 (the main vasoconstrictive prostaglandin produced in the lungs), but also, in addition to the action of T-prostanoid thromboxane A2 itself, inhibits oxidative stress-derived isoprostane 8-iso-prostaglandin F 2αIt may have additional advantages over other therapeutic agents for pulmonary arterial hypertension used in that it also inhibits the harmful effects. In addition to pulmonary arterial hypertension, replacing standard treatment aspirin with the formulations of the present invention in other diseases such as atherosclerotic thrombosis means that the formulations of the present invention can (i) not only block the actions of T-prostanoid thromboxane A2, prostaglandin G2 / prostaglandin H2, and 20-hydroxy eicosatetraenoic acid, but also block aspirin-insensitive thromboxane A2 receptor agonists (e.g., 8-iso-prostaglandin F 2α ) which are produced in large amounts by free radicals during oxidative injury; (ii) similarly (unlike aspirin), inhibit the thromboxane A2 receptor expressed in cells of the vascular bed and circulating macrophages / monocytes and present during inflammatory atherosclerotic thrombosis; (iii) overcome aspirin resistance which is predicted to occur in about 33% of the population, thus providing several advantages.

[0011] The polymer of the formulation of the present invention can be a vinyl pyrrolidone-vinyl acetate copolymer. The above vinyl pyrrolidone-vinyl acetate copolymer can be a vinyl pyrrolidone-vinyl acetate copolymer as sold under the trademark KOLLIDON VA64 by BASF SE (Ludwigshafen, Germany). The polymer of the formulation of the present invention can be a dimethylaminoethyl methacrylate copolymer (e.g., a dimethylaminoethyl methacrylate copolymer sold under the trademark EUDRAGIT EPO by Evonik Industries AG (Essen, Germany)).

[0012] The polymer of the formulation of the present invention can be an anionic copolymer of methacrylic acid and methyl methacrylate. The above copolymer of methacrylic acid and methyl methacrylate can be as sold under the trademark EUDRAGIT L100 by Evonik Industries AG (Essen, Germany).

[0013] The polymer of the formulation of the present invention can be a polymer, hydroxypropylmethylcellulose or hydroxypropylmethylcellulose acetate succinate.

[0014] The polymer of the formulation of the present invention can be combined with a plasticizer (e.g., a solubilizer and emulsifier such as polyoxyl 40 hydrogenated castor oil or macrogol glycerol hydroxystearate sold under the trademark KOLLIPHOR RH40 by BASF).

[0015] The formulation of the present invention can be an amorphous solid dispersion. The formulation of the present invention can be a spray-dried dispersion. Advantageously, the above formulation can be formulated into an oral dosage form.

[0016] The advantages of the formulation approach of the present invention, e.g., a spray solid dispersion formulation, are that the vinylpyrrolidone-vinyl acetate copolymer can impart protection to the benzenesulfonylurea, shielding the above formulation from the low pH of the stomach (e.g., as can be simulated through a drug dissolution test in Fasted State Simulated Gastric Fluid (FaSSGF) having a pH of about 1.6), and maintaining it in the benzenesulfonylurea:vinylpyrrolidone-vinyl acetate copolymer complex until substantially all of the benzenesulfonylurea is released upon passage to the higher pH of the small intestine (e.g., as simulated in Fasted State Simulated Intestinal Fluid (FaSSIF) having a pH of about 6.5). Advantageously, the benzenesulfonylurea in the benzenesulfonylurea:vinylpyrrolidone-vinyl acetate spray solid dispersion formulation is protected from the acidic environment of the stomach (about pH 1.6) and disperses in the higher pH environment of the intestine where it can be maximally absorbed.

[0017] The oral dosage form can further be in the form of tablets, vials, sachets or capsules. [[ID=1&]]

[0018] The above formulation may further include a ratio of benzenesulfonylurea to vinylpyrrolidone-vinyl acetate copolymer between 1:1 and 1:8. For example, the above formulation may include a benzenesulfonylurea:vinylpyrrolidone-vinyl acetate copolymer ratio of 1:4.

[0019] Advantageously, the formulations of the present invention may be used in patients in need of a method for treating a condition selected from the group consisting of pulmonary arterial hypertension, other lung and cardiopulmonary diseases, atherothrombosis, stroke, myocardial infarction, atherosclerosis, atherosclerotic vascular disease, thromboembolism, deep vein thrombosis, arterial thrombosis, ischemia, peripheral vascular disease, peripheral arterial occlusive disease, coronary artery disease, angina pectoris, kidney disease, urinary tract disease, and transient ischemic attack, or a method for use in treating such a condition, the method comprising the step of administering the formulations of the present invention to a patient.

[0020] Advantageously, the formulations of the present invention are methods for treating or for use in treating proliferative disorders selected from the group consisting of non-Hodgkin lymphoma, colorectal cancer, esophageal cancer, prostate cancer, ovarian cancer, breast cancer, pancreatic cancer, bladder cancer, colon cancer, lung cancer, and ovarian cancer (including, but not limited to, these), in patients in need, the method may be used in a method comprising the step of administering the formulations of the present invention to a patient.

[0021] Advantageously, the formulations of the present invention are methods for treating or for use in treating viral infections, inflammatory or fibrotic conditions selected from the group of lung conditions including, but not limited to, pneumonia, pulmonary hypertension, pulmonary arterial hypertension, interstitial lung disease, idiopathic pulmonary fibrosis, asthma, acute pneumonia, and chronic obstructive pulmonary disease (COPD), in patients in need, the method comprising the step of administering the formulations of the present invention to a patient.

[0022] In aspects of the present invention, the drug containing a substituted benzenesulfonylurea used in the formulation of the present invention is a compound of formula (I): [ka] And here R 1 This is a cycloalkyl group, alkyl group, heterocycloalkyl group, difluoromethyl group, trifluoromethyl group, halogenated cycloalkyl group, halogenated alkyl group, halogenated heterocycloalkyl group, methoxy group, halogenated methoxy group, ethoxy group, isopropoxy group, tert-butoxy group, halogenated ethoxy group, halogenated isopropoxy group, halogenated tert-butoxy group, primary amide (-CONH2), secondary amide (-CONHCH3), tertiary amide (-CONH(CH3)2), or nitrile group; R 2 These are alkyl groups of 2 to 6 carbon atoms, and alkyl halogens of 2 to 6 carbon atoms; and R 3 R is a compound that is a nitrile group or a nitro group, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, R 3 It is a nitrile group.

[0023] In aspects of the present invention, the above-mentioned benzenesulfonylurea is a compound of formula (IV): [ka] That is the case.

[0024] In one aspect of the present invention, a compound of formula (IV): [ka] and Compound of formula (IV) in a 1:4 ratio: vinylpyrrolidone-vinyl acetate copolymer, A formulation containing, Here, the above formulation is substantially insoluble at a pH of less than 2 and substantially soluble at a pH of greater than 5. The formulation is provided.

[0025] The above-mentioned formulation may be a spray-dried dispersion.

[0026] The above formulations may be further formulated as oral administration forms. These oral administration forms may be in the form of tablets, vials, sachets, or capsules.

[0027] Advantageously, the formulations of the present invention may be used in patients in need of a method for treating or for use in treating a condition selected from the group consisting of pulmonary arterial hypertension, other lung and cardiopulmonary diseases, atherothrombosis, stroke, myocardial infarction, atherosclerotic arteriosclerosis, atherosclerotic vascular disease, thromboembolism, deep vein thrombosis, arterial thrombosis, ischemia, peripheral vascular disease, peripheral arterial occlusive disease, coronary artery disease, angina pectoris, kidney disease, urinary tract disease, and transient ischemic attack, the method comprising the step of administering the formulations of the present invention to a patient.

[0028] Advantageously, the formulations of the present invention may be used in a method for treating or for use in treating proliferative disorders selected from the group consisting of non-Hodgkin lymphoma, colorectal cancer, esophageal cancer, prostate cancer, ovarian cancer, breast cancer, pancreatic cancer, bladder cancer, colon cancer, lung cancer, and ovarian cancer in patients in need, the method comprising the step of administering the formulations of the present invention to a patient.

[0029] Advantageously, the formulations of the present invention are methods for treating or for use in treating viral infections, inflammatory or fibrotic conditions selected from the group of lung conditions including, but not limited to, pneumonia, pulmonary hypertension, pulmonary arterial hypertension, interstitial lung disease, idiopathic pulmonary fibrosis, asthma, acute pneumonia, and chronic obstructive pulmonary disease (COPD), in patients in need, the method comprising the step of administering the formulations of the present invention to a patient. [Brief explanation of the drawing]

[0030] [Figure 1] Figure 1 shows a graph of the release rate of the formulation of the present invention.

[0031] [Figure 2] Figure 2 shows a graph of the release rate of the formulation of the present invention.

[0032] [Figure 3] Figure 3 shows a graph of the release rate of the formulation of the present invention.

[0033] [Figure 4] Figure 4 shows a graph of the release rate of the formulation of the present invention.

[0034] [Figure 5] Figure 5 shows a graph of the release rate of the formulation of the present invention.

[0035] [Figure 6] Figure 6 shows a table of pharmacokinetic data for the formulation of the present invention.

[0036] [Figure 7] Figure 7 shows the release rates of benzenesulfonylurea and polymer formulations.

[0037] [Figure 8] Figure 8 shows the release rates of benzenesulfonylurea and polymer formulations.

[0038] [Figure 9] Figure 9 shows the release rates of benzenesulfonylurea and polymer formulations.

[0039] [Figure 10] Figure 10 shows a graph of the release rate of the formulation of the present invention.

[0040] [Figure 11] Figure 11 shows a graph of the release rate of the formulation of the present invention.

[0041] [Figure 12] Figure 12 shows a graph of the release rate of the formulation of the present invention.

[0042] [Figure 13] Figure 13 shows a graph of the release rate of the formulation of the present invention.

[0043] [Figure 14] Figure 14 shows a table of pharmacokinetic data for the formulation of the present invention.

[0044] [Figure 15] Figure 15 illustrates the experimental design of the preclinical efficacy trial.

[0045] [Figure 16] Figure 16 shows the results for mean pulmonary artery pressure (mPAP).

[0046] [Figure 17] Figure 17 shows the results for right ventricular systolic pressure (RVSP).

