WO2025090400A1 - Agglomerated crystalline medium chain fatty acid salts - Google Patents

Abstract

The present disclosure provides compositions of agglomerated crystalline salts of medium chain fatty acids having improved properties relative to commercially available salts. These salts are useful as excipients in oral dosage forms of medicaments, including as permeation enhancers. This disclosure provides compositions of sodium caprate crystals having improved powder flow and compression behavior. This disclosure further provides oral tablets containing these sodium caprate compositions, including tablets that are substantially free of any compression aid excipient. In various embodiments, these tablets exhibit superior tensile strength and compaction performance than conventional tablets.

Description

AGGLOMERATED CRYSTALLINE MEDIUM CHAIN FATTY ACID SALTS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is an International Patent Application which claims priority from U.S. Provisional Application No. 63/593,167, filed October 25, 2023, and U.S. Provisional Application No. 63/706,065. filed October 11, 2024; each of which is incorporated by reference in its entirety herein.

BACKGROUND

[0002] Sodium salts of saturated medium-length chain (“medium chain”) organic acids are surprisingly difficult to crystallize. These molecules have a strong propensity towards gelling and making unstirrable batch conditions in many solvent systems. The natural crys tai line morphology for these compounds is long fibers/needles that tend to entrain solvent, are difficult to isolate in standard equipment trains, and have undesirable powder properties for formulation manufacturing. Most commercially available material of this kind is either highly expensive and isolated through spray-drying, or retains the suboptimal fiber-like morphology that form from thick unstirrable slurries.

[0003] Sodium caprate, or sodium decanoate, is the sodium salt of caproic acid, a 10-carbon saturated fatty acid, which can form micelles and liquid crystalline phases in aqueous solution. Sodium caprate may help the transport of biologically active molecules and, as an FDA-approved food additive and component of finished drug products, it may serve to enhance the bi oax ai 1 abil i t\ of an active agent. In addition, sodium caprate is a known intestinal permeation enhancer. While there are known processes for preparing sodium caprate, including the synthesis described in B. Zacharie, et al., Organic Process Research & Development 2009, 13. 581-583, unlike the present invention, these processes, using any of numerous solvent systems, result in gelling of the sodium caprate material. Gelling makes use of sodium caprate (powder) in manufacturing on large scales difficult and impractical. However, in the few solvent systems in which gelling can be suppressed, sodium caprate crystallizes as small, thin needles, or fibers, which results in unstirrable slurries. Consequently, these slurries present their own challenges, as it is difficult to transfer these from one equipment train to the other, for instance, from the crystallization tank to the filter/drier or the centrifuge. In addition, these particles filter poorly and entrap a significant amount of interstitial liquid, resulting in excessive agglomeration during drying. The cake that is formed requires a significant energy input to be broken up and results in the formation of widely-distributed, hard chunks of material, which impact the ability to formulate the material. These particles are also more vulnerable to cracking, or breakage. In total, sodium caprate is prodigiously difficult to isolate at industrial scale. As a potential consequence of these formulation challenges, there is limited GMP supply of sodium caprate.

[0004] As such, there are regulatory and technical barriers to the industrial use of medium chain fatty acid salts such as sodium caprate as an excipient in drug product formulations.

SUMMARY OF THE INVENTION

[0005] The present disclosure provides compositions of crystalline solids of salts of medium chain fatty acids. These solids, which are isolated in powder form, may be suitable as excipients in oral drug formulations containing one or more therapeutic macromolecules. In particular, they may function as permeation enhancers of poorly permeable macromolecules. The disclosed crystalline solids exhibit improved properties relative to existing medium chain fatty acid salt solids. The present disclosure also provides improved oral dosage forms, such as tablets, containing crystalline solids of medium chain fatty acid salts. The present disclosure further provides methods of formulating and/or making these dosage forms.

[0006] The present disclosure provides compositions of agglomerated crystalline particles of medium chain fatty acid salts having adjustable particle size, powder flow properties and compression behavior superior to those of commercially available alternatives. The present solid material compositions have excellent flow and compaction properties and is cost-effective to generate, making it suitable for use as an excipient in manufacturing processes and finished drug products. Thus, the present disclosure is directed to compositions useful as excipients for oral therapeutic drug products for administration to humans. The disclosed solid material is the product of novel processes for generating medium chain fatty acid salts using a medium-length aliphatic hydrocarbon solvent and polar aprotic solvent, as described herein. The disclosed material may be characterized as having spherical agglomerated morphology, i.e., the disclosed crystalline particles comprise spherical agglomerates. Stated another way, the disclosed agglomerated crystals are primarily spherical. This material may be substantially free of gelling or fiber- or needle-like dispersions of crystalline particles.

[0007] In various embodiments, the disclosed compositions comprise crystalline solids (e.g., solid powders) of aliphatic fatty acid salt of varying medium lengths, such as caprate, pelargonate, and laurate. In various embodiments, the disclosed solids are sodium salts of any of these fatty acids. In several embodiments, the disclosed solids are sodium caprate salts.

[0008] Further provided herein are tablets comprising the disclosed crystalline solid compositions. These tablets exhibit superior tensile strength, flow properties and compaction properties relative to tablets containing commercially available medium chain fatty acid sodium salts. These tablets may be substantially free of any excipients, other than the medium chain fatty acid salt itself, that enhance the compactability or mechanical integrity of the tablet. As such, the disclosed tablets may be substantially free of any compression aids. The disclosed tablets may further comprise a therapeutic macromolecule, such as a poorly permeable therapeutic peptide. [0009] This disclosure is based, at least in part, on the discovery that medium chain fatty acid salts exhibiting substantially high specific surface area (SSA), a spherical agglomerated morphology', high powder flowability, and/or a medium particle size yield oral tablets that exhibit unexpectedly high compaction behavior. These tablets have high breaking strength and/or tensile strength. As such, the disclosed crystalline solids provide for improved tabletability relative to existing crystalline solids of medium chain fatty⁷ acid salts.

[0010] In some aspects, the disclosed compositions comprise agglomerated crystalline solids of sodium caprate. Further disclosed are powder products containing this agglomerated crystalline sodium caprate. This powder product may be referred to herein as “Product AT The disclosed sodium caprate crystalline solids exhibit an SSA that is surprisingly an order of magnitude higher than commercially available sodium caprate solids, such as the sodium caprate material marketed and/or sold by Jost Chemical, TCI Chemicals, BioSpectra Inc., and Pfaltz and Bauer Inc. For example, it was found that material generated by the disclosed processes contained sodium caprate particles having a mean SSA of 5.9 m²/g and above exhibited superior flowability and compression properties. In particular, sodium caprate particles having a mean SSA of 9.9 m²/g and above exhibited excellent flowability' and compression properties.

[0011] Thus, in some aspects, provided herein are compositions comprising crystalline sodium caprate particles, wherein the sodium caprate particles exhibit a mean specific surface area of at least 5.9 m²/g. Further provided herein are compositions comprising crystalline sodium caprate particles, wherein the sodium caprate particles exhibit a mean specific surface area of at least 9.9 m²/g. In some embodiments, the sodium caprate particles exhibit a mean SSA of between 9.9 m²/g and about 37 m²/g. In some embodiments, the sodium caprate particles exhibit a mean SSA of at least about 15 m²/g.

[0012] In some embodiments, the sodium caprate particles exhibit a mean SSA of between 5.9 m²/g and about 56 m²/g. In some embodiments, the sodium caprate particles exhibit a mean SSA of between 9.9 m²/g and about 56 m²/g, between 5.9 and 37 m²/g, or between about 37 m²/g and 56 m²/g.

[0013] The disclosed sodium caprate cry stalline particles exhibit a morphology⁷ that differs from commercially available sodium caprate, that is, exhibit a morphology that comprises spherical agglomerates. In some embodiments, the disclosed particles exhibit a morphology characterized by spherical and irregularly shaped agglomerates. The morphology of these particles may be characterized as porous, i.e., having high internal macroscopic porosity. [0014] The disclosed particles may be of medium size. These particles may exhibit a combination of SSA and particle size distribution (PSD) that, together, substantially differs from that of commercially available sodium caprate. For example, it was found that material generated by the disclosed processes contained sodium caprate particles having a D90 of 565 pm or less that exhibited excellent flowability and compression properties. In some embodiments, the disclosed sodium caprate particles have a PSD having a D90 of 900 pm or less, 650 pm or less, such as 565 pm or less. In some embodiments, the D90 is 400 pm or less.

[0015] In some aspects, provided herein are tablets comprising any of the disclosed compositions of agglomerated crystalline particles of medium chain fatty acid salts. In various aspects, the tablets comprise any of the disclosed sodium caprate particles. It will be understood to those of skill in the art that agglomerated crystalline particles of any medium chain fatty acid salt may be used in the invention.

[0016] In some aspects, any of the disclosed particles are combined with a therapeutic macromolecule to form a mixture. This mixture may be formulated into an oral dosage form, such as an oral tablet for administration to a subject (e.g., a human subject) to treat or prevent a disease, disorder, or condition. Thus, provided herein are oral tablets comprising a therapeutic macromolecule and sodium caprate. These oral tablets may not require a compaction aid excipient, due to the improved compression behavior of the disclosed sodium caprate particles. As such, in various embodiments, the tablet is substantially free of a compression aid. In some aspects, provided herein are tablets containing a therapeutic macromolecule and sodium caprate, and no other components. In some embodiments, tablets consisting essentially of a therapeutic macromolecule and sodium caprate are provided.

[0017] In various aspects, the therapeutic macromolecule is poorly permeable, i.e., exhibits a low apparent permeability (Papp). This macromolecule may be a small organic molecule, a larger biologic, or a cyclic peptide (which has properties common to both small molecules and biologies). In some embodiments, the therapeutic macromolecule is a peptide, such as a macrocyclic peptide. In some embodiments, the therapeutic macromolecule is the compound of Formula I.

[0018] In some embodiments, the tablet exhibits a tensile strength of at least 1 MPa. For instance, the tablet may exhibit a tensile strength of at least 1 MPa. For example, the tablets may exhibit a tensile strength of 1.1 MPa, 1.2 MPa, 1.25 MPa. 1.5 MPa. 1.75 MPa. 1.9 MPa, 2 MPa. 2.1 MPa, 2.15 MPa, 2.25 MPa, or 2.5 MPa.

[0019] In some aspects, provided herein are sodium pelargonate particles having spherical agglomerated morphology and improved compression behavior. In other aspects, provided herein are sodium laurate particles having spherical agglomerated morphology and improved compression behavior. Further provided herein are oral tablets comprising these sodium pelargonate agglomerates, or sodium laurate agglomerates. It is hypothesized that agglomerated crystals of medium chain fatty acid salts generally exhibit substantially similar thermodynamics and kinetics. As such, it is hypothesized that oral tablets comprising sodium pelargonate agglomerates, or sodium laurate agglomerates, behave in similar fashion to oral tablets comprising sodium caprate.

[0020] Other embodiments, aspects and features of the present invention are further described in or will be apparent from the ensuing description, examples and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIG. 1 is a plot depicting the compression performance of a solid dosage form (platform dosage form) of an exemplary sodium caprate agglomerated material (i.e., Product A) containing one or more compression aids, in comparison to four commercially available forms of crystalline sodium caprate. Varying compressive stresses (pressures), as applied by a tablet press, are plotted on the x-axis.

[0022] FIG. 2A is a plot depicting the compression performance of 100% Product A tablets, in comparison to tablets containing one of three commercially available forms of crystalline sodium caprate (100% w/w). as a function of compressive pressure. FIG. 2B is a plot of tensile strength as a function of tablet density of tablets containing 100% Product A, 100% Commercial Material 3 and 100% Commercial Material 4.

[0023] FIG. 3 is a plot of the tabletability of a dosage form of 100% Product A tablets for four commercial-scale batches. This chart plots tensile strength against compressive pressure (as applied by a tablet press) to show the compression profiles of these batches.

[0024] FIG. 4 is a plot of particle size parameter D90 (x-axis) of commercial-scale batches of Product A against tensile strength of tablets containing Product A from corresponding batches in the absence of compression aids, to show changes in tensile strength as a function of particle size. [0025] FIG. 5 is a plot of specific surface area against tensile strength of tablets containing commercial-scale batches of Product A, in comparison to corresponding tablets containing Commercial Material 2 and Commercial Material 4, in the absence of compression aids. [0026] FIG. 6 is a plot that depicts the tabletabihty of a tablet containing 10% lactose and 90% Product A, relative to two corresponding dosage forms (“blends”) containing Commercial Material 2 and Commercial Material 4, respectively.

[0027] FIG. 7 depicts the compressibility of this 90%/10% Product A tablet, relative to the two corresponding dosage forms containing commercially available crystalline sodium caprate (Commercial Materials 2 and 4).

[0028] FIG. 8 depicts the friability of this 90%/10% Product A tablet, relative to the two corresponding dosage forms containing commercially available crystalline sodium caprate. [0029] FIGs. 9A-9C are representative scanning electron microscope (SEM) images (500x magnification) demonstrating differences in morphological attributes of sodium caprate sourced from (9 A) Commercial Material 2, (9B) Commercial Material 4 and (9C) Product A (agglomerated material). FIG. 9D is a representative SEM image of Product A that highlights a particle having spherical morphology.

[0030] FIG. 10 is a plot that depicts the tabletability (tensile strength) of tablet blends containing 80% Product A and (i) 20% lactose, (ii) 20% MCC and (iii) 20% HPMC.

[0031] FIG. 11 shows the tabletability of three tablet blends containing Product A and differing amounts of lactose: 20%, 50%, and 70% w/w.

[0032] FIG. 12 shows the X-Ray Powder Diffraction data for Product A, compared to commercially available alternatives of sodium caprate.

[0033] FIG. 13 is a differential scanning calorimetry (DSC) scan of Product A.

[0034] FIG. 14 depicts a thermogravimetric analy sis of the Product A.

[0035] FIG. 15 depicts a representative volume-weighted particle size analysis of small-scale batches of Product A.

[0036] FIG. 16 shows a representative SEM image of Product A illustrating agglomerated plate-like primary morphology' (from small-scale batch).

[0037] FIG. 17 depicts additional representative SEM images comparing commercially available sodium caprate crystalline material to Product A.

[0038] FIG. 18 shows light-microscope images depicting the formation of sodium caprate agglomerates using different aprotic polar organic solvents (NMP and DMAC) with heptane. [0039] FIG. 19 shows SEM images of sodium caprate crystals generated in acetonitrile and hexane. A reaction scheme for this embodiment of the process is shown at top.

[0040] FIG. 20 shows SEM images of sodium caprate crystals generated in acetonitrile and heptane using 1 L/kg (IV) and 2 L/kg (2V) of acetonitrile. [0041] FIG. 21 depicts photographs taken during the performance of an exemplary process used to generate about 1.0 kg of sodium caprate agglomerated crystal product. This product is shown in the rectangular glass dish, at bottom.

