WO2017035263A1

WO2017035263A1 - Compositions comprising a plasma kallikrein inhibitor

Info

Publication number: WO2017035263A1
Application number: PCT/US2016/048456
Authority: WO
Inventors: Yarlagadda S. Babu; Corey J. Bloom; Scott Joseph BONE; Aditya Mohan KAUSHAL
Original assignee: Biocryst Pharmaceuticals Inc
Current assignee: Biocryst Pharmaceuticals Inc
Priority date: 2015-08-24
Filing date: 2016-08-24
Publication date: 2017-03-02
Anticipated expiration: 2018-02-24

Abstract

The present disclosure provides for compositions comprising 3-[2-(4-carbamimidoyl- phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2- carboxylic acid, or a pharmaceutically acceptable form thereof, and a matrix, particularly compositions comprising a solid dispersion or combination of 3-[2-(4-carbamimidoyl- phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2- carboxylic acid, or a pharmaceutically acceptable form thereof, and a concentration enhancing polymer. The compositions provide for higher exposure of 3-[2-(4-carbamimidoyl- phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2- carboxylic acid in the blood for a given dose while at the same time provide for a higher concentration of 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]-6- (cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid in the blood over time. Dosage forms, dosing protocols and methods of treatment are also provided.

Description

COMPOSITIONS COMPRISING A PLASMA KALLIKREIN INHIBITOR

BACKGROUND

Hereditary angioedema (HAE) is a serious and potentially life-threatening rare genetic illness, caused by mutations in the CI -esterase inhibitor (CIINH) gene, located on chromosome l lq. HAE is inherited as an autosomal dominant condition, although one quarter of diagnosed cases arise from a new mutation. HAE has been classed as an orphan disease in Europe, with an estimated prevalence of 1 in 50,000. Individuals with HAE experience recurrent attacks of painful subcutaneous or submucosal edema of the face, larynx, gastrointestinal tract, limbs or genitalia which, if untreated, may last up to 5 days. Attacks vary in frequency, severity and location and can be life-threatening. Laryngeal attacks, with the potential for asphyxiation, pose the greatest risk. Abdominal attacks are especially painful, and often result in exploratory procedures or unnecessary surgery. Facial and peripheral attacks are disfiguring and debilitating.

HAE has a number of subtypes. HAE type I is defined by CIINH gene mutations which produce low levels of CI -inhibitor, whereas HAE type II is defined by mutations which produce normal levels of ineffective CI protein. HAE type III has separate pathogenesis, being caused by mutations in the F12 gene which codes for the serine protease known as Factor XII. Diagnostic criteria for distinguishing the subtypes of HAE, and distinguishing HAE from other angioedemas, can be found in Ann Allergy Asthma Immunol 2008; 100(Suppl 2): S30-S40 and J Allergy Clin Immunol 2004; 114: 629-37, incorporated herein by reference.

Current treatments for HAE fall into two main types. Older non-specific treatments including androgens and antifibrinolytics are associated with significant side effects, particularly in females. Newer treatments are based on an understanding of the molecular pathology of the disease, namely that CIINH is the most important inhibitor of plasma kallikrein and that CIINH deficiency leads to unopposed activation of the kallikrein-bradykinin cascade, with bradykinin the most important mediator of the locally increased vascular permeability that is the hallmark of an attack.

Approved therapies include purified plasma-derived CIINH (Cinryze®, Berinert), the recombinant peptide kallikrein inhibitor ecallantide (Kalbitor®), and the bradykinin receptor B2 inhibitor iticabant (Firazyr®). All of the currently available targeted therapies are administered by intravenous or subcutaneous injection. There is currently no specific targeted oral chronic therapy approved for treatment of HAE. For treatment of HAE, it is desirable to maintain a concentration of the drug in the bloodstream equal to or greater than a minimum therapeutic level continually during therapy. Furthermore, in order to reduce patient burden and increase compliance, it is desirable to provide a dosing regimen of less than or equal to three times per day, more preferably two times per day or less, or more preferably one time per day. Still further, it is desirable to administer as few dosage forms per administration as possible, for example four dosage forms or less, three dosage forms or less or two dosage forms or less or one dosage form, during each administration.

In the pharmaceutical arts, it is known that a number of APIs cannot be administered effectively by the oral route. The main reasons why these compounds cannot be administered by the oral route are: a) rapid enzymatic and metabolic degradation; b) chemical and/or biological instability; c) low solubility in aqueous medium; and/or d) limited permeability in the gastrointestinal tract.. For such compounds, non-oral routes of delivery, such as parenteral administration, mainly via intramuscular or subcutaneous injections, may be developed. However, non-oral administration poses a disadvantage for the patient as well as healthcare providers, and for this reason, it is important to develop alternative and effective oral routes of administration.

While the oral route of administration is the most convenient for the patient and the most economical, designing formulations for administration by the oral route involves many complications. Several methods are available to predict the ease by which an API may be formulated into a formulation suitable for administration by the oral route. Such methods include, but are not limited to, the Lipinski rule (also referred to as the Rule of Five) and the Biopharmaceutical Drug Disposition Classification System (BDDCS).

The BDDCS divides APIs into four classifications, depending on their solubility and permeability. Class I APIs have high solubility and high permeability; Class II APIs have low solubility and high permeability; Class III APIs have high solubility and low permeability; and Class IV APIs have low solubility and low permeability. APIs in higher classes in the BDDCS face greater challenges for formulating into an effective, pharmaceutically acceptable product than those in lower classes. Of the four classes, APIs falling into Class IV are the most difficult to formulate into a formulation for administration by the oral route that is capable of delivering an effective amount of the API as problems of both solubility and permeability must be addressed (note the BDDCS does not inherently address chemical stability). The role of BDDCS in drug development is described generally in L.Z. Benet J Pharm Set 2013, 102(1), Lipinski's rule (described in Lipinski et al. Adv. DrugDeliv. Rev. 46 (1-3): 3-26) states, in general, that in order to develop a successful formulation for administration by the oral route, an API can have no more than one violation of the following criteria:

i) not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms)

ii) not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms)

iii) a molecular mass less than 500 daltons

iv) an octanol- water partition coefficient log P not greater than 5.

J. Zhang et al. Medicinal Chemistry, 2006, 2, 545-553, describes a number of small molecule amidine compounds which have activity as inhibitors of plasma kallikrein. Specifically, 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]-6- (cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid (referred to herein as "Compound A"), one of the compounds described in Zhang et al., is a plasma kallikrein inhibitor. Compound A is a Class IV API and violates criteria iii) and iv) as set forth in the Lipinski Rule. Furthermore, Compound A exhibits poor solubility in aqueous and physiological fluids and is poorly permeable as demonstrated by oral dosing in rats and in vitro experiments with Caco-2 cells. Furthermore, Compound A exhibits poor stability with respect to oxidation in air, to light (photodegradation) and in aqueous and physiological fluids, as well as to elevated temperatures. Still further, Compound A exhibits a half-life in the blood for the initial phase of clearance of about 1.5 hours when administered orally. Therefore, Compound A not only exhibit poor solubility and permeability characteristics, but also poor stability characteristics. As a result, Compound A is especially difficult to formulate into an effective, orally deliverable pharmaceutical composition that is capable of delivering an effective amount of Compound A to a subject. Still further, as a result, Compound A is especially difficult to formulate into an effective, orally deliverable pharmaceutical composition that is capable of delivering an effective amount of Compound A to a subject and provide a dosing regimen of less than or equal to three administrations per day or less, two administrations per day or less, or one administrations per day. Even further, as a result, Compound A is especially difficult to formulate into an effective, orally deliverable pharmaceutical composition that is capable of delivering an effective amount of Compound A to a subject with a dosing regimen of three administrations or less per day (such as two or one administration per day) using as few dosage forms per administration as possible, for example four dosage forms or less, three dosage forms or less or two dosage forms or less or one dosage form, during each administration. Due to a combination of low aqueous solubility and relatively low permeability, Compound A is not well absorbed when dosed orally in crystalline form. A variety of oral formulations of Compound A have been made and tested. PCT Patent Application PCT/US 15/46578 describes various lipid based oral formulations of Compound A (which is hereby incorporated by reference for such teachings). One preferred composition within the scope of this PCT patent application has been successfully used in the clinic to demonstrate the safety and efficacy of Compound A to treat HAE patients. In these clinical studies, Compound A was dosed three times per day in a liquid formulation in hard gelatin capsule (hardgel) comprising 100 mg active as the HC1 salt in an excipient mixture of 46.3% polyethylene glycol 600, 2.2% sodium dodecyl sulfate, 4.4% ethanol, 17.7% 1,2-propanediol, 17.7% D-a- tocopherol polyethylene glycol 1000 succinate (Vitamin E TPGS) (the percentages referring to the total weight of the composition, including the active ingredient). In this clinical study, dosing 400 mg of Compound A (i.e., 4 hardgel capsules) three times a day was safe and effective for treatment of HAE patients. Methods for the manufacture of Compound A are disclosed in PCT Patent Application PCT US 15/46582 (which is hereby incorporated by reference for such teachings).

Although the administration of Compound A in a hard gelatin capsule formulation was effective, Compound A administered in this manner is not completely absorbed from the GI tract. Furthermore, the dose response of Compound A in the hard gelatin capsule formulation was saturable, as increasing the dose from 400 mg to 800 mg in healthy volunteer subjects did not result in increased exposure of Compound A. As stated above, Compound A showed a relatively rapid clearance. Even when dosed 3 times a day, blood levels peak approximately 1.5 hours after administration and decrease to levels at or below a minimum therapeutic level approximately 8 hours from administration. After administration of a 400 mg dose of Compound A in hard gelatin capsules in healthy volunteers, blood concentrations of Compound A were sufficient to inhibit approximately 75% of plasma kallikrein activity in subjects at 3 hours; however, by 8 hours blood concentrations of Compound A were sufficient to inhibit only approximately 40% of plasma kallikrein activity in subjects. As a result, Compound A formulated in this manner is required to be dosed every 8 hours (3 times per day) in order to maintain levels of Compound A in the blood that are sufficient for inhibition of plasma kallikrein activity. It is also necessary for the patient to take 4 to 5 dosage forms at each administration, or 12 to 15 dosage forms per day, to achieve the required blood concentrations of Compound A. In addition, in clinical studies in subjects suffering from HAE it was determined that for subjects suffering from HAE and administered a 500 mg dose of Compound A (in 5, 100 mg soft gelatin capsules containing a liquid formulation) three-times per day, the determined plasma concentration of Compound A showed significant variability from subject to subject. Such variability is a complicating factor in the administration of Compound A in the liquid oral formulations of the prior art. Furthermore, in this study it was shown that the 500 mg dose of Compound A administered three-times a day did not result in a reduction of HAE weekly attack frequency as compared to control.

Therefore, it would be beneficial to identify and develop an improved oral formulation of Compound A that achieves both:

i) a higher exposure of Compound A for a given dose (for example, a higher dose normalized AUC) as compared to previous oral liquid formulations; and ii) a higher concentration of Compound A in the blood over a dosing interval as compared to the liquid oral formulations of the prior art as compared to previous oral liquid formulations (for example a concentration of Compound A over 40 ng/ml over all or substantially all of the dosing interval).

In addition, in would also be beneficial to identify and develop an improved oral formulation of Compound A that provides for one or more of the following:

iii) blood concentrations of Compound A over the minimum therapeutic level for at least 12 hours after administration of a single dose of Compound A (the dose being delivered in 1 or more than 1 dosage form);

iv) blood concentrations of Compound A of at least 1.5 times or more over the minimum therapeutic level for at least 8 hours after administration of single dose of Compound A (the dose being delivered in 1 or more than 1 dosage form);

v) a prolonged dosing interval (for example, a period of 12 hours or more between administrations, such as a 2 administrations per day or 1 administration per day); vi) the amount of Compound A dosed per day or per administration to be reduced (for example as compared to amounts of Compound A required in liquid oral formulations, such as 500 mg/dose or 1,500 mg/day) while still maintaining blood concentrations of Compound A over a minimum therapeutic level over all or substantially all of the dosing interval as compared to a control composition; vii) the number of dosage forms dosed per day or per administration to be reduced (for example, 4 dosage forms per administration, 3 dosage forms per administration, 2 dosage forms per administration or 1 dosage form per administration, or for example, less than 15 dosage forms per day, less than 10 dosage forms per day, less than 5 dosage forms per day, less than 4 dosage forms per day, less than 3 dosage forms per day or less than 2 dosage forms per day); viii) a higher concentration of Compound A in each dosage form (for example as compared to the concentration of Compound A achievable in liquid oral formulations, such as 100 mg or 167 mg per dosage form);

ix) a Tmax that is delayed (for example as compared to the T_max of Compound A observed when a liquid oral formulation is administered) while still maintaining an exposure equal to or greater than the control composition over all or substantially all of a dosing interval;

x) a dosage form in which Compound A is physically and chemically stable upon storage, particularly storage at room temperature or ambient temperature; and xi) reduced variability in exposure between individual subjects ((for example as compared to the variability when Compound A is administered in liquid oral formulations).

The present disclosure provides pharmaceutical compositions that combine Compound A, including Compound A in an amorphous state, with a matrix, including a matrix comprising a concentration enhancing polymer. Such pharmaceutical compositions enhance the aqueous concentration of Compound A in a site of use (such as, but not limited to, the blood or gastrointestinal tract) and increase the bioavailability and/or absorption of Compound A in a site of use. Such pharmaceutical compositions may also influence the site of delivery of Compound A in a subject with beneficial effects (such as, but not limited to, increased bioavailability and/or absorption of Compound A in a site of use). Such pharmaceutical compositions may also eliminate and/or reduce possible off-target effects of Compound A in a subject. Such pharmaceutical compositions optionally enhance the stability of Compound A. SUMMARY OF THE DISCLOSURE

The present disclosure provides for improved oral pharmaceutical formulations of Compound A, dosage forms of Compound A, dosing protocols for the administration of Compound A and methods of treatment using the oral pharmaceutical formulations and dosage forms. In general, it is challenging to achieve both a high exposure of an active agent at a site of use (such as, but not limited to, the blood or gastrointestinal tract) at a given dose and at the same time achieve high (therapeutically effective) concentrations of the active agent at the site of use over time as these two properties usually run counter to each other. For example, it is common for a pharmaceutical composition to provide a concentration of an active agent at a site of use (such as providing a high C_max and/or AUC). Unfortunately, in most cases such formulations do not provide for a sufficient concentration of the active agent at a site of use over time. The converse is also true. Surprisingly, the oral pharmaceutical compositions of the present disclosure simultaneously provide for a higher exposure of Compound A at a site of use for a given dose while at the same time provide for a higher concentration of Compound A at a site of use over time, such as over the dosing interval. Such results are achieved without incorporating components specifically designed for delayed release. Such a result is unexpected.

In a first aspect, the present disclosure provides a solid dispersion comprising Compound A or a pharmaceutically acceptable form thereof, and a matrix or a combination comprising Compound A or a pharmaceutically acceptable form thereof, and a matrix.

In a second aspect, the present disclosure provides a solid dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer or a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer.

In a third aspect, the present disclosure provides a solid dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer and a stabilizing agent or a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer and a stabilizing agent.

In a fourth aspect, the present disclosure provides a solid amorphous dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer or a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer.

In a fifth aspect, the present disclosure provides a solid amorphous dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer and a stabilizing agent or a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer and a stabilizing agent. In a sixth aspect, the present disclosure provides a solid dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a noncellulosic concentration enhancing polymer or a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a noncellulosic concentration enhancing polymer.

In a seventh aspect, the present disclosure provides a solid dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a non- ionizable cellulosic concentration enhancing polymer or a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a non-ionizable cellulosic concentration enhancing polymer.

In an eighth aspect, the present disclosure provides a solid dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising an ionizable cellulosic concentration enhancing polymer or a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising an ionizable cellulosic concentration enhancing polymer.

In a ninth aspect, the present disclosure provides a solid dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a noncellulosic concentration enhancing polymer and a stabilizing agent or a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a noncellulosic concentration enhancing polymer and a stabilizing agent.

In a tenth aspect, the present disclosure provides a solid dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a non- ionizable cellulosic concentration enhancing polymer and a stabilizing agent or a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a non-ionizable cellulosic concentration enhancing polymer and a stabilizing agent.

In an eleventh aspect, the present disclosure provides a solid dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising an ionizable cellulosic concentration enhancing polymer and a stabilizing agent or a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising an ionizable cellulosic concentration enhancing polymer and a stabilizing agent.

In a twelfth aspect, the present disclosure provides a solid dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polyvinyl pyrrolidone polyvinyl acetate polymer and an optional stabilizing agent or a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polyvinyl pyrrolidone polyvinyl acetate polymer and an optional stabilizing agent.

In a thirteenth aspect, the present disclosure provides a solid dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing hydroxypropyl methyl cellulose acetate succinate polymer and an optional stabilizing agent or a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing hydroxypropyl methyl cellulose acetate succinate polymer and an optional stabilizing agent.

In a fourteenth aspect, the present disclosure provides a solid dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing hydroxypropyl methyl cellulose polymer and an optional stabilizing agent or a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing hydroxypropyl methyl cellulose polymer and an optional stabilizing agent.

In one embodiment of any of the first to fifth aspects, the concentration enhancing polymer is an ionizable cellulosic polymer, a non-ionizable cellulosic polymer or a noncellulosic polymer. In one embodiment of any of the first to fifth aspects, the concentration enhancing polymer is hydroxypropyl methyl cellulose acetate succinate (HPMC-AS). In one embodiment of any of the first to fifth aspects, the concentration enhancing polymer is polyvinyl pyrrolidone polyvinyl acetate copolymer (PVPVA). In one embodiment of any of the first to fifth aspects, the concentration enhancing polymer is hydroxypropyl methyl cellulose (HPMC). In one embodiment of the twelfth aspect, the PVPVA is PVPVA64. In one embodiment of the thirteenth aspect, the HPMC-AS is HPMC-AS-L or HPMC-AS-M. In one embodiment of the fourteenth aspect, the HPMC is HPMC-E3.

In one embodiment of any of the first to fourteenth aspects, the solid dispersion or combination may be part of a composition, including a dosage form as described herein. In one embodiment of any of the first to fourteenth aspects, the composition is a pharmaceutical composition. In one embodiment of any of the first to fourteenth aspects, the composition is a pharmaceutical composition comprising a solid dispersion, which may be a solid amorphous dispersion, or a combination. In one embodiment of any of the first to fourteenth aspects, the composition is a dosage form comprising a solid dispersion, which may be a solid amorphous dispersion, or a combination. In one embodiment of any of the first to fourteenth aspects, the composition is a pharmaceutical composition comprising a solid dispersion, which may be a solid amorphous dispersion, and a liquid or a combination and a liquid and the composition is a suspension; in certain embodiments, the solid dispersion or combination is one of the first to fifth aspects, the twelfth to fourteen aspects or the sixth to eleventh aspects, including further descriptions of those aspects. In one embodiment of any of the first to fourteenth aspects, the composition is a pharmaceutical composition consisting of or consisting essentially of a solid dispersion, which may be a solid amorphous dispersion, and a liquid or a combination and a liquid and the composition is a suspension; in certain embodiments, the solid dispersion or combination is one of the first to fifth aspects, the twelfth to fourteen aspects or the sixth to eleventh aspects, including further descriptions of those aspects.

In one embodiment of any of the first to fourteenth aspects, the solid dispersion or combination contains at least about 10 wt% Compound A, or a pharmaceutically acceptable form thereof. In one embodiment of any of the first to fourteenth aspects, the solid dispersion or combination contains at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, or at least about 95 wt% of Compound A, or a pharmaceutically acceptable form thereof. In one embodiment of any of the first to fourteenth aspects, the solid dispersion or combination contains from about 15 wt% to about 90 wt%, from about 20 wt% to about 80 wt%, from about 30 wt% to about 70 wt%, from about 30 wt% to about 60 wt%, from about 40 wt% to about 60 wt%, from about 50 wt% to about 80 wt% or from about 60 wt% to about 90 wt% of Compound A, or a pharmaceutically acceptable form thereof. The foregoing percentages are provided as wt% with respect to total content of the solid dispersion or combination.

In one embodiment of any of the first to third and sixth to fourteenth aspects, Compound A, or a pharmaceutically acceptable form thereof, is present, at least partially, in an amorphous form. In any of the foregoing aspects where a solid dispersion is recited, the solid dispersion may be a solid amorphous dispersion. In one embodiment of the first to fourteenth aspects, the Compound A in the combination is crystalline Compound A.

In one embodiment of any of the first to fourteenth aspects as they relate to solid dispersions (when Compound A is present in an amorphous form), Compound A, or a pharmaceutically acceptable form thereof, is present as an amorphous form at greater than or equal to 30 wt% (determined with respect to the total amount of Compound A in the dispersion). In one embodiment of any of the first to fourteenth aspects as they relate to solid dispersions (when Compound A is present in an amorphous form), at least about 5 wt% of the total amount of Compound A, or a pharmaceutically acceptable form thereof, is present in an amorphous form. Alternatively, at least about 10 wt%, or at least about 15 wt% or at least about 20 wt%, or at least about 30 wt%, or at least about 40 wt%, or at least about 50 wt%, or at least about 60 wt%, or at least about 70 wt%, or at least about 80 wt%, or at least about 90 wt%, or at least about 95 wt% or at least about 99 wt% of the total amount of Compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion is present is in an amorphous form. In one embodiment of any of the first to fourteenth aspects as they relate to solid dispersions (when Compound A is present in an amorphous form), Compound A, or a pharmaceutically acceptable form thereof, is present as an amorphous form at greater than or equal to 50 wt% and a solid amorphous dispersion is provided. The foregoing percentages are provided as wt% with respect to total amount of Compound A in the solid dispersion.

In one embodiment of any of the first to fourteenth aspects, the amount of compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion or combination is at least 20 mg or at least 50 mg. In one embodiment of any of the first to fourteenth aspects, the amount of compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion or combination is between 20 to 600 mg. In one embodiment of any of the first to fourteenth aspects, the amount of compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion or combination is at least 20 mg, at least 40 mg, at least 50 mg, at least 100 mg, at least 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg or greater, 800 mg or greater, 1000 mg or greater, 1500 mg or greater, 2000 mg or greater 2500 mg or greater, 3000 mg or greater or 4000 mg or greater, but less than 5000 mg. In one embodiment of any of the first to fourteenth aspects, the amount of compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion or combination is between about 20 mg to about 200 mg, between about 20 mg to about 100 mg, between about 50 mg to about 300 mg, between about 200 mg to about 400 mg, between about 300 mg to about 500 mg, between about 400 mg to about 600 mg, between about 500 mg to about 2500 mg, between about 400 mg to about 800 mg, between about 800 mg to about 1200 mg or between about 1800 mg to about 2200 mg. As discussed herein, Compound A, or a pharmaceutically acceptable form thereof, may be present in an amorphous form as described above and Compound A may be in a crystalline form when in a combination.

In one embodiment of any of the first to second, fourth, sixth to eighth, or twelfth to fourteenth aspects, the matrix consists or consists essentially of one or more concentration enhancing polymers. In one embodiment of any of the first to second, fourth, sixth to eighth, or twelfth to fourteenth aspects, the matrix consists or consists essentially of a single concentration enhancing polymer. In one embodiment of any of the first to fourteenth aspects, a single concentration enhancing polymer is present in the matrix, with optionally other ingredients. In one embodiment of any of the first to fourteenth aspects, more than one concentration enhancing polymer is present in the matrix. In one embodiment of the first to second, fourth, sixth to eighth, or twelfth to fourteenth aspects, the solid dispersion or solid amorphous dispersion further comprises a stabilizing agent. In one embodiment of the first to second, fourth, sixth to eighth, or twelfth to fourteenth aspects, the matrix consists essentially of or consists of a single concentration enhancing polymer or more than one concentration enhancing polymers and the solid dispersion or solid amorphous dispersion comprises a stabilizing agent.

In one embodiment of any of the first to fourteenth aspects, the solid dispersion or combination is suitable for oral delivery. In one embodiment of any of the first to fourteenth aspects, the solid dispersion or combination is suitable for oral delivery and is in a dosage form. In one embodiment of any of the first to fourteenth aspects, the solid dispersion or combination is suitable for oral delivery and the dosage form is a tablet or a suspension.

In one embodiment of any of the first to fourteenth aspects, the solid dispersion or combination may be present in a dosage form, such as for example, a tablet. In one embodiment of any of the first to fourteenth aspects, the solid dispersion or combination may be present in an immediate release dosage form, such as for example, a tablet. In one embodiments of any one of the first to fourteenth embodiments, the compositions may be present in a dosage form, such as for example, a suspension. Such dosage forms may contain additional excipient components as is customary for such dosage forms.

In one embodiment of any of the first to fourteenth aspects, the solid dispersion or combination may be used to form a suspension, comprising the solid dispersion or combination and a liquid vehicle. In one embodiment of any of the first to fourteenth aspects, the solid dispersion or combination may be used to form a suspension, consisting of or consisting essentially of the solid dispersion or combination and a liquid vehicle. Suitable liquid vehicles include, but are not limited to liquids with a pH range of from about 4 to about 8, from about 6 to about 7, from about 2 to about 4 or from about 6 to about 10. In one embodiment, the liquid vehicle is water or a liquid with a pH range of about 6 to about 7. In certain embodiments, the solid dispersion or combination is one of the first to fifth aspects, the twelfth to fourteen aspects or the sixth to eleventh aspects, including further descriptions of those aspects. In certain embodiments, the volume of the liquid present is from about 100 mis to about 2500 mis, such as for example, from about 200 mis to about 400 mis, from about 400 mis to about 600 mis, from about 600 mis to about 900 mis, from about 900 mis to about 1200 mis or from about 1200 mis to about 1500 mis. In a fifteenth aspect, the present disclosure provides a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix that when administered to a mammal, such as a human, provides for a concentration of Compound A in the plasma versus time area under the curve for a 24 hour period of time following a single oral administration of the composition that is greater than 1.5- fold that of a control composition, where the control composition consists essentially of an equivalent quantity of Compound A in an excipient mixture of 72.1 % polyethylene glycol 600, 27.2% D-a-tocopherol polyethylene glycol 1000 succinate and 0.7%) D-a-tocopherol (the excipient percentages referring to the total weight of the excipient mixture of the control composition, excluding the active ingredient).

In a sixteenth aspect, the present disclosure provides a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix that when administered to a mammal, such as a human, provides for a dose normalized exposure of Compound A in the plasma of the mammal above 2.0 ng-hr/ml- mg over a 24 hour period of time following a single oral administration of the composition.

In a seventeenth aspect the present disclosure provides a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix that when administered to a mammal, such as a human, provides for a plasma concentration of Compound A in the plasma of a mammal, such as a human, above a minimum therapeutic level for at least 8 hours following a single oral administration of the composition.

In an eighteenth aspect, the present disclosure provides a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix that when administered at selected dosing intervals to a mammal, such as a human, provides for a sustained average plasma concentration of Compound A in the plasma of a mammal, such as a human, above a minimum therapeutic level for a treatment period and/or the dosing interval.

In a nineteenth aspect, the present disclosure provides a composition comprising a solid dispersion or combination of Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing PVPVA, HPMC-AS or HPMC polymer that when administered at selected dosing intervals to a mammal, such as a human, provides for a sustained average plasma concentration of Compound A in the plasma of a mammal, such as a human, above a minimum therapeutic level for a treatment period and/or the dosing interval. In one embodiment of any of the fifteenth to nineteenth aspects, the composition is a pharmaceutical composition. In one embodiment of any of the fifteenth to nineteenth aspects, the composition is a dosage form. In one embodiment of any of the fifteenth to nineteenth aspects, the composition is a tablet. In one embodiment of any of the fifteenth to nineteenth aspects, the composition is a suspension. In one embodiment of any of the fifteenth to nineteenth aspects, the composition consists essentially of or consists of the recited ingredients.

