Agglomerated crystalline salt of medium chain fatty acid

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 pharmaceutical oral dosage forms, including as penetration enhancers. The present disclosure provides a sodium caprate crystalline composition having improved powder flowability and compression behavior. The disclosure further provides oral tablets comprising these sodium caprate compositions, including tablets substantially free of any tabletting aid excipients. In various embodiments, these tablets exhibit superior tensile strength and tableting properties than conventional tablets.

Description

Cross-references to related applications

[0001] This application is an international patent application claiming priority to 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, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0002] Sodium salts of saturated medium-chain (medium-chain) organic acids are surprisingly difficult to crystallize. These molecules exhibit a strong tendency to gel in many solvent systems, leading to an unstirrable batch condition. The natural crystalline morphology of these compounds is that of long fibers / needles, which easily trap solvent, are difficult to separate in standard equipment setups, and have powder properties that are detrimental to formulation production. Commercially available materials of this type are mostly extremely expensive and separated by spray drying, or retain a suboptimal fibrous morphology formed from a difficult-to-stir slurry.

[0003] Sodium caprate (or sodium decanoate) is the sodium salt of decanoic acid (a 10-carbon saturated fatty acid), which forms micelles and liquid crystal phases in aqueous solution. Sodium caprate can promote the transport of bioactive molecules and, as an FDA-approved food additive and component of finished pharmaceutical products, can be used to enhance the bioavailability of active agents. Furthermore, sodium caprate is a known intestinal permeability enhancer. Although there are known methods for preparing sodium caprate, including those described in B. Zacharie et al., Organic Process Research & Development 2009,... 13, The synthesis methods described in 581–583, but unlike the present invention, result in gelation of the sodium decanoate material (using any of a variety of solvent systems). Gelation makes the use of sodium decanoate (powder) in large-scale manufacturing difficult and impractical. However, in a few solvent systems that can suppress gelation, sodium decanoate crystallizes into small, thin needle-like or fibrous forms, resulting in slurries that cannot be stirred. Therefore, these slurries present their own challenges as they are difficult to transfer from one set of equipment to another, such as from a crystallizer to a filter / dryer or centrifuge. Furthermore, these particles are poorly filtered and trap large amounts of interstitial liquid, leading to excessive agglomeration during drying. The resulting cake requires a large energy input to break down and results in the formation of widely distributed, hard material clumps, affecting the ability to formulate the material. These particles are also more prone to cracking or breakage. In summary, sodium decanoate is extremely difficult to separate on an industrial scale. As a potential consequence of these formulation challenges, the GMP supply of sodium decanoate is limited.

[0004] Therefore, there are both regulatory and technical barriers to the industrial application of medium-chain fatty acid salts (such as sodium decanoate) as excipients in pharmaceutical formulations. Summary of the Invention

[0005] This disclosure provides crystalline solid compositions of medium-chain fatty acid salts. These solids, separated in powder form, are suitable for use as excipients in oral pharmaceutical formulations comprising one or more therapeutic macromolecules. Specifically, they can serve as permeation enhancers for poorly permeable macromolecules. The disclosed crystalline solids exhibit improved properties compared to existing medium-chain fatty acid salt solids. This disclosure also provides improved oral dosage forms, such as tablets, comprising crystalline solids of medium-chain fatty acid salts. This disclosure further provides methods for formulating and / or preparing these dosage forms.

[0006] This disclosure provides agglomerated crystalline particle compositions of medium-chain fatty acid salts, exhibiting superior performance in terms of adjustable particle size, powder flowability, and compression behavior compared to commercially available alternatives. The solid material compositions of this invention possess excellent flowability and compaction properties, and are produced at low cost, making them suitable as excipients in manufacturing processes and finished pharmaceutical products. Therefore, this disclosure relates to compositions that can be used as excipients in oral therapeutic pharmaceutical products for human use. As described herein, the disclosed solid material is the product of a novel method that uses medium-length aliphatic hydrocarbon solvents and polar aprotic solvents to generate medium-chain fatty acid salts. The disclosed material can be characterized as having a spherical agglomerated morphology, i.e., the disclosed crystalline particles comprise spherical aggregates. In other words, the disclosed agglomerated crystals are predominantly spherical. The material may be substantially non-gelatinized or free of fibrous or needle-like crystalline particle dispersions.

[0007] In various embodiments, the disclosed compositions comprise crystalline solids (e.g., solid powders) of aliphatic fatty acid salts of different intermediate chain lengths, such as decanoates, nonanoates, and laurates. In various embodiments, the disclosed solids are sodium salts of any of these fatty acids. In some embodiments, the disclosed solid is sodium decanoate.

[0008] This document further provides tablets comprising the disclosed crystalline solid composition. These tablets exhibit superior tensile strength, flow properties, and compaction properties compared to tablets containing commercially available sodium salts of medium-chain fatty acids. These tablets, apart from the medium-chain fatty acid salts themselves, may contain substantially no excipients that enhance the compactibility or mechanical integrity of the tablet. Therefore, the disclosed tablets may contain substantially no tableting aids. The disclosed tablets may also contain therapeutic macromolecules, such as poorly permeable therapeutic peptides.

[0009] This disclosure is based, in at least part, on the discovery that medium-chain fatty acid salts exhibiting significantly increased specific surface area (SSA), spherical agglomeration morphology, high powder flowability, and / or medium particle size can be used to produce oral tablets exhibiting remarkable compressibility under high pressure. The tablets possess high breaking strength and / or tensile strength. Therefore, the disclosed crystalline solids offer improved tabletability compared to existing medium-chain fatty acid salt crystalline solids.

[0010] In some aspects, the disclosed compositions comprise agglomerated crystalline solids of sodium decanoate. A powdered product containing such agglomerated crystalline sodium decanoate is also disclosed. This powdered product may be referred to herein as "Product A". The SSA of the disclosed sodium decanoate crystalline solid is remarkably higher than that of commercially available sodium decanoate solids (e.g., sodium decanoate materials manufactured and / or sold by Jost Chemical, TCI Chemicals, BioSpectra Inc., and Pfaltz and Bauer Inc.) by an order of magnitude. For example, the material produced by the disclosed method was found to contain sodium decanoate particles with a particle size of 5.9 μm. 2 With an average SSA of / g or higher, it exhibits excellent flowability and compressibility. Specifically, it has an average SSA of 9.9 m... 2 Sodium decanoate particles with an average SSA of / g or higher exhibit excellent flowability and compressibility.

[0011] Therefore, in some aspects, the compositions provided herein comprise sodium decanoate crystal particles, wherein the sodium decanoate particles have a density of at least 5.9 μm. 2 The average specific surface area is 9.9 m² / g. This document further provides compositions comprising sodium decanoate crystalline particles, wherein the sodium decanoate particles have a surface area of ​​at least 9.9 m² / g. 2 The average specific surface area is 9.9 m² / g. In some embodiments, the sodium decanoate particles have an average specific surface area of ​​9.9 m² / g. 2 / g to approximately 37 m 2 / g average SSA. In some embodiments, the sodium decanoate particles have at least about 15m 2 / g average SSA.

[0012] In some embodiments, the sodium decanoate particles have a diameter of 5.9 μm. 2 / g to approximately 56 m 2 The average SSA concentration is 9.9 μg. In some embodiments, the sodium decanoate particles have an average SSA concentration of 9.9 μg. 2 / g to approximately 56 m 2 / g, 5.9 to 37 m 2 / g, or approximately 37 m 2 / g to 56m 2 / g average SSA.

[0013] The disclosed sodium decanoate crystal particles have a morphology different from commercially available sodium decanoate, namely, a morphology containing spherical aggregates. In some embodiments, the disclosed particles have a morphology characterized by spherical and irregularly shaped aggregates. The morphology of these particles can be characterized as porous, i.e., having a high internal macroscopic porosity.

[0014] The disclosed particles can be of medium size. These particles have a combination of specific surface area and particle size distribution (PSD) that is substantially different overall from that of commercially available sodium decanoate. For example, materials produced by the disclosed method have been found to contain sodium decanoate particles with a density of 565 µm or less. 90 It also exhibits excellent flowability and compressibility. In some embodiments, the disclosed sodium decanoate particles have a PSD of 900 µm or less, 650 µm or less (e.g., 565 µm or less), and a D0.05. 90 In some implementations, the D 90 400 µm or smaller.

[0015] In some aspects, this document provides tablets comprising any of the disclosed medium-chain fatty acid salt agglomerated crystalline particle compositions. In various aspects, said tablets comprise any of the disclosed sodium decanoate particles. Those skilled in the art will understand that any agglomerated crystalline particle of a medium-chain fatty acid salt can be used in this invention.

[0016] In some aspects, any disclosed particles are combined with a therapeutic macromolecule to form a mixture. This mixture can 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, symptom, or condition. Therefore, this document provides oral tablets comprising a therapeutic macromolecule and sodium decanoate. Because the disclosed sodium decanoate particles have improved compression behavior, these oral tablets may not require tableting excipients. Therefore, in various embodiments, the tablets are substantially free of tableting excipients. In some aspects, this document provides tablets comprising a therapeutic macromolecule and sodium decanoate and free of other components. In some embodiments, tablets are provided that consist substantially of the following therapeutic macromolecule and sodium decanoate.

[0017] In several respects, the therapeutic macromolecule is poorly permeable, i.e., has low apparent permeability (Papp). The macromolecule can be a small organic molecule, a larger biologic, or a cyclic peptide (which shares characteristics with both small molecules and biologics). In some embodiments, the therapeutic macromolecule is a peptide, such as a macrocyclic peptide. In some embodiments, the therapeutic macromolecule is a compound of formula I.

[0018] In some embodiments, the tablet has a tensile strength of at least 1 MPa. For example, the tablet may exhibit a tensile strength of at least 1 MPa. For example, the tablet may exhibit tensile strengths 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 respects, this article provides sodium nonanoate particles with a spherical aggregate morphology and improved compression behavior. In other respects, this article provides sodium laurate particles with a spherical aggregate morphology and improved compression behavior. This article further provides oral tablets containing these sodium nonanoate or sodium laurate aggregates. It is presumed that aggregated crystals of medium-chain fatty acid salts generally exhibit substantially similar thermodynamic and kinetic properties. Therefore, it is presumed that oral tablets containing sodium nonanoate or sodium laurate aggregates behave similarly to oral tablets containing sodium decanoate.

[0020] Other embodiments, aspects and features of the invention will be further described or become clear in the following description, examples and appended claims. Attached Figure Description

[0021] Figure 1 This is a graph depicting the compression properties of an exemplary sodium decanoate agglomerate material (i.e., product A) in a solid dosage form (platform dosage form) containing one or more tableting aids, compared to four commercially available forms of crystalline sodium decanoate. Different compressive stresses (pressures) applied by the tableting machine are plotted on the x-axis.

[0022] Figure 2A This is a graph depicting the compressibility of 100% Product A tablets versus tablets containing one of the three commercially available forms of crystalline sodium decanoate (100% w / w) as a function of compression pressure. Figure 2B This is a graph showing the tensile strength of tablets containing 100% Product A, 100% Commercially Available Material 3, and 100% Commercially Available Material 4 as a function of tablet density.

[0023] Figure 3 This is a graph showing the compressibility of four commercial-scale batches of 100% Product A tablets. The graph plots tensile strength against compression pressure (applied by a tableting machine) to show the compression profiles of these batches.

[0024] Figure 4 The granularity parameter D of product A in commercial-scale batches. 90 The graph (x-axis) shows the relationship between the tensile strength of tablets containing product A in the corresponding batch without tableting aids, illustrating the change in tensile strength with particle size.

[0025] Figure 5This is a graph showing the relationship between the specific surface area and tensile strength of tablets containing commercially available batches of Product A without tableting aids, and comparing them with corresponding tablets containing commercially available material 2 and commercially available material 4.

[0026] Figure 6 This is a graph depicting the compressibility of a tablet containing 10% lactose and 90% product A, compared to two corresponding dosage forms (“mixtures”) containing commercially available material 2 and commercially available material 4, respectively.

[0027] Figure 7 The compressibility of the 90% / 10% Product A tablets was described, compared with two corresponding dosage forms containing commercially available crystalline sodium decanoate (commercial materials 2 and 4).

[0028] Figure 8 The friability of the 90% / 10% Product A tablets was described, compared to two corresponding dosage forms containing commercially available crystalline sodium decanoate.

[0029] Figures 9A-9C These are representative scanning electron microscope (SEM) images (500x magnification) showing the differences in morphological properties of sodium decanoate from (9A) commercial material 2, (9B) commercial material 4 and (9C) product A (agglomerated material). Figure 9D This is a representative SEM image of product A, showing particles with a spherical morphology.

[0030] Figure 10 It is a graph depicting the compressibility (tensile strength) of a tablet mixture containing 80% Product A with (i) 20% lactose, (ii) 20% MCC and (iii) 20% HPMC.

[0031] Figure 11 The compressibility of three tablet mixtures containing Product A and different amounts of lactose: 20%, 50%, and 70% (w / w) was shown.

[0032] Figure 12 The X-ray powder diffraction data for Product A are shown, compared to commercially available sodium decanoate alternatives.

[0033] Figure 13 This is a differential scanning calorimetry (DSC) scan of product A.

[0034] Figure 14 The thermogravimetric analysis results of product A are described.

[0035] Figure 15 A representative volume-weighted granularity analysis of a small batch of product A is presented.

[0036] Figure 16A representative SEM image of product A is shown, which demonstrates the aggregated, sheet-like primary morphology (from a small batch).

