Compressible sodium caprate formulation

Abstract

The present disclosure provides a method of making an oral tablet, comprising mixing a polymer with sodium caprate to form a mixture and compressing the mixture into a tablet, wherein the sodium caprate is Form A. The present disclosure also provides a tablet made by the process provided herein. Compositions comprising sodium caprate and a polymer are also provided.

Description

[Technical field]

[0001] The present disclosure provides a method for making an oral tablet, comprising mixing a polymer with a particular form of sodium caprate to form a mixture and compressing the mixture into a tablet. Also provided is a method for making an oral tablet, comprising mixing a polymer with Form A sodium caprate to form a mixture and compressing the mixture into a tablet. The present disclosure also provides a tablet made by the process provided herein. Also provided is a composition comprising sodium caprate and a polymer. The present disclosure also relates to a composition comprising Form A sodium caprate and a polymer. [Background technology]

[0002] Tablets are a popular pharmaceutical dosage form due to patient convenience, accurate dosing, non-bulky portability, innocuous taste, ease of administration, and neat and distinctive appearance. Tablets can be plain, film-coated or sugar-coated, layered, bipartite, embossed, and / or sustained-release. Tablets can be made in a variety of sizes, shapes, and colors. Oral tablets (i.e., tablets intended for oral administration) can be swallowed, chewed, or dissolved in the buccal cavity or under the tongue.

[0003] Generally, tablets contain an active or therapeutic ingredient and also usually contain any number of inactive materials known as excipients. Excipients can be classified according to their role in the final tablet. Examples of excipients include penetration enhancers, binders, lubricants, glidants, colorants, flavorings, diluents, and disintegrants. Examples of pharmaceutical excipients can be found, for example, in Non-Patent Document 1.

[0004] In terms of manufacturing, when preparing tablets, a tablet tensile strength of at least 1.7 MPa is usually desirable (see, for example, Non-Patent Document 2). Tablets with a tensile strength of 1.0-1.7 MPa are acceptable but may require additional care in handling. Therefore, to achieve a favorable tensile strength, the tablet additives and their concentrations are considered. When a particular component is present in a tablet at a high concentration, the component is evaluated for its mechanical properties and tabletability, in addition to its tendency to stick, which may depend on the crystal structure and size and / or shape of its particles. For example, sodium caprate may be used in oral tablets as a permeation enhancer, sometimes at high concentrations. In such cases, the tabletability of sodium caprate needs to be acceptable. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] American Pharmaceutical Review Pharmaceutical Excipients database [Non-Patent Document 2] Pitt et al.,Powder Tech 238:169-175(2013) Summary of the Invention [Problem to be solved by the invention]

[0006] The inventors have discovered that tablets comprising compositions comprising certain forms of sodium caprate have the unexpected benefit of greater physical integrity, e.g., greater hardness and less "stickiness" to tableting machines, e.g., tableting dies and presses. For example, in some embodiments, the present disclosure is directed to compositions comprising a polymer and sodium caprate, the sodium caprate having an X-ray powder diffraction (XRPD) spectrum comprising a peak at 4° 2θ, and / or a peak between 0.1 and 0.15 Å. -1 It contains peaks in the region of 0.12 and 0.23 Å. -1Form A sodium caprate is characterized by a wide angle X-ray scattering (WAXS) spectrum having a peak at: In some embodiments, the sodium caprate is Form A sodium caprate.

[0007] Thus, the present disclosure is directed to a method of making an oral tablet comprising a particular form of sodium caprate. In some embodiments, the present disclosure provides a method of making an oral tablet comprising the steps of (a) mixing a polymer with Form A sodium caprate to form a mixture, and (b) directly compressing the mixture to form a tablet. [Means for solving the problem]

[0008] In some embodiments, sodium caprate has a pH of 0.1 to 0.15 Å. -1 In some embodiments, sodium caprate form A is characterized by a small angle X-ray scattering (SAXS) spectrum containing peaks in the region of 0.12 and 0.23 Å. -1 It is characterized by a SAXS peak at

[0009] In some embodiments, the sodium caprate is Form A sodium caprate characterized by an X-ray powder diffraction (XRPD) spectrum including a peak at 4° 2θ.