In one embodiment of any of the fifteenth to eighteenth aspects, the solid dispersion or combination is one of the first to fourteenth aspects, including the further descriptions of such aspects. In one embodiment of any of the fifteenth to eighteenth aspects, the solid dispersion or combination is one of the first to fifth aspects, the sixth to eleventh aspects or the twelfth to fourteenth aspects, including the further descriptions of such aspects.

In one embodiment of any of the fifteenth to nineteenth aspects, the recited effects of the composition are achieved by administering to the mammal a dose containing an amount of Compound A, or a pharmaceutically acceptable form thereof, in the range of from about 100 mg to about 600 mg of Compound A, specifically including doses of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg. In one embodiment of any of the fifteenth to nineteenth aspects, the recited effects of the composition are achieved by administering to the mammal a dose containing an amount of Compound A, or a pharmaceutically acceptable form thereof, of at least 20 mg, at least 40 mg, at least 50 mg, at least 100 mg, at least 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg or greater, 800 mg or greater, 1000 mg or greater, 1500 mg or greater, 2000 mg or greater 2500 mg or greater, 3000 mg or greater or 4000 mg or greater, but less than 5000 mg. In one embodiment of any of the fifteenth to nineteenth aspects, the recited effects of the composition are achieved by administering to the mammal a dose containing an amount of Compound A, or a pharmaceutically acceptable form thereof, that is less than 600 mg, less than 500 mg, less than 400 mg, less than 300 mg, less than 200 mg or less than 100 mg. In one embodiment of any of the fifteenth to nineteenth aspects, the recited effects of the composition are achieved by administering to the mammal a dose containing an amount of Compound A, or a pharmaceutically acceptable form thereof, that is between about 20 mg to about 100 mg, between about 50 mg to about 300 mg, between about 200 mg to about 400 mg, between about 300 mg to about 500 mg, between about 400 mg to about 600 mg, between about 500 mg to about 2500 mg, between about 400 mg to about 800 mg, between about 800 mg to about 1200 mg or between about 1800 mg to about 2200 mg. Such dose may be provided in one or more than one dosage form (for example 1 tablet or more than 1 tablet). A single dose may be administered per day or multiple doses administered per day if allowed (such as two doses per day or three doses per day).

In one embodiment of the fifteenth aspect, the concentration of Compound A in the plasma versus time area under the curve for a 24 hour period of time following a single oral administration of the composition is greater than 2-fold, 3 -fold or 4-fold that of the control composition.

In one embodiment of the sixteenth aspect, the dose normalized exposure of Compound A in the plasma of a mammal is above 2.2 ng-hr/ml-mg, or above 2.5 ng-hr/ml-mg.

In one embodiment of any of the seventeenth to nineteenth aspects, the minimum therapeutic level is about 50 ng/ml. In one embodiment of any of the seventeenth to nineteenth aspects, the minimum therapeutic level is about 30 ng/ml. In one embodiment of any of the seventeenth to nineteenth aspects, the minimum therapeutic level is about 40 ng/ml, about 55 ng/ml, about 60 ng/ml or about 70 ng/ml. In one embodiment of any of the seventeenth to nineteenth aspects, the minimum therapeutic level is less than or equal to 40 ng/ml, less than or equal to 50 ng/ml, less than or equal to 55 ng/ml, less than or equal to 60 ng/ml or less than or equal to 70 ng/ml, but greater than or equal to 25 ng/ml.

In one embodiment of the seventeenth aspect, the plasma concentration of Compound A in the plasma of a mammal is maintained above a minimum therapeutic level for at least 10 hours, for at least 12 hours, for at least 16 hours or for at least 24 hours or greater following a single oral administration.

In one embodiment of the eighteenth or nineteenth aspects, the dosing interval may be every 8 hours (tid), every 12 hours (bid) or every 24 hours (qd). In one embodiment of the eighteenth or nineteenth aspects, the dosing interval may be equal to or greater than 12 hours.

In one embodiment of the eighteenth or nineteenth aspects, the treatment period refers to a prescribed course of treatment for a particular disease or condition as determined by a healthcare professional. The course of treatment can be for a single day, multiple days, weeks, months or continuous (the subject is administered the pharmaceutical composition for the remainder of life). In one embodiment, the treatment period is continuous. In another embodiment, the treatment period is for a period of months.

In one embodiment of any of the fifteenth to nineteenth aspects, the composition may be provided in a dosage form, such as for example, a tablet. In one embodiment of any of the fifteenth to nineteenth aspects, the composition is provided in an immediate release dosage form, such as for example, a tablet. In one embodiment of any of the fifteenth to nineteenth aspects, the compositions may be present in a dosage form, such as for example, a suspension. Such dosage forms may contain additional excipient components as is customary for such dosage forms.

In one embodiment of any of the fifteenth to nineteenth aspects, the composition is provided as a suspension, comprising the solid dispersion or combination and a liquid vehicle. In one embodiment of any of the fifteenth to nineteenth aspects, the composition is provided as a suspension, consisting of or consisting essentially of the solid dispersion or combination and a liquid vehicle. Suitable liquid vehicles include, but are not limited to liquids with a pH range of from about 4 to about 8, from about 6 to about 7, from about 2 to about 4 or from about 6 to about 10. In one embodiment, the liquid vehicle is water or a liquid with a pH range of about 6 to about 7. In certain embodiments, the solid dispersion or combination is one of the first to fifth aspects, the twelfth to fourteen aspects or the sixth to eleventh aspects, including further descriptions of those aspects. In certain embodiments, the volume of the liquid present is from about 100 mis to about 2500 mis, such as for example, from about 200 mis to about 400 mis, from about 400 mis to about 600 mis, from about 600 mis to about 900 mis, from about 900 mis to about 1200 mis or from about 1200 mis to about 1500 mis.

In a twentieth aspect, the present disclosure provides a method of achieving a concentration of Compound A, or a pharmaceutically acceptable form thereof, in the plasma versus time area under the curve for a 24 hour period of time following a single administration that is greater than 1.5-fold that of a control composition, the method comprising orally administering to the mammal a dose of a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (optionally comprising a concentration enhancing polymer), where the control composition consists essentially of an equivalent quantity of Compound A in an excipient mixture of 72.1% polyethylene glycol 600, 27.2% D-a-tocopherol polyethylene glycol 1000 succinate and 0.7% D-a-tocopherol (the excipient percentages referring to the total weight of the excipient mixture of the control composition, excluding the active ingredient).

In a twenty-first aspect, the present disclosure provides a method of achieving a dose normalized exposure of Compound A, or a pharmaceutically acceptable form thereof, in the plasma of the mammal above 2.0 ng-hr/ml-mg over a 24 hour period following a single oral administration, the method comprising orally administering to the mammal a dose of a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (optionally comprising a concentration enhancing polymer). In a twenty-second aspect, the present disclosure provides a method of achieving a plasma concentration of Compound A, or a pharmaceutically acceptable form thereof, in the plasma of a mammal, such as a human, above a minimum therapeutic level for at least 8 hours following a single oral administration, the method comprising orally administering to the mammal a dose of a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (optionally comprising a concentration enhancing polymer).

In a twenty-third aspect, the present disclosure provides a method of achieving a sustained average plasma concentration of Compound A, or a pharmaceutically acceptable form thereof, in the plasma of a mammal, such as a human, above a minimum therapeutic level for a treatment period and/or a dosing interval, the method comprising orally administering to the mammal at selected dosing intervals a dose of a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (optionally comprising a concentration enhancing polymer).

In a twenty-fourth aspect, the present disclosure provides a method of achieving a sustained average plasma concentration of Compound A, or a pharmaceutically acceptable form thereof, in the plasma of a mammal, such as a human, above a minimum therapeutic level for a treatment period and/or a 12 hour period, the method comprising orally administering to the mammal every 12 hours or greater a dose of a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing PVPVA, HPMC-AS or HPMC polymer.

In a twenty-fifth aspect, the present disclosure provided a method of treating a subject suffering from hereditary angioedema, the method comprising orally administering to the subject a dose of a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (optionally comprising a concentration enhancing polymer).

In a twenty-sixth aspect, the present disclosure provided methods of inhibiting plasma kallikrein activity in a subject, the method comprising orally administering to the subject a dose of a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (optionally comprising a concentration enhancing polymer).

In one embodiment of any of the twentieth to twenty-sixth aspects, the composition is a pharmaceutical composition. In one embodiment of any of the twentieth to twenty-sixth aspects, the composition is a dosage form. In one embodiment of any of the twentieth to twenty- sixth aspects, the composition is a suspension. In one embodiment of any of the twentieth to twenty-sixth aspects, the composition is a tablet. In one embodiment of any of the twentieth to twenty-sixth aspects, the composition consists essentially of or consists of the recited ingredients.

In one embodiment of any of the twentieth to twenty-sixth aspects, the composition may be provided in a dosage form, such as for example, a tablet. In one embodiment of any of the twentieth to twenty-sixth aspects, the composition is provided in an immediate release dosage form, such as for example, a tablet. Such dosage forms may contain additional excipient components as is customary for such dosage forms.

In one embodiment of any of the twentieth to twenty-sixth aspects, the composition is provided as a suspension, comprising the solid dispersion or combination and a liquid vehicle. In one embodiment of any of the twentieth to twenty-sixth aspects, the composition is provided as a suspension, consisting of or consisting essentially of the solid dispersion or combination and a liquid vehicle. Suitable liquid vehicles include, but are not limited to liquids with a pH range of from about 4 to about 8, from about 6 to about 7, from about 2 to about 4 or from about 6 to about 10. In one embodiment, the liquid vehicle is water or a liquid with a pH range of about 6 to about 7. In certain embodiments, the solid dispersion or combination is one of the first to fifth aspects, the twelfth to fourteen aspects or the sixth to eleventh aspects, including further descriptions of those aspects. In certain embodiments, the volume of the liquid present is from about 100 mis to about 2500 mis, such as for example, from about 200 mis to about 400 mis, from about 400 mis to about 600 mis, from about 600 mis to about 900 mis, from about 900 mis to about 1200 mis or from about 1200 mis to about 1500 mis.

In one embodiment of any of the twentieth to twenty-third of twenty-fifth to twenty- sixth aspects, the composition is a composition comprising a solid dispersion or combination according to any of the first to fourteenth aspects, the first to fifth aspects, the sixth to eleventh aspects or the twelfth to fourteenth aspects, including the further descriptions of such aspects.

In one embodiment of any of the twentieth to twenty-sixth aspects, the recited effects of the method are achieved by administering to the mammal a dose containing an amount of Compound A, or a pharmaceutically acceptable form thereof, in the range of from about 100 mg to about 600 mg of Compound A, specifically including doses of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg. In one embodiment of any of the twentieth to twenty-sixth aspects, the recited effects of the composition are achieved by administering to the mammal a dose containing an amount of Compound A, or a pharmaceutically acceptable form thereof, of at least 20 mg, at least 40 mg, at least 50 mg, at least 100 mg, at least 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg or greater, 800 mg or greater, 1000 mg or greater, 1500 mg or greater, 2000 mg or greater 2500 mg or greater, 3000 mg or greater or 4000 mg or greater, but less than 5000 mg. In one embodiment of any of the twentieth to twenty-sixth aspects, the recited effects of the method are achieved, by administering to the mammal a dose containing an amount of Compound A, or a pharmaceutically acceptable form thereof, that is less than 600 mg, less than 500 mg, less than 400 mg, less than 300 mg or less than 200 mg. In one embodiment of any of the twentieth to twenty-sixth aspects, the recited effects of the composition are achieved by administering to the mammal a dose containing an amount of Compound A, or a pharmaceutically acceptable form thereof, that is between about 20 mg to about 100 mg, between about 50 mg to about 300 mg, between about 200 mg to about 400 mg, between about 300 mg to about 500 mg, between about 400 mg to about 600 mg, between about 500 mg to about 2500 mg, between about 400 mg to about 800 mg, between about 800 mg to about 1200 mg or between about 1800 mg to about 2200 mg. Such dose may be provided in one or more than one dosage form (for example 1 tablet or more than 1 tablet). A single dose may be administered per day or multiple doses administered per day if allowed (such as two doses per day or three doses per day).

In one embodiment of the twentieth aspect, the concentration of Compound A in the plasma versus time area under the curve for a 24 hour period of time following a single oral administration of the composition is greater than 2-fold, 3 -fold or 4-fold that of the control composition.

In one embodiment of the twenty-first aspect, the dose normalized exposure of Compound A in the plasma of a mammal is above 2.2 ng-hr/ml-mg, or above 2.5 ng-hr/ml-mg.

In one embodiment of any of the twenty-second to twenty-fourth aspects, the minimum therapeutic level is about 50 ng/ml. In one embodiment of any of the twenty-second to twenty- fourth aspects, the minimum therapeutic level is about 30 ng/ml. In one embodiment of any of the twenty-second to twenty-fourth aspects, the minimum therapeutic level is about 40 ng/ml, about 55 ng/ml, about 60 ng/ml or about 70 ng/ml. In one embodiment of any of the twenty- second to twenty-fourth aspects, the minimum therapeutic level is less than or equal to 40 ng/ml, less than or equal to 50 ng/ml, less than or equal to 55 ng/ml, less than or equal to 60 ng/ml or less than or equal to 70 ng/ml, but greater than or equal to 25 ng/ml.

In one embodiment of the twenty-second aspect, the plasma concentration of Compound A in the plasma of a mammal is maintained above a minimum therapeutic level for at least 10 hours, for at least 12 hours, for at least 16 hours or for at least 24 hours or greater following a single oral administration.

In one embodiment of the twenty-third aspect, the dosing interval may be every 8 hours (tid), every 12 hours (bid) or every 24 hours (qd). In one embodiment of the twenty-third aspect, the dosing interval may be equal to or greater than 12 hours. In one embodiment of the twenty-fourth aspect, the method comprises administering a dose of the composition every 12 hours. In one embodiment of the twenty-fourth aspect, the method comprises administering a dose of the composition at a dosing interval that is greater than 12 hours, for example, every 24 hours (qd).

In one embodiment of the twenty-third to twenty-fourth aspects, the treatment period refers to a prescribed course of treatment for a particular disease or condition as determined by a healthcare professional. The course of treatment can be for a single day, multiple days, weeks, months or continuous (the subject is administered the pharmaceutical composition for the remainder of life). In one embodiment, the treatment period is continuous. In another embodiment, the treatment period is for a period of months.

In one embodiment of the twenty-fifth aspect, the hereditary angioedema is Type I, Type II or Type III. In one embodiment of the twenty-sixth aspect, the subject is suffering from hereditary angioedema (including Type I, Type II or Type III hereditary angioedema).

In a twenty-seventh aspect, the present disclosure provides a method for making a solid dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer, the method comprising the steps of: (i) dissolving Compound A and the matrix components in a spray solution comprising at least one solvent; and (ii) rapidly evaporating the at least one solvent from the spray solution to afford a solid dispersion comprising Compound A and the matrix comprising a concentration enhancing polymer.

In one embodiment of the twenty-seventh aspect, Compound A, or a pharmaceutically acceptable form thereof, is present, at least partially, in an amorphous form. In one embodiment of the twenty-seventh aspect, the solid dispersion contains at least about 10 wt% Compound A, or a pharmaceutically acceptable form thereof. In one embodiment of the twenty-seventh aspect, the solid dispersion contains at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, or at least about 95 wt% of Compound A, or a pharmaceutically acceptable form thereof. In one embodiment of the twenty-seventh aspect, the solid dispersion contains from about 15 wt% to about 90 wt%, from about 20 wt% to about 80 wt%, from about 30 wt% to about 70 wt%, from about 30 wt% to about 60 wt%, from about 40 wt% to about 60 wt%, from about 50 wt% to about 80 wt% or from about 60 wt% to about 90 wt% of Compound A, or a pharmaceutically acceptable form thereof. The foregoing percentages are provided as wt% with respect to total content of the solid dispersion or combination.

In one embodiment of the twenty-seventh aspect as it relates to a solid dispersion, Compound A, or a pharmaceutically acceptable form thereof, is present as an amorphous form at greater than or equal to 50 wt% (determined with respect to the total Compound A in the dispersion) and a solid amorphous dispersion is provided. In one embodiment of the twenty- seventh aspect as it relates to a solid dispersion, at least about 5 wt% of the total amount of Compound A, or a pharmaceutically acceptable form thereof, is present in an amorphous form. Alternatively, at least about 10 wt%, or at least about 15 wt% or at least about 20 wt%, or at least about 30 wt%, or at least about 40 wt%, or at least about 50 wt%, or at least about 60 wt%, or at least about 70 wt%, or at least about 80 wt%, or at least about 90 wt%, or at least about 95 wt% or at least about 99 wt% of the total amount of Compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion is present is in an amorphous form. The foregoing percentages are provided as wt% with respect to total amount of Compound A in the solid dispersion.

In one embodiment of the twenty-seventh aspect, the amount of Compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion is at least 20 mg or at least 50 mg. In one embodiment of the twenty-seventh aspect, the amount of Compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion is between 20 to 1000 mg. In one embodiment of the twenty-seventh aspect, the amount of Compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion is at least 20 mg, at least 40 mg, at least 50 mg, at least 100 mg, at least 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg or greater, 800 mg or greater, 1000 mg or greater, 1500 mg or greater, 2000 mg or greater 2500 mg or greater, 3000 mg or greater or 4000 mg or greater, but less than 5000 mg. In one embodiment of the twenty-seventh aspect, the amount of Compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion is between about 20 mg to about 200 mg, between about 20 mg to about 100 mg, is between about 50 mg to about 300 mg, between about 200 mg to about 400 mg, between about 300 mg to about 500 mg or between about 400 mg to 600 mg. In one embodiment of the twenty- seventh aspect, the amount of Compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion is between about 20 mg to about 100 mg, between about 50 mg to about 300 mg, between about 200 mg to about 400 mg, between about 300 mg to about 500 mg, between about 400 mg to about 600 mg, between about 500 mg to about 2500 mg, between about 400 mg to about 800 mg, between about 800 mg to about 1200 mg or between about 1800 mg to about 2200 mg. As discussed herein, Compound A, or a pharmaceutically acceptable form thereof, may be present in an amorphous form as described above.

In one embodiment of the twenty-seventh aspect, the concentration enhancing polymer is a cellulosic polymer, a non-ionizable cellulosic polymer or a noncellulosic polymer. In one embodiment of the twenty-seventh aspect, the concentration enhancing polymer is HPMC-AS. In one embodiment of the twenty-seventh aspect, the concentration enhancing polymer is PVPVA. In one embodiment of the twenty-seventh aspect, the concentration enhancing polymer is HPMC. In one embodiment of the twenty-seventh aspect, the concentration enhancing polymer is PVPVA64. In one embodiment of the twenty-seventh aspect, the concentration enhancing polymer is HPMC-AS-L or HPMC-AS-M. In one embodiment of the twenty-seventh aspect, the concentration enhancing polymer is HPMC-E3.

In one embodiment of the twenty-seventh aspect, the matrix consists or consists essentially of one or more concentration enhancing polymer. In one embodiment of the twenty- seventh aspect, the matrix consists or consists essentially of a single concentration enhancing polymer. In one embodiment of the twenty-seventh aspect, a single concentration enhancing polymer is present in the matrix, with optionally other ingredients. In one embodiment of the twenty-seventh aspect, more than one concentration enhancing polymer is present in the matrix, with optionally other ingredients. In one embodiment of the twenty-seventh aspect, a single concentration enhancing polymer is present in the matrix, with optionally other ingredients. In one embodiment of the twenty- seventh aspect, more than one concentration enhancing polymer is present in the matrix, with optionally other ingredients. In one embodiment of the twenty-seventh aspect, the solid dispersion further comprises a stabilizing agent. In one embodiment of the twenty-seventh aspect, the matrix consists essentially of or consists of a single concentration enhancing polymer or more than one concentration enhancing polymers and the solid dispersion comprises a stabilizing agent.

In one embodiment of the twenty-seventh aspect, the solid dispersion produced is incorporated in a dosage form, such as for example, a tablet. In one embodiment of the twenty- seventh aspect, the solid dispersion produced is incorporated in an immediate release dosage form, such as for example, a tablet. Such dosage forms may contain additional excipient components as is customary for such dosage forms.

In a twenty-eighth aspect, the present disclosure provides methods of using a solid dispersion ord combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (optionally comprising a concentration enhancing polymer) in the manufacture of a medicament for the treatment of hereditary angioedema in a subject.

In a twenty-ninth aspect, the present disclosure provides methods of using a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (optionally comprising a concentration enhancing polymer) in the manufacture of a medicament for the inhibition of plasma kallikrein activity in a subject.

In a thirtieth aspect, the present disclosure provides dosage forms comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (optionally comprising a concentration enhancing polymer).

In a thirty-first aspect, the present disclosure provides a suspension comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (optionally comprising a concentration enhancing polymer) and a liquid vehicle.

In one embodiment of any of the twenty-eighth to thirty-first aspects, the solid dispersion or combination is one according to any of the first to fourteenth aspects, including the further descriptions of such aspects. In one embodiment of any of the twenty-eighth to thirty-first aspects, the solid dispersion or combination is one according to any of the first to fifth aspects, the sixth to eleventh aspects, or the twelfth to fourteenth aspects, including the further descriptions of such aspects.

In one embodiment of the twenty-eighth aspect, the hereditary angioedema is Type I, Type II or Type III. In one embodiment of the twenty-ninth aspect, the subject is suffering from hereditary angioedema (including Type I, Type II or Type III hereditary angioedema).

In one embodiment of the thirtieth aspect, the dosage form is a tablet. In one embodiment of the thirtieth aspect, the dosage form is an immediate release dosage form. In one embodiment of the thirtieth aspect, the dosage form is an immediate release tablet. Such dosage forms may contain additional excipient components as is customary for such dosage forms.

In one embodiment of the thirtieth aspect, the dosage form is a tablet containing at least 7 wt% of Compound A. In one embodiment of the thirtieth aspect, the dosage form is an immediate release tablet containing at least 7 wt% of Compound A.

In one embodiment of the thirty-first aspect, the suspension comprises a solid dispersion or combination comprising Compound A and a liquid vehicle. In one embodiment of the thirty- first aspect, the suspension consists of or consists essentially of a solid dispersion or combination comprising Compound A and a liquid vehicle. Suitable liquid vehicles include, but are not limited to liquids with a pH range of from about 4 to about 8, from about 6 to about 7, from about 2 to about 4 or from about 6 to about 10. In one embodiment, the liquid vehicle is water or a liquid with a pH range of about 6 to about 7. In certain embodiments, the solid dispersion or combination is one of the first to fifth aspects, the twelfth to fourteen aspects or the sixth to eleventh aspects, including further descriptions of those aspects. In certain embodiments, the volume of the liquid present is from about 100 mis to about 2500 mis, such as for example, from about 200 mis to about 400 mis, from about 400 mis to about 600 mis, from about 600 mis to about 900 mis, from about 900 mis to about 1200 mis or from about 1200 mis to about 1500 mis.

BREIF DESCRIPTION OF THE FIGURES

FIG. 1 shows oral pharmacokinetic results of Compound A when administered to cynomolgus monkeys (Macaca fascicularis) as solid amorphous dispersions (BTAB-1 to BTAB-4) as compared to the control composition.

FIG. 2 shows a graphical comparison of exposure of the oral pharmaceutical compositions comprising solid amorphous dispersions of Compound A (BTAB-1 to BTAB-4) to the control composition.

FIG. 3 shows difference in exposure of the oral pharmaceutical compositions comprising solid amorphous dispersions of Compound A (BTAB-1 to BTAB-4) to the control composition. FIG. 4 shows concentration versus time profiles for Compound A (ng/ml) after administration of tablet formulations of Compound A as compared to a reference soft gelatin capsule formulation.

FIG. 5 shows concentration versus time profiles for Compound A (ng/ml) after administration of suspension formulations comprising solid dispersions of Compound A as compared to a reference soft gelatin capsule formulation.

FIG. 6 shows a concentration versus time profile for Compound A (ng/ml) after administration of a suspension formulation comprising crystalline Compound A mixed with PVPVA64 as compared to a reference soft gelatin capsule formulation.

DETAILED DESCRIPTION

As used herein, the term "exposure" refers to the concentration of Compound A in the plasma of a mammal as measured over a period of time. The exposure of a mammal to Compound A can be measured by administering a composition of the invention to a mammal in an appropriate form, withdrawing plasma samples at predetermined times, and measuring the amount of Compound A in the plasma using an appropriate analytical technique, such as liquid chromatography. The amount of Compound A in the plasma at a certain time is determined, and the concentration and time data from all the samples are plotted to afford a curve. The area under this curve is calculated and affords the exposure of the mammal to the compound. The terms "exposure," "area under the curve," and "area under the concentration/time curve" are intended to have the same meaning and may be used interchangeably throughout.

As used herein, the term "crystalline" means a particular solid form of a compound of the present disclosure that exhibits long-range order in three dimensions. Material that is crystalline may be characterized by techniques known in the art such as powder x-ray diffraction (PXRD) crystallography, solid state NMR, or thermal techniques such as differential scanning calorimetry (DSC). In one particular aspect, crystalline material is characterized by PXRD.

As used herein, the term "amorphous" means a particular solid form of a compound of the present disclosure that has essentially no order in three dimension and is therefore in a noncrystalline state. The term "amorphous" is intended to include not only material which has essentially no order, but also material which may have some small degree of order, but the order is in less than three dimensions and/or is only over short distances. Amorphous material may be characterized by techniques known in the art such as powder x-ray diffraction, crystallography, solid state NMR, or thermal techniques such as differential scanning calorimetry. In one particular aspect, amorphous material is characterized by PXRD.

As used herein, the term "equivalent quantity" refers to molar quantities of a compound, such as, but not limited to, Compound A, measured as the theoretical number of moles of parent compound, present in a given composition. For example, for a given amount of a composition comprising a salt or solvate of Compound A, an equivalent quantity of crystalline form of Compound A would be calculated by determining the theoretical number of moles of Compound A present in the composition and using an amount of a crystalline form of compound A that would afford the same theoretical number of moles of parent Compound A.

As used herein the term "about" is used herein to mean approximately, roughly, around, or in the region of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth by a variance of 10 percent up or down (higher or lower).

As used herein, the term "treating" or "treat" refers to improving a symptom of a disease or disorder and may comprise curing the disorder, substantially preventing the onset of the disorder, or improving the subject's condition. The term "treatment" as used herein, refers to the full spectrum of treatments for a given disorder from which the patient is suffering, including alleviation of one symptom or most of the symptoms resulting from that disorder, a cure for the particular disorder, or prevention of the onset of the disorder.

The term "in need of treatment" as used herein refers to a judgment made by a healthcare professional that a patient requires or will benefit from administration of a composition comprising Compound A, or a pharmaceutically acceptable form thereof. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the patient is ill, or will be ill, as the result of a disease or condition that is treatable by a method or composition of the disclosure. In a particular usage, the term "in need of treatment" indicates a patient has been diagnosed with HAE or determined to have excess plasma kallikrein activity or both.

The term "in need of prevention" as used herein refers to a judgment made by a healthcare professional that a patient requires or will benefit from administration of a composition comprising Compound A, or a pharmaceutically acceptable form thereof. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the patient will be ill or may become ill, as the result of a disease or condition that is preventable by a method or composition of the disclosure.

As used herein, the term an "effective amount" means the amount of Compound A that is effective for producing a desired effect in a subject. The term "therapeutically effective amount" denotes that amount of Compound A that will elicit a therapeutic response of a subject that is being sought. The actual dose which comprises the effective amount or therapeutically effective amount may depend upon the route of administration, the size and health of the subject, the disorder being treated, and the like.