[0042] FIG. 22 is an SEM image of sodium pelargonate crystals generated in acetonitrile and heptane.

[0043] FIG. 23 is an SEM image of sodium laurate crystals generated in acetonitrile and heptane.

DETAILED DESCRIPTION

[0044] The present disclosure provides compositions of agglomerated crystalline salts of medium chain fatty acids having improved properties relative to commercially available salts. These salts are useful as excipients in oral dosage forms of medicaments, including as permeation enhancers. This disclosure provides compositions of sodium caprate crystalline agglomerates having improved powder flow and tablet tensile strength. This disclosure further provides oral tablets containing these sodium caprate compositions, including tablets that are substantially free of any compression aid excipient. In various aspects, these tablets exhibit superior robustness, tensile strength and compaction performance than conventional tablets. [0045] By identifying a solvent composition that suppresses gel formation and entraps the solids within the dispersed droplets of the second phase, a single-pot, low -energy crystallization process using cheap, commercially accessible starting materials was achieved. The provided agglomerated sodium caprate cry stals behave like a traditional slurry and do not entrain solvent, allowing for mild stirring and facile isolation. The agglomerates exhibit sufficient hardness to retain their morphology during discharge and handling. In addition, the provided agglomerates have substantially homogenous morphologies and/or unimodal normal size distribution. The agglomerates also have superior powder flowability.

[0046] Described herein are powder products generated by any of the disclosed processes. In various embodiments, the products comprise any of the provided agglomerated crystals, such as agglomerated sodium caprate crystals.

[0047] Further provided herein are oral dosage forms comprising the product of any of the disclosed processes, e.g.. Product A. In some embodiments, tablets comprising Product A are described. Tablets are an oral dosage form that comprise a blend of therapeutic macromolecule, i.e., an active pharmaceutical ingredient (API) and excipients (lubricants, disintegrants, bulking agents, etc.) that has been compacted during manufacture. In some embodiments, tablets that comprise a blend of API, sodium caprate of Product A and additional excipients are provided. In some embodiments, these tablets do not contain a compression aid (e.g., lactose), or are substantially free of any compression aids. In some embodiments, disclosed are tablets that comprise lactose (e.g., lactose monohydrate) and/or MCC.

[0048] The tablets of the disclosure may contain 5% or less, 4.5% or less, 4.0% or less. 3.0% or less, 2.5% or less, 2.0% or less, 1.5% or less, or 1.0% or less of any compression aid. In some embodiments, the disclosed tablets are free of a compression aid, i.e., have roughly 0% of a compression aid.

[0049] Accordingly, the disclosed tablets may exhibit improved tensile strength and/or compactability relative to a corresponding tablet that contains commercial sodium caprate material and is substantially free of a compression aid. For instance, the disclosed tablets may exhibit a tensile strength that is 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold higher than the tensile strength of a corresponding tablet that comprises commercial sodium caprate (and is substantially free of a compression aid). The disclosed tablets may exhibit a tensile strength that is 6-fold, 7- fold, 8-fold, 9-fold, 10-fold, 11-fold, or 12-fold higher than the tensile strength of a corresponding tablet. In some embodiments, the tablets exhibit a 5-fold higher tensile strength than that of a corresponding tablet, such as a tablet comprising the same therapeutic molecule and sodium caprate material sold by Jost Chemical or material sold by BioSpectra, Inc. (See FIGs. 2A and 2B.) In some embodiments, the tablets exhibit a 6-fold to 11.7-fold higher tensile strength than the corresponding tablet, e.g., containing Jost Chemical material.

[0050] The tablets may exhibit a tensile strength of about 1 MPa, 1.1 MPa, 1.2 MPa, 1.25 MPa, 1.5 MPa, 1.75 MPa, 1.9 MPa, 2 MPa, 2.1 MPa, 2.15 MPa, 2.25 MPa, 2.5 MPa, or above 2.5 MPa (see FIG. 3). In particular embodiments, the tablets exhibit a mean tensile strength of about 2 MPa. In some embodiments, the tablets exhibit a tensile strength of about 2. 1 MPa. In some embodiments, the tablets exhibit a tensile strength of between 1.9 MPa and 2.15 MPa. In some embodiments, the tablets exhibit a tensile strength of between 1.27 MPa and 2.27 MPa. In some embodiments, the tablets exhibit a tensile strength of about 2. 1 MPa at a compressive stress of any value between 50 MPa and 130 MPa, e.g., between 115 MPa and 125 MPa. These tensile strengths may be determined using a tablet press at a compressive pressure value in the range of between 30 MPa and 140 MPa.

[0051] In various aspects, the tablets comprise sodium caprate particles having any of the properties described below. For example, disclosed are tablets that comprise sodium caprate particles. However, it will be understood to those of skill in the art that agglomerated crystalline particles of any medium chain fatty acid salt may be used in the invention. [0052] In some embodiments, these tablets exhibit superior tensile strength than corresponding (e.g., conventional) tablets comprising an API (such as a different API) and sodium caprate. The tensile strength (e.g., tensile strength) of the described tablets may exceed 1 megapascals (MPa) at a high compressive stress. In some embodiments, the tensile strength of the described tablets are an order of magnitude higher than the corresponding tensile strength of tablets comprising the same API and a commercially available sodium caprate, such as Sodium Caprate Purified Powder (Jost Code 2724). Any of the disclosed tablets may exhibit high resistance to breaking or cracking.

[0053] The described tablets may comprise any therapeutic macromolecule, or API, that maybe difficult to solubilize in oral formulations or exhibit poor oral bioavailability in the absence of a permeation enhancer, such as a peptide API (i.e., a therapeutic peptide).

[0054] The superior compression behavior of the disclosed medium chain fatty acid salt particles enables the generation of tablets comprising very' high concentrations of medium chain fatty acid salt. These types of tablets are desirable for patients, as they reduce the overall size of the tablet. From a commercial perspective, the reduction of excipient inventories through the removal of excipients from the tablet is highly desirable as it reduces overall operational cost, thus reducing the cost of goods. Formulations containing high levels (>90% w/w) of. e.g., sodium caprate cannot be manufactured with conventional sodium caprate grades used in the art, including the commercially available material described herein. Tablet concentrations as high as 99% of medium chain fatty acid salt have never before been reported. Thus, in some aspects, provided herein are tablets comprising up to 99% w/w of a medium chain fatty acid salt excipient, such as sodium caprate.

[0055] In some embodiments of the disclosed compositions, the amount of medium chain fatty acid salt, such as sodium caprate, can range from about 1% w/w to about 99% w/w. In various embodiments, tablets comprising between about 70 and 99% sodium caprate, or about 70 and 90% sodium caprate are provided. In particular embodiments, sodium caprate is present in the tablet in an amount of 79% w/w or greater. In some embodiments, tablets comprising between 80 and 99.5% w/w sodium caprate are provided. In certain embodiments, tablets comprising between 80 and 99% w/w sodium caprate are provided. In some embodiments, tablets comprising between 80 and 89% w/w sodium caprate are provided. In particular embodiments, tablets comprising between 88% and 89% sodium caprate are disclosed. In some embodiments, tablets comprising 96% sodium caprate are disclosed.

[0056] In one embodiment, tablets comprising 80% sodium caprate are provided. In some aspects of this embodiment, a tablet is provided that comprises 80% sodium caprate and 20% therapeutic macromolecule (w/w). In one embodiment, tablets comprising 90% sodium caprate are provided. In some aspects of this embodiment, a tablet is provided that comprises 90% sodium caprate and 10% therapeutic macromolecule (w/w). Further provided are tablets comprising between about 30% and 90% sodium caprate, and further comprising a therapeutic macromolecule. In some embodiments, tablets comprising about 30% or about 33% sodium caprate, and further comprising a therapeutic macromolecule, are provided.

[0057] In some embodiments, the disclosed tablets exhibit enhanced friability relative to corresponding tablets containing commercial sodium caprate. In some embodiments, the disclosed tablets exhibit enhanced plastic work of compaction relative to corresponding tablets containing commercial sodium caprate.

Properties of Sodium Caprate Particles

[0058] In some embodiments, the disclosed sodium caprate compositions have agglomerated particles that exhibit superior specific surface area (SSA) than commercially available sodium caprate. For instance, the disclosed sodium caprate may exhibit a higher specific surface area relative to commercial sodium caprate by about 3-fold, 4-fold, or 5-fold, e.g., 3.8-fold. Specific surface area may be measured by a Brunauer-Emmet-Teller (BET) method, e.g., a gas adsorption-BET method. In some embodiments, the specific surface area of the described sodium caprate compositions are an order of magnitude higher than the corresponding specific surface area of commercially available sodium caprate compositions. Without being bound by theory, by virtue of the disclosed particles’ higher SSA, tablets containing these particles have higher plastic work of compaction (and plastic deformation), and as a result greater tensile strength.

[0059] In some aspects, the disclosed sodium caprate particles exhibit a mean SSA of between 5.9 m²/g and about 56 m²/g. In exemplary aspects, the disclosed sodium caprate particles exhibit a mean SSA of between 5.9 m²/g (e.g., 5.96) and about 41 m²/g (e.g., 41.17). In some aspects, the disclosed sodium caprate particles exhibit a mean SSA of between 9.6 m²/g (e.g., 9.67) and about 41 m²/g (e.g„ 41.17).

[0060] For example, some of the disclosed sodium caprate particles exhibit a mean SSA of between 9.9 m²/g and about 37 m²/g. In some embodiments, the particles exhibit a mean SSA of at least 9.9 m²/g, or at least about 10 m²/g. In some embodiments, the particles exhibit a mean SSA of at least about 9.6, 10, 11, 12, 13, 14. 15. 16, 17.5, 20, 21, 22.5, 24, 25, 26, 28, 30, 32.5, 35, 36.5, 37.5, 38.5, 40, or 41 m²/g. The disclosed sodium caprate particles may exhibit a mean SSA of about 15, 21, or 37 m²/g. The disclosed sodium caprate particles may exhibit a mean SSA of about 10, about 16, about 24, or about 37 m²/g. The disclosed particles may exhibit a mean SSA of 15.9. 24. 1. or 36.7 m²/g (see FIG. 5). This stands in contrast to the mean SSAs of sodium caprate particles in material marketed by Jost Chemical and BioSpectra, Inc., each of which has an SSA of only 2.6 m²/g.

[0061] In some embodiments, the particles exhibit a mean SSA of at least 5.9 m²/g, or at least about 6 m²/g. For example, some of the disclosed sodium caprate particles exhibit a mean SSA of between 5.9 m²/g and about 37 m²/g.

[0062] In some embodiments, the disclosed particles exhibit an SSA within any of the following ranges of m²/g: 5.9-56, 5.9-41, 5.9-37, 5.9-30, 5.9-25, 5.9-21, 5.9-15, 9.9-56, 9.9-41, 9.9-37, 10-35, 9.9-21, 9.9-25, 15-41, 15-37, 15-35, 15-25, 20-25, 20-37, 20-41. 9.9-15. 24-37, 37-41, 30-37, 15-41, 21-41, 25-41, or 30-35.

[0063] In some embodiments, the agglomerated particles of the disclosed sodium caprate compositions have a substantially different morphology relative to commercially available sodium caprate. In particular embodiments, the disclosed particles are plate-like, homogenous and/or substantially free of fiber- or needle-like morphologies. In some embodiments, the disclosed crystals are substantially free of balloon-like morphologies.

[0064] The disclosed sodium caprate particles exhibit a morphology that comprises spherical agglomerates. In some embodiments, the disclosed particles exhibit a morphology characterized by spherical and irregularly shaped agglomerates (see FIG. 9D). In various embodiments, the morphology of these particles may be characterized as porous, i.e., having high internal porosity. The spherical morphology of these particles lends to favorable densification properties, resulting in a high Hausner Ratio.

[0065] In some embodiments, the disclosed sodium caprate particles have a particle size distribution having a D90 of 900 pm or less. 850 pm or less. 700 pm or less, 650 pm or less, 575 pm or less, 500 pm or less, 400 pm or less, 350 pm or less, 300 pm or less, 200 pm or less, 160 pm or less, 120 pm or less, or 85 pm or less. In particular embodiments, a D90 of 565 pm or less is observed. In some embodiments, a D90 of between 158 pm and 657 pm is observed. A particle size distribution from about 250 pm to about 900 pm. about 300 pm to about 700 pm, about 200 pm to about 700 pm, about 200 pm to about 300 pm, about 200 pm to about 565 pm, or about 350 pm to about 600 pm may be observed. For example, a particle size distribution from 289 pm to 863 pm may be observ ed (see FIG. 4).

[0066] In some embodiments, the disclosed sodium caprate particles exhibit a morphology that comprises spherical agglomerates and an SSA greater than 9.9 m²/g, e.g., an SSA greater than 15 m²/g. In some embodiments, the disclosed sodium caprate particles exhibit a morphology that comprises spherical agglomerates and a particle size distribution having a D90 of 565 pm or less. In some embodiments, the disclosed sodium caprate particles e hi bi t a morphology that comprises spherical agglomerates, an SSA greater than 9.9 m²/g, and a particle size distribution having a D90 of 565 gm or less. In some embodiments, the disclosed sodium caprate particles exhibit a morphology that comprises spherical agglomerates, an SSA greater than 15 m²/g. and a particle size distribution having a D90 of 400 pm or less.

[0067] In some embodiments, the disclosed sodium caprate particles exhibit a morphology that comprises spherical agglomerates, an SSA of between 9.6 m²/g and 41 m²/g, and a D90 of between 158 pm and 657 pm.

[0068] The disclosed solids further exhibit a powder flowability that is superior to commercially available sodium caprate from marketed and/or sold by Jost Chemical, TCI Chemicals, BioSpectra Inc., and Pfaltz and Bauer Inc. In some aspects, provided herein are composition comprising crystalline sodium caprate particles, wherein the sodium caprate particles exhibit a tap density of at least 0.15 g/mL, 0.20 g/mL, 0.25 g/mL, 0.32 g/mL, 0.35 g/mL, 0.45 g/mL, or 0.50 g/mL. In exemplary embodiments, the particles exhibit a tap density of at least 0.32 g/mL. In some embodiments, the particles exhibit a tap density of at least 0.5 g/mL, e.g., at least 0.54 g/mL. The disclosed particles have tap densities in the range of 0.50 to 0.69 g/mL.

[0069] In some aspects, the sodium caprate particles exhibit a Hausner Ratio of 2.6 or less. 2.2 or less, 2.0 or less, 1.8 or less, or 1.6 or less. In particular aspects, the sodium caprate particles exhibit a Hausner Ratio of 1.6 or less. In some embodiments, the particles exhibit a Hausner Ratio of 1.3 or less, 1.2 or less, 1.1 or less, or 1.05 or less. Hausner Ratios of 1.35 or 1.30 may be observed.

