Formulations of rock2 inhibitors for cns disorders

Abstract

The present disclosure provides methods of treating cerebral cavernous malformations and Devic's disease with ROCK2 inhibitors. The present disclosure also provides pharmaceutical formulations for oral administration of ROCK2 inhibitors for the treatment of cerebral cavernous malformations and Devic's disease.

Description

Technical Field

[0001] This disclosure provides a method for treating cavernous malformations and Derweal's disease with a ROCK2 inhibitor. This disclosure also provides pharmaceutical formulations of Rho-associated protein kinase (ROCK) inhibitors, particularly ROCK2 inhibitors, for oral administration in the treatment of cavernous malformations and Derweal's disease. Background Technology

[0002] Rho-associated coiled-coil kinase (ROCK) is a serine / threonine kinase from the AGC (PKA, PKG, and PKC) kinase family and includes two isoforms, ROCK1 and ROCK2. These two isoforms are expressed and regulated differently in specific tissues. For example, ROCK1 is generally expressed at relatively high levels, while ROCK2 is preferentially expressed in certain tissues, including the heart, brain, and skeletal muscle. ROCK is a target of the small GTPase Rho and is involved in various cellular activities through phosphorylation of downstream effector proteins (MLC, LIMK, ERM, MARCKS, CRMP-2, etc.). Studies have shown that many diseases (such as pulmonary fibrosis, cardiovascular and cerebrovascular diseases, neurological diseases, and cancer) are associated with ROCK-mediated pathways. Therefore, ROCK2 is considered an important target for developing potential drug therapies.

[0003] Many potential drugs have low bioavailability when taken orally. When taken orally, the bioavailability of a drug's active ingredient depends on the extent to which it is absorbed from the gastrointestinal environment through the gastrointestinal mucosa. Lipophilic drug substances may be difficult to absorb from the gastrointestinal tract, especially because of their poor solubility and / or dispersibility in water. For lipophilic and / or poorly soluble drugs, there is a need for oral formulations. Summary of the Invention

[0004] This disclosure provides a method for treating CNS diseases, including cerebral cavernous malformation (CCM) and Dervédex disease, by administering a pharmaceutical preparation for oral administration of a ROCK2 inhibitor to patients in need.

[0005] In one respect, pharmaceutical preparations used to treat CCM or Derweal's disease contain: (a) About 1% to 15% by weight of compounds having the following structure: Or its pharmaceutically acceptable salt; (b) Approximately 15% to 50% by weight of a fatty acid component comprising saturated and / or unsaturated C8-C 24 Fatty acids and / or their pharmaceutically acceptable salts; (c) About 30% to 50% by weight of a first glycerol ester component comprising one or more glycerol ester compounds having the structure of formula (I). (I) in: R 1 R 2 and R 3 Each is independently hydrogen or -C(O)-R A ; R A Each is independently a C7-C containing one or two double bonds. 21 alkenyl, The condition is R 1 R 2 and R 3 At least one of them is not hydrogen; and (d) About 10% to 35% by weight of a second glycerol ester component comprising one or more glycerol ester compounds having the structure of formula (II). (II) in: R 4 R 5 and R 6 Each is independently hydrogen or -C(O)-R B ; R B Each is independently C7-C 21 alkyl, The condition is R 4 R 5 and R 6 At least one of them is not hydrogen.

[0006] APIs can include the following pharmaceutically acceptable salts: , Especially its HCl salt.

[0007] In some embodiments, the pharmaceutical formulation may suitably include saturated or unsaturated C 12 -C 18 Fatty acids (e.g., oleic acid) and / or their pharmaceutically acceptable salts (e.g., sodium oleate).

[0008] In some embodiments, the pharmaceutical formulation may suitably include a first glycerol ester component comprising one or more of the following: mono-, di-, and / or tri-fatty acid esters of glycerol, comprising at least one unsaturated fatty acid (e.g., straight-chain or branched C7-C...). 21 (Alkenyl chain).

[0009] In some embodiments, the pharmaceutical formulation may suitably include a second glycerol ester component, the second glycerol ester component comprising one or more of the following: mono-, di-, and / or tri-fatty acid esters of glycerol, including saturated fatty acids (e.g., straight-chain or branched C7-C...). 21 Alkyl chain).

[0010] In one aspect, a method for treating neuromyelitis optica is provided by administering a pharmaceutical preparation, as described herein, to a patient in need.

[0011] In another aspect, a method for treating CCM is provided by administering a pharmaceutical preparation, as described herein, to a patient in need.

[0012] Other aspects of this disclosure are provided in [link to disclosure]. The following text . Attached Figure Description

[0013] Figure 1 The mean oral p-value profile of a 10 mg / kg formulation of compound A-HCl (F4 100% solid dispersion with nanosuspension) in male and female beagle dogs is shown.

[0014] Figure 2 The mean oral p-value profiles of 50 mg / kg formulations of compounds A-HCl (F4, F5, and F6) in SD rats are shown.

[0015] Figure 3 The mean oral p-value profiles of compound A-HCl formulations (F4, F5, and F6) at 10 mg / kg in beagle dogs are shown.

[0016] Figure 4 The mean oral PK profiles of compound A-HCl formulations (F4 and F4a) at 10 mg / kg in beagle dogs are shown.

[0017] Figure 5A and 5B The mean oral pharmacokinetic parameters (C10) of compound A-HCl formulations (F4, F4 50:50 molecular and solid dispersions, and F4 100% solid dispersion) in male and female beagle dogs are shown. max (and AUC).

[0018] Figures 6A-6P The tissue distribution of the formulations in Table 7 after oral administration is shown.

[0019] Figure 7 The diagram shows a timeline of the in vivo experimental protocol for testing compound A in a mouse model of cavernous malformation. Detailed Implementation

[0020] This disclosure provides a method for treating central nervous system disorders, particularly cavernous malformations and Derweal's disease, comprising orally administering to a patient in need a pharmaceutical composition comprising a therapeutically effective amount of a ROCK2 inhibitor, particularly (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-1H-indol-2-yl)(3,3-difluorozacyclobutane-1-yl) methyl ketone or a pharmaceutically acceptable salt thereof. The oral pharmaceutical formulations disclosed herein may provide enhanced bioavailability of the ROCK2 inhibitor and / or enhanced CNS exposure to the ROCK2 inhibitor.

[0021] definition As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen (N), oxygen (O), and sulfur (S).

[0022] The term "halogen" or "halogenated" refers to -F, -Cl, -Br, or -I. Preferred halogens are -F, -Cl, and -Br.

[0023] The term "hydroxyl" refers to -OH.

[0024] As used herein, the term "oxo" refers to an oxygen atom that forms a double bond with another atom (i.e., a substituent =O), particularly with carbon.

[0025] Unless otherwise stated, the term "alkyl" on its own, or as part of another substituent, means a fully saturated straight-chain (i.e., unbranched) or branched carbon chain (or carbon) or combination thereof. Alkyl groups may include a specified number of carbons (e.g., C1-C1). 10 (Represents one to ten carbons). Alkyl groups are uncyclic chains. Examples of alkyl radicals include, but are not limited to, homologues and isomers of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, methyl groups, such as n-pentyl, n-hexyl, n-heptyl, n-octyl groups, etc.

[0026] The term "alkoxy" refers to an alkyl group that is attached to the rest of the molecule via an oxygen linker (-O-).

[0027] The term "alkenyl" refers to a straight-chain or branched hydrocarbon chain having one or more carbon-carbon double bonds. Alkenyl groups can include a specified number of carbons (e.g., C2-C). 10 (Representing two to ten carbons). An alkenyl group is an uncyclic chain. Alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc. When the compounds of this disclosure contain an alkenyl group, the compounds may exist in E-form, Z-form, or any mixture thereof.

[0028] The term "alkynyl" refers to a straight-chain or branched hydrocarbon chain with a triple bond. Alynyl groups include ethynyl, propynyl, etc.

[0029] The term "cycloalkyl" refers to a saturated carbocyclic group having 3 to 7 carbons in its ring. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0030] As used herein, the term "aryl" includes 5- and 6-membered monocyclic aromatic groups that may contain zero to four heteroatoms, such as benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl groups having heteroatoms in their ring structures may also be referred to as "aryl heterocycles," "heteroaromatics," or "heteroaryl." The term "aryl" also includes 7- to 14-membered polycyclic cyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings (the rings are "fused rings"), wherein at least one ring is aromatic (including heteroaryl), for example, the other rings may be fused cycloalkyl, cycloalkenyl, aryl, heteroaryl, and / or heterocyclic groups. Monocyclic heteroaryl groups may have 1 to 3 ring heteroatoms, and fused polycyclic heteroaryl groups may have 1 to 5 ring heteroatoms, wherein the ring heteroatoms are selected from N, O, and S.

[0031] The terms "heterocyclic group," "heterocyclic," or "heterocyclic alkyl group" refer to a 3- to 10-membered ring structure, more preferably a 5- or 6-membered ring, whose ring structure includes one to four heteroatoms. Heterocycles can also be polycyclic. Heterocyclic groups include, for example, thiophene, thiathrone, furan, pyran, isobenzofuran, chromene, xanthan, phenothiazine, pyrrole, imidazole, pyrazole, isothiazine, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indoleazine, isoindole, indole, indazole, purine, quinazine, isoquinoline, quinoline, phthalazine, naphthidine, quinoxaline, quinoxaline, cyclophosphine, pteridine, carbazole, caroline, phenanthridine, acridine, pyrimidine, phenanthrene, phenazine, phenpyrazine, phenothiazine, furazine, phenothiazine, pyrrolidine, oxaloolidine, oxopentane, tetrahydrothiophene, oxazole, piperidine, piperazine, morpholine, lactone, lactam such as azacyclobutanone and pyrrolidone, sulopentatamide, sulfonyl lactone, etc.

[0032] As used herein, the terms “alkylaryl” and “aralkyl” refer to a C1-C6 alkyl group that has been substituted by an aryl group (e.g., an aromatic or heteroaromatic group).

[0033] As used herein, when each expression (e.g., alkyl, m, n, R, etc.) appears more than once in any structure, its definition is intended to be independent of its definition elsewhere in the same structure.

[0034] It should be understood that “substituted,” “replaced,” or “replaced by / through / by…” includes the implicit condition that such substitution is consistent with the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, which does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc.

[0035] The term "pharmaceutically acceptable salt" refers to the relatively non-toxic inorganic and organic acid addition salts of the compounds disclosed herein, as well as the inorganic and organic basic addition salts of the compounds disclosed herein. It should be understood that references to ROCK2 inhibitors include neutral compounds and any pharmaceutically acceptable salts of ROCK2 inhibitors. The form of a pharmaceutically acceptable salt may be selected based on the chosen route of administration and in accordance with standard pharmaceutical practice.