[0047] [Figure 18] Figure 18 shows the results of systemic arterial pressure.

[0048] [Figure 19] Figure 19 shows the results, including heart rate.

[0049] [Figure 20] Figure 20 shows pulmonary vascular remodeling (vascular occlusion).

[0050] [Figure 21] Figure 21 shows pulmonary vascular remodeling (muscularized vessels).

[0051] [Figure 22] Figure 22 shows the results indicating cardiac hypertrophy (Fulton index).

[0052] [Figure 23] Figure 23 shows results indicating right ventricular fibrosis.

[0053] [Figure 24] Figure 24 shows results indicating pulmonary fibrosis.

[0054] [Figure 25] Figure 25 shows results indicating lung inflammation (CD68+ macrophages).

[0055] [Figure 26] Figure 26 is a table showing the effect of NTP42:KVA4 on MCT PAH in rats.

[0056] [Figure 27] Figure 27 shows a section of lung tissue illustrating pulmonary vascular remodeling.

[0057] [Figure 28] Figure 28 shows the results of the whole blood platelet aggregation assay. [Modes for carrying out the invention]

[0058] Detailed explanation The present invention provides a formulation comprising a benzenesulfonylurea and a polymer, wherein the polymer is related to the bioavailability of the benzenesulfonylurea and is capable of binding to the prostaglandin thromboxane A2 receptor in a subject suffering from a disease indication associated with prostaglandin thromboxane A2 and the accidental thromboxane A2 receptor ligands listed below. The formulation comprises a solid dispersion comprising a benzenesulfonylurea and a polymer suitable for oral administration (e.g., vinylpyrrolidone-vinyl acetate). The benzenesulfonylurea is an antagonist of T prostaglandin thromboxane A2 and other accidental thromboxane A2 receptor ligands (which bind to the thromboxane A2 receptor and stimulate platelet activation and aggregation, thereby reducing the risk of clinically significant thrombus or embolism, or endoperoxide prostaglandin G2 / H2, 20-hydroxy eicosatetraenoic acid and isoprostane (e.g., 8-iso-prostaglandin F 2α ) that antagonize the thromboxane A2 receptor α and / or thromboxane A2 receptor β isoforms expressed in cells of the cardiovascular, renal, pulmonary or other systems (e.g., but not limited to, skin conditions)). Accordingly, the formulations of the present invention provide beneficial pharmaceutical properties for treating thrombosis, inflammation, fibrosis, cell proliferation, vascular remodeling and other events in the cardiovascular, renal, pulmonary, pruritus (itching), dermatitis, or other systems in which the thromboxane A2 receptor is expressed and / or its ligand is dysregulated.

[0059] The drug comprising a substituted benzenesulfonylurea used in the formulation of the present invention is a compound of formula (I):

Chemical formula

[0060] The formulation of the present invention is R 2 is a tert-butyl group, R 3 is a nitrile group; and R 1 This may include benzenesulfonylurea which is a cycloalkyl group, alkyl group, aryl group, heterocycloalkyl group, difluoromethyl group, trifluoromethyl group, halogenated cycloalkyl group, halogenated alkyl group, halogenated aryl group, halogenated heterocycloalkyl group, methoxy group, halogenated methoxy group, ethoxy group, isopropoxy group, tert-butoxy group, halogenated ethoxy group, halogenated isopropoxy group, halogenated tert-butoxy group, primary amide, secondary amide, tertiary amide, or nitrile group.

[0061] In aspects of the present invention, the above-mentioned substituted benzenesulfonylurea is a compound of formula (IV): [ka] That is the case.

[0062] Further benzenesulfonylureas may be used in the formulations of the present invention.

[0063] The above-mentioned substituted benzenesulfonylurea may be one or more of the compounds listed below. For example, the above-mentioned benzenesulfonylurea is a compound represented by formula (I): where R 1 is selected from the group consisting of halogens, alkyl groups, cycloalkyl groups, aryl groups, heterocycloalkyl groups, halogenated alkyl groups, halogenated cycloalkyl groups, halogenated aryl groups, halogenated heterocycloalkyl groups, methoxy groups, halogenated methoxy groups, ethoxy groups, isopropoxy groups, tert-butoxy groups, halogenated ethoxy groups, halogenated isopropoxy groups, halogenated tert-butoxy groups, primary amides, secondary amides, tertiary amides, OH, halogens, CO2H, methyl ketones, nitrile groups, methyl ester groups, ethyl ester groups, isopropyl ester groups, tert-butyl ester groups, halogenated methyl ester groups, halogenated ethyl ester groups, halogenated isopropyl ester groups, and halogenated tert-butyl ester groups; and R 2 R can be a compound selected from the group consisting of halogens, alkyl groups, alkyl halides, aryl groups, and aryl halides, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, R 1 is selected from the group consisting of halogens, alkyl groups, halogenated alkyl groups, halogenated cycloalkyl groups, halogenated aryl groups, halogenated heterocycloalkyl groups, methoxy groups, halogenated methoxy groups, ethoxy groups, isopropoxy groups, tert-butoxy groups, halogenated ethoxy groups, halogenated isopropoxy groups, halogenated tert-butoxy groups, primary amides, secondary amides, tertiary amides, and nitrile groups; and R 2 This can be a compound selected from the group consisting of halogens, alkyl groups, alkyl halides, aryl groups, and aryl halides, or a pharmaceutically acceptable salt thereof.

[0064] In a particular embodiment, the present invention is R 1However, it is selected from the group consisting of halogenated alkyl groups, halogenated methoxy groups, primary amides, secondary amides, tertiary amides, and nitrile groups; and R 2 The present invention provides a compound of formula (I) selected from the group consisting of an alkyl group of 3 to 6 carbon atoms and an alkyl halide of 3 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof.

[0065] In a particular embodiment, the present invention is R 1 However, it is selected from the group consisting of difluoromethyl group, trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, primary amide, secondary amide, tertiary amide, and nitrile group; and R 2 The present invention provides a compound of formula (I) selected from the group consisting of alkyl groups with six or fewer carbon atoms and alkyl halogenated groups with six or fewer carbon atoms, or a pharmaceutically acceptable salt thereof.

[0066] In other embodiments, the present invention relates to a compound of formula (II): [ka] And here R 1 is selected from the group consisting of halogens, alkyl groups, cycloalkyl groups, aryl groups, heterocycloalkyl groups, halogenated alkyl groups, halogenated cycloalkyl groups, halogenated aryl groups, halogenated heterocycloalkyl groups, methoxy groups, halogenated methoxy groups, ethoxy groups, isopropoxy groups, tert-butoxy groups, halogenated ethoxy groups, halogenated isopropoxy groups, halogenated tert-butoxy groups, primary amides, secondary amides, tertiary amides, OH, halogens, CO2H, methyl ketones, nitrile groups, methyl ester groups, ethyl ester groups, isopropyl ester groups, tert-butyl ester groups, halogenated methyl ester groups, halogenated ethyl ester groups, halogenated isopropyl ester groups, and halogenated tert-butyl ester groups; and R 2This provides compounds selected from the group consisting of halogens, alkyl groups, alkyl halides, aryl groups, and aryl halides, or pharmaceutically acceptable salts thereof.

[0067] In another embodiment, the present invention is R 1 However, selected from the group consisting of halogens, alkyl groups, halogenated alkyl groups, halogenated cycloalkyl groups, halogenated aryl groups, halogenated heterocycloalkyl groups, methoxy groups, halogenated methoxy groups, ethoxy groups, isopropoxy groups, tert-butoxy groups, halogenated ethoxy groups, halogenated isopropoxy groups, halogenated tert-butoxy groups, primary amides, secondary amides, tertiary amides, and nitrile groups; and R 2 The present invention provides a compound of formula (II) selected from the group consisting of alkyl groups of 2 to 6 carbon atoms and alkyl halogenated groups of 2 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof.

[0068] In another embodiment, the present invention is R 1 However, it is selected from the group consisting of halogenated alkyl groups, halogenated methoxy groups, primary amides, secondary amides, tertiary amides, and nitrile groups; and R 2 The present invention provides a compound of formula (II) in which is an alkyl group of 3 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof.

[0069] In a far more preferred embodiment, the present invention is R 1 However, it is selected from the group consisting of difluoromethyl group, trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, primary amide, secondary amide, tertiary amide, and nitrile group; and R 2 The present invention provides a compound of formula (II) selected from the group consisting of alkyl groups of 3 to 5 carbon atoms and alkyl halides of 3 to 5 carbon atoms, or a pharmaceutically acceptable salt thereof.

[0070] In embodiments, the present invention relates to a compound of formula (III): [ka] And here R 1 This provides compounds selected from the group consisting of difluoromethyl groups, trifluoromethyl groups, difluoromethoxy groups, trifluoromethoxy groups, primary amides, secondary amides, tertiary amides, and nitrile groups, or pharmaceutically acceptable salts thereof. For example, the above compounds are of formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI): [ka] [ka] [ka] [ka] It can be represented by:

[0071] Substituted benzenesulfonylureas that can be used in the formulations of the present invention may be those described in U.S. Patents No. 9,388,127; No. 9,522,877; No. 9,630,915; No. 9,738,599; No. 9,718,781; No. 9,932,304; No. 10,357,504; and No. 10,966,994, as well as WO 2015 / 185989 (all incorporated by reference).

[0072] The formulation of the present invention may act as a therapeutic agent for pulmonary arterial hypertension, not only inhibiting excessive vasoconstriction but also preventing microthrombosis, and potentially limiting pulmonary artery remodeling, right ventricular hypertrophy, endothelial cell dysfunction, fibrosis, and local inflammation found in pulmonary arterial hypertension. The formulation of the present invention may also directly suppress inflammatory or proliferative pathways associated with pulmonary arterial hypertension. The formulation of the present invention may also contain 8-iso-prostaglandin F 2αThe compounds of the present invention may antagonize or prevent the effects of free radical-derived isoprostanes (which are produced in large quantities in the clinical context of pulmonary arterial hypertension and in other diseases involving oxidative stress or injury that mediate effects similar to those of the T prostanoid thromboxane A2), and the compounds of the present invention also antagonize these effects in pulmonary arterial hypertension. Furthermore, since the T prostanoid thromboxane A2 is a potent pro-inflammatory, pro-fibrotic, and mitotic factor that promotes vascular remodeling, restenosis, and / or hypertrophy, and is the major cyclooxygenase-derived contractile prostanoid in the lungs, the formulations of the present invention may antagonize these effects. Furthermore, 8-iso-prostaglandin F 2α Since these are potent pro-inflammatory, pro-fibrotic, and pro-mitotic factors that promote vascular remodeling, restenosis, and / or hypertrophy, and are found in large quantities or elevated in patients with pulmonary arterial hypertension, the formulations of the present invention may counteract these effects.

