Solid dosage forms of plasma kallikrein inhibitors

Abstract

Described herein are stable solid dosage forms with high loadings of the plasma kallikrein inhibitor, 1-benzyl-1H-pyrazole-4-carboxylic acid 4-carbamimidoyl benzylamide (Compound 1), or a pharmaceutically acceptable salt thereof. Methods of treating patients who would benefit from a plasma kallikrein inhibitor are also disclosed. JPEG2025538540000017.jpg44170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 384,641, filed November 22, 2022, the entire contents of which are incorporated herein for all purposes.

[0002] STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT Not applicable

[0003] Reference to a "Sequence Listing," table, or computer program listing attachment submitted on a compact disc Not applicable [Background technology]

[0004] Background of the Invention Plasma kallikrein (PK) is a serine protease synthesized primarily in the liver from the proenzyme prekallikrein. Proteolytic processing of prekallikrein plays a crucial role in maintaining health and is implicated in a wide range of disease states. For example, in hereditary angioedema (HAE), there is a deficiency of C1, an endogenous inhibitor of plasma kallikrein, which results in bradykinin-mediated edema. HAE and other disease states resulting from vascular hyperpermeability, such as diabetes-induced retinal vascular hyperpermeability (e.g., diabetic macular edema or DME), can be controlled by supplementing C1 or administering plasma kallikrein inhibitors (PKi).

[0005] Numerous small molecule PKi have been disclosed, several in clinical development, and one approved. See, for example, U.S. Patent Nos. 7,625,944, 8,258,170, 9,533,987, 9,738,641, 9,834,513, 10,759,759, 10,125,102, 10,221,161, 10,364,238, 10,562,850, and 11,180,484. Patients in need of PKi can be treated by a variety of administration routes. One preferred route is oral administration of the PKi to patients. For such treatment to be commercially successful, the PKi must be produced in a pure, stable, orally bioavailable form and administered to patients in appropriate amounts and frequency. Administering PKi as an orally ingested solid dosage form is a particularly desirable and convenient method. There is a great deal of information regarding the formulation and preparation of oral solid dosage forms, and many disclosures exist regarding the composition and preparation of solid dosage forms of specific compounds, but the specific formulation with the desired properties will vary depending on the specific compound and dosage form being delivered.

[0006] 1-Benzyl-1H-pyrazole-4-carboxylic acid 4-carbamimidoyl benzylamide (Compound 1) is useful as a plasma kallikrein inhibitor (PKi) for the prevention and treatment of PK-dependent diseases. The nonclinical in vivo properties of Compound 1, also known as RZ402, are described in "Nonclinical safety and pharmacology of RZ402, a plasma kallikrein inhibitor, for the treatment of diabetic macular edema as a daily oral therapy" (ARVO Annual Meeting Abstracts, June 2020). Compound 1 is useful as a PKi for the prevention and treatment of plasma kallikrein-dependent diseases or conditions, including blood clotting disorders such as thrombosis and other PK-dependent diseases and conditions. For example, these compounds inhibit thrombin formation via the intrinsic pathway, thus reducing the risk of new pathogenic thrombus formation (reocclusion) and also ameliorating fibrinolysis-induced reperfusion when administered as adjunctive therapy with fibrinolytic therapy.Compound 1 is also useful for the treatment of other diseases and disorders mediated by plasma kallikrein, including, but not limited to, diabetic macular edema, diabetic retinopathy, hereditary angioedema with inhibitor deficiency, acute liver injury, inflammation and anaphylaxis, hemorrhagic transformation and exacerbation of cerebral edema after treatment with recombinant tissue plasminogen activator (DPA), chemosensitized nephropathy, ischemic stroke, hemorrhagic stroke, hypertension and its vascular complications (including retinopathy and nephropathy), cerebral angioedema, pulmonary hypertension, inflammation, pain, acute myocardial infarction (MI), deep vein thrombosis (DVT), cerebral vasculitis, and pulmonary hypertension. These include stroke or myocardial infarction, angina pectoris, angioedema, sepsis, complications of fibrinolytic therapy (e.g., with tissue plasminogen activator, streptokinase) after arthritis, complications of cardiopulmonary bypass, capillary leak syndrome, inflammatory bowel disease, diabetes and its vascular complications (including retinopathy, diabetic macular edema, nephropathy, and neuropathy), age-related macular degeneration, retinal vein occlusion, cerebral edema, ischemia-reperfusion injury, angiogenesis (such as in cancer), asthma, anaphylaxis, and cerebrovascular complications of neurological diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, central nervous system infections, and glioblastoma multiforme).

[0007] Compound 1 was first disclosed in application Ser. No. 11 / 830,539, filed Jul. 30, 2007, published as US2008 / 0038276A1 on Feb. 14, 2008, and is currently registered as U.S. Patent No. 7,625,944. Despite the disclosure of this compound, an improved pharmaceutical formulation that provides the desired stability, manufacturability, solubility, pharmacokinetics, and compactness has yet to be discovered.

[0008] Thus, there exists a need to prepare pharmaceutical formulations suitable for administration to humans or other animals. The present disclosure addresses these needs and provides related advantages as well. Summary of the Invention

[0009] In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising: a) 1-benzyl-1H-pyrazole-4-carboxylic acid 4-carbamimidoyl benzylamide (Compound 1) [ka] b) flow aids; c) a disintegrant, and d) Lubricants.

[0010] In some embodiments, the pharmaceutical composition further comprises: e) brittle fillers, f) ductile fillers, and g) Anti-adhesion agents.

[0011] In some embodiments, the present invention provides a solid dosage form for oral administration comprising the following ingredients: a) 1-benzyl-1H-pyrazole-4-carboxylic acid 4-carbamimidoyl benzylamide (compound 1), [ka] b) flow aids; c) a disintegrant, and d) Lubricants.

[0012] In some embodiments, the solid dosage form for oral administration further comprises: e) brittle fillers, f) ductile fillers, and g) Anti-adhesion agents.

[0013] In some embodiments, the solid dosage form is a tablet.

[0014] In some embodiments, kits are provided that include the pharmaceutical compositions or solid dosage forms described herein.

[0015] In some embodiments, methods are provided for treating a plasma kallikrein-dependent condition or disease, comprising orally administering a formulation, composition, or dosage form described herein.

[0016] Other objects, features, and advantages of the present disclosure will become apparent to those skilled in the art from the following detailed description and drawings. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 illustrates an exemplary dissolution profile of an encapsulated powder containing Compound 1 (open triangles) as described in Example 3 compared to Compound 1 tablets (open circles and open squares) as described in Example 2.

[0018] [Figure 2] FIG. 2 illustrates an exemplary dissolution profile of an encapsulated powder containing Compound 1 (open triangles) as described in Example 3 compared to a tablet of Compound 1 (open circles) as described in Example 2.

[0019] [Figure 3] FIG. 3 shows an exemplary dissolution profile of Compound 1 tablets (open circles) described in Example 2 compared to the same tablets (open squares) tested after aging at 40° C. and 75% RH for 4 weeks.

[0020] [Figure 4] FIG. 4 shows two different sizes of tablet punches used to prepare tablet compressions of the presently described pharmaceutical composition. DETAILED DESCRIPTION OF THE INVENTION

[0021] Detailed Description of the Invention I. Overview During the development of Compound 1 for therapeutic use, Applicant discovered that Compound 1 possesses various properties that make its delivery challenging. Specifically, crystalline forms of Compound 1, such as the crystalline acetate and chloride salts, have poor flow properties, necessitating formulation with various excipients and special processing techniques to mitigate these problems. Compound 1 also exhibits chemical instability when stored in the presence of formulation excipients, particularly excipients preferred for mitigating poor flow properties. Furthermore, while Compound 1 has low intestinal permeability and high solubility (i.e., classified as a "BCS Class 3 drug"), rapid dissolution upon ingestion is desirable to maximize absorption of Compound 1 into the systemic circulation.

[0022] Disclosed herein are formulations, dosage forms, and methods of treating patients using such dosage forms. The formulation comprises Compound 1, a disintegrant, a flow aid, and a lubricant. Optionally, the formulation may comprise one or more fillers. Such fillers include brittle fillers and ductile fillers. Additionally, the formulation may optionally comprise an anti-adherent agent. In describing the invention, the inventors describe classes of materials that comprise the formulation and dosage form and provide examples of such materials. The dosage form is an oral dosage form, such as a compressed solid formulation, that contains the formulation. A method of treating a plasma kallikrein-dependent disease or condition in a subject comprises orally administering the formulation or dosage form to the subject.

[0023] The formulations disclosed herein have improved physical stability. That is, the physical form and properties of the formulation change little over time. When Compound 1 is in an amorphous form, this means that the dosage form remains substantially amorphous. When Compound 1 is in a crystalline form, this means that the drug remains in the crystalline form used in the preparation of the formulation. Improved physical stability can also be reflected and measured by in vitro dissolution tests or dissolution in the in vivo environment of use, such as the gastrointestinal tract. Generally, the formulations of the present invention maintain rapid dissolution over time.