[0036] As described above, certain embodiments of ROCK2 inhibitors may contain a basic functional group, such as an amino group, and be capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. These salts may be prepared in situ in an administration medium or during a dosage form manufacturing process, or by reacting the purified compound of the invention, in its free base form, alone with a suitable organic or inorganic acid and separating the resulting salt during subsequent purification. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, methanesulfonate, gluconate, lactobionate, and laurylsulfonate, etc. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).

[0037] Pharmaceutically acceptable salts of the compounds of this invention include, for example, conventional non-toxic salts or ammonium salts derived from non-toxic organic or inorganic acids. Such conventional non-toxic salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethylsulfonic acid, etc.

[0038] In other cases, the compounds provided in this disclosure may contain one or more acidic functional groups, thus enabling them to form pharmaceutically acceptable salts with pharmaceutically acceptable bases. These salts can also be prepared in situ during the manufacture of the administration medium or dosage form, or by reacting a purified compound in its free acid form with a suitable base (e.g., a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation), ammonia, or a pharmaceutically acceptable primary, secondary, or tertiary organic amine alone. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (See, for example, Berge et al. above).

[0039] Some of the compounds provided in this disclosure may exist in specific geometric or stereoisomeric forms. This disclosure contemplates all such compounds falling within the scope of the invention, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, racemic mixtures thereof, and other mixtures thereof. Other asymmetric carbon atoms may be present in substituents, such as alkyl groups. All such isomers and mixtures thereof are included in this invention.

[0040] Unless otherwise stated, all percentages are weight percentages (wt%). Regarding the amount of components in a pharmaceutical preparation (e.g., API, fatty acid component, primary glyceride component, secondary glyceride component, etc.), the weight percentage of the component does not include the weight of the capsule shell or coating. In other words, the total weight of the pharmaceutical preparation used to calculate the weight % of each component includes the filling component (e.g., API, fatty acid component, primary glyceride component, secondary glyceride component, etc.), but excludes the capsule shell or coating.

[0041] Active pharmaceutical ingredient (API) This disclosure provides a method for treating central nervous system disorders, particularly cavernous malformations and Derweal's disease, the method comprising administering a pharmaceutical preparation containing one or more ROCK2 inhibitors to a patient in need.

[0042] In one respect, ROCK2 inhibitors have a structure of formula (AI): (AI) Or its pharmaceutically acceptable salt, wherein: R A1 Choose from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halogenated, -CN, C1-C3 perfluoroalkyl, -OR A11 -O-(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-ORA11 -NR A11 R A12 -O-(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl) x -C(=O)R A11 -O-(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 -C(=O)OR A11 -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 -NR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 , and -NR A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 ; R A2 Choose from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halogenated, -CN, C1-C3 perfluoroalkyl, -OR A11 -O-(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-OR A11 -NR A11 R A12 -O-(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl) x1 -C(=O)RA11 -O-(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 -C(=O)OR A11 -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 -NR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 , and -NR A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 ; Alternatively, R A1 and R A2 Together, they form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0 to 2 cyclic heteroatoms selected from the group consisting of N, O, and S, and the fused ring is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halogenated, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR A11 R A12 -O-(C1-C6 alkyl)-NR A11 R A12 C1-C3 perfluoroalkyl, -NR A11 -(C1-C6 alkyl)NR A11 R A12 , and -NR A11 -(C1-C6 alkyl)-OR A11 ; R A3 and R A4 Each is independently selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclic groups, C6-C 10 Aryl, 5- to 14-membered heteroaryl, C 6-12 Aryl, -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1-C(=O)OR A11 and -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 ; Alternative R A3 and R A4 Together with the nitrogen attached thereto, they provide (i) 4- to 6-membered heterocycles having 0 to 2 additional cyclic heteroatoms selected from N, O, and S, or (ii) 5- to 10-membered heterobicyclic systems having 0 to 3 additional cyclic heteroatoms selected from N, O, and S; wherein said heterocycles or said bicyclic systems are unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of: halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halogenated, -CN, C1-C3 perfluoroalkyl, -OR A11 , O-O-(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-OR A11 -NR A11 R A12 -O-(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 -O-(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 -C(=O)OR A11 -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 -NR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 , and -NR A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 ; Dashed lines represent optional double bonds; RA5 Each is independently selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halogenated, -CN, C1-C3 perfluoroalkyl, oxo, -OR A11 -O-(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-OR A11 -NR A11 R A12 -O-(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 -O-(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 -C(=O)OR A11 -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 -NR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 , and -NR A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 ; n1 It is 0 to 3; R A7 Independently selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1 -C(=O)OR A11and -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 ; x1 Each is independently selected from 0 and 1; and R A11 and R A12 Each is independently selected from the group consisting of: H and C1-C6 alkyl groups; Alternatively, R A11 and R A12 When both are attached to the same nitrogen atom, they form a 4- to 7-membered heterocycle having 0 to 2 additional cyclic heteroatoms selected from the group consisting of N, O, and S, and the heterocycle is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.

[0043] In some implementation schemes, R A3 and R A4 Together with the nitrogen to which they are attached, they provide optionally substituted 4- to 6-membered heterocycles. In some embodiments, -NR A3 R A4 yes It can be substituted or unsubstituted. In some implementations, -NR A3 R A4 yes .

[0044] In some implementation schemes, R A1 and R A2 It is hydrogen.

[0045] In some implementation schemes, R A7 It is an unsubstituted C1-C3 alkyl group. In some embodiments, R A7 It is an unsubstituted methyl group.

[0046] In some implementation schemes, R A5 It is hydrogen, or n1 is 0.

[0047] In some implementations, ROCK2 inhibitors have the following structure: (Compound A) or a pharmaceutically acceptable salt thereof. This compound has the chemical name (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-1H-indol-2-yl)(3,3-difluoroazacyclobutane-1-yl) methyl ketone.

[0048] In some implementations, the pharmaceutically acceptable salt is HCl.

[0049] In some implementations, the API includes HCl salt.

[0050] Compounds of the following synthetic formula (AI) and other disclosed ROCK2 inhibitors may be used and their in vitro ROCK2 inhibitory activity may be determined: for example, WO2019 / 000682, WO 2019 / 000683, WO2019 / 001572, WO2020 / 094111, WO2020 / 177587, WO2020 / 259528, WO2022 / 042711, WO2022 / 042712 and U.S. Patent Nos. 10,323,023, 10,329,282 and 11,390,609, the entire contents of which are incorporated herein by reference.

[0051] ROCK2 inhibitors may comprise about 1% to 15% by weight of the pharmaceutical formulation, or about 1% to 10% by weight of the pharmaceutical formulation, or about 2% to 8% by weight of the pharmaceutical formulation, or about 5% to 7% by weight of the pharmaceutical formulation.

[0052] pharmaceutical preparations This article provides Among other things The pharmaceutical formulation is intended for oral administration to a patient in need, who suffers from cavernous malformation or Dweck's disease. In one aspect, the pharmaceutical formulation comprises (i) an active pharmaceutical ingredient (API) (e.g., a ROCK2 inhibitor, particularly compound A) and (ii) a pharmaceutically acceptable excipient (e.g., a lipid formulation comprising a fatty acid component and / or a glyceride component).

[0053] Pharmaceutical formulations may suitably include additional excipients, such as surfactants, solvents, solubilizers, preservatives, antioxidants, fillers, solubilizers, wetting agents, emulsifiers, suspending agents, antimicrobial agents, pH buffers, sweeteners, flavoring agents, and combinations thereof.

[0054] This disclosure provides a pharmaceutical formulation that enhances the absorption, controlled release, and performance of an API (i.e., a compound of formula (AI), particularly compound A). In some embodiments, the pharmaceutical formulation can improve lymphatic uptake pathways and avoid drug uptake via the portal vein, thereby improving first-pass metabolism.

[0055] For example, the pharmaceutical formulations provided herein can improve the absorption of compound IA (especially compound A) from the gastrointestinal tract after oral administration, and exemplary components of the lipid formulations include, but are not limited to: triglycerides (e.g., tri-fatty acid esters of glycerol, such as saturated or unsaturated esters), monoglycerides (e.g., mono-fatty acid esters of glycerol, such as saturated or unsaturated esters), saturated or unsaturated fatty acids, phospholipids, bile salts, and functionalized lipids (such as phospholipids). These lipid components can be completely or partially digested upon oral ingestion, for example, and ultimately release fatty acids.

[0056] The absorption of ingested fatty acids can depend on the characteristics of the hydrocarbon chain, such as chain length, structure, and geometry. For example, short-chain (e.g., C2 to C6) fatty acids and medium-chain (e.g., C8 to C6) fatty acids... 12 Fatty acids are preferably absorbed via the portal vein during digestion, while long-chain fatty acids (such as C16) are absorbed more readily. 14 To C 22 Fatty acids are primarily absorbed via the lymphatic system. Therefore, during the digestion of lipid formulations of APIs, a micellar mixture of fatty acids and derivatives is generated, allowing the digestive components bound to the API to be absorbed by lipid transporters. This results in the formation of API-containing lipid droplets in the mucosal epithelial cells, which are packaged into neolipoproteins called chylomicrons. These API-loaded chylomicrons are then secreted into the lacteals of the intestinal lymphatic system, where they feed back into the central venous return, allowing the API to distribute throughout the body.

[0057] This disclosure provides a method for treating cerebral cavernous malformations and Dweck's disease, the method comprising administering to a patient in need an oral composition comprising an API comprising compound A or a pharmaceutically acceptable salt thereof (e.g., compound A-HCl), together with a lipid excipient or component, such as a mixture of medium-chain or long-chain mono-, di-, or tri-glycerides, or long-chain fatty acids (C8 to C4). 22 Fatty acids, such as oleic acid), medium-chain or long-chain triglycerides (such as Gelucire 43 / 01), and long-chain surfactants (C 14 To C 22 Fatty acid salts, such as sodium oleate. In some embodiments, the API can be formed as a solid dispersion, a molecular dispersion, a solution, or a combination thereof.

[0058] As used herein, the term "molecular dispersion" refers to a solution (liquid phase) containing a solute (e.g., API, such as compound A, compound A-HCl, etc.) dispersed in a solvent. The dispersed phase (solute, such as API) may be uniformly dispersed in an aqueous solution or an water-based solvent phase or an oil-based solvent phase.

[0059] As used herein, the term "solid dispersion" refers to a system containing a hydrophobic component (e.g., API) dispersed in a matrix, which can be prepared by melt (melt) methods, solvent evaporation, melt extrusion, freeze drying, electrospinning, etc. Solid dispersions may contain particles, for example, having a particle size distribution D. 90 Less than about 100 micrometers, less than about 90 micrometers, less than about 80 micrometers, less than about 70 micrometers, less than about 60 micrometers, less than about 50 micrometers, less than about 40 micrometers, less than about 30 micrometers, less than about 20 micrometers, or less than about 10 micrometers.