As used herein, the term "site of use" means either an in vivo environment of a subject, such as, but not limited to, the gastrointestinal tract, subcutaneous spaces, blood, plasma obtained from blood, arterial and venous blood vessels, pulmonary tract or intramuscular tissue or an in vitro environment of a test solution, such as, but not limited to, simulated intestinal fluid or simulated gastric fluid. When referring to methods of treatment or methods of use carried out on a subject, the term refers to an in vivo environment.

As used herein, the term "subject" means any mammal, including, but not limited to, humans, non-human primates, canines, felines, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the term "subject" is used in reference to a human subject.

As used herein, the term "a major portion" means that at least 60wt% (as determined with respect to the total amount of Compound A present in the solid amorphous dispersion) of Compound A in the solid amorphous dispersion is in an amorphous form, rather than a crystalline or non-amorphous form.

As used herein, the term "substantially amorphous" means that the amount of Compound A in a solid amorphous dispersion in a crystalline form or non-amorphous form does not exceed about 25wt% (as determined with respect to the total amount of Compound A present in the solid amorphous dispersion).

As used herein, the term "almost completely amorphous" means that the amount of Compound A in a solid amorphous dispersion in a crystalline form or non-amorphous form does not exceed about 10wt% (as determined with respect to the total amount of Compound A present in the solid amorphous dispersion).

As used herein, the term "pharmaceutically acceptable" when modifying an item (such as a composition, compound, chemical or the like) means that the recited item is safe and nontoxic to a subject and is suitable for use in a composition (for example, a solid dispersion or solid amorphous dispersion) for administration to a subject, particularly a human subject.

As used herein, the term "manufacturing acceptable" when modifying an item (such as a composition, compound, chemical or the like) means that the recited item is compatible with a manufacturing process for the making of a solid dispersion or solid amorphous dispersion, or a composition including the foregoing; for example, a "manufacturing acceptable" solvent additive is a solvent that can be used in the manufacture of a solid dispersion or solid amorphous dispersion i) without unwanted reactions with and/or damage to the machinery and apparatus used in the manufacturing process; and/or ii) without unwanted reactions and/or degradation of the other chemical components present in the manufacturing steps.

Compound A

Compound A is 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinyl- phenyl] -6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid. Compound A has the following structure:

As used herein, the term "compound" is conventional, denoting the chemical species shown above and should be understood to include any pharmaceutically acceptable forms. By "pharmaceutically acceptable forms" is meant any stereoisomers, stereoisomer mixtures, enantiomers, solvates, hydrates, isomorphs, polymorphs, pseudomorphs, neutral forms, and salt forms. Therefore, Compound A includes the recited pharmaceutically acceptable forms. In certain embodiments, the pharmaceutically acceptable forms of Compound A are limited to pharmaceutically acceptable salts and solvates. In certain embodiments, the pharmaceutically acceptable forms of Compound A are limited to pharmaceutically acceptable salts. In certain embodiments, the pharmaceutically acceptable forms of Compound A are limited to pharmaceutically acceptable salts, solvates and hydrates.

The present disclosure provides solid dispersions and combinations comprising Compound A, or pharmaceutically acceptable forms thereof, as well as compositions and pharmaceutical compositions comprising the foregoing. In one embodiment, at least a portion of the Compound A present in the solid dispersion is present as an amorphous form as described in more detail herein. In one embodiment, the Compound A present in the combination is present in a crystalline form as described in more detail herein.

In one embodiment, solid dispersions or combinations comprising Compound A, or pharmaceutically acceptable forms thereof, when dosed orally to a human or other animal provide improved exposure of Compound.

In some embodiments, Compound A is present in the solid dispersions or combinations of the present disclosure as a free base. However, the solubility of the free base form of Compound A at neutral pH ranges (for example from 5 to 7) in a number of solvents commonly used in manufacturing solid dispersions and solid amorphous dispersions (for example methanol) is extremely low. The use of a salt form of Compound A is useful to increase the solubility of Compound A in such solvents as compared to the free base form of Compound A. For example, in the examples describing an exemplary manufacture of a solid amorphous dispersion of Compound A, the HCl salt is used. When the HCl salt of Compound A is added to a solvent (such as methanol), the salt disassociates into the free base form of Compound A and free HCL. The free HCl lowers the pH of the solvent so that the pH is no longer in the neutral range and the solubility of the free base form of Compound A is increased to an acceptable level. Therefore, various pharmaceutically acceptable salt forms of Compound A may be useful in preparing the solid dispersions and solid amorphous dispersions disclosed in order to enhance the solubility of Compound A and it may be advantageous to choose a particular salt form of Compound A for use in preparing the solid dispersions or solid amorphous dispersions comprising Compound A (depending on for example, the choice of solvent used in the manufacturing process).

In addition, the free base form of Compound A may also be used with certain solvents compatible with the production of solid dispersions and solid amorphous dispersions regardless of the pH of the solvent. Further, the free base form of Compound A may also be used in solvents commonly used in manufacturing solid dispersions and solid amorphous dispersions (for example methanol) when a "solvent additive" is used to increase the solubility of Compound A in the solvent solution (for example methanol). In one embodiment, the solvent additive adjusts the pH of the solvent solution to a range less than pH 5 (for example, a pH of 4, 3 2 or lower) or greater than pH 7 (for example, a pH of 8, 9, 10 or higher) resulting in acceptable solubility of Compound A in the solvent solution. For example, the free base form of Compound A may be used with methanol as a solvent if the pH is adjusted to less than 5 (for example, a pH of 4, 3 2 or lower) by an acid (suitable acids include, but are not limited to citric acid and HCl) or if the pH is adjusted to greater than 7 (for example, a pH of 8, 9, 10 or higher) by a base (suitable bases include, but are not limited to, NaOH and KOH). The solvent additive is selected to be both pharmaceutically acceptable and manufacturing acceptable. The determination of a manufacturing acceptable solvent additive may depend in part on the nature of the manufacturing equipment, the solvent used and/or the nature of the other components used in the manufacturing process.

In one embodiment, the solvent additive may serve additional functions in the solid dispersion or solid amorphous dispersion. For example, when citric acid is used as a solvent additive, the citric acid may also act as a stabilizing agent as discussed herein. In one embodiment, Compound A may be used as a free base form in the manufacture of the solid dispersions or combinations of the present disclosure. In another embodiment, Compound A may be used as a free acid form in the manufacture of the solid dispersions or combinations of the present disclosure.

Alternatively, in another embodiment, Compound A may be used as a pharmaceutically acceptable and/or manufacturing acceptable salt form in the manufacture of the solid dispersions or combinations of the present disclosure. Suitable pharmaceutically acceptable and/or manufacturing acceptable salt forms include, but are not limited to, acid addition salts and base addition salts. The determination of a manufacturing acceptable salt form of Compound A may depend in part on the nature of the manufacturing equipment, the solvent used and/or the nature of the other components used in the manufacturing process.

Suitable pharmaceutically acceptable and/or manufacturing acceptable acid additional salts can be prepared by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Examples of pharmaceutically acceptable acid addition salts include hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding salts such as sulfate, nitrate, phosphate, etc.; alkyl and monoarylsulfonates such as methanesulfonate, ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate. Further acid addition salts of the present invention include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, butyrate, camphorate, camphorsulfonate, caprylate, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, 1,2-ethanedisulfonate (edisylate), fumarate, galacterate (from mucic acid), galacturonate, gentisate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, 2-hydroxyethanesulfonate, isethionate, iso- butyrate, lactate, lactobionate, malate, malonate, mandelate, metaphosphate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphonate, phthalate, and vanillate. In one embodiment, the acid addition salt is a hydrochloride salt.

Suitable pharmaceutically acceptable and/or manufacturing acceptable base addition salts can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Examples of such base addition salts are alkali metal salts, such as lithium, sodium and potassium salts, typically formed by reaction with alkali metal hydroxides such as potassium, sodium and lithium hydroxides or alkali metal alkoxides, such as potassium ethanolate and sodium propanolate; alkaline earth metal salts, such as magnesium, calcium and barium salts typically formed by reaction with alkaline earth metal hydroxides such as calcium hydroxides; salts of other metal ions such as aluminium, copper, ferric (Fe³⁺), ferrous (Fe²⁺) and zinc salts; ammonium (NH₄ ⁺) salts; organic base salts including, but not limited to, salts of primary, secondary and tertiary amines including, as primary amines, methylamine, ethylamine, propylamine, benzylamine, aniline and butylamine, as secondary amines dimethylamine, and diethylamine, and as tertiary amines trimethylamine and triethylamine, quaternary ammonium salts such as tetramethylammonium salts, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g., arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris-(hydroxymethyl)-methylamine (tromethamine).

Solid Dispersions and Combinations

The present disclosure provides solid dispersions and combinations comprising Compound A, or a pharmaceutically acceptable form thereof, and optionally additional components. In one embodiment, the present disclosure provides for solid dispersions and combinations comprising Compound A, or a pharmaceutically acceptable form thereof, and one or more additional components, which are collectively referred to as the "matrix."

By "solid dispersion" is meant that at least a portion of Compound A is dispersed in the matrix. In certain embodiments, 80% or more, 90% or more, 95% or more or 99% or more of Compound A is dispersed in the matrix. In another embodiment, the present disclosure provides for solid amorphous dispersions comprising Compound A and a matrix. By "solid amorphous dispersion" is meant that at least 50% of the total amount of Compound A present is present in the amorphous form and dispersed in the matrix. In certain embodiments, at least 75% of the total amount of Compound A present is present in the amorphous form and 80% or more, 90% or more, 95% or more or 99% or more of the total amount of Compound A is dispersed in the matrix. The foregoing percentages are vvt% and are determined with respect to the total amount of Compound A present in the solid dispersion or solid amorphous dispersion.

The term "combination" as it refers to Compound A and a matrix, including a matrix comprising a concentration enhancing polymer, refers to a mixture of Compound A and the matrix wherein Compound A and the matrix are not co-dissolved to together in a common solvent to form the combination; as such Compound A is not dispersed in the matrix as is the case for a solid dispersion. Such "combinations" may be formed by adding bulk Compound A to bulk matrix components and blending or admixing in a dry state (without the addition of a solvent). In certain embodiments, the Compound A in a "combination" is crystalline Compound A. In certain embodiments, the crystalline Compound A is crystalline Form A. In one particular aspect, Form A is a variable hydrate. In another particular aspect, Form A has a chloride content greater than 0.65 and less than or equal to 1.0 (salt to API). Crystalline form A is described in PCTYUS2015/046578, which is hereby incorporated by reference for such teaching.

The solid dispersions and combinations may be used to prepare various compositions. In one embodiment, the composition is a pharmaceutical composition comprising the solid dispersions or combinations. In one embodiment, the pharmaceutical composition is a dosage form comprising the solid dispersions or combinations. In one embodiment, the pharmaceutical composition is a tablet dosage form comprising the solid dispersions or combinations. In one embodiment, the pharmaceutical composition is a suspension comprising the solid dispersion or combination and a liquid vehicle. In one embodiment, the pharmaceutical composition is a suspension consisting essentially of the solid dispersion or combination and a liquid vehicle. In one embodiment, the pharmaceutical composition is a suspension consisting of the solid dispersion or combination and a liquid vehicle.

In a preferred embodiment, the matrix is selected such that the solid dispersion or combination provides either improved physical stability, improved chemical stability, improved exposure, improved concentration enhancement, or any combination of these or all four for Compound A. The matrix may comprise a single component or it may be a mixture of two or more components. The components of the matrix may be intimately mixed to form a single phase or molecular dispersion or they may exist as two or more distinct phases with differing compositions. In certain preferred embodiments, the components of the matrix are intimately mixed to form a single phase or molecular dispersion. In certain embodiments, the matrix comprises a concentration enhancing polymer. In certain embodiments, the matrix consists or consists essentially of a concentration enhancing polymer. In certain embodiments, the matrix may comprise components in addition to the concentration enhancing polymer; such additional components may be, for example, stabilizing agents, pH adjusting agents, excipients and the like. In certain embodiments, the matrix consists or consists essentially of a concentration enhancing polymer and a stabilizing agent. In certain embodiments, a single concentration enhancing polymer is present in the matrix and optionally other components. In certain embodiments, more than one concentration enhancing polymer is present in the matrix and optionally other components.

As stated above, a "solid dispersion" is a mixture of Compound A, or a pharmaceutically acceptable form thereof, and a matrix wherein at least a portion of Compound A (for example, 80% or more, 90% or more, 95% or more or 99% or more) is dispersed in the matrix. A solid dispersion includes those in which Compound A is present in a non-amorphous form, an amorphous form or a combination of the foregoing. Therefore, a dispersion is considered a solid dispersion regardless of the form of Compound A that is present in the dispersion. The foregoing percentages are provided as wt% with respect to total amount of Compound A in the solid dispersion. Compound A can exist within the solid dispersion in relatively pure drug domains or regions, as a solid solution of the drug homogeneously distributed throughout the matrix or any combination of these states or those states that lie intermediate between them.

In certain embodiments, the solid dispersion is a solid amorphous dispersion. A solid amorphous dispersion refers to a solid dispersion containing Compound A, or a pharmaceutically acceptable form thereof, wherein greater than or equal to 50 wt% of the total amount of Compound A present in the solid dispersion is in an amorphous form. In certain embodiments, when Compound A is present in an amorphous form in a solid amorphous dispersion, at least about 60 wt%, at least about 65 wt%, or at least about 70 wt%, at least about 75 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt% or at least about 99 wt% of the total amount of Compound A, or a pharmaceutically acceptable form thereof, is present in an amorphous form. In certain embodiments, at least a major portion of Compound A present is in an amorphous form in the solid amorphous dispersions. Alternatively, the solid amorphous dispersions may comprise Compound A that is substantially amorphous. Additionally the solid amorphous dispersions may comprise Compound A that is almost completely amorphous. An amorphous form of Compound A can exist within the solid amorphous dispersion in relatively pure amorphous drug domains or regions, as a solid solution of drug homogeneously distributed throughout the matrix or any combination of these states or those states that lie intermediate between them. The foregoing wt% are determined with respect to the total amount of Compound A present in the solid amorphous dispersion.

When the term "solid dispersion" is used herein, it is meant to include "solid amorphous dispersion" unless specifically stated otherwise. As such, when a range of variables, a list of components or the like is referred to as being applicable to a solid dispersion, the range of variables, the list of components or the like is also applicable to a solid amorphous dispersion unless specifically stated otherwise.

The percentage of Compound A present in the solid dispersions or combinations of the present disclosure may also vary, depending on the nature of the matrix, such as a concentration enhancing polymer, and the amount of Compound A to be included. In certain embodiments, the solid dispersions or combinations described herein contain at least about 15 wt% Compound A, or a pharmaceutically acceptable form thereof. In certain embodiments, the solid dispersions or combinations described herein contain at least about 20%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, or at least about 95 wt% of Compound A, or a pharmaceutically acceptable form thereof. In certain embodiments, the solid dispersions or combinations described herein contain from about 15 wt% to about 90 wt%, from about 20 wt% to about 80 wt%, from about 30 wt% to about 70 wt%, from about 30 wt% to about 60 wt%, from about 40 wt% to about 60 wt%, from about 50 wt% to about 80 wt% or from about 60 wt% to about 90 wt% of Compound A, or a pharmaceutically acceptable form thereof. In certain embodiments, the solid dispersions or combinations described herein contain about 40 wt% or about 60 wt% of Compound A, or a pharmaceutically acceptable form thereof. The foregoing percentages are provided as wt% with respect to total content of the solid dispersion or combination.

In one embodiment, the amount of Compound A, or a pharmaceutically acceptable form thereof, in the solid dispersions or combinations is at least 20 mg. In one embodiment, the amount of Compound A, or a pharmaceutically acceptable form thereof, in the solid dispersions or combinations is at least 50 mg. In one embodiment, the amount of Compound A, or a pharmaceutically acceptable form thereof, in the solid dispersions or combinations is between 20 to 5000 mg. In one embodiment, the amount of Compound A, or a pharmaceutically acceptable form thereof, in the solid dispersions or combinations is at least 20 mg, at least 40 mg, at least 50 mg, at least 100 mg, at least 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg or greater, 800 mg or greater, 1000 mg or greater, 1500 mg or greater, 2000 mg or greater 2500 mg or greater, 3000 mg or greater or 4000 mg or greater, but less than 5000 mg. In another embodiment, the amount of Compound A, or a pharmaceutically acceptable form thereof, in the solid dispersions or combinations is between about 20 mg to about 200 mg, between about 20 mg to about 100 mg, between about 50 mg to about 300 mg, between about 200 mg to about 400 mg, between about 300 mg to about 500 mg or between about 400 mg to 600 mg, between about 500 mg to about 2500 mg, between about 400 mg to about 800 mg, between about 800 mg to about 1200 mg or between about 1800 mg to about 2200 mg. As discussed herein, Compound A, or pharmaceutically acceptable salt or solvate thereof, may be present in an amorphous form as described above.

In one embodiment, the solid dispersions or combinations comprise Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer and an optional stabilizing agent. In one embodiment, the solid dispersions or combinations comprise Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer and a stabilizing agent. Suitable stabilizing agents are described herein. In certain embodiments where the matrix comprises a concentration enhancing polymer and an optional stabilizing agent, a major portion of Compound A is in the amorphous form, Compound A is substantially amorphous or Compound A is almost completely amorphous and the dispersion is a solid amorphous dispersion. Suitable concentration enhancing polymers are described herein. The concentration enhancing polymer is capable of further improving the concentration of dissolved Compound A in a site of use. In particular, an advantage of including a concentration enhancing polymer in the solid dispersions or combinations of the present disclosure is to improve the exposure and/or AUC of Compound A as compared to solid dispersions or combinations comprising Compound A that do not include such a concentration enhancing polymer. As discussed above, Compound A when provided in liquid formulations administered orally provides an initial concentration of Compound A that decreases substantially over time. Without wishing to be bound by theory, it is believed that the addition of a concentration enhancing polymer in the solid dispersions or combinations of the present disclosure retards the rate at which the initial dissolved drug concentration decreases or delays the time at which the maximum drug concentration is reached. The result is that the solid dispersions or combinations comprising Compound A and a matrix comprising a concentration enhancing polymer provide an improved exposure and/or AUC that is greater than that provided by pharmaceutical compositions containing Compound A without a concentration enhancing polymer.

By improving the AUC, the solid dispersions or combinations comprising Compound A and a matrix comprising a concentration enhancing polymer also provide enhanced bioavailability of Compound A by increasing the concentration of drug which remains dissolved in a use environment, particularly in the blood and the gastrointestinal tract of a mammal, such as a human. Improving the concentration of Compound A in solution allows higher blood levels in a mammal to be achieved, in some cases enabling an effective blood level (such as a minimum therapeutic amount) to be reached, allows an effective blood levels to be reached with less frequent dosing intervals (for example 2 times per day or less) or in other cases, allowing an effective blood levels to be reached at lower drug dosage levels, which in turn decreases the amount of drug that must be dosed, reduces concentration variability, and also decreases the size of the dosage form.

Concentration Enhancing Polymers

In certain embodiments as discussed above, the solid dispersions or combinations disclosed comprise a matrix comprising a concentration enhancing polymer. The concentration enhancing polymer further improves the concentration of dissolved Compound A in a site of use (such as, but not limited to, the blood or the gastrointestinal tract). It has been found that only relatively small amounts of concentration enhancing polymer are needed to sustain the high dissolved drug concentration of Compound A at a site of use. Solid dispersions or combinations comprising Compound A and a concentration enhancing polymer provide not only an initially enhanced dissolved concentration at the site of use but also a sustained dissolved concentration over a physiologically relevant time (for example, during the dosing interval) at the site of use. In certain embodiments, the concentration enhancing polymer in the solid dispersion or combination is present at less than 95%, less than 90%, less than 80 wt%, less than 60 wt%, less than 50 wt%, less than 40 wt%, less than 30 wt% or less than 20 wt% (wt% with respect to total content of the solid dispersion or combination). In certain embodiments, the concentration enhancing polymer in the solid dispersion or combination is present at less than or equal to 60 wt% and greater than or equal to 20 wt% or at less than or equal to 95 wt% and greater than or equal to 60 wt% (wt% with respect to total content of the solid dispersion or combination). In certain embodiments, the concentration enhancing polymer in the solid dispersion or combination is present at 55 wt% to 65 wt%, 65 wt% to 80 wt%, 15 wt% to 35 wt% or 35 wt% to 45 wt% (wt% with respect to total content of the solid dispersion or combination). In certain embodiments, the concentration enhancing polymer in the solid dispersion or combination is present at about 40 wt% or about 60 wt% (wt% with respect to total content of the solid dispersion or combination). Such percentages of concentration enhancing polymer result in substantial improvements in dissolution characteristics of Compound A relative to compositions lacking the concentration enhancing polymer (such as, but not limited to, the liquid formulations discussed previously). Concentration enhancing polymers suitable for use in the pharmaceutical compositions of the present disclosure should be inert, in the sense that they do not chemically react with Compound A in an adverse manner, and are pharmaceutically acceptable. In certain embodiments, the solid dispersion or combination contains at least about 15 wt% Compound A, or a pharmaceutically acceptable form thereof. In certain embodiments, the solid dispersion or combination contains at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, or at least about 95 wt% of Compound A, or a pharmaceutically acceptable form thereof. In certain embodiments, the solid dispersion or combination contains from about 15 wt% to about 90 wt%, from about 20 wt% to about 80 wt%, from about 30 wt% to about 70 wt%, from about 30 wt% to about 60 wt%, from about 40 wt% to about 60 wt%, from about 50 wt% to about 80 wt% or from about 60 wt% to about 90 wt% of Compound A, or a pharmaceutically acceptable form thereof. The foregoing percentages are provided as wt% with respect to total content of the solid dispersion or combination.

In certain embodiments of the solid dispersion, Compound A, or a pharmaceutically acceptable form thereof, is present, at least partially, in an amorphous form. In certain embodiments, where a solid dispersion is recited, the solid dispersion may be a solid amorphous dispersion. In certain embodiments, Compound A is present as a crystalline form in a combination.

In certain embodiments of the solid dispersion, (when Compound A is present in an amorphous form), Compound A, or a pharmaceutically acceptable form thereof, is present as an amorphous form at greater than or equal to 30 wt% (determined with respect to the total amount of Compound A in the dispersion). In certain embodiments of the solid dispersion, (when Compound A is present in an amorphous form), at least about 5 wt% of the total amount of Compound A, or a pharmaceutically acceptable form thereof, is present in an amorphous form. Alternatively, at least about 10 wt%, or at least about 15 wt% or at least about 20 wt%, or at least about 30 wt%, or at least about 40 wt%, or at least about 50 wt%, or at least about 60 wt%, or at least about 70 wt%, or at least about 80 wt%, or at least about 90 wt%, or at least about 95 wt% or at least about 99 wt% of the total amount of Compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion is present is in an amorphous form. In certain embodiments of the solid dispersion, (when Compound A is present in an amorphous form), Compound A, or a pharmaceutically acceptable form thereof, is present as an amorphous form at greater than or equal to 50 wt% and a solid amorphous dispersion is provided. The foregoing percentages are provided as wt% with respect to total amount of Compound A in the solid dispersion. In certain embodiments, the amount of compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion or combination is at least 20 mg or at least 50 mg. In certain embodiments, the amount of compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion or combination is between 20 to 600 mg. In certain embodiments, the amount of compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion or combination is at least 20 mg, at least 40 mg, at least 50 mg, at least 100 mg, at least 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg or greater, 800 mg or greater, 1000 mg or greater, 1500 mg or greater, 2000 mg or greater 2500 mg or greater, 3000 mg or greater or 4000 mg or greater, but less than 5000 mg. In certain embodiments, the amount of compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion or combination is between about 20 mg to about 200 mg, between about 20 mg to about 100 mg, between about 50 mg to about 300 mg, between about 200 mg to about 400 mg, between about 300 mg to about 500 mg, between about 400 mg to about 600 mg, between about 500 mg to about 2500 mg, between about 400 mg to about 800 mg, between about 800 mg to about 1200 mg or between about 1800 mg to about 2200 mg. As discussed herein, Compound A, or a pharmaceutically acceptable form thereof, may be present in an amorphous form.

The concentration enhancing polymer can be neutral or ionizable, and should have an aqueous-solubility of at least about 0.1 mg/mL over at least a portion of the pH range of about 1-8. Concentration enhancing polymers suitable for use with the present invention may be cellulosic or non-cellulosic. By "cellulosic" it is meant a cellulose polymer that has been modified by reaction of at least a portion of the hydroxyl groups on the saccharide repeating units with a compound to form an ester or an ether substituent.

Representative concentration enhancing polymers include, but are not limited to, an ionizable cellulosic polymer, a non-ionizable cellulosic polymer and a noncellulosic polymer.

One class of polymers suitable for use with the present invention comprises noncellulosic polymers. Exemplary noncellulosic polymers include, but are not limited to, polyvinyl pyrrolidone polyvinyl acetate copolymers; vinyl polymers and copolymers having substituents of hydroxyl, alkylacyloxy, or cyclicamido; polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinyl pyrrolidone; and polyethylene polyvinyl alcohol copolymers.

In one aspect, the noncellulosic polymer is a polyvinyl pyrrolidone polyvinyl acetate copolymers (PVPVA) polymer. In another aspect, the noncellulosic polymer is a PVPVA polymer having the structure below, wherein m and n assume any integer value greater than 1 and the polymer is a random, linear copolymerization of the two monomers, N-vinyl-2- pyrrolidone and vinyl acetate.

The copolymer containing the specific ratio of 60% N-vinyl-2-pyrrolidone and 40% vinyl acetate is also known as copovidone or PVPVA64. Commercially manufactured PVPVA copolymer includes Plasdone® S-630 by International Specialty Products, and Kollidon® VA64 by BASF, both of which contain the ratio 60% N-vinyl-2-pyrrolidone:40% vinyl acetate. Ratios of N-vinyl-2-pyrrolidone and vinyl acetate other than 60/40 may also be used. In the descriptions above, the method for measuring the molecular weight distribution of PVPVA copolymer is gel permeation chromato graph employing multi-angle light scattering detection. The weight average molecular weight (M_w) of PVP/VA copolymer as measured by this method is about 35,000-65,000 atomic mass units (amu).

Another class of polymers suitable for use in the present disclosure comprises non- ionizable cellulosic polymers. Exemplary ether-linked non-ionizable substituents include: alkyl groups, such as methyl, ethyl, propyl, butyl, etc.; hydroxy alkyl groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.; and aryl groups such as phenyl. Exemplary ester-linked non-ionizable substituents include: alkyl groups, such as acetate, propionate, butyrate, etc.; and aryl groups such as phenylate. However, when aryl groups are included, the polymer may need to include a sufficient amount of a hydrophilic substituent so that the polymer has at least some water solubility at any physiologically relevant pH of from 1 to 8.

Exemplary non-ionizable cellulosic polymers include, but are not limited to, hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose.

In one aspect, the non-ionizable cellulosic polymer is a hydroxypropyl methyl cellulose (HPMC) polymer. In another aspect, the non-ionizable cellulosic polymer is a HPMC polymer having the structure below, wherein n is an integer greater than 1 and R represents either— H, -

CH₃ or -CH₂CH(CH₃)OH.