[0010] In some embodiments, sodium caprate has a pH of 0.1 to 0.15 Å. -1 Form A sodium caprate is characterized by a wide angle X-ray scattering (WAXS) spectrum containing peaks in the region of 0.12 and 0.23 Å. In some embodiments, the sodium caprate is Form A sodium caprate characterized by a wide angle X-ray scattering (WAXS) spectrum containing peaks in the region of 0.12 and 0.23 Å. -1 Form A sodium caprate is characterized by a wide angle X-ray scattering (WAXS) spectrum containing a peak at

[0011] In some embodiments, the sodium caprate has a water content of less than about 3.5% as determined by Karl Fischer titration. In some embodiments, the sodium caprate has a water content of less than about 2% as determined by Karl Fischer titration. In some embodiments, the sodium caprate has a water content of less than about 1.5% as determined by Karl Fischer titration.

[0012] In some embodiments, the sodium caprate of step (a) is sieved or milled to obtain a desired particle size prior to (b) direct compression to form a tablet. In some embodiments, the mixture of step (a) is sieved or milled to obtain a desired particle size prior to (b) direct compression to form a tablet. In some embodiments, the sodium caprate has a particle size of about 10 μm to about 1300 μm prior to step (b). In some embodiments, the sodium caprate has a particle size of about 35 μm to about 850 μm prior to step (b). In some embodiments, the sodium caprate has a particle size of about 50 μm to about 700 μm prior to step (b).

[0013] In some embodiments, a coating is applied to the tablets after compression of the tablets in (b).

[0014] In some embodiments, the method does not include a grinding step after the mixing of step (a). In some embodiments, the direct compressing step is carried out at a pressure in the range of about 15 MPa to 500 MPa. In some embodiments, the direct compressing step is carried out at a pressure in the range of about 25 MPa to 300 MPa. In some embodiments, the direct compressing step is carried out at a pressure in the range of about 50 MPa to 200 MPa.

[0015] In some embodiments, the mixing step of (a) further comprises a polyol. In some embodiments, the polyol is sorbitol, mannitol, maltitol, xylitol, or a combination thereof. In some embodiments, the polyol is mannitol. In some embodiments, the mixing step of (a) further comprises additional additives, such as glidants and / or lubricants and / or other fillers and / or disintegrants.

[0016] Non-limiting examples of pharma- ceutically acceptable excipients include microcrystalline cellulose, dicalcium phosphate, lactose, mannitol, sodium stearyl fumarate (PRUV), magnesium stearate, hydrous colloidal silica, crospovidone, croscarmellose sodium, sodium bicarbonate, low-substituted hydroxypropylcellulose (L-HPC), sodium starch glycolate, water, ethanol, isopropyl alcohol or other solvents, polyvinylpyrrolidone (PVP), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), (tromethamine) (TRIS), any salt of carbonate, borate, or phosphate, tartaric acid, magnesium hydroxide, magnesium oxide, sodium bicarbonate, propyl gallate, alpha-tocopherol, butylated hydroxyanisole (BHA), ascorbic acid, solutol, polysorbate 80, and ethylenediaminetetraacetic acid (EDTA).

[0017] In some embodiments, the polymer is about 0.1% to about 12% by weight of the tablet. In some embodiments, the sodium caprate is about 30% to about 99% by weight of the tablet. In some embodiments, the additional additives range from about 0.001% to about 50% by weight of the tablet.

[0018] In some embodiments, the polymer is about 0.1% to about 12% by weight of the tablet. In some embodiments, the sodium caprate is about 30% to about 99% by weight of the tablet. In some embodiments, the polyol is about 0.001% to about 50% by weight of the tablet. In some embodiments, the additional additives are in the range of about 0.001% to about 50% by weight of the tablet.

[0019] In some embodiments, the polymer is a peptide or an oligonucleotide. In some embodiments, the polymer is an oligonucleotide. In certain embodiments, the oligonucleotide is 8-100 nucleotides in length, e.g., 10-80 nucleotides in length, e.g., 12-40 nucleotides in length, e.g., 15-30 nucleotides in length, e.g., about 12 nucleotides in length, about 15 nucleotides in length, about 18 nucleotides in length, or about 20 nucleotides in length. In certain embodiments, the oligonucleotide is modified, e.g., the oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, or at least one modified nucleobase. In certain embodiments, the oligonucleotide is single-stranded or double-stranded. In certain embodiments, the oligonucleotide is an antisense nucleotide, an miRNA antagonist, or an miRNA mimic.