[0060] Pharmaceutical formulations may contain one or more fatty acid components, comprising fatty acids and / or pharmaceutically acceptable salts thereof. Pharmaceutical formulations may also contain a first glycerol ester component, comprising a mixture of mono-, di-, or triglyceride esters of glycerol, wherein at least one unsaturated fatty acid (e.g., straight-chain or branched C7-C...) is present. 21 C9-C 21 C 11 -C 21 C 13 -C 17 Or C 15 -C 17 (Alkenyl chain). Pharmaceutical formulations may also contain a second glycerol ester component, which comprises a mixture of mono-, di-, or tri-fatty acid esters of glycerol, wherein these fatty acid esters are saturated fatty acids (e.g., straight-chain or branched C7-C). 21 C7-C 17 Or C7-C 17 Alkyl chain).

[0061] In some respects, a pharmaceutical preparation may include: (i) One or more fatty acid components, comprising fatty acids and / or pharmaceutically acceptable salts thereof; (ii) A first glycerol ester component comprising a mixture of mono-, di-, or triglyceride esters of glycerol, wherein at least one unsaturated fatty acid (e.g., straight-chain or branched C7-C) is present. 21 C9-C 21 C 11 -C 21 C 13 -C 17 Or C 15 -C 17 (alkenyl chain); and (iii) A second glycerol ester component comprising a mixture of mono-, di-, or triglyceride esters of glycerol containing unsaturated fatty acids (e.g., straight-chain or branched C7-C). 21 C7-C 19 C7-C 17 C9-C 21 C9-C19 C9-C 19 C 11 -C 21 C 11 -C 19 Or C 11 -C 17 Alkyl chain).

[0062] Fatty acids may suitably include saturated or unsaturated hydrocarbon chains, such as saturated or unsaturated C8-C... 24 fatty acid.

[0063] As used in this article, "fatty acid" refers to fatty acids containing carboxyl groups (-COOH, -COO). - ) is attached to a hydrocarbon chain (e.g., saturated or unsaturated and straight or branched, preferably straight C7-C). 23 C 11 -C 21 C 13 -C 19 or C 15 -C 17 Compounds or portions thereof (alkyl or alkenyl chains). Fatty acids may exist in pharmaceutically acceptable salt forms (e.g., sodium salts). As those skilled in the art will understand, the number of carbon atoms specified for a particular fatty acid is one more than the number of carbon atoms in its alkyl or alkenyl chain to indicate the carbonyl carbon (i.e., C) of the fatty acid. 18 Fatty acids have C 17 Alkyl or alkenyl chains). Therefore, the fatty acid component may contain one or more of the following: C8-C 24 Fatty acids or C 12 -C 22 Fatty acids or C 14 -C 20 Fatty acids or C 16 -C 18 Fatty acids, which may be saturated or unsaturated, preferably unsaturated, and linear or branched, preferably linear.

[0064] In some embodiments, the fatty acid may be present in a pharmaceutically acceptable salt form (e.g., a sodium salt). In some embodiments, the fatty acid component may include the fatty acid. In some embodiments, the fatty acid component may be a pharmaceutically acceptable salt form of the fatty acid (e.g., a sodium salt). In some embodiments, the fatty acid component may comprise both the fatty acid and a pharmaceutically acceptable salt form of the fatty acid (e.g., a sodium salt).

[0065] Exemplary saturated C8-C 24 Fatty acids include octanoic acid (CH3(CH2)6COOH), capric acid (CH3(CH2)8COOH), and lauric acid (CH3(CH2)6COOH).10 COOH), myristic acid (CH3(CH2)) 12 COOH), palmitic acid (CH3(CH2)) 14 COOH), stearic acid (CH3(CH2)) 16 COOH), arachidic acid (CH3(CH2)) 18 COOH), benzolic acid (CH3(CH2)) 20 COOH), or teicosic acid (CH3(CH2)). 22 COOH). Exemplary saturated C8-C 24 Fatty acids include myristone acid (CH3(CH2)3CH=CH(CH2)7COOH), palmitic acid (CH3(CH2)5CH=CH(CH2)7COOH), hexadecenoic acid (CH3(CH2)8CH=CH(CH2)4COOH), oleic acid (CH3(CH2)7CH=CH(CH2)7COOH), transoleic acid (CH3(CH2)7CH=CH(CH2)7COOH), acetic acid (CH3(CH2)5CH=CH(CH2)9COOH), and linoleic acid (CH3(CH2)4CH=CHCH2CH=CH(CH2)7COOH). Trans-linoleic acid (CH3(CH2)4CH=CHCH2CH=CH(CH2)7COOH), α-linolenic acid (CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7COOH), arachidonic acid (CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3COOH), eicosapentaenoic acid (CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3COOH), erucic acid (CH3(CH2)7CH=CH(CH2) 11 COOH), or docosahexaenoic acid (CH3CH3CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)2COOH).

[0066] In some implementations, the fatty acid may be unsaturated C8-C. 24 C 12 -C 22 C 14 -C 20 or C 16 -C 18 Fatty acids. In some embodiments, the fatty acid may be one or more unsaturated C64 fatty acids. 12 -C 24 C 12 -C22、 C 12 -C 20 or C 12 -C 18 Fatty acids. In some embodiments, the fatty acid may be one or more unsaturated C64 fatty acids. 12 -C 20 Fatty acids. In some implementations, the fatty acid may be unsaturated C. 14 -C 24 C 14 -C 22 C 14 -C 20 or C 14 -C 18 Fatty acids. Preferred fatty acids include unsaturated C. 18 Fatty acids, especially oleic acid (CH3(CH2)7CH=CH(CH2)7COOH).

[0067] In some embodiments, the fatty acid salt contains one or more unsaturated C8-C salts. 24 C 12 -C 22 C 14 -C 20 or C 16 -C 18 Sodium salts of fatty acids. In some embodiments, the fatty acid salt may be an unsaturated C2O2 salt. 12 -C 24 C 12 -C 22、 C 12 -C 20 or C 12 -C 18 Sodium salts of fatty acids. In some embodiments, the fatty acid salt may be an unsaturated C2O2 salt. 14 -C 24 C 14 -C 22 C 14 -C 20 or C 14 -C 18 Sodium salts of fatty acids. Preferred fatty acid salts include unsaturated C64S salts. 18 Sodium salts of fatty acids, especially sodium oleate (CH3(CH2)7CH=CH(CH2)7COONa).

[0068] In the implementation scheme, the fatty acid component comprises a combination of fatty acids and fatty acid salts, examples of which are provided in the preceding paragraphs.

[0069] In one respect, the amount of fatty acid component contained in a pharmaceutical preparation, based on the total weight of the pharmaceutical preparation (i.e., excluding the weight of capsule shells or coatings), is about 15% to 50% by weight, about 20% to 45% by weight, about 30% to 45% by weight, about 35% to 45% by weight, or about 35% to 40% by weight. As used herein, a pharmaceutical preparation refers to a composition comprising an API, fatty acid and triglyceride components, and any other excipients, but excluding capsule shells or coatings.

[0070] In the embodiments, the fatty acid component comprises a combination of fatty acids and fatty acid salts, examples of which are provided in the preceding paragraphs. Based on the weight of the pharmaceutical formulation, the pharmaceutical formulation may contain fatty acids in amounts of about 12% to 48% by weight, about 15% to 45% by weight, about 25% to 40% by weight, about 30% to 40% by weight, or about 35% to 40% by weight. Based on the weight of the pharmaceutical formulation, the pharmaceutical formulation may contain sodium salts of fatty acids in amounts of about 1% to 5% by weight, or about 2% to 4% by weight, or about 2% to 3% by weight. The pharmaceutical formulation may contain oleic acid and sodium oleate.

[0071] The pharmaceutical formulation contains a glyceride component (e.g., a first glyceride component and a second glyceride component), which includes a mixture of mono-, di-, and / or tri-fatty acid esters of glycerol.

[0072] The term "glycerol" refers to compounds containing triols (three -OH groups) and having the following structure: As used herein, the term "glyceride" refers to a compound or portion formed by one to three ester bonds between glycerol and a fatty acid (e.g., one, two, or three fatty acids) and having the following structure: Where R, R′, and R″ are each hydrogen or -C(O)-R AA and R AA It is an alkyl or alkenyl group (e.g., saturated or unsaturated, and straight-chain or branched C7-C). 21 C7-C 19 C7-C 17 C 11 -C 17 C9-C 21 C 11 -C 21 C 13 -C 17 C 15 -C 17 (alkyl and / or alkenyl) and at least one of R, R′ and R″ is not hydrogen.

[0073] As used herein, the terms "monoglyceric ester of glycerol" or "monofatty acid ester of glycerol" refer to compounds or molecules of glycerol linked to a single fatty acid. Monoglycerides can have the following structures: or Each R is independently represented as -C(O)-R AA And R AA It is an alkyl or alkenyl group (e.g., saturated or unsaturated, and straight-chain or branched C7-C). 21 C7-C 19 C7-C 17 C 11 -C 17 C9-C 21 C 11 -C 21 C 13 -C 17 C 15 -C 17 (alkyl and / or alkenyl groups).

[0074] As used herein, the term "diglyceride" or "difatty acid ester of glycerol" refers to a compound or molecule of glycerol linked to two fatty acids, which may be the same or different. Diglycerides can have the following structures: R, R′, and R″ are each independently represented as hydrogen or -C(O)-R AA And R AA It is an alkyl or alkenyl group (e.g., saturated or unsaturated, and straight-chain or branched C7-C). 21 C7-C 19 C7-C 17 C 11 -C 17 C9-C 21 C 11 -C 21 C 13 -C 17 C 15 -C 17 Alkyl and / or alkenyl groups), and one of R, R′, and R″ is hydrogen. Diglycerides can have the following structures: or Where R and R′ are each independently represented as -C(O)-R AA And R AA It is an alkyl or alkenyl group (e.g., saturated or unsaturated, and straight-chain or branched C7-C). 21 (alkyl and / or alkenyl groups).

[0075] As used herein, the term "triglyceride" or "trifatty acid ester of glycerol" refers to a compound or molecule of glycerol linked to three fatty acids, which may be the same or different. Triglycerides can have the following structures: Where R, R′, and R″ are each independently represented as -C(O)-R AA And R AA It is an alkylalkenyl group (e.g., saturated or unsaturated, and straight or branched C7-C). 21 (alkyl and / or alkenyl groups).