[0024] The formulations of the present disclosure are chemically stable compared to other formulations of Compound 1. In general, formulations of the present disclosure exhibit a reduced increase in the amount of degradants present over time during storage. Chemical stability can be assessed by measuring 1) the rate of increase in total degradants, or 2) the rate of increase in "RZ402 amide impurity," or 3) the rate of decrease in Compound 1. Without wishing to be bound by any particular theory, it is believed that the amount of degradants is generated by hydrolysis and loss of ammonia. Such hydrolysis reactions can be catalyzed by base or acid. It is believed that a high amount of a flow aid, such as silicon dioxide, increases the rate of "amide degradant" formation.

[0025] It is desirable for the formulations and dosage forms of the present invention to have a high drug loading to allow for acceptably small amounts of administered material, yet a low enough loading to achieve acceptable ease of manufacturing and acceptable dissolution and in vivo behavior. Accordingly, the formulations and dosage forms of the present invention have a drug loading of greater than about 25% by weight. The inventors of the present invention have found that at high loadings of up to 50% Compound 1, the dosage form disintegrates and dissolves while maintaining a rapid dissolution rate (see, e.g., Figures 1 and 2). However, high drug loadings in the dosage form can cause manufacturing problems, such as poor flowability, adhesion to punches used to form compressed tablets, and "banding" (separation of tablet material into distinct horizontal layers rather than a homogeneous mixture). Therefore, it is also desirable that the amount of Compound 1 in the formulation or dosage form not be too high. Accordingly, the compositions and dosage forms of the present invention contain less than about 70% by weight of Compound 1. In some embodiments, the compositions and dosage forms of the present invention contain more than about 30% but less than about 50% Compound 1.

[0026] The formulations of the present invention have sufficient flowability to be acceptably easy to manufacture. In this regard, flowability can be measured by measuring bulk density and tapped density and using the industry standard Carr Index calculation. Additionally, material in and out of the granular material can be manually sieved.

[0027] The dosage forms of the present invention disintegrate and dissolve to deliver Compound 1 to the use environment, thereby achieving a target concentration of Compound 1 in the use environment over time. <721> Dissolution can be measured by the USP-2 dissolution test described in. Preferred formulations and dosage forms are those in which at least 80% of Compound 1 dissolves in the dissolution medium within 30 minutes in a sink environment when tested using the above method. Examples of acceptable immediate-release dissolution are shown in Figures 1 and 2. II. Definition

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Furthermore, methods or materials similar or equivalent to those described herein can be used in the practice of the present invention. For purposes of the present invention, the following terms are defined:

[0029] As used herein, the terms "a," "an," or "the" include not only embodiments containing one member but also embodiments containing two or more members. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "a cell" includes a plurality of such cells, a reference to "the agent" includes a reference to one or more agents known to those of skill in the art, and so forth.

[0030] As used herein, the term "about" refers to a range of values ​​that includes the specified value that one of ordinary skill in the art would consider reasonably close to the specified value. In some embodiments, the term "about" refers to within a standard deviation using measurements generally accepted in the art. In some embodiments, "about" refers to a range of up to ±10% of the specified value. In some embodiments, "about" refers to the specified value.

[0031] The term "treating" or "treatment" encompasses both disease-modifying and symptomatic treatment, either of which may be prophylactic (i.e., before the onset of symptoms to prevent, delay, or reduce the severity of symptoms) or therapeutic (i.e., after the onset of symptoms to reduce the severity and / or duration of symptoms).

[0032] The term "pharmaceutically acceptable salts" is meant to include salts of active compounds prepared with relatively non-toxic acids or bases. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginic acid, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge, SM, et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19, or P. Heinrich, Stahl, Camille G. Wemouth, Handbook of Pharmaceutical Salts, 2002. Wiley-VCH).

[0033] The neutral form of Compound 1 can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of Compound 1 differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise, for purposes of this disclosure, these salts are equivalent to the parent form of Compound 1. In the examples of this disclosure, the acetate salt of Compound 1 is used. Those skilled in the art will recognize that administering Compound 1 as the free base or a different salt form requires some adjustment in the overall dosage. For example, 100 mg of the acetate salt of Compound 1 corresponds to approximately 85 mg of Compound 1 as the free base and approximately 90 mg of Compound 1 as the chloride salt.

[0034] The term "individual" refers to mammals, including primates (especially humans), domesticated companion animals (e.g., dogs, cats, horses), and livestock (e.g., cows, pigs, sheep, etc.), using the dosages described herein. In some embodiments, the term "individual" refers to a human. III. Detailed Description of the Preferred Embodiments

[0035] A. Pharmaceutical Preparations The composition of the present disclosure comprises Compound 1, a flow aid, a disintegrant, and a lubricant. Other excipients known in the pharmaceutical arts may also be added. Compound 1 may be in amorphous or crystalline form. When Compound 1 is in crystalline form, it is preferably in acetate or chloride salt form. The flow aid is selected from, but not limited to, colloidal silicon dioxide, magnesium trisilicate, and calcium phosphate. The disintegrant is selected from, but not limited to, croscarmellose sodium, crospovidone, sodium starch glycolate, and carboxymethylcellulose. The lubricant is selected from, but not limited to, sodium stearyl fumarate and magnesium stearate. Any additional excipients are preferably selected from brittle fillers, such as, but not limited to, mannitol and lactose, and ductile fillers, such as, but not limited to, microcrystalline cellulose. The formulation of the present disclosure is further described in the following paragraphs.

[0036] In some embodiments, provided herein is a pharmaceutical composition of Compound 1 or a pharmaceutically acceptable salt thereof. Compound 1 is a compound having the following formula: [ka]

[0037] In some embodiments, a pharmaceutically acceptable salt of Compound 1 corresponds to Formula I: [ka] wherein X is a pharmaceutically acceptable anion of a protic acid.

[0038] A variety of protic acids are suitable for preparing pharmaceutically acceptable salts of Formula I. It will be appreciated that the pharmaceutically acceptable anion of the protic acid will depend on the protic acid used. For example, protic acids useful in the present disclosure include hydrochloric acid, hydrobromic acid, sulfonic acid, tosylic acid (p-toluenesulfonic acid), methanesulfonic acid, nitric acid, or acetic acid. Thus, pharmaceutically acceptable anions of the protic acids include chloride (Cl). - ), bromide (Br - ), sulfonates (HS(O)2O - ), tosylate (TsO - ), mesylate (MsO - ), nitrate (NO3 - ), and acetate (CHC(O)O - ), or a combination thereof.

[0039] In some embodiments, the pharmaceutically acceptable anion of the protic acid is acetate, and the pharmaceutically acceptable salt of Formula I is represented by Formula Ia: [ka]

[0040] Pharmaceutically acceptable salts of Formula I can be prepared using several conventional methods in the art. For example, the free base form of Compound 1 can be contacted with a stoichiometric amount of an appropriate acid in water, an organic solvent, or a mixture of the two. In some embodiments, pharmaceutically acceptable salts of Formula I are prepared in a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. In some embodiments, pharmaceutically acceptable salts of Formula I are prepared by dissolving Compound 1 in water, adding an appropriate amount of HX to form a mixture, and then adding a non-aqueous solvent, such as the non-aqueous medium described above, to crystallize the salt. In some embodiments, the appropriate amount of HX is a stoichiometric amount. It is understood that HX contains hydrogen, and X is a pharmaceutically acceptable anion of the protic acid defined above.

[0041] Compound 1 can be formulated and delivered in a variety of forms, including amorphous and crystalline forms. Amorphous forms of Compound 1 can include and be produced by any known compositions and methods. Such amorphous forms include those consisting essentially of Compound 1 and those consisting of Compound 1 dispersed in a matrix. Such amorphous forms can be produced by thermal or solvent treatments known in the art. In particular, amorphous forms of Compound 1 disclosed in U.S. Patent Application Publication No. 2021 / 0009525, published January 14, 2021, are included.

[0042] The crystalline form of Compound 1 may be any known form. Such forms include neutral forms, called free base forms or salt forms. In some embodiments, the salt forms of Compound 1 include crystalline acetate and chloride forms. In some embodiments, the crystalline salt form is the acetate form disclosed in U.S. Patent Application Publication No. 2021 / 0009525, which is incorporated herein by reference. For example, the crystalline acetate form used in the examples is included in such preferred salt forms.

[0043] In some embodiments, provided herein is a pharmaceutical composition for oral administration comprising: a) 1-benzyl-1H-pyrazole-4-carboxylic acid 4-carbamimidoyl benzylamide (Compound 1) [ka] b) flow aids; c) a disintegrant, and d) Lubricants.

[0044] In some embodiments, the pharmaceutical composition further comprises: e) brittle fillers, f) ductile fillers, and g) Anti-adhesion agents.

[0045] When referring to weight percentages of the encapsulated powders, and compositions, formulations, and solid dosage forms described herein, it is understood that the weight percentage does not include the weight of the capsule.