[0073] The formulations of the present invention exhibit potent thromboxane A2 receptor antagonist activity, for example, exovivotion, resulting in 1-10 nM IC2. 50 It inhibits the aggregation of human platelets. The formulations of the present invention have excellent specificity, pharmacokinetics, pharmacodynamics, and toxicological profiles (including in the treatment of pulmonary arterial hypertension, thrombosis and cardiovascular disease, renal disease, lung disease, and breast cancer, lung cancer, prostate cancer, bladder cancer, and other cancers).

[0074] The formulations of the present invention, in addition to certain other associated ligands (e.g., endoperoxide prostaglandin G2 / prostaglandin H2 (each of which acts as an agonist or partial agonist of the thromboxane A2 receptor)), include T prostanoid thromboxane A2 and free radical-derived isoprostane 8-iso-prostaglandin (prostaglandin) F 2αIt inhibits the action of thromboxane A2 receptor. The thromboxane A2 receptor is expressed throughout the body in a range of specific cell types, and its expression is altered in several disease indications. The formulations of the present invention target thromboxane A2 receptors (including thromboxane A2 receptor α and / or thromboxane A2 receptor β) expressed in each of those cell types and in different disease situations (e.g., pulmonary arterial hypertension). The benzenesulfonylurea of ​​the formulations of the present invention may be used in the treatment of other diseases in which the T prostanoid thromboxane A2, 8-iso-prostaglandin F2α, or the thromboxane A2 receptor itself is associated. These include, but are not limited to, various cardiovascular diseases (including thrombosis, various types of hypertension (systemic hypertension and pregnancy-induced hypertension, and arterial peripheral disease)), lung diseases (including asthma, pulmonary hypertension, pulmonary arterial hypertension, chronic obstructive pulmonary disease, interstitial lung disease, and idiopathic pulmonary fibrosis) and kidney diseases (including glomerulonephritis and renal hypertension). The formulations of the present invention are also applicable in the treatment of prostate diseases (e.g., benign prostatic hyperplasia), various pro-inflammatory diseases (including, but not limited to, inflammatory cardiovascular, renal, pulmonary, and post-viral / microbial infections) and neoplasms (e.g., prostate cancer, including breast cancer, lung cancer, or castration-resistant prostate cancer).

[0075] The formulations of the present invention can be used in any drug form (e.g., orally, intravenously, intraperitoneally, pulmonaryly, cutaneously, in transdermal delivery systems, in intrathecal devices, or on medical devices (e.g., on pumps, slow-release pumps, stents, or drug-eluting stents)). Advantageously, the formulations of the present invention provide increased bioavailability with respect to oral administration forms. In a preferred aspect of the present invention, the formulations are formulated as oral administration forms.

[0076] The above formulations may be in oral administration form, which may be tablets, vials, sachets, or capsules. The above formulations may be in the form of powders, pellets, multi-particulates, beads, emulsions, spheres, or any combination thereof. Oral solid administration forms may be formulated as immediate-release formulations, controlled-release formulations, sustained-release (long-release) formulations, or modified-release formulations.

[0077] The effective dose of the above formulation can be easily determined by those skilled in the art, taking into account typical factors such as the patient's age, weight, sex, and clinical history. Typical doses may be, for example, 1 to 1,000 mg / kg, preferably 5 to 500 mg / kg / day, or less than about 5 mg / kg of benzenesulfonylurea, and may be administered, for example, once daily, several times daily, every two days, every few days, once a week, twice every two weeks, or once a month, or a limited number of times (e.g., once, two or three times, or more times).

[0078] The formulations of the present invention may be in forms suitable for oral use, such as tablets, lozenges, fast-melts, sachets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Formulations intended for oral use may be prepared according to any method known in the art with respect to the manufacture of formulations, and such compositions may contain one or more active ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide pharmaceutically refined and palatable preparations. Tablets contain the active ingredient in mixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate); granulators and disintegrants (e.g., corn starch, or alginic acid); binders (e.g., starch, gelatin, or acacia gum); and lubricants (e.g., magnesium stearate, stearic acid, or talc). The above tablets or capsules may not be coated, or they may be coated by known techniques to slow disintegration in the stomach and absorption in the lower gastrointestinal tract, thereby providing a sustained effect over a long period. For example, time-delay materials (e.g., glyceryl monostearate or glyceryl distearate) may be used. They may also be coated by techniques described in U.S. Patents No. 4,256,108 and No. 4,265,874 to form osmotic therapeutic tablets for controlled release. The preparation and administration of the compound are discussed in U.S. Patent No. 6,214,841 and U.S. Patent Application Publication 2003 / 0232877 (both incorporated herein by reference).

[0079] Formulations for oral use may also be presented as rigid gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0080] Alternative oral formulations requiring control of gastrointestinal hydrolysis of the above-mentioned compounds or active ingredients can be achieved using a controlled-release formulation in which the compounds of the present invention are encapsulated in an enteric coating (for example, an enteric coating containing a drug complex comprising substituted benzenesulfonylurea and vinylpyrrolidone-vinyl acetate copolymer).

[0081] The aqueous suspension may contain the above-mentioned formulation in a state mixed with an excipient suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, tragacanth gum, and acacia gum); dispersing agents or wetting agents (e.g., naturally occurring phosphatides (e.g., lecithin), or condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxides and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), or condensation products of ethylene oxides and partial esters obtained from fatty acids and hexitol (e.g., polyoxyethylene and partial esters obtained from polyoxyethylene and hexitol anhydrides) (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives (e.g., ethyl or n-propyl p-hydroxybenzoate), or one or more colorants, one or more flavoring agents, and one or more sweeteners (e.g., sucrose or saccharin).

[0082] Oily suspensions can be formulated by suspending the above formulation in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or in a mineral oil (e.g., liquid paraffin). The oily suspensions may contain thickeners (e.g., beeswax, solid paraffin, or cetyl alcohol). Sweeteners (e.g., those indicated above) and flavoring agents may be added to provide an oral preparation with a pleasant mouthfeel. These formulations can be preserved by the addition of antioxidants (e.g., ascorbic acid).

[0083] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water are provided in a state mixed with a dispersant or humectant, a suspending agent and one or more preservatives. Suitable dispersants or humectants and suspending agents have been demonstrated, and for example, sweeteners, flavoring agents and coloring agents may also be present.

[0084] The formulations of the present invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil (e.g., olive oil or peanut oil), a mineral oil (e.g., liquid paraffin), or a mixture thereof. Suitable emulsifiers may be naturally occurring gums (e.g., acacia gum or tragacanth gum), naturally occurring phosphatides (e.g., soy lecithin), and esters or partial esters obtained from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate) and condensation products of the above partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsion may also contain sweeteners and flavoring / odorizing agents.

[0085] Syrups and elixirs can be formulated with sweeteners (e.g., glycerol, propylene glycol, sorbitol, or sucrose). Such formulations may also contain lubricants, preservatives, and flavoring and coloring agents. The formulations may be in the form of sterile aqueous or oily suspensions for injection. These suspensions may be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents as described above. Suitable sterile injection preparations may also be sterile injection solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents (e.g., as solutions in 1,3-butanediol). Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solutions. Furthermore, sterile non-volatile oils have been conventionally used as solvents or suspension media. For this purpose, any non-irritating non-volatile oil can be used (e.g., synthetic monoglycerides or diglycerides). Furthermore, fatty acids (e.g., oleic acid) have found applications in the preparation of injections.

[0086] The above formulations may also be administered in the form of suppositories for rectal administration of the drug. These formulations may be prepared by mixing the above formulations with a suitable non-irritating excipient that is solid at normal temperatures but liquid at rectal temperatures and therefore melts in the rectum to release the drug. Examples of such substances are cocoa butter and polyethylene glycol.

[0087] The above formulations can be modified by changing the particle size, thereby facilitating delivery in various forms, for example, through the pulmonary route. Advantageously, the above formulations may be suitable for administration via the pulmonary route (e.g., using an inhalable aerosol or nebulizer system). Advantageously, the above formulations may have applications in a wide range of disease situations.

[0088] The formulations of the present invention can be scaled up in manufacturing and may be suitable for use in humans via oral administration. Scaled-up manufacturing of the formulations of the present invention has provided high-quality formulations in an efficient, reproducible, and robust chemical process. The formulations of the present invention are suitable for industrial manufacturing and can comply with the procedures of the standards for manufacturing and quality control of pharmaceuticals and the regulatory guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.

[0089] In aspects of the present invention, the polymer in the formulation of the present invention may be a vinylpyrrolidone-vinyl acetate copolymer. The vinylpyrrolidone-vinyl acetate copolymer is a linear copolymer produced by the free radical polymerization of vinylpyrrolidone and vinyl acetate. The ratio of vinylpyrrolidone to vinyl acetate in the above vinylpyrrolidone-vinyl acetate copolymer may be in the range of vinylpyrrolidone to vinyl acetate, from 7:3 to 3:7.

[0090] The vinylpyrrolidone-vinyl acetate copolymer described above may be the vinylpyrrolidone-vinyl acetate copolymer as marketed by BASF SE in Ludwigshafen, Germany (e.g., the product marketed under the trademark KOLLIDON VA64). The vinylpyrrolidone-vinyl acetate copolymer may contain vinylpyrrolidone:vinyl acetate in a 6:4 ratio. The vinylpyrrolidone-vinyl acetate copolymer may be as described in Buehler, 2009, Kollidon: Polyvinylpyrrolidone excipients for the pharmaceutical industry, BASF SE Pharma Ingredients & Services, 9th edition (available on the BASF SE website under the product guide for the product marketed as KOLLIDON VA64) (the contents of which are incorporated herein by reference).