[0076] The pharmaceutical formulation may contain up to about 75% glycerides, or up to about 70% glycerides, or up to about 65% glycerides, or up to about 60% glycerides, or up to about 55% glycerides, or up to about 50% glycerides. The formulation may contain at least about 40% glycerides, or at least about 45% glycerides, or at least about 50% glycerides. The glycerides may comprise a first glyceride component and a second glyceride component.

[0077] The first glyceride component may suitably include one or more monoglycerides, diglycerides, and / or triglycerides, comprising at least one C7-C 21 Alkenyl group (including one or two double bonds). The first glycerol ester component comprises one or more glycerol ester compounds having the structure of formula (I). (I) in: R 1 R 2 and R 3 Each is independently hydrogen or -C(O)-R A ; R A Each is independently a C7-C containing one or two double bonds. 21 alkenyl, The condition is R 1 R 2 and R 3 At least one of them is not hydrogen.

[0078] In some implementations, in equation (I), R A Each is independently C7-C 21 C9-C 21 C 11 -C 21 C 13 -C 17 Or C 15 -C 17 Alkenyl (e.g., linear or branched, preferably linear). In some embodiments, R in formula (I)A Each is independently C7-C 21 C7-C 19 C 11 -C 19 , or C 11 -C 17 Alkenyl groups, which include one or two double bonds. In some embodiments, at least one R A Includes C7 alkenyl, C9 alkenyl, C 11 alkenyl, C 13 alkenyl, C 15 alkenyl, C 17 One or more of alkenyl groups and combinations thereof. In some embodiments, at least one R A It is C 17 Alkenyl groups, which include one or two double bonds.

[0079] In one respect, the first glyceride component comprises one or more compounds having one of the following structures: (Ia) (Ib) and (Ic). R 1 R 2 and R 3 As stated above.

[0080] The first glyceride component includes C7-C 21 The weight ratio of at least one monoglyceride, diglyceride, and / or triglyceride compound in the alkenyl group may be about 32 to 52:40 to 55:5 to 20. In some embodiments, the first glyceride component may include compounds of formula (Ia), formula (Ib), and formula (Ic) in a weight ratio of about 32 to 52:40 to 55:5 to 20.

[0081] The first glyceride component includes C7-C 21 The weight ratio of at least one monoglyceride, diglyceride, and / or triglyceride in the alkenyl group may be about 32 to 52: 40 to 55: 5 to 20. In some embodiments, the first glyceride component may alternatively include compounds of formula (Ia), formula (Ib), and formula (Ic) having the following weight ratio: about 32 to 52: 40 to 55: 5 to 20.

[0082] Alternatively, the first glycerol ester component may primarily (i.e., greater than 50% by weight) comprise monoglycerides, which include C7-C 21 At least one of the alkenyl groups. In some embodiments, the first glycerol ester component may primarily comprise a diglyceride, which includes C7-C... 21At least one of the alkenyl groups. In some embodiments, the first glycerol ester component may primarily comprise a triglyceride comprising C7-C... 21 At least one of the alkenyl groups.

[0083] In the implementation scheme, the first glyceride component comprises monoglycerides, diglycerides, and triglycerides of oleic acid and linoleic acid. The relative amounts of monoglycerides, diglycerides, and triglycerides may be approximately 32%-52% monoglycerides, approximately 40%-55% diglycerides, and approximately 5%-20% triglycerides. The first glyceride component may be Maisine CC.

[0084] In one respect, based on the weight of the pharmaceutical preparation, the pharmaceutical preparation contains the following amounts of the first glyceride component: about 30% to 50% by weight, or about 30% to 45% by weight, or about 32% to 40% by weight, or about 35% to 40% by weight.

[0085] The second glyceride component may suitably include C8 to C9. 22 One or more of monoglycerides, diglycerides, and / or triglycerides of saturated fatty acids. The second glyceride component comprises one or more glyceride compounds having the structure of formula (II): (II) in: R 4 R 5 and R 6 Each is independently hydrogen or -C(O)-R B ; R B Each is independently either hydrogen or C7-C. 21 alkyl, The condition is R 4 R 5 and R 6 At least one of them is not hydrogen.

[0086] In some implementations, in formula (II), R B Each is independently C7-C 21 C7-C 19 C7-C 17 C9-C 21 C9-C 19 C9-C 19 C 11 -C 21 C 11 -C 19 Or C 11 -C 17 Alkyl groups (e.g., straight-chain or branched). In some embodiments, R in formula (II)B Each is independently C7-C 21 C7-C 19 C7-C 17 C7-C 15 C7-C 13 C7-C 11 C9-C 21 C 11 -C 17 C 11 -C 21 or C 13 -C 21 Alkyl group. In some embodiments, R B One of them is C 21 Alkyl group. In some embodiments, R B One of them is a C7 alkyl group. In some embodiments, R B One of them is a C9 alkyl group. In some embodiments, R B One of them is C 11 Alkyl group. In some embodiments, R B One of them is C 13 Alkyl group. In some embodiments, R B One of them is C 15 Alkyl group. In some embodiments, R B One of them is C 17 Alkyl group. In some embodiments, R B One of them is C 19 alkyl.

[0087] In one respect, the second glyceride component comprises one or more compounds having one of the following structures: (II-a) (II-b) and (II-c). R 4 R 5 and R 6 As stated above.

[0088] In some embodiments, the second glyceride component may primarily (i.e., greater than 50% by weight) comprise monoglycerides, said monoglycerides comprising at least one C7-C 21 Alkyl group. In some embodiments, the second glycerol ester component may primarily comprise a diglyceride, said diglyceride comprising at least one C7-C group. 21 Alkyl group. In some embodiments, the second glycerol ester component may primarily comprise a triglyceride, said triglyceride comprising at least one C7-C alkyl group. 21 alkyl.

[0089] In the implementation scheme, the second glyceride component comprises C8 to C96. 18 Saturated fatty acid triglycerides. The second glyceride component may be Gelucire 43 / 01.

[0090] In one respect, based on the weight of the pharmaceutical preparation, the pharmaceutical preparation contains the following amounts of the second glyceride component: about 10% to 35% by weight, or about 10% to 30% by weight, or about 10% to 20% by weight, or about 15% to 18% by weight.

[0091] In one respect, pharmaceutical preparations include: (i) About 1% to 15% by weight, or about 1% to 10% by weight, or about 2% to 8% by weight, or about 5% to 7% by weight of a compound having the following structure in a pharmaceutical preparation: Or its pharmaceutically acceptable salt, and (ii) a fatty acid component comprising about 15% to 50% by weight, or about 20% to 45% by weight, or about 30% to 45% by weight, or about 35% to 45% by weight, or about 35% to 40% by weight of the pharmaceutical formulation, said fatty acid component comprising saturated or unsaturated C8-C 24 Fatty acids and / or their pharmaceutically acceptable salts; (iii) a first glycerol ester component comprising about 30% to 50% by weight, or about 30% to 45% by weight, or about 32% to 40% by weight, or about 35% to 40% by weight of a pharmaceutical formulation, wherein the first glycerol ester component comprises one or more compounds having the structure of formula (I). (I) in: R 1 R 2 and R 3 Each is independently hydrogen or -C(O)-R A ; R A Each is independently a C7-C containing one or two double bonds. 21 alkenyl, The condition is R 1 R 2 and R 3 At least one of them is not hydrogen; and (iv) A second glyceride component comprising about 10% to 35% by weight, or about 10% to 30% by weight, or about 10% to 20% by weight, or about 15% to 18% by weight of the pharmaceutical formulation, the second glyceride component comprising: One or more compounds having the structure of formula (II) (II) in: R 4 R 5 and R 6 Each is independently hydrogen or -C(O)-R B ; R B Each is independently C7-C 21 alkyl, The condition is R 4 R 5 and R 6 At least one of them is not hydrogen.

[0092] In one respect, pharmaceutical preparations include: (i) About 1% to 15% by weight, or about 1% to 10% by weight, or about 2% to 8% by weight, or about 5% to 7% by weight of a compound having the following structure in a pharmaceutical preparation: Or its pharmaceutically acceptable salt, and (ii) Fatty acid components, comprising: Saturated or unsaturated C8-C 24 Fatty acids, in amounts of about 12% to 48% by weight, about 15% to 45% by weight, about 25% to 40% by weight, about 30% to 40% by weight, or about 35% to 40% by weight of the pharmaceutical preparation; and Saturated or unsaturated C8-C 24 Sodium salts of fatty acids, in amounts of about 1% to 5% by weight, or about 2% to 4% by weight, or about 2% to 3% by weight of the pharmaceutical preparation; (iii) a first glycerol ester component comprising about 30% to 50% by weight, or about 30% to 45% by weight, or about 32% to 40% by weight, or about 35% to 40% by weight of a pharmaceutical formulation, wherein the first glycerol ester component comprises one or more compounds having the structure of formula (I). (I) in: R 1 R 2 and R 3 Each is independently hydrogen or -C(O)-R A ; R A Each is independently a C7-C containing one or two double bonds. 21 alkenyl, The condition is R 1 R 2 and R 3 At least one of them is not hydrogen; and (iv) A second glyceride component comprising about 10% to 35% by weight, or about 10% to 30% by weight, or about 10% to 20% by weight, or about 15% to 18% by weight of the pharmaceutical formulation, the second glyceride component comprising: One or more compounds having the structure of formula (II) (II) in: R 4 R 5 and R 6 Each is independently hydrogen or -C(O)-R B ; R B Each is independently C7-C 21 alkyl, The condition is R 4 R 5 and R 6 At least one of them is not hydrogen.

[0093] Dosage form This disclosure also provides semi-solid or liquid-based formulations in which a ROCK2 inhibitor (e.g., compound A) is dissolved and / or suspended when formulated into emulsions, suspensions, solutions, elixirs, or syrups, and in methods of treating CCM or Dervéd's disease.

[0094] The dosage form comprises a compound of formula I, particularly compound A or its salt, and may be in the form of a solution, suspension, emulsion, capsule, soft elastic or hard gelatin capsule, suspension, etc., preferably a unit dosage form suitable for simple administration with precise dosage control. The composition may be in the form of liquid or semi-solid filled capsules for oral administration.

[0095] Capsule dosage forms can include soft capsules and hard capsules. Capsules are oral dosage forms for administering Formula I compounds, particularly Compound A or its salts in methods for treating CCM or Derweal's disease. Capsules can be filled with an active ingredient in liquid form or filled with a powder suspended in a liquid. Hard capsules can be prepared from unplasticized or low-plasticized gelatin and water to form hard capsules that can be filled with powder or liquid. Soft capsules can be prepared from highly plasticized, flexible gelatin and can contain liquid or semi-solid components. These capsules are commonly referred to as "soft capsules" or "gelatin capsules."