[0046] In some embodiments, the compositions, formulations, and dosage forms described herein contain about 20-70% by weight of Compound 1. In some embodiments, the pharmaceutical composition contains about 25-50% by weight of Compound 1. In some embodiments, the pharmaceutical composition contains about 25-45% by weight of Compound 1. In some embodiments, the pharmaceutical composition contains about 50% by weight of Compound 1. In some embodiments, the pharmaceutical composition contains about 33.3% by weight of Compound 1. In some embodiments, the weight percent of Compound 1 is the amount of Compound 1 in the acetate salt form. In some embodiments, the weight percent of Compound 1 is the amount of Compound 1 in the free base form. In some embodiments, the acetate salt form of Compound 1 is anhydrous crystalline Form I, characterized in that its X-ray powder diffraction (XRPD) pattern contains peaks at 10.0, 18.1, 18.6, 20.1, and 23.9 degrees ±0.5 degrees 2θ, wherein the XRPD is performed using CuKα radiation. In some embodiments, the XRPD pattern further contains a peak at 20.5 degrees ±0.5 degrees 2θ. In some embodiments, the anhydrous crystalline Form I of Compound 1 is further characterized by a melting point of about 253°C and an aqueous solubility of about 8.3 mg / mL at 25°C.

[0047] In some embodiments, the compositions, formulations, and dosage forms of the present invention contain a disintegrant. Disintegrants are a type of pharmaceutical excipient incorporated into pharmaceutical formulations and solid dosage forms. Examples of disintegrants include, but are not limited to, croscarmellose sodium, crospovidone, sodium starch glycolate, carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose, starch, lower alkyl-substituted hydroxypropylcellulose, microcrystalline cellulose, and powdered cellulose. A specific disintegrant present at an appropriate concentration can help provide the above-mentioned advantages of the formulation and dosage form, including good physical and chemical stability and good dissolution characteristics. In some embodiments, the disintegrant is selected from croscarmellose sodium, crospovidone, sodium starch glycolate, and carboxymethylcellulose. Carboxymethylcellulose can be in sodium or calcium form. Generally, any product within the scope of the definition of these substances in the USP or the Pharmaceutical Excipient Handbook can be formulated. In some embodiments, the disintegrant is croscarmellose sodium or crospovidone. In some embodiments, the disintegrant is croscarmellose sodium. While a single disintegrant is often used, mixtures of disintegrants can also be used. The amount of disintegrant included in a formulation or dosage form can vary substantially as long as the desired properties of the composition are met. In some embodiments, the disintegrant comprises about 4% to about 20% by weight of the composition. In some embodiments, the disintegrant comprises about 3% to about 15% by weight of the composition. In some embodiments, the disintegrant comprises about 5% to about 10% by weight of the composition. In some embodiments, the disintegrant comprises about 6% to about 8% by weight of the composition. In some embodiments, the disintegrant comprises about 7.3% by weight of the composition.

[0048] In some embodiments, the formulations and dosage forms of the present invention contain a flow aid. A flow aid is also called a glidant. The inventors have discovered that various forms of Compound 1 have poor flow properties and can impart this poor flow properties to mixtures used as formulations or in the manufacture of dosage forms. This poor flow properties tend to increase with increasing drug content in the formulation. In particular, the crystalline form of acetate salt of Compound 1 imparts poor flow properties to formulations and mixtures used to form dosage forms of the present invention. It has been found that the addition of appropriate amounts of certain flow aids can improve the flow properties of compositions used to form dosage forms such as encapsulated powders and compressed tablets, enabling efficient manufacturing. However, increased amounts of flow aids tend to accelerate the degradation and reduce the chemical stability of Compound 1 during storage, especially when stored in the presence of water. Therefore, the present disclosure describes formulations that balance the needs of manufacturing and processing with maintaining the stability and chemical integrity of the active substance, Compound 1.

[0049] One indicator of poor chemical stability is the presence of an increasing amount of "amidation degradants" in a sample over time. As discussed above, the addition of a flow aid (e.g., various forms of colloidal silicon dioxide) to a formulation or dosage form of Compound 1 can decrease the chemical stability of the composition, as evidenced by an increased rate of increase in amidation degradants during storage. However, careful control of the amount of flow aid (e.g., colloidal silicon dioxide) can result in acceptable flow properties while maintaining acceptable chemical stability.

[0050] Exemplary flow aids include, but are not limited to, cellulose (including microcrystalline and silicified forms), colloidal silicon dioxide, magnesium trisilicate, and calcium phosphate. In some embodiments, adding about 5% to about 0.25% by weight of a flow aid provides a combination of acceptable flowability and acceptable chemical stability. In some embodiments, adding about 5% to about 0.5% by weight of a flow aid provides a combination of acceptable flowability and acceptable chemical stability. In some embodiments, the compositions disclosed herein comprise about 0.5% to about 3% by weight of a flow aid. In some embodiments, the compositions disclosed herein comprise about 1% to about 3% by weight of a flow aid. In some embodiments, the formulations and dosage forms of the present invention comprise about 1% to about 3% by weight of a flow aid (e.g., colloidal silicon dioxide). In some embodiments, the compositions disclosed herein comprise about 1% by weight of a flow aid. In some embodiments, the formulations and dosage forms of the present invention comprise about 1 wt% of a flow aid (e.g., colloidal silicon dioxide). In some embodiments, the compositions disclosed herein comprise about 1.5 wt% of a flow aid. In some embodiments, the formulations and dosage forms of the present invention comprise about 1.5 wt% of a flow aid (e.g., colloidal silicon dioxide). In some embodiments, the compositions disclosed herein comprise about 2 wt% of a flow aid. In some embodiments, the formulations and dosage forms of the present invention comprise about 2 wt% of a flow aid (e.g., colloidal silicon dioxide). In some embodiments, the compositions disclosed herein comprise about 3 wt% of a flow aid. In some embodiments, the formulations and dosage forms of the present invention comprise about 3 wt% of a flow aid (e.g., colloidal silicon dioxide).

[0051] In some embodiments, the formulations and dosage forms of the present invention contain a lubricant. Examples of lubricants include, but are not limited to, sodium stearyl fumarate, magnesium stearate, stearic acid, zinc stearate, sodium lauryl sulfate, magnesium oxide, poloxamer, and polyethylene glycol, each of which can be incorporated into the formulations disclosed herein. In some embodiments, the lubricant is sodium stearyl fumarate or magnesium stearate. The amount of lubricant present in the formulations and dosage forms of the present invention can vary widely depending on the formulation, method, and lubricant selected. However, generally, the amount of lubricant present in the compositions of the present invention is about 0.5 to about 10% by weight. In some embodiments, the composition contains about 0.5 to about 5.0% by weight of lubricant. In some embodiments, the composition contains about 0.25 to about 5.0% by weight of lubricant. In some embodiments, the composition contains about 1.0 to about 3.0% by weight of lubricant. In some embodiments, the composition contains about 1.0 to about 4.0% by weight of lubricant. In some embodiments, the compositions of the present invention comprise about 2.5% by weight of sodium stearyl fumarate, hi some embodiments, the compositions comprise about 1.5% by weight of a lubricant.

[0052] In some embodiments, the formulations and dosage forms of the present invention include a brittle filler. In some embodiments, a brittle filler is not required. Examples of brittle fillers include, but are not limited to, mannitol, lactose, dicalcium phosphate, and calcium carbonate. Such excipients can exist in various forms, all of which are included in the present invention. For example, "dicalcium phosphate" includes various forms, including, but not limited to, dicalcium phosphate anhydrous (DCPA), dihydrogen phosphate dihydrate, tricalcium phosphate, and functionalized forms such as Fujicalin (manufactured by Fuji Chemical Industries Company); "calcium carbonate" includes functionalized forms such as Omyapharm (manufactured by Omya International AG); and "lactose" includes, but is not limited to, anhydrous and monohydrate forms, as well as modified forms such as Fast-Flo Lactose, Modified (manufactured by Foremost Farms, USA). The compositions of the present invention can include 0.0 to about 40% by weight of a brittle filler. In some embodiments, the compositions include about 5 to about 35% by weight of a brittle filler. In some embodiments, the composition comprises about 10 to about 30% by weight of a brittle filler. In some embodiments, the composition comprises about 10 to about 25% by weight of a brittle filler. In some embodiments, the composition comprises about 5 to about 17.5% by weight of a brittle filler. In some embodiments, the composition comprises about 7.5 to about 15% by weight of a brittle filler. In some embodiments, the composition comprises about 15 to about 20% by weight of a brittle filler. In some embodiments, the composition comprises about 5 to about 11.5% by weight of a brittle filler.

[0053] In some embodiments, the formulations and dosage forms of the present invention include a ductile filler. In some embodiments, a ductile filler is not required. Examples of ductile fillers include, but are not limited to, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, and starch. Such materials can exist in a variety of forms. For example, microcrystalline cellulose is sold under the brand name Avicel (Dupont Pharma Solutions) in a wide range of grades. Many of these grades contain additives in addition to microcrystalline cellulose. Generally, any grade approved for oral pharmaceutical use can be used as long as the additives do not adversely affect the properties of the composition. In some embodiments, the ductile filler is microcrystalline cellulose. The compositions of the present invention may contain 0 to about 50% by weight of a ductile filler. In some embodiments, when a composition includes a ductile filler, the ductile filler is present in an amount of about 5 to about 45% by weight. In some embodiments, when a composition includes a ductile filler, the ductile filler is present in an amount of about 15 to about 45% by weight. In some embodiments, when the composition includes a ductile filler, the ductile filler is present in an amount of about 25 to about 40 weight percent. In some embodiments, when the composition includes a ductile filler, the ductile filler is present in an amount of about 20 to about 37.5 weight percent. In some embodiments, when the composition includes a ductile filler, the ductile filler is present in an amount of about 30 to about 40 weight percent. In some embodiments, when the composition includes a ductile filler, the ductile filler is present in an amount of about 34.4 weight percent.