[0091] Vinylpyrrolidone-vinyl acetate copolymer is a copolymer used as a soluble binder for granulation, a drying-binder in direct compression techniques, a film-forming agent in sprays, a pore-forming agent in coatings, in taste-masking applications, and as a solubilizer in hot-melt extrusion processes. Vinylpyrrolidone-vinyl acetate copolymer is readily soluble in all hydrophilic solvents, and solutions at concentrations greater than 10% can be prepared in water, ethanol, isopropanol, methylene chloride, glycerol, and propylene glycol. Vinylpyrrolidone-vinyl acetate copolymer may be less soluble in ethers, cyclic, aliphatic, and alicyclic hydrocarbons. Advantageously, vinylpyrrolidone-vinyl acetate copolymer may be more cost-effective than natural binders.

[0092] In aspects of the present invention, the polymer in the formulation of the present invention may be a dimethylaminoethyl methacrylate copolymer. Dimethylaminoethyl methacrylate copolymer is a copolymer produced by polymerization of acrylic acid and methacrylic acid or esters thereof. Certain embodiments include cationic copolymers based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. For example, the polymer may have the IUPAC name: poly(butyl methacrylate-co-(2-demethylaminoethyl(demethylaminoeethyl)) methacrylate-co-methyl methacrylate) 1:2:1, dimethylaminoethyl methacrylate copolymer. Such polymers may be characterized by low viscosity, high pigment binding ability, good adhesion, and low polymer weight increase. Embodiments have CAS number 24938-16-7 and INCI name: acrylate / dimethylaminoethyl methacrylate copolymer. Certain embodiments utilize dimethylaminoethyl methacrylate copolymer as sold by Evonik Industries AG (Essen, Germany) under the trademark EUDRAGIT® EPO. EUDRAGIT® EPO (EE) cationic polymer has an average relative molecular weight of approximately 150,000 and is prepared by copolymerization of butyl methacrylate, 2-dimethylaminoethyl methacrylate, and methyl methacrylate. The ratio of dimethylaminoethyl methacrylate groups to butyl methacrylate and methyl methacrylate groups is approximately 2:1:1. See Chang, 2009, Polymethacrylates, monograph at pp. 525–533 of Handbook of Pharmaceutical Excipients, 6th edition, edited by Rowe et al., Pharmaceutical Press (London, UK) (as referenced).

[0093] Dimethylaminoethyl methacrylate copolymer is a copolymer used in film coating, melting, wet or dry granulation, hot melt extrusion, microencapsulation, and spray drying.

[0094] The formulation of the present invention may be an amorphous solid dispersion. The solid dispersion is a dispersion of one or more hydrophobic active components in a hydrophilic inert carrier in a solid state. The solid dispersion can be prepared, for example, by melting, solvent evaporation, fusion, kneading, melting, spray drying, co-grinding, freeze-drying, hot-melt extrusion, melt agglomeration, or supercritical fluid technology. The amorphous solid dispersion is a molecular system containing an active pharmaceutical component stabilized by an excipient (generally a polymer) to produce a system with improved physical stability compared to an amorphous active pharmaceutical component. In the amorphous solid dispersion, the system preferably does not show evidence of crystallinity.

[0095] The above formulation may include a spray-dried dispersion. A spray-dried dispersion is a dispersion formed by co-precipitating an active pharmaceutical ingredient and a polymer in a stable, amorphous solid dispersion. Spray drying can improve dissolution rates and enhance the bioavailability of compounds with insufficient solubility.

[0096] The spray-dried dispersion can be formed by first preparing a solvent solution of the substituted benzenesulfonylurea and the polymer. This can be done by weighing the required amount of benzenesulfonylurea, adding it to the solvent solution, mechanically mixing the solution, weighing the polymer, adding the polymer to the benzenesulfonylurea-solvent solution, and mechanically mixing the solution. In aspects of the present invention, the solvent may be acetone. In aspects of the present invention, the acetone constitutes more than 90% of the solvent solution. In aspects of the present invention, the solvent may be dichloromethane:methanol in a 3:1 ratio.

[0097] The solution may then be spray-dried to produce a substituted benzenesulfonylurea:polymer bulk intermediate. Spray drying may be carried out at a high inlet temperature (e.g., about 80°C or higher) and an outlet temperature of about 45°C. Spray drying may be carried out at an evaporation temperature of about 55°C or 60°C.

[0098] The bulk intermediate may then be subjected to secondary drying to form a sprayed solid dispersion powder. The sprayed solid dispersion powder offers the advantage of being easily packaged in a primary container or delivery vehicle. Secondary drying may be carried out by a rotary dryer to evaporate the residual solvent (e.g., acetone, if acetone is used as the solvent). In a preferred aspect of the present invention, the sprayed solid dispersion formulation contains less than 5,000 ppm of solvent.

[0099] In an alternative aspect of the present invention, the amorphous solid dispersion formulation may be formed by solvent-free hot-melt extrusion. In hot-melt extrusion, the drug and polymer are melted and mixed together to form an amorphous solid in the absence of a solvent. Advantageously, in the hot-melt extrusion process, the introduction of water is reduced or eliminated from the manufacturing process due to the absence of a solvent.

[0100] In another alternative aspect of the above manufacturing process, a solvent / surfactant process may be used to form the formulation of the present invention. In the solvent / surfactant process, a self-emulsifying drug delivery system or self-microemulsifying-drug delivery system (SMEDDS) is used to encapsulate the formulation of the present invention within a hydrophobic phase surrounded by a hydrophilic phase containing a surfactant. The hydrophilic phase may also contain a co-solvent, particularly in the SMEDDS process.

[0101] The above formulation may comprise a drug containing a substituted benzenesulfonylurea and a spray-dried dispersion of a pharmaceutically acceptable vinylpyrrolidone-vinyl acetate copolymer (e.g., vinylpyrrolidone-vinyl acetate copolymer marketed by BASF SE (headquartered in Ludwigshafen, Germany), e.g., a product marketed under the trademark KOLLIDON® VA64). The ratio of the benzenesulfonylurea drug to the vinylpyrrolidone-vinyl acetate copolymer may be 1:4. For example, the above formulation may comprise a compound of formula (IV): [ka] The compound may also contain vinylpyrrolidone-vinyl acetate in a ratio of 1:4 of the compound of formula (IV) to vinylpyrrolidone-vinyl acetate copolymer.

[0102] The advantage of the formulation approach of the present invention, for example, a spray solid dispersion formulation, is that the vinylpyrrolidone-vinyl acetate copolymer can form a specific complex with the benzenesulfonylurea drug, thereby providing protection for the benzenesulfonylurea, shielding or masking it from the low pH of the stomach (for example, as can be mimicked through drug dissolution tests in fasting-mimicking gastric juice (FaSSGF) having a pH of approximately 1.6), and maintaining the benzenesulfonylurea in the benzenesulfonylurea:vinylpyrrolidone-vinyl acetate copolymer complex until it is substantially released upon passage to the higher pH of the small intestine (for example, as can be mimicked in fasting-mimicking intestinal juice (FaSSIF) having a pH of approximately 6.5). Advantageously, in the benzenesulfonylurea:vinylpyrrolidone-vinyl acetate copolymer spray solid dispersion formulation, the benzenesulfonylurea is protected from the acidic environment of the stomach (approximately pH 1.6) and disperses the drug from the drug-polymer complex into the higher pH environment of the intestines where it can be absorbed to the maximum extent, rather than releasing the drug from the drug-polymer complex into the gastric juice itself.

[0103] The formulations of the present invention may be more insoluble in lower pH environments than in higher pH environments. Lower pH environments are those with a pH lower than approximately 5. For example, the formulations of the present invention may be substantially insoluble at pH less than 2. Higher pH environments are those with a pH higher than p5. For example, the formulations of the present invention may be substantially soluble at pH higher than 5.3.

[0104] Solubility is the amount of a substance that dissolves in a given amount of another substance (e.g., a solvent). The solvent may be water, gastric juice, or intestinal juice.

[0105] Substantially insoluble may mean that less than 10% of the formulation or benzenesulfonylurea dissolves in the solvent in 75 minutes. Substantially insoluble may mean that less than 30% of the formulation or benzenesulfonylurea dissolves in the solvent in 75 minutes. Substantially insoluble may mean that less than 30% of the formulation or benzenesulfonylurea dissolves in the solvent in 90 minutes. Substantially soluble may mean that more than 60% of the formulation dissolves in the solvent in 25 minutes or less. Substantially soluble may mean that more than 60% of the formulation dissolves in the solvent in less than 20 minutes. Substantially soluble may mean that more than 60% of the formulation dissolves in the solvent in less than 15 minutes. Substantially soluble may mean that more than 60% of the formulation dissolves in the solvent in less than 10 minutes. Substantially soluble may mean that more than 70% of the formulation dissolves in the solvent in less than 25 minutes.