[0020] In embodiments, the oligonucleotide is an antisense oligonucleotide targeting metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) that includes at least one nucleic acid with a locked sugar modification moiety ("LNA"). In such embodiments, the antisense oligonucleotide targets MALAT1 and has the sequence: GM5CAttctaatagcAGM5C (where m5c is 5-methylcytidine and uppercase letters are LNA nucleosides) (SEQ ID NO: 1). In embodiments, the oligonucleotide is an antisense oligonucleotide that targets MALAT1 and reduces expression of MALAT1 in cells by about 1% to about 100%. In embodiments, the oligonucleotide is an antisense oligonucleotide that targets MALAT1 and reduces expression of MALAT1 in cells by about 1%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 100%.

[0021] In certain embodiments, the polymer is a peptide. In certain embodiments, the peptide is 5 to 3000 amino acids long or 10 to 2000 amino acids long, such as 10 to 150 amino acids long, such as 20 to 100 amino acids long, such as 30 to 75 amino acids long, such as about 20 amino acids long, about 30 amino acids long, about 40 amino acids long, about 50 amino acids long, about 60 amino acids long, about 70 amino acids long, about 80 amino acids long, about 90 amino acids long, or about 100 amino acids long.

[0022] In certain embodiments, the peptide comprises the amino acid sequence HAibEGS-(αMeF)TSDV-(αMeS)SX13LE-GEAA(αMeK)-E(αMeF)IAX25-VVEGG; wherein X13 is a lipid-modified K, X25 is a lipid-modified K, "αM" is an alpha-methyl functionalized amino acid, and the two lipid-modified K residues are the same or different and are selected from the group consisting of K(ε-(PEG)2-(PEG)2-γE-lauroyl), K(ε-(PEG)2-(PEG)2-γE-myristoyl), K(ε-(PEG)2-(PEG)2-γE-palmitoyl), K(ε-(PEG)2-(PEG)2-γE-stearoyl), and any combination thereof.

[0023] In some embodiments, the oral tablet has a tablet tensile strength of about 0.5 to 5.0 MPa. In some embodiments, the oral tablet has a tablet tensile strength of about 0.75 MPa to about 3 MPa. In at least one embodiment, a tablet tensile strength of about 1 MPa to about 2.5 MPa.

[0024] In some embodiments, the present disclosure provides a method for making an oral tablet, comprising the steps of: (a) sieving or milling sodium caprate to obtain sodium caprate particles having a particle size in the range of about 10 μm to about 1300 μm, e.g., in the range of about 35 μm to about 850 μm, e.g., in the range of about 50 μm to about 750 μm; (b) mixing the sodium caprate particles with a polymer and other excipients to form a mixture; and (c) directly compressing the mixture to form a tablet, wherein the sodium caprate has an X-ray powder diffraction (XRPD) spectrum comprising peaks at 4° 2θ and / or a peak between 0.1 and 0.15 Å. -1 It contains peaks in the region of 0.12 and 0.23 Å. -1 and wherein the process does not include any wet granulation, drying or milling steps after the mixing of step (b).

[0025] In some embodiments, the present disclosure is directed to a tablet made by the methods described herein.

[0026] In some embodiments, the present disclosure is directed to a method of making an oral tablet comprising: a) mixing sodium caprate particles with additional additives to form a mixture; b) granulating the mixture with an organic non-aqueous solvent to form granules; c) drying the granules; d) sieving or milling the granules to obtain granules having a particle size of about 100 μm to 2000 μm; e) blending with a polymer and / or additional additives; and f) compressing the mixture to form a tablet, wherein the sodium caprate after step c) is sodium caprate Form A. In some embodiments, sodium caprate Form A is characterized by an X-ray powder diffraction (XRPD) spectrum comprising a peak at 4° 2θ. In some embodiments, the organic solvent is selected from methanol (MeOH), ethanol (EtOH), 2-propanol (IPA), toluene, cyclohexane, dioxane, dimethylformamide (DMF), acetonitrile (ACN), tetrahydrofuran (THF), methyl isobutyl ketone (MIBK), ethyl acetate (EtOAc), and diethyl ether. In at least one embodiment, the organic solvent is ethanol. In some embodiments, the additional additive is a polyol. In some embodiments, the polyol is mannitol.