[0054] In some embodiments, the formulations and dosage forms of the present invention include an anti-adherent agent. In some embodiments, an anti-adherent agent is not required. If all or part of the composition is granulated during processing, the inclusion of an anti-adherent agent is often desirable. Examples of anti-adherent agents include, but are not limited to, talc, cornstarch, colloidal silica, DL-leucine, sodium lauryl sulfate, and various stearates. In some embodiments, if an anti-adherent agent is included in the composition, it is talc. In some embodiments, if the composition includes an anti-adherent agent, the anti-adherent agent is present in an amount of about 3% to about 15% by weight. In some embodiments, if the composition includes an anti-adherent agent, the anti-adherent agent is present in an amount of about 5% to about 10% by weight. In some embodiments, if the composition includes an anti-adherent agent, the anti-adherent agent is present in an amount of from about 8% by weight. In some embodiments, if the composition includes an anti-adherent agent, the anti-adherent agent is present in an amount of from about 5% by weight.

[0055] In some embodiments, the composition comprises about 0.25 to about 5% by weight colloidal silicon dioxide, about 0.5 to about 5% by weight sodium stearyl fumarate, and about 4 to about 10% by weight croscarmellose sodium.

[0056] In some embodiments, the composition comprises about 1.5% by weight colloidal silicon dioxide, about 1.5% by weight sodium stearyl fumarate, and about 7.3% by weight croscarmellose sodium.

[0057] In some embodiments, the composition comprises about 30-50% by weight of Compound 1, 30-40% by weight of a ductile filler, 10-20% by weight of a brittle filler, about 2-10% by weight of an anti-adherent agent, about 4 to about 10% by weight of a disintegrant, about 0.25 to about 5% by weight of a flow aid, and about 0.5 to about 5% by weight of a lubricant.

[0058] In some embodiments, the composition comprises about 33.3% by weight of Compound 1, 34.2% by weight of a ductile filler, 17.1% by weight of a brittle filler, about 5% by weight of an anti-adherent agent, about 7.3% by weight of a disintegrant, about 1.5% by weight of a flow aid, and about 1.5% by weight of a lubricant.

[0059] In some embodiments, the composition comprises about 50% by weight of Compound 1, 23.1% by weight of a ductile filler, 11.6% by weight of a brittle filler, about 5% by weight of an anti-adherent agent, about 7.3% by weight of a disintegrant, about 1.5% by weight of a flow aid, and about 1.5% by weight of a lubricant.

[0060] In some embodiments, the composition comprises about 34.8% by weight of Compound 1, 30.6% by weight of a ductile filler, 15.3% by weight of a brittle filler, about 8% by weight of an anti-adherent agent, about 7.3% by weight of a disintegrant, about 1.5% by weight of a flow aid, and about 2.5% by weight of a lubricant.

[0061] In some embodiments, the composition comprises about 34.8% by weight of Compound 1, 34.4% by weight of a ductile filler, 11.5% by weight of a brittle filler, about 8% by weight of an anti-adherent agent, about 7.3% by weight of a disintegrant, about 1.5% by weight of a flow aid, and about 2.5% by weight of a lubricant.

[0062] In some embodiments, the composition comprises about 30-50% by weight of Compound 1, 30-40% by weight of microcrystalline cellulose, about 10-20% by weight of mannitol, about 2-10% by weight of talc, about 4 to about 10% by weight of croscarmellose sodium, about 0.25 to about 5% by weight of colloidal silicon dioxide, and about 0.5 to about 5% by weight of sodium stearyl fumarate.

[0063] In some embodiments, the composition comprises about 33.3% by weight of Compound 1, 34.2% by weight of microcrystalline cellulose, 17.1% by weight of mannitol, about 5% by weight of talc, about 7.3% by weight of croscarmellose sodium, about 1.5% by weight of colloidal silicon dioxide, and about 1.5% by weight of sodium stearyl fumarate.

[0064] In some embodiments, the composition comprises about 50% by weight of Compound 1, 23.1% by weight of microcrystalline cellulose, 11.6% by weight of mannitol, about 5% by weight of talc, about 7.3% by weight of croscarmellose sodium, about 1.5% by weight of colloidal silicon dioxide, and about 1.5% by weight of sodium stearyl fumarate.

[0065] In some embodiments, the composition comprises about 34.8% by weight of Compound 1, 30.6% by weight of microcrystalline cellulose, 15.3% by weight of mannitol, about 8% by weight of talc, about 7.3% by weight of croscarmellose sodium, about 1.5% by weight of colloidal silicon dioxide, and about 2.5% by weight of sodium stearyl fumarate.

[0066] In some embodiments, the composition comprises about 34.8% by weight of Compound 1, 34.4% by weight of microcrystalline cellulose, 11.5% by weight of mannitol, about 8% by weight of talc, about 7.3% by weight of croscarmellose sodium, about 1.5% by weight of colloidal silicon dioxide, and about 2.5% by weight of sodium stearyl fumarate.

[0067] B. Solid dosage form The dosage form of the present invention is a solid dosage form intended for oral administration. Typically, the solid dosage form is selected from compressed tablets or encapsulated powders. The dosage form includes the formulations described above. The dosage form of the present disclosure includes Compound 1, a flow aid, a disintegrant, and a lubricant. In addition, other excipients known in the pharmaceutical arts may be added. Compound 1 may be in amorphous or crystalline form. When Compound 1 is in crystalline form, it is preferably in acetate or chloride salt form. The flow aid is selected from, but is not limited to, colloidal silicon dioxide, magnesium trisilicate, and calcium phosphate. The disintegrant is selected from, but is not limited to, croscarmellose sodium, crospovidone, sodium starch glycolate, and carboxymethylcellulose. The lubricant is selected from, but is not limited to, sodium stearyl fumarate and magnesium stearate. Optional additional excipients are preferably selected from brittle fillers, such as, but not limited to, mannitol and lactose, and ductile fillers, such as, but not limited to, microcrystalline cellulose. Solid dosage forms of the present disclosure are further described in the following paragraphs.

[0068] The formulations of the present invention are well suited for preparing dosage forms intended for oral administration to a subject of Compound 1. Accordingly, the present disclosure includes solid dosage forms that include the formulations and pharmaceutical compositions of Compound 1 described herein.

[0069] In some embodiments, Compound 1 is an acetate salt of Compound 1. In some embodiments, the acetate salt form of Compound 1 is anhydrous crystalline Form I, characterized in that its X-ray powder diffraction (XRPD) pattern includes peaks at 10.0, 18.1, 18.6, 20.1, and 23.9 degrees ±0.5 degrees 2θ, wherein the XRPD is performed using CuKα radiation. In some embodiments, the XRPD pattern further includes a peak at 20.5 degrees ±0.5 degrees 2θ. In some embodiments, anhydrous crystalline Form I of Compound 1 is further characterized by a melting point of about 253°C and an aqueous solubility of about 8.3 mg / mL at 25°C.

[0070] The dosage forms of the present disclosure can take a wide variety of forms, including hard and soft dry-filled capsules, compressed compacts, compressed tablets, compressed caplets, and similar forms. Compressed dosage forms can be single-layer or multi-layer tablets, which can be coated or uncoated. Particularly preferred dosage forms are compressed forms such as tablets or caplets.

[0071] In some embodiments, the solid dosage form is a compressed tablet. The amount of Compound 1 or a pharmaceutically acceptable salt thereof in the tablet can be about 0.1 to about 500 mg, about 0.1 to about 250 mg, or about 0.1 to about 100 mg. In some embodiments, the amount of Compound 1 present in the tablet is about 10, 25, 50, 100, 200, 300, 400, or 500 mg. In some embodiments, the amount of Compound 1 present in the tablet is about 50, 100, 200, or 400 mg. In some embodiments, the total weight of the tablet (e.g., including the active ingredient and excipients, excluding the coating) is about 50 to about 1500 mg. For example, the total weight of the solid dosage form is about 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or 1500 mg.