[0106] The formulations of the present invention may be used to treat human diseases in which human thromboxane A2 receptors and prostanoid receptors play a role. The formulations of the present invention may be used to treat human diseases in which altered expression levels of human thromboxane A2 receptors are present. The formulations of the present invention may be used to treat human diseases in which levels of the prostanoid thromboxane A2 are elevated. The formulations of the present invention may be used to treat other biochemical entities / ligands that act through the human thromboxane A2 receptor (e.g., prostaglandin G2 / prostaglandin H2, 20-hydroxyeicosatetraenoic acid, or 8-isoprostaglandin F2). 2α The formulations of the present invention may be used to treat human diseases characterized by elevated levels of isoprostanes (including 8-iso-prostaglandin F2) derived from non-enzymatic free radicals that signal through the human thromboxane A2 receptor. 2αIt can be used to treat human diseases in which the level of ) is elevated. The formulations of the present invention can be used to antagonize the thromboxane A2 receptor for use in the treatment of pulmonary arterial hypertension. The formulations of the present invention can be used to treat thrombosis, either alone or in combination with other therapeutic agents. The formulations of the present invention can be used to treat microvascular thrombosis, either alone or in combination with other therapeutic agents. The formulations of the present invention can be used to treat other cardiovascular diseases (including cardiovascular diseases associated with type 1 and type 2 diabetes). Examples of the field of application include, but are not limited to, the treatment of various cardiovascular diseases (including atherothrombosis associated with excessive platelet aggregation, ischemic stroke, transient ischemic attack (TIA), and prevention of acute coronary syndrome). With respect to these conditions, the formulations of the present invention can be used either alone or in combination with other therapeutic agents. The formulations of the present invention may be used to treat other lung diseases (including, but not limited to, asthma, pulmonary hypertension, pulmonary arterial hypertension, interstitial lung disease, and idiopathic pulmonary fibrosis), either alone or in combination with other therapeutic agents. The formulations of the present invention may be used to treat kidney diseases, either alone or in combination with other therapeutic agents. The formulations of the present invention may be used to treat prostate diseases (including, but not limited to, benign prostatic hyperplasia), either alone or in combination with other therapeutic agents. The formulations of the present invention may be used to treat inflammatory diseases, either alone or in combination with other therapeutic agents. The formulations of the present invention may be used to treat neoplasms, including cancer, either alone or in combination with other therapeutic agents. The formulations of the present invention may be used to treat stroke and transient ischemic attacks, either alone or in combination with other therapeutic agents. The formulations of the present invention may be used in combination with an immunomodulator to treat cancer. The formulations of the present invention may be used to treat dysregulated smooth muscle cell function (including, but not limited to, various types of hypertension and restenosis after surgical stent placement).The formulations of the present invention may be used to treat dysregulated endothelial cell function.

[0107] Supporting display References and citations to other documents (e.g., patents, patent applications, patent publications, journals, books, articles, web content) are made throughout this disclosure. All such documents are incorporated herein by reference in their entirety for all purposes.

[0108] Equal portions Various modifications of the present invention and many further embodiments will be apparent to those skilled in the art from the entirety of this document, including references to scientific and patent documents cited herein, in addition to those shown and described herein. The subject matter herein includes important information, illustrations and guidance that can adapt the implementation of the present invention in its various embodiments and equivalents. [Examples]

[0109] Examples This invention provides for the production and biological evaluation of formulations of benzenesulfonylurea and vinylpyrrolidone-vinyl acetate copolymer that act as antagonists of the thromboxane A2 receptor α and / or thromboxane A2 receptor β (iso) forms of the human thromboxane A2 receptor (also known as the T prostanoid receptor). These thromboxane A2 receptor antagonists are derived from the above receptor and free radicals, as well as from isoprostane 8-iso-prostaglandin (prostaglandin) F 2αFurthermore, they inhibit (antagonize) the action of all other accompanying agents (e.g., endoperoxide prostaglandin G2 / prostaglandin H2 and 20-hydroxyeicosatetraenoic acid) that activate the thromboxane A2 receptor (acting as agonists or partial agonists). The thromboxane A2 receptor is expressed in a range of cell types throughout the body, and the compounds described herein (thromboxane A2 receptor antagonists) target the thromboxane A2 receptor (including thromboxane A2 receptor α and / or thromboxane A2 receptor β) expressed in all of those cell types. Furthermore, alterations in thromboxane A2 receptor expression occur in a range of disease conditions, and the compounds described herein (thromboxane A2 receptor antagonists) target thromboxane A2 receptors (including thromboxane A2 receptor α and / or thromboxane A2 receptor β) expressed in all of these cell types and in different disease conditions, including those in inflammation and cancer. Moreover, these compounds may be used in oral formulations.

[0110] Example 1: Evaluation of the dissolution rate of NTP42:KVA4 Formulations containing a drug with a substituted benzenesulfoneurea of ​​formula IV (hereinafter referred to as NTP42) and a vinylpyrrolidone-vinyl acetate copolymer were successfully prepared. The vinylpyrrolidone-vinyl acetate copolymer was vinylpyrrolidone-vinyl acetate marketed by BASF SE (headquartered in Ludwigshafen, Germany) under the trademark KOLLIDON® VA64 (hereinafter referred to as "KVA"). Formulations containing a pharmaceutically acceptable vinylpyrrolidone-vinyl acetate copolymer KVA (also referred to as NTP42:KVA4) with an NTP42:polymer ratio of 1:4 were prepared using an amorphous solid dispersion approach and a spray-dried dispersion. The above formulations were tested for solubility.

[0111] Figure 1 shows the dissolution rates of two batches of NTP42:KVA4 in biologically simulated fasting state intestinal fluid (FaSSIF; pH 6.5). Samples (10 mg) of NTP42:KVA4 from two demonstration batches (referred to as PSD-1, batch #1 and PSD-1, batch #2) were placed in hydroxypropyl methylcellulose capsules, and their dissolution capacity was evaluated in FaSSIF, pH 6.5. At multiple time points, samples of the above medium were taken for high-performance liquid chromatography (HPLC) analysis to determine the amount of NTP42 released from the sprayed solid dispersion. The data shown are the mean ± mean standard error (SEM) from three independent dissolution experiments for each sprayed solid dispersion.

[0112] In detailed follow-up studies (including pH switching tests) aimed at evaluating the solubility of NTP42:KVA4 in bio-related media with different pH levels that mimic various stages of drug passage through the gastrointestinal tract, NTP42, which remained as the desired amorphous drug product without crystallization or precipitation, was released into media with a pH of ≥ 4.

[0113] Figure 2 shows a graph of the dissolution rate of NTP42:KVA4 at pH 6.5. A sample of NTP42:KVA4 (10 mg) was placed in hydroxypropyl methylcellulose capsules (solid line) or vials (dashed line), and their dissolution was evaluated only using FaSSIF (pH 6.5). At the indicated time points, samples of the media were taken for HPLC analysis to determine the amount of NTP42 released from the sprayed solid dispersion.

[0114] Figure 3 shows a graph of the dissolution rate of NTP42:KVA4 as the pH was changed from pH 1.6 to pH 6.5 over 75 minutes. A sample of NTP42:KVA4 (10 mg) was placed in hydroxypropyl methylcellulose capsules (solid line) or vials (dashed line), and their dissolution was evaluated first in a fasting-mimicking gastric juice (FaSSGF) at pH 1.6, followed by FaSSIF at pH 6.5. At the indicated time points, samples of the respective media were taken for HPLC analysis to determine the amount of NTP42 released from the sprayed solid dispersion.

[0115] Figure 4 shows a graph of the dissolution rate of NTP42:KVA4 at pH 5. A sample of NTP42:KVA4 (10 mg) was placed in hydroxypropyl methylcellulose capsules, and their dissolution was evaluated only in fecal-assisted feeding fluid (FeSSIF) at pH 5. At the indicated time points, samples of the above medium were taken for HPLC analysis to determine the amount of NTP42 released from the sprayed solid dispersion.

[0116] Figure 5 shows a graph of the dissolution rate of NTP42:KVA4 as the pH was changed from pH 4.5 to pH 5 over 75 minutes. A sample of NTP42:KVA4 (10 mg) was placed in hydroxypropyl methylcellulose capsules, and their dissolution was evaluated first in Fed Gastric Dissolution Media (FEDGAS) at pH 4.5, and then switched to FeSSIF at pH 5. At the indicated time points, samples of each medium were taken for HPLC analysis to determine the amount of NTP42 released from the sprayed solid dispersion.

[0117] As shown, dissolution of NTP42:KVA4 did not occur at low pH, i.e., FaSSGF, pH 1.6. Vinylpyrrolidone-vinyl acetate copolymer is highly water-soluble, and its solubility is independent of pH. Therefore, the lack of dissolution of NTP42:KVA4 in FaSSGF, pH 1.6 was surprising. Furthermore, in a test where the pH was switched from FaSSGF, pH 1.6 to FaSSIF, pH 6.5, NTP42 was readily released from NTP42:KVA4. This indicates that vinylpyrrolidone-vinyl acetate copolymer confers a protective effect on NTP42, shielding it from the low pH of FaSSGF, pH 1.6 and retaining it in the complex for release at higher pH (e.g., FaSSIF, pH 6.5).

[0118] Example 2: Rat pharmacokinetic (PK) study NTP42:KVA4 was evaluated in a rat pharmacokinetic study. This study confirmed superior bioavailability and NTP42 drug exposure when administered orally to animals as both a "drug-in-bottle" suspension and a "drug-in-capsule" formulation. NTP42 was administered IV (1 mg / kg) in a dosing vehicle consisting of DMSO, Cremophor-EL, and PBS (10%:10%:80% v / v / v ratio). For the evaluation of sprayed solid dispersion formulations as "drug-in-bottle" and "drug-in-capsule" forms in an in vivo rat pharmacokinetic study, the sprayed-dried material was filled into (ii) gelatin capsules and (iii) hydroxypropyl methylcellulose capsules for the "drug-in-capsule" form, compared to (i) the "drug-in-bottle" form. Here, the sprayed solid dispersion material was administered as a suspension in a 0.5% hydroxypropyl methylcellulose-E3 (w / v) dosing vehicle. Note that the rats were fasted for 16 hours before drug administration.

[0119] The results are shown in Figure 6. This summarizes the pharmacokinetic data of NTP42:KVA4 orally delivered to fasted rats as a suspension in a bottle or as a capsule in a capsule, as shown in Table 1. The data shown are the mean values ​​from four independent animals from each dose group. In Table 1, AUC means area under the curve; Cmax means maximum plasma concentration of NTP42; HPMC means hydroxypropyl methylcellulose; IV means intravenous; and Tmax means the time it takes for the plasma concentration of NTP42 to reach Cmax.

[0120] Example 3: Polymer dissolution comparison Formulations of polymers including NTP42 and polymers, vinylpyrrolidone-vinyl acetate as marketed by BASF SE (headquartered in Ludwigshafen, Germany) (e.g., products marketed under the trademark KOLLIDON® VA64 (abbreviated as "KVA")), polymers marketed by Evonik Industries AG (headquartered in Essen, Germany) under the trademark EUDRAGIT® EPO (hereinafter referred to as "EPO"), polymer hydroxypropyl methylcellulose, polymer hydroxypropyl methylcellulose acetate succinate, and polymer formulations marketed by Evonik Industries AG (headquartered in Essen, Germany) under the trademark EUDRAGIT® L100 were tested. The polymers were tested alone or in the presence of plasticizers (e.g., polyethylene glycol and polyoxyl 40 hydrogenated castor oil or macroglycerol hydroxystearate marketed under the trademark KOLLIPHOR RH40).