Definitions

[0070] Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary’ skill in the art. Generally, the nomenclature used herein and the laboratory’ procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. [0071] As used herein. “Product A” refers to the agglomerated crystalline form of sodium caprate that results from the disclosed processes. In some embodiments, “Product A” is synonymous with “Agglomerated Material.”

[0072] As used herein, term “medium chain fatty' acid” is intended to mean an aliphatic carbohydrate with a primary carboxylic group and between five and fifteen carbon atoms. Examples include capric acid, lauric acid, pelargonic acid, and undecylic acid. In some embodiments of the instant invention, the medium chain fatty⁷ acid is capric acid, pelargonic acid or lauric acid. In further embodiments, the medium chain fatty⁷ acid is capric acid. In some embodiments, the medium chain fatty acid is pelargonic acid or lauric acid.

[0073] As used herein, the term “permeation enhancer” refers to a pharmaceutically acceptable excipient that improves the absorption of an active ingredient from the GI tract. Several medium chain fatty⁷ acids, and salts thereof, are suitable as permeation enhancers for oral delivery. This term further encompasses derivatives of medium chain fatty acids. Examples of permeation enhancers include sodium caprate (Cio). sodium caprylate (Cs). sodium laurate (C12). sodium undecylate (Ci 1) docusate sodium, sodium lauryl sulfate, myristate, and Labrasol®. Additional examples include caprate, caprylate, laurate, and docusate as free bases. In some embodiments, the permeation enhancer sodium caprate (which is also referred to herein as “caprate”) is used. [0074] As used herein, the term “fatty acid salt” refers to a salt of an aliphatic carboxylate that is saturated or unsaturated. This term encompasses the anionic, free basic form of the carboxylate, as well as the neutral salt form (i.e., containing a counterion). For example, as used herein, myristate anion and potassium myristate are fatty⁷ acid salts.

[0075] As used herein in reference to a therapeutic macromolecule, the term “poorly permeable” means resistant to permeability or absorption into the Gl tract of a subject, or otherwise resistant to formulation with solubilizing excipients typically⁷ used for small molecule active ingredients. A macromolecule, such as a peptide, that is poorly permeable may have an apparent permeability lower than 10.0.

[0076] As used herein, the term “apparent permeability” (Papp) refers to the permeability of a macromolecule to translocate across an intestinal epithelial cell membrane. Those skilled in the art will appreciate that Papp may be measured using a Transwell™ culture system of the human colonic adenocarcinoma cell line Caco-2 (see, e g., Pires et al. , Pharmaceutics . 2021 Oct; 13(10): 1563). The unit of measure for apparent permeability may be I0’⁸ cm/s, or 10’⁶ cm/s. In various embodiments, the unit of measure is 10’⁸ cm/s. The therapeutic macromolecule of the present disclosure may⁷ have a Papp below 10.0 x 10'⁸ cm/s, below 7.5 x 10‘⁸ cm/s, below 5.0 x 10'⁸ cm/s, below 3.0 x 10'⁸ cm/s, below 2.0 x 10’⁸ cm/s, or below 1.0 x 10'⁸ cm/s. Papp may be otherwise measured in accordance with any suitable method known in the art. including an MDCK 11 culture system.

[0077] A “tablet” is an oral dosage form that comprises a blend of active ingredient and excipients (polymers, disintegrants, bulking agents, etc.) that has been compacted during manufacture. This term encompasses oral compressed tablets and film-coated tablets. In some embodiments, tablets that comprise a blend of therapeutic macromolecule, sodium caprate, and additional excipients are provided. The tablets of the disclosure may be manufactured by compaction in a tableting press that contains one or more punches and dies.

[0078] As used herein, the term “compression aid” refers to an excipient of an oral dosage form, such as a tablet, that enhances the mechanical integrity or compactability of the dosage form. Examples of compression aids are lactose and microcrystalline cellulose (MCC). A material may be well-known to be a compression aid, and/or may be determined to be a compression aid by measuring the compactability of a dosage form in the presence or absence of the excipient (e.g.. using a tablet press at a compressive stress value in the range of 30 MPa to 250 MPa, or 50 MPa to 250 MPa).

[0079] As used herein in the context of oral dosage forms, the term “substantially free” refers to containing 3% or less of a component, on a weight/weight (w/w) basis. For example, a tablet that is “substantially free of a compression aid” refers to a tablet that contains 3% or less of any compression aid, such as 3% or less of lactose or MCC. The tablets of the disclosure may contain 3.0% or less, 2.5% or less, 2.0% or less, 1.5% or less, 1.0% or less, or 0.5% or less of any compression aid. As such, the disclosed tablets may be substantially free of a compression aid. In some embodiments, the disclosed tablets are free of a compression aid, i.e.. have roughly 0% of a compression aid.

[0080] As used herein, the term “compactability” refers to the ability of the powdered material to be compressed into a tablet of specified strength. It is synonymous with tablet tensile strength, diametrical tensile strength, and deformation hardness. Compactability may further be expressed using plastic work of compaction, which is a measure of how much irreversible work is performed during the compression process (expressed in units of Joules per gram). Compactability may be measured by any method known in the art, such as by a compaction simulator, such as a tablet press. The compactability, or tensile strength, of the described tablets may exceed 1 megapascals (MPa) at a compressive stress in the range of between 30 MPa and 140 MPa. The compactability, or tensile strength, of the described tablets may exceed 1 megapascals (MPa) at a compressive stress in the range of between 6 MPa and 180 MPa. For instance, compactability may be measured at a compressive stress of 6 MPa, 10 MPa, 20 MPa, 30 MPa. 40 MPa. 50 MPa, 60 MPa. 70 MPa. 75 MPa, 80 MPa, 85 MPa. 90 MPa, 95 MPa, 100 MPa, 110 MPa, 120 MPa, 130 MPa, 140 MPa, 150 MPa, 160 MPa, 170 MPa, or 180 MPa. In preferred embodiments, compactability is measured by compressing the material into cylindrical compacts using a tablet press tooling (e.g., a 9.525 mm round flat-face tablet press) using a range of compression stresses between 6 and 180 MPa under force control. Tablet tensile strength (T. or TS) may be determined using the following equation:

T= IB I TT/ID. where B is the load required to break the tablet diametrically, h is the thickness of the tablet, and D is the diameter of the tablet. See Micharfy et al. , Int J Pharm. 2007 Mar 21 ; 333 ( 1 -2) : 118-26, which is incorporated herein by reference.

[0081] As used herein, the terms “commercial sodium caprate” and “commercially available sodium caprate” refer to any lot of any sodium caprate material marketed and/or sold by chemical manufacturers in the United States as of October 2023. In various embodiments, these terms refer to sodium caprate material marketed and/or sold by Jost Chemical, TCI Chemicals, BioSpectra Inc., and Pfaltz and Bauer Inc. between January and October 2023. In particular embodiments, these terms may refer to Sodium Caprate Purified Powder (Jost Code 2724), sold by Jost Chemical. In some embodiments, these terms may refer to TCI Chemicals Sodium Decanoate. Product Number D0024; BioSpectra Sodium Decanoate GMP Excipient Grade, Product Code NDEC-3220; or Pfaltz & Bauer Sodium Caprate 97%, Product Code S04460.

[0082] As used herein, the term “dose” means a quantity of an API or pharmaceutical composition administered or recommended to be administered at a particular time.

[0083] As used herein, the term “treating” or “treatment” refers to inhibiting or ameliorating symptoms of a disease, condition or disorder in a subject who is experiencing or displaying the pathology or symptoms of the disease, condition or disorder. For example, inhibiting a disease, condition, or disorder refers to arresting further development of the pathology⁷ and/or symptoms of said disease, condition or disorder. Additionally, ameliorating a disease, condition or disorder, for example, refers to reversing the pathology and/or symptoms, such as decreasing the severity of the disease.

[0084] As used herein, the term “therapeutically effective amount” refers to an amount of the therapeutic macromolecule API (e.g., peptide) sufficient to produce the desired therapeutic effect in a human or animal, e.g.. the amount necessary to treat, cure, prevent, or inhibit development and progression of a disease or the symptoms thereof and/or the amount necessary to ameliorate symptoms or cause regression of a disease. “Therapeutically effective amount” may vary depending on the structure and potency of the active ingredient and the contemplated mode of administration. One of skill in the art can readily determine a therapeutically effective amount of a given API.

[0085] As used herein, “subject” refers to an animal, such as a human or a non-human animal to whom an experimental or approved treatment is administered. In various embodiments, the subject is mammalian. “Subjects” may include livestock animals and domestic (companion) animals including, but not limited to, cattle, horses, sheep, swine, goats, rabbits, cats, dogs, and other mammals. “Subjects” may include experimental animals, such as rodents and non-human primates (NHPs). In some embodiments, the subject is a mouse or rat. In some embodiments, the subject is a primate. In some embodiments, the subject is a rhesus macaque. In some embodiments, the subject is in need of treatment of a disease, disorder, or condition. In some embodiments, the subject is a human. Whether a subject is “in need” of treatment of a disease, disorder, or condition encompasses both a determination of need by a medical professional and a desire of the subject for such treatment. In some embodiments, a subject is suffering from, or is susceptible to, a disease, disorder or condition. In some embodiments, a subject does not display a symptom of a disease, disorder, or condition.

[0086] As used herein, the term “administration” and variants thereof (e.g., “administering”) in reference to the disclosed tablet compositions refers to providing the composition to a subject in need of treatment. As used herein, “oral” refers to administration via the mouth, i.e., administration of the composition through the mouth.

[0087] As used herein, “% w/w” and “wt%” refer to the weight percent of an ingredient relative to the total weight of the composition.

[0088] As used herein, the term “short chain alcohol” refers to a linear saturated hydrocarbon with one to three carbon atoms and a terminal hydroxide functional group. Examples include methanol or ethanol. In an embodiment of the instant invention, short chain alcohol is methanol. In an embodiment, a sodium salt of a short chain alcohol is sodium methoxide.

[0089] As used herein, the term “aprotic solar solvent” refers to a compound or mixture of compounds used as a process solvent with a chemical structure that lacks an acidic proton, are polar, and may serve as hydrogen bond acceptors. Examples include dimethylformamide, dimethylacetamide, tetrahydrofuran, or acetonitrile. In an embodiment of the instant invention, aprotic polar solvent is acetonitrile.

[0090] As used herein, the term “medium chain aliphatic hydrocarbon solvent” refers to a compound or a of mixture of compounds used as a process solvent with a chemical structure composed of five to nine carbon atoms connected to form non-aromatic chains and bonded only to each other and hydrogen atoms. Examples include heptane, 2-methylhexane, hexane, octane, and cyclohexane. As used herein, “heptane” may encompass linear heptane, branched heptane, n- heptane, or a blend of heptane isomers (e.g., commercial heptane blends such as “Heptanes, mixture of isomers,” as sold by Thermo Scientific Chemicals). As used herein, “hexane” may encompass linear hexane, branched hexane, n-hexane, or a blend of hexane isomers. In an embodiment of the instant invention, medium chain aliphatic hydrocarbon solvent is n-heptane (which is referred to in the Examples as simply “heptane”). In another embodiment of the instant invention, medium chain aliphatic hydrocarbon solvent is n-hexane.

[0091] As used herein, the phrase “controlled rate” refers to an addition of solution using flow rates planned prior to the start of the batch, typically delivered using a pump or flow controller and dosed following a program or schedule.

[0092] As used herein, the phrase “constant stirring” refers to a stirring of the solution substantially without intermption. This phrase encompasses the occurrence of one or more interruptions to the stirring, these interruptions collectively having insubstantial impact to the production of an intended slurry (e.g.. a few intermptions of 1-3 seconds each). Constant stirring may be performed mechanically (e.g., by magnetic stir bar) or manually.

[0093] As used herein, including the appended claims, the singular forms of words such as “a,” “an,” and “the,” include their corresponding plural references unless the context clearly dictates otherwise. Any example(s) following the term “e.g..” or “for example” is not meant to be exhaustive or limiting.

[0094] As used herein, the terms “at least one” item or “one or more” item each include a single item selected from the list as well as mixtures of two or more items selected from the list.

[0095] Unless expressly stated to the contrary, all ranges cited herein are inclusive; i.e., the range includes the values for the upper and lower endpoints of the range as well as all values in between. All ranges also are intended to include all included sub-ranges, although not necessarily explicitly set forth. As an example, temperature ranges, percentages, ranges of equivalents, and the like described herein include the upper and lower limits of the range and any value in the continuum there between. Numerical values provided herein, and the use of the term “about”, may include variations of ± 1%, ± 2%, ±3%, ± 4%, ± 5%, and ± 10% and their numerical equivalents.

[0096] “About” when used to modify a numerically defined parameter (e.g., the temperature, or the length of time for a reaction, as described herein) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter; where appropriate, the stated parameter may be rounded to the nearest whole number. For example, a temperature of about 30°C may vary' between 25°C and 35°C. In addition, the term “or,” as used herein, denotes alternatives that may, where appropriate, be combined; that is, the term “or⁷’ includes each listed alternative separately.

[0097] As used herein, the term “comprising” may include the embodiments “consisting of’ and “consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients/steps and permit the presence of other ingredients/steps. However, such description should be construed as also encompassing compositions or methods as “consisting of’ the enumerated components, which allows the presence of only the named components or compounds, along with any combinations of pharmaceutical acceptable excipients, and excludes non-enumerated components or compounds. Such description should further be construed as also encompassing compositions or methods that “consist essentially of the enumerated components. As used herein, “consisting essentially of’ means that the disclosed compositions may include small amounts (e.g., 3% or less w/w) of other components that do not materially alter the properties of the composition.

Therapeutic Macromolecules

[0098] Provided herein are oral tablets comprising a therapeutic macromolecule and sodium caprate, wherein the tablet is substantially free of a compression aid, and wherein the therapeutic macromolecule exhibits a low apparent permeability (Papp). For example, the therapeutic macromolecule may have a Papp of less than 10 x 10'⁸ cm/s. The disclosed compositions are suitable for formulation with any poorly permeable therapeutic macromolecule. The therapeutic macromolecule of the disclosure may comprise a peptide, protein, or oligonucleotide.

[0099] In some embodiments, the therapeutic macromolecule may comprise an oligonucleotide, such as an antisense oligonucleotide (ASO). In some embodiments, the oligonucleotide may be a deoxyribonucleic acid (DNA) molecule or a ribonucleic acid (RNA) molecule.