[0072] In some embodiments, the solid dosage forms described herein have particular dissolution characteristics when dissolved in an aqueous dissolution medium. In some embodiments, the aqueous dissolution medium is 20 mM sodium phosphate buffer (pH 6.8). In some embodiments, the solid dosage form of the present disclosure is at least 75% dissolved after 5 minutes in an aqueous medium at 37±0.5°C in an Apparatus-II (paddle) with a paddle speed of about 75 rpm. In some embodiments, the solid dosage form of the present disclosure is at least 85% dissolved after 5 minutes in an aqueous medium at 37±0.5°C in an Apparatus-II (paddle) with a paddle speed of about 75 rpm. In some embodiments, the solid dosage form of the present disclosure is at least 95% dissolved after 5 minutes in an aqueous medium at 37±0.5°C in an Apparatus-II (paddle) with a paddle speed of about 75 rpm. In some embodiments, the solid dosage form tested was prepared within one week of the dissolution test. In some embodiments, the solid dosage form tested was prepared at least one month before the dissolution test. In some embodiments, the solid dosage form tested was prepared at least three months before the dissolution test. In some embodiments, the solid dosage form tested was prepared at least six months before the dissolution test. In some embodiments, the solid dosage form was incubated at 25°C and 60% relative humidity (RH) for one month before conducting the dissolution test. In some embodiments, the solid dosage form was incubated at 25°C and 60% relative humidity (RH) for two months before conducting the dissolution test. In some embodiments, the solid dosage form was incubated at 25°C and 60% relative humidity (RH) for three months before conducting the dissolution test. In some embodiments, the solid dosage form was incubated at 40°C and 75% relative humidity (RH) for about one month before conducting the dissolution test. In some embodiments, the solid dosage form was incubated at 40°C and 75% relative humidity (RH) for about three months before conducting the dissolution test. In some embodiments, the solid dosage form was incubated at 40°C and 75% relative humidity (RH) for six months before conducting the dissolution test. In some embodiments, the solid dosage form is a tablet.

[0073] C. Manufacturing Methods for Solid Dosage Forms The formulations and dosage forms of the present invention can generally be processed using any method known in the art to form Compound 1 for oral administration to a subject. The formulations of the present invention can be administered as various types of powders or suspensions, or can be formed into solid dosage forms such as beads, encapsulated powders, or tablets. In either case, any method known in the art can be used to mix the components of the formulation and modify their density and particle size to facilitate administration, and to facilitate manufacturing of the dosage form when the formulation is formed into a dosage form.

[0074] Granulation of various types is optional but is often a preferred processing method to utilize. In the case of powder or particulate formulations, granulation often improves the homogeneity and flowability of the mixture. Additionally, when the formulation is administered as a reconstituted solution or suspension, granulation can improve the solubility or dispersibility of the material. When the formulation is used to form a solid dosage form, granulating all or a portion of the formulation improves flowability, facilitating capsule filling or the manufacture of compressed tablets or caplets. The formulations of the present invention can be granulated by "dry methods" or "mechanical methods," in which all or a portion of the formulation is compressed. For example, the materials to be granulated can be compressed by "slugging" or roller compaction, followed by milling to form granules. Wet granulation methods can also be used. Examples of wet granulation methods include fluidized bed granulation and high shear granulation. Granulation is often combined with milling and sieving to obtain granules of a desired size. Granules formed by such techniques generally have improved flowability, wettability, and dispersibility. In making the solid dosage forms of the present invention, the flowability of the formulation for filling into capsules or forming compressed tablets can be improved by granulating some or all of the formulation.

[0075] The Examples of this application contain further details regarding the processes used to prepare the compositions and formulations of the present disclosure.

[0076] D. Treatment method The therapeutic method of the present invention is generally a method for preventing or treating a subject having a plasma kallikrein-dependent condition or disease, which comprises orally administering to the subject an effective amount of Compound 1 at an effective administration frequency to the subject. Preferably, Compound 1 is administered in the form of a dosage form intended for oral ingestion. The therapeutic method of the present disclosure is further described in the following paragraphs.

[0077] Thus, in some embodiments, methods are provided for treating plasma kallikrein-dependent diseases or conditions using Compound 1 in a tablet pharmaceutical dosage form as described herein.

[0078] Plasma kallikrein-dependent diseases or conditions include blood coagulation disorders such as thrombosis and other PK-dependent diseases and conditions. For example, the compound inhibits thrombin formation via the intrinsic pathway, thereby reducing the risk of new pathogenic thrombus formation (reocclusion) and, when administered as an adjunct to fibrinolytic therapy, improves fibrinolysis-induced reperfusion. Compound 1 is also useful for treating other diseases and disorders mediated by plasma kallikrein, including, but not limited to, diabetic macular edema, diabetic retinopathy, hereditary angioedema with C1 inhibitor deficiency, acute liver injury, inflammation and anaphylaxis, hemorrhagic transformation and exacerbation of cerebral edema after treatment with recombinant tissue plasminogen activator (tPA), chemosensitized nephropathy, ischemic stroke, hemorrhagic stroke, hypertension and its vascular complications (including retinopathy and nephropathy), cerebral angioedema, pulmonary hypertension, inflammation, pain, acute myocardial infarction (MI), and deep vein thrombosis (DVT). ), complications of fibrinolytic therapy (e.g., with tissue plasminogen activator, streptokinase) after stroke or myocardial infarction, angina pectoris, angioedema, sepsis, arthritis, complications of cardiopulmonary surgery, capillary leak syndrome, inflammatory bowel disease, diabetes and its vascular complications (including retinopathy, diabetic macular edema, nephropathy, and neuropathy), age-related macular degeneration, retinal vein occlusion, cerebral edema, ischemia-reperfusion injury, angiogenesis (such as in cancer), asthma, anaphylaxis, and cerebrovascular complications of neurological diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, central nervous system infections, and glioblastoma multiforme).

[0079] Plasma kallikrein (PK) is a serine protease present in plasma as an inactive zymogen precursor, plasma prekallikrein (prePK), which is proteolytically activated by FXIIa. In a positive feedback loop, PK proteolytically activates the zymogen FXII, promoting the formation of additional FXIIa and further amplifying PK's own activation. FXIIa also activates the zymogen FXI to active FXIa, which initiates the intrinsic (contact) pathway of blood coagulation, leading to the generation of thrombin and the cleavage of fibrinogen. Importantly, PK cleaves high-molecular-weight kininogen (HMWK) to produce bradykinin. Bradykinin activates its receptors B1 and B2 on the surface of vascular endothelial cells, opening tight junctions between endothelial cells lining blood vessels and allowing leakage of fluid and plasma proteins into tissues. This condition is called vascular hyperpermeability. Disruption of tight junctions in the blood-brain barrier and the resulting leakage of plasma and proteins into the brain (edema) have been linked to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis (MS), as well as central nervous system infections and brain tumors. For example, peritumoral brain edema in patients with glioblastoma multiforme leads to poor prognosis (K. Schoenegger et al., Eur J Neurol. (2009) 16(7):874-78). Increased vascular permeability caused by bradykinin production can lead to excess fluid accumulation in many tissues and organs in various diseases, such as angioedema, cystoid macular edema, diabetic macular edema, macular edema after retinal vein occlusion, cerebral angioedema after stroke or head trauma, and capillary leak syndrome. For example, compound 1 has been shown to reduce retinal vascular permeability in rodents treated with angiotensin II, similar to the BK receptor antagonist Hoe-140 (JA Phipps et al., Hypertension (2009) 53:175-81).Activation of the pre-PK and contact systems has also been shown to cause anaphylaxis, for example, in patients treated with contaminated heparin (TK Kishimoto et al., N. Engl. J. Med. (2008) 358:2457-67).

[0080] The importance of BK in angioedema is even more pronounced in hereditary angioedema, where patients have little or no functional C1 inhibitor (the major endogenous inhibitor of PK). High levels of bradykinin are produced in these patients, causing fluid and protein leakage from the plasma into soft tissues, resulting in life-threatening edema. C1 inhibitor is also known to be involved in the pathology of age-related macular degeneration (S. Ennis et al., Lancet (2008) 372:1828-34) and ischemia-reperfusion injury after organ transplantation or myocardial infarction (D. Inderbitzin et al., Eur. Surg. Res. (2004) 36:142-47; G. Horstick et al., Circulation (2001) 104:3125-31). Bradykinin and its receptors have been shown to be involved in tumor angiogenesis (Y. Ikeda et al. Cancer Res (2004) 64:5178-85), pulmonary hypertension (L. Taraseviciene-Stewart et al. Peptides (2005) 26:1292-300), and asthma (PJ Barnes, "Recent Progress on Kinins", (1992) AAS38 / III, Birkhauser Verlag, Basel).

[0081] In patients with angioedema, small polypeptide PK inhibitors (DX-88, ecallantide) reduce edema in patients with hereditary angioedema (A. Williams et al., Transfus. Apher. Sci. (2003) 29:255-58; L. Schneider et al., J Allergy Clin Immunol. (2007) 120(2):416-22; JH Levy et al., Expert Opin. Invest. Drugs (2006) 15:1077-90). Icatibant, a bradykinin B2 receptor antagonist, is also effective in treating hereditary angioedema (K. Bork et al., J Allergy Clin. Immunol. (2007) 119:1497-503). PK produces bradykinin, so inhibiting PK also inhibits bradykinin production.

[0082] It has been reported that PK levels are elevated in patients receiving fibrinolysis following thrombus formation due to fibrinolytic therapy (e.g., tissue plasminogen activator, streptokinase) (HM Hoffmeister et al., J. Cardiovasc. Pharmacol. (1998) 31:764-72). Plasmin-mediated activation of the intrinsic pathway has been shown to occur in plasma and blood, and this activation was significantly attenuated in the plasma of patients lacking any of the components of the intrinsic pathway (GA Ewald et al., Circulation (1995) 91:28-36). Elevated levels of activated PK and thrombin were observed in patients with acute myocardial infarction (HM Hoffmeister et al., Circulation (1998) 98:2527-33).