[0037] Figure 17 Other representative SEM images depicting a comparison of commercially available sodium decanoate crystals with product A are presented.

[0038] Figure 18 Optical microscopic images of sodium decanoate aggregates formed with heptane using different aprotic polar organic solvents (NMP and DMAC) are shown.

[0039] Figure 19 SEM images of sodium decanoate crystals formed in acetonitrile and hexane are shown. The reaction scheme for this embodiment of the process is shown in the top figure.

[0040] Figure 20 SEM images of sodium decanoate crystals produced in acetonitrile and heptane using 1 L / kg (1V) and 2 L / kg (2V) acetonitrile are shown.

[0041] Figure 21 A photograph is depicted during the implementation of an exemplary process for producing approximately 1.0 kg of sodium decanoate aggregate crystals. The product is shown in a rectangular glass dish in the bottom image.

[0042] Figure 22 This is a SEM image of sodium nonanoate crystals formed in acetonitrile and heptane.

[0043] Figure 23 This is a SEM image of sodium lauryl crystals formed in acetonitrile and heptane. Detailed Implementation

[0044] This disclosure provides compositions of aggregated crystalline salts of medium-chain fatty acids that have improved properties relative to commercially available salts. These salts can be used as excipients in oral pharmaceutical dosage forms, including as penetration enhancers. This disclosure provides compositions of sodium decanoate crystal aggregates having improved powder flowability and tablet tensile strength. This disclosure further provides oral tablets comprising these sodium decanoate compositions, including tablets substantially free of any compression adjuvants or excipients. In all respects, these tablets exhibit superior robustness, tensile strength, and compaction properties compared to conventional tablets.

[0045] By identifying a solvent composition that inhibits gel formation and traps solids in the dispersed droplets of the second phase, a method for single-pot, low-energy crystallization using inexpensive and commercially available starting materials was achieved. The provided sodium decanoate agglomerates behave like conventional slurries, without solvent entrainment, thus allowing for gentle stirring and easy separation. The agglomerates possess sufficient hardness to maintain their morphology during discharge and handling. Furthermore, the provided agglomerates exhibit a substantially uniform morphology and / or a unimodal normal particle size distribution. The agglomerates also demonstrate excellent powder flowability.

[0046] This document describes powder products produced by any of the disclosed methods. In various embodiments, the product comprises any provided agglomerated crystals, such as agglomerated sodium decanoate crystals.

[0047] This document further provides oral dosage forms comprising the product (e.g., product A) of any of the disclosed methods. In some embodiments, tablets comprising product A are described. A tablet is an oral dosage form comprising a mixture of a therapeutic macromolecule (i.e., the active pharmaceutical ingredient (API)) and excipients (lubricants, disintegrants, bulking agents, etc.) that is compressed during manufacturing. In some embodiments, tablets comprising a mixture of API, product A sodium decanoate, and additional excipients are provided. In some embodiments, these tablets do not contain tableting aids (e.g., lactose), or are substantially free of any tableting aids. In some embodiments, tablets comprising lactose (e.g., lactose monohydrate) and / or MCC are disclosed.

[0048] The tablets disclosed herein 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 tableting adjuvant. In some embodiments, the disclosed tablets are free of tableting adjuvants, i.e., have about 0% tableting adjuvants.

[0049] Therefore, compared to corresponding tablets containing commercially available sodium decanoate material and substantially free of compression adjuvants, the disclosed tablets may exhibit improved tensile strength and / or compressibility. For example, the tensile strength of the disclosed tablets may be 2, 3, 4, 5, or 6 times higher than that of corresponding tablets containing commercially available sodium decanoate (and substantially free of compression adjuvants). The tensile strength of the disclosed tablets may be 6, 7, 8, 9, 10, 11, or 12 times higher than that of corresponding tablets. In some embodiments, the tensile strength of the tablets is 5 times higher than that of corresponding tablets (e.g., tablets containing the same therapeutic molecule and sodium decanoate sold by Jost Chemical or material sold by BioSpectra, Inc.) (see [link to relevant documentation]). Figure 2Aand 2B In some embodiments, the tablet has a tensile strength that is 6 to 11.7 times higher than that of a corresponding tablet (e.g., a tablet containing Jost Chemical material).

[0050] The tablet may have 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 higher (see [reference]). Figure 3 In certain embodiments, the tablet has an average tensile strength of about 2 MPa. In some embodiments, the tablet has a tensile strength of about 2.1 MPa. In some embodiments, the tablet has a tensile strength of 1.9 MPa to 2.15 MPa. In some embodiments, the tablet has a tensile strength of 1.27 MPa to 2.27 MPa. In some embodiments, the tablet has a tensile strength of about 2.1 MPa at any compressive stress value (e.g., 115 MPa to 125 MPa) from 50 MPa to 130 MPa. These tensile strengths can be determined using a tablet press within a compression pressure range of 30 MPa to 140 MPa.

[0051] In all aspects, the tablets comprise sodium decanoate particles having any of the properties described below. For example, tablets comprising sodium decanoate particles are disclosed. However, those skilled in the art will understand that any aggregated crystalline particles of medium-chain fatty acid salts may be used in this invention.

[0052] In some embodiments, these tablets have superior tensile strength compared to corresponding (e.g., conventional) tablets containing an API (e.g., a different API) and sodium decanoate. Under high compressive stress, the tensile strength (e.g., tensile strength) of said tablets can exceed 1 MPa. In some embodiments, the tensile strength of said tablets is an order of magnitude higher than that of tablets containing the same API and commercially available sodium decanoate (e.g., purified sodium decanoate powder (Jost code 2724)). Any tablet disclosed herein may have high resistance to fracture or cracking.

[0053] The tablet may contain any therapeutic macromolecule or API that may be poorly soluble in oral formulations or have poor oral bioavailability in the absence of a penetration enhancer, such as peptide APIs (i.e., therapeutic peptides).

[0054] The superior compression behavior of the disclosed medium-chain fatty acid salt particles enables the production of tablets containing very high concentrations of medium-chain fatty acid salts. These tablets are ideal for patients because they reduce the overall size of the tablet. From a commercial perspective, reducing excipient inventory by removing excipients from the tablet is highly desirable, as it lowers overall operating costs and thus product costs. Formulations containing high levels (≥90% w / w) of, for example, sodium decanoate cannot be manufactured using conventional sodium decanoate grades used in the art (including commercially available materials described herein). Concentrations of medium-chain fatty acid salts up to 99% in tablets have never been reported before. Therefore, in some respects, this document provides tablets containing up to 99% w / w of medium-chain fatty acid salt excipients (e.g., sodium decanoate).

[0055] In some embodiments of the disclosed compositions, the amount of a medium-chain fatty acid salt (e.g., sodium decanoate) can be from about 1% w / w to about 99% w / w. In various embodiments, tablets containing about 70% to 99% sodium decanoate or about 70% to 90% sodium decanoate are provided. In a specific embodiment, the sodium decanoate content in the tablet is 79% w / w or higher. In some embodiments, tablets containing 80% to 99.5% w / w sodium decanoate are provided. In some embodiments, tablets containing 80% to 99% w / w sodium decanoate are provided. In some embodiments, tablets containing 80% to 89% w / w sodium decanoate are provided. In a specific embodiment, tablets containing 88% to 89% sodium decanoate are disclosed. In some embodiments, tablets containing 96% sodium decanoate are disclosed.

[0056] In one embodiment, a tablet comprising 80% sodium decanoate is provided. In some aspects of this embodiment, a tablet comprising 80% sodium decanoate and 20% therapeutic macromolecule (w / w) is provided. In one embodiment, a tablet comprising 90% sodium decanoate is provided. In some aspects of this embodiment, a tablet comprising 90% sodium decanoate and 10% therapeutic macromolecule (w / w) is provided. Further, a tablet comprising about 30% to 90% sodium decanoate and also comprising a therapeutic macromolecule is provided. In some embodiments, a tablet comprising about 30% or about 33% sodium decanoate and also comprising a therapeutic macromolecule is provided.

[0057] In some embodiments, the disclosed tablets have enhanced friability compared to corresponding tablets containing commercially available sodium decanoate. In some embodiments, the disclosed tablets have enhanced plastic work of compaction compared to corresponding tablets containing commercially available sodium decanoate.

[0058] Properties of sodium decanoate particles In some embodiments, the disclosed sodium decanoate compositions have agglomerated particles with a superior specific surface area (SSA) compared to commercially available sodium decanoate. For example, the disclosed sodium decanoate may have a specific surface area that is about 3, 4, or 5 times higher than that of commercially available sodium decanoate, such as 3.8 times. The specific surface area can be determined by a Brunauer-Emmet-Teller (BET) method (e.g., gas adsorption BET). In some embodiments, the specific surface area of ​​the sodium decanoate composition is an order of magnitude higher than that of the corresponding specific surface area of ​​commercially available sodium decanoate compositions. Without wishing to be bound by any particular theory, with the higher specific surface area of ​​the disclosed particles, tablets containing these particles have higher compaction plastic work (and plastic deformation), and therefore greater tensile strength.

[0059] In some respects, the disclosed sodium decanoate particles have a diameter of 5.9 m. 2 / g to approximately 56 m 2 The average SSA concentration is 5.9 m / g. In an exemplary aspect, the disclosed sodium decanoate particles have an average SSA concentration of 5.9 m / g. 2 / g (e.g. 5.96) to approximately 41 m 2 The average SSA was 41.17 g / g (e.g., 41.17). In some respects, the disclosed sodium decanoate particles have a m... 2 / g (e.g. 9.67) to approximately 41 m 2 Average SSA / g (e.g., 41.17).

[0060] For example, some disclosed sodium decanoate particles have a diameter of 9.9 μm. 2 / g to approximately 37 m 2 The average SSA is 9.9 m / g. In some embodiments, the particles have an average SSA of at least 9.9 m / g. 2 / g, or at least about 10 m 2 The average SSA per g. In some embodiments, the particles have an average 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 μm. 2 The average SSA per g of the disclosed sodium decanoate particles may have an average SSA of about 15, 21, or 37 μm. 2 The average SSA per g is 10, 16, 24, or 37 μm. The disclosed sodium decanoate particles may have an average SSA of about 10, 16, 24, or 37 μm. 2 The average SSA per g is [value missing]. The disclosed particle size can be 15.9, 24.1, or 36.7 m. 2 Average SSA / g (see Figure 5This contrasts with the average SSA of sodium decanoate particles produced by Jost Chemical and BioSpectra, Inc., whose SSA is only 2.6 m. 2 / g.

[0061] In some embodiments, the particles have a diameter of at least 5.9 m. 2 / g, or at least about 6 m 2 The average SSA is 5.9 m / g. For example, some disclosed sodium decanoate particles have an average SSA of 5.9 m / g. 2 / g to approximately 37 m 2 / g average SSA.

[0062] In some embodiments, the disclosed particles have an SSA within any of the following ranges: 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 m. 2 / g.

[0063] In some embodiments, the agglomerated particles of the disclosed sodium decanoate composition have a morphology substantially different from commercially available sodium decanoate. In certain embodiments, the disclosed particles are flake-like, homogeneous, and / or substantially free of fibrous or needle-like morphologies. In some embodiments, the disclosed crystals are substantially free of balloon-like morphologies.

[0064] The disclosed sodium decanoate particles exhibit a morphology comprising spherical aggregates. In some embodiments, the disclosed particles exhibit a morphology characterized by spherical and irregularly shaped aggregates (see [link to relevant documentation]). Figure 9D In various implementations, the morphology of these particles can be characterized as porous, i.e., having high internal porosity. The spherical morphology of these particles endows them with good densification properties, thereby producing a high Hausner ratio.

[0065] In some embodiments, the disclosed sodium decanoate particles have D 90Particle size distributions of 900 µm or less, 850 µm or less, 700 µm or less, 650 µm or less, 575 µm or less, 500 µm or less, 400 µm or less, 350 µm or less, 300 µm or less, 200 µm or less, 160 µm or less, 120 µm or less, or 85 µm or less. In a particular embodiment, D was observed. 90 It is 565 µm or smaller. In some implementations, D was observed. 90 The particle size ranges from 158 µm to 657 µm. Particle size distributions ranging from approximately 250 µm to approximately 900 µm, approximately 300 µm to approximately 700 µm, approximately 200 µm to approximately 700 µm, approximately 200 µm to approximately 300 µm, approximately 200 µm to approximately 565 µm, or approximately 350 µm to approximately 600 µm can be observed. For example, a particle size distribution from 289 µm to 863 µm can be observed (see...). Figure 4 ).

[0066] In some embodiments, the disclosed sodium decanoate particles exhibit a morphology comprising spherical aggregates and a particle size greater than 9.9 μm. 2 / g (e.g., greater than 15 m) 2 / g) of SSA. In some embodiments, the disclosed sodium decanoate particles exhibit a morphology comprising spherical aggregates and D 90 The particle size distribution is 565 µm or smaller. In some embodiments, the disclosed sodium decanoate particles exhibit a morphology comprising spherical aggregates larger than 9.9 µm. 2 / g of SSA and D 90 The particle size distribution is 565 µm or smaller. In some embodiments, the disclosed sodium decanoate particles exhibit a morphology comprising spherical aggregates larger than 15 µm. 2 / g of SSA and D 90 The particle size distribution is 400 µm or smaller.

[0067] In some embodiments, the disclosed sodium decanoate particles exhibit a morphology comprising spherical aggregates, 9.6 μm in size. 2 / g to 41 m 2 / g of SSA and D from 158 µm to 657 µm 90 .