[0100] In various embodiments, the therapeutic macromolecule may be a peptide. The disclosed compositions may be suitable for use with any poorly soluble, high molecular-weight, and/or poorly permeable therapeutic peptide. In some embodiments, the disclosed therapeutic peptides are linear in structure. In some embodiments, the disclosed peptides are not linear. In various embodiments, the disclosed peptides are cyclic. In some embodiments, the disclosed peptides are macrocyclic. Macrocyclic peptides have gained significant interest among medicinal chemists because these molecules exhibit biologic-like specificity while boasting the size and biodistribution of many small molecules. Thus, in some embodiments, the macromolecule is a macrocyclic peptide. The disclosed cyclic peptides may be natural or synthetic. [0101] In some embodiments, the therapeutic macromolecules of the disclosed compositions are approved for use in human subjects by a health authority, such as the FDA or EMA. In some embodiments, the therapeutic macromolecules are not approved for use in humans by a health authority. The disclosed macromolecules may have demonstrated safety, absence of toxicity, and/or activity in non-human animal and/or human animal subjects, following an oral administration in the presence or absence of a permeation enhancer.

[0102] In various embodiments, the therapeutic peptides of the disclosed compositions have a low apparent permeability (Papp). For example, the therapeutic peptides of the disclosure may have a Papp below 10.0 (x 10^-8 cm/s). For example, the peptides of the disclosure may have a Papp below 3.0. In some embodiments, the peptides have a Papp of about 1.0, 0.95, 0.92, 0.85, or 0.80. In some embodiments, the peptides have a Papp of about 9.5 or 9.6 (e.g., 9.568). In some aspects, the peptides have a Papp between 0.92 and 9.6. The therapeutic macromolecule of the present disclosure may have a Papp below 10.0 x 10'⁸ cm/s. below 7.5 x 10'⁸ cm/s, below 5.0 x 10’⁸ cm/s, below 3.0 x 10‘⁸ cm/s. below 2.0 x 10’⁸ cm/s. or below 1.0 x 10‘⁸ cm.

[0103] In various embodiments, the disclosed therapeutic peptides have a high molecular weight. For example, the peptides of the disclosure may have a molecular weight of at least 1000 g/mol (or 1000 Da. or 1 kDa). In some embodiments, the peptides of the disclosure have a molecular weight of at least 1025, 1050. 1100, 1150, 1200, 1250. 1300, 1350, 1400, 1450, 1500. 1550, 1750, 2000, 2100, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2560, 2600 g/mol, or above 2600 g/mol.

[0104] The disclosed peptides may contain or comprise 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids. In some embodiments, the peptide comprises 13, 14, or 15 amino acids. In some embodiments, the cyclic peptide consists of 13 ammo acids or 14 amino acids.

[0105] The disclosed peptides may have a low lipophilicity at physiological pH (e g., a pH of 7.4). Stated another way, the disclosed peptides may have a low hydrophobicity at physiological pH. In some embodiments, the peptides of the disclosure have a logD (at pH 7.4) below 5.0. In some embodiments, the peptides of the disclosure have a logD at pH 7.4 between about 1.5 and about 2.0 (e g., a logD of 1.67).

[0106] The therapeutic peptides of the disclosed compositions and methods may be highly polar, e.g., may have a high isoelectric point (pl). In some embodiments, the therapeutic peptide of the disclosed compositions has a pl between 3.0 and 9.0. In some embodiments, the therapeutic peptide of the disclosed compositions has a pl between 8.0 and 9.0.

[0107] In some embodiments, the therapeutic peptides have inhibitory activity against a protein ligand or receptor, such as a membrane-bound receptor. In some embodiments, the disclosed therapeutic peptides are agonists of a protein ligand or receptor. In some embodiments, the peptide exhibits inhibitory activity⁷ against Proprotein convertase subtilisin-kexin type 9 (PCSK9), a ligand involved in the mammalian cholesterol metabolic pathway. For example, International Patent Publication No. WO 2019/246349, published December 26, 2019, which is incorporated herein by reference, discloses cyclic peptide compounds having inhibitory activity against PCSK9.

[0108] In some embodiments, the therapeutic peptide has the chemical structure provided below. In some embodiments, the therapeutic peptide is the compound of Formula (I). This compound is disclosed in International Publication Nos. WO 2019/246349 and WO 2023/023245, published February 23, 2023, and Johns et al., Circulation 147:00 (May 2023), each of which is incorporated herein by reference. Methods of making the compound of Formula I are disclosed in WO 2019/246349. Formula I exhibits inhibitory' activity' against PCSK9. It has a molecular weight of 1550.87 g/mol and a Papp of 9.568.

[0109] A ternary' mixture of sodium caprate, lubricant, and Formula I - the composition described in Table A - w as generated in a compaction simulator as a proof of concept for macrocyclic peptide-containing sodium caprate dosage forms. These materials were blended in a suitable blender and subsequently compressed using standard tableting equipment. This roughly 200 mg tablet contains about 11% compound of Formula I and 88% sodium caprate by weight. Table A

[0110] In some embodiments, the therapeutic peptide has the chemical structure provided below as Formula II. Formula II is (37S',42S)-37,42-Dicarboxy-l-

[(1 IS, 17 , 205*, 235,275,395', 42S',63S,66J?)-47-fluoro-20-[(lJ?)-l-hydroxyethyl]-17-[(4- methoxyphenyl)methyl]- 11 ,63- dimethyl- 10, 16.19,22,30.40,58.61 ,64,67.70-undecaoxo-28-oxa- 1,9,15,18,21,24,31,41,51,62,65,68- dodecaazanonacyclo[37.18. 11.23,6. 124,42. 133,37.144,51.011,15.023,27.045,50]triheptac onta- 3,5,33(71),34,36,44(69),45,47,49,72-decaen-66-yl]-12,12-dimethyl-3,16,25,34,39,44-hexaoxo- 6,9,18,21,27.30-hexaoxa-2,12.15,24,33,38,43-heptaazahenhexacontan-12-ium-61-oate. Formula II is a lipidated version of Formula I, in that it consists of Formula I covalently attached to a long chain fatty acid. Methods of making Formula II are disclosed in International Publication No. WO 2021/041770, published March 4, 2021, which is incorporated herein by reference (see Example 34). Formula II exhibits inhibitory activity against PCSK9. It has a molecular weight of 2470 g/mol and a Papp of 0.9200. In some embodiments, the therapeutic peptide is a lipidated peptide.

[0111] Thus, in some embodiments, the therapeutic macromolecule of the disclosed tablets is the compound of Formula I. In some embodiments, the macromolecule is the compound of Formula II.

[0112] It will be understood that the disclosed tablets may comprise the therapeutic macromolecule in any suitable amount. In various embodiments, the tablet comprises the therapeutic macromolecule in a range of amounts between 1% and 50% w/w. For example, the macromolecule (e.g., peptide) may be present in an amount between 1% and 5%, 1% and 4%, 4% and 5%, 5% and 10%. 8% and 10%. 10% and 11%. 10% and 12%. 10% and 15%. 10% and 30%, 20% and 30%, 15% and 20%, or 20% and 40% w/w. In particular embodiments, tablet comprises about 4% of therapeutic peptide (w/w). In some embodiments, tablet comprises between 10% and 12% of therapeutic peptide (w/w). For example, the tablet may comprise between 10% and 12% of the compound of Formula I. For example, the tablet may comprise between 10% and 12% of the compound of Formula I. In some embodiments, the tablet comprises about 1% of therapeutic peptide, such as the compound of Formula I. In some embodiments, the tablet comprises 4% of the compound of Formula I. In some embodiments, the tablet comprises about 4.5% of the compound of Formula I. In some embodiments, the tablet comprises 10% or 20% of the compound of Formula I.

[0113] Each of the above-described macromolecules may exhibit poor solubility, poor permeability, and/or a fast release profile even when combined with a permeation enhancer. It will be appreciated by the skilled artisan that any poorly permeable therapeutic macromolecule may be used in accordance with the invention.

Oral Tablets

[0114] Additional excipients are contemplated for any of the disclosed oral dosage forms, e.g., oral tablets. The dosage forms described herein may be formulated as the active pharmaceutical ingredient and may be administered in a mixture with suitable pharmaceutical diluents, binders, excipients, or carriers (collectively referred to herein as “excipients”) suitably selected with respect to the intended form of administration and consistent with conventional pharmaceutical practices, that is, oral tablets, oral capsules, oral suspensions, or oral formulations. In some embodiments, the disclosed tablets comprise a compression aid excipient.

[0115] For instance, for oral administration in the form of a tablet, the tablet may comprise one or more oral, non-toxic, pharmaceutically acceptable excipients, such as lactose, starch, sucrose, glucose, magnesium (Mg) stearate, di calcium phosphate, calcium sulfate, mannitol, sorbitol, and the like. In some embodiments, the disclosed tablets comprise lactose. In some embodiments, the disclosed tablets comprise a cellulose-derived polymer, such as hydroxypropyl methyl cellulose (HPMC, or hypromellose) or microcrystalline cellulose (MCC). In some embodiments, the disclosed tablets comprise HPMC. In some embodiments, the disclosed tablets comprise MCC. In some embodiments, the disclosed tablets comprise HPMC and MCC.

[0116] In some embodiments, the tablets comprise an excipient that is one or more of mannitol, starch, dicalcium phosphate, calcium carbonate, sodium carbonate, lactose, casein, caseinate, albumin, gelatin, acacia, mesoporous silica, colloidal silica, or combinations thereof. In some embodiments, the tablets comprise mannitol and/or lactose. In some embodiments, the disclosed tablets comprise HPMC, MCC, mannitol, and/or lactose.

[0117] In some embodiments, the disclosed compositions comprise a lubricant selected from magnesium stearate or sodium stearyl fumarate, or both. In various embodiments, the disclosed tablets comprise magnesium stearate. In some embodiments, the disclosed tablets comprise HPMC, MCC, lactose, and magnesium stearate. In some embodiments, the disclosed tablets comprise HPMC, MCC, mannitol, and magnesium stearate.

[0118] In some embodiments, the disclosed compositions comprise a diluent selected from a polyethylene glycol (e.g., PEG300), macrogol (PEG4000)). mannitol, lactose, or combinations thereof. In some embodiments, the disclosed compositions comprise a lubricant excipient. The disintegrant may be selected from croscarmellose sodium, crospovidone, or sodium starch glycolate. In a further embodiment, the disintegrant is croscarmellose sodium. In some embodiments, the disclosed compositions comprise a glidant selected from silicon dioxide, starch, talc, or tricalcium phosphate. The disclosed compositions may comprise a solubilizing agent selected from propylene glycol, polysorbate 80, sorbitol, cremophor EL, castor oil, com oil, cottonseed oil, safflower oil, sesame oil, soybean oil, peppermint oil, olive oil, miglyol, glycerin, or combinations thereof.

[0119] Additional pharmaceutically acceptable excipients that may be included as appropriate include one or more tableting agents, bulking agents, osmotic agents, tonicity enhancing agents, flavoring agents, chelating agents, sugars, surfactants, polyols, stabilizers, emulsifiers, salts, fillers, and preservatives. In some embodiments, a microcrystalline cellulose polymer, such as Avicel® (e.g., Avicel® PH101 and PH 102), is included.

[0120] In some embodiments, the disclosed tablets comprise multiparticulates. In some embodiments, the disclosed tablets comprise a matrix. In some embodiments, the disclosed tablets do not contain nanoparticulates.

[0121] It will be appreciated that the disclosed tablets may be administered to a subject according to any dosage schedule or regimen. In some embodiments, one or more tablets (such as two tablets) are administered to the subject simultaneously or sequentially.

[0122] It will be appreciated that the disclosed compositions are suitable for treatment of any of various diseases, disorders, or conditions. In some aspects, the disclosed tablets are suitable for treatment of a cardiovascular disease. In some aspects, the disclosed tablets are suitable for treatment of atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, and related cardiovascular disease and cardiometabolic conditions in an animal or human subject. For example, the disclosed tablets may be used to treat hypercholesterolemia.

[0123] The disclosed tablets may have a total weight that is suitable for oral administration to a subject, e.g., a human subject. The tablet may have a total weight between about 200 mg and about 1000 mg. The tablet may have a total weight in one of the following ranges: 200-225 mg, 225-300 mg, 200-300 mg, 200-400 mg, 400-800 mg, 500-1000 mg, or 300-800 mg. In some embodiments, the tablet has a total weight of 200 mg, 205 mg, 210 mg, or 225 mg. In some embodiments, the tablet has a total weight of about 800 mg.

[0124] It will be understood that tablets of any shape may be generated in accordance with the disclosure. For example, the disclosed tablets may have a round flat face shape, a round standard concave shape, and/or an oval shape.

[0125] The disclosed tablets may be coated in any matter known in the art. In some aspects, the any of the disclosed tablets are film-coated (FCT). Any conventional film coating system, such as an enteric coat, may be used in these FCTs. In some aspects, the tablets are oral compressed tablets (OCTs), which do not have a coating.

[0126] In some aspects, methods of formulating or generating oral dosage forms comprising any of the disclosed tablets are provided. For example, disclosed herein are methods for mixing or blending a therapeutic macromolecule, any of the disclosed sodium caprate particle compositions, and one or more additional excipients into a mixture and pressing this mixture into a tablet that exhibits improved tensile strength or compactability relative to a corresponding tablet that contains commercial sodium caprate material.

Processes for Generating Medium Chain Fatty Acid Salt Agglomerates

[0127] The described processes for generating the described medium chain fatty acid salts is scalable, as it is capable of generating large volumes of solid material. In various embodiments, the disclosed processes comprises a method of producing medium chain fatty acid sodium salts, such as sodium caprate.

[0128] The disclosed spherical agglomerated crystals of sodium salt of a medium chain fatty acid were generated using the following general process: a) dissolving a medium chain fatty' acid in a first solvent to produce a first solution, wherein the first solvent is an aprotic polar solvent selected from acetonitrile, DMF, DMAC, and NMP to produce a first solution; b) adding to the first solution (i) a second solvent, wherein the second solvent is a medium chain aliphatic hydrocarbon solvent, and wherein the second solvent is selected from heptane, hexane, and octane, and (ii) a solution containing a sodium salt of a short chain alcohol to create a resulting slurry; and c) isolating the agglomerated crystals from the resulting slurry.

[0129] In a first embodiment of this process, the first solvent of the present process is acetonitrile, and the second solvent is heptane. Thus, in this embodiment is provided a process for preparing agglomerated crystals of a sodium salt of a medium chain fatty acid comprising the steps of: a) dissolving a medium chain fatty' acid in acetonitrile to produce a first solution; b) adding heptane and a solution containing a sodium salt of a short chain alcohol to the first solution to create a resulting slurry'; and c) isolating agglomerated crystals from the resulting slurry'.

[0130] In a further aspect of the first embodiment, in step b, heptane and the solution containing a sodium salt of a short chain alcohol (e.g., sodium methoxide in methanol) are added to the first solution to induce a liquid-liquid phase separation and to create a resulting slurry. In some aspects, the solution containing a sodium salt of a short chain alcohol is 15 wt% to 40 wt% sodium methoxide. In particular aspects, about 1 molar equivalent of a solution containing 15 wt% to 40 wt% sodium methoxide is added.