[0096] As used herein, the term "capsule" refers to any suitable capsule container or box suitable for oral ingestion, such as those suitable for use in conjunction with liquid-filled compositions. The term "capsule" can include a capsule having a shell composed of soft and / or hard materials, such as gelatin, starch, cellulose, cellulose derivatives (e.g., hydroxypropyl methylcellulose), hydrocolloids, gums, carrageenan, or any other natural or synthetic material suitable for encapsulating a liquid composition and being ingested by an animal. Optionally, the shell material may be gelatin and / or hydroxypropyl methylcellulose. In one embodiment, the shell material is gelatin. The term "capsule" also includes a variety of capsule shapes and sizes. This disclosure does not limit the dosage form to a particular type or shape. Any commercially available capsule shell or shell material may be used.

[0097] In one embodiment, the dosage form of this disclosure is a soft capsule. In another embodiment, the dosage form of this disclosure is a coated liquid-filled soft capsule. The coated capsule may include a liquid filler encapsulated in a soft capsule shell. The outer surface of the soft capsule shell may be coated with one or more layers of coating.

[0098] Suitable materials for encapsulating liquid fillers may include heat-sealable polymers and gelatin. Examples of heat-sealable polymers include, but are not limited to, modified starch, cellulose polymers, and carrageenan. In one embodiment, the material is gelatin. Gelatin may be natural gelatin, chemically modified gelatin, enzyme-modified gelatin, or a combination thereof.

[0099] The material forming the capsule shell may further contain water. Prior to capsule preparation, the raw material mass may contain sufficient water to allow for processing on a sealing machine. After capsule formation, most of the moisture can be removed during the drying process.

[0100] Water can have a plasticizing effect on materials. Additionally, non-volatile plasticizers or mixtures of plasticizers can be added to the material forming the capsule shell. The non-volatile plasticizer can be any plasticizer compatible with the material of the capsule shell. For example, a non-volatile plasticizer can be glycerol, maltitol, anhydrous sorbitol, sorbitol, or similar low molecular weight polyols and mixtures thereof. In embodiments, the ratio of plasticizer to material can determine the hardness or softness of the shell.

[0101] The ratio of plasticizer to material in the shell is sufficient to provide a capsule that is not too rigid—too rigid, which would make the capsule brittle and prone to breakage under stress during transport and handling—and not too soft, which would cause the capsule to deform during transport and handling. Non-volatile plasticizers can be present in the capsule shell at approximately 8% to 65% of its weight, or approximately 10% to 35% of its weight.

[0102] The material forming the capsule shell may further contain a expander. The expander can be any expander compatible with the material. Examples of expanders may include natural or modified natural biopolymers and synthetic polymers. Natural biopolymers may include, for example, cellulose, starch, starch derivatives, bacterial polysaccharides (such as xanthan gum and gellan gum), and plant gums (such as guar gum, locust bean gum, tragacanth gum, and gum arabic), and animal-derived polymers (such as chondroitin sulfate, hyaluronic acid, heparin, collagen, and chitosan). Examples of modified natural biopolymers may be modified cellulose. Examples of synthetic polymers may include carbon-chain polymers of vinyl and acrylic acids, and heterochain polymers of polyoxides and polyamines.

[0103] A coating can be applied to the outer surface of the soft capsule shell. The coating may contain one or more layers. Any coating suitable for soft capsules can be applied to the capsule. The coating may provide liquid-filled capsules with properties such as water resistance and sealing, smoothness, polishing, enteric protection, and / or delayed release. Delayed release may be affected by, for example, temperature or pH. In one embodiment, the coating is an enteric coating.

[0104] Coatings can be prepared using any standard coating ingredients known to those skilled in the art. Coating ingredients may include, but are not limited to, fats, fatty acids, waxes, shellac, ammoniated shellac, cellulose acetate phthalate, cellulose, vinyl resins, ethylene glycol, acrylic resins, and carbohydrate polymers, polymers and copolymers containing methacrylic acid and alkyl methacrylates, hydroxypropyl methylcellulose (HPMC), and combinations thereof.

[0105] The coated capsule may further comprise a finishing coating. In one embodiment, a finishing layer is applied to the coated capsule. Examples of substances suitable for finishing coating include, but are not limited to, cellulose, vinyl resins, ethylene glycol, acrylic resins, and carbohydrate polymers and / or combinations thereof.

[0106] Liquid or semi-solid fillers can be encapsulated in soft capsule shells using any method known in the art. For example, soft capsules can be prepared using a standard transfer molding soft gelatin capsule machine, as described in *The Theory and Practice of Industrial Pharmacy*, edited by Lachman et al., 2nd edition, Part II, 404-420, Lea and Febbiger, 1976. Additional methods include the use of a flat-plate process (see *The Theory and Practice of Industrial Pharmacy*, edited by Lachman et al., 2nd edition, Part II, 405, Lea and Febbiger, 1976), as well as Globex-type seamless capsule machines for manufacturing large microcapsules (see U.S. Patent No. 5,254,294), non-standard transfer molding machines for manufacturing gel strips using extrusion techniques (see U.S. Patent Nos. 6,183,845 and 6,340,473), and other methods for manufacturing capsules using high-frequency, ultrasonic, or induction welding to seal the capsules (see U.S. Patent No. 6,352,719). The U.S. patents and books listed above are hereby incorporated by reference.

[0107] As used herein, the phrase "liquid hard capsule" refers to a hard capsule encapsulating a liquid or semi-solid formulation. Hard capsules can be a single-unit dosage form and may include a cap and body, which can be manufactured separately and supplied in empty form for filling liquid or semi-solid compositions. In some embodiments, hard capsules are prepared from polymers such as gelatin. An additional component may be water, which acts as a plasticizer. Another type of hard capsule may be made from hydroxypropyl methylcellulose (HPMC). Liquid-filled hard capsules can be filled on a filling machine, such as a high-speed filling machine.

[0108] In one example, this document discloses a method for preparing filled hard capsules. Empty capsules are supplied to a filling machine under pre-locked conditions, wherein the capsule body has a cap loosely attached thereto. A series of rings or protrusions are provided in the mating surface of the cap or body. These rings are configured to allow the cap to loosely attach to the body, such that the cap and body remain together during storage, but allow the cap to be removed prior to capsule filling. Once the capsule is filled, the cap can be replaced and forced out of the pre-locked position into a fully locked position. Alternatively, other types of capsule filling machines can be used to accept separate supplies of the capsule body and cap.

[0109] The capsule can be sealed at high speed after the formulated composition is filled. During the sealing process, a cap is placed over the body, and the body is pushed upwards until it locks onto the cap. The cap can fit snugly and can be approximately half the length of the body, allowing it to travel a considerable distance downwards along the capsule body before locking. This can function as a piston to trap and pressurize the capsule. Excess gas can escape through the gap between the cap and the body, and a vent can be provided in this area to facilitate the escape of excess pressure. Alternatively, the capsule can utilize a particularly tight locking mechanism instead of a vent.

[0110] In one embodiment, the capsule is banded by applying a blot of polymer solution around the connection between the cap and body. The polymer solution may be a solution of the same polymer as the capsule cap and / or body in its solvent. The banding provides a smooth surface to the capsule coating, which may prevent relative movement between the capsule cap and the capsule body.

[0111] When preparing filled capsules containing a composition comprising compound A, it is preferred that the composition be in liquid form at least during the encapsulation process. In one embodiment, the final capsule contains the composition in liquid form. In another embodiment, the final capsule contains the composition in a semi-solid form at room temperature.

[0112] The dosage and frequency (single or multiple doses) of compounds used to treat CCM or Dweck's disease (e.g., compound A) can vary due to a variety of factors, including the route of administration; the recipient's body type, age, sex, health status, weight, body mass index, and diet; the presence of other diseases or other health-related problems; the type of concurrent treatments; and any complications arising from any disease or treatment regimen. Other treatment regimens or agents may be used in combination with the methods and compounds disclosed herein.

[0113] As is well known in the art, therapeutically effective doses for humans can also be determined from animal models. For example, human doses can be formulated to achieve concentrations that have been found to be effective in animals. As described above, human doses can be adjusted by monitoring the effectiveness of the compound and adjusting the dose upwards or downwards. Adjusting the dose based on the methods described above and others to obtain maximum efficacy in humans is entirely within the capabilities of a person skilled in the art.

[0114] Application method Pharmaceutical formulations containing ROCK2 inhibitors (such as compound A) for the treatment of CCM or Derweal disease may be administered orally. In one respect, the route of administration is oral, and the pharmaceutical formulation is provided in capsule form, such as soft elastic or hard gelatin capsules.

[0115] Treatment This disclosure provides a method for treating CCM, wherein the method comprises orally administering to a subject in need an effective amount of a ROCK2 inhibitor as disclosed herein or a pharmaceutically acceptable salt thereof in a formulation provided herein.

[0116] Cavernous malformations (CCMs)—also known as cavernous hemangiomas—are abnormal clusters of tightly packed capillaries that can occur in the brain, spinal cord, or other parts of the body. These lesions contain slow-flowing or clotted blood. Cavernous malformations are characterized by multiple dilated, "sponge-like" vascular structures filled with blood, through which blood flows very slowly. The vessels in cavernous malformation lesions lack proper connections between adjacent cells and the necessary structural support from smooth muscle and stretchable material (elastin). These characteristics lead to leakage in cavernous malformations. This leakage (hemorrhagic bleeding) is the underlying cause of the clinical symptoms associated with the disease. While most commonly found in the brain, cavernous malformations can also occur in the spinal cord, skin, and, more rarely, the retina.

[0117] Lesions in the brain and spinal cord are particularly vulnerable and prone to bleeding. Brain cerebral hemorrhage (CCM) can lead to: brain hemorrhage (hemorrhagic stroke), seizures, headaches, back pain, hearing or vision changes, and paralysis. CCM can be fatal, especially when it causes severe brain hemorrhage.

[0118] Cavernous malformations (CCM) account for approximately 0.2% of the general population and represent a significant proportion (8-15%) of all cerebral and spinal vascular malformations. Most CCM patients have only a single lesion, no family history of the disease, and no genetic mutations. These cases are referred to as "sporadic." Individuals with a familial (hereditary) form of cavernous malformation often have multiple lesions and may be more prone to symptoms associated with the condition. Cavernous malformations can affect people of all ages, with children accounting for approximately 25% of all diagnosed cases.

[0119] Cavernous malformations are typically diagnosed using magnetic resonance imaging (MRI). Repeat MRI scans may be necessary to confirm any changes in size, recent bleeding, or the formation of new lesions. Unlike arteriovenous malformations (AVMs), cavernous malformations are not visualized using angiography because blood flow is too slow to be observed on angiography.

[0120] This disclosure also provides a method for treating Dervédria disease, wherein the method comprises orally administering to a subject in need an effective amount of a ROCK2 inhibitor as disclosed herein or a pharmaceutically acceptable salt thereof in a formulation provided herein.