In one embodiment, the HPMC has a methoxy content of 18% to 32% and a hydroxypropoxyl content of 5% to 25% (the foregoing percentages expressed by weight). In one embodiment, the HPMC has a methoxy content of 19% to 24% and a hydroxypropoxyl content of 7% to 12% (the foregoing percentages expressed by weight). In one embodiment, the HPMC has a methoxy content of 28% to 30% and a hydroxypropoxyl content of 7% to 12%) (the foregoing percentages expressed by weight). In one embodiment, the HPMC has a methoxy content of 27% to 30% and a hydroxypropoxyl content of 4% to 7.5%> (the foregoing percentages expressed by weight). In one embodiment, the HPMC is HPMC-E3 (available from Ashland).

One class of polymers suitable for use in the present disclosure comprises ionizable cellulosic polymers. "Ionizable cellulosic polymers" are those cellulosic polymers that are at least partially ionizable at physiologically relevant pH and include at least one ionizable substituent, which may be either ether-linked or ester-linked. Exemplary ether-linked ionizable substituents include: carboxylic acids, such as acetic acid, propionic acid, benzoic acid, salicylic acid, alkoxybenzoic acids such as ethoxybenzoic acid or propoxybenzoic acid, the various isomers of alkoxyphthalic acid such as ethoxyphthalic acid and ethoxyisophthalic acid, the various isomers of alkoxynicotinic acid such as ethoxynicotinic acid, and the various isomers of picolinic acid such as ethoxypicolinic acid, etc.; thiocarboxylic acids, such as thioacetic acid; substituted phenoxy groups, such as hydroxyphenoxy, etc.; phosphates, such as phosphate ethoxy; and sulfonates, such as sulphonate ethoxy. Exemplary ester-linked ionizable substituents include: carboxylic acids, such as succinate, citrate, phthalate, terephthalate, isophthalate, trimellitate, and the various isomers of pyridinedicarboxylic acid, etc.; thiocarboxylic acids, such as thiosuccinate; substituted phenoxy groups, such as amino salicylic acid; phosphates, such as acetyl phosphate; and sulfonates, such as acetyl sulfonate Exemplary ionizable cellulosic polymers include, but are not limited to, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl methyl cellulose acetate succinate, , hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, ethyl carboxymethyl cellulose, carboxymethyl ethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methyl cellulose acetate succinate phthalate, hydroxypropyl methyl cellulose succinate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, and ethyl picolinic acid cellulose acetate.

In one aspect, the ionizable cellulosic polymer is a hydroxypropyl methyl cellulose acetate succinate (HPMC-AS) polymer. In another aspect, the ionizable cellulosic polymer is an HPMC-AS polymer having the structure below, wherein n is an integer greater than 1, R is independently selected from -H, -CH₃, -COCH₃, -COCH₂CH₂COOH and - [CH₂CH(CH₃)0]_mR_l5 where Ri is -H, -CH₃, -COCH₃, -COCH₂CH₂COOH and m is any integer greater than 1. Other substituents can be optionally included on the polymer in small amounts, provided they do not materially affect the performance and properties of the polymer.

In one embodiment, the HPMC-AS has an acetyl content of 3-16%, a succinoyl content of 2-20%, a methoxyl content of 18-28% and a hydroxypropoxy content of 3-12% (the foregoing percentages expressed by weight). In one embodiment, the HPMC-AS has an acetyl content of 5-9%, a succinoyl content of 14-18%, a methoxyl content of 20-24% and a hydroxypropoxy content of 5-9% (the foregoing percentages expressed by weight). In one embodiment, the HPMC-AS has an acetyl content of 7-11%, a succinoyl content of 10-14%, a methoxyl content of 21-25% and a hydroxypropoxy content of 5-9% (the foregoing percentages expressed by weight). In one embodiment, the HPMC-AS has an acetyl content of 10-14%), a succinoyl content of 4-8%, a methoxyl content of 22-26%) and a hydroxypropoxy content of 6-10% (the foregoing percentages expressed by weight). In certain embodiments, the HPMC-AS is HPMC-AS-L, HPMC-AS-M or HPMC-AS-H (available from Ashland).

In certain embodiments, the matrix consists of or consists essentially of one or more concentration enhancing polymers. In certain embodiments, the matrix consists of or consists essentially of a single concentration enhancing polymer. In certain embodiments, a single concentration enhancing polymer is present in the matrix, with optionally other ingredients. In certain embodiments, more than one concentration enhancing polymer is present in the matrix. In certain embodiments, the solid dispersion or combination further comprises a stabilizing agent. In certain embodiments, the matrix consists essentially of or consists of a single concentration enhancing polymer or more than one concentration enhancing polymers and the solid dispersion or combination comprises a stabilizing agent.

In certain embodiments, the matrix may comprise components in addition to the concentration enhancing polymer; such additional components may be, for example, stabilizing agents, pH adjusting agents, excipients and the like. In certain embodiments, a single concentration enhancing polymer may be present in the matrix or more than one concentration enhancing polymer may be present in the matrix.

In certain embodiments, the concentration enhancing polymer is PVPVA, HPMC-AS or HPMC. In certain embodiments, the concentration enhancing polymer is PVPVA. In certain embodiments, the concentration enhancing polymer is PVPVA64. In certain embodiments, the concentration enhancing polymer is HPMC-AS-L. In certain embodiments, the concentration enhancing polymer is HPMC-AS-M. In certain embodiments, the concentration enhancing polymer is HPMC-AS-H. In certain embodiments, the concentration enhancing polymer is HPMC-E3.

Combinations of the foregoing concentration enhancing polymers may also be used. In certain embodiments, the combination is a PVPVA polymer and an HPMC-AS polymer or a PVPVA polymer and an HPMC polymer. In such embodiments, the PVPVA polymer may comprise 5% to 99% of the concentration enhancing polymers present (as determined on a weight % basis of all the concentration enhancing polymers present). The specific forms of each polymer as described herein may also be used in the recited combinations.

In certain embodiments, the combinations is a HPMC-AS polymer and an HPMC polymer or an HPMC-AS polymer and a PVPVA polymer. In such embodiments, the HPMC- AS polymer may comprise 5% to 99% of the concentration enhancing polymers (as determined on a weight % basis of all the concentration enhancing polymers present). The specific forms of each polymer as described herein may also be used in the recited combinations.

In certain embodiments, the combinations is a HPMC polymer and an HPMC-AS polymer or an HPMC polymer and a PVPVA polymer. In such embodiments, the HPMC polymer may comprise 5% to 99% of the concentration enhancing polymers (as determined on a weight % basis of all the concentration enhancing polymers present). The specific forms of each polymer as described herein may also be used in the recited combinations.

Stab ilizing Agents

In certain embodiments, the solid dispersions or combination described herein further comprise a stabilizing agent. In certain embodiments, the stabilizing agent is a component of the matrix. Therefore, the present disclosure provides solid dispersions or combinations comprising Compound A and a matrix comprising a concentration enhancing polymer and a stabilizing agent. In another embodiment, the stabilizing agent is added as an excipient, such as to a dosage form. In another embodiment, the stabilizing agent is a component of the matrix and is added as an excipient, such as to a dosage form. The stabilizing agent may improve the stability of Compound A in the solid dispersion or combination. Specifically, the stabilizing agent may improve the chemical stability of Compound A in the solid dispersion or combination or prevent Compound A in an amorphous form from being converted into a non- amorphous form. By "improve the chemical stability" of Compound A is meant slowing the rate of degradation of Compound A into another chemical compound or compounds.

In one embodiment, the stabilizing agent is present at less than 10 wt%. In another embodiment, the stabilizing agent is present at less than 9 wt%, less than 8 wt%, less than 7 wt%, less than 6 wt%, less than 5 wt%, less than 4 wt%, less than 3 wt%, less than 2 wt% or less than 1 wt%. In certain embodiments the stabilizing agent is present from about 0.01 wt% to 10 wt%. In certain embodiments, the stabilizing agent is present from about 0.01 wt%> to about 5 wt%, from about from about 0.1 wt% to about 5 wt%, from about 0.1 wt% to about 4 wt%, from about 0.1 wt% to about 3 wt%, from about 0.1 wt% to about 2 wt% or from about 0.01 wt% to about 1 wt%. The foregoing percentages are provided as wt% with respect to the total weight of the solid dispersion or combination.

The stabilizing agent may be any stabilizing agent known in the art. In certain embodiments, the stabilizing agent is a base or an anti-oxidant. Exemplary stabilizing agents include, but are not limited to, ascorbic acid derivatives such as ascorbic acid and salts thereof (such as sodium ascorbate), citric acid and derivatives thereof, erythorbic acid, thiol derivatives such as thioglycerol, cysteine, acetylcysteine, cystine, dithioerythreitol, dithiothreitol and glutathione, vitamin E in all its forms (tocopherols or tocotrienols) and derivatives thereof, phenols, especially those substituted with at least one tertiary alkyl group (preferably a tert- butyl group), sulfurous acid salts such as sodium sulfite, sodium bisulfite, acetone sodium bisulfite, sodium metabisulfite, sodium sulfite, sodium formaldehyde sulfoxylate, and sodium thiosulfate and nordihydroguaiaretic acid. Stabilizing agents may also be employed in conjunction with chelating agents, e.g. ethylenediamine tetraacetic acid (EDTA) that act to form complexes with heavy-metal ions and other ions that are normally involved in oxidative degradation of active pharmaceutical ingredients.

In one embodiment, the stabilizing agent is a substituted phenol (i.e., a benzene ring substituted with 1 to 3 hydroxyl groups) which is further substituted with at least one tertiary alkyl group (preferably a tert-butyl group) or an alkyl ester (preferably a propyl ester) and, optionally, a (C_1-4) alkyl and/or a (d-4) alkoxy group. Examples of compounds in this class include phenols substituted with a single hydroxyl group further substituted with one tert-butyl group and a methoxy group, such as tert-butyl 4-hydroxyanisole (also known as butylated hydroxyanisole or BHA), which typically comprises a mixture of 2-tert-butyl-4- hydroxyanisole and 3-fert-butyl-4-hydroxyanisole, and phenols substituted with a single hydroxyl group further substituted with two tert-butyl groups and a methyl group, such as 2,6- di-tert-butyl-4-methylphenol (also known as butylated hydroxytoluene, BHT). Examples of compounds in this class include phenols substituted with a single hydroxyl group further substituted with a propyl ester group, such as propyl gallate. In one embodiment, the stabilizing agent is BHA. In one embodiment, the stabilizing agent is BHT. In one embodiment, the stabilizing agent is propyl gallate.

In one embodiment, the stabilizing agent is vitamin E or a vitamin E derivative. The term vitamin E includes tocopherols and tocotrienols. a-tocopherol is the most abundant and active form of this family of compounds. Tocopherol and tocotrienol are chemically similar to one another, with tocotrienols containing three unsaturated bonds in the alkyl tail. The generic structure of tocopherol and tocotrienol are given below, where \ to R₃ are each independently H or a Ci_-3 alykl. In certain embodiments, Ri to R₃ are each independently H or a CH3. Derivatives of tocopherol and tocotrienol are also included where the OH group of the tocopherol and tocotrienol is substituted with moieties including acetate, phosphate, succinate, nicotinate and linoleate.

Tocopherols and/or tocotrienols each comprise a family of 4 compounds, identified by prefixes alpha- (a-), beta- (β-), gamma- (γ-), and delta- (δ-); each of the foregoing may be suitable for use as a stabilizing agent. The tocopherol and/or tocotrienol may have the D or L configuration. The tocopherol and/or tocotrienol may be a single stereoisomer or a mixture of stereoisomers. Natural tocopherols occur in the (R),(R),(R)-configuration only. A synthetic form contains eight different stereoisomers and is called 'all-rac'-a-tocopherol. Therefore, vitamin E compounds useful in the solid dispersions or combinations of the present disclosure include the family of naturally occurring tocopherols and/or tocotrienols, as well as derivatives thereof. In one embodiment, the stabilizing agent is a-tocopherol.

Specific Embodiments

The present disclosure therefore provides for the following specific solid dispersions and combinations:

i) a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix, wherein the matrix comprises, consists of or consists essentially of PVPVA as the concentration enhancing polymer and an optional stabilizing agent and Compound A is present at 10 wt% to 80 wt%, such as 35 wt% to 45 wt% or 55 wt% to 65 wt%;

ii) a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix, wherein the matrix comprises, consists of or consists essentially of PVPVA64 as the concentration enhancing polymer and an . optional stabilizing agent and Compound A is present at 10 wt% to 80 wt%, such as 35 wt% to 45 wt% or 55 wt% to 65 wt%; iii) a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, wherein the matrix comprises, consists of or consists essentially of HPMC-AS as the concentration enhancing polymer and an optional stabilizing agent and Compound A is present at 10 wt% to 80 wt%, such as 35 wt% to 45 wt% or 55 wt% to 65 wt%;

iv) a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, wherein the matrix comprises, consists of or consists essentially of HPMC-AS-L as the concentration enhancing polymer and an optional stabilizing agent and Compound A is present at 10 wt% to 80 wt%, such as 35 wt% to 45 wt% or 55 wt% to 65 wt%;

v) a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix, wherein the matrix comprises, consists of or consists essentially of HPMC-AS-M as the concentration enhancing polymer and an optional stabilizing agent and Compound A is present at 10 wt% to 80 wt%, such as 35 wt% to 45 wt% or 55 wt% to 65 wt%;

vi) a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix, wherein the matrix comprises, consists of or consists essentially of a HPMC as the concentration enhancing polymer and an optional stabilizing agent and Compound A is present at 10 wt% to 80 wt%, such as 35 wt% to 45 wt% or 55 wt% to 65 wt%; and

vii) a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix, wherein the matrix comprises, consists of or consists essentially of a HPMC-E3 as the concentration enhancing polymer and an optional stabilizing agent and Compound A is present at 10 wt% to 80 wt%, such as 35 wt% to 45 wt% or 55 wt% to 65 wt%.

In one embodiment, the solid dispersions are solid amorphous dispersions. Suitable stabilizing agents include BHT, BHA, propyl gallate, citric acid and vitamin E and its derivatives. In the foregoing, wt% is determined with respect to the total weight of the solid dispersion or combination.

Formation of Solid Dispersions and Combinations

Solid dispersions or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix, such as a matrix comprising a concentration enhancing polymer, may be produced in any manner. In one embodiment, Compound A and the concentration enhancing polymer are combined and formed into a solid dispersion. Solid amorphous dispersions comprising Compound A and a matrix comprising a concentration enhancing polymer are preferred.

The solid dispersions comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix, including a matrix comprising a concentration enhancing polymer may, contain the wt% of Compound A as discussed herein. Solid dispersions or combinations comprising Compound A in a matrix, such as a matrix comprising a concentration enhancing polymer, are preferably physically stable. By "physically stable" it is meant that the solid dispersions continue to provide improved dissolution performance of Compound A even after storage for extended periods of time (such as a period of 1 year or more at room temperature). Further, the solid amorphous dispersions in addition to being physically stable as defined above, retain at least a portion of the Compound A originally present in an amorphous form in an amorphous form after storage for extended periods of time (such as a period of 1 year or more at room temperature); in one embodiment, such percentage is 50 wt% or greater (the wt% determined with respect to the total Compound A in the solid amorphous dispersion).

A preferred method for forming solid dispersions, including solid amorphous dispersions, is solvent processing, which consists of dissolution of at least a portion of Compound A, or a pharmaceutically acceptable form thereof, and at least a portion of the matrix components in a common solvent. The term "solvent" is used broadly and includes mixtures of solvents. "Common" here means that the solvent will dissolve at least a portion of Compound A and the matrix material(s). After at least a portion of Compound A and the matrix components have been dissolved, the solvent is removed. Exemplary processes for solvent removal are spray-drying, spray-coating (pan-coating, fluidized bed coating, etc.), and precipitation by rapid mixing of the solvent solution with C0₂, hexane, heptane, water of appropriate pH, or some other non-solvent. Preferably, removal of the solvent results in a solid dispersion that is substantially homogeneous. To achieve this end, it is generally desirable to rapidly remove the solvent from the solution such as in a process where the solution is atomized and the Compound A and matrix rapidly solidify.

In a preferred embodiment, the solvent is removed by spray-drying. The term "spray- drying" is used conventionally and broadly refers to processes involving breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture in a spray-drying apparatus where there is a strong driving force for evaporation of solvent from the droplets. Spray-drying processes and spray-drying equipment are described generally in Perry's Chemical Engineers' Handbook, pages 20-54 to 20-57 (Sixth Edition 1984) (which is incorporated by reference for such teachings). More details on spray-drying processes and equipment are reviewed by Marshall, "Atomization and Spray-Drying," 50 Chem. Eng. Prog. Monogr. Series 2 (1954), and Masters, Spray Drying Handbook (Fourth Edition 1985) (both of which are incorporated by reference for such teachings). The strong driving force for solvent evaporation is generally provided by maintaining the partial pressure of the solvent in the spray-drying apparatus well below the vapor pressure of the solvent at the temperature of the drying droplets. This is accomplished by (1) maintaining the pressure in the spray-drying apparatus at a partial vacuum (e.g., 0.01 to 0.50 atm); or (2) mixing the liquid droplets with a warm drying gas; or (3) both (1) and (2). In addition, at least a portion of the heat required for evaporation of solvent may be provided by heating the spray solution.

Solvents suitable for spray-drying can be any solvent in which Compound A, or a pharmaceutically acceptable form thereof, and the matrix component(s) are mutually soluble. Preferably, the solvent is also volatile with a boiling point of 150°C or less. In addition, the solvent should have relatively low toxicity and be removed from the solid dispersion to a level that is acceptable according to The International Committee on Harmonization (ICH) guidelines. Removal of solvent to this level may require a subsequent processing step such as further drying. Suitable solvents include, but are not limited to, alcohols such as methanol, ethanol, n-propanol, iso-propanol, and butanol; ketones such as acetone, methyl ethyl ketone and methyl iso-butyl ketone; esters such as ethyl acetate and propylacetate; and various other solvents such as acetonitrile, methylene chloride, toluene, and 1,1,1-trichloroethane. Lower volatility solvents such as dimethyl acetamide or dimethylsulfoxide can also be used. Mixtures of solvents, such as 50% methanol and 50% acetone, can also be used, as can mixtures with water, so long as the matrix component(s) and Compound A are sufficiently soluble to make the spray-drying process practicable.

Another method for improving the chemical stability of the resulting solid dispersion is to purge the spray solution of oxygen by bubbling an inert gas such as nitrogen through the spray solution.

The amount of Compound A and matrix component(s) in the spray solution depends on the solubility of each in the spray solution and the desired ratio of Compound A to matrix components in the resulting solid dispersion. Preferably, the spray solution comprises at least about 1 wt%, more preferably at least about 3 wt%, and even more preferably at least about 10 wt% dissolved solids.

The solvent feed can be spray-dried under a wide variety of conditions and yet still yield solid dispersions with acceptable properties. For example, various types of nozzles can be used to atomize the spray solution, thereby introducing the spray solution into the spray-dry chamber as a collection of small droplets. Essentially any type of nozzle may be used to spray the solution as long as the droplets that are formed are sufficiently small that they dry sufficiently (due to evaporation of solvent) such that they do not stick to or coat the spray- drying chamber wall.

Although the maximum droplet size varies widely as a function of the size, shape and flow pattern within the spray-dryer, generally droplets should be less than about 500 μιη in diameter when they exit the nozzle. Examples of types of nozzles that may be used to form the solid dispersions include the two-fluid nozzle, the fountain-type nozzle, the flat fan-type nozzle, the pressure nozzle and the rotary atomizer. In a preferred embodiment, a pressure nozzle is used, as disclosed in detail inU.S. Patent No. 7,780,988 (which is incorporated herein by reference for such teaching).

The spray solution can be delivered to the spray nozzle or nozzles at a wide range of temperatures and flow rates. Generally, the spray solution temperature can range anywhere from just above the solvent's freezing point to about 20°C above its ambient pressure boiling point (by pressurizing the solution) and in some cases even higher. Spray solution flow rates to the spray nozzle can vary over a wide range depending on the type of nozzle, spray-dryer size and spray-dry conditions such as the inlet temperature and flow rate of the drying gas. Generally, the energy for evaporation of solvent from the spray solution in a spray-drying process comes primarily from the drying gas. The drying gas, in principle, can be essentially any gas, but for safety reasons and to minimize undesirable oxidation of Compound A or other materials in the solid dispersion, an inert gas such as nitrogen, nitrogen-enriched air or argon may be utilized. The drying gas is typically introduced into the drying chamber at a temperature between about 60°C and about 300°C and preferably between about 80°C and about 240°C.

The large surface-to-volume ratio of the droplets and the large driving force for evaporation of solvent leads to rapid solidification times for the droplets. Solidification times should be less than about 20 seconds, preferably less than about 10 seconds, and more preferably less than 1 second. This rapid solidification is often critical to the particles maintaining a uniform, homogeneous dispersion instead of separating into Compound A-rich and matrix component-rich phases. In a preferred embodiment, the height and volume of the spray-dryer are adjusted to provide sufficient time for the droplets to dry prior to impinging on an internal surface of the spray-dryer, as described in detail inU.S. Patent No. 6,763,607 (which is incorporated herein by reference for such teaching). As noted above, to obtain large enhancements in concentration and bioavailability it is advantageous to obtain as homogeneous a solid dispersion as possible.

Following solidification, the solid powder typically stays in the spray-drying chamber for about 5 to 60 seconds, further evaporating solvent from the solid powder. The final solvent content of the solid dispersion as it exits the dryer should be low, since this reduces the mobility of Compound A in the solid dispersion, thereby improving its stability. Generally, the solvent content of the solid dispersion as it leaves the spray-drying chamber should be less than 10 wt% and preferably less than 2 wt% (the percentage determined with respect to the total weight of the solid dispersion). Following formation, the solid dispersion can be dried to remove residual solvent using suitable drying processes, such as tray drying, vacuum drying, fluid bed drying, microwave drying, belt drying, rotary drying, and other drying processes known in the art.

The solid dispersions produced may be phase separated, meaning Compound A and the matrix component(s) are each in separate domains within the solid dispersion. Alternatively, the solid dispersions produced may have Compound A and the matrix components homogeneously distributed throughout each other to form a single phase or molecular dispersion. Further the solid dispersions produced may be a combination of these states or those states that lie intermediate. Preferably, removal of the solvent results in the formation of a substantially homogeneous solid dispersion such that Compound A and the matrix components are dispersed as homogeneously as possible throughout each other and can be thought of as a molecular dispersion or solid solution of Compound A dispersed in the matrix, wherein the dispersion is thermodynamically stable.

The solid dispersion may be in the form of small particles. The mean size of the particles may be less than 500 μηι in diameter, or less than 100 μπι in diameter, less than 50 μιη in diameter or less than 25 μπι in diameter. When the solid dispersion is formed by spray-drying, the resulting dispersion is in the form of such small particles. The resulting dispersion may optionally be sieved, ground, milled, or otherwise processed to yield a plurality of smaller particles.

Combinations of Compound A and a matrix, including a matrix comprising a concentration enhancing polymer, may be produced by blending or admixing Compound A and the matrix components. In one embodiment, Compound A and the matrix components are subject to blending or admixing in a dry state (without the addition of a solvent). The combination may be subject to grinding, milling or like processes to produce a desired particle size for one or more of the components. In one embodiment, the Compound A added to the matrix components is crystalline Compound A. In one embodiment, the Compound A added to the matrix components is crystalline form A.

Compositions

The present disclosure provides for a variety of compositions comprising a solid dispersion or combination of Compound A, or a pharmaceutically acceptable form thereof. The compositions may be used as is or in a pharmaceutical composition for oral administration to a mammal, such as a human. In one embodiment, the compositions are in the form of solid dispersions. In another embodiment, the compositions are in the form of combinations. In certain embodiments, the compositions are solid dispersions or combinations and are provided in a dosage form, such as for example, a tablet with customary excipients. In certain embodiments, the compositions are solid amorphous dispersions and are provided in a dosage form, such as for example, a tablet with customary excipients. In certain embodiments, the compositions are suspensions and are provided by mixing a solid dispersion or combination with a liquid vehicle. In certain embodiments, the compositions are suspensions and are provided by mixing a solid amorphous dispersion or combination comprising crystalline Compound A with a liquid vehicle.

In one embodiment, the present disclosure provides a composition comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix, including a matrix comprising a concentration enhancing polymer. In another embodiment, the present disclosure provides a composition comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix, including a matrix comprising a concentration enhancing polymer, in the form of a solid dispersion or combination as described herein. In another embodiment, the present disclosure provides a composition comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix, including a matrix comprising a concentration enhancing polymer and a stabilizing agent, in the form of a solid dispersion or combination as described herein. Included are any of the solid dispersions or combinations disclosed herein. Preferred solid dispersions and combinations are those listed under the "Specific Embodiments" subheading above in either their broadest or narrowest forms and as described in the first to fifth aspects, the twelfth to fourteen aspects or the sixth to eleventh aspects, including further descriptions of those aspects, in the Summary of the Invention.

In still a further embodiment, the present disclosure provides a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising PVPVA or PVPVA64 and an optional stabilizing agent. In a preferred aspect of this embodiment, the solid dispersion is a solid amorphous dispersion and the combination contains crystalline Compound A.

In still a further embodiment, the present disclosure provides a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising HPMC-AS, HPMC-AS-L or HPMC-AS-M and an optional stabilizing agent. In a preferred aspect of this embodiment, the solid dispersion is a solid amorphous dispersion and the combination contains crystalline Compound A.

In still a further embodiment, the present disclosure provides a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising HPMC or HPMC-E3 and an optional stabilizing agent. In a preferred aspect of this embodiment, the solid dispersion is a solid amorphous dispersion and the combination contains crystalline Compound A.

In certain embodiments, the compositions may be present in a dosage form, such as for example, a tablet. In certain embodiments, the compositions may be present in an immediate release dosage form, such as for example, a tablet. In certain embodiments, the compositions may be present in a dosage form, such as for example, a suspension. Such dosage forms may contain additional excipient components as is customary for such dosage forms.

Such compositions, particularly compositions present in a dosage form, may be used as a composition or pharmaceutical composition in the methods described herein.

In one embodiment, the solid dispersions or combinations of the present disclosure are used to prepare a suspension comprising the solid dispersion or combination and a liquid vehicle. In one embodiment, the solid dispersions or combinations of the present disclosure are used to prepare a suspension, consisting of or consisting essentially of the solid dispersion or combination and a liquid vehicle. Suitable liquid vehicles include, but are not limited to liquids with a pH range of from about 4 to about 8, from about 6 to about 7, from about 2 to about 4 or from about 6 to about 10. In one embodiment, the liquid vehicle is water or a liquid with a pH range of about 6 to about 7. In certain embodiments, the solid dispersion or combination used to prepare the suspension may be one described under the sub-heading "Specific Embodiments" above in either the broadest or narrowest aspects. In certain embodiments, the solid dispersion or combination used to prepare the suspension may be as described in the first to fifth aspects, the twelfth to fourteen aspects or the sixth to eleventh aspects, including further descriptions of those aspects, in the Summary of the Invention. In certain embodiments, the volume of the liquid present is from about 100 mis to about 2500 mis, such as for example, from about 200 mis to about 400 mis, from about 400 mis to about 600 mis, from about 600 mis to about 900 mis, from about 900 mis to about 1200 mis or from about 1200 mis to about 1500 mis. Such suspensions may be used as a composition or pharmaceutical composition in the methods described herein.

In still a further embodiment, the present disclosure provides a suspension comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising PVPVA or PVPVA64 and an optional stabilizing agent. In a preferred aspect of this embodiment, the solid dispersion is a solid amorphous dispersion and the combination contains crystalline Compound A.

In still a further embodiment, the present disclosure provides a suspension comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising HPMC-AS, HPMC-AS-L or HPMC-AS-M and an optional stabilizing agent. In a preferred aspect of this embodiment, the solid dispersion is a solid amorphous dispersion and the combination contains crystalline Compound A.