[0083] Ecallantide reduced cerebral edema, infarct volume, and neurological deficits in an animal model of ischemic stroke (C. Storini et al., J. Pharm. Exp. Ther. (2006) 318:849-54). C1-INH reduced infarct size in a mouse model of middle cerebral artery occlusion (M.G. De Simoni et al., Am. J. Pathol. (2004) 164:1857-63; N. Akita et al., Neurosurg. (2003) 52:395-400). Compound 1 was shown to reduce infarct volume and cerebral angioedema in a rat ischemic stroke model and to inhibit the expansion of intracerebral hemorrhage in a hemorrhagic stroke model (WO2009 / 0971). B2 receptor antagonists have demonstrated neuroprotective effects in animal models of ischemic stroke, reducing infarct volume, brain swelling, and neutrophil accumulation (S. Zausinger et al., Acta Neurochir. Suppl. (2003) 86:205-07; D.B. Lumenta et al., Brain Res. (2006) 1069:227-34; L. Ding-Zhou et al., Br. J. Pharmacol. (2003) 139:1539-47).

[0084] PrePK levels have been found to be elevated in diabetic patients, particularly those with proliferative retinopathy, and correlate with fructosamine levels (B.-B. Gao et al., Nature Med. (2007) 13:181-88; K. Kedzierska et al., Archives Med. Res. (2005) 36:539-43). PrePK levels are also elevated in diabetic patients, with the highest levels found in patients with sensorimotor neuropathy (M. Christie et al., Thromb. Haemostas. (1984) 52:221-23). ​​PrePK levels are also elevated in diabetic patients, associated with elevated blood pressure, independently correlated with albumin excretion rate, and elevated in diabetic patients with macroalbuminuria, suggesting that prePK may be a marker of progressive nephropathy (AA Jaffa et al., Diabetes (2003) 52:1215-21). B1 receptor antagonists have been reported to suppress vascular hyperpermeability and plasma leakage into various organs, including the skin and retina, in streptozotocin-induced diabetic rats (SR Lawson et al., Eur. J. Pharmacol. (2005) 514:69-78; SR Lawson et al., Regul Pept. (2005) 124:221-24). B1 receptor antagonists can also prevent the development of hyperglycemia and renal dysfunction in streptozotocin-treated mice (A. Zuccollo et al., Can. J. Physiol. Pharmacol. (1996) 74:586-89).

[0085] E. Kit The present disclosure also encompasses kits comprising at least one pharmaceutical dosage form described herein.

[0086] In some embodiments, a kit is provided that includes a tablet comprising Compound 1 as described herein. In some embodiments, one or more unit dose tablets as described herein are provided.

[0087] Some kits described herein include a label that describes a method for administering the pharmaceutical formulations described herein. Some kits described herein include a label that describes a method for treating a plasma kallikrein-dependent disease or condition.

[0088] Pharmaceutical dosage forms comprising Compound 1 of the present disclosure can be packaged in bottles, jars, vials, ampoules, tubes, blister packs, or other container and closure systems approved by the U.S. Food and Drug Administration (FDA) or other regulatory agencies and can provide one or more unit doses, including tablets, comprising Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, tablets comprising Compound 1 are packaged in a bottle. The package or dispenser can also have a notice attached to the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, the notice indicating approval by that agency. In certain embodiments, a kit can include a tablet comprising Compound 1, a container closure system comprising a formulation, or one or more dosage unit forms comprising a formulation described herein, and a notice or instructions describing the methods of use described herein. IV. Working Examples

[0089] The following examples are provided to illustrate, but not to limit, the present disclosure.

[0090] Example 1: Chemical stability of molded body and decomposed amide Compacts containing Compound 1 and various tablet excipients were prepared and placed in a temperature- and humidity-controlled environment to determine the effect on the stability of Compound 1. The excipients used fell into five categories: 1) brittle fillers, 2) ductile fillers, 3) disintegrants, 4) lubricants, and 5) flow aids. Excipients from each of these five categories were not used in each compact.

[0091] Manufacturing of molded bodies Compacts were made by mixing the ingredients listed in Table 1 in glass vials using a Turbula T2C blender, and then compressing 100 mg of each mixture using a 1 / 4 inch circular flat tool at a compression force of 1 kN.

[0092] Each excipient listed in Table 1 is described below. 1) "Lactose," commonly referred to as a "brittle filler," was a monohydrate form manufactured by Sheffield and met the USP definition of "lactose monohydrate" (see Handbook of Pharmaceutical Excipients (HPE)). 2) "Mannitol," commonly referred to as a "brittle filler," is manufactured by Millipore and meets the USP definition of "mannitol" (see HPE). 3) "MCC," commonly referred to as "ductile filler," is microcrystalline cellulose manufactured by DuPont and meets the USP definition of "cellulose, microcrystalline" (see HPE). 4) "CSS," commonly referred to as a "disintegrant," is croscarmellose sodium manufactured by FMC Corporation, and meets the USP definition of "croscarmellose sodium" (see HPE). 5) "Crospov," commonly referred to as a "disintegrant," is crospovidone manufactured by BASF and meets the USP definition of "crospovidone" (see HPE). 6) "SSF," commonly referred to as a "lubricant," is sodium stearyl fumarate manufactured by JRS Pharma, and meets the USP definition of "sodium stearyl fumarate" (see HPE). 7) "Talc," commonly referred to as an "anti-adherent," is a natural hydropolysilicate mineral manufactured by Barretts and meets the USP definition of "talc" (see HPE). 8) "SiO2," commonly referred to as a "flow aid," is colloidal silicon dioxide manufactured by Evonik and meets the USP definition of "colloidal silicon dioxide" (see HPE). 9) "Syloid," commonly referred to as a "flow aid," is colloidal silicon dioxide (Syloid 244FP) manufactured by WR Grace, which meets the USP definition of "colloidal silicon dioxide" (see HPE).

[0093] Chemical Stability Test The prepared compacts were exposed to an environment of 40°C and 75% RH for 8 weeks. After 8 weeks, for purity testing, the compacts were crushed and dissolved in acetonitrile / water (4 / 1) at a final concentration of 0.4 mg / mL for compound 1. All undissolved excipients were separated by centrifugation, and the supernatant was analyzed by reverse-phase HPLC. A Zorbax Eclipse XDB-C18, 4.6 x 50 mm column was used with a gradient method, using 0.1% aqueous formic acid (mobile phase A) and acetonitrile (mobile phase B) as the mobile phase. The gradient program varied the concentration of mobile phase B from 5% to 80% over 8 minutes. The retention time of the main degradant observed was 1.25 times that of the active substance. The structure of this degradant (hereinafter referred to as the "amide degradant") was determined to be the following: [ka]

[0094] result Table 1 below shows the composition of the six compacts tested and the amount of the major degradant, called "amide degradant," after the compacts were exposed to 40°C and 75% relative humidity for 8 weeks. Data for the drug alone (hereafter referred to as the "control") are also shown. [Table 1]

[0095] The first thing to note in Table 1 is that the amount of the major degradant, "amide degradant," was highest in compact 1F, which contained 15% Syloid, a proprietary flow aid consisting of colloidal silicon oxide. Compacts 1D and 1E produced the next highest amount of degradants. Both of these compacts contained a non-proprietary colloidal silicon oxide flow aid. However, the addition of colloidal silicon oxide to the excipient / Compound 1 mixture significantly improved flowability.

[0096] Thus, these results indicated that, although some undesirable amide degradants were produced, the addition of silicon oxide was necessary to obtain good flowability for practical tablet manufacturing.

[0097] Example 2: Selective Tablets The following examples describe methods for making select tablets.

[0098] Tablets 1 and 2 were prepared by blending Compound 1 with the excipients, except for sodium stearyl fumarate (excipients are listed in the tables for Tablets 1 and 2—see table below), sieving through a #25 mesh screen, and tumble blending (Turbula T2F, 49 rpm for 15 minutes). Sodium stearyl fumarate was then sieved through a #25 mesh screen, added to the blend, tumble blended (Turbula T2F, 49 rpm for 2 minutes), and directly compressed (Natoli RD10A, 1.9-2.1 MPa tensile strength; 7.20 mm x 14.60 mm Mod Oval and 8.00 mm x 16.50 mm Mod Oval: Natoli HOB numbers 182421 and 190767, respectively).

[0099] Tablets 3 and 4 were manufactured by blending Compound 1 with the listed excipients in the intragranular portion of Tablets 3 and 4 (the excipients are listed in the Tablets 3 and 4 tables—see table below) to generate the intragranular material (which comprised 92.17% of the total final mass of the intragranular blend). The raw materials were premixed in the V-shell of a Vanguard Lab Interchangeable V-blender at a rotation speed set at 10 RPM for up to 30 minutes. The main blend was performed using a Quadro SLS mill at a rotation speed set at 10 RPM for up to 30 minutes. Dry granulation by roller compaction and milling was performed using a Gerteis Mini-Polygran (conditions available upon request). The final granules were then blended with the corresponding extragranular blends listed for Tablets 3 and 4 (table below) in the V-shell of a Vanguard Lab Interchangeable V-blender at a rotation speed set at 10 RPM for up to 30 minutes. These operations produced a common blend for use in downstream processes.