[0121] Dwek's disease, also known as neuromyelitis optica (NMO), is a rare neurological disorder that affects both the eye and the spinal cord. It causes optic neuritis, an inflammation of the optic nerve that connects the eye to the brain, which typically results in loss of vision in one or both eyes. Dwek's disease also causes inflammation of the spinal cord, called myelitis. This usually occurs simultaneously with optic neuritis, but it can also occur before or after.

[0122] The hallmark symptom of Derweald's disease is sudden blindness in both eyes. Other symptoms may include: balance disorders, bladder or bowel dysfunction, weakness in the arms and / or legs, numbness in the arms and legs, and sudden, transient, and / or repetitive spasms in the arms and legs.

[0123] Dwek's disease is characterized by simultaneous or consecutive episodes of acute optic neuritis (ON) and transverse myelitis (TM). In over 80% of cases, Dwek's disease is caused by pathogenic IgG autoantibodies against aquaporin 4 (AQP4-IgG). In Dwek's disease patients lacking AQP4-IgG, approximately 10%–40% have IgG autoantibodies against myelin oligodendrocyte glycoproteins (MOG-IgG). AQP4-IgG positive disease is primarily an autoimmune astropathy, although secondary damage to oligodendrocytes and neurons can occur due to astrocyte dysfunction and loss, as well as possible bystander inflammation. In contrast, primary demyelinating lesions are observed in MOG-IgG positive patients. In a small subgroup of patients, the etiology remains unknown (referred to as idiopathic NMO).

[0124] DRVD can occur at any age. In two large European cohorts, primarily composed of adults, the median age of onset was 40 years for AQP4-IgG positive patients and 31 years for MOG-IgG positive patients, but this may be lower in Asian and Black AQP4-IgG9 positive patients. DRVD is more common in women than men, particularly in AQP4-IgG positive patients (male-to-female ratio 1:9 to 1:10). The female predominance is significantly reduced in seronegative NMO and MOG-IgG patients. Example Example 1: HCl formulation of compound A (solid dispersion composition) Developing lipid formulations to enhance the absorption, exposure, and performance of compound I, particularly compound A and its salts, is crucial because oral bioavailability of these compounds can be challenging. The formulation targets lymphatic uptake channels, a largely unsaturated pathway that allows for alternative routes of drug absorption. It also minimizes drug uptake via the portal vein, minimizing first-pass metabolism. These two properties of the formulation can be combined to increase drug exposure.

[0125] A. Pharmaceutical excipients Maisine® CC: The chemical name of this excipient is glyceryl monolinoleate, which can enhance the lymphatic absorption of lipophilic, poorly absorbed drugs (such as compound A), increase oral absorption, and at the same time minimize various toxicities (such as hepatic toxicity).

[0126] Oleic acid: The fatty acid component of the formulation can also promote lymphatic drug uptake. The efficiency of fatty acid lymphatic uptake can depend on a variety of factors, including chain length and saturation state, affecting their ability to form mixed micelles. During digestion, oleic acid (C18:1) interacts with lipid transporters to maximize the efficiency of lipid uptake. Oleic acid signals through CD36 receptors to enhance chylomicron formation, and an oleic acid-rich diet produces large chylomicrons, thus maximizing drug loading capacity.

[0127] Gelucire® 43 / 01: Belonging to the "hard fat" category, Gelucire® 43 / 01 can be used as an excipient to ensure that lipid formulations solidify at room temperature, thereby ensuring physical stability. Gelucire® 43 / 01 is a long-chain triglyceride that releases long-chain fatty acids (mainly C45C4) during digestion. 12 To C 18 It has the correct chain length that helps with lymphatic absorption.

[0128] Sodium oleate: The use of lipid-based surfactants in formulations intended for lymphatic uptake can have variable results and may negatively impact absorption. Therefore, it is important to select surfactants in the composition that provide the desired functionality without affecting performance. The performance of sodium oleate is evaluated based on the results of in vivo pharmacokinetic studies.

[0129] B. Lipid solid dispersion Lipid excipients are used to enhance the absorption of the API solid dispersions provided herein. We have demonstrated that lipid compositions containing fatty acids and lipid surfactants increase absorption in beagle dogs compared to aqueous suspensions. Figure 1 ).

[0130] C. In vivo data supporting formulation development Compound A-HCl was formulated into a fine dispersion. Compound A-HCl API naturally exists as small, low-density, non-static drug particles (typically D90 less than 20 micrometers). Their dispersion in lipids was initially achieved by adding solid compound A-HCl to a cooled F4 formulation (approximately 40°C) and sonicating with a high-power acoustic probe. The in vivo pharmacokinetics of the composition were evaluated in beagle dogs compared to an aqueous nanosuspension formulation of compound A-HCl.

[0131] Table 1: Mean oral pharmacokinetic parameters of compound A-HCl formulation at 10 mg / kg in male and female beagle dogs.

[0132] D. Conclusion The sodium oleate-based composition (F4) of compound A-HCl as a 50:50 solid dispersion exhibits superior exposure to aqueous nanosuspensions compared to F4 alone (delivered dose completely dissolved). Therefore, the solid dispersion formulation was selected as the clinical formulation for production as a supply for clinical trials.

[0133] When selecting an F4 50:50 lipid solid dispersion composition (see...), Figure 1 Subsequently, it was discovered that increasing the unit dose strength was necessary to improve the efficiency of large-scale capsule production by reducing capsule filler volume, provided that the clinical development pathway for compound A-HCl selected capsule number 00 with a target dose of 50 mg / capsule. To achieve this dose strength, the amount of compound A-HCl to be dissolved in the composition needed to be increased by approximately 20%. The initial feasibility study of increasing the solubility load of compound A-HCl was successful; however, precipitation events occurred during further scaling up, likely due to prolonged heating. The F4 100% solid dispersion formulation does not involve prolonged heating steps. Therefore, to achieve the required 50 mg unit dose and avoid potential precipitation issues during the process, the F4 100% solid dispersion formulation was selected as the lead formulation. The clinical trial provider, CMO (Asymchem), successfully conducted a feasibility test on this formulation variant, supporting the selection of the F4 100% solid dispersion as the lead formulation.

[0134] Example 2: HCl preparation of compound A A. Pharmaceutical excipients Maisine® CC: This excipient chemical contains monolinoleic glycerides, which can be used to enhance lymphatic absorption of highly lipophilic and poorly absorbed drugs, increase oral absorption, and minimize various toxicities (such as hepatotoxicity).

[0135] Oleic acid: Fatty acids have been studied to understand their effects on promoting lymphatic drug uptake. The efficiency of fatty acid lymphatic uptake can depend on a variety of factors, including chain length and saturation state, affecting their ability to form mixed micelles. During digestion, oleic acid (C18:1) interacts extensively with lipid transporters to maximize lipid uptake efficiency. Oleic acid signals via CD36 receptors to enhance chylomicron formation, and diets rich in oleic acid produce large chylomicrons, thus maximizing drug loading capacity.

[0136] Gelucire® 43 / 01: Gelucire 43 / 01 belongs to the "hard fat" category and is an excipient primarily used to ensure that liquid lipid formulations solidify at room temperature and to ensure the physical stability of highly saturated formulations. Gelucire 43 / 01 is a long-chain triglyceride that releases long-chain fatty acids (C14 to C18) during digestion, which have the correct chain length to facilitate lymphatic absorption.

[0137] Sodium oleate: The use of lipid-based surfactants in pharmaceutical formulations intended for lymphatic uptake can have variable results and is known to negatively impact absorption. Therefore, it is important to select surfactants in the composition that provide the desired functionality without affecting performance. Such selections should only be based on the results of in vivo pharmacokinetic studies as described in Section 3.0.

[0138] B. Lipid dispersions and suspensions: The solubility of compound A-HCl in a range of excipients and formulations was evaluated to assess how the API dissolves and what unit dosage strengths can be obtained, with an initial focus on achieving stable molecular dispersions as described in the literature.

[0139] Formulation tests determined that oleic acid and Maisine® CC provided minimal solubility as solvents for compound A-HCl, even upon heating. To achieve preclinical (10 mg / ml and higher) and clinical (30 mg / ml) dosage specifications, compound A-HCl benefits from lipid-based surfactants that allow for complete dissolution within the composition. The most effective compound A-HCl solubilizers for oleic acid and Maisine® CC are sodium oleate and sodium stearate (see Tables 1 and 2). Bile acids require the presence of either sodium oleate or sodium stearate to be considered functional.

[0140] Subsequently, various oleic acid and Maisine® CC compositions, along with various lipid-compatible surfactants, were heated to approximately 130°C to prepare a preclinical formulation (10 mg / ml). Compound A-HCl was added under heating and stirring until dissolved. Finally, Gelucire® 43 / 01 was added, and the composition was cooled and solidified. The initial formulation was evaluated in a rat pharmacokinetic model and compared with an alternative compound A-HCl nanosuspension formulation.

[0141] C. Rat composition: Table 2. Composition of the preclinical formulation administered to rats in oral pharmacokinetic studies (see also...) Figure 2 and Figure 3 )

[0142] Table 3: Mean oral PK parameters of compound A-HCl formulations at 50 mg / kg (F4, F5 and F6) in SD rats.

[0143] D. Beagle composition and results Table 4.

[0144] Table 5: Mean oral pharmacokinetic parameters (F4, F5, and F6) of compound A-HCl formulation at 10 mg / kg in beagle dogs.

[0145] Table 6: Mean oral pharmacokinetic parameters (F4 and F4a) of compound A-HCl formulation at 10 mg / kg in beagle dogs.

[0146] E. Molecular / solid dispersion combination formulations The sodium oleate-containing formulation (F4) showed comparable exposure in rats to the sodium stearate-based formulation (F5) (see Table 2). However, in higher mammalian species (beagles), the F4 formulation clearly achieved the highest exposure, indicating that sodium oleate does not impede the lymphatic uptake properties of the lipid composition (see Table 2). Figures 3 to 4 Halving the amount of oleic acid (F4a) does not improve absorption (see [link]). Figure 4 ).

[0147] Therefore, F4 was chosen as the lead prototype formulation composition. However, when fully dissolved, F4 provides a limited unit dose strength in capsule #00 (approximately 15 mg–20 mg). Therefore, in investigating the feasibility of a higher unit dose strength in the clinical composition for capsule #00, it was decided to evaluate how incorporating an additional solid dispersion of compound A-HCl into the F4 formulation would affect the pharmacokinetic parameters of compound A-HCl.