[0131] In a further aspect of the first embodiment, in step b. heptane and the solution containing a sodium salt of a short chain alcohol are added at a temperature below about 40°C. [0132] In a second embodiment, the instant invention is directed to a process for preparing agglomerated cry stals of sodium caprate (Product A) comprising the steps of: a) dissolving capric acid in a first solvent to produce a first solution, wherein the first solvent is acetonitrile; b) adding a second solvent and a solution containing sodium methoxide to the first solution to create a resulting slurry', wherein the second solvent is heptane; and c) isolating the agglomerated crystals of sodium caprate (Product A) from the resulting slurry.

[0133] In a further aspect of the second embodiment, the agglomerated crystals are sodium caprate. As such, a process is provided for preparing agglomerated crystals of sodium caprate (Product A) comprises the steps of: a) dissolving capric acid in acetonitrile to produce a first solution; b) adding heptane and about 0.9 to about 1.5 molar equivalent of a solution containing sodium methoxide to the first solution at a temperature below about 40°C and create a resulting slurry; and c) isolating the agglomerated crystals of sodium caprate (Product A) from the resulting slurry.

[0134] In the second embodiment, the addition of heptane induces a liquid-liquid phase separation. In some aspects, the addition of the heptane and the sodium methoxide at a temperature below about 40°C induces a liquid-liquid phase separation. In a further aspect of the first or the second embodiment, after step b, the resulting slurry is stirred for at least one hour. In some aspects, the resulting slurry is stirred for between 1 and 30 hours, 5 and 25 hours, 5 and 15 hours, 10 and 25 hours, 10 and 15 hours, 15 and 25 hours, 20 hours and 25 hours, 25 hours and 30 hours. 20 hours and 30 hours, 20 hours and 24 hours, or 21 hours and 24 hours. In some aspects, the resulting slurry is stirred for about 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 25 hours. In particular aspects, the slurry is stirred between 20 hours and 24 hours.

[0135] In a third embodiment, the process for preparing agglomerated crystals of sodium caprate (Product A) comprises the steps of: a) dissolving capric acid in 1 L/kg to 50 L/kg of acetonitrile to produce a first solution; b) adding 1.5 L/kg to 5 L/kg of heptane and about 0.94 to 1.2 molar equivalent of a solution containing about 20 wt% to about 40 wt% of sodium methoxide to the first solution to create a resulting slurry, c) stirring the resulting slurry for at least one hour; and d) filtering the resulting slurry to provide agglomerated sodium caprate crystals (Product A).

[0136] In some aspects of the above-described embodiments, the addition in step b is performed at a temperature at or below about 60 °C. In some aspects of the above-described embodiments, the addition in step b is performed at a temperature at or below about 50 °C, at or below about 45 °C, at or below about 40 °C, or at or below about 35°C. In some aspects of the above-described embodiments, the addition in step b is performed at a temperature at or below about 40 °C. In some aspects, the addition in step b is performed at about 40 °C. In some aspects, the addition in step b is performed at about 35 °C. In some aspects, the addition in step b is performed at room temperature. In some aspects, the addition in step b is performed at about 22°C to about 35 °C. In some aspects, the addition in step b is performed at about 22 °C. 23 °C, 24 °C, 25 °C, 27.5 °C, 30 °C, 32.5 °C, 35 °C, 37.5 °C, or 40 °C.

[0137] In a fourth embodiment, the process for preparing agglomerated sodium caprate cry stals comprises the steps of: a) dissolving capric acid in 4 L/kg to 8 L/kg of acetonitrile, to produce a first solution; b) adding to the first solution about 1.5 L/kg to about 2.5 L/kg of heptane and about 0.96 to 1.05 molar equivalent of a solution containing about 25 wt% to about 30 wt% sodium methoxide, over about 1.0 to about 10.0 hours, at a temperature of about 22°C to about 35 °C, with constant stirring to produce a resulting slurry; c) stirring the resulting slurry' for at least one hour, optionally between 20 hours and 24 hours; and d) filtering the resulting slurry to separate resulting solids and drying said resulting solids to provide agglomerated crystals of sodium caprate.

[0138] In any of the embodiments, within step d, after filtering the solids that result from the stirring of the slurry⁷, the resulting solids may be washed to remove any residual chemicals (e.g., residual methoxide). In some embodiments, the solids are washed with a solution containing acetonitrile and methanol. As such, in a fifth embodiment, the process for preparing agglomerated sodium caprate crystals comprises the steps of: a) dissolving capric acid in 4 L/kg to 8 L/kg of acetonitrile, to produce a first solution; b) adding to the first solution about 1.5 L/kg to about 2.5 L/kg of heptane and about 0.96 to 1.05 molar equivalent of a solution containing about 25 wt% to about 30 wt% sodium methoxide, over about 1.0 to about 10.0 hours, at a temperature of about 22°C to about 35 °C, with constant stirring to produce a resulting slurry ; c) stirring the resulting slurry between 20 hours and 24 hours; d) filtering the resulting slurry to separate resulting solids; e) washing the resulting solids with a solution containing acetonitrile and methanol; and f) drying the resulting solids to provide agglomerated cry stals of sodium caprate. [0139] For example, in step e of the fifth embodiment, the resulting solids may be washed with a solution containing 2 L/kg to 10 L/kg of acetonitrile and methanol. In some embodiments, two washes of 2 L/kg each are performed. In some embodiments, the wash solution comprises about 10: 1, 9: 1, or 8: 1 parts acetonitrile to methanol, by volume. In particular embodiments, the wash solution comprises 9 parts acetonitrile to 1 part methanol (v/v) (9: 1). In some embodiments, this washing step is omitted.

[0140] In any of the described embodiments, in step a, capric acid is dissolved in 1 L/kg to 50 L/kg of acetonitrile to produce the first solution. In any of the embodiments, capric acid is dissolved in 3 L/kg to 30 L/kg of acetonitrile to produce a first solution. In any of the embodiments, capric acid is dissolved in 6 L/kg to 30 L/kg of acetonitrile to produce a first solution. In any of the embodiments, capric acid is dissolved in 7.5 L/kg to 25 L/kg of acetonitrile to produce a first solution. In any of the embodiments, capric acid is dissolved in 10 L/kg to 25 L/kg of acetonitrile to produce a first solution. In any of the embodiments, capric acid is dissolved in 10 L/kg to 20 L/kg of acetonitrile to produce a first solution. In any of the embodiments, capric acid is dissolved in about 25 L/kg of acetonitrile to produce a first solution. In any of the embodiments, capric acid is dissolved in about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8. 8.5, 9, 10, 12, 15, 20, 25, or 30 L/kg of acetonitrile. In some aspects, 1. 2, or 3 L/kg of acetonitrile may be used. In some aspects, about 3 L/kg of acetonitrile is used.

[0141] In any of the embodiments, capric acid is dissolved in 6 L/kg to 8 L/kg of acetonitrile to produce a first solution. In some aspects, about 6.0 L/kg of acetonitrile is used. About 7.0 L/kg or 8.0 L/kg of acetonitrile may be used.

[0142] In various aspects, the solution containing a sodium salt of a short chain alcohol (e.g.. sodium methoxide) is added over about 1.0 to about 10.0 hours, at a temperature of 5 °C to 40 °C, with constant stirring. In any of the embodiments, 0.5 to 1.5 molar equivalent of a solution containing sodium methoxide is added to the first solution. In any of the embodiments, about 0.75 to about 1.5 molar equivalent of a solution containing about 15 wt% to 40 wt%. about 20 wt% to 40 wt%, about 15 wt% to 35 wt%, about 15 wt% to 30 wt%, or about 25 wt% to 30 wt%, sodium methoxide is added. In some embodiments, about 0.9 to about 1.00 molar equivalent, or about 0.93 to about 1.00 molar equivalent, of a solution containing 15 wt% to 40 wt%, or 25 wt% to 30 wt%, sodium methoxide is added. In particular embodiments, 0.97 molar equivalent of 25 wt% to 30 wt% sodium methoxide is added. In some embodiments, the solution containing a sodium salt of a short chain alcohol (e g., sodium methoxide) is added over at least 2.0 hours. In any of the embodiments, the sodium methoxide is added over about 4 to about 6 hours, with constant stirring. In some embodiments, the sodium methoxide is added over about 4 hours to about 6 hours, or about 5 to 5.5 hours, at a temperature of about 20 °C to about 30 °C. In some embodiments, the sodium methoxide is added over 4.0 hours. In some embodiments, the sodium methoxide is added over about 5 to 5.5 hours.

[0143] In any of the embodiments, the second solvent is added to the solution about 1 hour after the solution containing sodium methoxide is added in step b. In some embodiments, step b comprises adding a second solvent at a controlled rate about 1 hour after sodium methoxide is added, with constant stirring, wherein the second solvent is heptane. Step b may comprise adding 1.5 L/kg to 5.0 L/kg of heptane over 3 to 5 hours at a controlled rate, with constant stirring, about 1 hour after adding the solution containing sodium methoxide. In any of the embodiments, about

1.5 L/kg to about 2.5 L/kg of heptane is added over 3 to 5 hours at a controlled rate, with constant stirring, about 1 hour after sodium methoxide is added. In any of the embodiments, about 1.9 L/kg of heptane is added over 3 to 5 hours at a controlled rate, about an hour after sodium methoxide is added. In any of the embodiments, about 3.5 L/kg to about 4.0 L/kg of heptane is added over 3 to 5 hours at a controlled rate, with constant stirring.

[0144] In some embodiments, about 1.5 L/kg to 5.0 L/kg, 1.5 L/kg to 4 L/kg, 1.5 L/kg to 2.5 L/kg, 1.7 L/kg to 2.1 L/kg, or 3.5 L/kg to 4.0 L/kg of heptane is added over between about 1.5 and about 5 hours at a controlled rate, with constant stirring. In some embodiments, about 1.5 L/kg to 5.0 L/kg, 1.5 L/kg to 4 L/kg, 1.5 L/kg to 2.5 L/kg, or 3.5 L/kg to 4.0 L/kg of heptane is added over about 3.5 to about 4.5 hours, or over about 4.5 to about 5.5 hours, at a controlled rate, with constant stirring. In some embodiments, about 1.7 L/kg to 2.1 L/kg of heptane is added over about 3.5 to about 4.5 hours, over about 4.5 to 5 hours, or over about 4.5 to 5.5 hours. In some embodiments, about 3.7 L/kg of heptane is added over about 3.5 to about 4.5 hours, or over about

4.5 to 5 hours. In some embodiments, about 1.9, 2.0, or 2.5 L/kg of heptane is added over about

4.5 to 5 hours.

[0145] In a further aspect of the fourth embodiment, in step c, the heptane is added over about

3.5 to about 4.5 hours at a controlled rate, with constant stirring.

[0146] In some embodiments, the second solvent (e.g., heptane) is added to the solution less than 1 hour after adding the solution containing sodium methoxide. In some embodiments, the second solvent (e.g., heptane) is added to the solution about 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 40 minutes, 50 minutes, or 55 minutes after adding the solution containing sodium methoxide. In some embodiments, the second solvent is added to the solution approximately simultaneously with the solution containing sodium methoxide.

[0147] The process of the present invention allows for the direct crystallization of agglomerated, crystalline particles of medium chain fatty acid sodium salts, such as sodium caprate. This process avoids the formation of gels and other undesirable processing challenges typically seen with the manufacture of sodium caprate. The instant invention for crystallization of this kind of compound leverages particle agglomeration induced by liquid-liquid phase separation. The disclosed processes may be used to generate commercial-scale amounts of agglomerated particles of medium chain fatty acid sodium salts, such as sodium caprate. For instance, the disclosed processes may be used to generate weights of sodium caprate that include about 0.5 kg (Example 2A), 1.0 kg (Example 2B), 50 kg, 100 kg, 150 kg, 200 kg, 250 kg, 300 kg, 340 kg, 350 kg, 360 kg, 375 kg, 390 kg, or 400 kg in a single batch. The disclosed processes may be used to generate weights of sodium caprate in two or more batches that include about 800 kg, 900 kg, 1000 kg, or 1100 kg (or 1. 1 metric tons).

[0148] Any of the disclosed processes may be modified in accordance with knowledge in the art to incorporate wet granulation, dry granulation, or roller compaction manufacturing process trains.

[0149] Methods for preparing the agglomerated crystals of a sodium salt of a medium chain fatty acid, particularly crystals of sodium caprate, are illustrated in the following Schemes and Examples. Starting materials are made according to procedures known in the art or as illustrated herein. The following abbreviations are used herein:

DMAC dimethylacetamide

DMF dimethylformamide

DSC Differential Scanning Calorimeter

FID Flame Ionization Detector

GC Gas Chromatography

GMP Good Manufacturing Procedures

IPA Isopropyl Alcohol

LOQ Limit of Quantitation

Me methyl

MeCN acetonitrile

MeOH methanol

NMP n-methyl-2-pyrrolidone

RI Refractive Index rt room temperature

TGA Thermogravimetric analysis v/v volume/volume

XRPD X-ray Powder Diffraction

[0150] In some cases, the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.

EXAMPLES [0151] The following examples are meant to be illustrative and should not be construed as further limiting. The contents of the figures and all references, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference.

EXAMPLE 1A

Sodium caprate (3)

[0152] Capric acid (1) (10 g, 58.5 mmol) and acetonitrile (10 ml) were combined in an appropriate vessel with a suitable agitator. The batch was stirred at 40 °C until complete dissolution was achieved. Sodium methoxide (2) (3.17 g, 58.5 mmol) was added as a 30 wt% solution in methanol (10.57 g) over a period of 5.5 hours under vigorous agitation, forming a si rn Simultaneously to the addition of (2), heptane (15.15 ml) was concurrently added over a period of 5 hours using a separate feed line. The resulting slurry' was stirred for an additional 24 hours. Solids were filtered, washed with a solution of acetonitrile:methanol (9: 1 by volume), 20 ml twice, then dried under vacuum with a nitrogen sweep at 35-40 °C to afford crystalline sodium caprate (3, Product A) (9,48 g, 83 % yield). FIG. 20 depicts material made using this procedure.

[0153] The manufacturing process train for all studied blends and formulations was direct compression. For oral tablet formulations containing sodium caprate mixtures containing an additional component (i.e., a binary' mixture containing a therapeutic peptide, or a ternary' mixture containing a therapeutic peptide and lubricant) the materials were blended in a suitable blender and subsequently compressed using standard tableting equipment.

Compression Performance

[0154] Sodium caprate powder samples and formulations containing sodium caprate samples were compressed into cylindrical compacts using a single-station compaction simulator. Samples were compressed into compact using a 9.525 mm round flat-face tablet press tooling using a range of compression pressures between 10 and 400 MPa. Compaction simulation of the formulations were performed under force control. Combined punch velocities were ranged between 50 and 100 mm/s. Weight (W), thickness (h), diameter (D) and hardness (B) of the resulting compacts were measured. Hardness is defined as the peak force needed to fracture the cylindrical compact. Compact weights were controlled between 225 and 375 mg. The resulting values for thickness and hardness were used to compute the tablet tensile strength (T) using Equation X. The resulting tablet tensile strength and compression pressures are combined into a tabletability curve.