In still a further embodiment, the present disclosure provides a suspension comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising HPMC or HPMC-E3 and an optional stabilizing agent. In a preferred aspect of this embodiment, the solid dispersion is a solid amorphous dispersion and the combination contains crystalline Compound A.

In certain preferred embodiments, the compositions are suitable for oral delivery. In certain preferred embodiments, the compositions are suitable for oral delivery when included in a dosage form. In certain preferred embodiments, the compositions are suitable for oral delivery when provided in a suspension with a liquid vehicle.

In certain embodiments of the composition described herein, Compound A, or a pharmaceutically acceptable form thereof, is present in an amorphous form or at least partially in an amorphous form.

The amount of Compound A, or a pharmaceutically acceptable form thereof, present in the composition comprising a solid dispersion or combination of Compound A and a matrix may vary depending on the nature of the matrix, such as a concentration enhancing polymer, and the amount of Compound A to be included. In certain embodiments of the compositions comprising a solid dispersion or combination of Compound A, or a pharmaceutically acceptable form thereof, and a matrix, the amount of Compound A in the composition is at least 20 mg or at least 50 mg. In further embodiments, the amount of Compound A, or a pharmaceutically acceptable form thereof, in the composition comprising a solid dispersion or combination of Compound A and a matrix is between 20 to 5000 mg. In further embodiments, the amount of Compound A, or a pharmaceutically acceptable form thereof, in the composition comprising a solid dispersion or combination of Compound A and a matrix is at least 20 mg, at least 40 mg, at least 50 mg, at least 100 mg, at least 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg or greater, 800 mg or greater, 1000 mg or greater, 1500 mg or greater, 2000 mg or greater 2500 mg or greater, 3000 mg or greater or 4000 mg or greater, but less than 5000 mg. In further embodiments, the amount of Compound A, or a pharmaceutically acceptable form thereof, in the composition comprising a solid dispersion or combination of Compound A and a matrix is between about 20 mg to about 200 mg, between about 20 mg to about 100 mg, between about 50 mg to about 300 mg, between about 200 mg to about 400 mg, between about 300 mg to about 500 mg or between about 400 mg to about 600 mg, between about 500 mg to about 2500 mg, between about 400 mg to about 800 mg, between about 800 mg to about 1200 mg or between about 1800 mg to about 2200 mg. As discussed herein, Compound A, or a pharmaceutically acceptable form thereof, may be present in an amorphous form or at least partially in an amorphous form.

The percentage of Compound A, or a pharmaceutically acceptable form thereof, present in the composition may also vary, depending on the nature of the matrix, such as a concentration enhancing polymer, and the amount of Compound A to be included. In certain embodiments of the compositions comprising a solid dispersion or combination of Compound A and a matrix, the compositions contain at least about 7 wt% Compound A. In certain embodiments, the compositions comprising a solid dispersion or combination of Compound A and a matrix contain at least about 10%, at least about 15 wt%, at least about 20 wt%, at least about 25 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, or at least about 60 wt% of Compound A, or a pharmaceutically acceptable form thereof. In certain embodiments, the compositions comprising a solid dispersion or combination of Compound A and a matrix contain from about 7 wt% to about 55 wt%, from about 7 wt% to about 15 wt%, from about 17 wt% to about 43 wt% or from about 27 wt% to about 33 wt% of Compound A, or a pharmaceutically acceptable form thereof. In certain embodiments, the compositions comprising a solid dispersion or combination of Compound A and a matrix contain from about 8 wt% to about 12 wt%, from about 18 wt% to about 22 wt%, from about 28 wt% to about 32 wt%, from about 20 wt% to about 30 wt% or from about 55 wt% to about 65 wt% of Compound A, or a pharmaceutically acceptable form thereof. The foregoing percentages are provided as wt% with respect to total content of the composition (including the solid dispersion or combination and additional excipients and additives as described herein). In preferred embodiments, the compositions comprise a solid dispersion, particularly a solid amorphous dispersion, or combination comprising Compound A and a matrix comprising a concentration enhancing polymer and an optional stabilizing agent. In certain embodiments, the solid dispersion or combination contains at least about 10 wt% of Compound A (such as at least about 20 wt% at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, or at least about 95 wt%). In certain preferred embodiments, the solid dispersion or combination contains less than about 80 wt% but greater than 20 wt% of Compound A (such as between about 30 wt% and 70 wt%, between about 35 wt% and 65 wt% or between about 40 wt% and 60 wt%). In certain preferred embodiments the solid dispersion or combination contains at least about 20 wt% of Compound A (such as at least about 30%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, or at least about 95 wt%) and the matrix comprises only PVPVA, PVPVA64, HPMC, HPMC-E3, HPMC- AS, HPMC-AS-L, HPMC-AS-M or combinations thereof as the concentration enhancing polymer and an optional stabilizing agent. In certain preferred embodiments, the solid dispersion or combination contains less than about 80 wt% but greater than 20 wt% of Compound A (such as between about 30 wt% and 70 wt%, between about 35 wt% and 65 wt% or between about 40 wt% and 60 wt%) and the matrix comprises only PVPVA, PVPVA64, HPMC, HPMC-E3, HPMC-AS, HPMC-AS-L, HPMC-AS-M or combinations thereof as the concentration enhancing polymer and an optional stabilizing agent. Characterization of the Solid Dispersions, Combinations and Methods of Use

The compositions of the present disclosure, particularly those comprising solid dispersions or combinations, provide advantageous properties when dosed orally to a mammal, such as a human. The disclosed compositions provide both a higher exposure of Compound A for a given dose (for example, a higher dose normalized AUC) and a higher concentration of Compound A in the blood over all or substantially all of the dosing interval such that the concentration of Compound A in the blood remains higher over all or substantially all of the dosing interval. The foregoing comparisons may be made with respect to liquid oral formulations of Compound A described in the art. Furthermore, the disclosed compositions provide for one or more of the following: (i) blood concentrations of Compound A over the minimum therapeutic level for at least 12 hours after administration of single dose of Compound A (the dose being delivered in 1 or more than 1 dosage form) when administered orally to a mammal, such as a human; (ii) blood concentrations of Compound A of at least 1.5 times or more over the minimum therapeutic level for at least 8 hours after administration of single dose of Compound A (the dose being delivered in 1 or more than 1 dosage form) when administered orally to a mammal, such as a human; (iii) a prolonged dosing interval (for example, a period of 12 hours or more between administrations, such as a 2 administrations per day or 1 administration per day) while still maintaining blood concentrations of Compound A over a minimum therapeutic level over all or substantially all of the dosing interval; (iv) the amount of Compound A dosed per day or per administration to be reduced as compared to a control composition while still maintaining blood concentrations of Compound A over a minimum therapeutic level over all or substantially all of the dosing interval as compared to a control composition; (v) the number of dosage forms dosed per day or per administration to be reduced as compared to a control composition, for example 4 dosage forms per administration, 3 dosage forms per administration, 2 dosage forms per administration or 1 dosage form per administration, or for example, less than 15 dosage forms per day, less than 12 dosage forms per day, less than 10 dosage forms per day, less than 8 dosage forms per day, less than 6 dosage forms per day, less than 4 dosage forms per day; (vi) a T_max that is delayed compared to a control composition while still maintaining an exposure equal to a greater than the control composition over all or substantially all of a dosing interval; (vii) a higher concentration of Compound A in each dosage form as compared to a control composition; (viii) a dosage form in which Compound A is physically and chemically stable upon storage, particularly storage at room temperature or ambient temperature; and ix) reduced variability in exposure between individual subjects as compared to a control composition.

In such uses any composition of the present disclosure may be used. In a particular embodiment, the composition is a solid dispersion or combination described under the subheading "Specific Embodiments" above in either the broadest or narrowest aspects. In another particular embodiment, the composition is a solid dispersion or combination is as described in the first to fifth aspects, the twelfth to fourteen aspects or the sixth to eleventh aspects, including further descriptions of those aspects, in the Summary of the Invention. In another particular embodiment, the composition is any solid dispersion or combination described herein. In another particular embodiment, the composition is one comprising a solid dispersion or combination described under the sub-heading "Specific Embodiments" above in either the broadest or narrowest aspects. In another particular embodiment, the solid dispersion or combination is as described in the first to fifth aspects, the twelfth to fourteen aspects or the sixth to eleventh aspects, including further descriptions of those aspects, in the Summary of the Invention. In another specific embodiment, the composition is one comprising any solid dispersion or combination described herein. As discussed above, a hard gelatin capsule comprising Compound A in a liquid formulation has been developed and used with success in the clinic to demonstrate the safety and effectiveness of Compound A to treat HAE patients. However, while effective, Compound A administered in capsules comprising liquid oral formulations is not completely absorbed from the GI tract and the dose response of Compound A is saturable in healthy subjects. In addition, when Compound A is administered in capsules containing a liquid oral formulation, blood concentrations of Compound A were sufficient to inhibit approximately 75% of plasma kallikrein activity in subjects at 3 hours; however, by 8 hours blood concentrations of Compound A were sufficient to inhibit only approximately 40% of plasma kallikrein activity in subjects. The compositions of the present disclosure provides for Compound A to be orally administered in a more effective manner.

As a result of the beneficial properties discussed herein, the present disclosure provides solid dispersions or combinations of Compound A, or a pharmaceutically acceptable form thereof, and a matrix, including a matrix comprising a concentration enhancing polymer, and compositions comprising such solid dispersions or combinations, that exhibit unique pharmacokinetic properties after oral administration to a mammal, such as a human that enable a variety of uses and methods of treatments. Such results are surprising and unexpected given the difficulty in orally administering Compound A in liquid oral formulations.

Characterization of Compositions Comprising a Solid Dispersion or Combination

In one embodiment, the present disclosure provides a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer) that when administered to a mammal, such as a human, provides for a concentration of Compound A in the plasma versus time area under the curve for a 24 hour period of time following administration of a single oral dose of the composition that is greater than 1.5-fold that of the control composition.

Further, the concentration of Compound A in the plasma versus time area under the curve for a 24 hour period of time following administration of a single oral dose of the composition is greater than 2-fold that of the control composition. Still further, the concentration of Compound A in the plasma versus time area under the curve for a 24 hour period of time following administration of a single oral dose of the composition is greater than 2.5 -fold that of the control composition.

In another embodiment, the present disclosure provides a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer) that when administered to a mammal, such as a human, provides a prolonged dosing interval (for example, a period of 12 hours or more between administration of doses, such as a 2 administrations per day or 1 administration per day) while still maintaining blood concentrations of Compound A over a minimum therapeutic level over all or substantially all of the dosing interval as compared to a control composition. For example, the dosing interval may be 12 hours, or 24 hours.

In another embodiment, the present disclosure provides a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer) that when administered to a mammal, such as a human, provides for the amount of Compound A dosed per day or per administration to be reduced as compared to a control composition while still maintaining blood concentrations of Compound A over a minimum therapeutic level over all or substantially all of the dosing interval. For example, the amount of Compound A dosed per day may be less than 1500 mg, such as less than 1200 mg or less than 1000 mg or less than 700 mg or the amount of Compound A dosed at each administration (i.e., the start of each dosing interval) may be 500 mg or less, such as 400 mg or less, 350 mg or less or 300 mg or less.

In another embodiment, the present disclosure provides a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer) that when administered to a mammal, such as a human, provides for a dose normalized exposure of Compound A in the plasma of the mammal above 2.0 ng-hr/ml-mg over a 24 hour period of time following administration of a single oral dose of the composition.

Further, the dose normalized exposure of Compound A in the plasma of the mammal is above 2.2 ng-hr/ml-mg. Still further, the dose normalized exposure of Compound A in the plasma of the mammal is above 2.5 ng-hr/ml-mg.

In another embodiment, the present disclosure provides a composition comprising a solid dispersion or combination Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer) that when administered to a mammal, such as a human, provides for the number of dosage forms dosed per day or per administration to be reduced as compared to a control composition. For example, the number of dosage forms administered per administration may be less than 4 dosage forms, less than or equal to 3 dosage forms, less than or equal to 2 dosage forms or 1 dosage form or the number of dosage forms dosed per day may be, for example, less than 12 dosage forms, less than or equal to 10 dosage forms, less than or equal to 8 dosage forms, less than or equal to 6 dosage forms, less than or equal to 4 dosage forms or less than or equal to 2 dosage forms.

In another embodiment, the present disclosure provides a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer) that when administered to a mammal, such as a human, provides for a plasma concentration of Compound A in the plasma of a mammal, such as a human, above a minimum therapeutic level for at least 8 hours following administration of a single oral dose of the composition.

Further, the plasma concentration of Compound A in the plasma of the mammal may be maintained above a minimum therapeutic level for at least 10 hours, for at least 12 hours, for at least 16 hours or for at least 24 hours or greater following administration.

In another embodiment, the present disclosure provides a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer) that when administered to a mammal, such as a human, provides a T_max for Compound A after administration of a single oral dose of the composition that is delayed as compared to a control composition, while still maintaining an exposure of Compound A equal to a greater than the control composition. For example, the Tm_ax may be observed at greater than 0.5 hours, greater than 1 hour, greater than 2 hours or greater than 3 hours after the Tmax for the control composition.

In another embodiment, the present disclosure provides a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer) that provides for a higher concentration of Compound A in each dosage form as compared to a control composition. For example, the concentration of Compound A in each dosage form may be greater than 100 mg, such as greater than 150 mg, greater than 200 mg, greater than 300 mg, greater than 400 mg or greater than 500 mg, but less than 1000 mg.

In another embodiment, the present disclosure provides a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer) that when administered to a mammal, such as a human, provides for a sustained average plasma concentration of Compound A in the plasma of a mammal, such as a human, following administration of a single oral dose of the composition above a minimum therapeutic level for all or substantially all of a dosing interval. In one embodiment, the dosing interval is 12 hours or greater. In one embodiment, the dosing interval is greater than 12 hours but less than or equal to 24 hours.

In another embodiment, the present disclosure provides a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer) that when administered at selected dosing intervals to a mammal, such as a human, provides for a sustained average plasma concentration of Compound A in the plasma of a mammal, such as a human, above a minimum therapeutic level for all or substantially all of a treatment period or dosing interval.

Methods o f Use

Certain solid dispersions or combinations and compositions comprising the solid dispersions or combinations have shown enhanced concentrations of Compound A as compared to crystalline forms of Compound A (administered with no added excipients or other agents) in a use environment in vitro/vivo tests (see Examples 2, 4 and 11-17 herein). Such tests have been shown to be good indicators of in vivo performance and bioavailability. Therefore, the present disclosure provides solid dispersions or combinations and compositions comprising the solid dispersions or combinations that when dosed orally to a mammal, such as a human, provide superior pharmacokinetic properties and other advantages. As a result, the foregoing may be used in various methods to increase the concentration and/or exposure of Compound A in a mammal as well as in various methods of treatment and/or prevention.

In one embodiment, the present disclosure provides a method of achieving a concentration of Compound A, or a pharmaceutically acceptable salt thereof, in the plasma versus time area under the curve for a 12 hour period of time following administration of a single oral dose of composition comprising Compound A that is greater than 1.5-fold that of a control composition, the method comprising orally administering to the mammal a single dose of a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer).

Further, the concentration of Compound A in the plasma versus time area under the curve for a 12 hour period of time following a single oral administration of the dose is greater than 2-fold that of the control composition. Still further, the concentration of Compound A in the plasma versus time area under the curve for a 12 hour period of time following a single oral administration of the composition is greater than 2.5 -fold that of the control composition.

In another embodiment, the present disclosure provides a method of achieving a dose normalized exposure of Compound A in the plasma of the mammal above 2.0 ng-hr/ml-mg over a 24 hour period following administration of a single oral dose of composition comprising Compound A, the method comprising orally administering to the mammal a single dose of a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer).

Further, the dose,normalized exposure of Compound A in the plasma of a mammal is above 2.2 ng-hr/ml-mg. Still further, the dose normalized exposure of Compound A in the plasma of a mammal is above 2.5 ng-hr/ml-mg.

In a further embodiment, the present disclosure provides a method of achieving a plasma concentration of Compound A in the plasma of a mammal, such as a human, above a minimum therapeutic level for at least 8 hours following administration of a single oral dose of composition comprising Compound A, the method comprising orally administering to the mammal a single dose of a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer).

Further the plasma concentration of Compound A in the plasma of a mammal may be maintained above a minimum therapeutic level for at least 10 hours, for at least 12 hours, for at least 16 hours or for at least 24 hours or greater following administration.

In another embodiment, the present disclosure provides a method for achieving a T_max for Compound A that is delayed as compared to a control composition while still maintaining an exposure of Compound A equal to a greater than the control composition over all or substantially all of a dosing interval, the method comprising orally administering to the mammal a single dose of a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer). For example, the 1 max may be observed at greater than 0.5 hours, greater than 1 hour, greater than 2 hours or greater than 3 hours after the Tmax for the control composition.

In still a further embodiment, the present disclosure provides a method of achieving a sustained average plasma concentration of Compound A in the plasma of a mammal, such as a human, above a minimum therapeutic level for all or substantially all of a treatment period, the method comprising orally administering to the mammal at selected dosing intervals a single dose of composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer). In one embodiment, the selected dosing interval is 12 hours or greater (for example BID).

In yet a further embodiment, the present disclosure provides a method of achieving a sustained average plasma concentration of Compound A in the plasma of a mammal, such as a human, above a minimum therapeutic level for substantially all of dosing interval, the method comprising orally administering to the mammal a single dose of a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer). In one embodiment, the dosing interval is 12 hours or greater. In one embodiment, the dosing interval is greater than 12 hours but less than or equal to 24 hours.

The improved pharmacokinetic properties of the solid dispersions or combinations comprising Compound A, or a pharmaceutically acceptable salt thereof, and a matrix (including a matrix comprising a concentration enhancing polymer) and compositions comprising such solid dispersions or combinations, allow the foregoing to be provided at dosing intervals greater than 8 hours, for example dosing intervals of 12 hours or greater, while still maintaining plasma concentrations of Compound A in a site of use that are above a minimum therapeutic level for substantially all of the dosing interval. As discussed in Example 11, certain tablet formulations comprising solid amorphous of Compound A and a concentration enhancing polymer provided increased exposure as determined by an increased AUC_0-24 and increased drug concentrations at multiple time points 12 hours or more after administration. Significantly, such formulations provided a longer duration of exposure above 60 ng/ml concentrations in the blood.

Fuithermore, improved pharmacokinetic properties of the solid dispersions or combinations comprising Compound A, or a pharmaceutically acceptable salt thereof, and a matrix (including a matrix comprising a concentration enhancing polymer) and compositions comprising such solid dispersions or combinations, allow such solid dispersions or combinations and compositions comprising the solid dispersions or combinations to be provided at dosing intervals of 8 hours (tid) while providing for significantly increased plasma concentrations of Compound A in the blood that are above a minimum therapeutic level. As discussed in Example 11, certain tablet formulations comprising solid dispersions of Compound A and a concentration enhancing polymer and suspension formulations of Compound A and a concentration enhancing polymer provided significantly increased drug concentrations at 8 hours after administration as compared to the control composition. While in certain embodiments, a dosing interval over 8 hours is preferred, in some embodiments providing a dosing interval of 8 hours while providing significantly increased blood concentrations of Compound A is also preferred.

The compositions of the present disclosure overcome the disadvantages associated with the previously used formulations for orally administering Compound A and therefore provides for improved methods of treatment and/or prevention that are not only more efficacious but also more convenient to the patient.

In one embodiment, the present disclosure provides a method of treating or preventing hereditaiy angioedema in a subject, the method comprising orally administering to the subject a dose of a composition comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer).

In another embodiment, the present disclosure provides a method of treating or preventing hereditary angioedema in a subject, the method comprising orally administering to the subject a dose of a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer).

In another embodiment, the present disclosure provides a method of treating or preventing hereditary angioedema in a subject, the method comprising orally administering to the subject a dose of a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising PVPVA, PVPVA64, HPMC, HPMC-E3, HPMC-AS, HPMC-AS-L or HPMC-AS-M.

The composition may be administered at selected dosing intervals and/or for a treatment period. In the above methods of treatment or prevention, the subject may be determined to be in need of such treatment or prevention by a healthcare professional. In the above methods of treatment or prevention, the dose of the composition may contain a therapeutically effective amount of Compound A.

The methods of the present disclosure include methods for the treatment of acute HAE attacks and methods of prophylactic therapy to prevent and/or reduce the frequency of HAE attacks.

The present disclosure also provides for methods of inhibiting plasma kallikrein activity in vivo. In one embodiment, the present disclosure provides methods of inhibiting plasma kallikrein activity in a subject, the method comprising orally administering to the subject a dose of a composition comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer).

In another embodiment, the present disclosure provides methods of inhibiting plasma kallikrein activity in a subject, the method comprising orally administering to the subject a dose of a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer).

In yet another embodiment, the present disclosure provides methods of inhibiting plasma kallikrein activity in a subject, the method comprising orally administering to the subject a dose of a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising P VP VA, PVPVA64, HPMC, HPMC-E3, HPMC-AS, HPMC-AS-L or HPMC-AS-M.

The composition may be administered at selected dosing intervals and/or for a treatment period. In the above methods of inhibition, the subject may be determined to be in need of such inhibition by a healthcare professional. In the above methods of inhibition, the dose of the composition may contain a therapeutically effective amount of Compound A.

In certain embodiments of the above characterizations of the solid dispersions, combinations and methods, the administration results in a plasma concentration of Compound A in the blood of the subject that is above a minimum therapeutic level for all or substantially all of the period of time in which the subject is undergoing treatment (for example a treatment period). In certain embodiments of the above methods, the administration results in a plasma concentration of Compound A in the blood of the subject that is above 50 ng/ml for all or substantially all of the period of time in which the subject is undergoing treatment. In certain embodiments of the above methods, the administration results in a plasma concentration of Compound A in the blood of the subject that is above 30 ng/ml for all or substantially all of the period of time in which the subject is undergoing treatment. In certain embodiments, the administration results in a plasma concentration of Compound A in the blood of the subject that is above 60 ng/ml for all or substantially all of the period of time in which the subject is undergoing treatment. In certain embodiments, the administration results in a plasma concentration of Compound A in the blood of the subject that is above 40 ng/ml for all or substantially all of the period of time in which the subject is undergoing treatment. In certain embodiments of the above characterizations of the solid dispersions, combinations and methods, the administration results in a plasma concentration of Compound A in the blood of the subject that is above a minimum therapeutic level for all or substantially all of a dosing interval (for example if the dosing interval is every 12 hours, the plasma concentration of Compound A is above a minimum therapeutic level for all or substantially all of the 12 hour period between doses). In certain embodiments, the administration results in a plasma concentration of Compound A in the blood of the subject that is above 30 ng/ml for all or substantially all of a dosing interval. In certain embodiments, the administration results in a plasma concentration of Compound A in the blood of the subject that is above 50 ng/ml for all or substantially all of a dosing interval. In certain embodiments, the administration results in a plasma concentration of Compound A in the blood of the subject that is above 60 ng/ml for all or substantially all of a dosing interval. In certain embodiments, the administration results in a plasma concentration of Compound A in the blood of the subject that is above 40 ng/ml for all or substantially all of a dosing interval.

The compositions used in the above characterizations of the solid dispersions, combinations and methods may be provided in a dosage form. In certain embodiments, the subject is administered 4 or fewer dosage forms, 3 or fewer, 2 or fewer dosage forms per dosing interval or a single dosage form per administration. Such decreased amounts of dosage forms are possible due to the provision of compositions that contain higher amounts of Compound A and/or due to the need to provide decreased amounts of Compound A for effective treatment due to the improved pharmacokinetic properties provided by the compositions of the present disclosure.

In certain embodiments of the methods of treatment and prevention, the HAE is Type I. In certain embodiments of the methods of treatment, the HAE is Type II. In certain embodiments of the methods of treatment, the HAE is Type III.

In certain embodiments of the methods of inhibition, the subject is suffering from HAE. The HAE may be Type I, Type II or Type III.

Certain of the embodiments of the above characterizations of the solid dispersions, combinations and methods refer to a control composition. The term "control composition" means a composition consisting essentially of an equivalent quantity of Compound A in an excipient mixture of 72.1% polyethylene glycol 600, 27.2% D-a-tocopherol polyethylene glycol 1000 succinate and 0.7% D-a-tocopherol (the excipient percentages referring to the total weight of the excipient mixture of the control composition, excluding the active ingredient). Certain embodiments of the above characterizations of the solid dispersions, combinations and methods refer to the term substantially all in relation to a time period, such as a dosing interval or treatment period. The term "substantially all" means at least 80% or more, such as 80%, 85%, 90% or 95% or more of the recited time period.

Certain of the embodiments of the above characterizations of the solid dispersions, combinations and methods refer to a minimum therapeutic level. The term "minimum therapeutic level" means the concentration of Compound A, or a pharmaceutically acceptable form thereof, required to be present in a use environment (for example, the gastrointestinal tract or in the blood) to provide effective treatment of a disease. With regard to treatment of HAE, the term "minimum therapeutic level" means the concentration of Compound A required to be present in a use environment, (for example, the gastrointestinal tract or in the blood) to provide effective inhibition of plasma kallikrein activity, reduction of HAE attack frequency, alleviation of HAE symptoms (as may be measured by a healthcare provide or subjective questionnaires, such as but not limited to the Angioedema Quality of Life, AEQoL, Index total score), reduction in HAE attack severity (as may be measured by a healthcare provide or subjective questionnaires, such as but not limited to the AEQoL Index total score), and/or reduction in HAE attack duration (as may be measured by a healthcare provide or subjective questionnaires, such as but not limited to the AEQoL Index total score). Such "minimum therapeutic level" may vary depending on conditions intrinsic to the subject, such as, but not limited to, the presence of another disease or condition, the concurrent use of other medications, steroid hormone levels, the frequency of HAE attacks experienced by a subject, environmental stimuli to which the subject is exposed and/or the lifestyle of the subject. Therefore, the minimum therapeutic level may vary between subjects and/or for a given subject over time. However, in general for an HAE subject, the minimum therapeutic level of Compound A as determined by the blood or plasma concentration is generally in the range of between 25 ng/ml and 50 ng/ml. In one embodiment, the minimum therapeutic level is greater than or equal to about 50 ng/ml. However, the minimum therapeutic level may be as low as about 25 to 30 ng/ml or may be as high about 60 ng/ml or about 70 ng/ml. When no other value is specified, the "minimum therapeutic level" for treatment of HAE is defined to be greater than or equal to 30 ng/ml.

Certain of the embodiments of the above characterizations of the solid dispersions, combinations and methods refer to a treatment period. The term "treatment period" means the duration of a prescribed course of treatment for a particular disease or condition, for example HAE, as determined by a healthcare professional. The duration of the course of treatment may vary. For example, the treatment period can be for a single day, multiple days or weeks. Further, the treatment period may be months. Still further, the treatment period may be continuous (the subject is administered the pharmaceutical composition for the remainder of life). In one embodiment, the treatment period is continuous. In another embodiment, the treatment period is for a period of months.

Certain of the embodiments of the above characterizations of the solid dispersions, combinations and methods refer to a dosing interval. The term "dosing interval" means the period of time in between administered doses. In certain embodiments, the dosing interval is every 8 hours or 8 hours (tid). In certain embodiments, the dosing interval is every 12 hours or 12 hours (bid). In certain embodiments, the dosing interval is every 24 hours or 24 hours (qd). In a preferred embodiment, the dosing interval is equal to or greater than every 12 hours or 12 hours. When a concentration or other characteristic is discussed in relation to a dosing interval, the concentration/characteristic is determined with respect to the period of time between administered doses.

Certain of the embodiments of the above characterizations of the solid dispersions, combinations and methods refer to a single administration or administration of a single oral dose. The terms "single" administration or "administration of a single oral dose," mean an administration of a dose of a composition of the present disclosure that occurs at one time point; one or more than 1 dosage form of the composition may be administered in a dose.