[0068] The disclosed solid also has superior powder flowability compared to commercially available sodium decanoate, which is manufactured and / or sold by Jost Chemical, TCI Chemicals, BioSpectra Inc., and Pfaltz and Bauer Inc. In some aspects, compositions comprising crystalline particles of sodium decanoate are provided herein, wherein the sodium decanoate particles have 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 an exemplary embodiment, the particles have a tap density of at least 0.32 g / mL. In some embodiments, the particles have a tap density of at least 0.5 g / mL, for example, at least 0.54 g / mL. The disclosed particles have a tap density in the range of 0.50 to 0.69 g / mL.

[0069] In some aspects, the sodium decanoate particles have 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 certain aspects, the sodium decanoate particles have a Hausner ratio of 1.6 or less. In some embodiments, the particles have 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 can be observed.

[0070] definition The following lists the definitions of various terms used herein. Unless otherwise limited individually or as part of a larger group in a particular case, these definitions apply to terms used throughout this specification and claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein, as well as laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry, are well-known and commonly used in the art. Chemical names, common names, and chemical structures are used interchangeably to describe the same structure.

[0071] As used herein, “Product A” refers to the agglomerated crystalline form of sodium decanoate obtained by the disclosed method. In some embodiments, “Product A” is synonymous with “agglomerated material”.

[0072] As used herein, the term "medium-chain fatty acid" refers to an aliphatic carbohydrate having a primary carboxyl group and between five and fifteen carbon atoms. Examples include decanoic acid, lauric acid, nonanoic acid, and undecanoic acid. In some embodiments of the invention, the medium-chain fatty acid is decanoic acid, nonanoic acid, or lauric acid. In further embodiments, the medium-chain fatty acid is decanoic acid. In some embodiments, the medium-chain fatty acid is nonanoic acid or lauric acid.

[0073] As used herein, the term "permeability enhancer" refers to a pharmaceutically acceptable excipient that improves the absorption of the active ingredient from the gastrointestinal tract. Several medium-chain fatty acids and their salts are suitable as permeability enhancers for oral delivery. The term also covers derivatives of medium-chain fatty acids. Examples of permeability enhancers include sodium decanoate (C64- ... 10 Sodium octanoate (C8), sodium lauryl laurate (C8) 12 Sodium undecanoate (C) 11 Docusate sodium, sodium lauryl sulfate, myristate, and Labrasol ® Other examples include caprate, caprylate, laurate, and docusate in their free base forms. In some embodiments, sodium decanoate (also referred to herein as "decate") is used as a penetration enhancer.

[0074] As used herein, the term "fatty acid salt" refers to a saturated or unsaturated aliphatic carboxylate. This term encompasses the anionic form of the carboxylate group, the free base form, and the neutral salt form (i.e., containing a counterion). For example, myristicate anion and potassium myristicate used herein are both fatty acid salts.

[0075] As used in this article with respect to therapeutic macromolecules, the term "poorly permeable" means resistant to permeation or absorption in the gastrointestinal tract of a subject, or resistant to formulation with solubilizing excipients commonly used for small molecule active ingredients. Poorly permeable macromolecules (e.g., peptides) may have an apparent permeability of less than 10.0.

[0076] As used herein, the term “apparent permeability” (Papp) refers to the permeability of macromolecules transported across the intestinal epithelial cell membrane. Those skilled in the art will understand that Papp can be determined using the Transwell™ culture system of the human colon adenocarcinoma cell line Caco-2 (see, for example, Pires et al.). Pharmaceutics October 2021; 13(10): 1563). Apparent permeability can be measured in units of 10. -8 cm / s or 10 -6 cm / s. In various implementation schemes, the unit of measurement is 10. -8 The therapeutic macromolecules of this disclosure can have a density of less than 10.0 x 10 cm / s. -8 cm / s, less than 7.5 x 10 -8 cm / s, less than 5.0 x 10 -8 cm / s, less than 3.0 x 10 -8 cm / s, less than 2.0 x 10 -8cm / s or less than 1.0 x 10 -8 The Papp value is measured in cm / s. Papp can be determined by any suitable method known in the art, including the MDCK II culture system.

[0077] "Tablet" is an oral dosage form that contains a mixture of an active ingredient and excipients (polymers, disintegrants, fillers, etc.) and is compressed during the manufacturing process. The term includes oral compressed tablets and film-coated tablets. In some embodiments, tablets comprising a mixture of a therapeutic macromolecule, sodium decanoate, and additional excipients are provided. The tablets of this disclosure can be prepared by compression in a tableting machine comprising one or more punches and dies.

[0078] As used herein, the term "compression adjuvant" refers to an excipient in an oral dosage form (e.g., tablet) that enhances the mechanical integrity or compressibility of said dosage form. Examples of compression adjuvants include lactose and microcrystalline cellulose (MCC). The material may be a known compression adjuvant, and / or may be determined to be a compression adjuvant by measuring the compressibility of the dosage form with or without the excipient (e.g., using a tablet press at compressive stress values ​​in the range of 30 MPa to 250 MPa or 50 MPa to 250 MPa).

[0079] As used herein in oral dosage forms, the term "substantially free" means containing 3% or less of a component on a weight / w / w basis. For example, a tablet "substantially free of tableting adjuvants" means a tablet containing 3% or less of any tableting adjuvant, such as 3% or less of lactose or MCC. The tablets of this 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 tableting adjuvant. Therefore, the disclosed tablets may be substantially free of tableting adjuvants. In some embodiments, the disclosed tablets are free of tableting adjuvants, i.e., have about 0% tableting adjuvants.

[0080] As used herein, the term "compressibility" refers to the ability of a powder material to be compressed into a tablet with a specified strength. It is synonymous with tablet tensile strength, diametrical tensile strength, and deformation hardness. Compactibility can also be expressed using compaction plastic work, a parameter that measures the amount of irreversible work (expressed in joules per gram) required during compression. Compactibility can be determined by any method known in the art, such as by a tableting simulator, for example, a tableting machine. At compressive stresses of 30 MPa to 140 MPa, the compactibility or tensile strength of the tablet may exceed 1 MPa. At compressive stresses of 6 MPa to 180 MPa, the compactibility or tensile strength of the tablet may exceed 1 MPa. For example, compactability can be determined under compressive stresses 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 a preferred embodiment, compactability is determined by compressing the material into a cylindrical tablet under force control using a tableting tool (e.g., a 9.525 mm circular flatbed tablet press). The tablet tensile strength (T or TS) can be determined using the following equation: T= 2 B / π hD in B The load required for radial fracture of the tablet. h For the thickness of the tablet, D This refers to the diameter of the tablet. See Micharfy et al. Int J Pharm. March 21, 2007; 333(1-2):118-26, which is incorporated herein by reference.

[0081] As used herein, the terms “commercially available sodium decanoate” and “commercially available sodium decanoate” refer to any batch of sodium decanoate material manufactured and / or sold by a chemical manufacturer in the United States as of October 2023. In various embodiments, these terms refer to sodium decanoate material manufactured and / or sold by Jost Chemical, TCI Chemicals, BioSpectra Inc., and Pfaltz and Bauer Inc. during the period from January to October 2023. In certain embodiments, these terms may refer to purified sodium decanoate powder (Jost code 2724) sold by Jost Chemical. In some embodiments, these terms may refer to TCI Chemicals sodium decanoate, product number D0024; BioSpectra GMP excipient grade sodium decanoate, product code NDEC-3220; or Pfaltz & Bauer 97% sodium decanoate, product code S04460.

[0082] As used herein, the term “dosage” refers to the amount of an API or pharmaceutical composition administered or recommended for administration at a specific time.

[0083] As used herein, the terms “treatment” or “curing” refer to suppressing or improving the symptoms of a disease, condition, or symptom in a subject who is experiencing or exhibiting the pathology or symptoms of that disease, condition, or symptom. For example, suppressing a disease, condition, or symptom means preventing the further development of the pathology and / or symptoms of that disease, condition, or symptom. Furthermore, improving a disease, condition, or symptom means reversing the pathology and / or symptoms, such as reducing the severity of the disease.

[0084] As used herein, the term "therapeutic effective amount" refers to an amount of a therapeutic macromolecular API (e.g., a peptide) sufficient in a human or animal to produce the desired therapeutic effect, such as the amount required to treat, cure, prevent, or inhibit the development and progression of a disease or its symptoms, and / or the amount required to improve symptoms or lead to disease remission. "Therapeutic effective amount" can vary depending on the structure and potency of the active ingredient and the intended route of administration. Those skilled in the art can readily determine the therapeutic effective amount of a given API.

[0085] As used herein, "subject" refers to an animal, such as a human or non-human animal, to which an experimental or approved treatment is administered. In various embodiments, the subject is a mammal. "Subject" can include livestock and domestic (companion) animals, including but not limited to cattle, horses, sheep, pigs, goats, rabbits, cats, dogs, and other mammals. "Subject" can include laboratory 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 monkey. In some embodiments, the subject requires treatment for a disease, symptom, or condition. In some embodiments, the subject is a human. Whether a subject "requires" treatment for a disease, symptom, or condition includes both a medical professional's assessment of the need and the subject's willingness to receive such treatment. In some embodiments, the subject has a disease, symptom, or condition, or is susceptible to such a disease, symptom, or condition. In some embodiments, the subject does not exhibit symptoms of a disease, symptom, or condition.

[0086] As used herein, the term "administration" and its variations (e.g., "dosage"), when referring to the disclosed tablet composition, means providing the composition to a subject in need of treatment. "Oral administration" herein means oral administration, i.e., oral administration of the composition.

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

[0088] As used herein, the term "short-chain alcohol" refers to a straight-chain saturated hydrocarbon having 1 to 3 carbon atoms and a terminal hydroxyl functional group. Examples include methanol or ethanol. In one embodiment of the invention, the short-chain alcohol is methanol. In one embodiment, the sodium salt of the short-chain alcohol is sodium methoxide.

[0089] As used herein, the term "aprotic polar solvent" refers to a compound or mixture of compounds used as a process solvent that has a chemical structure lacking an acidic proton, is polar, and can act as a hydrogen bond acceptor. Examples include dimethylformamide, dimethylacetamide, tetrahydrofuran, or acetonitrile. In one embodiment of the invention, the aprotic polar solvent is acetonitrile.

[0090] As used herein, the term "medium-chain aliphatic hydrocarbon solvent" refers to a compound or mixture of compounds used as a process solvent, whose chemical structure consists of five to nine carbon atoms linked together to form a non-aromatic chain and bonded only to each other and to hydrogen atoms. Examples include heptane, 2-methylhexane, hexane, octane, and cyclohexane. "Heptane" as used herein may comprise straight-chain heptane, branched heptane, n-heptane, or mixtures of heptane isomers (e.g., commercially available heptane mixtures, such as "Heptane, Isomer Mixtures" sold by Thermo Scientific Chemicals). "Hexane" as used herein may comprise straight-chain hexane, branched hexane, n-hexane, or mixtures of hexane isomers. In one embodiment of the invention, the medium-chain aliphatic hydrocarbon solvent is n-heptane (referred to simply as "heptane" in the examples). In another embodiment of the invention, the medium-chain aliphatic hydrocarbon solvent is n-hexane.

[0091] As used in this article, the phrase “controlled rate” refers to adding solution at a pre-planned flow rate before the start of a batch, typically delivered using a pump or flow controller and fed according to a procedure or schedule.

[0092] As used herein, the phrase “continuous stirring” refers to substantially uninterrupted stirring of the solution. This phrase includes one or more interruptions in the stirring process that, overall, have no material impact on the expected production of the slurry (e.g., minor interruptions of 1-3 seconds each). Continuous stirring can be performed mechanically (e.g., by means of a magnetic stirring rod) or manually.

[0093] As used herein, including in the appended claims, unless the context clearly specifies otherwise, the singular forms of words such as “an,” “a,” and “the / that” include their corresponding plural references. Any examples listed after the terms “for example” or “for instance” are not intended to be exhaustive or limiting.

[0094] As used herein, the terms “at least one” or “one or more” each include a single entry selected from the list and a combination of two or more entries selected from the list.

[0095] Unless explicitly stated otherwise, all ranges referenced herein are inclusive; that is, the range includes the upper and lower limits of the range and all values ​​in between. While not necessarily explicitly listed, all ranges are also intended to include all subranges contained therein. As an example, temperature ranges, percentages, equivalent ranges, etc., as described herein include the upper and lower limits of the range and any continuous values ​​in 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] When “about” is used to modify a numerically defined parameter (such as temperature or reaction time as described herein), it means that the parameter may fluctuate by no more than 10% above or below the stated value; where appropriate, the parameter may be rounded to the nearest integer. For example, a temperature of about 30°C may vary from 25°C to 35°C. Furthermore, the term “or” as used herein indicates that alternatives may be combined where appropriate; that is, the term “or” includes each alternative listed individually.

[0097] As used herein, the term "comprising" may include embodiments of "consisting of" and "substantially consisting of". As used herein, the terms "comprising", "including", "having", "having", "may", "containing", and variations thereof are intended as open-ended transitional phrases, terms, or words that require the presence of the specified ingredient / step and allow for the presence of other ingredients / steps. However, such descriptions should be construed as also covering compositions or methods "consisting of the listed components", which allow for the presence of only the listed components or compounds and any pharmaceutically acceptable excipients, and exclude unlisted components or compounds. Such descriptions should also be construed as also encompassing compositions or methods "substantially consisting of the listed components". As used herein, "substantially consisting of" means that the disclosed composition may contain small amounts (e.g., 3% or less w / w) of other components that do not materially alter the properties of the composition.