T = — -

TtllD Equation X

[0155] Table 1 shows the general (platform) composition of tested example commercial tablet formulations containing sodium caprate products. These formulations contain a disintegrant, a glidant, a magnesium stearate lubricant, lactose and microcrystalline cellulose. Four of these formulations contained commercially available sodium caprate lots, and one used Agglomerated Material Product A. Commercial Material 1 is sodium caprate material sold by (and acquired from) Pfaltz & Bauer Inc. Commercial Material 2 is sodium caprate sold by (and acquired from) BioSpectra Inc. (BSI). Commercial Material 3 is sodium caprate sold by TCI Chemicals (TCI America). And Commercial Material 4 is sodium caprate sold by Jost Chemical.

Table 1. Composition of Formulated Products Containing Sodium Caprate from Different Sources

[0156] The plot in Figure 1 shows the compaction profiles results of the five formulations. These results show that Product A (solid circles) had superior performance when compared to all tested commercial materials. Figure 1 reflects the tensile strength of a tablet formulated with sources of sodium caprate (including Product A). The image shows that the materials produced with Product A (depicted as solid circles) yielded the toughest material within a relevant processing range of compression pressures. The in-die powder bulk densities of these five formulations were estimated using the compact mass and the fill die-volume before compression. The in-die bulk density for Formulation containing Commercial Material 2 w as the lowest of all tested materials, nominally 0.39 g/mL. The in-die bulk density of the remaining four formulations ranged between 0.44 and 0.47 g/mL. All observed in-die bulk densities show acceptable values for processing these blends through tableting. [0157] FIGs. 2A and 2B show the compression performance of tablets containing 100% Product A, Commercial Material 2 (sodium caprate acquired from BSI), Commercial Material 3 (sodium caprate from TCI Chemicals), and Commercial Material 4 (sodium caprate from Jost), in the absence of compression aids. FIG. 2A shows that product A (depicted as solid circles) has excellent strength development by itself, as reflected by the substantially high tensile strength. For instance, tensile strengths of between 1.9 MPa and 2.1 MPa were reached at compressive stress measurements of between 40 MPa and 80 MPa. In the case of Commercial Material 2 (depicted as crosses) it was not possible to produce compacts that did not break upon ejection. In the case of Commercial Material 3 (depicted as empty squares) and Commercial Material 4 (depicted as empty triangles), it was possible to produce tablets with low strength, but these tablets were not amenable for further processing.

[0158] As shown in FIG. 2B, 100% Product A tablets exhibited a maximum tensile strength of about 2.1 MPa at about 1.03 g/mL tablet density . In all instances, tablets generated with Product A exhibited higher strengths than corresponding tablets generated with Commercial Materials 3 and 4 at equivalent macroscopic porosity (e.g., density). This indicates that, even though all the tablets w ere generated to have the same porosity, the local particle-to-particle contacts in Product A are driving significantly higher tablet strength.

[0159] In combination, the results from FIGs. 1. 2A and 2B indicate that Product A yields superior physical strength and toughness of compacts (i.e., tablets). Tablets containing Product A exhibit higher tensile strength and thus allow for better downstream processing and improved phy sical robustness. In addition, the excellent strength development shown by Product A makes it more amenable for manufacture of tablets requiring a dry granulation process.

[0160] Tablets of different shapes and sizes were manufactured using materials from product A. 100% sodium caprate tablets (which may be referred to herein as ‘'neat” or ‘'single-entity” caprate tablets) ranging in weights between 200 and 800 mg w ere generated. Tablets with round flat face, round standard concave, and oval shapes were successfully manufactured.

Flowability

[0161] The flow properties of Product A and sodium caprate materials from different commercial sources were compared using bulk and tapped (tap) density measurements. Bulk and tap densities refer to the density with which the pow der packs onto itself. Low densities are a sign of material that will not flow or pack well. The Carr’s Index and Hausner Ratio are indices calculated using bulk and tapped density. For example, Hausner Ratio is calculated as tap density divided by bulk density. Low values for both indices suggest excellent flow properties. Bulk densities were measured using a lOOmL graduated cylinder and no less than 50 of powder material. Powder material was dispensed into the graduated cylinder and both the mass and volume of material were recorded. Calculating the ratio of mass and volume yielded the resulting bulk density of the powder. The graduated cylinder was then tapped for 1,250 events using a Tapped Density apparatus following U.S. Pharmacopoeia (USP) <661>. The resulting volume of the material was then used to compute the resulting tapped density value. Small-scale batches of Product A (in the amount of about 1 kg) were analyzed in this experiment.

[0162] Table 2 reports the bulk and tap densities of the material and the calculated Carr’s Index and Hausner Ratio. As shown in Table 2, both the Carr's Index and Hausner Ratio for Product A are significantly lower than those of Commercial Materials 1-4. indicating that Product A exhibits superior powder flowability. In spite of its low density, the agglomerated crystalline sodium caprate material provided herein has excellent flow properties, which are reflected by its low Carr’s Index and Hausner Ratio.

Table 2. Flowability Measurements of Sodium Caprate from Different Sources

[0163] Next, the flow properties of commercial-scale batches of Product A were compared using bulk and tap density measurements. Bulk and tap densities were evaluated for ten batches of Product A that were manufactured under GMP conditions, wherein each batch contained betw een 60 and 543 kilograms (theoretical) of material. The bulk density w as measured using a 10 mL graduated cylinder and no less than 6 mL of pow der material. The powder material was dispensed into the graduated cylinder and both the mass and volume of material were recorded. The graduated cylinder was then tapped for 2,500 events using a Tapped Density apparatus following US Pharmacopeia (USP) <661>. Table 3 reports the flowability indices for these batches of material. [0164] As shown, commercial-scale batches of the provided sodium caprate material exhibited tap densities greater than 0.50 g/mL, many of them greater than 0.55 g/mL. A tap density' of 0.69 g/mL was reached in the 001L021 batch. Batches that performed best during compression pressure experiments (see below) exhibited a tap density' in the range of 0.50 to 0.69 g/mL. Thus, the commercial scale batches exhibit substantially higher densities than those of the small-scale batches reported in Table 2. The Hausner Ratios of these ten batches were, in the main, less than 1.60 — and reached as low as 1.35. These results further support that Product A has excellent powder flowability properties.

Table 3. Flowability Measurements of larger batches of Product A

[0165] FIG. 17 shows SEM images of sodium caprate from Commercial Materials 1-4, providing a comparison of their respective morphologies. The method of preparation for this compound has significant impact on the structure and physical appearance of the material. Commercial Material 2 (sodium caprate from BSI) was smooth spheres, made through spraydrying. Commercial Material 3 (sodium caprate from TCI Chemical) and Commercial Material 4 (sodium caprate from Jost) were large elongated, thin plates. Product A constituted an agglomerated solid, with a rough surface area and no elongation in any axis. The disclosed processes enables this unique morphology' of Product A, which is amenable to, or suitable for, manufacturing and handling in standard equipment and has desirable properties for formulation manufacturing.

Impact of material attributes (SSA and D90): [0166] The particle size of Product A was measured by laser diffraction (Malvern Mastersizer 3000, Malvern Instruments Ltd. UK) using the AeroS dry dispersion unit at a feed pressure of 3 bar and feed rate of 40%. Samples were analyzed in triplicate with obscuration values between 1% and 10%. Specific surface area (SSA) of the sodium caprate solid samples was determined by gas adsorption-BET method (Tristar II Plus. Micromeritics) using nitrogen. Prior to the measurement, the samples were degassed under nitrogen at 35 °C for 1-2 hours.

[0167] Compression behavior for multiple batches of Product A having SSA values ranging between 9.9 m²/g to 36.7 m²/g and particle size distributions with D90 ranging from 289 pm to 863 pm were evaluated. FIG. 3 shows the compression behavior of Product A from four commercial-scale batches. In all cases, tablets with tensile strength of 1 MPa or higher are produced. As shown, a tensile strength of about 2.1 MPa was achieved in Example Nos. 1, 2 and 3 at compressive stresses between 80 MPa and 130 MPa. The Example No. 2 batch reached a strength of about 2.15 MPa at a compressive stress of 95 MPa. Table 4 provides the batch numbers and reports the SSA and D90 values for the four Examples listed in the legend of FIG. 3.

Table 4. Material Attributes of Commercial-Scale Caprate Batches

[0168] Error! Reference source not found.FIG. 4 shows tensile strength of tablets without compression aids containing Product A manufactured utilizing compressive stresses in the range of 30 MPa to 50 MPa, as a function of D90. Here, it was seen that tensile strength decreases with D90.

[0169] Table 5 provides a comparison indicating that Product A has higher SSA compared to commercial material 2 and commercial material 4. The SSA for Product A is at least 3.8-fold higher compared to commercial materials 2 and 4. This high SSA values for the particle size range of Product A reflected in this table are a reflection of the porous structure produced through the process for preparing agglomerated crystals in accordance with the invention. FIG 5 show s the tensile strengths of sodium caprate tablets manufactured utilizing compressive stresses in the range of 30 MPa to 50 MPa as a function of SSA. This data indicates that tensile strength of the tablets increases as SSA of Sodium Caprate increases. [0170] The results from FIG. 5 indicate that Product A yields superior physical strength and toughness of the compacts due to higher SSA. Tablets containing Product A with SSA greater than 13 m²/g (5-fold higher than commercial materials 2 and 4) exhibit tensile strength of 1 MPa or higher (5.8-fold to 11.7-fold higher compared to commercial material 4 (Jost)) and thus allow for better downstream processing and improved physical robustness.

Table 5. Specific surface area of sodium caprate Agglomerated Material (Product A), in comparison with commercially available forms of crystalline sodium caprate

[0171] Without being bound by any particular theory, the improved tensile strengths observed for tablets containing Product A compared with tablets containing commercially available sodium caprates is linked to the high SSA of the agglomerated particles, in part due to their internal porosity. Higher SSA enables greater degree of plastic deformation during the powder compaction and increased strength development. This theory is supported by the results of the plastic work of compaction evaluations, as described below.

[0172] Notwithstanding this theory, it is hypothesized that a higher SSA, spherical agglomerated morphology, medium-size particle distribution, and/or superior powder flowability together contribute to the observed enhanced tensile strength.

Plastic work of compaction

[0173] Plastic work of compaction is a measure of how much irreversible work is performed during the compression process. The values reported in Table 2 are normalized by the tablet mass and are shown in units of Joules per gram of material compacted. The plastic work of compaction indicates how much energy goes into the system, which is responsible for plastic deformation of particles, breaking of particles thus creating new surfaces, and the generation of heat. High values of plastic work of compaction indicate that as the powder undergoes compression there is significant particle deformation, rearrangement, and breakage. Consequently, materials which exhibit higher plastic work of compaction tend to show greater robustness.

[0174] Results in Table 6 show that the plastic work of compaction for Product A is 2.3-fold higher compared to Commercial Material 4. These results indicate that tablets produced with product A without compression aids exhibit higher robustness.

Table 6. Plastic work of compaction for Agglomerated Material (Product A) in comparison to commercially available sodium caprate

Friability' and Tensile Strength Evaluations with High-Concentration Caprate Tablets

90/10 formulation example

[0175] Sodium caprate (Product A) powder samples were blended with lactose monohydrate to produce blends as described in Table 7. Blends were compressed into cylindrical compacts using a 9.525 mm round flat-face tablet press tooling using a range of compression pressures (stresses) between 6 and 180 MPa under force control and controlled weight between 225 and 375mg. Weight, thickness, diameter, and hardness for compacts were measured and tensile strength was computed as described above.

[0176] FIGs. 6 and 7 show the tabletability and compressibility of these blends containing 90% Product A, Commercial Material 2, and Commercial Material 4. Consistent with the observations of the neat material, blends containing 90% Product A exhibit vastly superior strength development compared to those comprised of Commercial Material 2 or Commercial Material 4. Based on these data, tablets were produced using 7. 144 mm standard round concave tooling at a controlled weight between 150 and 250 mg. Compression pressures for each blend were selected to maintain similar tablet densities of approximately 1.0 g/rnL. Friability testing was then performed upon the tablets, with friable losses measured after 100, 200 and 500 revolutions, as shown in FIG. 8. These data indicate superior robustness for tablets comprised of 90% Product A compared to those comprised of 90% of Commercial Material 2 or Commercial Material 4. The latter two tablets containing commercial materials failed friability' criteria as set forth in USP <1216>.

Table 71. Composition of Formulated Products Containing Sodium Caprate from Different Sources

80/20 formulations example

[0177] Sodium caprate (Product A) powder samples were blended with microcry stalline cellulose, lactose monohydrate, and HPMC (Hypromellose) to produce blends as described in Table 8. Blends were compressed into cylindrical compacts using a 10 mm round flat-face tablet press tooling using a range of compression pressures between 35 and 200 MPa and a controlled weight between 275 and 375 mg. Weight, thickness, diameter, and hardness for compacts were measured and tensile strength was computed as described above.

[0178] FIG. 10 shows the tabletability of these blends containing 80% Product A. Tablet strength development is consistent with the data generated from the 100% Product A and 90% Product A dosage forms, as illustrated in FIGs. 3 and 6, respectively. The data in the figure suggests the suitability of formulating with excipients having different material properties (such as MCC and lactose), where those excipients can serve other functional purposes and not as compression aids.

Table 82. Composition of Formulated Products Containing Sodium Caprate and Different Excipients

Further Evaluations of the Role of Lactose

[0179] In an effort to further understand the role of lactose in the disclosed oral tablets, sodium caprate (Product A) powder was blended with lactose monohydrate in different amounts (w/w) to produce blends as described in Table 9. Blends were compressed into cylindrical compacts using a 10 mm round flat-face tablet press tooling using a range of compression pressures between 35 and 150 MPa and a controlled weight between 275 and 375 mg. Weight, thickness, diameter, and hardness for compacts were measured and tensile strength was calculated as described above.