[0100] To obtain a 50 mg tablet of Compound 1, 175 mg of the common granules are compressed into a predetermined mold. To obtain a 200 mg tablet of Compound 1, 700 mg of the common granules are compressed into a predetermined mold.

[0101] The compound 1 common granules were loaded into the gravity feeder of a Korsch XL 100 tablet press (tablet press operating conditions for compound 1 strength are available upon request). Several in-process checks were performed during the tablet compression operation. Manual tablet weight (±5%), thickness, hardness, and friability were analyzed periodically during the tablet compression operation to ensure that each met the operating criteria. Tablet thickness and hardness were evaluated using a SOTAX ST50. Friability evaluation was performed according to USP <1216> The study was conducted in accordance with the guidelines set out in the The collected tablets were subjected to full sorting using the SADE-P4 sorter, based on the same target values ​​used for in-process testing, with a 5% weight variation to ensure that the tablet strength was within the appropriate strength range.

[0102] The effect of formulation composition on disintegration and dissolution was investigated for tablets and capsules containing Compound 1. Immediate-release prototype tablets containing 33% and 50% Compound 1 and capsules containing 50% Compound 1 were further tested in the USP Apparatus 2 dissolution test (details are provided in Example 4). [Table 2-1] [Table 2-2] [Table 2-3] Example 3: Encapsulated Select Powder The raw materials were premixed in a Vanguard Lab Interchangeable V Blender V-Shell at a rotation speed setting of 10 RPM for a maximum of 30 minutes. The blended powder was manually filled into size 0 capsules using a Torpac ProFunnel single-station capsule filler. These capsules were prepared as tablet comparators for the purpose of understanding in vitro dissolution. [Table 3]

[0103] Example 4: Dissolution testing of tablets and capsules from Examples 2 and 3 USP <711> Dissolution tests were performed according to the method described in Table 1. Tablets containing both 50% and 33% active ingredient disintegrated within minutes and dissolved within 5 minutes. A graph of the dissolved formulation has been added to the text. In contrast, the encapsulated formulation was not "released" and the material remained in the capsule, forming a gummy mass that did not completely dissolve. Compare Figures 1 and 2.

[0104] Example 5: Dissolution consistency and stability of tablets from Example 2 under accelerated conditions For Tablet 4, USP <711> According to the method described above, dissolution tests were conducted before and after aging in a stability test chamber for 4 weeks. Tablet 4 initially disintegrated within a few minutes and dissolved within 5 minutes. This tablet was then aged in a stability test chamber at 40°C and 75% RH for 4 weeks. After aging, the tablet also disintegrated within a few minutes and dissolved within 5 minutes. A comparison of the initial tablet 4 and tablet 4 aged at 40°C and 75% RH is shown in Figure 3.

[0105] The amide degradant formation was also evaluated as a function of time when incubated at 40° C., 75% RH for 2, 4, and 13 weeks for tablet 4. The results showed that there was little amide degradant by 13 weeks, as shown in the table below. [Table 4]

[0106] Although the foregoing invention has been described in some detail, using illustrations and examples, for ease of understanding, those skilled in the art will recognize that certain changes and modifications can be practiced within the scope of the appended claims. Furthermore, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In the event of a conflict between this application and a reference described herein, this application shall control.

Claims

1. a) 1-benzyl-1H-pyrazole-4-carboxylic acid 4-carbamimidoyl benzylamide (Compound 1) 【Chemistry 1】 b) flow aids; c) a disintegrant, and d) a lubricant, wherein Compound 1 is in an amorphous form or a crystalline salt form.

2. 2. The pharmaceutical composition of claim 1, wherein the form of Compound 1 is a crystalline salt form selected from an acetate salt form or a chloride salt form.

3. 2. The pharmaceutical composition of claim 1, wherein said form of Compound 1 is an acetate salt form.

4. 4. The pharmaceutical composition of claim 3, wherein the form of Compound 1 is anhydrous crystalline Form I, characterized in that its X-ray powder diffraction (XRPD) pattern includes peaks at 10.0, 18.1, 18.6, 20.1, and 23.9 degrees, ±0.5 degrees 2θ, and wherein the XRPD is performed using CuKα radiation.

5. 5. The pharmaceutical composition of claim 4, wherein crystalline Form I is substantially free of other polymorphic forms of Compound 1.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the amount of Compound 1 in the pharmaceutical composition is 20% to 70% by weight.

7. The pharmaceutical composition according to any one of claims 1 to 5, wherein the amount of Compound 1 in the pharmaceutical composition is 25% to 50% by weight.

8. The pharmaceutical composition of any one of claims 1 to 5, wherein the amount of Compound 1 in the pharmaceutical composition is at least 25% to 45% by weight.

9. The pharmaceutical composition according to any one of claims 1 to 5, wherein the amount of Compound 1 in the pharmaceutical composition is about 50% by weight.

10. The pharmaceutical composition of any one of claims 1 to 5, wherein the amount of Compound 1 in the pharmaceutical composition is about 33.3% by weight.

11. The pharmaceutical composition of any one of claims 1 to 5, wherein the amount of Compound 1 in the pharmaceutical composition is about 34.8% by weight.

12. 12. The pharmaceutical composition of any one of claims 1 to 11, wherein the flow aid is selected from colloidal silicon dioxide, magnesium trisilicate, and calcium phosphate.

13. 13. The pharmaceutical composition of claim 12, wherein the flow aid is colloidal silicon dioxide.

14. 14. The pharmaceutical composition of any one of claims 1 to 13, comprising from about 0.25% to about 5% by weight of a flow aid.

15. 15. The pharmaceutical composition of claim 14, comprising from about 0.5% to about 3% by weight of a flow aid.

16. 15. The pharmaceutical composition of claim 14, comprising about 1.5% by weight of a flow aid.

17. 17. The pharmaceutical composition of any one of claims 1 to 16, wherein the disintegrant is selected from croscarmellose sodium, crospovidone, sodium starch glycolate, and carboxymethylcellulose.

18. 18. The pharmaceutical composition of claim 17, wherein the disintegrant is selected from croscarmellose sodium and crospovidone.

19. 19. The pharmaceutical composition of any one of claims 1 to 18, comprising about 3% to about 15% by weight of a disintegrant.

20. 20. The pharmaceutical composition of claim 19, comprising about 5% to about 10% by weight of a disintegrant.

21. 20. The pharmaceutical composition of claim 19, comprising about 7.3% by weight of a disintegrant.

22. 22. The pharmaceutical composition according to any one of claims 1 to 21, wherein the lubricant is selected from sodium stearyl fumarate and magnesium stearate.

23. 23. The pharmaceutical composition of claim 22, wherein the lubricant is sodium stearyl fumarate.

24. 19. The pharmaceutical composition of any one of claims 1 to 18, comprising about 0.25% to 5% by weight of a lubricant.

25. 20. The pharmaceutical composition of claim 19, comprising about 1% to 4% by weight of a lubricant.

26. 20. The pharmaceutical composition of claim 19, comprising about 2.5% by weight of a lubricant.

27. 27. The pharmaceutical composition of any one of claims 1 to 11, 14 to 16, 19 to 21, and 24 to 26, wherein the flow aid is colloidal silicon dioxide, the lubricant is sodium stearyl fumarate, and the disintegrant is croscarmellose sodium.

28. 28. The pharmaceutical composition of any one of claims 1 to 27, wherein the composition further comprises one or more of the following: e) brittle fillers; f) a ductile filler, and g) Anti-adherent agents.

29. 29. The pharmaceutical composition of claim 28, wherein the brittle filler is selected from mannitol, lactose, dicalcium phosphate, and calcium carbonate.

30. 30. The pharmaceutical composition of claim 29, wherein the brittle filler is mannitol.

31. 31. The pharmaceutical composition of any one of claims 28 to 30, comprising from about 5% to about 17.5% by weight of a brittle filler.

32. 32. The pharmaceutical composition of claim 31, comprising from about 7.5% to about 15% by weight of a brittle filler.

33. 32. The pharmaceutical composition of claim 31, comprising about 11.5% by weight of a brittle filler.

34. 34. The pharmaceutical composition of any one of claims 28 to 33, wherein the ductile filler is selected from microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, and starch.

35. 35. The pharmaceutical composition of claim 34, wherein the ductile filler is microcrystalline cellulose.

36. 36. The pharmaceutical composition of any one of claims 28 to 35, comprising about 15% to 45% by weight of a ductile filler.

37. 37. The pharmaceutical composition of claim 36, comprising about 20% to 37.5% by weight of the ductile filler.

38. 37. The pharmaceutical composition of claim 36, comprising about 34.4% by weight of a ductile filler.

39. 39. The pharmaceutical composition of any one of claims 28 to 38, wherein the anti-adherent agent is selected from talc, corn starch, colloidal silica, DL-leucine, sodium lauryl sulfate, and various stearates.

40. 40. The pharmaceutical composition of claim 39, wherein the anti-adherent agent is talc.