[0098] Therapeutic macromolecules This article provides an oral tablet comprising a therapeutic macromolecule and sodium decanoate, wherein the tablet is substantially free of tableting excipients, and wherein the therapeutic macromolecule has low apparent permeability (Papp). For example, the therapeutic macromolecule may have a Papp of less than 10 x 10⁻⁶. -8 Papp at cm / s. The disclosed compositions are suitable for formulation with any poorly permeable therapeutic macromolecule. The therapeutic macromolecules disclosed herein may comprise peptides, proteins, or oligonucleotides.

[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 are applicable to any poorly soluble, high-molecular-weight, and / or poorly permeable therapeutic peptide. In some embodiments, the disclosed therapeutic peptide is structurally linear. In some embodiments, the disclosed peptide is not linear. In various embodiments, the disclosed peptide is cyclic. In some embodiments, the disclosed peptide is macrocyclic. Macrocyclic peptides have attracted great interest from medicinal chemists because these molecules exhibit biospecificity similar to that of biological agents while possessing the size and biodistribution characteristics of many small molecules. Therefore, in some embodiments, the macromolecule is a macrocyclic peptide. The disclosed cyclic peptide may be natural or synthetic.

[0101] In some embodiments, the therapeutic macromolecule in the disclosed compositions has been approved by a health regulatory agency (e.g., the FDA or EMA) for use in human subjects. In some embodiments, the therapeutic macromolecule has not been approved by a health regulatory agency for use in humans. With oral administration of the disclosed macromolecules, with or without a penetration enhancer, safety, non-toxicity, and / or activity have been demonstrated in non-human animals and / or human animal subjects.

[0102] In various embodiments, the therapeutic peptides of the disclosed compositions have low apparent permeability (Papp). For example, the Papp of the therapeutic peptides of this disclosure may be less than 10.0 (x 10⁻¹²). -8 (cm / s). For example, the Papp of the peptides disclosed herein may be less than 3.0. In some embodiments, the Papp of the peptide is about 1.0, 0.95, 0.92, 0.85, or 0.80. In some embodiments, the Papp of the peptide is about 9.5 or 9.6 (e.g., 9.568). In some aspects, the Papp of the peptide is from 0.92 to 9.6. The therapeutic macromolecules of this disclosure may have a Papp of less than 10.0 x 10⁻⁶. -8 cm / s, less than 7.5 x10 -8 cm / s, less than 5.0 x 10 -8 cm / s, less than 3.0 x 10 -8 cm / s, less than 2.0 x 10 -8 cm / s or less than 1.0 x 10 -8 cm of Papp.

[0103] In various embodiments, the disclosed therapeutic peptides have high molecular weights. For example, the molecular weight of the peptides disclosed herein may be at least 1000 g / mol (or 1000 Da, or 1 kDa). In some embodiments, the peptides disclosed herein 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 a molecular weight higher than 2600 g / mol.

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

[0105] The disclosed peptides may exhibit low lipophilicity at physiological pH values ​​(e.g., pH 7.4). In other words, the disclosed peptides may exhibit low hydrophobicity at physiological pH values. In some embodiments, the disclosed peptides have a logD of less than 5.0 (at pH 7.4). In some embodiments, the disclosed peptides have a logD of about 1.5 to about 2.0 at pH 7.4 (e.g., a logD of 1.67).

[0106] The therapeutic peptides in the disclosed compositions and methods can be highly polar, for example, they can have a high isoelectric point (pI). In some embodiments, the pI of the therapeutic peptides in the disclosed compositions is 3.0 to 9.0. In some embodiments, the pI of the therapeutic peptides in the disclosed compositions is 8.0 to 9.0.

[0107] In some embodiments, the disclosed therapeutic peptide has inhibitory activity against protein ligands or receptors (e.g., membrane-bound receptors). In some embodiments, the disclosed therapeutic peptide is an agonist of a protein ligand or receptor. In some embodiments, the peptide exhibits inhibitory activity against proprotein convertase subtilisin-kexin type 9 (PCSK9), a ligand involved in the mammalian cholesterol metabolism pathway. For example, International Patent Publication No. WO 2019 / 246349, published on December 26, 2019 (incorporated herein by reference), discloses a cyclic peptide compound with inhibitory activity against PCSK9.

[0108] In some embodiments, the therapeutic peptide has the chemical structure shown below. In some embodiments, the therapeutic peptide is a compound of formula (I). This compound is disclosed in International Publication Nos. WO 2019 / 246349 and WO 2023 / 023245, published on February 23, 2019, and in Johns et al. Circulation ; 147:00 (May 2023), each of which is incorporated herein by reference. The method for preparing compound I is disclosed in WO 2019 / 246349. Formula I exhibits inhibitory activity against PCSK9. Its molecular weight is 1550.87 g / mol, and its Papp value is 9.568.

[0109] I A ternary mixture of sodium decanoate, a lubricant, and Formula I, as described in Table A, was prepared in a tableting simulator as a proof-of-concept for a sodium decanoate dosage form containing a macrocyclic peptide. These materials were mixed in a suitable mixer and then compressed using standard tableting equipment. The approximately 200 mg tablet contained approximately 11% of the Formula I compound and 88% sodium decanoate by weight.

[0110] Table A

[0111] In some embodiments, the therapeutic peptide has the chemical structure of Formula II as shown below. Formula II is (37 S 42 S )-37,42-dicarboxy-1-[(11 S 17 S 20 S ,twenty three S 27 S 39 S 42 S ,63 S ,66 R )-47-Fluoro-20-[(1 R[-1-hydroxyethyl]-17-[(4-methoxyphenyl)methyl]-11,63-dimethyl-10,16,19,22,30,40,58,61,64,67,70-undecano-28-oxa-1,9,15,18,21,24,31,41,51,62,65,68-dodecazanonacyclo[37.18.11.23,6.124,42.133,37.144,51.011,15.023,27. [045,50] Heptadecano-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-heptaazahexacontan-12-onthium-61-acid salt. Formula II is an esterified version of Formula I, consisting of Formula I covalently linked to a long-chain fatty acid. The method for preparing Formula II is disclosed in International Publication No. WO 2021 / 041770, published on March 4, 2021, which is incorporated herein by reference (see Example 34). Formula II exhibits inhibitory activity against PCSK9. Its molecular weight is 2470 g / mol, and its Papp value is 0.9200. In some embodiments, the therapeutic peptide is an esterified peptide.

[0112] II Therefore, in some embodiments, the therapeutic macromolecule in the disclosed tablet is a compound of formula I. In some embodiments, the macromolecule is a compound of formula II.

[0113] It should be understood that the disclosed tablets may contain any suitable amount of the therapeutic macromolecule. In various embodiments, the amount of the therapeutic macromolecule contained in the tablet ranges from 1% to 50% w / w. For example, the macromolecule (e.g., peptide) may be present in amounts of 1% to 5%, 1% to 4%, 4% to 5%, 5% to 10%, 8% to 10%, 10% to 11%, 10% to 12%, 10% to 15%, 10% to 30%, 20% to 30%, 15% to 20%, or 20% to 40% (w / w). In a particular embodiment, the tablet contains about 4% (w / w) of the therapeutic peptide. In some embodiments, the tablet contains 10% to 12% (w / w) of the therapeutic peptide. For example, the tablet may contain 10% to 12% of a compound of formula I. For example, the tablet may contain 10% to 12% of a compound of formula I. In some embodiments, the tablet contains about 1% of the therapeutic peptide, such as a compound of formula I. In some embodiments, the tablet contains 4% of the Formula I compound. In some embodiments, the tablet contains about 4.5% of the Formula I compound. In some embodiments, the tablet contains 10% or 20% of the Formula I compound.

[0114] Even when combined with penetration enhancers, each of the aforementioned macromolecules may still exhibit poor solubility, poor permeability, and / or rapid release characteristics. Those skilled in the art will understand that any poorly permeable therapeutic macromolecule can be used according to the present invention.

[0115] oral tablets For any disclosed oral dosage form (e.g., oral tablets), additional excipients are considered. The dosage forms described herein are formulated to contain the active pharmaceutical ingredient and can be administered with a mixture of suitable pharmaceutical diluents, binders, excipients, or carriers (collectively, “excipients”), appropriately selected according to the intended form of administration and in accordance with conventional pharmaceutical practice, i.e., oral tablets, oral capsules, oral suspensions, or oral formulations. In some embodiments, the disclosed tablets contain tableting excipients.

[0116] For example, for oral administration in tablet form, the tablet may contain one or more orally administered, non-toxic, pharmaceutically acceptable excipients, such as lactose, starch, sucrose, glucose, magnesium stearate (Mg), dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. In some embodiments, the disclosed tablets contain lactose. In some embodiments, the disclosed tablets contain cellulose-derived polymers, such as hydroxypropyl methylcellulose (HPMC) or microcrystalline cellulose (MCC). In some embodiments, the disclosed tablets contain HPMC. In some embodiments, the disclosed tablets contain MCC. In some embodiments, the disclosed tablets contain both HPMC and MCC.

[0117] In some embodiments, the tablet comprises one or more excipients selected from mannitol, starch, dicalcium phosphate, calcium carbonate, sodium carbonate, lactose, casein, caseinate, albumin, gelatin, gum arabic, mesoporous silica, and colloidal silica, or a combination thereof. In some embodiments, the tablet comprises mannitol and / or lactose. In some embodiments, the disclosed tablet comprises HPMC, MCC, mannitol, and / or lactose.

[0118] In some embodiments, the disclosed composition comprises a lubricant selected from magnesium stearate or sodium stearoyl fumarate or both. In various embodiments, the disclosed tablet comprises magnesium stearate. In some embodiments, the disclosed tablet comprises HPMC, MCC, lactose, and magnesium stearate. In some embodiments, the disclosed tablet comprises HPMC, MCC, mannitol, and magnesium stearate.

[0119] In some embodiments, the disclosed compositions comprise a diluent selected from polyethylene glycol (e.g., PEG300), polyethylene glycol (PEG4000), mannitol, lactose, or combinations thereof. In some embodiments, the disclosed compositions comprise a lubricating excipient. The disintegrant may be selected from croscarmellose sodium, croscarmellose, or carboxymethyl starch sodium. In another embodiment, the disintegrant is croscarmellose sodium. In some embodiments, the disclosed compositions comprise a flow aid selected from silica, starch, talc, or tricalcium phosphate. The disclosed compositions may comprise a solubilizer selected from propylene glycol, polysorbate 80, sorbitol, castor oil cremophor EL, castor oil, corn oil, cottonseed oil, safflower oil, sesame oil, soybean oil, peppermint oil, olive oil, medium-chain triglycerides (miglyol), glycerin, or combinations thereof.

[0120] Additional pharmaceutically acceptable excipients that may be included, as appropriate, include one or more tableting agents, fillers, penetrants, tension enhancers, flavoring agents, chelating agents, sugars, surfactants, polyols, stabilizers, emulsifiers, salts, fillers, and preservatives. In some embodiments, microcrystalline cellulose polymers, such as Avicel, are included. ® (e.g., Avicel) ® PH101 and PH102).

[0121] 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 comprise nanoparticles.

[0122] It should be understood that the disclosed tablets can be administered to the subject according to any dosage or treatment regimen. In some embodiments, one or more tablets (e.g., two tablets) are administered to the subject simultaneously or sequentially.

[0123] It should be understood that the disclosed compositions are suitable for treating any of a variety of diseases, conditions, or illnesses. In some aspects, the disclosed tablets are suitable for treating cardiovascular diseases. In some aspects, the disclosed tablets are suitable for treating atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, and related cardiovascular and cardiometabolic diseases in animal or human subjects. For example, the disclosed tablets can be used to treat hypercholesterolemia.

[0124] The disclosed tablets may have a total weight suitable for oral administration to a subject (e.g., a human subject). The total weight of the tablets may be from about 200 mg to about 1000 mg. The total weight of the tablets may be 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 total weight of the tablets is 200 mg, 205 mg, 210 mg, or 225 mg. In some embodiments, the total weight of the tablets is about 800 mg.

[0125] It should be understood that tablets of any shape can be prepared according to this disclosure. For example, tablets may have a circular planar shape, a circular standard concave shape, and / or an ellipse.

[0126] The disclosed tablets can be coated in any manner known in the art. In some aspects, any of the disclosed tablets is a film-coated tablet (FCT). Any conventional film coating system, such as enteric coating, can be used in these FCTs. In some aspects, the tablets are oral compression tablets (OCT) that are not coated.

[0127] In some aspects, methods are provided for formulating or generating oral dosage forms comprising any of the disclosed tablets. For example, this document discloses a method for mixing or blending a therapeutic macromolecule, any of the disclosed sodium decanoate granular compositions, and one or more additional excipients into a mixture, and compressing the mixture into tablets having improved tensile strength or compressibility relative to corresponding tablets containing commercially available sodium decanoate material.

[0128] Methods for generating medium-chain fatty acid salt aggregates The method for generating the medium-chain fatty acid salts is scalable because it can produce large quantities of solid material. In various embodiments, the disclosed method includes a method for producing sodium salts of medium-chain fatty acids (such as sodium decanoate).

[0129] The disclosed spherical aggregated crystals of medium-chain fatty acid sodium salts are produced using the following general method: 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 the 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 short-chain sodium alkoxide to form the resulting slurry; and c) Separate the agglomerated crystals from the resulting slurry.

[0130] In a first embodiment of this method, the first solvent is acetonitrile, and the second solvent is heptane. Therefore, this embodiment provides a method for preparing agglomerated crystals of medium-chain fatty acid sodium salts, the method comprising the following steps: a) Dissolve medium-chain fatty acids in acetonitrile to produce a first solution; b) Add heptane and a solution containing a short-chain sodium alkoxide to the first solution to form the resulting slurry; and c) Separate the agglomerated crystals from the obtained slurry.