[0180] FIG. 11 shows the tabletability of these blends containing Product A and differing amounts of lactose. These data demonstrate that under compression conditions commensurate with those of the other examples, increasing the sodium caprate concentration results in improved tablet strength development. Therefore, in these dosage forms. Product A is more integral to the mechanical strength and integrity of the formulation than lactose, which thus does not serve the function of a compression aid. Table 9. Composition of Formulated Products Containing Sodium Caprate and Different Levels of Lactose

Film Coated Tablets

[0181] Sodium caprate powder (Product A) was successfully compressed into round bi-convex compacts using a rotary tablet press in a direct compression process. Product A was compressed into compact using a 9.525 mm round standard concave tablet press tooling. A range of compression pressures between 40 and 270 MPa were evaluated during the manufacturing campaign. The target weight of the compacts was 250 mg tablets. Weight, thickness, diameter, and hardness for compacts were measured and tensile strength was computed as described above. Tablets displayed good tabletability with average tensile strengths ranging between 1.6 and 1.8 MPa. Tablet production throughputs ranged between 4,800 and 14,400 tablets per hour. Neat sodium caprate tablets were film coated with enteric and non-enteric film coat systems. Three film coat compositions were evaluated: a non-enteric film coat as a seal coat, an enteric film coat, and a combination of the two film coat systems. The composition of the evaluated coats and composition are shown in Table 10.

Table 10. Composition of Film Coated Tablets of Neat Sodium Caprate

Evaluation of Compaction Parameters for Batches of Product A

[0182] Several compaction performance parameters, including SSA, PSD, bulk density (BD), and tap density (TD), of 14 exemplary batches of Product A material were determined using the methods described above (supra at paragraphs [ 163] -[164]). Each of these samples were compacted into a neat (100% Product A) tablet, and the tensile strength (TS) under a compressive stress of 80 MPa of each resulting tablet was evaluated. [0183] Bulk densities were measured using a 10 mL graduated cylinder with at least 60% fill volume. The mass and volume of the material were recorded, and the ratio of mass and volume yielded the material’s bulk density. The graduated cylinder was then tapped for 2,000 events using a tap density apparatus. The resulting volume was subsequently used to determine the material’s tap density.

[0184] The compaction performance parameters of each of the sample batches are listed in Table 11 in order of increasing SSA.

Table 11. Compaction performance assessments of exemplary batch samples

[0185] Batch samples listed in Table 11 that yielded compacts exhibiting tensile strength values above 1.3 were featured. Among these 13 samples (Nos. 2-14), SSA values ranging from -5.9 m²/g (Sample 2) to as high as ~41 m²/g (Sample 14) were observed. The D90 values of these samples ranged from -158 pm (Sample 6) to as high as 657 pm (Sample 9). The BD values for the samples ranged from 0. 15 g/mL (Sample 6) to 0.40 g/mL (Samples 2 and 4). The TD values for the samples ranged from 0.32 g/mL (Sample 13) to 0.54 g/mL (Samples 2 and 4). The Hausner Ratio values for the samples ranged from 1.30 (Sample 9) to 2.20 (Sample 6). This data suggests that compositions comprising crystalline sodium caprate particles, wherein the sodium caprate particles exhibit a mean SSA of between 5.9 m²/g (and preferably between 9.6 m²/g) and 41 m²/g, a tap density of at least 0.32 g/mL. and a D90 of between 158 pm and 657 pm generates tablets having excellent compaction performance.

[0186] Each of the 14 samples listed in Table 11 were successfully compacted and were identified to have tensile strength ranging from 1.27 MPa (Sample 1) to 2.27 MPa (Sample 11). Each exhibited a spherical agglomerate morphology.

EXAMPLE IB

X-ray Powder Diffraction (XRPD)

[0187] X-ray Powder Diffraction (XRPD) data, as seen in FIG. 1. were acquired on a Panalaytical X-Pert configured in the Bragg-Brentano configuration and equipped with a Cu radiation source with monochromatization to Ka achieved using a Nickel filter. A fixed slit optical configuration was employed for data acquisition. Data were acquired between 2 and 40° 29. Samples were prepared by gently pressing the sample onto a zero background silicon holder. All samples presented in FIG. 12 were obtained in this manner, for comparisons of material made within the disclosed processes and commercial material.

[0188] FIG. 12 depicts the XRPD pattern for Product A and shows a stacked comparison with the XPRD patterns of commercially available alternatives of sodium caprate (such as those obtained from Jost and BSI) made by different processes. This figure demonstrates there are differences in the intensity of the reflections, indicating that the preferred phases generated vary, but the overall “fingerprint” of the crystal patterns is the same. The disclosed processes generated sodium caprate cry stals with a vastly different morphology than commercially available embodiments made by more costly procedures.

Differential Scanning Calorimeter (DSC)

[0189] A TA Instruments Discovery⁷ Differential Scanning Calorimeter (DSC) was used to monitor the thermal events as a function of temperature increase. Samples of Product A (2-5 mg) in closed non-hermetic aluminum pans with 2-pinholes were cycled twice from 10 to 300°C at a heating rate of 10°C/min.

[0190] The image of FIG. 21 shows two heat cycles and one cooling cycle performed on the sodium caprate material from room temperature up to 300 °C. The down-facing peaks are endotherms, showing that the material is absorbing heat, which suggests a change in the crystal/solid state, or a phase change (e.g., melting or boiling). The curve on the top is what happens to the same sample as it is cooling. During cooling, there are upward peaks (exotherms, where heat is released). These are the reversals of the physical phenomena that took place during the heating. The presence of a hysteresis between the onset and reversal temperatures typically occurs due to differences in kinetic barriers between the forward and backward processes. The width of the hysteresis is usually dependent on the rate at which the temperature is being changed during the DSC scan. There are two heating curves (below zero in the y axis) overlay ed in FIG. 21. The overlap of the two lines demonstrates that the changes experienced by Product A during the experiment were reversible and Product A was not destroyed during the scan. The change in width of the first downward peaks between the two heating curves is related to the presence of some absorbed w ater in the initial scan. The DSC pattern can be used as a characterization technique because the position and area of the peaks, and the overall shape of the scan are specific to sodium caprate.

Residual Solvent by Gas Chromatography (GO

[0191] Standard Preparation: By serial dilution prepare a 0.01% v/v standard of n-heptane, methanol and acetonitrile in diluent for quantitation and a 0.001% v/v Limit of Quantitation (LOQ) for limit reporting.

[0192] Sample Preparation: ~20 mg/mL sample dissolved in diluent. Vortex and sonicate as needed to dissolve sample.

Instrument Conditions:

[0193] Results of this GC evaluation are shown in the below table:

LOQ (limit of quantitation): 393 ppm for acetonitrile

Thermogravimetric analysis

[0194] Thermogravimetric analysis (TGA) of Product A was carried out on a TA Q 500 Thermogravimetric Analyzer (TA Instrument). Samples (5-15 mg) in were heated from 25 to 320°C at 10°C/min, with a nitrogen purge of 200 mL/min. As seen in FIG. 14, the curve at the top of FIG. 14 monitored the change in mass of Product A as it was heated under a nitrogen atmosphere. The gentle mass loss (0.8 wt%) in the first 250 °C matched well with the expected absorbed surface water in the material. The onset of a drop-off after 250 °C indicated the beginning of decomposition or evaporation. The curve at the bottom of the graph corresponds to the derivative of the change in mass, capturing the rate of change of the top curve.

Particle Size Analysis bv Microtrac FlowSync

[0195] Approximately 50 mg powder sample was transferred into a 20 mL scintillation vial and

5 rnL of IsoparG/0.25 %w/v lecithin fluid was added into the vial followed by gentle shaking to disperse the particles. After instrument initialization and background measurement (30 seconds), the suspension was poured into the flow cell unit. The vial was triple-rinsed with 1 rnL of IsoparG/0.25 %Lecithin fluid (total 3 mL) and all the rinsate was poured into the FlowSync. Measurement parameters included volume distribution, geometric 8 root progression between 0.0215 and 2000 pm, residuals disabled, standard filter enabled, particle RI = 1.51: irregular shape; fluid RI = 1.42, flow 60%. Particle size distributions were calculated as the average of three 30 second scans. The results were reported as volume distributions. Samples were analyzed without sonication. 30 seconds, 60 seconds and 90 seconds sonication powder of 25%. The instrument make and model is Microtrac, M5001-3L Sync +FlowSync.

[0196] Sonication is a standard laboratory technique in which vibrational energy is applied to the powder to help disperse lumps within the material and ensure that the particle size measurements capture the true size of the product particles. Lumping is commonly observed for dry solids due to natural adhesion and can skew measurements to overestimate the size of powder particles, thus inducing sufficient sonication can be important for analytical accuracy. FIG. 15 shows a representative volume-weighted particle size distribution results for a small-scale batch of Product A. The curves show the probability density' of a particle of the product to have a radius of the size specified in the x-axis. The curves also show the impact of sonication on the measured particle size. The reduction and normalization of particle size with increased sonication was typical behavior that showed de-agglomeration of the dry solids towards the '‘true” distribution of primary particles, which was best captured by the curves labelled for 60 s and 90 s. FIG. 15 shows that the particle size distribution is the same at 60 s and 90 s of sonication, indicating that samples of this material need at least 60 s for adequate measurement.

[0197] FIG. 15 also demonstrates how the disclosed processes generated primary particles with a unimodal normal size distribution, which are desirable for manufacturing processes. Unimodal distributions are desirable since they indicate uniformity of the particles, with minimal fines or large agglomerates, which would lead to uneven flow, filtration, and compression behavior. Uniform distributions are also an indication of proper control during the crystallization and agglomeration processes, since they provide evidence that undesirable particle-generating phenomena, such as attrition, are not taking place, and the overall particle size and morphology are set by the controlled variables manipulated during batch design.

Scanning Electron Microscope (SEM) Images

[0198] Sodium caprate powder samples were mounted on SEM stubs (32 mm) using a carbon sticky. The samples were sputter coated with platinum. The samples were loaded into the Hitachi TM3030 Tabletop Scanning Electron Microscope. The samples were imaged in high vacuum mode and images were acquired using the secondary electron (SE) detector. The voltage was set to 2 kV and the Spot Intensity was set to 30 (unities). Images were acquired at several magnifications.

[0199] Imaging in FIG. 16 demonstrated the morphology of Product A can exist as well- defined agglomerated plate-like primary particles. Such a morphology is extremely difficult to achieve without spray drying and is desirable over elongated plates or needles. The demonstrated morphology' reflects superior compression performance in manufacturing procedures and dosage forms that contain Product A.

[0200] The particle morphology of commercial-scale sodium caprate batches was visualized by a Hitachi SU5000 SEM. Powder samples were mounted on SEM stubs using adhesive carbon tape and sputter coated with platinum before imaging. The particle imaging was performed using an acceleration voltage of 3kV and a secondary electron detector.

[0201] FIGs. 9A-9C show representative SEM images acquired for sodium caprate sourced from (A) Commercial Material 2, (B) Commercial Material 4 and (C) Product A (agglomerated material). Particle morphology' of Commercial Material 2 is characteristic of spray-dried material, with spherical shaped particles having a smooth surface, while that of Commercial Material 4 has flat, irregularly shaped larger particles. The morphology of Product A is a combination of spherical to irregularly shaped porous agglomerates as shown in FIG. 9D, with SSAs between 9.9 m²/g and 36.7 m²/g.

EXAMPLE 2A

Sodium caprate (3)

[0202] Capric acid (1) (25 g. 145 mmol) and acetonitrile (630 ml) were combined in an appropriate vessel with a suitable agitator. The batch was stirred at room temperature until complete dissolution was achieved. Sodium methoxide (2) (8.23 g, 152 mmol) was added as a 25 wt% solution in methanol (32.92 g) over a period of 5 hours under vigorous agitation, forming a slurry. After the first hour of the addition of (2) had elapsed, heptane (93-103 ml) was concurrently added over a period of four hours using a separate feed line. The resulting slurry was stirred for an additional hour. Solids were filtered, washed with acetonitrile (100 ml twice), then dried under vacuum with a nitrogen sweep at 35-40 °C to afford crystalline sodium caprate (3, Product A) (27.79 g, 99 % yield).

EXAMPLE 2B

Na⁺ Sodium caprate (3)

[0203] Capric acid (1) (1.00 kg, 5.81 mol) and acetonitrile (6.0 L) were combined in an appropriate vessel with a suitable agitator. The batch was stirred at room temperature until complete dissolution was achieved. Sodium methoxide (2) (0.304 g, 5.63 mol) was added as a 30 wt% solution in methanol (1.01 kg) over a period of 5.5 hours under vigorous agitation. Starting simultaneously with the addition of (2), heptane (1.9 L) was concurrently added over a period of 5 hours using a separate feed line. The resulting slurry' was stirred for an additional 24 hours. Solids were fdtered, washed with a solution of acetonitrile:methanol (9: 1 by volume), 2 L twice, then dried under vacuum with a nitrogen sweep at 35-40 °C to afford crystalline sodium caprate (3, Product A) (1.09 kg, 97 % yield). Photographs of the slurry and isolated sodium caprate crystalline material generated using this procedure is shown in FIG. 21. A 1.0 kg scale of product was generated.

EXAMPLE 2C

O

Na⁺ Sodium caprate (3)

[0204] Capric acid (1) (5.02 g, 29. 1 mmol) and acetonitrile (30 ml) were combined in an appropriate vessel with a suitable agitator, a homogeneous solution develops. Charged sodium methoxide (2) (28.3 mmol) as a 30 wt% solution in methanol over a period of 5 hours under vigorous agitation, forming a slurry. Starting simultaneously with the addition of (2), hexane (10.54 ml) was concurrently added over a period of 5 hours using a separate feed line. The resulting slurry was stirred for an additional 17 hours. Solids were then filtered, washed with a solution of acetonitrile: methanol (9: 1 by volume). 15 ml twice, then dried under vacuum with a nitrogen overhead sweep at 40 °C to afford crystalline sodium caprate (3, Product A) (5.24 g, 93 % yield). FIG. 19 depicts material generated using this procedure.

EXAMPLE 2D

Sodium caprate (3)

[0205] Capric acid (1) (5 g, 29 mmol) and acetonitrile (10 ml) were combined in an appropriate vessel with a suitable agitator. The batch was stirred at 35 °C until complete dissolution was achieved. Sodium methoxide (2) (1.55 g, 29 mmol) was added as a 30 wt% solution in methanol (5.18 g) over a period of 5.5 hours under vigorous agitation, forming a slurry. Simultaneously to the addition of (2), heptane (7.4 ml) was concurrently added over a period of 5 hours using a separate feed line. The resulting slurry was stirred for an additional 15 hours. After the age, an additional 1 ml of heptane was added and the batch heated to 40 °C. The slurry was aged for an additional 3 hours. Solids were fdtered, washed with acetonitrile (10 ml twice), then dried under vacuum with a nitrogen sweep at 35-40 °C to afford crystalline sodium caprate (3, Product A) (4.1 g, 74 % yield). FIG. 20 depicts material made using this procedure.

EXAMPLE 2E

[0206] Sodium caprate (3) (77 mg, 0.40 mmol) and dimethylacetamide (DMAc) (1 ml) were combined in a 4 mL vial to form a slurry. Charged n-heptane (0.3 mL) to the vial, forming a slurry of agglomerated particles. A light microscope image depicting these particles is shown in FIG. 10, top panel.