[0148] The F4 composition, selected based on its improved PK performance in rats and dogs, was then studied in vivo, allowing for the formulation of fine dispersions of compound A-HCl at varying percentage delivery doses. Compound A-HCl naturally forms small, low-density, non-static drug particles (typically D...). 90 (Size less than 20 micrometers). Their dispersion in lipids was achieved by adding solid compound A-HCl to a cooled F4 formulation (approximately 40°C) and sonicating with a high-power acoustic probe. 50:50 and 100% solid dispersions of F4-based lipid formulations were prepared, and their pharmacokinetic properties were compared with those of F4.

[0149] F. Conclusion Sodium oleate-based molecular dispersion formulations containing an additional equal amount of compound A-HCl solid dispersion (50% of the delivery dose in solution to 50% of the delivery dose in suspension) exhibit superior exposure profiles compared to F4 formulations containing only compound A-HCl as a molecular dispersion. These results were confirmed in multiple studies across multiple species and dosages.

[0150] Example 3 To further improve the formulation capabilities of the API (compound A-HCl salt), a further composition was prepared. The dosage form comprises hard gelatin capsules in which 50% of the API is in a solid dispersion. The strength is 50 mg / capsule. The capsule size is 00. The formulation components and amounts are provided in Table 7 below: Table 7: Composition of Compound A-HCl Capsules

[0151] a The 50 mg specification in Compound A capsules is calculated based on its free base.

[0152] The tissue distribution of the formulation when administered orally to experimental animals is shown in Figure 6.

[0153] Example 3. CCM mouse model according to Figure 7 The proposed method is used to evaluate ROCK2 inhibitor compound A.

[0154] Animals: C57BL / 6J mice were purchased or bred internally. Sex-matched mice were used for AAV infection on day 35. Mice were housed under standard pathogen-free conditions with a 12-hour light / dark cycle, free access to food and water, and temperatures maintained between 20°C and 24°C, with relative humidity between 45% and 65% rH. All experimental and nursing procedures were performed in accordance with protocols approved by the Institutional Animal Care and Use Committee (IACUC) of the Chinese Brain Science Institute, Beijing.

[0155] The mice were divided into the following cohorts: 1. Sham-operated control group: A total of 20 sham-operated mice were not treated in any way until they were sacrificed at P63 or P77.

[0156] 2. Carrier group: A total of 20 mice were orally administered the carrier [0.3% Tween-80 (w / v)] once daily at a volume of 10 mL / kg.

[0157] 3. Compound A, 150 mg / kg: Mice were orally administered a medium supplemented with compound A once daily at a dose of 150 mg / kg and a volume of 10 mL / kg.

[0158] 4. Compound A, 300 mg / kg: Mice were orally administered a medium supplemented with compound A once daily at a dose of 300 mg / kg and a volume of 10 mL / kg.

[0159] Plasmid construction, adeno-associated virus packaging and injection: Preparation of the construct pAAV-CAG-MAP3K3 I441M -P2A-eGFP and helper vector (pAdDeltaF6). Provides the construct pXX2-187-NRGTEWD(BR1) that induces endothelial cell-specific infection. These constructs are used to generate AAV-BR1-MAP3K3. I441M -P2A-eGFP. The purified virus particles (3 × 10⁻⁶ per mouse) were... 11 (One genome copy) was injected into mice via the superficial temporal vein at P35.

[0160] MRI Evaluation: MRI scans were performed on a Bruker 7.0T MRI scanner. Mice were anesthetized with 5% isoflurane / 95% oxygen, followed by maintenance anesthesia with 2% isoflurane / 98% oxygen during MRI. MRI parameters were as follows: repetition time: 350 ms, echo time: 33 ms, RARE factor: 4, field of view: 21x21 mm, acquisition matrix: 256x256, slice thickness: 0.5 mm. The number of lesions was quantified from T2-weighted images. MRI showed a significant, dose-dependent reduction in lesions in the mouse cohort receiving compound A compared to the mediator cohort.

[0161] CCM Symptom Measurement: Prior to perfusion, 200 µL of blood was aspirated via the tail vein and transferred to EDAT tubes containing K2EDTA, followed by freezing with dry ice. Mice placed on ice were perfused with 50 mL of ice-cold 1xPBS to flush the blood. Brain tissue was removed immediately after perfusion. One hemisphere was flash-frozen with dry ice. The other hemisphere was fixed in 10% neutral buffered formalin for sectioning. Prussian blue staining was performed to determine the percentage of hemorrhagic lesions. For vascular observation, an anti-CD31 antibody conjugated with Alexa-594 was used. The size of GFP / CD31 positive cells was measured and compared with CD31 positive cells to determine whether the treatment reversed the enlarged endothelial cells induced by mutant human MAP3K3. To quantify cells expressing pMLC, the percentage of infected cells expressing pMLC was quantified using an anti-pMLC antibody and an Alexa-594 secondary antibody. The size of GFP / CD31 positive cells compared to CD31 positive cells indicates that compound A reversed the enlarged endothelial cells induced by mutant human MAP3K3.

[0162] Isolation of brain endothelial cells: Brain endothelial cells were isolated by enzymatic digestion, followed by separation using magnetically activated cell sorting. Mice were anesthetized with isoflurane and perfused with sterile PBS. Brain tissue was harvested and digested in complete DMEM with 1 mg / mL collagenase / dispersin and 0.02 mg / mL DNase I at 37°C with gentle shaking for 10 min. The digest was then passed through a 70 µm cell filter. Cells were centrifuged, resuspended, and incubated with anti-mouse CD31 conjugated microbeads at 4°C for 15 min. Following the supplier's (Miltenyi Biotec) protocol, the microbeads were washed and separated using a MACS MS column. Cells bound to the magnetic column were eluted and centrifuged for total protein extraction.

Claims

1. A method for treating cerebral cavernous malformation (CCM), the method comprising orally administering to a patient in need a pharmaceutical preparation containing a therapeutically effective amount of a ROCK2 inhibitor.

2. The method of claim 1, wherein the ROCK2 inhibitor has the structure of formula (AI): (A-I) Or its pharmaceutically acceptable salt, wherein: R A1 Choose from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halogenated, -CN, C1-C3 perfluoroalkyl, -OR A11 -O-(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-OR A11 -NR A11 R A12 -O-(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl) x -C(=O)R A11 -O-(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 -C(=O)OR A11 -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 -NR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 , and -NR A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 ; R A2 Choose from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halogenated, -CN, C1-C3 perfluoroalkyl, -OR A11 -O-(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-OR A11 -NR A11 R A12 -O-(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 -O-(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 -C(=O)OR A11 -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 -NR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 , and -NR A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 ; Alternatively, R A1 and R A2 Together, they form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0 to 2 cyclic heteroatoms selected from the group consisting of N, O, and S, and the fused ring is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halogenated, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR A11 R A12 -O-(C1-C6 alkyl)-NR A11 R A12 C1-C3 perfluoroalkyl, -NR A11 -(C1-C6 alkyl)NR A11 R A12 , and -NR A11 -(C1-C6 alkyl)-OR A11 ; R A3 and R A4 Each is independently selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclic groups, C6-C 10 Aryl, 5- to 14-membered heteroaryl, C 6-12 Aryl, -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 and -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 ; Alternative R A3 and R A4 Together with the nitrogen attached thereto, they provide (i) 4- to 6-membered heterocycles having 0 to 2 additional cyclic heteroatoms selected from N, O, and S, or (ii) 5- to 10-membered heterobicyclic systems having 0 to 3 additional cyclic heteroatoms selected from N, O, and S; wherein said heterocycle or said bicyclic system is unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of: halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, halogenated, -CN, C1-C3 perfluoroalkyl, -OR A11 , O-O-(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-OR A11 -NR A11 R A12 -O-(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 -O-(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 -C(=O)OR A11 -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 -NR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 , and -NR A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 ; Dashed lines represent optional double bonds; R A5 Each is independently selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halogenated, -CN, C1-C3 perfluoroalkyl, oxo, -OR A11 -O-(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-OR A11 -NR A11 R A12 -O-(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 -O-(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 -C(=O)OR A11 -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 -NR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 , and -NR A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 ; n1 It is 0 to 3; R A7 Independently selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 and -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 ; x1 Each is independently selected from 0 and 1; and R A11 and R A12 Each is independently selected from the group consisting of: H and C1-C6 alkyl groups; Alternatively, R A11 and R A12 When both are attached to the same nitrogen atom, they form a 4- to 7-membered heterocycle having 0 to 2 additional cyclic heteroatoms selected from the group consisting of N, O, and S, and the heterocycle is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.

3. The method of claim 2, wherein the ROCK2 inhibitor has the following formula: Or its pharmaceutically acceptable salt.

4. A method for treating cerebral cavernous malformation (CCM), the method comprising orally administering a pharmaceutical preparation comprising the following to a patient in need: (e) About 1% to 15% by weight of compounds having the following structure: Or its pharmaceutically acceptable salt; (a) Approximately 15% to 50% by weight of a fatty acid component comprising saturated and / or unsaturated C8-C 24 Fatty acids and / or their pharmaceutically acceptable salts; (b) About 30% to 50% by weight of a first glycerol ester component comprising one or more glycerol ester compounds having the structure of formula (I). (I) in: R 1 R 2 and R 3 Each is independently hydrogen or -C(O)-R A ; R A Each is independently a C7-C containing one or two double bonds. 21 alkenyl, The condition is R 1 R 2 and R 3 At least one of them is not hydrogen; and (c) About 10% to 35% by weight of a second glycerol ester component comprising one or more glycerol ester compounds having the structure of formula (II). (II) in: R 4 R 5 and R 6 Each is independently hydrogen or -C(O)-R B ; R B Each is independently C7-C 21 alkyl, The condition is R 4 R 5 and R 6 At least one of them is not hydrogen.

5. The method of claim 4, wherein the API includes HCl salt.

6. The method of claim 4 or claim 5, wherein the fatty acid component comprises saturated or unsaturated C 12 -C 18 Fatty acids and / or their pharmaceutically acceptable salts.

7. The method of claim 4, wherein the fatty acid component comprises oleic acid, sodium oleate, or a combination thereof.

8. The method of claim 4, wherein the first glyceride component comprises one or more glyceride compounds having the structure of formula (I), and R A Each is independently a C7-C containing one or two double bonds. 21 Alkenyl group.

9. The method of claim 4, wherein the first glyceride component comprises one or more glyceride compounds having the following structure: (Ia), (I-b) and (I-c).

10. The method of claim 9, wherein the ratio of the compound of formula (Ia), the compound of formula (Ib), and the compound of formula (Ic) is about 32 to 52: 40 to 55: 5 to 20.

11. The method of claim 4, wherein the second glyceride component comprises one or more compounds having the structure of formula (II), and R B Each is independently C7-C 21 alkyl.