In certain embodiments, the recited effects in the above characterizations of the solid dispersions, combinations and methods are achieved by administering to the mammal a dose of a composition comprising a solid dispersion or combination of Compound A, or a pharmaceutically acceptable form thereof. The term "dose" means the total amount of composition administered to the mammal at a single time (for example, at each administration or the beginning of a dosing interval). In certain embodiments, the dose contains an amount of Compound A, or a pharmaceutically acceptable form thereof, in the range of from about 20 mg to about 1000 mg of Compound A, specifically including 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg. In certain embodiments, the dose contains an amount of Compound A, or a pharmaceutically acceptable form thereof, of at least 20 mg, at least 40 mg, at least 50 mg, at least 100 mg, at least 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg or greater, 800 mg or greater, 1000 mg or greater, 1500 mg or greater, 2000 mg or greater 2500 mg or greater, 3000 mg or greater or 4000 mg or greater, but less than 5000 mg. In certain embodiments, the dose contains an amount of Compound A, or a pharmaceutically acceptable form thereof, that is less than 600 mg, less than 500 mg, less than 400 mg, less than 300 mg or less than 200 mg. Such dose may be provided in one or more than one dosage form (for example 1 tablet or more than 1 tablet).

In the foregoing characterizations of the solid dispersions, combinations and methods referring to a composition comprising a solid dispersion or combination, the solid dispersion or combination may be one described under the sub-heading "Specific Embodiments" above in either the broadest or narrowest aspects. In certain embodiments, the solid dispersion or combination may be as described in the first to fifth aspects, the twelfth to fourteen aspects or the sixth to eleventh aspects, including further descriptions of those aspects, in the Summary of the Invention. In the foregoing characterizations of the solid dispersions, combinations and methods referring to a composition comprising a solid dispersion or combination, the matrix may comprise PVPVA, PVPVA64, HPMC, HPMC-E3, HPMC-AS, HPMC-AS-L, HPMC- AS-M or combinations of the foregoing as the concentration enhancing polymer. In the foregoing characterizations of the solid dispersions, combinations and methods referring to a composition comprising a solid dispersion or combination, Compound A, or a pharmaceutically acceptable form thereof, may be present at 30 wt% to 80 wt% of the solid dispersion or combination, such as about 40 wt% or 60 wt% of the solid dispersion or combination.

In certain preferred embodiments, any of the foregoing compositions described in the characterization of the solid dispersions, combinations or methods are provided in a dosage form with customary excipients where the dosage form contains at least 7 wt% of Compound A (based on the total content of the dosage form, including excipients). In certain preferred embodiments, the dosing form is a tablet, including an immediate release tablet. Exemplary tablet formulations that are particularly preferred are provided herein and in the Examples and include tablet formulations identified as BTAB-1 to BTAB-4.

In certain preferred embodiments, any of the foregoing compositions described in the characterization of the solid dispersions, combinations or methods are provided in the form of a suspension as discussed herein.

Dosage Forms

The solid dispersions or combinations of the present disclosure may be used to formulate any conventional known dosage form. In certain embodiments, the solid dispersion or combination may be one described under the sub-heading "Specific Embodiments" above in either the broadest or narrowest aspects. In certain embodiments, the solid dispersion or combination may be as described in the first to fifth aspects, the twelfth to fourteen aspects or the sixth to eleventh aspects, including further descriptions of those aspects, in the Summary of the Invention. Any of the solid dispersions or combinations described herein may be present in a dosage form. In general, many conventional materials and procedures for formulation and preparation of oral dosage forms of drugs may be used by simply substituting the solid dispersions or combinations of the present disclosure for the drug or active agent that is to be dispensed from the known dosage form. Exemplary dosage forms are powders or granules that may be taken orally, tablets, capsules, multiparticulates, and pills. Various additives may be mixed, ground, or granulated with the compositions of this invention to form a material suitable for the above dosage forms.

In one embodiment, the solid dispersions or combinations of the present disclosure are formulated into immediate release dosage forms. Such dosage forms are formed with no components or structures specifically incoiporated or designed for delayed release. In one embodiment, the solid dispersions or combinations of the present disclosure are formulated into immediate release tablets. In one embodiment, the solid dispersions or combinations of the present disclosure are formulated into immediate release capsule. In some cases, a combination of such dosage forms may be used. For example, one or more types of multiparticulates or a suspension may be formed and then incorporated into a capsule or simply be packaged as an OPC or a sachet.

Tablets are generally formed by blending the solid dispersions or combinations with appropriate excipients and then compressing the powder to form tablets using any of a wide variety of presses used in the fabrication of pharmaceutical dosage forms. Often it is desirable to granulate the solid dispersions or combinations themselves, with or without the addition of excipients prior to compression. For example, the solid dispersions or mixtures may be granulated by mechanical means by, for example, roller compaction or "slugging," followed by milling to form granules. The granules typically have improved flow, handling, blending and compression properties relative to the ungranulated materials. In addition, improved wetting, disintegrating, dispersing and dissolution properties may be obtained by the inclusion of excipients in addition to the solid dispersion or combination alone.

Excipients that may be included in the immediate-release dosage forms include any of those known in the pharmaceutical arts and include, but are not limited to, wetting agents surfactants, pH modifiers, matrix materials, fillers, diluents, complexing agents, solubilizers, disintegrating aids, disintegrating agents (disintegrants), glidants, binders, stabilizing agents and lubricants. Other conventional formulation excipients may be employed, including those excipients well-known in the art (e.g., as described in Remington's Pharmaceutical Sciences (16^th ed. 1980). Generally, the excipients may be used for customary purposes and in typical amounts without adversely affecting the properties of the solid dispersions or combinations described herein.

The addition of conventional excipients may be added as part of the solid dispersion or combination itself, added by granulation or added by other means. When such excipients are included as part of the solid dispersion itself, they may be mixed with drug and concentration enhancing polymer(s) in the solvent, and may or may not dissolve along with the drug and concentration enhancing polymer(s) prior to forming the dispersion, such as by spray-drying. When such excipients are included as part of the combination itself, they may be mixed with drug and concentration enhancing polymer(s) in a dry state (without the addition of a solvent).

The excipients may comprise an intragranular excipient mixture, an extragranular excipient mixture or a combination of both.

One useful class of excipients is surfactants. Suitable surfactants include fatty acids and alkyl sulfonates (including but not limited to sodium dodecyl sulfate), commercial surfactants such as benzalkonium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid esters and natural surfactants such as sodium taurocholic acid, l-palmitoyl-2-oleoyl-sn- glycero-3-phosphocholine, lecithin, and other phospholipids and mono- and diglycerides. Such materials can advantageously be employed to increase the rate of dissolution by, for example, facilitating wetting. As such in certain embodiments, surfactants may act as wetting agents.

Addition of pH modifiers such as acids, bases, or buffers may also be beneficial. Such pH modifiers may retard the dissolution of the dosage form (e.g., acids such as citric acid or succinic acid when the concentration enhancing polymer is anionic) or, alternatively, enhance the rate of dissolution of the dosage form (e.g., bases such as sodium acetate or amines). In certain embodiments, the pH modifier may also act as a stabilizing agent.

Examples of matrix materials, fillers, or diluents include, but are not limited to, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar, microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers such as polyethylene oxide, and hydroxypropyl methyl cellulose.

Examples of wetting agents include, but are not limited to, sodium lauryl sulfate and polysorbate 80.

Examples of drug complexing agents or solubilizers include, but are not limited to, the polyethylene glycols, caffeine, xanthene, gentisic acid and cylodextrins. Examples of disintegrants include, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone (polyvinylpolypyrrolidone), methyl cellulose, microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, and sodium alginate.

Examples of tablet binders include, but are not limited to, acacia, alginic acid, carbomer, carboxymethyl cellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, hydrogenatetd vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, liquid glucose, maltodextrin, polymethacrylates, povidone, pregelatinized starch, sodium alginate, starch, sucrose, tragacanth, and zein.

Examples of lubricants include, but are not limited to, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, magnesium stearate and zinc stearate.

Examples of glidants include, but are not limited to, silicon dioxide, colloidal silicon dioxide, talc and cornstarch.

A variety of methods may be used for forming the dosage forms of the present disclosure.

The following are exemplary methods for forming suspensions of the present disclosure comprising a solid dispersion or combination of Compound A and a concentration enhancing polymer. In one embodiment, the solid dispersion or combination may be used to form a suspension, comprising the solid dispersion or combination and a liquid vehicle. The solid dispersion or combination may be used to form a suspension, consisting of or consisting essentially of the solid dispersion or combination and a liquid vehicle. Suitable liquid vehicles include, but are not limited to liquids with a pH range of from about 4 to about 8, from about 6 to about 7, from about 2 to about 4 or from about 6 to about 10. In one embodiment, the liquid vehicle is water or a liquid with a pH range of about 6 to about 7. Preferred solid dispersions and combinations are those listed under the "Specific Embodiments" subheading above in either their broadest or narrowest forms and as described in the first to fifth aspects, the twelfth to fourteen aspects or the sixth to eleventh aspects, including further descriptions of those aspects, in the Summary of the Invention. In certain embodiments, the volume of the liquid present is from about 100 mis to about 2500 mis, such as for example, from about 200 mis to about 400 mis, from about 400 mis to about 600 mis, from about 600 mis to about 900 mis, from about 900 mis to about 1200 mis or from about 1200 mis to about 1500 mis. The following are exemplary methods for forming immediate release tablets of the present disclosure comprising a solid dispersion of compound A and a concentration enhancing polymer formed by a spray-drying process or a combination of Compound A and a concentration enhancing polymer.

In one method, the solid dispersion or combination alone is first granulated such as by roller compacting and the resulting ribbon is milled (such as in a Comill mill) to produce a desired mean particle size. The resulting material is then blended with the desired intragranular excipients (for example, ductile filler, wetting agent, disintegration aid, disintegrant, glidant and lubricant). The blends are then compressed into tablets weighing from about 200 to 800 mg on a tablet press such as a Kilian T-l 00. Compression force is generally adjusted to achieve a tablet hardness of about 5 to 20 kP. Alternatively, certain excipients and the dispersion may first be blended in, for example, a V-blender followed by the formation of granules by roller compaction of the blend followed by milling as described above to form an intragranular mixture. Additional excipients (for example, additional disintegrant, glidant and/or lubricant) may then be added and blended with the granulated material prior to tableting as described above.

The amounts of each ingredient may vary depending on the amount of Compound A desired in the final dosage form. However, generally the following ranges apply. The solid dispersion or combination may be present from about 5 to about 80 wt% of the dosage form, such as from about 10 to about 70 wt%, from about 10 to about 40 wt%, from about 10 to about 30 wt%, from about 20 to about 35 wt%, from about 15 to about 60 wt% or from about 20 to about 55 wt%. The wetting agent may be present at from about 0 to about 20 wt% of the dosage form, such as from about 1 to about 15 wt%, from about 2 to about 10 wt% or from about 3 to about 6 wt%. The disintegration aid may be present from about 0 to about 30 wt% of the dosage form, such as from about 1 to about 25 wt%, from about 10 to about 25 wt% or from about 7 to about 17 wt%. The disintegrant may be present at from about 1 to about 25 wt% of the dosage form, such as from about 3 to about 20 wt%, from about 5 to about 10 wt% or from about 10 to about 15 wt%. The glidant may be present from about 0 to about 5% of the dosage form, such as from about 0.1 to about 4 wt%, from about 0.5 to about 3 wt% or from about 1 to about 2 wt%. The lubricant may be present from about 0 to about 5 wt% of the dosage form, such as from about 0.1 to about 4 wt%, from about 0.25 to about 3 wt% or from about 0.25 to about 1 wt%. A stabilizing agent may be present from about 0 to about 5 wt% of the dosage form, such as from about 0.1 to about 4 wt%, from about 0.25 to about 3 wt% or from about 0.25 to about 2 wt%. The filler making up the balance of the blend. In certain embodiments the filler may comprise from about 15 to about 70 wt% of the dosage form. The foregoing wt% are determined with respect to the total weight of the dosage form.

The total weight of Compound A in the dosage form may be from 5 to 60 wt% (based on the total weight of the dosage form), such as about 5 to about 25 wt%, about 15 to about 35 wt% or about 20 to about 40 wt%. In certain embodiments, the dosage form is prepared using an solid dispersion or combination of 60 wt% Compound A and 40 wt% of a concentration enhancing polymer (wt% in respect to the total weight of the solid dispersion or combination) such as, but not limited to, PVPVA, PVPVA64, HPMC, HPMC-E3, HPMC-AS, HPMC-AS- L or HPMC-AS-M, plus added excipients and Compound A is present at 5 wt% to 25 wt% of the total weight of the dosage form. In certain embodiments, the dosage form is prepared using an solid amorphous dispersion of 60 wt% Compound A and 40 wt% of a concentration enhancing polymer (wt% in respect to the total weight of the solid dispersion or combination) such as, but not limited to, PVPVA, PVPVA64, HPMC, HPMC-E3, HPMC-AS, HPMC-AS- L or HPMC-AS-M, plus added excipients and Compound A is present at 20 wt% to 40 wt% of the total weight of the dosage form. In certain embodiments, the dosage form is prepared using an solid amorphous dispersion or combination of 40 wt% Compound A and 60 wt% of a concentration enhancing polymer (wt% in respect to the total weight of the solid dispersion or combination) such as, but not limited to, PVPVA, PVPVA64, HPMC, HPMC-E3, HPMC-AS, HPMC-AS-L or HPMC-AS-M, plus added excipients and Compound A is present at 5 wt% to 25 wt% of the total weight of the dosage form.

Of course, other choices of excipients and processes as are known in the pharmaceutical arts and are described briefly above may be substituted for the exemplary tablets and process described above.

In one embodiment, the dosage forms of the present disclosure are enteric coated. An enteric coating is a barrier applied to an oral medication that controls the location in the digestive system where it is absorbed. Most enteric coatings work by presenting a surface that is stable at the highly acidic pH found in the stomach, but breaks down rapidly at a less acidic (relatively more basic) pH. For example, enteric coatings will not dissolve in the acidic juices of the stomach, but will in the alkaline environment present in the small intestine. Materials used for enteric coatings include fatty acids, waxes, shellac, plastics, and plant fibres. Particular examples of materials used to form enteric coatings include methyl acrylate- methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, and sodium alginate and stearic acid.

Exemplary tablet formulations 1 to 4 incorporating certain solid dispersions of the present disclosure are provided below. The following are exemplary in nature only and are not meant to limit the scope of the composition of the dosage forms.

Table 1

Tablet Formulation 1 (tablet weight 400 mg)

] J gredient ¹ ½ of Blend

Intragranular

Solid Dispersion 50% Compound A:40% PVPVA 16.67

Ductile filler Viicrocrystalline cellulose 51.33

Disintegration aid Sodium chloride, Powder 20

Disintegrant Crospovidone 6

Glidant Colloidal silicon dioxide 1

Lubricant Mag stearate, veg source 0.25

Extragranular

Disintegrant Crospovidone 4

Glidant Colloidal silicon-di-oxide 0.5

Lubricant Mag stearate, veg source 0.25

Total 100

Table 2

Tablet Formulation 2 (tablet weight 400 mg)

Ingredient % of Blend

Intragranular

Solid Dispersion 60% Compound A:40% PVPVA 16.67

Ductile filler Macrocrystalline cellulose 46.33

Wetting agent Sodium dodecyl sulfate 5

Disintegration aid Sodium chloride, Powder 20

Disintegrant Croscarmellose Sodium 6

Table 3

Tablet Formulation 3 (tablet weight 400 mg)

[ngredient % of Blend

Intragranular

Solid Dispersion 40% Compound A: 60% PVPVA 25.0

Ductile filler icrocrystalline cellulose 43.0

Disintegration aid Sodium chloride, Powder 20

Disintegrant Crospovidone 6

Glidant Colloidal silicon dioxide 1

Lubricant Mag stearate, veg source 0.25

Extragranular

Disintegrant Crospovidone 4

Glidant Colloidal silicon-di-oxide 0.5

Lubricant Mag stearate, veg source 0.25

Total 100

Table 4

Tablet Formulation 4 (tablet weight 133 mg)

Ingredient % of Blend

Intragranular

Solid Dispersion 60% Compound A:40% PVPVA 50.0

Ductile filler Microcrystalline cellulose 17 Wetting agent Sodium dodecyl sulfate 5

Disintegration aid Sodium chloride, Powder 16

Disintegrant Croscarmellose Sodium 6

Glidant Colloidal silicon dioxide 1

Lubricant Mag stearate, veg source 0.25

Extragranular

Disintegrant Croscarmellose Sodium 4

Glidant Colloidal silicon-di-oxide 0.5

Lubricant Mag stearate, veg source 0.25

Total 100

Methods of Making Solid Dispersions

The present disclosure provides a method for making a solid dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer). As discussed above, the foregoing solid dispersions may be used in compositions described herein. In one embodiment, the method comprises the steps of: (i) dissolving Compound A and the matrix component(s) in a spray solution comprising at least one solvent; and (ii) rapidly evaporating the at least one solvent from the spray solution to afford a solid dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer).

Methods of forming solid dispersions are provided herein. In one embodiment, a solid amorphous dispersion is produced.

In one embodiment, the solid dispersion further comprises a stabilizing agent to improve the chemical stability of Compound A. In one embodiment, the solid dispersion further comprises a solvent additive. In certain embodiments, the solvent additive may also be a stabilizing agent. In one embodiment, the solvent is methanol.

In one embodiment, the free base form of Compound A is used in the manufacture of the solid dispersion provided herein. In another embodiment, the free acid form of Compound A is used in the manufacture of the solid dispersion provided herein. In another embodiment, a salt form of Compound A is used in the manufacture of the solid provided herein. Salt forms of Compound A include, but are not limited to, acid addition salts of Compound and base addition salts of Compound A. Suitable pharmaceutically acceptable and/or manufacturing acceptable salt forms of Compound A, including acid addition and base addition salts, are provided herein.

In a particular embodiment, a salt form of Compound A, including an acid addition and a base addition salt, is used in the manufacture of the solid dispersion provided herein when the solubility of the free base form of Compound A in a desired solvent solution is less than desired. In another particular embodiment, a salt form of Compound A, including an acid addition and a base addition salt, is used in the manufacture of the solid dispersion provided herein when it is desired to increase the solubility of Compound A in a desired solvent solution.

In another embodiment, the free base form of Compound A is used in the manufacture of the solid dispersion provided herein in conjunction with a solvent additive. For example, the free base form of Compound A is used in conjunction with a solvent additive that adjusts the pH of the solvent solution to a range less than pH 5 (for example, a pH of 4, 3 2 or lower) or the free base form of Compound A is used in conjunction with a solvent additive that adjusts the pH of the solvent solution to a range greater than pH 7 (for example, a pH of 8, 9, 10 or higher). Suitable pharmaceutically acceptable and/or manufacturing acceptable solvent additives are provided herein. In one embodiment, the solvent additive is citric acid. In another embodiment, the solvent additive is HC1.

In a particular embodiment, a solvent additive is used in the manufacture of the solid dispersion provided herein when the solubility of the free base form of Compound A in a desired solvent solution is less than desired. In another particular embodiment, a solvent additive is used in the manufacture of the solid dispersion provided herein when it is desired to increase the solubility of the free base form of Compound A in a desired solvent solution. Solvent solutions in which a solvent additive may be useful when the free base form of Compound A is used include, but are not limited to, methanol, ethanol, n-propanol, iso- propanol, butanol, acetone, methyl ethyl ketone and methyl iso-butyl ketone.

In one embodiment, the solid dispersions contain at least about 15 wt% Compound A, or a pharmaceutically acceptable form thereof, such as at least about 20 wt%, such as at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, or at least about 95 wt% of Compound A, or a pharmaceutically acceptable form thereof. In one embodiment, the solid dispersions contain from about 15 wt% to about 90 wt%, from about 20 wt% to about 80 wt%, from about 30 wt% to about 70 wt%, from about 30 wt% to about 60 wt%, from about 40 wt% to about 60 wt%, from about 50 wt% to about 80 wt% or from about 60 wt% to about 90 wt% of Compound A, or a pharmaceutically acceptable form thereof. In one embodiment, the solid dispersions contain 40 wt% or 60 wt% of Compound A, or a pharmaceutically acceptable form thereof. The foregoing percentages are provided as wt% with respect to total content of the solid dispersion or combination.

In one embodiment, a solid amorphous dispersion of Compound A, or a pharmaceutically acceptable form thereof, is provided. In such embodiments, at least about 50 wt%, at least about 55 wt%, or at least about 60 wt%, or at least about 70 wt%, or at least about 80 wt%, or at least about 90 wt%, or at least about 95 wt% or at least about 99 wt% of the total amount of Compound A, or a pharmaceutically acceptable form thereof, present is in an amorphous form. The foregoing percentages are provided as wt% with respect to total amount of Compound A in the dispersion. In certain embodiments, a major portion of Compound A is in the amorphous form. In certain embodiments, Compound A is substantially amorphous. In certain embodiments, Compound A is almost completely amorphous. An amorphous form of Compound A can exist within the solid dispersion in relatively pure amorphous drug domains or regions, as a solid solution of drug homogeneously distributed throughout the matrix or any combination of these states or those states that lie intermediate between them.

In one embodiment, the amount of Compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion is at least 20 mg. In one embodiment, the amount of Compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion is at least 50 mg. In one embodiment, the amount of Compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion is between 20 to 1000 mg. In one embodiment, the amount of compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion is at least 20 mg, at least 40 mg, at least 50 mg, at least 100 mg, at least 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg or greater, but less than 1000 mg. In another embodiment, the amount of Compound A, or a pharmaceutically acceptable form thereof, in the solid dispersion is between about 20 mg to about 200 mg, between about 20 mg to about 100 mg, between about 50 mg to about 300 mg, between about 200 mg to about 400 mg, between about 300 mg to about 500 mg or between about 400 mg to 600 mg. As discussed herein, Compound A, or a pharmaceutically acceptable form thereof, may be present in an amorphous form as described above.

Suitable concentration enhancing polymers are described herein for inclusion in the matrix. In one embodiment, the concentration enhancing polymer is an ionizable cellulosic polymer, a non-ionizable cellulosic polymer or a noncellulosic polymer. In one embodiment, the concentration enhancing polymer is HPMC-AS, HPMC-AS-L or HPMC-AS-M. In one embodiment, the concentration enhancing polymer is PVPVA or PVPVA64. In one embodiment, the concentration enhancing polymer is HPMC or HPMC-E3.

In one embodiment, the matrix consists essentially of the concentration enhancing polymer. In one embodiment, the matrix consists solely of the concentration enhancing polymer. In one embodiment, a single concentration enhancing polymer is present in the matrix. In one embodiment, more than one concentration enhancing polymer is present in the matrix.

Suitable dosing forms for the solid dispersions are described herein.

Medicaments

The present disclosure provides a method of using a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer) and a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer) in the manufacture of a medicament for the treatment of hereditary angioedema in a subj ect. As discussed herein, such a medicament may be used for the treatment of acute attacks or for prophylactic therapy to prevent and/or reduce the frequency of HAE attacks.

The present disclosure provides a method of using a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer) and a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer) in the manufacture of a medicament for the inhibition of plasma kallikrein activity in a subject.

Any of the solid dispersions or combinations described herein may be used in the manufacture of the medicaments. In certain preferred embodiments, the medicament is a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a comprising a concentration enhancing polymer. In certain preferred embodiments, the medicament is a composition comprising a solid dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer. In certain preferred embodiments, the medicament is a composition comprising a solid amorphous dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer, wherein Compound A is present at 30 wt% to 80 wt% of the dispersion, such as about 40 wt% or 60 wt% of the dispersion. In certain preferred embodiments, the medicament is a composition comprising a solid amorphous dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer, wherein Compound A is present at 30 wt% to 80 wt% of the dispersion, such as about 40 wt% or 60 wt% of the dispersion and the matrix comprises only PVPVA, PVPVA64, HPMC, HPMC-AS, HPMC- AS-L or HPMC-AS-M as the concentration enhancing polymer. In certain preferred embodiments, the medicament is a composition comprising a solid amorphous dispersion or combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix (including a matrix comprising a concentration enhancing polymer) wherein the Compound A is substantially amorphous or almost completely amorphous, is present at 30 wt% to 80 wt% of the dispersion, such as about 40 wt% or 60 wt% of the dispersion and the matrix comprises only PVPVA, PVPVA64, HPMC, HPMC-AS, HPMC-AS-L or HPMC-AS-M as the concentration enhancing polymer.

In certain preferred embodiments, any of the foregoing medicaments are provided in a dosage form with customary excipients where the dosage form contains at least 7 wt% Compound A (based on the total content of the dosage form, including excipients). In certain preferred embodiments, the dosing form is a tablet, including an immediate release tablet. Exemplary tablet formulations that are particularly preferred are provided herein and in the Examples and include tablet formulations identified as BTAB-1 to BTAB-4. In certain preferred embodiments, the medicament is a suspension as described herein.

EXAMPLES

Example 1- Preparation of Solid Amorphous Dispersion (40% Compound A)

A solid amorphous dispersion of 40% Compound A in PVPVA64 was prepared as follows. First, a spray solution was formed containing 10.7 g Compound A (as an HCL salt), 14.3 g PVPVA64, and 287.5 g methanol. The solution was fed into a lab scale spray-drying apparatus via nitrogen head pressure. The drug/polymer solution was atomized through a Schlick pressure nozzle, Model No. 121. A heated nitrogen stream flowing at 450 g/min was used to evaporate the solvent. The heated gas entered the chamber at an inlet temperature of 132°C and exited at an outlet temperature of 52°C. The resulting solid amorphous dispersion was collected via a 2" cyclone, dried in a convection tray dryer with air at ambient pressure and 40°C for 15 hours, and stored in a refrigerator. The yield was about 84%. The finished solid amorphous dispersion was 40% compound A and 60% PVPVA64.

Example 2- In vitro Dissolution Test of the Solid Dispersion of Example 1

An in vitro dissolution test was performed using the product of Example 1 to determine whether the solid amorphous dispersion of Example 1 provides concentration enhancement relative to a crystalline form of Compound A (Form A). For this test, a sufficient amount of the solid dispersion of Example 1 and the crystalline form of Compound A was added to a microcentrifuge test tube so that the concentration of Compound A would have been 4000 μg/mL in the gastric media and 2000 μg/mL in the intestinal media, if all of the drug had dissolved. The test was run in duplicate. The tubes were placed in a 37°C temperature- controlled chamber, and 0.9 mL of 0.01N HC1 at pH = 2 was added. After 30 minutes an addition 0.9 mL 2X PBS at pH 6.55 was added to each respective tube. At each time point, the samples were quickly mixed using a vortex mixer for about 60 seconds. The samples were centrifuged at 13,000 G at 37°C for 1 minute. The resulting supernatant solution was then sampled and diluted 1 :6 (by volume) with methanol and then analyzed by high-performance liquid chromatography (HPLC). HPLC analysis was performed using an Eclipse Plus CI 8, 50 x 4.6 mm, 3.5 μιη particle size column. The mobile phase consisted of 55% Methanol and 45% water. UV absorbance was measured at 300 nm. The contents of each tube were mixed on the vortex mixer and allowed to stand undisturbed at 37°C until the next sample was taken. Samples were collected at the indicated times in minutes. The results are shown in Table 5. As can be seen, the solid amorphous dispersion of Example 1 provided concentration enhancement.