[0207] Sodium caprate (3) (78 mg, 0.40 mmol) and dimethylformamide (DMF) (1 ml) were combined in a 4 mL vial to form a slurry. Charged n-heptane (0.2 mL) to the vial, forming a slurry of agglomerated particles.

[0208] Sodium caprate (3) (88 mg, 0.45 mmol) and n-methyl-2-pyrrolidone (NMP) (1 ml) were combined in a 4 mL vial to form a slurry. Charged n-heptane (0.2 mL) to the vial, forming a slurry of agglomerated particles. A light microscope image depicting these particles is show n in FIG. 18, bottom panel.

[0209] Each of DMAc. DMF, and NMP are polar aprotic solvents. As underscored by the images shown in FIG. 18, a combination of sodium caprate w ith heptane and a polar aprotic solvent yields agglomerated crystalline sodium caprate product. As such, any of several polar aprotic solvents may be used in the disclosed process of manufacturing sodium caprate agglomerates.

EXAMPLE 3: Sodium pelargonate (C9) Material

[0210] Provided herein are agglomerated crystalline particles of sodium pelargonate, and powder materials comprising these particles. These particles exhibit superior flowability and/or compression properties. These sodium pelargonate particles exhibit a morphology that comprises spherical agglomerates. They may have a morphology characterized by spherical and irregularly shaped agglomerates, and/or porous. These sodium pelargonate particles may exhibit an SSA that is surprisingly an order of magnitude higher than commercially available sodium pelargonate materials. These particles may exhibit a D90 of 900 pm or less.

[0211] In some aspects, any of the disclosed sodium pelargonate particles are combined with a therapeutic macromolecule to form a mixture. This mixture may be formulated into an oral dosage form, such as an oral tablet for administration to a subject (e.g.. a human subject) to treat or prevent a disease, disorder, or condition. Thus, provided herein are oral tablets comprising a therapeutic macromolecule and sodium pelargonate. These oral tablets may not require a compression aid, by virtue of the improved compression behavior of the particles.

[0212] As such, provided herein are oral tablets comprising a therapeutic macromolecule and sodium pelargonate, wherein the tablet is substantially free of a compression aid, and wherein the therapeutic macromolecule exhibits a low Papp (e.g., a Papp of less than 10 x 10'⁸ cm/s). The therapeutic macromolecule may comprise a macrocyclic peptide. The therapeutic macromolecule may be the compound of Formula I.

[0213] In some embodiments, the tablet exhibits a tensile strength that is 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold higher than the tensile strength of a corresponding tablet comprising commercial sodium pelargonate. In some aspect, the tablet comprises between about 80 and 99% sodium pelargonate, or between about 80% and 90% sodium pelargonate (w/w). In some embodiments, the tablet exhibits a tensile strength of 1 MPa. 1.1 MPa. 1.2 MPa. 1.25 MPa, 1.4 MPa, 1.5 MPa, 1.75 MPa, 1.9 MPa, 2 MPa, 2. 1 MPa, 2. 15 MPa, 2.25 MPa. 2.5 MPa. or above 2.5 MPa. In some embodiments, the tablet exhibits a tensile strength of at least 1.3 MPa, or at least 1.4 MPa. In some embodiments, the tablet exhibits a tensile strength of at least about 1.4 MPa, 1.55 MPa, 1.65 MPa, 1.7 MPa, 1.77 MPa, 1.8 MPa, 1.9 MPa, 2.0 MPa, 2.1 MPa, 2.2 MPa, 2.25 MPa, or 2.3 MPa. In some embodiments, the disclosed tablets comprising sodium pelargonate comprise additional excipients. For example, the disclosed tablets may comprise magnesium stearate, lactose, mannitol, HPMC, and/or MCC.

Preparation of sodium pelargonate

[0214] Pelargonic acid (4) (2.51 g. 15.9 mmol) and acetonitrile (63.5 ml) were combined in an appropriate vessel with a suitable agitator, resulting in a homogeneous solution. The solution was charged with sodium methoxide (2) (15.9 mmol) as a 25 wt% solution in methanol over a period of 5 hours under vigorous agitation, forming a slurry. After the first hour of the addition of (2) had elapsed, the solution was charged with heptane (9.3 ml) concurrently over a period of four hours. The slurry was stirred for an additional hour. Solids were filtered, washed with acetonitrile (15 ml twice), then dried under vacuum with a nitrogen sweep at 35-40 °C to afford sodium pelargonate (5) (2.68 g, 94 % yield).

[0215] Sodium pelargonate powder samples were mounted on SEM stubs (32 mm) using a carbon sticky. The samples were sputter coated with platinum. The samples were loaded into the Hitachi TM3030 Tabletop Scanning Electron Microscope. The samples were imaged in high vacuum mode and images were acquired using the secondary electron (SE) detector. The voltage was set to 2 kV and the Spot Intensity was set to 30 (unities). Images were acquired at several magnifications. Imaging in FIG. 22 demonstrated the morphology of the agglomerated crystals of sodium pelargonate existed as well-defined plate-like primary particles. Such a morphology is extremely difficult to achieve without spray drying and is desirable over elongates, plates or needles because it tends to display superior compression performance in manufacturing procedures and therapeutic dosage forms.

EXAMPLE 4: Sodium laurate (C12) material

[0216] Provided herein are agglomerated crystalline particles of sodium laurate, and powder materials comprising these particles. These particles exhibit superior flowability and/or compression properties. These sodium laurate particles exhibit a morphology that comprises spherical agglomerates. They may have a morphology characterized by spherical and irregularly shaped agglomerates, and/or porous. These sodium laurate particles may exhibit an SSA that is surprisingly an order of magnitude higher than commercially available sodium laurate materials. These particles may exhibit a D90 of 900 pm or less.

[0217] In some aspects, any of the disclosed sodium laurate particles are combined with a therapeutic macromolecule to form a mixture. This mixture may be formulated into an oral dosage form, such as an oral tablet for administration to a subject (e.g., a human subject) to treat or prevent a disease, disorder, or condition. Thus, provided herein are oral tablets comprising a therapeutic macromolecule and sodium laurate. These oral tablets may not require a compression aid, by virtue of the improved compression behavior of the particles.

[0218] As such, provided herein are oral tablets comprising a therapeutic macromolecule and sodium laurate, wherein the tablet is substantially free of a compression aid, and wherein the therapeutic macromolecule exhibits a low Papp (e.g., a Papp of less than 10 x 10'⁸ cm/s). The therapeutic macromolecule may comprise a macrocyclic peptide, such as the compound of Formula I.

[0219] In some embodiments, the tablet exhibits a tensile strength that is 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold higher than the tensile strength of a corresponding tablet comprising commercial sodium laurate. In some aspect, the tablet comprises between about 80 and 99% sodium laurate, or between about 80% and 90% sodium laurate (w/w). In some embodiments, the tablet exhibits a tensile strength of 1 MPa, 1.1 MPa, 1.2 MPa, 1.25 MPa, 1.5 MPa, 1.75 MPa, 1.9 MPa, 2 MPa, 2.1 MPa, 2.15 MPa, 2.25 MPa, 2.5 MPa, or above 2.5 MPa. In some embodiments, the disclosed tablets comprising sodium laurate comprise additional excipients. For example, the disclosed tablets may comprise magnesium stearate, lactose, mannitol, HPMC, and/or MCC. Preparation of sodium laurate

[0220] Lauric acid (6) (2.5 g, 12.5 mmol) and acetonitrile (63.3 ml) were combined in an appropriate vessel with a suitable agitator. The batch was stirred at 30 °C until complete dissolution was achieved then cooled to room temperature. The solution was charged with sodium methoxide (2) (12.48 mmol) as a 25 wt% solution in methanol over a period of 5 hours under vigorous agitation, forming a slurry. After the first hour of the addition of (2) had elapsed, the solution was charged with heptane (9.3 ml) concurrently over a period of four hours. The slurry was stirred for an additional hour. Solids were filtered, washed with acetonitrile (15 ml twice), then dried under vacuum with a nitrogen sweep at 35-40 °C to afford sodium laurate (7) (2.7 g, 97 % yield).

[0221] Sodium laurate powder samples were mounted on SEM stubs (32 mm) using a carbon sticky. The samples were sputter coated with platinum. The samples were loaded into the Hitachi SU5000 Scanning Electron Microscope. The samples were imaged in high vacuum mode and images were acquired using the secondary electron (SE) detector. The voltage was set to 2 kV and the Spot Intensity was set to 30 (unities). Images were acquired at several magnifications. Imaging in FIG. 23 demonstrated the morphology of the agglomerated crystals of sodium laurate existed as well-defined plate-like primary particles.

[0222] The disclosed subject matter is not to be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

[0223] All references (e.g.. publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims.

Claims

What Is Claimed Is:

1. A composition comprising cry stalline sodium caprate particles, wherein the sodium caprate particles exhibit a mean specific surface area (SSA) of at least 5.9 m²/g.

2. The composition of claim 1, wherein the sodium caprate particles exhibit a mean SSA of between 5.9 m²/g and about 41 m²/g.

3. A composition comprising crystalline sodium caprate particles, wherein the sodium caprate particles exhibit a mean specific surface area (SSA) of at least 9.9 m²/g.

4. The composition of any one of claims 1-3, wherein the sodium caprate particles exhibit a mean SSA of between 9.9 m²/g and about 41 m²/g.

5. The composition of any one of claims 1-4, wherein the sodium caprate particles exhibit a mean SSA of between 9.9 m²/g and about 37 m²/g.

6. The composition of claim 1 or 3, wherein the sodium caprate particles exhibit a mean SSA of at least about 15 m²/g.

7. The composition of any one of claims 1-6. wherein the sodium caprate particles exhibit a mean SSA of about 15, 21, or 37 m²/g.

8. The composition of any one of claims 1-7, wherein the sodium caprate particles exhibit a morphology that comprises spherical agglomerates.

9. The composition of any one of claims 1-8, wherein the sodium caprate particles exhibit a particle size distribution having a D90 of 565 pm or less.

10. The composition of any one of claims 1-9, wherein the composition exhibits a Hausner Ratio of 1.6 or less.

11. The composition of any one of claims 1-10, wherein the composition exhibits a tap density of at least 0.32 g/mL.

12. The composition of any one of claims 1-11, wherein the composition exhibits a tap density of at least 0.50 g/mL.

13. A composition comprising crystalline sodium caprate particles, wherein the sodium caprate particles exhibit a mean SSA of between 9.6 m²/g and 41 m²/g, a tap density of at least 0.32 g/rnL, and a D90 of between 158 pm and 657 pm.

14. An oral tablet comprising the composition of any one of claims 1-13.

15. An oral tablet comprising a therapeutic macromolecule and sodium caprate, wherein the tablet is substantially free of a compression aid, and wherein the therapeutic macromolecule exhibits a low apparent permeability (Papp).

16. The oral tablet of claim 15, wherein the therapeutic macromolecule is a peptide.

17. The oral tablet of claim 15 or 16, wherein the therapeutic macromolecule is a Biopharmaceutics Classification System (BCS) Class III or Class IV compound.

18. The tablet of any one of claims 14-17, wherein the therapeutic macromolecule is a macrocyclic peptide.

19. The tablet of any one of claims 14-18, wherein the therapeutic macromolecule comprises Formula I.

20. The tablet of any one of claims 14-19, wherein the tablet exhibits a tensile strength of at least 1 MPa.

21. The tablet of any one of claims 14-20, wherein the tablet exhibits a tensile strength of 1.1 MPa, 1.2 MPa, 1.25 MPa, 1.4 MPa, 1.5 MPa, 1.75 MPa, 1.9 MPa, 2 MPa, 2.1 MPa, 2.15 MPa, 2.25 MPa, or 2.5 MPa.

22. The tablet of any one of claims 14-21 , wherein the tablet exhibits a tensile strength that is 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold higher than the tensile strength of a corresponding tablet comprising commercial sodium caprate.

23. The tablet of any one of claims 14-22, wherein the tablet comprises between about 80 and 99% sodium caprate (w/w), or between about 80% and 90% sodium caprate (w/w).

24. The tablet of any one of claims 14-23, wherein the tablet comprises between 88% and 89% sodium caprate (w/w).

25. The tablet of any one of claims 14-24, wherein the tablet further comprises a lubricant, wherein the lubricant is magnesium stearate.

26. The tablet of any one of claims 14-25, wherein the tablet further comprises lactose, mannitol, hydroxypropyl methylcellulose (HPMC) or microcrystalline cellulose (MCC).

27. The tablet of any one of claims 14-26, wherein the tablet comprises lactose.

28. The tablet of any one of claims 14-27, wherein the tablet comprises between 10% and 12% w/w of therapeutic macromolecule.

29. The tablet of any one of claims 14-27, wherein the tablet is an oral compressed tablet (OCT).

30. The tablet of any one of claims 14-27, wherein the tablet is a film-coated tablet (FCT).

31. An oral tablet consisting essentially of a therapeutic macromolecule and sodium caprate, wherein the tablet is substantially free of a compression aid, and wherein the therapeutic macromolecule exhibits a low apparent permeability' (Papp).

32. An oral tablet comprising a therapeutic macromolecule and sodium pelargonate, wherein the tablet is substantially free of a compression aid, and wherein the therapeutic macromolecule exhibits a low Papp.

33. The tablet of claim 32, wherein the tablet exhibits a tensile strength that is 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold higher than the tensile strength of a corresponding tablet comprising commercial sodium pelargonate.

34. The tablet of claim 32 or 33, wherein the tablet comprises between about 80 and 99% sodium pelargonate, or between about 80% and 90% sodium pelargonate (w/w).

35. An oral tablet comprising a therapeutic macromolecule and sodium laurate, wherein the tablet is substantially free of a compression aid, and wherein the therapeutic macromolecule exhibits a low⁷ Papp.

36. The tablet of claim 35, wherein the tablet exhibits a tensile strength that is 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold higher than the tensile strength of a corresponding tablet comprising commercial sodium laurate.

37. The tablet of claim 35 or 36, wherein the tablet comprises between about 80 and 99% sodium laurate, or between about 80% and 90% sodium laurate (w/w).

38. The tablet of any one of claims 35-37, wherein the tablet exhibits a tensile strength of 1.1 MPa, 1.2 MPa, 1.25 MPa, 1.4 MPa, 1.5 MPa, 1.75 MPa, 1.9 MPa, 2 MPa, 2.1 MPa, 2. 15 MPa, 2.25 MPa, or 2.5 MPa.

39. The tablet of any one of claims 32-38, wherein the tablet further comprises a lubricant, wherein the lubricant is magnesium stearate.

40. The tablet of any one of claims 31-34 and 36-39, wherein the tablet further comprises HPMC, MCC, or lactose.

41. The tablet of any one of claims 32-40, wherein the therapeutic macromolecule is a macrocyclic peptide.

42. The tablet of any one of claims 32-41, wherein the therapeutic macromolecule comprises Formula I.