[0121] Figure 7 shows graphs of the dissolution rates of the above formulations. Samples of each amorphous solid dispersion formulation were placed in a basket, and their dissolution capacity was evaluated only in phosphate buffer, pH 6.5. At the indicated time points, samples of the medium were taken for HPLC analysis to determine the amount of NTP42 released from the amorphous solid dispersion. The graphs are representative of three independent dissolution experiments for each amorphous solid dispersion.

[0122] All NTP42 polymer formulations produced amorphous material. Low levels of degradation were observed in formulations containing KVA and EPO, and these were selected for further testing.

[0123] The solubility of NTP42 and KVA formulations at 1:1, 1:4, and 1:8 NTP42:KVA ratios was compared with that of NTP42 and EPO formulations at 1:4, 1:9, and 1:19 NTP42:EPO ratios. Furthermore, to reduce the level of exposure of the above formulations to moisture during the spray-drying process, formulations incorporating the excipient Syloid were evaluated at 1:1:4 NTP42:Syloid:KVA64 and 1:1:4 NTP42:Syloid:EPO ratios.

[0124] Figure 8 shows graphs of the dissolution rates of the above formulations. Samples of each spray solid dispersion formulation were placed in hydroxypropyl methylcellulose capsules, and their dissolution capacity was evaluated in FaSSIF, pH 6.5 medium alone. At the indicated time points, samples of the medium were taken for HPLC analysis to determine the amount of NTP42 released from the spray solid dispersion. The graphs are representative of three independent dissolution experiments for each spray solid dispersion.

[0125] Figure 9 shows graphs of the dissolution rates of the above formulations. Samples of each spray solid dispersion formulation were placed in hydroxypropyl methylcellulose capsules, and their dissolution capacity was evaluated, first in FaSSGF, pH 1.6 medium, and then switched to FaSSIF, pH 6.5 medium. At the indicated time points, samples of the above medium were taken for HPLC analysis to determine the amount of NTP42 released from the spray solid dispersion. The graphs are representative of three independent dissolution experiments for each spray solid dispersion.

[0126] As shown, the SSD formulation was evaluated for solubility in bio-related FaSSIF (pH 6.5) and in pH switching experiments. Here, solubility was evaluated in FaSSGF (pH 1.6) medium, followed by FaSSIF, pH 6.5. Maximum solubility (≧80%) of NTP42 in FaSSIF, pH 6.5 was observed for NTP42:vinylpyrrolidone-vinyl acetate copolymer at a drug:polymer ratio of 1:8. Regarding pH switching evaluation, maximum solubility of the EPO-based spray solid dispersion formulation was observed in FaSSGF pH 1.6 medium, which released approximately 80% of NTP42.

[0127] However, after approximately 30 minutes, recrystallization occurred, as indicated by a rapid decrease in NTP42 present in the medium. Furthermore, dissolution increased with the pH change from FaSSGF, pH 1.6 to FaSSIF, pH 6.5, but this was transient, and a decrease in soluble NTP42 was observed.

[0128] At low pH levels, the vinylpyrrolidone-vinyl acetate copolymer-based spray solid dispersion formulation did not dissolve, but dissolution occurred in FaSSIF (pH 6.5) medium. Since the solubility of vinylpyrrolidone-vinyl acetate copolymer is pH-independent, the lack of dissolution of NTP42 in FaSSGF (pH 1.6) medium was surprising. Furthermore, dissolution occurred after the pH change, although it was reduced compared to the dissolution that occurred with FaSSIF, pH 6.5 alone.

[0129] In light of the surprising findings regarding dissolution data in FaSSIF (pH 6.5) (where nearly 100% dissolution of NTP42 was observed at NTP42:KVA in a 1:8 drug:polymer ratio) and the lack of dissolution of vinylpyrrolidone-vinyl acetate copolymer-based spray solid dispersions in FaSSGF (pH 1.6), further dissolution tests were conducted comparing NTP42:KVA at 1:4 and 1:8 drug:polymer ratios.

[0130] These included the following surveys: (i) Repeated dissolution of FaSSIF (pH 6.5) and bio-related FaSSGF in a pH switching medium from pH 1.6 to FaSSIF (pH 6.5) (here, the dissolution of sprayed solid dispersion material in capsules was compared to that of its powder in vials). (ii) Dissolution in feeding-mimicking intestinal fluid (FeSSIF; pH 5.0) and by switching the pH from a biological feeding-mimicking gastric lysis medium (FEDGAS, pH 4.5) to a FeSSIF (pH 5.0) medium.

[0131] Figure 10 shows a graph of the dissolution rate of NTP42 from NTP42:KVA formulations in FaSSGF. Samples of NTP42:KVA formulations with 1:4 (NTP42:KVA4) and 1:8 (NTP42:KVA8) drug-to-polymer ratios were placed in vials (solid line) or, for comparison, in hydroxypropyl methylcellulose capsules (dashed line), and their dissolution capacity was evaluated in FaSSGF, pH 6.5 medium alone. At the indicated time points, samples of the above medium were taken for HPLC analysis to determine the amount of NTP42 released from the sprayed solid dispersion. The graph is representative of three independent dissolution experiments for each sprayed solid dispersion.

[0132] Figure 11 shows a graph of the dissolution rates of NTP42:KVA formulations in the FASSGF to FASSIF test. Samples of NTP42:KVA formulations with 1:4 (NTP42:KVA4) and 1:8 (NTP42:KVA8) drug-to-polymer ratios were placed in vials (solid line) or, for comparison, in hydroxypropyl methylcellulose capsules (dashed line). Their dissolution capacity was evaluated, first in FaSSGF, pH 1.6 medium, and then switching to FaSSIF, pH 6.5 medium. At the indicated time points, samples of the above mediums were taken for HPLC analysis to determine the amount of NTP42 released from the sprayed solid dispersion. The graph is representative of three independent dissolution experiments for each sprayed solid dispersion.

[0133] Consistent with the findings of the NTP42 and EPO comparative study, dissolution of both NTP42:KVA spray solid dispersion formulations occurred in the FaSSIF medium alone, where the degree of dissolution was greater for the spray solid dispersion powder in the vial compared to the powder in the capsule. Maximum dissolution of both NTP42:KVA formulations was observed in the pH switching dissolution test. A significant improvement was observed here for the 1:4 ratio of NTP42:KVA. From these dissolution tests, it was concluded that KVA conferred protection on NTP42, shielding it from the acidic environment of the stomach (i.e., FaSSGF, pH 1.6) and maintaining it in the complex for release at higher pH (e.g., FaSSIF, pH 6.5).

[0134] Figure 12 shows a graph of the dissolution rates of NTP42:KVA formulations in FeSSIF, pH 5. Samples of NTP42:KVA formulations with 1:4 (NTP42:KVA4) and 1:8 (NTP42:KVA8) drug-to-polymer ratios were placed in hydroxypropyl methylcellulose capsules, and their dissolution capacity was evaluated in FeSSIF, pH 5 medium alone. At the indicated time points, samples of the medium were taken for HPLC analysis to determine the amount of NTP42 released from the sprayed solid dispersion. The graph is representative of three independent dissolution experiments for each sprayed solid dispersion.

[0135] Figure 13 shows graphs of the dissolution rates of NTP42:KVA formulations in FEDGAS, pH 4.5 to FeSSIF, pH 5 tests. Samples of spray solid dispersion formulations (NTP42:KVA at 1:4 and 1:8 drug:polymer ratios) were placed in hydroxypropyl methylcellulose capsules, and their dissolution capacity was evaluated in FeSSIF, pH 5 alone. At the indicated time points, samples of the above media were taken for HPLC analysis to determine the amount of NTP42 released from the spray solid dispersion. The graphs are representative of three independent dissolution experiments for each spray solid dispersion.

[0136] In FeSSIF medium (pH 5), the dissolution of NTP42:KVA4 was greater than that of NTP42:KVA8, but at the lower pH of FEDGAS (pH 4.5), the dissolution of NTP42:KVA4 was slower than that of NTP42:KVA8.

[0137] Example 4: Rat pharmacokinetic (PK) study for polymer comparison Furthermore, NTP42:KVA spray solid dispersion formulations at 1:4 and 1:8 drug:polymer ratios were confirmed to provide good exposure to rats after oral delivery in PK studies. NTP42 was administered IV (1 mg / kg) in a dosing vehicle consisting of DMSO, Cremophor-EL, and PBS (10%:10%:80% v / v / v ratio). For evaluation of the spray solid dispersion formulation as a "drug in a bottle" form in in vivo rat pharmacokinetic (PK) studies, spray-dried material was administered in a dosing vehicle, 0.5% hydroxypropyl methylcellulose-E3.

[0138] Figure 14 shows a summary of pharmacokinetic data for NTP42:KVA4 at 1:4 and 1:8 drug:polymer ratios, as shown in Table 2. The data shown are the mean values ​​from four independent animals from each dose group. In Table 2, AUC represents the area under the curve; Cmax represents the maximum plasma concentration of NTP42; IV represents intravenous; and Tmax represents the time it takes for the plasma concentration of NTP42 to reach Cmax.

[0139] Example 5: Human oral administration study NTP42:KVA4 was administered to human subjects in an oral form. NTP42:KVA4 was found to be suitable for oral administration. NTP42:KVA4 remained intact as a drug:polymer complex, protected in the low pH of the stomach, but ready to dissolve in the higher pH of the intestines for maximum absorption.

[0140] Example 6: Demonstration of in vivo efficacy of NTP42:KVA4 in a rat monoclotaline (MCT) model of pulmonary arterial hypertension (PAH) NTP42:KVA4 will be evaluated in preclinical efficacy trials in monocrotaline (MCT) models of pulmonary arterial hypertension (PAH). The data presented here are shown in these examples.

[0141] As an unformulated drug, NTP42 demonstrated efficacy in both monoclotaline (MCT) and Sugen5416 / hypoxia (Su / Hx)-inducible models of PAH in rats. See Mulvaney et al. BMC Pulmonary Medicine (2020) 20:85 & Mulvaney et al. Eur J Pharmacol (2020) 889:173658 (both cited as references).