-30 0 0

-25 479 1197

-15 538 6282

-5 580 11875

Control 1

4 248 15603

(crystalline

10 494 17830

Compound A)

20 533 22968

40 564 33941

90 250 54281

1200 45 217665

Example 3- Preparation of Solid Amorphous Dispersion (60% Compound A)

A solid amorphous dispersion of 60% Compound A in PVPVA64 was prepared as follows. First, a spray solution was formed containing 38.6g Compound A (as an HCL salt), 21.4 g PVPVA64, and 690.0 g methanol. The solution was fed into a lab scale spray-drying apparatus via nitrogen head pressure. The drug/polymer solution was atomized through a Schlick pressure nozzle, Model No. 121. A heated nitrogen stream flowing at 450 g/min was used to evaporate the solvent. The heated gas entered the chamber at an inlet temperature of 145°C and exited at an outlet temperature of 53°C. The resulting solid amorphous dispersion was collected via a 2" cyclone, dried in a convection tray dryer with air at ambient pressure and 40°C for 15 hours, and stored in a refrigerator. The yield was about 98%. The finished solid amorphous dispersion was 60% compound A and 40% PVPVA64.

Example 4- In vitro Dissolution Test of the Solid Dispersion of Example 3

An in vitro dissolution test was performed using the product of Example 3 to determine whether the solid amorphous dispersion of Example 3 provides concentration enhancement relative to a crystalline form of Compound A (Form A). For this test, a sufficient amount of the solid dispersion of Example 1 and the crystalline form of Compound A was added to a microcentrifuge test tube so that the concentration of Compound A would have been 4000 μg/mL in the gastric media and 2000 μg/mL in the intestinal media, if all of the drug had dissolved. The test was run in duplicate. The analysis was carried out as described in Example 2. The results are shown in Table 6. As can be seen, the solid amorphous dispersion of Example 3 provided concentration enhancement.

-30 0 0

-25 1267 3168

-15 1299 15999

-5 1300 28992

Example 2

4 534 37241

(amorphous

10 540 40462

BCX4161)

20 526 45791

40 525 56294

90 518 82361

1200 466 628455

-30 0 0

-25 575 1437

-15 590 7264

-5 275 11592

Control 2

4 154 13524

(crystalline

10 191 14559

Compound A)

20 219 16606

40 211 20904

90 189 30908

1200 87 183887

Example 5- Preparation of Tablet Formulation 1 (BTAB 1)

A tablet dosage form was prepared using the solid amorphous dispersion of Example

3. The content of the tablet is shown in Table 7. The tablet contained 40 mg of Compound A.

The tablets were prepared as follows. The solid amorphous dispersion of Example 3 and colloidal silicon dioxide were co-screened through a #25 mesh screen. The screen was rinsed with remaining intragranular excipients except magnesium stearate. The intragranular ingredients (except magnesium stearate) were blended in a glass bottle in Turbula mixer for 15 minutes at 32 rpm. The magnesium stearate was screened through a #25 mesh screen, added to the mixture above and blended in Turbula mixer for 4 min at 32 rpm. The mixture was compressed into slugs using ½" flat faced tooling to a tensile strength of approximately 0.5 to 0.7 MPa. The slug was milled using mortar and pestle and passed through a #20 mesh screen. The extragranular components were screened and added as above and the mixture blended in a Turbula for 10 minutes at 32 rpm to yield the final blend. The final blend was compressed into tablets using 0.3000" x 6000" Caplet tooling to approximately 2.0 MPa tensile strength. Example 6- In vitro Dissolution Test of Tablet Formulation 1

An in vitro dissolution test was performed to determine whether the tablet formulation of Example 5 provided rapid disintegration and dissolution. For this test, tablets were tested in 50 mM phosphate buffer pH = 6.5 with 0.5 wt% simulated intestinal fluid at a temperature of 37°C. The test was performed in duplicate using a USP type II apparatus with paddle speed of 75 RPM and 400 mL of media in 500 mL vessels. Samples were taken by auto sampler, using a 10 μπι full flow filter. The resulting samples were directly transferred into HPLC vials and analyzed by high-performance liquid chromatography (HPLC). HPLC analysis was performed using an Eclipse Plus CI 8, 50 x 4.6 mm, 3.5 μπι particle size column. The mobile phase consisted of 55% Methanol and 45% water. UV absorbance was measured at 300 nm. The contents of each tube were mixed on the vortex mixer and allowed to stand undisturbed at 37°C until the next sample was taken. Samples were collected at the indicated time in minutes. A control sample consisted of the solid dispersion that was included in tablets alone and an amount of this material was added to match the amount included in the tablets. The results are shown in Table 8. As can be seen, the tablets provided good disintegration and dissolution.

90 94

0 0

10 54

20 76

3

40 90

60 94

90 96

0 0

10 99

20 99

Control 1

40 100

60 100

90 100

Example 7- Preparation of Tablet Formulation 4 (BTAB-4

3. The content of the tablet is shown in Table 9. The tablet contained 40 mg of Compound A.

The tablets were prepared as described in Example 5 with the exception that the final blend was compressed into tablets using 0.250" Caplet tooling to approximately 2.0 MPa tensile strength.

Example 8- In vitro Dissolution Test of Tablet Formulation 4

An in vitro dissolution test was performed to determine whether the tablet formulation of Example 7 provided rapid disintegration and dissolution. The analysis was performed as in Example 6. A control sample consisted of the solid dispersion that was included in tablets alone and an amount of this material was added to match the amount included in the tablets. The results are shown in Table 10. As can be seen, the tablets provided good disintegration and dissolution.

Example 9- Preparation of Tablet Formulation 2 (BTAB-2)

The tablets were prepared generally as described in Example 5. The tablets showed disintegration and dissolution characteristics similar to those shown in Examples 6 and 8. Example 10- Preparation of Tablet Formulation 3 (BTAB-3 A tablet dosage form was prepared using the solid amorphous dispersion of Example 1. The content of the tablet is shown in Table 10. The tablet contained 40 mg of Compound A.

The tablets were prepared generally as described in Example 5. The tablets showed disintegration and dissolution characteristics similar to those shown in Examples 6 and 8. Example 11- Primate Studies

The dosage forms of Example 5 (BTAB-1), Example 7 (BTAB-4), Example 9 (BTAB- 2 and Example 10 (BTAB-3) were used in oral pharmacokinetic studies with cynomolgus monkeys (Macaca fascicularis). Cynomolgus monkeys have been shown to be a suitable test system for pharmacokinetic studies of Compound A. It was determined that the exposure at 500 mg doses of Compound A was approximately 1.5-fold that observed in humans at a corresponding dose. As discussed above, each tablet contained 40 mg Compound A in a solid dispersion. A control composition containing 40 mg crystalline Compound A as the HCL salt (Form A) in a soft gelatin capsule containing a liquid excipient mixture of 72.1 % polyethylene glycol 600, 27.2% D-a-tocopherol polyethylene glycol 1000 succinate and 0.7% D-a- tocopherol (the excipient percentages referring to the total weight of the excipient mixture of the control composition, excluding the active ingredient) was used as a comparator.

Monkeys were dosed orally at 10 mg/kg Compound A using BTAB-1 to BTAB-4 and the control composition. Each test group comprised three monkeys. All studies were conducted by Covance according to internal standard operating procedures. Blood samples were collected pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose. The blood samples were processed to separate the plasma fraction. The level of Compound A in the plasma samples was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS).

A PK time course illustrating the results of the study is shown in FIG. 1. The average plasma exposure of Compound A for each group at the indicated time points is shown in Table 11 (results shown in ng/ml) and descriptive statistics of the AUC_0-24 (hr*ng/ml) by formulation are given in Table 12.

FIG. 2 shows a graphical comparison of exposure of the oral pharmaceutical impositions comprising solid amorphous dispersions of Compound A (BTAB-1 to BTAB-4) to the control composition. As can be seen, the exposure observed using the oral pharmaceutical compositions comprising solid amorphous dispersions of Compound A to the control composition (BTAB-1 to BTAB-4) were greater than the control composition.

As can be seen from FIGS. 1 and 2 and Tables 11-12, the oral pharmaceutical compositions comprising solid amorphous dispersions of Compound A were superior to the control composition. The Cmax was approximately equal in all formulations. The AUC_0-2₄ values for BTAB-1 to BTAB-4 were all greater as compared to the control composition. The mean AUC_0-24 (hr-ng/ml) values for BTAB-1 to BTAB-4 were 3221, 2793, 3896 and 2398, respectively, as compared to 1551 for the control composition. FIG. 1 and Table 11 also show that the Tma is delayed in the BTAB-1 to BTAB 4 formulations to 2 to 4 hours as compared to about 1 hour for the control composition. The delayed T_max translates to increased exposure of Compound A in the blood as compared to the control formulation.

FIG. 3 shows difference in exposure of the oral pharmaceutical compositions comprising solid amorphous dispersions of Compound A (BTAB-1 to BTAB-4) to the control composition. The difference in exposure for BTAB-1 and BTAB-3 was statistically significant. For BTAB-1 the mean difference with the control formulation was 1169 (95% CI of difference 424.9 to 2914; adjusted p value 0.0086). For BTAB-3 the mean difference with the control formulation was 2344 (95% CI of difference 1100 to 35891; adjusted p value 0.0006). While the differences for BTAB-2 and BTAB-4 were not significant, the exposure with these formulations was still greater than that achieved with the control formulation. For BTAB-2 the mean difference with the control formulation was 1242 (95% CI of difference - 2.756 to 2486; adjusted p value 0.0506). For BTAB-4, the mean difference with the control formulation was 847.2 (95% CI of difference -397.3 to 2092; adjusted p value 0.2287).

Furthermore, irrespective of exposure, each of the BTAB-1 to BTAB-4 formulations showed approximately 3-fold higher drug levels at the 8 hour time point and approximately 2- fold higher drug levels at the 12 hour time point as compared to the control composition. In paiticular, the BTAB-1 to BTAB-4 formulations showed significantly longer duration of exposure (shown in hours) above 60 ng/ml as compared to the control formulation (data shown in Table 13). Table 13

BTAB-1 BTAB-2 BTAB-3 BTAB-4 Control

Number of values 3 3 3 3 6

Minimum 7 7 7 7 2

25% Percentile 7 7 7 7 3

Median 11 8 8 11 4

75% Percentile 23 8 8 11 5

Maximum 23 8 8 11 5

Mean 13.7 7.3 7.3 9.7 3.8

Std. Deviation 8.3 0.3 0.3 2.3 1.3

Std. Error of Mean 4.8 0.2 0.2 1.3 0.5

The data presented in this Example show that the oral pharmaceutical formulations of the present disclosure may be used to provide therapeutically effective amounts of Compound A to subjects, including human subjects, for the treatment of HAE and other diseases where inhibition of plasma kallikrein activity is desirable. Importantly, the oral pharmaceutical formulations disclosed provide for plasma concentrations of Compound A well above the minimum inhibitory level for inhibition of plasma kallikrein activity at both the 8 and 12 hour time points. As a result, the oral pharmaceutical compositions disclosed provide the opportunity for a dosing regimen of two times per day.

Example 12- Preparation of Additional Solid Dispersions of Compound A.

The solid dispersions of Compound A described below were prepared generally as described in Examples 1 and 3 above using solvent dispersion and spray-drying using a feed solution of 5 wt% solids (compound A + other compounds) in methanol/water (9 to 1) and subject to spray-drying. All solid dispersions appeared amorphous by powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM) analysis.

Example 13 - Gastric to Intestinal Buffer Dissolution Studies

In order to evaluate the ability of the solid dispersion of the present disclosure to sustain levels of Compound A in a soluble form in the gastrointestinal tract of a subject, gastric to intestinal buffer dissolution studies were performed. The solid dispersions of Compound A as described in Example 12 were tested and compared to Compound A in a control composition (crystalline Compound A as the HCL salt (Form A)).

In these experiments, simulated gastric fluid (0.01N HCL, pH 2.0) and simulated intestinal fluid (0.5 weight% bile salts in phosphate buffered saline, pH 6.5, 290 mOsm) were used. Experiments were conducted at 37 degrees C. The solid dispersions of Compound A and the control composition (4 mg/ml) were measured and placed in a suitable vessel (for example a microcentrifuge tube). To the solid dispersion was added 0.9 ml of 0.0 IN HCL (pH 2.0); the sample was capped and vortexed for 60 seconds and allowed to stand undisturbed. At selected time points, an aliquot of the sample was taken for analysis to determine the total solubilized levels of Compound A in the simulated gastric fluid. In the sampling step, the sample was centrifuged at 13,500 RPM for 60 seconds and two 50 μΐ aliquots were removed for analysis. The first sample, was immediately diluted into 250 μΐ of organic solvent and the amount of soluble Compound A was determined. The second sample was subject to ultracentrifugation and the amount of soluble Compound A was determined. After the aliquots for analysis were removed, the sample was capped and vortexed for 20 seconds to resuspend the sample and the sample was allowed to stand undisturbed until the next time point for gastric analysis. This process was repeated for selected time points. Incubation in the simulated gastric media continued for 30 minutes. Generally, 3-4 samples were taken during this period.

To simulate the transition to the intestinal compartment, 0.9 ml of the simulated intestinal fluid was added to the sample (bringing the concentration of compound A to 2 mg/ml). An aliquot was immediately taken following addition of the simulated intestinal fluid. The sampling procedure was as described above. After the aliquot was taken, the sample was capped and vortexed for 20 seconds to resuspend the sample and the sample was allowed to stand undisturbed until the next time point for intestinal analysis. Incubation in the simulated intestinal fluid continued for 1200 minutes. Generally, 5-7 samples were taken during this period.

The C90 and C1200 values indicate the amount of drug solubilized at 90 and 1200 minutes incubation, respectively, from analysis of the first aliquot taken for sampling (mild centrifugation conditions) and includes free solubilized Compound A as well as Compound A contained in colloidal particles and nanoparticles with the concentration enhancing polymer. The Ultra90 and Ultral200 values indicate the amount of drug solubilized at 90 and 1200 minutes incubation, respectively, from analysis of the second aliquot taken for sampling (ultracentrifugation conditions) and includes free solubilized Compound A only. The C_max GB, Cmax 90IB and AUC4-90 IB indicate the maximum concentration of Compound A attained in the simulated gastric fluid, the maximum concentration of Compound A attained in the simulated intestinal fluid within 90 minutes of addition of the simulated intestinal fluid and the area under the curve of Compound A from 4-90 minutes after the addition of the simulated intestinal fluid.

The results are shown below for selected solid dispersions.

As can be seen in Table 15, the solid dispersions tested provided generally improved dissolution properties as compared to control (Compound A alone). Suitable solid dispersions provide for solubility in simulated gastric fluid at least as good as the control composition as well as providing for equal or enhanced solubility in simulated intestinal fluid. All formulations tested provided for solubility in gastric buffer comparable to the control composition. Furthermore, the solid dispersions tested provided for enhanced solubility in simulated intestinal fluid as indicated by C_max 90IB, AUC_4-90, C90, Ultra90, C1200 and Ultral200 values. This example shows that the solid dispersions tested were capable of providing enhanced solublization of Compound A in the gastrointestinal tract of a subject. Example 14- In vivo Pharmacokinetic Studies in Rats

Solid dispersions of Compound A (prepared as described in Example 12) were administered to rats to determine plasma concentrations of Compound A over time as compared to Compound A in a control formulation.

The solid dispersions were prepared as suspensions in water and dosed orally at 10 mg/kg Compound A. Doing volume concentrations was 1.25 mg/ml and dosing volume was 8 ml/kg. A control composition containing crystalline Compound A as the HCL salt (Form A) in a soft gelatin capsule containing a liquid excipient mixture of 72.1% polyethylene glycol 600, 27.2% D-a-tocopherol polyethylene glycol 1000 succinate and 0.7% D-a-tocopherol (the excipient percentages referring to the total weight of the excipient mixture of the control composition, excluding the active ingredient) was used as a comparator. The control composition was dosed orally at 10 mg/kg Compound A.

Each test group comprised four rats (male, Sprague Dawley from Charles River). Blood samples were collected at 0 (pre-dose) and 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose. The blood samples were processed to separate the plasma fraction. For the control 1 composition and solid dispersion 1 , 2 and 6 the plasma level of compound A was determined for all four samples at each time point and the individual values averaged to yield the plasma level of Compound A for each time point (for these values, the number in parentheses indicates standard error). For the control 2 composition and solid dispersions 3 and 4, equal volumes of plasma from the four animals at each time point were combined into a single sample and the plasma level of Compound A was determined from this combined sample.

Table 16 shows the result, providing plasma concentrations of Compound A at the indicated time points (in ng/ml) and the AUC_0-24 (hr*ng/ml) by formulation.

can be seen from Table 16, the solid amorphous dispersions of Compound A were comparable to the control composition. It should also be noted that the test articles in this experiment were solely the solid amorphous dispersions alone in an aqueous solution (in other words, no additional agents to assist in delivery were provided). Such additional agents have been shown to increase the effectiveness of the solid amorphous dispersions described. For example, solid amorphous dispersion 2 (containing 40% Compound A and 60% PVPVA64) was the same solid amorphous dispersion used to prepare tablet formulation 3 in Example 10, which was tested in primates in Example 11. Likewise, solid amorphous dispersion 3 (containing 60% Compound A and 40% PVPVA64) was the same solid amorphous dispersion used to prepare tablet formulations 1, 2 and 4 in Examples 5, 9 and 7, respectively, which were tested in primates in Example 11. While these solid amorphous dispersions alone in aqueous solution provided AUC_0-24 values slightly above (solid dispersion 2) or below (solid dispersion 3) the AUC_0-24 values for the control formulation in this example, when combined with additional agents in the described tablet formulations, solid amorphous dispersion 2 and 3 provided AUCo_-24 values that exceeded the AUCo-24 value observed with the control formulation.

Example 15- In vivo Pharmacokinetic Studies in Primates

Cynomolgus monkeys have been shown to be a suitable test system for pharmacokinetic studies of Compound A. Solid dispersions of Compound A (prepared as described in Example 12) were administered to cynomolgus monkeys to determine plasma concentrations of Compound A over time as compared to Compound A in a control formulation.

The solid dispersions were prepared as suspensions in water and dosed orally at 10 mg kg Compound A. Dosing volume concentration was 2 mg/ml and dosing volume was 5 ml/kg. A control composition containing crystalline Compound A as the HCL salt (Form A) in a soft gelatin capsule containing a liquid excipient mixture of 72.1% polyethylene glycol 600, 27.2% D-a-tocopherol polyethylene glycol 1000 succinate and 0.7% D-a-tocopherol (the excipient percentages referring to the total weight of the excipient mixture of the control composition, excluding the active ingredient) was used as a comparator. The control composition was dosed orally at 10 mg/kg.

Each test group comprised three monkeys. Blood samples were collected pre-dose and at 0 (pre-dose) and 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose.

The blood samples were processed to separate the plasma fraction. The level of Compound A in the plasma samples was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). For the control composition and solid dispersion 1, the plasma level of compound A was determined for all three samples at each time point and the individual values averaged to yield the plasma level of Compound A for each time point (for these values, the number in parentheses indicates standard error). For solid dispersions 2-4, equal volumes of plasma from the four animals at each time point were combined into a single sample and the plasma level of Compound A was determined from this combined sample.

Table 17 shows the result, providing plasma concentrations of Compound A at the indicated time points (in ng/ml) and the AUCo-24 (hr*ng/ml) by formulation.

As can be seen from Table 17, the solid amorphous dispersions of Compound A were comparable to the control composition.

As discussed above, it should be noted that the test articles in this experiment were solely the solid amorphous dispersions alone in an aqueous solution (in other words, no additional agents to assist in delivery were provided). Such additional agents have been shown to increase the effectiveness of the solid amorphous dispersions described. For example, solid amorphous dispersion 2 (containing 40% Compound A and 60% PVPVA64) was the same solid amorphous dispersion used to prepare tablet formulation 3 in Example 10, which was tested in primates in Example 11. Likewise, solid amorphous dispersion 3 (containing 60% Compound A and 40% PVPVA64) was the same solid amorphous dispersion used to prepare tablet formulations 1, 2 and 4 in Examples 5, 9 and 7, respectively, which were tested in primates in Example 11. While these solid amorphous dispersions alone in aqueous solution provided AUCo-₂₄ values slightly above (solid dispersion 2) or below (solid dispersion 3) the AUC_0-24 values for the control formulation in this example, when combined with additional agents in the described tablet formulations, solid amorphous dispersion 2 and 3 provided AUCo- 2₄ values that exceeded the AUCo-24 value observed with the control formulation.

Example 16- Human Pharmacokinetics with BTAB-1 and BTAB-4 Tablet Formulations in Healthy Subjects

A two-part, open-label, non-randomized, fixed sequence Phase 1 study to examine the relative bioavailability of Compound A in tablet formulations A (BTAB-1) and B (BTAB-4) was conducted in healthy subjects. Tablet formulation A (BTAB-1 as described in Example 5) and tablet formulation B (BTAB-4 as described in Example 7) were compared to a reference product, 5 x 100 mg soft gelatin capsules containing Compound A in a liquid excipient mixture of 72.1% polyethylene glycol 600, 27.2% D-a-tocopherol polyethylene glycol 1000 succinate and 0.7% D-a-tocopherol (the excipient percentages referring to the total weight of the excipient mixture of the composition, excluding the active ingredient). Tablet formulations A and B were administered with varying volumes of liquid (for example water) to assess the impact of this parameter on bioavailability of Compound A. As discussed in Example 11 , BTAB-1 and BTAB 4 provided levels of Compound A in the serum greater than 60 ng/ml for a period of at least 12 hours after administration in non-human primates (as compared to 4 hours for the control composition). This study allows the evaluation of alternate formulations of Compound A as well as alternate dosage forms (tablets versus soft gelatin capsules). Furthermore, this study evaluates the feasibility of reducing the number of dosage forms administered to a subject at the beginning of each dosing interval (for example, from 5 dosage forms as used with the reference soft gelatin capsules to fewer than 5 dosage forms, such as 2 to 4 dosage forms, with the tablet formulations) and/or a reduction in the number of times the subject is dosed per day (for example, from TID as used with the reference soft gelatin capsules to BID). Still further, this study allows for the evaluation of the impact of the volume of liquid (for example water) used to administer the various tablet formulations on bioavailability of Compound A.

Both Parts 1 and 2 of the study comprised multiple regimens of the tablet formulations A and B of varying strengths and using varying volumes of liquid to administer the tablet formulations, and one regimen of the reference product. Part 1 investigated tablet formulation A at different dose strengths and different volumes of liquid used to administer the tablet formulations compared to the reference product. Part 2 investigated tablet formulation B at different dose strengths and different volumes of liquid used to administer the tablet formulations compared to the reference product.

The primary endpoints of the study are (i) the relative bioavailability of each test tablet formulation A and B in comparison with the reference product when administered following an overnight fast in healthy subjects; and (ii) calculation of the following PK parameters, using plasma concentration vs. time data for Compound A in tablet and suspension formulations: AUCo-inf, AUCo-iast, AUC_0-8, AUCo-i₂, % AUC_eXp, Ciast, Cmax, t_1/2, CL/F, lambda-z, Vz/F, T_max, Tiast, AUCtau,ss, AUCo_-24,ss, C8_tau, C12_tau and Frel. Secondary endpoints are to collect information on the safety and tolerability of Compound A as assessed by: AEs, laboratory findings, vital signs, electrocardiograms (ECGs) and physical examination findings.

Subject Criteria:

Within 30 days preceding the first dose, all subjects were required to undergo a screening visit to assess whether the subject meets the eligibility criteria. The primary inclusion criteria were healthy male and non-pregnant, non-lactating females between the age of 18 and 65 years that were non-smokers with a body mass index (BMI) of 18.0 to 32.0 kg/m². Exclusion criteria included clinically significant laboratory abnormalities on screening, use of over-the-counter medications for a period of 7 days prior to Day 1 through follow-up (except for limited acetaminophen use), use of prescription medications for a period of 14 days prior to Day 1 through follow-up (except for contraception use as required), use of vitamins for a period of 7 days prior to Day 1 through follow-up and use of herbal supplements for a period of 14 days prior to Day 1 through follow-up.

Pre-dose Procedures:

Subjects were admitted to the clinical research unit (CRU) on Day -1 of each treatment period and remained in the CRU until the morning of Day 2 after the collection of the 24 hour PK sample and all assessments were complete. Subjects were observed by study staff to assure compliance to all study procedures, including dose administration. The calorie/fat content of meals was not required to be controlled during the study and meals were provided at nominal times. Subjects fasted from all food and drink (except water) for a minimum of 10 hours on the day prior to dosing and water was not allowed 2 hours before the scheduled dosing time. Subjects were provided 240 mL of water at 2 hours post dose. If, for technical reasons, dosing was delayed for more than 2 hours beyond the expected dosing time, subjects received 200 mL Lucozade Sport as of the originally scheduled dosing time, or earlier. Decaffeinated fluids were allowed ad libitum from lunch time on the day of dosing. Lunch was provided (4 hours post- dose), then an evening meal (9 hours post-dose), and an evening snack (14 hours post-dose). Sampling:

Assessment of PK and PD in the subjects was accomplished through a pre-dose and post-dose blood sampling. Venous blood samples were withdrawn via an indwelling cannula (if an indwelling cannula was used, saline was used to keep the vein open) or by venipuncture at less than 1 hr pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24 (time of discharge), 36 (outpatient), and 48 (outpatient) hours post-dose. The acceptable deviations from the nominal post-dose sampling times were as follows: the pre-dose sample was taken lh or less before dosing; 0 to 1 hour post-dose samples were taken within ± 2 min of the nominal post-dose sampling time; 1 to 12 hours post-dose samples were taken within ± 10 min of the nominal post-dose sampling time; 12 to 24 hours post-dose samples were taken within ± 30 min of the nominal post-dose sampling time; and 36 and 48 hour post-dose samples (outpatient visits) were taken within ± 2 hours of the nominal post-dose sampling time. Data Analysis

Concentrations of Compound A were determined by a validated plasma assay. The plasma concentration data for Compound A was analyzed using Phoenix WinNonlin v6.3 or a more recent version (Certara USA, Inc., USA). Steady state plasma concentration data were simulated and PK parameters were estimated using Phoenix WinNonlin v6.3 or a more recent version (Certara USA, Inc., USA). Plasma concentration data and simulated plasma concentration data were tabulated and plotted for each subject for whom concentrations are quantifiable. The analysis was performed separately for Part 1 and Part 2.

Part 1 of the Study:

Part 1 evaluated the safety, tolerability and PK of multiple treatment regimens of different strengths of tablet formulation A and different volumes of liquid used to administer tablet formulation A and one (1) regimen of the reference soft gelatin product, each following a 10 hour fast. Tablet formulation A had a dose-bracketed range to allow the tablet dose of Compounds A (100 mg to 250 mg) to be varied.

Period 1 : Regimen A: 2 x Compound A 250 mg tablets (tablet formulation A) in 240 ml water (n=10)

Period 2: Regimen B: 5 x Compound A 100 mg soft gelatin capsules (reference product) in 240 ml water (n= 12)

Period 3 : Regimen C: 2 x Compound A 250 mg tablets (tablet formulation A) in 350 ml water (n=5)

Period 4: Regimen D: 2 x Compound A 250 mg tablets (tablet formulation A) in 500 ml water (n=5)

Period 5: Regimen E: 5 x Compound A 100 mg tablets (tablet formulation A) in 500 ml water (n=5)

Period 6: Regimen F: 9 x Compound A 100 mg tablets (tablet formulation A) in 500 ml water (n=5)

Enrolled subjects were administered Regimens A to F with a minimum washout period of 7 days between doses when a single subject participated in more than one Regimen. An interim review of PK and safety data following was conducted following each Regimen before proceeding to the next.