[0027] In some embodiments, the present disclosure is directed to a method of making an oral tablet comprising the steps of: a) granulating sodium caprate particles with an organic non-aqueous solvent to form granules, b) drying the granules, c) sieving or milling the granules to obtain granules having a particle size of about 100 μm to 2000 μm, d) blending the granules with a polymer and / or additional excipients to form a mixture, and e) compressing the mixture to form a tablet, wherein the sodium caprate after step (b) is sodium caprate Form A. In some embodiments, sodium caprate Form A has an X-ray powder diffraction (XRPD) spectrum comprising a peak at 4° 2θ and / or a peak between 0.1 and 0.15 Å. -1 It contains peaks in the region of 0.12 and 0.23 Å. -1The solvent is characterized by a wide angle X-ray scattering (WAXS) spectrum with a peak at 1000 nm. In some embodiments, the organic solvent is selected from methanol (MeOH), ethanol (EtOH), 2-propanol (IPA), toluene, cyclohexane, dioxane, dimethylformamide (DMF), acetonitrile (ACN), tetrahydrofuran (THF), methyl isobutyl ketone (MIBK), ethyl acetate (EtOAc), and diethyl ether. In at least one embodiment, the organic solvent is ethanol. In some embodiments, the additional additive is a polyol. In some embodiments, the polyol is mannitol.

[0028] In some embodiments, the present disclosure is directed to a method of making an oral tablet comprising the steps of: a) mixing sodium caprate particles with additional additives and a polymer to form a mixture; b) granulating the mixture with an organic non-aqueous solvent to form granules; c) drying the granules; d) sieving or milling the granules to obtain granules having a particle size of about 100 μm to 2000 μm; e) blending the granules with additional additives to form a mixture; and f) compressing the mixture to form a tablet, wherein the sodium caprate after step c) is Form A sodium caprate. In some embodiments, the sodium caprate is characterized by an X-ray powder diffraction (XRPD) spectrum comprising a peak at 4° 2θ. In some embodiments, the organic non-aqueous solvent is selected from methanol (MeOH), ethanol (EtOH), 2-propanol (IPA), toluene, cyclohexane, dioxane, dimethylformamide (DMF), acetonitrile (ACN), tetrahydrofuran (THF), methyl isobutyl ketone (MIBK), ethyl acetate (EtOAc), and diethyl ether. In at least one embodiment, the organic non-aqueous solvent is ethanol. In at least one embodiment, the organic non-aqueous solvent is isopropyl alcohol.

[0029] In some embodiments, the present disclosure provides a composition comprising a polymer and sodium caprate, wherein the sodium caprate has an X-ray powder diffraction (XRPD) spectrum comprising a peak at 4° 2θ and / or a peak between 0.1 and 0.15 Å. -1 It contains peaks in the region of 0.12 and 0.23 Å. -1 The present invention is directed to a composition, the composition being sodium caprate form A characterized by a wide angle X-ray scattering (WAXS) spectrum having a peak at 10 ...

[0030] In some embodiments, the composition is in the form of an oral tablet, the oral tablet having a tablet tensile strength in the range of about 0.5 MPa to about 5.0 MPa, such as from about 0.75 MPa to about 3 MPa, and in at least one embodiment, from about 1 MPa to about 2.5 MPa. [Brief description of the drawings]