[0142] Following the development and manufacture of the formulated drug product, NTP42:KVA4, the above-mentioned MCT-induced PAH rat model was used to demonstrate its efficacy in a preclinical model of PAH. MCT is a known toxin that selectively induces pulmonary artery injury characterized by endothelial and vascular damage, in situ thrombosis at narrowing sites, and the development of pulmonary edema. Remodeling of damaged endothelial and vascular cells leads to obliteration of the vascular lumen, thereby restricting blood flow through the pulmonary artery and increasing pulmonary artery pressure (PAP). This, in turn, increases right ventricular (RV) afterload, resulting in the development of significant RV hypertrophy in MCT-treated rats.

[0143] To evaluate the efficacy of NTP42 when delivered as the oral formulation NTP42:KVA4 in an MCT-induced model of PAH, rats received a single subcutaneous injection of either MCT (60 mg / kg) solution or saline (without MCT) at the start of the study.

[0144] Figure 15 illustrates the experimental design of a preclinical efficacy trial in a rat monoclotaline (MCT)-induced pulmonary arterial hypertension (PAH) model.

[0145] On day 0, male Sprague-Dawley rats (7-9 weeks old and weighing 284g-424g) were subcutaneously injected with either monoclotaline (MCT; 60mg / kg) as a single dose or with control saline (without MCT).

[0146] Drug treatment was initiated on day 7, during which animals were treated twice daily (BID) for 22 days with either NTP42:KVA4 (1 mg / kg) or a placebo (30 mg / kg BID KOLLIDON VA 64) as a negative control. All treatments were administered orally via gastric tube as a suspension in 0.5% (w / v) hydroxypropyl methylcellulose (HPMC).

[0147] On day 29, after MCT induction, rats were anesthetized for cardiac surgery, and hemodynamic parameters were recorded. Baseline echocardiographic (ECHO) evaluations were performed on five randomly selected animals from each group on day 6 and on day 29, prior to the final hemodynamic surgery.

[0148] On the day of surgery (day 29), hemodynamic parameters (systemic arterial pressure, right ventricular blood pressure, and pulmonary blood pressure; as well as heart rate) were recorded in anesthetized rats. The lungs and hearts were then removed and weighed. The left lung was washed with saline solution and then perfused with 10% unbuffered formalin (NBF). The heart was resected to facilitate measurements of the right ventricle (RV) and left ventricle + septum in order to determine the Fulton index. Histological analysis was performed within the lungs for pulmonary vascular remodeling (vascular morphometry and α-smooth muscle actin (SMA) expression), lung inflammation (CD68+ macrophages), and pulmonary fibrosis (Mason's trichrome staining). Further histological analysis was performed within the RV for cardiac fibrosis (Mason's trichrome staining).

[0149] The above data (shown in Figures 16-25 and 26) demonstrate that NTP42:KVA4 (1 mg / kg, BID) provides a significant therapeutic benefit and reduces the severity of MCT-induced PAH across numerous disease parameters.

[0150] This includes a reduction in MCT-induced increases in hemodynamic measurements of mean pulmonary pressure (mPAP; Figure 16) and right ventricular systolic pressure (RVSP; Figure 17), without adverse effects on either mean systemic arterial pressure (mAP; Figure 18) or heart rate (HR; Figure 19). NTP42:KVA4 significantly reduced MCT-induced vascular remodeling, as assessed through two histological methods: morphometry (Figure 20) and α-smooth muscle actin expression (Figure 21). Representative histology of lung tissue stained with H&E and α-SMA is shown in Figure 27. Here, treatment with NTP42:KVA4 produced tissue that appeared similar to that of non-pathological (MCT-free control) and was substantially healthier than the placebo control with MCT alone.

[0151] In the heart, NTP42:KVA4 reduced RV hypertrophy as assayed using the Fulton index, and histological evaluation of RV fibrosis demonstrated a significant treatment benefit of NTP42:KVA4 (Figures 22 and 23).

[0152] Further quantitative histological analysis showed that NTP42:KVA4 significantly reduced the degree of fibrosis around small pulmonary arterioles and reduced the MCT-induced increase in CD68+ macrophage infiltration (Figures 24 and 25).

[0153] Figures 16–25 show the effect of NTP42:KVA4 on monocotaline-induced pulmonary arterial hypertension in rats. Male Sprague-Dawley rats were subcutaneously injected with either a single dose of monocotaline (MCT; 60 mg / kg) or no saline (MCT) as a control. From day 7 after MCT injection, the animals were treated twice daily for 22 days with either NTP42:KVA4 (1 mg / kg) or placebo (30 mg / kg BID KOLLIDON VA 64) as a negative control. All treatments were administered orally via gastric tube as a suspension in 0.5% (w / v) hydroxypropyl methylcellulose (HPMC). On day 29, after MCT induction, the rats were anesthetized for cardiac surgery and hemodynamic parameters were recorded. Subsequently, the heart and lungs were removed together, their wet weights were recorded, and then they were fixed and processed for histopathology. The data included in this figure includes the following:

[0154] Figure 16 shows the mean pulmonary artery pressure (mPAP).

[0155] Figure 17 shows the right ventricular systolic pressure (RVSP).

[0156] Figure 18 shows the mean systemic arterial pressure (mAP).

[0157] Figure 19 shows heart rate (HR).

[0158] Figure 20 shows pulmonary vascular remodeling as vascular occlusion measured by morphometric evaluation on hematoxylin and eosin (H&E) stained sections.

[0159] Figure 21 shows pulmonary vascular remodeling as measured by the assessment of the degree of muscle hypertrophy on anti-α-SMA stained sections.

[0160] Figure 22 shows the Fulton index for RV hypertrophy.

[0161] Figure 23 shows cardiac (RV) fibrosis.

[0162] Figure 24 shows the degree of lung inflammation based on an analysis of CD68+ macrophage density.

[0163] Figure 25 shows pulmonary fibrosis. For all of Figures 16-25, mean (±SEM) data are shown, where asterisks indicate a significant difference from the control group without MCT, and hashes indicate a significant difference from the placebo group with MCT only, where * / #, ** / ##, *** / ###, and **** / #### correspond to p<0.05, p<0.01, p<0.001, and p<0.0001, respectively.

[0164] Figure 26 is a table showing the effect of NTP42:KVA4 on monoclotaline-induced pulmonary arterial hypertension in rats.

[0165] Abbreviations: BID, bis in die; bpm, heart rate per minute; CD68, surface antigen classification 68; HR, heart rate; mAP, mean systemic arterial pressure; MCT, monoclotaline; mPAP, mean pulmonary pressure; RVSP, right ventricular systolic pressure; SMA, alpha-smooth muscle actin.

[0166] Figure 27 shows lung tissue sections illustrating the effect of NTP42:KVA4 on pulmonary vascular remodeling in an MCT-induced PAH rat model.

[0167] Formalin-fixed, paraffin-embedded (FFPE) lung tissue sections were stained with H&E and anti-α-smooth muscle actin and digitally scanned using the Aperio system. Representative images show the degree of pulmonary vascular remodeling (H&E, left panel) and muscle hypertrophy (anti-α-SMA, right panel) in small pulmonary arterioles (10–50 μm) within the left lung. Morphometric evaluation of H&E-stained slides and evaluation of muscle hypertrophy on anti-α-SMA-stained sections confirmed that NTP42:KVA4 significantly reduced MCT-induced vascular remodeling. For example, MCT-induced increase in percentage vascular occlusion was significantly reduced in animals treated with NTP42:KVA4 (1 mg / kg, BID; p=0.0019). The horizontal scale bar in each image corresponds to 20 μm, and all images were acquired at 40× magnification.

[0168] Example 7: Demonstration of in vivo efficacy of NTP42:KVA4 in inhibiting platelet aggregation ex vivo in non-human primate (NHP) cynomolgus monkeys. The ability of the formulated drug product NTP42:KVA4 to inhibit thromboxane (TX)A2 or its receptor TP-induced platelet aggregation was demonstrated in non-human primate (NHP) cynomolgus monkeys after oral administration. Whole blood platelet aggregation assays were performed ex vivo (n=3) in blood samples collected from NHPs administered 100 mg / kg NTP42:KVA4, BID (200 mg / kg / day) for 14 days. In this type of platelet aggregation assay, a reduction in platelet count indicates platelet aggregation. Blood was collected before the first daily dose (pre-dose) and 45 minutes and 24 hours after the first daily dose. Platelet counts were determined in baseline (untreated) blood samples and in blood samples incubated with the drug vehicle, thromboxane mimic U46619, or other platelet agonists (e.g., ADP, collagen, thrombin, ristocetin, epinephrine) as controls. Baseline platelet count: 120–190 × 10⁶ 3 The levels ranged from platelets / μl.

[0169] As shown in Figure 28, administration of the formulated drug product NTP42:KVA4 ex vivo inhibits TXA2(U46619)-induced platelet aggregation on day 14 post-administration (as measured by a decrease in platelet count), but is ineffective against aggregation induced by other platelet agonists in blood from the same animals.

[0170] Figure 28 shows the whole blood platelet coagulation assay at day 14 after twice-daily oral administration of 100 mg / kg / dose of NTP42:KVA4 in NHP cynomolgus monkeys. The whole blood platelet coagulation assay was performed ex vivo on blood samples collected from NHP (n=3) administered 100 mg / kg NTP42:KVA4, BID (200 mg / kg / day) for 14 days. Blood was collected before the first daily dose (pre-dose) and 45 minutes and 24 hours after the first daily dose. Platelet counts were determined in baseline (untreated) blood samples and in blood samples incubated with the drug vehicle, thromboxane mimic U46619, or 50 μM ADP as a control. In this assay, a decrease in platelet count indicates platelet aggregation.