12. The method of claim 4, wherein the second glyceride component comprises one or more glyceride compounds having one of the following structures: (II-a), (II-b) and (II-c).

13. The method of claim 4, wherein the API is formulated as a solid dispersion, a solution, or a combination thereof.

14. The method of claim 4, wherein the pharmaceutical formulation comprises a compound having the following structure Or a pharmaceutically acceptable salt thereof, in an amount of about 1% to 10% by weight of the pharmaceutical preparation, or about 2% to 8% by weight of the pharmaceutical preparation, or about 5% to 7% by weight of the pharmaceutical preparation.

15. The method of claim 4, wherein, based on the weight of the pharmaceutical formulation, the pharmaceutical formulation comprises a fatty acid component in amounts of about 20% to 45% by weight, about 30% to 45% by weight, about 35% to 45% by weight, or about 35% to 40% by weight.

16. The method of claim 4, wherein, based on the weight of the pharmaceutical formulation, the pharmaceutical formulation comprises: Fatty acids having saturated or unsaturated C content of 12% to 48% by weight, about 15% to 45% by weight, about 25% to 40% by weight, about 30% to 40% by weight, or about 35% to 40% by weight. 12 -C 18 fatty acids; and Sodium salts of fatty acids, wherein the fatty acids have an amount of saturated or unsaturated C64% from about 1% to 5% by weight, or about 2% to 4% by weight, or about 2% to 3% by weight. 12 -C 18 fatty acid.

17. The method of claim 4, wherein, based on the weight of the pharmaceutical formulation, the pharmaceutical formulation comprises the first glyceride component in amounts of about 30% to 45% by weight, or about 32% to 40% by weight, or about 35% to 40% by weight.

18. The method of claim 4, wherein, based on the weight of the pharmaceutical formulation, the pharmaceutical formulation comprises the second glyceride component in amounts of: about 10% to 30% by weight, or about 10% to 20% by weight, or about 15% to 18% by weight.

19. The method of claim 4, wherein, based on the weight of the pharmaceutical formulation, the pharmaceutical formulation comprises: About 1% to 15% by weight of compound A or a pharmaceutically acceptable salt; Having saturated or unsaturated C in amounts ranging from 12% to 48% by weight 12 -C 18 Fatty acids; It contains approximately 1% to 5% by weight of saturated or unsaturated C 12 -C 18 Sodium salts of fatty acids; The first glyceride component is present in an amount of approximately 30% to 50% by weight; and The second glyceride component is present in an amount of approximately 10% to 35% by weight.

20. A method for treating Dervédria disease, the method comprising orally administering to a patient in need a pharmaceutical preparation comprising a therapeutically effective amount of a ROCK2 inhibitor.

21. The method of claim 20, wherein the ROCK2 inhibitor has the structure of formula (AI): (A-I) Or its pharmaceutically acceptable salt. in: R A1 Choose from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halogenated, -CN, C1-C3 perfluoroalkyl, -OR A11 -O-(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-OR A11 -NR A11 R A12 -O-(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl) x -C(=O)R A11 -O-(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 -C(=O)OR A11 -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 -NR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 , and -NR A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 ; R A2 Choose from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halogenated, -CN, C1-C3 perfluoroalkyl, -OR A11 -O-(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-OR A11 -NR A11 R A12 -O-(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 -O-(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 -C(=O)OR A11 -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 -NR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 , and -NR A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 ; Alternatively, R A1 and R A2 Together, they form a 5- or 6-membered saturated or unsaturated fused ring, which may contain 0 to 2 cyclic heteroatoms selected from the group consisting of N, O, and S, and the fused ring is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halogenated, -CN, -OH, oxo, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-OH, -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -NR A11 R A12 -O-(C1-C6 alkyl)-NR A11 R A12 C1-C3 perfluoroalkyl, -NR A11 -(C1-C6 alkyl)NR A11 R A12 , and -NR A11 -(C1-C6 alkyl)-OR A11 ; R A3 and R A4 Each is independently selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, 3- to 10-membered heterocyclic groups, C6-C 10 Aryl, 5- to 14-membered heteroaryl, C 6-12 Aryl, -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 and -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 ; Alternative R A3 and R A4 Together with the nitrogen attached thereto, they provide (i) 4- to 6-membered heterocycles having 0 to 2 additional cyclic heteroatoms selected from N, O, and S, or (ii) 5- to 10-membered heterobicyclic systems having 0 to 3 additional cyclic heteroatoms selected from N, O, and S; wherein said heterocycles or said bicyclic systems are unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of: halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halogenated, -CN, C1-C3 perfluoroalkyl, -OR A11 , O-O-(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-OR A11 -NR A11 R A12 -O-(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 -O-(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 -C(=O)OR A11 -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 -NR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 , and -NR A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 ; Dashed lines represent optional double bonds; R A5 Each is independently selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, halogenated, -CN, C1-C3 perfluoroalkyl, oxo, -OR A11 -O-(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-OR A11 -NR A11 R A12 -O-(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-NR A11 R A12 -NR A11 -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 -O-(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 -C(=O)-R A11 -C(=O)OR A11 -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 -NR A11 -(C1-C6 alkyl) x1 -C(=O)R A11 , and -NR A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 ; n1 It is 0 to 3; R A7 Independently selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, -(C1-C6 alkyl)-OR A11 -(C1-C6 alkyl)-NR A11 R A12 -(C1-C6 alkyl) x1 -C(=O)R A11 -(C1-C6 alkyl) x1 -C(=O)OR A11 and -(C1-C6 alkyl) x1 -C(=O)NR A11 R A12 ; x1 Each is independently selected from 0 and 1; and R A11 and R A12 Each is independently selected from the group consisting of: H and C1-C6 alkyl groups; Alternatively, R A11 and R A12 When both are attached to the same nitrogen atom, they form a 4- to 7-membered heterocycle having 0 to 2 additional cyclic heteroatoms selected from the group consisting of N, O, and S, and the heterocycle is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, -CN, -NH2, C1-C3 perfluoroalkyl, -OH, -O-(C1-C6 alkyl), and -(C1-C6 alkyl)-OH.

22. The method of claim 21, wherein the ROCK2 inhibitor has the following formula: Or its pharmaceutically acceptable salt.

23. A method for treating Dervédria disease, comprising orally administering to a patient in need a pharmaceutical preparation comprising: (a) About 1% to 15% by weight of compounds having the following structure: Or its pharmaceutically acceptable salt; (b) Approximately 15% to 50% by weight of a fatty acid component comprising saturated and / or unsaturated C8-C 24 Fatty acids and / or their pharmaceutically acceptable salts; (c) About 30% to 50% by weight of a first glycerol ester component comprising one or more glycerol ester compounds having the structure of formula (I). (I) in: R 1 R 2 and R 3 Each is independently hydrogen or -C(O)-R A ; R A Each is independently a C7-C containing one or two double bonds. 21 alkenyl, The condition is R 1 R 2 and R 3 At least one of them is not hydrogen; and (d) About 10% to 35% by weight of a second glycerol ester component comprising one or more glycerol ester compounds having the structure of formula (II). (II) in: R 4 R 5 and R 6 Each is independently hydrogen or -C(O)-R B ; R B Each is independently C7-C 21 alkyl, The condition is R 4 R 5 and R 6 At least one of them is not hydrogen.

24. The method of claim 23, wherein the API includes HCl salt.

25. The method of claim 23 or claim 24, wherein the fatty acid component comprises saturated or unsaturated C 12 -C 18 Fatty acids and / or their pharmaceutically acceptable salts.

26. The method of claim 23, wherein the fatty acid component comprises oleic acid, sodium oleate, or a combination thereof.

27. The method of claim 23, wherein the first glyceride component comprises one or more glyceride compounds having the structure of formula (I), and R A Each is independently a C7-C containing one or two double bonds. 21 Alkenyl group.

28. The method of claim 23, wherein the first glyceride component comprises one or more glyceride compounds having the following structure: (Ia), (I-b) and (I-c).

29. The method of claim 28, wherein the ratio of the compound of formula (Ia), the compound of formula (Ib), and the compound of formula (Ic) is about 32 to 52: 40 to 55: 5 to 20.

30. The method of claim 23, wherein the second glyceride component comprises one or more compounds having the structure of formula (II), and R B Each is independently C7-C 21 alkyl.

31. The method of claim 23, wherein the second glyceride component comprises one or more glyceride compounds having one of the following structures: (II-a), (II-b) and (II-c).

32. The method of claim 23, wherein the API is formulated as a solid dispersion, a solution, or a combination thereof.

33. The method of claim 23, wherein the pharmaceutical formulation comprises a compound having the following structure Or a pharmaceutically acceptable salt thereof, in an amount of about 1% to 15% by weight of the pharmaceutical preparation, or about 1% to 10% by weight of the pharmaceutical preparation, or about 2% to 8% by weight of the pharmaceutical preparation, or about 5% to 7% by weight of the pharmaceutical preparation.

34. The method of claim 23, wherein, based on the weight of the pharmaceutical formulation, the pharmaceutical formulation comprises a fatty acid component in amounts of about 20% to 45% by weight, about 30% to 45% by weight, about 35% to 45% by weight, or about 35% to 40% by weight.

35. The method of claim 23, wherein, based on the weight of the pharmaceutical formulation, the pharmaceutical formulation comprises: Fatty acids having saturated or unsaturated C content of 12% to 48% by weight, about 15% to 45% by weight, about 25% to 40% by weight, about 30% to 40% by weight, or about 35% to 40% by weight. 12 -C 18 fatty acids; and Sodium salts of fatty acids, wherein the fatty acids have an amount of saturated or unsaturated C64% from about 1% to 5% by weight, or about 2% to 4% by weight, or about 2% to 3% by weight. 12 -C 18 fatty acid.

36. The method of claim 23, wherein, based on the weight of the pharmaceutical formulation, the pharmaceutical formulation comprises the first glyceride component in amounts of about 30% to 45% by weight, or about 32% to 40% by weight, or about 35% to 40% by weight.

37. The method of claim 23, wherein, based on the weight of the pharmaceutical formulation, the pharmaceutical formulation comprises the second glyceride component in amounts of: about 10% to 30% by weight, or about 10% to 20% by weight, or about 15% to 18% by weight.

38. The method of claim 23, wherein, based on the weight of the pharmaceutical formulation, the pharmaceutical formulation comprises: About 1% to 15% by weight of compound A or a pharmaceutically acceptable salt; Having saturated or unsaturated C in amounts ranging from 12% to 48% by weight 12 -C 18 Fatty acids; It contains approximately 1% to 5% by weight of saturated or unsaturated C 12 -C 18 Sodium salts of fatty acids; The first glyceride component is present in an amount of approximately 30% to 50% by weight; and The second glyceride component is present in an amount of approximately 10% to 35% by weight.

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