41. 41. The pharmaceutical composition of any one of claims 28 to 40, comprising about 3% to 15% by weight of an anti-adherent agent.

42. 42. The pharmaceutical composition of claim 41, comprising about 5% to 10% by weight of an anti-adherent agent.

43. 42. The pharmaceutical composition of claim 41, comprising about 8% by weight of an anti-adherent agent.

44. a) 1-benzyl-1H-pyrazole-4-carboxylic acid 4-carbamimidoyl benzylamide (Compound 1) 【Chemistry 2】 b) flow aids; c) a disintegrant, and d) a lubricant, wherein the form of Compound 1 is selected from an amorphous form or a crystalline salt form.

45. 45. The solid dosage form of claim 44, selected from a compressed tablet, a powder, and a dry-filled capsule.

46. 46. ​​The solid dosage form of claim 45, which is a compressed tablet.

47. 47. The solid dosage form of any one of claims 44 to 46, wherein the form of Compound 1 is a crystalline salt form selected from an acetate salt form or a chloride salt form.

48. 47. The solid dosage form of any one of claims 44 to 46, wherein the solid dosage form of Compound 1 is the acetate salt form.

49. 49. The solid dosage form of claim 48, wherein the form of Compound 1 is anhydrous crystalline Form I, characterized in that its X-ray powder diffraction (XRPD) pattern includes peaks at 10.0, 18.1, 18.6, 20.1, and 23.9 degrees, ±0.5 degrees 2θ, wherein the XRPD is performed using CuKα radiation.

50. 50. The solid dosage form of claim 49, wherein crystalline Form I is substantially free of other polymorphic forms of Compound 1.

51. 51. The solid dosage form of any one of claims 44 to 50, wherein the amount of Compound 1 in the pharmaceutical composition is 20% to 70% by weight.

52. 51. The solid dosage form of any one of claims 44 to 50, wherein the amount of Compound 1 in the pharmaceutical composition is 25% to 50% by weight.

53. 51. The solid dosage form of any one of claims 44 to 50, wherein the amount of Compound 1 in the pharmaceutical composition is at least 25% to 45% by weight.

54. 51. The solid dosage form of any one of claims 44 to 50, wherein the amount of Compound 1 in the pharmaceutical composition is about 50% by weight.

55. 51. The solid dosage form of any one of claims 44-50, wherein the amount of Compound 1 in the pharmaceutical composition is about 33.3% by weight.

56. 51. The solid dosage form of any one of claims 44-50, wherein the amount of Compound 1 in the pharmaceutical composition is about 34.8% by weight.

57. 57. The solid dosage form of any one of claims 44 to 56, wherein the flow aid is selected from colloidal silicon dioxide, magnesium trisilicate, and calcium phosphate.

58. 58. The solid dosage form of claim 57, wherein the flow aid is colloidal silicon dioxide.

59. 59. The solid dosage form of any one of claims 44-58, wherein the pharmaceutical composition comprises from about 0.25% to about 5% by weight of a flow aid.

60. 60. The solid dosage form of claim 59, wherein the pharmaceutical composition comprises from about 0.5% to about 3% by weight of a flow aid.

61. 60. The solid dosage form of claim 59, wherein the pharmaceutical composition comprises about 1.5% by weight of a flow aid.

62. 62. The solid dosage form of any one of claims 44 to 61, wherein the disintegrant is selected from croscarmellose sodium, crospovidone, sodium starch glycolate, and carboxymethylcellulose.

63. 63. The solid dosage form of claim 62, wherein the disintegrant is selected from croscarmellose sodium and crospovidone.

64. 64. The solid dosage form of any one of claims 44 to 63, wherein the pharmaceutical composition comprises from about 3% to about 15% by weight of a disintegrant.

65. 65. The solid dosage form of claim 64, wherein the pharmaceutical composition comprises about 5% to about 10% by weight of a disintegrant.

66. 65. The solid dosage form of claim 64, wherein the pharmaceutical composition comprises about 7.3% by weight of a disintegrant.

67. 67. The solid dosage form of any one of claims 44 to 66, wherein the lubricant is selected from sodium stearyl fumarate and magnesium stearate.

68. 68. The solid dosage form of claim 67, wherein the lubricant is sodium stearyl fumarate.

69. 69. The solid dosage form of any one of claims 44-68, wherein the pharmaceutical composition comprises about 0.25% to 5% by weight of a lubricant.

70. 70. The solid dosage form of claim 69, wherein the pharmaceutical composition comprises about 1% to 4% by weight of a lubricant.

71. 71. The solid dosage form of claim 70, wherein the pharmaceutical composition comprises about 2.5% by weight of a lubricant.

72. 72. The solid dosage form of any one of claims 44-56, 59-61, 64-66, 69-71, wherein the flow aid is colloidal silicon dioxide, the lubricant is sodium stearyl fumarate, and the disintegrant is croscarmellose sodium.

73. 73. The solid dosage form of any one of claims 44 to 72, wherein the composition further comprises one or more of the following: e) brittle fillers; f) a ductile filler, and g) Anti-adherent agents.

74. 74. The solid dosage form of claim 73, wherein the brittle filler is selected from mannitol, lactose, dicalcium phosphate, and calcium carbonate. Solid dosage form.

75. 75. The solid dosage form of claim 74, wherein the brittle filler is mannitol.

76. 76. The solid dosage form of any one of claims 73-75, wherein the pharmaceutical composition comprises from about 5% to about 17.5% by weight of a brittle filler.

77. 77. The solid dosage form of claim 76, wherein the pharmaceutical composition comprises from about 7.5% to about 15% by weight of a brittle filler.

78. 77. The solid dosage form of claim 76, wherein the pharmaceutical composition comprises about 11.5% by weight of a brittle filler.

79. 79. The solid dosage form of any one of claims 73 to 78, wherein the ductile filler is selected from microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, and starch.

80. 80. The solid dosage form of claim 79, wherein the ductile filler is microcrystalline cellulose.

81. 81. The solid dosage form of any one of claims 73 to 80, wherein the pharmaceutical composition comprises about 15% to 45% by weight of a ductile filler.

82. 82. The solid dosage form of claim 81, wherein the pharmaceutical composition comprises about 20% to 37.5% by weight of a ductile filler.

83. 82. The solid dosage form of claim 81, wherein the pharmaceutical composition comprises about 34.4% by weight of a ductile filler.

84. 84. The solid dosage form of any one of claims 73 to 83, wherein the anti-adherent agent is selected from talc, corn starch, colloidal silica, DL-leucine, sodium lauryl sulfate, and various stearates.

85. 85. The solid dosage form of claim 84, wherein the anti-adherent agent is talc.

86. 86. The solid dosage form of any one of claims 73 to 85, wherein the pharmaceutical composition comprises about 3% to 15% by weight of the anti-adherent agent.

87. 87. The solid dosage form of claim 86, wherein the pharmaceutical composition comprises about 5% to 10% by weight of the anti-adherent agent.

88. 87. The solid dosage form of claim 86, wherein the pharmaceutical composition comprises about 8% by weight of the anti-adherent agent.

89. 89. The solid dosage form of any one of claims 44-88, wherein the solid dosage form is at least 80% dissolved after dissolution testing in an aqueous dissolution medium using a USP Apparatus-II (paddle) at a paddle speed of about 75 rpm for 30 minutes.

90. 90. The solid dosage form of claim 89, wherein the solid dosage form is a tablet, and the tablet was prepared at least one month before conducting the dissolution test.

91. 91. A method of preventing or treating a subject having a plasma kallikrein dependent condition or disease, comprising orally administering an effective amount of the pharmaceutical composition of any one of claims 1 to 43 or the solid dosage form of any one of claims 44 to 90.

92. 92. The method of claim 91, wherein the plasma kallikrein-dependent disease or condition is selected from the group consisting of diabetic macular edema, diabetic retinopathy, hereditary angioedema associated with C1 inhibitor deficiency, acute liver damage, inflammation, anaphylaxis, chemosensitized nephropathy, ischemic stroke, hemorrhagic stroke, hypertension, vascular complications of hypertension, retinopathy, nephropathy, cerebral angioedema, pulmonary hypertension, inflammation, pain, acute myocardial infarction, deep vein thrombosis, complications of fibrinolytic therapy, angina pectoris, angioedema, sepsis, arthritis, complications of cardiopulmonary bypass surgery, capillary leak syndrome, inflammatory bowel disease, diabetes, diabetic nephropathy, diabetic neuropathy, age-related macular degeneration, retinal vein occlusion, cerebral edema, ischemia-reperfusion injury, cancer-associated angiogenesis, asthma, and cerebrovascular complications of Alzheimer's disease, Parkinson's disease, multiple sclerosis, central nervous system infections, and glioblastoma multiforme.

93. A pharmaceutical composition according to any one of claims 1 to 43 or a solid dosage form according to any one of claims 44 to 90 for use in the treatment of a plasma kallikrein dependent disease or condition.

94. Use of a pharmaceutical composition according to any one of claims 1 to 43, or of a solid dosage form according to any one of claims 44 to 90, for the manufacture of a medicament for the treatment of a plasma kallikrein dependent disease or condition.

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