[0171] Specifically, after vehicle treatment, platelet counts were similar to baseline values, indicating that, as predicted, aggregation did not occur in response to the drug vehicle. No reduction in platelet count was observed at any point in time, even before administration, in response to incubation of blood samples with 1 μM U46619. Supporting pharmacokinetic data confirmed that NTP42 was present in NHP plasma prior to the first daily dose and at levels sufficient to inhibit U46619-mediated platelet aggregation. In contrast, platelet counts were significantly reduced in response to incubation with other platelet agonists. For example, as shown in Figure 28, platelet counts were significantly reduced in response to 50 μM ADP, indicating that platelet aggregation occurred in response to this agonist. After repeated administration of 200 mg / kg / day for 14 days, NTP42 levels in NHP plasma (equivalent to 25 μM), corresponding to a Cmax value of 13,200 ng / ml, were still detectable 24 hours post-administration. Therefore, as predicted, the drug NTP42 selectively inhibited TP-mediated platelet aggregation but did not affect aggregation induced by other platelet agonists (e.g., 50 μM ADP). Definitively, the study concluded that "the absence of U46619-induced platelet aggregation suggests that NTP42 inhibited TP-induced platelet aggregation and may be considered as a pharmacokinetic indicator of TP receptor target engagement."

[0172] Example 8: Formulation for use in treatment The results presented herein indicate that the formulations of this disclosure demonstrate significant cardiovascular and pulmonary benefits and may be used to mitigate the adverse effects of various cardiopulmonary disorders.

[0173] Therefore, embodiments of the present disclosure provide any of the formulations of the present disclosure for use in the treatment of cardiopulmonary conditions. The results show evidence of reduction of pulmonary and cardiac fibrosis after NTP42 / NTP42:KVA4 treatment, which is beneficial in treating pulmonary or cardiac conditions.

[0174] Some embodiments provide formulations of the present disclosure for use in the treatment of pulmonary conditions. Exemplary pulmonary conditions include idiopathic pulmonary fibrosis (IPF); sarcoidosis; autoimmune and connective tissue diseases, e.g., lupus, scleroderma, polymyositis and dermatomyositis, rheumatoid arthritis; exposure / occupational interstitial lung diseases, e.g., asbestosis, silicosis, hypersensitivity pneumonitis; and treatment-related interstitial lung diseases, e.g., after chemotherapy, radiotherapy, or certain drug therapies.

[0175] Certain embodiments provide formulations of the present disclosure for use in the treatment of cardiac conditions. Exemplary cardiac conditions include hypertensive cardiac conditions (e.g., other PH groups other than PAH), as well as left ventricular conditions including heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF); muscular dystrophy (MD) associated with cardiomyopathy (e.g., Duchenne muscular dystrophy (DMD), limb-girdle muscular dystrophy (LGMD), Becker muscular dystrophy (BMD)); idiopathic dilated cardiomyopathy (DCM); diabetic cardiomyopathy; and scarring after myocardial infarction (MI).

[0176] Accordingly, embodiments of the present disclosure provide any of the formulations of the present disclosure for use in methods of treating pulmonary conditions. The pulmonary conditions may be selected from the group consisting of bronchial asthma, chronic obstructive pulmonary disease, COVID-19-related pulmonary hypertension, COVID-19-related pulmonary microembolism, COVID-19-related pulmonary fibrosis, inflammation of the lung, dermatomyositis, idiopathic pulmonary fibrosis, exposure / occupational interstitial lung disease, treatment-related interstitial lung disease, polymyositis, pulmonary arterial hypertension, pulmonary fibrosis, pulmonary hypertension, rheumatoid arthritis, sarcoidosis, scleroderma, and systemic lupus erythematosus.

[0177] Furthermore, embodiments of the present disclosure provide any of the formulations of the present disclosure for use in methods of treating cardiovascular conditions. The cardiovascular conditions may be selected from the group consisting of heart failure, muscular dystrophy, idiopathic dilated cardiomyopathy, diabetic cardiomyopathy, atherothrombosis, stroke, myocardial infarction, atherosclerosis, atherosclerotic vascular disease, thromboembolism, deep vein thrombosis, arterial thrombosis, COVID-19-related cardiovascular microthrombosis, COVID-19-related systemic microvascular thrombosis, ischemia, peripheral vascular disease, peripheral arterial occlusive disease, coronary artery disease, angina pectoris, and transient ischemic attack.

[0178] Consideration The above formulation provides a high-quality drug product suitable for first-in-human Phase 1 clinical trials to evaluate the safety and tolerability of the formulation in a clinical setting.

[0179] Using an amorphous solid dispersion approach, a spray-dried dispersion formulation containing a pharmaceutically acceptable vinylpyrrolidone-vinyl acetate copolymer in a 1:4 NTP42:polymer ratio (referred to as NTP42:KVA4, where the vinylpyrrolidone-vinyl acetate copolymer is abbreviated as KVA and 4 represents the drug:polymer ratio) was found to have improved bioavailability compared to NTP42 alone. As illustrated in Figure 1, NTP42:KVA4 showed enhanced solubility compared to the active pharmaceutical component alone in a biocompatible medium, e.g., fasting-mimicking intestinal fluid (FaSSIF; pH 6.5).

[0180] This invention describes a formulation that provides enhanced solubility and superior exposure and oral bioavailability compared to the active pharmaceutical ingredient NTP42 alone. Furthermore, the candidate drug product, NTP42:KVA4, was found to possess advantageous properties over formulations containing different polymers and different ratios of active pharmaceutical ingredient to polymer. The drug may be administered orally in a "drug in a bottle" form, where NTP42:KVA4 is administered in an appropriate dosing vehicle (e.g., 0.5% hydroxypropyl methylcellulose E3).

[0181] A remarkable advantage of the spray solid dispersion formulation is that the vinylpyrrolidone-vinyl acetate copolymer provides a protective effect to benzenesulfonylurea, shielding it from low pH (e.g., FaSSGF, pH 1.6) and maintaining it within the complex for release at higher pH (e.g., FaSSIF, pH 6.5). Therefore, based on solubility data, benzenesulfonylurea in the complex with vinylpyrrolidone-vinyl acetate in the spray solid dispersion material is protected from the acidic environment of the stomach, pH 1.6, and dispersed in the higher pH environment of the intestine where it can be absorbed to the maximum extent. The pH-dependent solubility and release of benzenesulfonylurea in formulations containing benzenesulfonylurea and vinylpyrrolidone-vinyl acetate copolymer have been discovered.

[0182] Surprisingly, reducing the drug load (for example, in the case of benzenesulfonylurea in a vinylpyrrolidone-vinyl acetate complex at a 1:8 ratio (benzenesulfonylurea:vinylpyrrolidone-vinyl acetate)) did not result in enhanced solubility at low pH (e.g., FaSSGF, pH 1.6). Furthermore, increasing the drug load (for example, in the case of benzenesulfonylurea in a vinylpyrrolidone-vinyl acetate complex at a 1:1 ratio (benzenesulfonylurea:vinylpyrrolidone-vinyl acetate)) did not alter the release of benzenesulfonylurea or enhance its solubility when switching from a low pH (e.g., FaSSGF, pH 1.6) to a higher pH (e.g., FaSSIF, pH 6.5).

[0183] In contrast, formulations of nonsteroidal anti-inflammatory drugs (NSAIDs) and NSAIDs in polymer complexes exhibit drug load-dependent dissolution rates. For example, NSAIDs with low drug loads often dissolve entirely in a low pH environment, regardless of the complex in which they are formulated. Therefore, the dissolution properties of the formulations of the present invention are unique and completely different from those observed in other drug and drug-polymer formulations.

[0184] Furthermore, many drugs, such as nonsteroidal anti-inflammatory drugs, are preferably formulated from compressed / compacted materials and hot-melt extrusion manufacturing processes. In contrast, the benzenesulfonylurea:vinylpyrrolidone-vinyl acetate formulation of the present invention has been found to have improved solubility and bioavailability when formulated as an amorphous solid dispersion, such as a spray-dried dispersion. This process, in contrast to hot-melt extrusion, allows the complex to be formed at a controlled temperature to preserve the internal chemistry of the benzenesulfonylurea so that it can effectively act as an antagonist of the T prostanoid receptor when maximally released in the intestine.

[0185] The various embodiments of the present invention described herein may be used in combination with one or more other embodiments, provided that they do not conflict with technical specifications. The present invention provides, for example, the following items: (Item 1) Drugs containing substituted benzenesulfonylureas; and Pharmacologically acceptable polymers, A formulation containing a solid dispersion containing [a specific substance]. (Item 2) The formulation according to item 1, wherein the polymer is vinylpyrrolidone-vinyl acetate copolymer, dimethylaminoethyl methacrylate copolymer, or hydroxypropyl methylcellulose. (Item 3) The formulation according to item 1, wherein the pharmaceutically acceptable polymer is a vinylpyrrolidone-vinyl acetate copolymer. (Item 4) The formulation is an amorphous solid dispersion, as described in item 3. (Item 5) The formulation is a spray-dried dispersion, as described in item 4. (Item 6) The formulation described in item 5, which is formulated for oral administration. (Item 7) The formulation according to item 6, wherein the oral administration form is in the form of a tablet, vial, sachet, or capsule. (Item 8) The formulation described in item 1, wherein the formulation is less soluble in a lower pH environment than in a higher pH environment. (Item 9) The formulation described in item 3 does not dissolve at a pH of less than 2. (Item 10) The formulation according to item 9, wherein the formulation is substantially soluble at a pH higher than 5. (Item 11) The formulation according to item 5, wherein the ratio of benzenesulfonylurea to polymer is between about 1:1 and about 1:8, preferably about 1:4. (Item 12) The formulation according to item 5, wherein the ratio of benzenesulfonylurea to polymer is 1:4. (Item 13) The aforementioned benzenesulfonylurea is a compound of formula (I):

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Claims

1. Formula (IV): 【Chemistry 16】 Compounds containing substituted benzenesulfonylurea or pharmaceutically acceptable salts thereof; and Vinylpyrrolidone-vinyl acetate copolymer, A formulation comprising a spray-dried amorphous solid dispersion containing the substituted benzenesulfonylurea, wherein the ratio of the substituted benzenesulfonylurea to the vinylpyrrolidone-vinyl acetate copolymer is 1:4 or 1:

8.

2. The formulation according to claim 1, wherein the ratio is 1:4; the formulation does not dissolve at a pH less than 2; and more than 60% of the formulation dissolves in 25 minutes or less at a pH greater than 5.

3. The formulation according to claim 2, which is formulated for oral administration.

4. The formulation according to claim 2 for use in the treatment of pulmonary conditions.

5. The formulation according to claim 2 for use in the treatment of pulmonary arterial hypertension.

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