[0131] In another aspect of the first embodiment, in step b, heptane and a solution containing a short-chain sodium alkoxide (e.g., a methanolic solution of sodium methoxide) are added to the first solution to induce liquid-liquid phase separation and form the resulting slurry. In some aspects, the solution containing the short-chain sodium alkoxide is 15 wt% to 40 wt% sodium methoxide. In a particular aspect, about 1 molar equivalent of a solution containing 15 wt% to 40 wt% sodium methoxide is added.

[0132] In another aspect of the first embodiment, in step b, heptane and a solution containing a sodium salt of a short-chain alcohol are added at a temperature below about 40°C.

[0133] In a second embodiment, the present invention relates to a method for preparing sodium decanoate (product A) aggregated crystals, comprising the following steps: a) Dissolving decanoic acid in a first solvent to produce a first solution, wherein the first solvent is acetonitrile; b) Adding a second solvent and a sodium methoxide solution to the first solution to form the resulting slurry, wherein the second solvent is heptane; and c) Separate sodium decanoate agglomerates (product A) from the obtained slurry.

[0134] In another aspect of the second embodiment, the agglomerated crystal is sodium decanoate. Therefore, a method for preparing agglomerated crystals of sodium decanoate (product A) is provided, comprising the following steps: a) Dissolve decanoic acid in acetonitrile to produce the first solution; b) Heptane and about 0.9 to about 1.5 molar equivalents of a sodium methoxide solution are added to the first solution at a temperature below about 40°C to form the resulting slurry; and c) Separate sodium decanoate agglomerates (product A) from the obtained slurry.

[0135] In a second embodiment, the addition of heptane induces liquid-liquid phase separation. In some aspects, the addition of heptane and sodium methoxide at a temperature below about 40°C induces liquid-liquid phase separation. In another aspect of the first or second embodiment, after step b, the resulting slurry is stirred for at least one hour. In some aspects, the resulting slurry is stirred for 1 to 30 hours, 5 to 25 hours, 5 to 15 hours, 10 to 25 hours, 10 to 15 hours, 15 to 25 hours, 20 to 25 hours, 25 to 30 hours, 20 to 30 hours, 20 to 24 hours, or 21 to 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 a particular aspect, the slurry is stirred for 20 to 24 hours.

[0136] In the third embodiment, the method for preparing sodium decanoate aggregate crystals (product A) includes the following steps: a) Dissolve decanoic acid in acetonitrile at a concentration of 1 L / kg to 50 L / kg to produce a first solution; b) Add 1.5 L / kg to 5 L / kg of heptane and about 0.94 to 1.2 molar equivalents of a solution containing about 20 wt% to about 40 wt% sodium methoxide to the first solution to form the resulting slurry. c) Stir the resulting slurry for at least one hour; and d) The resulting slurry is filtered to provide sodium decanoate agglomerated crystals (product A).

[0137] In some aspects of the above embodiments, the addition in step b is carried out at a temperature of about 60°C or lower. In some aspects of the above embodiments, the addition in step b is carried out at a temperature of about 50°C or lower, about 45°C or lower, about 40°C or lower, or about 35°C or lower. In some aspects of the above embodiments, the addition in step b is carried out at a temperature of about 40°C or lower. In some aspects, the addition in step b is carried out at about 40°C. In some aspects, the addition in step b is carried out at about 35°C. In some aspects, the addition in step b is carried out at room temperature. In some aspects, the addition in step b is carried out at about 22°C to about 35°C. In some aspects, the addition in step b is carried out 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.

[0138] In the fourth embodiment, the method for preparing sodium decanoate crystal aggregates includes the following steps: a) Dissolve decanoic acid in acetonitrile at a concentration of 4 L / kg to 8 L / kg to produce a first solution; b) While stirring continuously at a temperature of about 22°C to about 35°C, add about 1.5 L / kg to about 2.5 L / kg of heptane and about 0.96 to 1.05 molar equivalents of a solution containing about 25 wt% to about 30 wt% sodium methoxide to the first solution for about 1.0 to about 10.0 hours to produce the resulting slurry; c) Stir the resulting slurry for at least one hour, optionally for 20 to 24 hours; and d) Filter the resulting slurry to separate the resulting solids, and dry the resulting solids to provide sodium decanoate agglomerated crystals.

[0139] In any embodiment, in step d, after filtering the solids produced by the stirred slurry, the resulting solids may be washed to remove any residual chemicals (e.g., residual methacrylates). In some embodiments, the solids are washed with a solution containing acetonitrile and methanol. Therefore, in a fifth embodiment, the method for preparing sodium decanoate crystal aggregates comprises the following steps: a) Dissolve decanoic acid in acetonitrile at a concentration of 4 L / kg to 8 L / kg to produce a first solution; b) While stirring continuously at a temperature of about 22°C to about 35°C, add about 1.5 L / kg to about 2.5 L / kg of heptane and about 0.96 to 1.05 molar equivalents of a solution containing about 25 wt% to about 30 wt% sodium methoxide to the first solution for about 1.0 to about 10.0 hours to produce the resulting slurry; c) Stir the resulting slurry for 20 to 24 hours; d) Filter the resulting slurry to separate the resulting solids; e) Wash the resulting solid with a solution containing acetonitrile and methanol; and f) Dry the resulting solid to provide sodium decanoate aggregate crystals.

[0140] For example, in step e of the fifth embodiment, the obtained solid can be washed with a solution containing 2 L / kg to 10 L / kg acetonitrile and methanol. In some embodiments, two washes are performed, each using 2 L / kg. In some embodiments, the washing solution contains acetonitrile and methanol in a volume ratio of about 10:1, 9:1, or 8:1. In a particular embodiment, the washing solution contains 9 parts acetonitrile and 1 part methanol (v / v) (9:1). In some embodiments, this washing step is omitted.

[0141] In any of the embodiments described, in step a, decanoic acid is dissolved in 1 L / kg to 50 L / kg acetonitrile to produce a first solution. In any of the embodiments described, decanoic acid is dissolved in 3 L / kg to 30 L / kg acetonitrile to produce a first solution. In any of the embodiments described, decanoic acid is dissolved in 6 L / kg to 30 L / kg acetonitrile to produce a first solution. In any of the embodiments described, decanoic acid is dissolved in 7.5 L / kg to 25 L / kg acetonitrile to produce a first solution. In any of the embodiments described, decanoic acid is dissolved in 10 L / kg to 25 L / kg acetonitrile to produce a first solution. In any of the embodiments described, decanoic acid is dissolved in 10 L / kg to 20 L / kg acetonitrile to produce a first solution. In any of the embodiments described, decanoic acid is dissolved in about 25 L / kg acetonitrile to produce a first solution. In any of the described embodiments, decanoic 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 acetonitrile. In some aspects, 1, 2, or 3 L / kg acetonitrile may be used. In some aspects, about 3 L / kg acetonitrile may be used.

[0142] In any embodiment, decanoic acid is dissolved in acetonitrile at 6 L / kg to 8 L / kg 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 can also be used.

[0143] In various embodiments, a solution containing a sodium salt of a short-chain alcohol (e.g., sodium methoxide) is added at a temperature of 5°C to 40°C with continuous stirring for about 1.0 to about 10.0 hours. In any embodiment, 0.5 to 1.5 molar equivalents of a solution containing sodium methoxide are added to the first solution. In any embodiment, about 0.75 to about 1.5 molar equivalents 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 are added. In some embodiments, about 0.9 to about 1.00 molar equivalents, or about 0.93 to about 1.00 molar equivalents of a solution containing 15 wt% to 40 wt%, or 25 wt% to 30 wt% sodium methoxide are added. In a particular embodiment, 0.97 molar equivalents of 25 wt% to 30 wt% sodium methoxide are added. In some embodiments, the solution containing the sodium salt of a short-chain alcohol (e.g., sodium methoxide) is added over at least 2.0 hours. In any embodiment, sodium methoxide is added over about 4 to about 6 hours with continuous stirring. In some embodiments, sodium methoxide is added at a temperature of about 20°C to about 30°C over about 4 to about 6 hours, or about 5 to 5.5 hours. In some embodiments, sodium methoxide is added over 4.0 hours. In some embodiments, sodium methoxide is added over about 5 to 5.5 hours.

[0144] In any embodiment, in step b, a second solvent is added to the solution approximately 1 hour after the addition of the sodium methoxide-containing solution. In some embodiments, step b includes adding a second solvent, heptane, at a controlled rate over a period of 3 to 5 hours after the addition of sodium methoxide, while continuously stirring. Step b may include adding heptane at a controlled rate of 1.5 L / kg to 5.0 L / kg over a period of 3 to 5 hours after the addition of sodium methoxide, while continuously stirring. In any embodiment, heptane at a controlled rate of approximately 1.5 L / kg to approximately 2.5 L / kg over a period of 3 to 5 hours after the addition of sodium methoxide, while continuously stirring. In any embodiment, heptane at a controlled rate of approximately 1.9 L / kg over a period of 3 to 5 hours after the addition of sodium methoxide, while continuously stirring. In any embodiment, heptane at a controlled rate of approximately 3.5 L / kg to approximately 4.0 L / kg over a period of 3 to 5 hours, while continuously stirring.

[0145] In some embodiments, heptane is added at a controlled rate over a period of about 1.5 to 5.0 L / kg, 1.5 to 4 L / kg, 1.5 to 2.5 L / kg, 1.7 to 2.1 L / kg, or 3.5 to 4.0 L / kg over a period of about 1.5 to 5 hours, while continuously stirring. In some embodiments, heptane is added at a controlled rate over a period of about 3.5 to 4.5 hours, or over a period of about 4.5 to 5.5 hours, while continuously stirring. In some embodiments, heptane is added at a controlled rate over a period of about 3.5 to 4.5 hours, or over a period of about 4.5 to 5.5 hours, while continuously stirring. 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.

[0146] In another aspect of the fourth embodiment, in step c, heptane is added at a controlled rate over a period of about 3.5 to about 4.5 hours, while stirring is continued.

[0147] In some embodiments, a second solvent (e.g., heptane) is added to the solution less than one hour after the addition of the sodium methoxide-containing solution. In some embodiments, the second solvent (e.g., heptane) is added to the solution approximately 10, 15, 20, 30, 45, 40, 50, or 55 minutes after the addition of the sodium methoxide-containing solution. In some embodiments, the second solvent and the sodium methoxide-containing solution are added to the solution substantially simultaneously.

[0148] The method of this invention allows for the direct crystallization of agglomerated crystalline particles of medium-chain fatty acid sodium salts (e.g., sodium decanoate). This method avoids gel formation and other undesirable processing difficulties commonly encountered in the manufacture of sodium decanoate. The present invention utilizes liquid-liquid phase separation-induced particle agglomeration for the crystallization of such compounds. The disclosed method can be used to produce commercial-scale quantities of agglomerated particles of medium-chain fatty acid sodium salts, such as sodium decanoate. For example, the disclosed method can be used to produce single batches of sodium decanoate containing approximately 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. The disclosed method can be used to produce given weights of sodium decanoate in two or more batches, with batch weights including approximately 800 kg, 900 kg, 1000 kg, or 1100 kg (or 1.1 metric ton).

[0149] Any disclosed method may be modified based on knowledge in the art to include wet granulation, dry granulation, or roll forming process flow.

[0150] Methods for preparing aggregated crystals of medium-chain fatty acid sodium salts (particularly sodium decanoate crystals) are described in the following schemes and examples. Starting materials are prepared according to methods known in the art or methods described herein. The following abbreviations are used herein:

[0151] In some cases, the order of the aforementioned reaction schemes can be altered to promote the reaction or avoid the formation of unwanted byproducts. The following examples are provided to provide a more complete understanding of the invention. These examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0152] Example The following examples are for illustrative purposes only and should not be construed as further limitations. All figures, references, patents, and published patent applications cited in this application are expressly incorporated herein by reference.

[0153] Example 1A Decanoic acid (1) (10 g, 58.5 mmol) was mixed with acetonitrile (10 ml) in a suitable container equipped with a suitable stirrer. The batch was stirred at 40 °C until completely dissolved. Sodium methoxide (2) (3.17 g, 58.5 mmol) was added as a 30 wt% methanol solution (10.57 g) over a period of 5.5 hours under vigorous stirring to form a slurry. Simultaneously with the addition of (2), heptane (15.15 ml) was added over a period of 5 hours using a separate feed line. The resulting slurry was stirred for another 24 hours. The solid was filtered, washed twice with 20 ml of acetonitrile:methanol (9:1 v / v) solution, and then dried under vacuum at 35–40 °C and purged with nitrogen to give crystalline sodium decanoate (3, product A) (9.48 g, yield 83%). Figure 20 The materials prepared using this procedure are shown.

[0154] All the mixtures and formulations studied were manufactured using direct compression. For oral tablet formulations containing sodium decanoate mixtures and additional components (i.e., binary mixtures containing therapeutic peptides, or ternary mixtures containing therapeutic peptides and lubricants), the materials were mixed in a suitable mixer and then compressed using standard tableting equipment.