Part 2 of the Study:

Part 2 evaluated the safety, tolerability and PK of multiple treatment regimens of different strengths of tablet formulation B and different volumes of liquid used to administer tablet formulation B and one (1) regimen of the reference soft gelatin product, each following a 10 hour fast. Tablet formulation B had a dose-bracketed range to allow the tablet dose of Compounds A (100 mg to 250 mg) to be varied.

Period 1 : Regimen G: 2 x Compound A 250 mg tablets (tablet formulation B) in 240 ml water (n=18)

Period 2: Regimen B: 5 x Compound A 100 mg soft gelatin capsules (reference product) in 240 ml water (n=18)

Period 3: Regimen H: 2 x Compound A 100 mg tablets (tablet formulation B) in 240 ml water (n=9)

Period 4: Regimen I: 5 x Compound A 100 mg tablets (tablet formulation B) in 500 ml water (n= )

Period 5: Regimen J: 10 x Compound A 100 mg tablets (tablet formulation B) in 500 ml water (n=8)

Enrolled subjects were administered Regimens G to J with a minimum washout period of 7 days between doses when a single subject participated in more than one Regimen. An interim review of PK and safety data following was conducted following each Regimen before proceeding to the next.

Results of Part 1

The results of Part 1 of the study are shown below. All doses formulations were well tolerated with no clinically significant adverse events. FIG. 4 shows the concentration versus time profiles of Compound A after of administration of the various tablet formulations of Regimens A to F; the results are expressed as the mean value (in ng/ml) of all results obtained + standard deviation with the shaded region indicating target concentrations for inhibition of plasma kallikrein activity. Table 18A provides Compound A concentrations for the individual time points illustrated in FIG. 4 (expressed as the mean value in ng/ml of all results obtained + standard deviation) and Table 18B provides select pharmacokinetic parameters from the study (Cmax, in ng/ml, and AUC_0-8, AUCo-12 and AUC_0-8 in ng*h/mi); the recited ratios are provided with respect to the corresponding values for the reference product (Regimen B). As can be seen in FIG. 4 and Tables 18A and B, all Regimens tested showed increased bioavailability relative to the reference product (Regimen B). In addition, Regimens D (2 x 250 mg tablets in 500 ml water), E (5 x 100 mg tablets in 500 ml water) and F (9 x 100 mg tablets in 500 ml water) showed significantly increased bioavailability relative to the reference product (Regimen B). Increasing the volume of liquid used to administer the tablet formulations also generally resulted in higher bioavailability of Compound A. For example, increasing the volume of liquid used to administer the tablet formulation from 240 mis (Regimen A, 2 x Compound A 250 mg tablets) to 500 mis (Regimen D, 2 x Compound A 250 mg tablets) increased bioavailability of Compound A.

* mean value in ng/ml of all results obtained + standard deviation

values are presented as geometric mean

Results of Part 2

The results of Part 2 of the study are shown below. All dose formulations were well tolerated with no clinically significant adverse events. FIG. 4 shows the concentration versus time profiles of Compound A after of administration of the various table formulations of Regimens G to J; the results are expressed as the mean value of all results obtained + standard deviation with the shaded region indicating target concentrations for inhibition of plasma kallikrein activity. Table 19A provides Compound A concentrations for the individual time points illustrated in FIG. 4 (expressed as the mean value of all results obtained + standard deviation) and Table 19B provides select pharmacokinetic parameters from the study (C_max, in ng/ml, and AUC_0-8, AUC_0-12 and AUCo-8 in ng*h/ml); the recited ratios are provided with respect to the corresponding values for the reference product (Regimen B, parts 1 and 2 combined). As can be seen in FIG. 4 and Tables 19A and B, all Regimens tested showed increased bioavailability relative to the reference product (Regimen B) except for Regimen H. In addition, Regimens I (5 x 100 mg tablets in 500 ml water) and J (10 x 100 mg tablets in 500 ml water) showed significantly increased bioavailability relative to the reference product (Regimen B). As with the results of part 1, increasing the volume of liquid used to administer the tablet formulations also generally resulted in higher bioavailability of Compound A.

* mean value in ng/ml of all results obtained + standard deviation

* values are presented as geometric mean

Example 17- Human Pharmacokinetics with Suspension Formulations of Spray Dry Dispersions of Compound A in Healthy Sub ects

The two-part, open-label, non-randomized, fixed sequence Phase 1 study to examine the relative bioavailability of Compound A as described in Example 16 was extended to examine suspension formulations of Compound A. These studies used the solid amorphous dispersion of Example 3 (60% Compound A/40% PVPVA64, hereinafter referred to as the "SD") suspended in various volumes of a liquid (for example water) and was conducted in healthy subjects. The SD was used to prepare the Tablets BTAB-1 (as described in Example 5) and BTAB-4 (as described in Example 7) as well as the tablet formulations A and B in Example 16. The suspension formulations of Compound A were compared to a reference product, 5 x 100 mg soft gelatin capsules containing Compound A in a liquid excipient mixture as described in Example 16. The suspension formulations were prepared by adding an amount of the SD required to reach the stated concentration of Compound A (for example 1000 mg) to varying volumes of liquid (for example water). The suspension formulations were then administered to subject in a single dose by drinking the liquid. In certain Regimens, additional PVPVA64 was added to the SD to increase the concentration of concentration enhancing polymer PVPVA64 in the suspension formulation.

As with Example 16, this study allows the evaluation of alternate formulations of

Compound A (suspension formulations vs tablets and soft gelatin capsules). Furthermore, this study evaluates the feasibility of a simpler dosing platform through ingestion of a liquid rather than taking multiple capsules or tablets and/or a reduction in the number of times the subject is dosed per day (for example, from TID as used with the reference soft gelatin capsules to BID). Still further, this study allows for the evaluation of the impact of the volume of liquid (for example water) used to prepare the various suspension formulations on bioavailability of Compound A. Further still, this study allows for the evaluation of an acidic liquid vehicle on bioavailability of Compound A. This study comprised multiple regimens of suspension formulations of the SD comprising Compound A of varying strengths prepared by varying volume of liquid used to prepare the suspension formulations, and one regimen of the reference product in soft gelatin capsules.

The primary endpoints of the study are (i) the relative bioavailability of each test suspension formulation in comparison with the reference product when administered following an overnight fast in healthy subjects; and (ii) calculation of the following PK parameters, using plasma concentration vs. time data for Compound A in tablet and suspension formulations: AUCo-inf, AUCo-iast, AUC_0-8, AUC_0-12, % AUC_exp, Ci_ast, C_max, tin, CL/F, lambda-z, Vz/F, T_max, Tiast, AUCtau,ss, AUCo-24,ss, C8_tau, C12t_au and Frel. Secondary endpoints are to collect information on the safety and tolerability of Compound A as assessed by: AEs, laboratory findings, vital signs, electrocardiograms (ECGs) and physical examination findings.

The subject criteria, pre-dose procedures, sampling and data analysis were as described in Example 16.

Study:

This study evaluated the safety, tolerability and PK of multiple treatment regimens of different strengths of suspension formulations prepared using the SD when administered in varying volumes of liquid and one (1) regimen of the reference soft gelatin product (Regimen B as described in part 1 and part 2 of Example 16), each following a 10 hour fast. Amounts of SD required to reach the stated Compound A concentration were suspended in water (except for Regimen 5 where the SD was dissolved in Coca-Cola to provide an acidic liquid vehicle) allowing the dose of Compound A (500 mg to 2000 mg) to be varied. In addition, for Regimens 9 to 12, additional PVPVA64 was added to the SD prior to suspension in water to provide for increased concentrations of the concentration enhancing polymer PVPVA64.

Regimen 1 : 1000 mg Compound A as a suspension of 40% PVPVA64:60% Compound A in 235 ml water (n=5)

Regimen 2: 1000 mg Compound A as a suspension of 40% PVPVA64:60% Compound A in 500 ml water (n=3)

Regimen 3: 1000 mg Compound A as a suspension of 40% PVPVA64:60% Compound A in 500 ml water (n=5)

Regimen 4: 1000 mg Compound A as a suspension of 40% PVPVA64:60% Compound A in 500 ml Coca-Cola (n=4)

Regimen 5: 950 mg Compound A as a suspension of 40% PVPVA64:60% Compound A in 500 ml water (n=5) Regimen 6: 500 mg Compound A as a suspension of 40% PVPVA64:60% Compound A in 500 ml water (n=5)

Regimen 7: 2000 mg Compound A as a suspension of 40% PVPVA64:60% Compound A in 235 ml water (n=9)

Regimen 8: 2000 mg Compound A as a suspension of 40% PVPVA64:60% Compound A in 500 ml water (n=9)

Regimen 9: 1667 mg Compound A as a suspension of 68% PVPVA64:32% Compound A in 235 ml water (n=6)

Regimen 10: 1000 mg Compound A as a suspension of 75% PVPVA64:25% Compound A in 235 ml water (n=6)

Regimen 1 1 : 500 mg Compound A as a suspension of 90% PVPVA64:10% Compound A in 235 ml water (n=6)

Regimen 12: 1000 mg Compound A as a suspension of 90% PVPVA64:10% Compound A in 235 ml water (n=6)

Data for Regimen B (from both part 1 and part 2 of Example 16) was used as the reference product.

Enrolled subjects were administered Regimens 1 to 12 with a minimum washout period of 7 days between doses when a single subject participated in more than one Regimen. An interim review of PK and safety data following was conducted following each Regimen before proceeding to the next.

Results

The results of the study are shown below. All dose formulations were well tolerated with no clinically significant adverse events. FIG. 5 shows the concentration versus time profiles of Compound A after administration of the various suspension formulations of Regimens 1 to 12; the results are expressed as the mean value (in ng/ml) of all results obtained + standard deviation with the shaded region indicating target concentrations for inhibition of plasma kallikrein activity. Table 20A provides Compound A concentrations for the individual time points illustrated in FIG. 5 (expressed as the mean value in ng/ml of all results obtained + standard deviation) and Table 20B provides select pharmacokinetic parameters from the study (Cmax, in ng/ml, and AUCo-8, AUCo-12 and AUC_0-8 in ng*h/ml); the recited ratios are provided with respect to the corresponding values for the reference product (Regimen B, parts 1 and 2 combined). As can be seen in FIG. 5 and Tables 20A and B, all Regimens tested showed increased bioavailability relative to the control formulation (Regimen B) except for Regimen 11. All Regimens except Regimens 11 and 5 showed greater bioavailability at 6 hours after administration relative to the reference product (Regimen B), with Regimens 2 (1000 mg Compound A as a suspension of 40% PVPVA64:60% Compound A in 500 ml water), 8 (2000 mg Compound A as a suspension of 40% PVPVA64:60% Compound A in 500 ml water) and 9 (1667 mg Compound A as a suspension of 68% PVPVA64:32% Compound A in 235 ml water) showing significantly increased bioavailability relative to the reference product at 10 hours after administration. Regimen 2 showed significantly increased bioavailability relative to the reference product at 12 hours after administration. These results show that Regimens 8 and 9 provided concentrations of Compound A within the range required for inhibition of plasma kallikrein activity for at least 10 hour's after administration and Regimen 2 provided concentrations of Compound A within the range required for inhibition of plasma kallikrein activity for at least 12 hour's after administration. Furthermore increasing the volume of liquid used to suspend the SD for administration generally increased the bioavailability of Compound A (compare Regimen 1 suspending 1000 mg SD in 235 mis water to Regimen 2 suspending 1000 mg SD in 500 mis water). Increasing the concentration of the concentration enhancing polymer PVPVA64 also increased bioavailability of Compound A. In Regimen 9, 1667 mg Compound A administered as a suspension of 68% PVPVA64:32% Compound A in 235 mis water provided increased bioavailability as compared to 2000 mg Compound A administered as a suspension of 40% PVPVA64:60% Compound A in 235 mis of water (Regimen 7).

3.00 125.18 40.14 188.60 55.82 196.89 103.34 319.11 165.67

4.00 86.88 26.00 141.14 63.56 169.19 113.92 278.67 184.17

6.00 33.80 9.84 53.26 20.61 71.36 61.51 120.30 129.52

8.00 19.46 7.11 28.28 11.70 36.99 34.20 58.76 67.30

10.00 12.83 6.94 20.42 12.31 22.78 19.93 36.29 45.23

12.00 8.85 3.62 11.38 7.48 15.74 13.78 24.07 34.36

Reg 9 (n=6) Reg 10 (n=6) Reg 11 (n=6) Reg 12 (n=6)

Time Mean* S.D. Mean* S.D. Mean* S.D. Mean* S.D.

0.50 83.03 66.62 46.85 13.61 39.85 19.36 41.80 18.53

1.00 151.82 91.28 114.07 45.26 87.92 17.25 96.90 44.47

1.50 197.00 107.78 163.18 66.67 110.57 21.87 143.97 58.31

2.00 226.50 122.39 178.83 96.15 91.27 28.59 185.93 91.88

2.50 240.68 137.71 204.17 149.03 75.33 23.69 191.30 95.44

3.00 212.90 88.59 183.73 160.96 60.20 21.69 174.28 87.75

4.00 170.98 65.49 149.57 146.71 42.48 15.76 144.53 71.51

6.00 85.93 47.68 59.13 53.65 18.80 6.07 47.15 23.60

8.00 50.95 40.38 31.45 32.76 11.11 3.54 24.18 12.58

10.00 36.25 32.12 16.74 14.85 7.92 2.40 13.95 7.32

12.00 23.03 16.81 11.64 10.14 6.13 2.06 8.74 4.74

Reg B part 1 Reg B part 2

(n=12) (n=18)

Time Mean* S.D. Mean* S.D.

0.50 21.48 14.16 21.48 14.16

1.00 65.66 26.28 65.66 26.28

1.50 93.18 46.12 93.18 46.12

2.00 108.82 61.84 108.82 61.84

2.50 104.60 72.84 104.60 72.84

3.00 89.14 66.89 89.14 66.89

4.00 66.36 57.63 66.36 57.63

6.00 27.77 25.28 27.77 25.28

8.00 15.91 15.35 15.91 15.35

10.00 10.69 9.85 10.69 9.85

12.00 7.54 7.71 7.54 7.71

mean value in ng/ml of all results obtained + standard deviation

9 256.7 999.7 1132.1 1259.1 2.5 2.9 3.0 3.0

10 194.9 728.4 788.5 860.5 1.9 2.1 2.1 2.1

11 110.6 345.5 377.7 426.5 1.1 1.0 1.0 1.0

12 199.4 715.2 769.3 825.1 2.0 2.1 2.0 2.0

B 101.6 348.4 381.7 419.5 - - - -

* values are presented as geometric mean

Example 18- Human Pharmacokinetics with Suspension Formulations of Crystalline Compound A in Healthy Subjects

The two-part, open-label, non-randomized, fixed sequence Phase 1 study to examine the relative bioavailability of Compound A as described in Example 16 was extended to examine suspension formulations of crystalline Compound A. These studies used crystalline Compound A mixed with the concentration of concentration enhancing polymer PVPVA64 (60% Compound A:40% PVPVA64) as a suspension in water and was conducted in healthy subjects. The suspension formulations were then administered to subject in a single dose by drinking the liquid.

As with Examples 16 and 17, this study allows the evaluation of alternate formulations of Compound A (suspension formulations of crystalline Compound A vs tablets, soft gelatin capsules and suspension formulations of Compound A as a SD). As with Example 17, this study evaluates the feasibility of a simpler dosing platform through ingestion of a liquid rather than taking multiple capsules or tablets and/or a reduction in the number of times the subject is dosed per day (for example, from TID as used with the reference soft gelatin capsules to BID).

This study comprised a single regimen of a suspension formulation comprising 1000 mg crystalline Compound A mixed with PVPVA64 (60% Compound A:40% PVPVA64) and one regimen of the reference product in soft gelatin capsules.

The primary endpoints of the study are as described in Example 17. The subject criteria, pre-dose procedures, sampling and data analysis were as described in Example 16.

Study:

This study evaluated the safety, tolerability and PK of one (1) regimen of a suspension formulation prepared using crystalline Compound A when administered in 235 mis of water and one (1) regimen of the reference soft gelatin product (Regimen B as described in part 1 and part 2 of Example 16), each following a 10 hour fast. Regimen 13: 1000 mg crystalline Compound A mixed with PVPVA64 (40% PVPVA64:60% Compound A) as a suspension of in 235 ml water (n=6)

Enrolled subjects were administered Regimen 13. An interim review of PK and safety data following was conducted following each Regimen before proceeding to the next.

Results

The results of the study are shown below. All dose formulations were well tolerated with no clinically significant adverse events. FIG. 6 shows the concentration versus time profiles of Compound A after administration of the suspension formulation of Regimen 13; the results are expressed as the mean value (in ng/ml) of all results obtained + standard deviation with the shaded region indicating target concentrations for inhibition of plasma kallikrein activity. Table 21 A provides Compound A concentrations for the each subject at the individual time points illustrated in FIG. 6 (expressed as the mean value in ng/ml of all results obtained + standard deviation) and Table 2 IB provides select pharmacokinetic parameters from the study (Cmax, in ng/ml, and AUC_0-8, AUC_0-12 and AUC_0-8 in ng*h/ml); the recited ratios are provided with respect to the corresponding values for the reference product (Regimen B, parts 1 and 2 combined). As can be seen in FIG. 6 and Tables 21A and B, Regimen 13 showed increased bioavailability relative to the control formulation (Regimen B).

Claims

CLAIMS What is claimed:

1. A method of treating hereditary angioedema (HAE) in a subj ect, the method comprising orally administering to the subject at a dosing interval a dose of a composition comprising: i) a solid dispersion comprising 3-[2-(4-carbamimidoyl- phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]-6-(cyclopropylmethyl-carbamoyl)- pyridine-2-carboxylic acid (Compound A), or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer; or ii) a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer, wherein a plasma concentration of the administered Compound A is greater than ύ minimum therapeutic level during all or substantially all of the dosing interval.

2. A method of inhibiting plasma kallikrein activity in a subject, the method comprising orally administering to the subject at a dosing interval a dose of a composition comprising: i) a solid dispersion comprising 3-[2-(4-carbamimidoyl- phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]-6-(cyclopropylmethyl-carbamoyl)- pyridine-2-carboxylic acid (Compound A), or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer; or ii) a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer, wherein a plasma concentration of the administered Compound A is greater than a minimum therapeutic level during all or substantially all of the dosing interval.

3. A method of achieving a plasma concentration of 3-[2-(4-carbamimidoyl- phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]-6-(cyclopropylmethyl-carbamoyl)- pyridine-2-carboxylic acid (Compound A) in a subject above a minimum therapeutic level for at least 8 hours following a single administration, the method comprising orally administering to the subject a dose of a composition comprising: i) a solid dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer; or ii) a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer.

4. A method of achieving a sustained average plasma concentration of 3-[2-(4- carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]-6-(cyclopropylmethyl- carbamoyl)-pyridine-2-carboxylic acid (Compound A) in a subject above a minimum therapeutic level for all or substantially all of a treatment period, the method comprising orally administering to the subject at a dosing interval a dose of a composition comprising: i) a solid dispersion comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer; or ii) a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer.

5. The method of any one of claims 1, 2 or 4, wherein the dosing interval is every 8 hours or greater.

6. The method of any one of claims 1 , 2 or 4, wherein the dosing interval is every 12 hours or greater.

7. The method of any one of claims 1 to 4, wherein the minimum therapeutic level is 30 ng/ml.

8. The method of any one of claims 1 to 4, wherein the minimum therapeutic level is 40 ng/ml.

9. The method of any one of claims 1, 2 or 4, wherein the dosing interval is every 8 hours or every 12 hours and the minimum therapeutic level is 30 ng/ml.

10. The method of any one of claims 1 to 4, wherein the dose is provided in at least one dosage form.

11. The method of any one of claims 1 to 4, wherein the composition is a tablet.

12. The method of any one of claims 1 to 4, wherein the composition is a suspension.

13. The method of any one of claims 1 to 4, wherein the composition is a suspension comprising a liquid vehicle and the solid dispersion, wherein the solid dispersion comprises Compound A, or a pharmaceutically form thereof, and a polyvinyl pyrrolidone polyvinyl acetate copolymer.

14. The method of any one of claims 1 to 4, wherein the composition is a suspension comprising a liquid vehicle and the combination, wherein the combination comprises crystalline Compound A, or a pharmaceutically acceptable form thereof, and a polyvinyl pyrrolidone polyvinyl acetate copolymer and a liquid vehicle.

15. The method of any one of claims 1 to 4, wherein the dose contains between 100 to 2000 mg of Compound A, or a pharmaceutically acceptable form thereof.

16. The method of any one of claims 1 to 4, wherein the dose contains between 300 and 600 mg of Compound A, or a pharmaceutically acceptable form thereof.

17. The method of any one of claims 1 to 4, wherein the concentration enhancing polymer is an ionizable cellulosic polymer, a non-ionizable cellulosic polymer or a noncellulosic polymer.

18. The method of any one of claims 1 to 4, wherein the concentration enhancing polymer comprises a polyvinyl pyrrolidone polyvinyl acetate (PVPVA) copolymer.

19. The method of claim 18, wherein the PVPVA copolymer is PVPVA64.

20. The method of any one of claims 1 to 4, wherein the concentration enhancing polymer comprises a hydroxypropyl methyl cellulose acetate succinate (HPMC-AS) polymer or a hydroxypropyl methyl cellulose (HPMC) polymer.

21. The method of claim 20, wherein the HPMC-AS is HPMC-AS-L, HPMC-AS-M or HPMC-AS-H.

22. The method of claim 20, wherein the HPMC is HPMC-E3.

23. The method of any one of claims 1 to 4, wherein the solid dispersion is a solid amorphous dispersion.

24. The method of any one of claims 1 to 4, wherein the Compound A in the combination is crystalline Compound A.

25. The method of claim 24, wherein the crystalline Compound A is crystalline Form A.

26. The method of any one of claims 1 to 4, wherein the concentration of Compound A in the solid dispersion is at least 30 weight percent with respect to the total content of the solid dispersion.

27. The method of claim 26, wherein the solid dispersion is a solid amorphous dispersion.

28. The method of any one of claims 1 to 4, wherein the concentration of Compound A in the solid dispersion is at least 60 weight percent with respect to the total content of the solid dispersion.

29. The method of claim 28, wherein the solid dispersion is a solid amorphous dispersion.

30. The method of any one of claims 1 to 4, wherein the concentration of Compound A in the combination is at least 50 weight percent with respect to the total content of the combination.

31. The method of claim 30, wherein the Compound A in the combination is crystalline Compound A.

32. The method of claim 31, wherein the crystalline Compound A is crystalline Form A.

33. The method of any one of claims 1 to 4, wherein the solid dispersion or combination further comprises a stabilizing agent.

I l l

34. The method of any one of claims 2 to 4, wherein the subject is suffering from hereditary angioedema (HAE).

35. The method of claim 34, wherein the HAE is type I HAE or type II HAE.

36. The method of claim 1, wherein the HAE is type I HAE or type II HAE.

37. The method of any one of claims 1 to 36, wherein the subject is a human.

38. A pharmaceutical composition comprising: i) a solid dispersion comprising 3-[2-(4- carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]-6-(cyclopropylmethyl- carbamoyl)-pyridine-2-carboxylic acid (Compound A), or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer; or ii) a combination comprising Compound A, or a pharmaceutically acceptable form thereof, and a matrix comprising a concentration enhancing polymer, wherein:

a. the concentration of Compound A in the solid dispersion or combination is at least 30 weight percent; and

b. when a single dose of the composition is administered to a subject, a concentration of Compound A in the blood versus time area under the curve for a 24 hour period following administration is greater than or equal to 1.5 -fold that of a control composition consisting essentially of an equivalent quantity of Compound A in an excipient mixture of 72.1% polyethylene glycol 600, 27.2% D-a-tocopherol polyethylene glycol 1000 succinate and 0.7%) D-a-tocopherol, where the excipient percentages refer to the total weight of the excipient mixture of the control composition, excluding the active ingredient.

39. The pharmaceutical composition of claim 38, wherein the composition is a tablet.

40. The pharmaceutical composition of claim 38, wherein the composition is a suspension.

41. The pharmaceutical composition of claim 38, wherein the composition is a suspension comprising a liquid vehicle and the solid dispersion, wherein the solid dispersion comprises Compound A, or a pharmaceutically form thereof, and a polyvinyl pyrrolidone polyvinyl acetate copolymer.

42. The pharmaceutical composition of claim 38, wherein the composition is a suspension comprising a liquid vehicle and the combination, wherein the combination comprises crystalline Compound A, or a pharmaceutically acceptable form thereof, and a polyvinyl pyrrolidone polyvinyl acetate copolymer and a liquid vehicle.

43. The pharmaceutical composition of claim 42, wherein the crystalline Compound A is crystalline form A.

44. The pharmaceutical composition of claim 38, wherein the dose contains between 100 to 2000 mg of Compound A, or a pharmaceutically acceptable form thereof.

45. The pharmaceutical composition of claim 38, wherein the dose contains between 300 and 600 mg of Compound A, or a pharmaceutically acceptable form thereof.

46. The pharmaceutical composition of claim 38, wherein the concentration enhancing polymer is an ionizable cellulosic polymer, a non-ionizable cellulosic polymer or a noncellulosic polymer.

47. The pharmaceutical composition of claim 38, wherein the concentration enhancing polymer comprises a polyvinyl pyrrolidone polyvinyl acetate (PVPVA) copolymer.

48. The pharmaceutical composition of claim 47, wherein the PVPVA copolymer is PVPVA64.

49. The pharmaceutical composition of claim 38, wherein the concentration enhancing polymer comprises a hydroxypropyl methyl cellulose acetate succinate (HPMC-AS) polymer or a hydroxypropyl methyl cellulose (HPMC) polymer.

50. The pharmaceutical composition of claim 49, wherein the HPMC-AS is HPMC-AS-L, HPMC-AS-M or HPMC-AS-H.

51. The pharmaceutical composition of claim 49, wherein the HPMC is HPMC-E3.

52. The pharmaceutical composition of claim 38, wherein the solid dispersion is a solid amorphous dispersion.

53. The pharmaceutical composition of claim 38, wherein the Compound A in the combination is crystalline Compound A.

54. The pharmaceutical composition of claim 53, wherein the crystalline Compound A is crystalline Form A.

55. The pharmaceutical composition of claim 38, wherein the concentration of Compound A in the solid dispersion is at least 30 weight percent with respect to the total content of the solid dispersion.

56. The pharmaceutical composition of claim 55, wherein the solid dispersion is a solid amorphous dispersion.

57. The pharmaceutical composition of claim 38, wherein the concentration of Compound A in the solid dispersion is at least 60 weight percent with respect to the total content of the solid dispersion.

58. The pharmaceutical composition of claim 57, wherein the solid dispersion is a solid amorphous dispersion.

59. The pharmaceutical composition of claim 38, wherein the concentration of Compound A in the combination is at least 50 weight percent with respect to the total content of the combination.

60. The pharmaceutical composition of claim 59, wherein the Compound A in the combination is crystalline Compound A.

61. The pharmaceutical composition of claim 60, wherein the crystalline Compound A is crystalline Form A.

62. The pharmaceutical composition of claim 38, wherein the solid dispersion or combination further comprises a stabilizing agent.

63. The pharmaceutical composition of claim 38, wherein the concentration of Compound

A in the blood versus time area under the curve for a 24 hour period following administration is greater than or equal to 2-fold that of a control composition.

64. The pharmaceutical composition of claim 38, wherein the concentration of Compound A in the blood versus time area under the curve for a 24 hour period following administration is greater than or equal to 3 -fold that of a control composition.

65. The pharmaceutical composition of claim 38, wherein the concentration of Compound A in the blood versus time area under the curve for a 24 hour period following administration is greater than or equal to 4-fold that of a control composition.

66. The pharmaceutical composition of claim 38-65, wherein the subject is a human.