[0155] Compression performance Sodium decanoate powder samples and formulations containing sodium decanoate samples were compressed into cylindrical tablets using a single-station compaction simulator. The samples were compressed into tablets using a 9.525 mm circular flat tableting die within a compression pressure range of 10 to 400 MPa. Tableting simulation of the formulation was performed under force control. The combined punch speed was set to 50 to 100 mm / s. The weight (W), thickness (h), diameter (D), and hardness (B) of the resulting tablets were measured. Hardness was defined as the peak force required to break the cylindrical tablet. The tablet weight was controlled between 225 and 375 mg. The obtained thickness and hardness values ​​were used to calculate the tablet tensile strength (T) using equation X. The obtained tablet tensile strength was combined with the compression pressure to form a tabletability curve.

[0156] --- Equation X Table 1 shows the generic (platform) composition of commercial tablet formulations containing sodium decanoate products. These formulations contain disintegrants, glidants, magnesium stearate lubricant, lactose, and microcrystalline cellulose. Four of these formulations contain commercially available sodium decanoate, and one uses agglomerating material product A. Commercially available material 1 is sodium decanoate material sold (and sourced from) Pfaltz & Bauer Inc. Commercially available material 2 is sodium decanoate sold (and sourced from) BioSpectra Inc. (BSI). Commercially available material 3 is sodium decanoate sold by TCI Chemicals (TCI America). And commercially available material 4 is sodium decanoate sold by Jost Chemical.

[0157] Table 1. Composition of formulations containing sodium decanoate from different sources

[0158] Figure 1 The figure shows the tableting characteristics of the five formulations. These results indicate that Product A (solid circle) has superior performance compared to all commercially available materials tested. Figure 1 This reflects the tensile strength of tablets formulated using sodium decanoate sources (including Product A). The image shows that the material generated using Product A (represented by solid circles) produced the toughest material within the relevant compression pressure processing range. The in-mold bulk density of the five formulations was estimated using the tablet mass and the volume of the filling die before compression. The formulation containing commercially available material 2 had the lowest in-mold bulk density of all tested materials, with a nominal value of 0.39 g / mL. The in-mold bulk densities of the other four formulations ranged from 0.44 to 0.47 g / mL. All observed in-mold bulk densities showed acceptable values ​​for processing these mixtures via tableting.

[0159] Figure 2A and 2B The compressibility of tablets without tableting aids was demonstrated. These tablets contained 100% Product A, commercially available Material 2 (sodium decanoate from BSI), commercially available Material 3 (sodium decanoate from TCI Chemicals), and commercially available Material 4 (sodium decanoate from Jost). Figure 2AProduct A (represented by solid circles) exhibits excellent strength development, reflected in its significantly improved tensile strength. For example, it achieves tensile strengths of 1.9 MPa to 2.1 MPa within a compressive stress range of 40 MPa to 80 MPa. For commercially available material 2 (represented by crosses), it is not possible to prepare tablets that do not rupture upon ejection. For commercially available materials 3 (represented by hollow squares) and 4 (represented by hollow triangles), it is possible to prepare low-strength tablets, but these tablets are not suitable for further processing.

[0160] like Figure 2B As shown, 100% Product A tablets exhibit a maximum tensile strength of approximately 2.1 MPa at a tablet density of approximately 1.03 g / mL. In all cases, tablets prepared using Product A showed higher strength compared to corresponding tablets prepared from commercially available materials 3 and 4 at the same macroscopic porosity (e.g., density). This indicates that although all tablets were prepared to have the same porosity, the localized particle-to-particle contact in Product A significantly improved tablet strength.

[0161] In summary, Figure 1 , Figure 2A and Figure 2B The results show that Product A produces superior physical strength and toughness in compressed tablets. Tablets containing Product A exhibit higher tensile strength, thus enabling better downstream processing and improved physical robustness. Furthermore, the superior strength development demonstrated by Product A makes it more suitable for tablet manufacturing requiring dry granulation processes.

[0162] Tablets of different shapes and sizes were prepared using the material from Product A. 100% sodium decanoate tablets (referred to herein as “pure” or “single-entity” decanoate tablets) with weights ranging from 200 to 800 mg were prepared. Round planar, round standard concave, and elliptical tablets were successfully prepared.

[0163] Liquidity The flow properties of Product A were compared with those of sodium decanoate from different commercial sources by determining bulk density and tap density. Bulk density and tap density refer to the density of the powder when it is packed together. Low density indicates poor flowability or packing properties. Carr's Index and Hausner ratio are indices calculated using bulk density and tap density. For example, Hausner ratio is calculated by dividing tap density by bulk density. Low values ​​of both indices indicate excellent flow properties. Bulk density was determined using a 100 mL graduated cylinder and at least 50 mL of powder material. The powder material was loaded into the graduated cylinder, and the mass and volume of the material were recorded. The mass-to-volume ratio was calculated to obtain the bulk density of the powder. The density was then determined according to the United States Pharmacopeia (USP). <661> According to the specifications, the graduated cylinder was tapped 1,250 times using a tapped density meter. The tapped density value was then calculated based on the resulting material volume. This experiment analyzed a small batch (approximately 1 kg) of product A.

[0164] Table 2 reports the bulk density and tap density of the materials, as well as the calculated Karl Fischer index and Hausner ratio. As shown in Table 2, the Karl Fischer index and Hausner ratio of Product A are significantly lower than those of commercially available materials 1-4, indicating that Product A has superior powder flowability. Despite its lower density, the sodium decanoate agglomerated crystalline material presented in this paper still exhibits excellent flow characteristics, as reflected in its lower Karl Fischer index and Hausner ratio.

[0165] Table 2. Flowability determination of sodium decanoate from different sources

[0166] Next, the flow characteristics of commercial-scale batches of Product A were compared using bulk density and tap density determinations. The bulk density and tap density of ten batches of Product A produced under GMP conditions were evaluated, each containing 60 to 543 kg (theoretical value) of material. Bulk density was determined using a 10 mL graduated cylinder and at least 6 mL of powder material. The powder material was loaded into the graduated cylinder, and the mass and volume of the material were recorded. Then, the determination was performed according to the United States Pharmacopeia (USP). <661> The graduated cylinders were tapped 2,500 times using a tap density meter. Table 3 reports the flowability index of these batches of material.

[0167] As shown in the figure, the provided sodium decanoate material exhibits a tap density greater than 0.50 g / mL in commercial-scale batches, with many batches exceeding 0.55 g / mL. Batch 001L021 achieves a tap density of 0.69 g / mL. The batch that performed best in the compression stress test (see below) shows a tap density in the range of 0.50 to 0.69 g / mL. Therefore, the density of these commercial-scale batches is significantly higher than that of the smaller-scale batches reported in Table 2. The overall Hausner ratio for these ten batches is less than 1.60, even as low as 1.35. These results further demonstrate the excellent powder flowability of Product A.

[0168] Table 3. Flowability determination of larger batches of Product A

[0169] Figure 17 SEM images of sodium decanoate from commercially available materials 1-4 are shown, providing a comparison of their respective morphologies. The preparation method of this compound has a significant impact on the structure and physical appearance of the materials. Commercially available material 2 (sodium decanoate from BSI) is a smooth sphere, obtained by spray drying. Commercially available materials 3 (sodium decanoate from TCI Chemical) and 4 (sodium decanoate from Jost) are large, elongated flakes. Product A constitutes an aggregated solid with a rough surface and no elongation in any axial direction. The disclosed process enables the realization of this unique morphology of product A, is suitable for manufacturing and operation in standard equipment, and possesses the ideal characteristics required for formulation production.

[0170] Influence of material properties (SSA and D) 90 ): The particle size of product A was determined by laser diffraction (Malvern Mastersizer 3000, Malvern Instruments Ltd., UK) at a feed pressure of 3 bar and a feed rate of 40% using an AeroS dry dispersion unit. The samples were measured three times repeatedly, with opacity values ​​ranging from 1% to 10%. The specific surface area (SSA) of the sodium decanoate solid samples was determined using the gas adsorption-BET method (Tristar II Plus, Micromeritics) under nitrogen. Prior to measurement, the samples were degassed in a nitrogen atmosphere at 35°C for 1–2 hours.

[0171] For SSA at 9.9 m 2 / g to 36.7 m 2 Between / g and particle size distribution D 90 The compression behavior of multiple batches of Product A, ranging from 289 µm to 863 µm, was evaluated. Figure 3The compression behavior of four commercial-scale batches of Product A is shown. In all cases, tablets with a tensile strength of 1 MPa or higher were obtained. As shown, in Examples 1, 2, and 3, a tensile strength of approximately 2.1 MPa was achieved at compressive stresses between 80 MPa and 130 MPa. The batch of Example 2 achieved a strength of approximately 2.15 MPa at a compressive stress of 95 MPa. Table 4 provides the batch numbers and reports. Figure 3 The SSA and D of the four embodiments listed in the illustration 90 value.

[0172] Table 4. Material properties of commercial-scale decanoate batches

[0173] Figure 4 The tensile strength of tablets containing product A without tableting aids, prepared under compressive stress ranging from 30 MPa to 50 MPa, is shown as a function of D. 90 The relationship between tensile strength and D can be seen from this. 90 It decreases as it increases.

[0174] The comparison provided in Table 5 shows that Product A has a higher SSA than commercially available materials 2 and 4. Product A has an SSA at least 3.8 times higher than commercially available materials 2 and 4. The high SSA value of Product A within this particle size range shown in this table reflects the porous structure produced by the method for preparing agglomerated crystals according to the present invention. Figure 5 The tensile strength of sodium decanoate tablets prepared under compressive stresses ranging from 30 MPa to 50 MPa is shown as a function of salicylic acid stress (SSA). This data indicates that the tensile strength of the tablets increases with increasing SSA of sodium decanoate.

[0175] Figure 5 The results show that, due to its higher SSA (Surface Area Satiety), Product A exhibits excellent physical strength and toughness in tablet compression. SSA is greater than 13 μm. 2 Tablets containing Product A at / g (5 times higher than commercially available materials 2 and 4) have a tensile strength of 1 MPa or higher (5.8 to 11.7 times higher than commercially available material 4 (Jost), thus enabling better downstream processing and improved physical robustness.

[0176] Table 5. Comparison of specific surface area between sodium decanoate agglomerates (Product A) and commercially available crystalline sodium decanoate.

[0177] Without being bound by any particular theory, the improved tensile strength observed in tablets containing Product A, compared to tablets containing commercially available sodium decanoate, is related to the high specific surface area of ​​the agglomerated particles, partly attributed to their internal porosity. A higher specific surface area enables greater plastic deformation and enhanced strength development during powder compression. This theory is supported by the results of the compaction plasticity work assessment described below.

[0178] Despite the existence of this theory, it is still assumed that a high specific surface area, spherical agglomeration morphology, moderate particle size distribution, and / or excellent powder flowability contribute to the observed enhanced tensile strength.

[0179] Compaction plastic work Compaction plastic work is an indicator of the amount of irreversible work performed during compression. The values ​​reported in Table 2 have been normalized by tablet mass and are presented in joules per gram (gram of compressed material). The compaction plastic work indicates how much energy enters the system, responsible for the plastic deformation of particles, particle breakage to create new surfaces, and heat generation. High compaction plastic work values ​​indicate significant particle deformation, rearrangement, and breakage during powder compression. Therefore, materials with higher compaction plastic work tend to have greater robustness.

[0180] The results in Table 6 show that Product A has a compaction work 2.3 times higher than that of commercially available Material 4. These results indicate that tablets produced using Product A have greater robustness without the use of tableting aids.

[0181] Table 6. Compaction plasticity work of agglomerated material (Product A) compared to commercially available sodium decanoate.

[0182] Evaluation of friability and tensile strength in high-concentration decanoate tablets 90 / 10 Formulation Example Sodium decanoate (Product A) powder sample was mixed with lactose monohydrate to prepare the mixture as shown in Table 7. Using a 9.525 mm circular flat tableting die, the mixture was compressed into cylindrical tablets under controlled force, with a compression pressure (stress) ranging from 6 to 180 MPa, and the weight was controlled between 225 and 375 mg. The weight, thickness, diameter, and hardness of the tablets were determined, and the tensile strength was calculated as described above.

[0183] Figure 6 and Figure 7The compressibility and tabletability of these mixtures containing 90% Product A, commercially available material 2, and commercially available material 4 were demonstrated. Consistent with observations of the pure substances, the blends containing 90% Product A exhibited significantly better strength development than those composed of commercially available material 2 or commercially available material 4. Based on these data, tablets were prepared using a 7.144 mm standard circular concave die at controlled weights between 150 and 250 mg. Compression pressures were selected for each blend to maintain a similar tablet density of approximately 1.0 g / mL. The tablets were then subjected to a friability test, with friability loss measured after 100, 200, and 500 revolutions. Figure 8 As shown. These data indicate that tablets containing 90% Product A have superior robustness compared to tablets containing 90% of commercially available material 2 or 90% of commercially available material 4. The latter two types of tablets containing commercially available materials failed to meet the United States Pharmacopeia (USP) requirements. <1216> The standard for friability specified in the document.

[0184] Table 7. Composition of formulations containing sodium decanoate from different sources

[0185] 80 / 20 Formulation Example Sodium decanoate (Product A) powder was mixed with microcrystalline cellulose, lactose monohydrate, and hydroxypropyl methylcellulose (HPMC) to prepare the mixtures described in Table 8. Using a 10 mm circular flat tableting die, the mixture was compressed into cylindrical tablets at a compression pressure ranging from 35 to 200 MPa, with a weight controlled between 275 and 375 mg. The weight, thickness, diameter, and hardness of the tablets were measured, and the tensile strength was calculated as described above.

[0186] Figure 10 The compressibility of these mixtures containing 80% Product A was demonstrated. See below. Figure 3 and 6 As shown, tablet strength development is consistent with data from 100% Product A and 90% Product A dosage forms. The data in the figure indicate the suitability of formulations using excipients with different material properties (such as MCC and lactose) that can perform other functional uses rather than acting as tableting aids.

[0187] Table 8. Composition of pharmaceutical products containing sodium decanoate and different excipients

[0188] Further evaluation of the effects of lactose To further understand the role of lactose in the disclosed oral tablets, sodium decanoate (Product A) powder was mixed with lactose monohydrate in different amounts (w / w) to prepare mixtures as described in Table 9. Using a 10 mm circular flat tableting tool, the mixtures were compressed into cylindrical tablets at a compression pressure ranging from 35 to 150 MPa, with a weight controlled between 275 and 375 mg. The weight, thickness, diameter, and hardness of the tablets were measured, and the tensile strength was calculated as described above.

[0189] Figure 11 The compressibility of these mixtures containing Product A and varying amounts of lactose was demonstrated. These data indicate that, under compression conditions comparable to other examples, increasing the sodium decanoate concentration improves tablet strength development. Therefore, in these dosage forms, Product A contributes more to the mechanical strength and integrity of the formulation than lactose, thus lactose does not function as a tableting aid.

[0190] Table 9. Composition of pharmaceutical preparations containing sodium decanoate and different amounts of lactose

[0191] Film-coated tablets In the direct compression process, sodium decanoate powder (Product A) was successfully compressed into round biconvex tablets using a rotary tablet press. Product A was compressed into tablets using a 9.525 mm circular standard concave tableting die. Compression pressures ranging from 40 to 270 MPa were evaluated during manufacturing. The target tablet weight was 250 mg. The weight, thickness, diameter, and hardness of the tablets were determined, and tensile strength was calculated as described above. The tablets exhibited good compressibility, with an average tensile strength ranging from 1.6 to 1.8 MPa. Tablet production yields ranged from 4,800 to 14,400 tablets per hour. Pure (neat) sodium decanoate tablets were film-coated using enteric and non-enteric film coating systems. Three film coating compositions were evaluated: non-enteric film coating as a sealing coating, enteric film coating, and a combination of both film coating systems. The compositions and components of the evaluated coatings are shown in Table 10.

[0192] Table 10. Composition of sodium decanoate film-coated tablets

[0193] Evaluation of tableting parameters for batch A of product Several tableting performance parameters, including SSA, PSD, bulk density (BD), and tap density (TD), were determined for 14 exemplary batches of Product A material using the methods described above (see paragraphs

[163] -

[164] ). Each sample was compressed into pure (100% Product A) tablets, and the tensile strength (TS) of each resulting tablet at 80 MPa compressive stress was evaluated.

[0194] Measure the bulk density using a 10 mL graduated cylinder, with a filling volume of at least 60%. Record the mass and volume of the material; the mass-to-volume ratio provides the bulk density. Then, tap the graduated cylinder 2000 times using a tap density meter. The resulting volume is then used to determine the tap density of the material.

[0195] The tableting performance parameters of each sample batch are listed in Table 11 in ascending order of SSA.

[0196] Table 11. Evaluation of tableting performance of exemplary batch samples

[0197] Table 11 lists batches of samples, specifically those producing tablets with a tensile strength higher than 1.3. Of these 13 samples (numbered 2-14), the observed SSA values ​​ranged from ~5.9 m. 2 / g (sample 2) up to ~41 m 2 / g (sample 14). The D of these samples 90 The values ​​ranged from ~158 µm (sample 6) to as high as 657 µm (sample 9). The BD values ​​of the samples ranged from 0.15 g / mL (sample 6) to 0.40 g / mL (samples 2 and 4). The TD values ​​of the samples ranged from 0.32 g / mL (sample 13) to 0.54 g / mL (samples 2 and 4). The Hausner ratio of the samples ranged from 1.30 (sample 9) to 2.20 (sample 6). These data indicate that the composition containing sodium decanoate crystal particles (wherein the sodium decanoate particles have a diameter of 5.9 µm) is suitable for use in this composition. 2 / g (preferably 9.6 m 2 / g) to 41m 2 Average SSA per g, tap density of at least 0.32 g / mL, and Dm of 158 µm to 657 µm 90 It can produce tablets with excellent compression properties.

[0198] All 14 samples listed in Table 11 were successfully tableted and their tensile strength was measured to be in the range of 1.27 MPa (sample 1) to 2.27 MPa (sample 11). Each sample exhibited a spherical aggregate morphology.

[0199] Example 1B X-ray powder diffraction (XRPD) like Figure 1 The X-ray powder diffraction (XRPD) data shown were acquired on a Panalaytical X-Pert equipped with a Bragg-Brentano configuration and a copper radiation source, with Kα monochromaticity achieved through a nickel filter. A fixed slit optical configuration was used for data acquisition. The data acquisition angle ranged from 2 to 40° (2θ). Sample preparation involved gently pressing the sample onto a zero-background silicon support. Figure 12 All samples shown were obtained in this manner to compare materials prepared using the disclosed process with commercially available materials.

[0200] Figure 12 The XRPD pattern of Product A is shown, along with a stacked comparison of its XRPD patterns with those of commercially available sodium decanoate substitutes (e.g., those from Jost and BSI) prepared by different processes. The figure shows differences in reflectance intensity, indicating different preferred generating phases, but the overall "fingerprint" of the crystal pattern is the same. The sodium decanoate crystals produced by the disclosed method have a completely different morphology from commercially available products prepared by more expensive methods.

[0201] Differential Scanning Calorimeter (DSC) Thermal events occurring with increasing temperature were monitored using a TA Instruments Discovery differential scanning calorimeter (DSC). Samples of 2–5 mg of product A were placed in a closed, non-hermetic aluminum dish with two small holes and cyclically heated twice from 10 to 300 °C at a heating rate of 10 °C / min.

[0202] Figure 21 The images show two heating cycles and one cooling cycle performed on sodium decanoate material, ranging in temperature from room temperature to 300 °C. The downward peaks are endothermic, indicating that the material is absorbing heat, suggesting a crystal / solid change or a phase transition (e.g., melting or boiling). The top curves represent what happens when the same sample is cooled. During cooling, there are upward peaks (exothermic, i.e., heat release). These are reversals of the physical phenomena that occur during heating. The hysteresis between the onset and reversal temperatures is usually due to the difference in kinetic barriers between the forward and reverse processes. The width of the hysteresis typically depends on the rate of temperature change during the DSC scan. Figure 21Two overlapping heating curves (y-axis below zero) are observed. The overlap of the two lines indicates that the changes experienced by product A during the experiment were reversible and that product A was not destroyed during the scan. The variation in the width of the first downward peak between the two heating curves is related to the presence of some absorbed water in the initial scan. DSC spectra can be used as a characterization tool because the peak positions and areas, as well as the overall shape of the scan, are characteristic of sodium decanoate.

[0203] Gas chromatography (GC) for the determination of residual solvents Preparation of standards: 0.01% v / v n-heptane, methanol and acetonitrile standards for quantification and 0.001% v / v limit of quantitation (LOQ) standards for limit reporting are prepared in diluents by serial dilution.

[0204] Sample preparation: Dissolve ~20 mg / mL of sample in diluent. Vortex and sonicate as needed to dissolve the sample.

[0205] Instrument conditions:

[0206] The GC evaluation results are shown in the table below:

[0207] LOQ (Limit of Quantification): Acetonitrile 393 ppm Thermogravimetric analysis Thermogravimetric analysis (TGA) of product A was performed using a TA Q 500 thermogravimetric analyzer (TA Instrument). Samples (5-15 mg) were heated from 25°C to 320°C at a rate of 10°C / min, with nitrogen purging at a rate of 200 mL / min. Figure 14 As shown, Figure 14 The top curve monitors the mass change of product A when heated under a nitrogen atmosphere. The slight mass loss (0.8 wt%) within the first 250°C corresponds to the expected presence of surface-adsorbed water in the material. The decrease that occurs after 250°C indicates the onset of decomposition or evaporation. The bottom curve corresponds to the derivative of the mass change, capturing the rate of change of the top curve.

[0208] Granularity analysis using Microtrac FlowSync Approximately 50 mg of powder sample was transferred to a 20 mL scintillation vial. 5 mL of IsoparG / 0.25% w / v lecithin fluid was added to the vial, followed by gentle agitation to disperse the particles. After instrument initialization and background measurements (30 seconds), the suspension was poured into the flow cell unit. The vial was rinsed three times with 1 mL of IsoparG / 0.25% lecithin fluid (total 3 mL), and all rinses were poured into FlowSync. Measurement parameters included: volumetric distribution, geometric 8-root progression from 0.0215 to 2000 µm, residuals disabled, standard filter enabled, particle RI = 1.51 (irregular shape), fluid RI = 1.42, and flow rate 60%. Particle size distribution was calculated as the average of three 30-second scans. Results were reported as volumetric distribution. Samples were analyzed under the following conditions: untreated, sonicated at 25% power for 30, 60, and 90 seconds. The instrument used was a Microtrac M5001-3L Sync + FlowSync.

[0209] Ultrasonication is a standard laboratory technique in which vibrational energy is applied to powder to help disperse agglomerates within the material and ensure that particle size measurements capture the true size of the product particles. Agglomeration is often observed in dry solids due to natural adhesion, which can bias measurement results and lead to an overestimation of powder particle size. Therefore, applying adequate ultrasonication may be important for analytical accuracy. Figure 15 The results show representative volume-weighted particle size distributions of a small batch of product A. The curves show the probability density of product particles having a specified radius on the x-axis. The curves also show the effect of ultrasonic treatment on the measured particle size. As the ultrasonic treatment time increases, the particle size decreases and tends to normalize, which is typical behavior of dry solids undergoing deagglomeration and tending towards a "true" distribution of primary particles, best illustrated in the curves labeled 60 seconds and 90 seconds. Figure 15 The results showed that the particle size distribution was the same after 60 and 90 seconds of ultrasonic treatment, indicating that the sample of this material requires at least 60 seconds to be adequately measured.

[0210] Figure 15The process also demonstrates how the disclosed process generates primary particles with a unimodal normal particle size distribution, which is ideal for manufacturing processes. A unimodal distribution is ideal because it indicates particle homogeneity, with minimal fine powder or large agglomerates that would otherwise lead to non-uniform flow, filtration, and compression behavior. Uniform distribution is also a sign of proper control during crystallization and agglomeration, as it provides evidence that undesirable particle formation phenomena (such as abrasion) have not occurred, and that the overall particle size and morphology are set by controlled variables manipulated during batch design.

[0211] Scanning electron microscope (SEM) images Sodium decanoate powder samples were fixed onto a 32 mm SEM stage using carbon sticky adhesive. A platinum sputtering coating was then applied to the samples. The samples were loaded into a Hitachi TM3030 Tabletop scanning electron microscope. Imaging of the samples was performed in high vacuum mode using a secondary electron (SE) detector. The voltage was set to 2 kV and the spot intensity to 30 units. Images were acquired at different magnifications.

[0212] Figure 16 The images show that Product A can be clearly present as agglomerated, flaky primary particles. This morphology is extremely difficult to achieve without spray drying and is more desirable than elongated, flaky or needle-like structures. The exhibited morphology reflects excellent compressibility in manufacturing processes and dosage forms containing Product A.

[0213] The particle morphology of commercially produced sodium decanoate batches was observed using a Hitachi SU5000 SEM. Powder samples were fixed to the SEM stage using adhesive carbon tape and coated with platinum by sputtering before imaging. Particle imaging was performed using an accelerating voltage of 3 kV and a secondary electron detector.

[0214] Figures 9A-9C Representative SEM images of sodium decanoate obtained from (A) commercially available material 2, (B) commercially available material 4, and (C) product A (agglomerated material) are shown. The particle morphology of commercially available material 2 is characteristic of spray-dried materials, consisting of smooth, spherical particles, while commercially available material 4 consists of flat, irregularly shaped large particles. Figure 9D As shown, product A has a morphology consisting of a combination of porous aggregates ranging from spherical to irregular shapes, with a surface area (SSA) of 9.9 μm. 2 / g to 36.7 m 2 Between / g.

[0215] Example 2A Decanoic acid (1) (25 g, 145 mmol) was mixed with acetonitrile (630 ml) in a suitable container equipped with a suitable stirrer. The batch was stirred at room temperature until completely dissolved. Sodium methoxide (2) (8.23 g, 152 mmol) was added as a 25 wt% methanol solution (32.92 g) over a period of 5 hours with vigorous stirring to form a slurry. Heptane (93-103 ml) was added simultaneously over a period of 4 hours using a separate feed line after the first hour of adding (2). The resulting slurry was stirred for another hour. The solid was filtered, washed with acetonitrile (100 ml each time, twice), dried under vacuum at 35-40 °C and purged with nitrogen to give crystalline sodium decanoate (3, product A) (27.79 g, 99% yield).

[0216] Example 2B Decanoic acid (1) (1.00 kg, 5.81 mol) was mixed with acetonitrile (6.0 L) in a suitable container equipped with a suitable stirrer. The batch was stirred at room temperature until completely dissolved. Sodium methoxide (2) (0.304 g, 5.63 mol) was added as a 30 wt% methanol solution (1.01 kg) over a period of 5.5 hours under vigorous stirring. Simultaneously with the addition of (2), heptane (1.9 L) was added over a period of 5 hours via a separate feed line. The resulting slurry was stirred for another 24 hours. The solid was filtered, washed twice with acetonitrile:methanol (9:1 v / v) solution, 2 L each time, and then vacuum dried at 35–40 °C and purged with nitrogen to obtain crystalline sodium decanoate (3, product A) (1.09 kg, yield 97%). A photograph of the slurry prepared by this method and the separated sodium decanoate crystals is shown below. Figure 21 As shown. A product with a scale of 1.0 kg was prepared.

[0217] Example 2C Decanoic acid (1) (5.02 g, 29.1 mmol) was mixed with acetonitrile (30 ml) in a suitable container equipped with a suitable stirrer to form a homogeneous solution. Sodium methoxide (2) (28.3 mmol) was added as a 30 wt% methanol solution over a period of 5 hours under vigorous stirring to form a slurry. Simultaneously with the addition of (2), hexane (10.54 ml) was added over a period of 5 hours using a separate feed line. The resulting slurry was stirred for another 17 hours. The solid was then filtered, washed twice with 15 ml of acetonitrile:methanol (9:1 v / v) solution, and then dried under vacuum at 40 °C and purged with nitrogen to obtain crystalline sodium decanoate (3, product A) (5.24 g, 93% yield). Figure 19 The materials prepared using this step are described.

[0218] Example 2D Decanoic acid (1) (5 g, 29 mmol) was mixed with acetonitrile (10 ml) in a suitable container equipped with a suitable stirrer. The batch was stirred at 35 °C until completely dissolved. Sodium methoxide (2) (1.55 g, 29 mmol) was added as a 30 wt% methanol solution (5.18 g) over a time of 5.5 h with vigorous stirring to form a slurry. Simultaneously with the addition of (2), heptane (7.4 ml) was added over a time of 5 h using a separate feed line. The resulting slurry was stirred for another 15 h. After aging, an additional 1 ml of heptane was added and the batch was heated to 40 °C. The slurry was aged for another 3 h. The solid was filtered, washed with acetonitrile (10 ml, twice), and then vacuum dried at 35–40 °C and purged with nitrogen to give crystalline sodium decanoate (3, product A) (4.1 g, yield 74%). Figure 20 The materials prepared using this step are described.

[0219] Example 2E Sodium decanoate (3) (77 mg, 0.40 mmol) was mixed with dimethylacetamide (DMAc) (1 ml) in a 4 mL vial to form a slurry. Heptane (0.3 mL) was then added to the vial to form a slurry of agglomerated particles. Optical microscopic images showing these particles are shown below. Figure 10 (Top image)

[0220] Sodium decanoate (3) (78 mg, 0.40 mmol) was mixed with dimethylformamide (DMF) (1 ml) in a 4 mL vial to form a slurry. Heptane (0.2 mL) was then added to the vial to form a slurry of agglomerated particles.

[0221] Sodium decanoate (3) (88 mg, 0.45 mmol) was mixed with n-methyl-2-pyrrolidone (NMP) (1 ml) in a 4 mL vial to form a slurry. Heptane (0.2 mL) was then added to the vial to form a slurry of agglomerated particles. Figure 18 The bottom image shows a microscope image depicting these particles.

[0222] DMAc, DMF, and NMP are all polar aprotic solvents. For example... Figure 18As highlighted in the image, the combination of sodium decanoate with heptane and a polar aprotic solvent produces aggregated crystalline sodium decanoate products. Therefore, in the disclosed method for producing sodium decanoate aggregates, any of several polar aprotic solvents can be used.

[0223] Example 3: Sodium nonanoate (C9) material This article provides agglomerated crystalline particles of sodium nonanoate, and powder materials containing these particles. These particles exhibit excellent flowability and / or compressibility. These sodium nonanoate particles exhibit a morphology comprising spherical aggregates. They can have morphologies characterized by spherical and irregularly shaped aggregates, and / or porous morphologies. These sodium nonanoate particles can have an astonishing SSA (Surface Area Satiety) one order of magnitude higher than commercially available sodium nonanoate materials. These particles have a D (Density Scale) of 900 µm or less. 90 .

[0224] In some respects, any disclosed sodium nonanoate particles are combined with a therapeutic macromolecule to form a mixture. This mixture can 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, condition, or illness. Therefore, this document provides oral tablets comprising a therapeutic macromolecule and sodium nonanoate. Due to the improved compression behavior of these particles, these oral tablets do not require tableting aids.

[0225] Therefore, this article provides oral tablets comprising a therapeutic macromolecule and sodium nonanoate, wherein the tablets are substantially free of tableting excipients, and wherein the therapeutic macromolecule exhibits low Papp (e.g., Papp less than 10 × 10⁻⁶). -8 (cm / s). Therapeutic macromolecules may contain macrocyclic peptides. Therapeutic macromolecules may be compounds of formula I.

[0226] In some embodiments, the tablet has a tensile strength that is 2, 3, 4, 5, or 6 times higher than that of a corresponding tablet containing commercially available sodium nonanoate. In some aspects, the tablet contains about 80% to 99% sodium nonanoate, or about 80% to 90% sodium nonanoate (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 higher than 2.5 MPa. In some embodiments, the tablet has a tensile strength of at least 1.3 MPa or at least 1.4 MPa. In some embodiments, the tablets have 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 containing sodium nonanoate contain additional excipients. For example, the disclosed tablets may contain magnesium stearate, lactose, mannitol, HPMC, and / or MCC.

[0227] Preparation of sodium nonanoate Nonanoic acid (4) (2.51 g, 15.9 mmol) and acetonitrile (63.5 ml) were mixed in a suitable container equipped with a suitable stirrer to form a homogeneous solution. A 25 wt% methanol solution of sodium methoxide (2) (15.9 mmol) was added to the solution over a period of 5 hours with vigorous stirring to form a slurry. Heptane (9.3 ml) was added to the solution simultaneously over a period of four hours after the addition of (2). The slurry was stirred for another hour. The solid was filtered, washed with acetonitrile (15 ml, twice), dried under vacuum at 35–40 °C, and purged with nitrogen to give sodium nonanoate (5) (2.68 g, 94% yield).

[0228] Sodium nonanoate powder samples were fixed onto a 32 mm SEM stage using carbon conductive adhesive. A platinum sputtering coating was then applied to the samples. The samples were loaded into a Hitachi TM3030 benchtop scanning electron microscope. Imaging was performed on the samples in high vacuum mode using a secondary electron (SE) detector. The voltage was set to 2 kV and the spot intensity to 30 units. Images were acquired at different magnifications. Figure 22Imaging revealed that the aggregated crystal morphology of sodium nonanoate consisted of well-defined, plate-like primary particles. This morphology is extremely difficult to obtain without spray drying and is more desirable than elongated, plate-like, or needle-like morphologies because it often exhibits superior compressibility in manufacturing processes and therapeutic formulations.

[0229] Example 4: Sodium lauryl (C 12 )Material This article provides agglomerated crystalline particles of sodium laurate, and powder materials containing these particles. These particles exhibit excellent flowability and / or compressibility. These sodium laurate particles exhibit a morphology comprising spherical aggregates. They can have morphologies characterized by spherical and irregularly shaped aggregates, and / or porous morphologies. These sodium laurate particles can have an astonishing SSA (Surface Area Sag) one order of magnitude higher than commercially available sodium laurate materials. These particles have a D (Density Scale) of 900 µm or less. 90 .

[0230] In some respects, any disclosed sodium laurate particles are combined with a therapeutic macromolecule to form a mixture. This mixture can be formulated into an oral dosage form, such as an oral tablet intended for administration to a subject (e.g., a human subject) to treat or prevent a disease, condition, or illness. Therefore, this document provides oral tablets comprising a therapeutic macromolecule and sodium laurate. Due to the improved compression behavior of these particles, these oral tablets do not require tableting aids.

[0231] Therefore, this article provides oral tablets comprising a therapeutic macromolecule and sodium lauryl laurate, wherein the tablets are substantially free of tableting excipients, and wherein the therapeutic macromolecule has a low Papp (e.g., Papp less than 10 × 10⁻⁶). -8 (cm / s). Therapeutic macromolecules may contain macrocyclic peptides, such as compounds of formula I.

[0232] In some embodiments, the tablet has a tensile strength that is 2, 3, 4, 5, or 6 times higher than that of a corresponding tablet containing commercially available sodium lauryl laurate. In some aspects, the tablet contains about 80% to 99% sodium lauryl laurate, or about 80% to 90% sodium lauryl laurate (w / w). In some embodiments, the tablet has 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 higher than 2.5 MPa. In some embodiments, the disclosed sodium lauryl laurate-containing tablets contain additional excipients. For example, the disclosed tablets may contain magnesium stearate, lactose, mannitol, HPMC, and / or MCC.

[0233] Preparation of sodium laurate Lauric acid (6) (2.5 g, 12.5 mmol) was mixed with acetonitrile (63.3 ml) in a suitable container equipped with a suitable stirrer. The batch was stirred at 30 °C until completely dissolved, and then cooled to room temperature. A 25 wt% methanol solution of sodium methoxide (2) (12.48 mmol) was added to the solution over a period of 5 hours with vigorous stirring to form a slurry. Heptane (9.3 ml) was added to the solution simultaneously over a period of four hours after the first hour of adding (2). The slurry was stirred for another hour. The solid was filtered, washed with acetonitrile (15 ml, twice), and then dried under vacuum at 35–40 °C and purged with nitrogen to give sodium laurate (7) (2.7 g, 97% yield).

[0234] Sodium lauryl powder samples were fixed onto a 32 mm SEM stage using carbon conductive adhesive. A platinum sputtering coating was then applied to the samples. The samples were loaded into a Hitachi SU5000 scanning electron microscope. Imaging was performed on the samples in high vacuum mode using a secondary electron (SE) detector. The voltage was set to 2 kV and the spot intensity to 30 units. Images were acquired at different magnifications. Figure 23 Imaging showed that the aggregated crystals of sodium laurylate existed as clear, plate-like primary particles.

[0235] The subject matter disclosed is not limited to the specific embodiments and examples described herein. In fact, various modifications to this disclosure will become apparent to those skilled in the art from the foregoing description and drawings, in addition to those described. Such modifications are intended to fall within the scope of the appended claims.

[0236] All references cited herein (e.g., publications, patents, or patent applications) are incorporated herein in full for all purposes, as if each individual reference (e.g., publications, patents, or patent applications) were specifically and individually indicated to be incorporated herein in full for all purposes. Other embodiments are included in the appended claims.

Claims

1. A composition comprising crystalline sodium decanoate particles, wherein the sodium decanoate particles have a particle size of at least 5.9 μm. 2 / g average specific surface area (SSA).

2. The composition of claim 1, wherein the sodium decanoate particles have a particle size of 5.9 μm. 2 / g to approximately 41 m 2 / g average SSA.

3. A composition comprising crystalline sodium decanoate particles, wherein the sodium decanoate particles have a particle size of at least 9.9 μm. 2 / g average specific surface area (SSA).

4. The composition according to any one of claims 1-3, wherein the sodium decanoate particles have a particle size of 9.9 μm. 2 / g to approximately 41m 2 / g average SSA.

5. The composition according to any one of claims 1-4, wherein the sodium decanoate particles have a particle size of 9.9 μm. 2 / g to approximately 37m 2 / g average SSA.

6. The composition of claim 1 or 3, wherein the sodium decanoate particles have a particle size of at least about 15 μm. 2 / g average SSA.

7. The composition according to any one of claims 1-6, wherein the sodium decanoate particles have a particle size of about 15, 21, or 37 μm. 2 / g average SSA.

8. The composition according to any one of claims 1-7, wherein the sodium decanoate particles have a morphology comprising spherical aggregates.

9. The composition according to any one of claims 1-8, wherein the sodium decanoate particles have D 90 The particle size distribution is 565 µm or smaller.

10. The composition of any one of claims 1-9, wherein the composition has a hausnab ratio of 1.6 or less.

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

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

13. A composition comprising crystalline sodium decanoate particles, wherein the sodium decanoate particles have a particle size of 9.6 μm. 2 / g to 41m 2 Average SSA per g, tap density of at least 0.32 g / mL, and Dm of 158 µm to 657 µm 90 .

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

15. An oral tablet comprising a therapeutic macromolecule and sodium decanoate, wherein the tablet is substantially free of tableting adjuvants, and wherein the therapeutic macromolecule has 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 Class III or IV compound of the Biopharmaceutics Classification System (BCS).

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 has a tensile strength of at least 1 MPa.

21. The tablet according to any one of claims 14-20, wherein the tablet has 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 has a tensile strength that is 2, 3, 4, 5, or 6 times higher than that of a corresponding tablet comprising commercially available sodium decanoate.

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

24. The tablet of any one of claims 14-23, wherein the tablet comprises 88% to 89% sodium decanoate (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 10% to 12% w / w of a 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 comprising essentially a therapeutic macromolecule and sodium decanoate, wherein the tablet is substantially free of tableting adjuvants and wherein the therapeutic macromolecule has low apparent permeability (Papp).

32. An oral tablet comprising a therapeutic macromolecule and sodium nonanoate, wherein the tablet is substantially free of tableting adjuvants, and wherein the therapeutic macromolecule has a low Papp content.

33. The tablet of claim 32, wherein the tablet has a tensile strength that is 2, 3, 4, 5, or 6 times higher than that of a corresponding tablet comprising commercially available sodium nonanoate.

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

35. An oral tablet comprising a therapeutic macromolecule and sodium lauryl laurate, wherein the tablet is substantially free of tableting excipients, and wherein the therapeutic macromolecule has a low Papp content.

36. The tablet of claim 35, wherein the tablet has a tensile strength that is 2, 3, 4, 5, or 6 times higher than that of a corresponding tablet comprising commercially available sodium lauryl oleate.

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

38. The tablet according to any one of claims 35-37, wherein the tablet has 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.

Images