[0031] [Figure 1] Figure 1 relates to Example 1. Figure 1 shows the X-ray powder diffraction (XRPD) patterns of sodium caprate obtained from five different suppliers. [Figures 2A-2D]Figures 2A-2D relate to Example 1. Figure 2A shows the XRPD pattern of sodium caprate form A, Figure 2B shows the XRPD pattern of sodium caprate form B, Figure 2C shows the XRPD pattern of sodium caprate form C, and Figure 2D shows the XRPD pattern of sodium caprate form D. [Figure 3A-3D] Figures 3A-3D relate to Example 2. Figure 3A shows the wide angle X-ray scattering (WAXS) spectrum of sodium caprate form A, Figure 3B shows the wide angle X-ray scattering (WAXS) spectrum of sodium caprate form B, Figure 3C shows the wide angle X-ray scattering (WAXS) spectrum of sodium caprate form C, and Figure 3D shows the wide angle X-ray scattering (WAXS) spectrum of sodium caprate form D. [Figure 4A-4D] Figures 4A-4D relate to Example 3. Figure 4A shows the small angle x-ray scattering (SAXS) spectrum of sodium caprate form A, Figure 4B shows the small angle x-ray scattering (SAXS) spectrum of sodium caprate form B, Figure 4C shows the small angle x-ray scattering (SAXS) spectrum of sodium caprate form C, and Figure 4D shows the small angle x-ray scattering (SAXS) spectrum of sodium caprate form D. [Figure 5A-5C] Figures 5A-5C relate to Example 5. Figures 5A-5C show the compactibility of sodium caprate forms A, B, C and D as measured by tablet tensile strength. Figure 5A shows particle sizes of about 37 to about 53 μm, Figure 5B shows particle sizes of about 150 to about 300 μm and Figure 5C shows particle sizes of about 600 to about 710 μm. [Figure 6]Figure 6 relates to Example 6. Figure 6 shows the XRPD patterns of sodium caprate treated with various solvents. Solvent list (from bottom to top): diethyl ether (form A), EtOAc (form A), MIBK (form A), THF (form A), acetone (form A), can (form A), DMF (form A), DMSO (non-crystalline), dioxane (form A) cyclohexane, toluene, EtOH (form A), MeOH (form A), water (form C). Abbreviations used - MeOH: methanol, EtOH: ethanol, DMSO: dimethylsulfoxide, DMF: dimethylformamide, ACN: acetonitrile, THF: tetrahydrofuran, MIBK: methyl isobutyl ketone, EtOAc: ethyl acetate. [Figure 7] Figure 7 relates to Example 6. Figure 7 shows the XRPD patterns of sodium caprate treated with various solvents. Solvent list (from bottom to top): acetone (form A), acetonitrile (form A), EtOH (form A), toluene (form A), water (form C). [Figure 8] Figure 8 relates to Example 7. Figure 8 shows the compactability, as measured by tablet tensile strength, of sodium caprate wet granulated with ethanol and sodium caprate granulated with water. [Figure 9] Figure 9 relates to Example 7. Figure 9 shows the compactability as measured by tablet tensile strength of sodium caprate Form A, sodium caprate Form B, sodium caprate Form C, and sodium caprate Form D after wet granulation with ethanol, and sodium caprate Form A, sodium caprate Form C, and sodium caprate Form D after wet granulation with 2-propanol. [Figure 10A-10G]Figures 10A-10G relate to Example 7. Figure 10A shows the WAXS spectrum of form A sodium caprate granulated with ethanol, Figure 10B shows the WAXS spectrum of form B sodium caprate granulated with ethanol, Figure 10C shows the WAXS spectrum of form C sodium caprate granulated with ethanol, Figure 10D shows the WAXS spectrum of form D sodium caprate granulated with ethanol, Figure 10E shows the WAXS spectrum of form A sodium caprate granulated with 2-propanol, Figure 10F shows the WAXS spectrum of form C sodium caprate granulated with 2-propanol, and Figure 10G shows the WAXS spectrum of form D sodium caprate granulated with 2-propanol. [Figures 11A-11G] Figures 11A-11G relate to Example 7. Figure 11A shows the XRPD pattern of sodium caprate form A granulated with ethanol, Figure 11B shows the XRPD pattern of sodium caprate form B granulated with ethanol, Figure 11C shows the XRPD pattern of sodium caprate form C granulated with ethanol, Figure 11D shows the XRPD pattern of sodium caprate form D granulated with ethanol, Figure 11E shows the XRPD pattern of sodium caprate form A granulated with 2-propanol, Figure 11F shows the XRPD pattern of sodium caprate form C granulated with 2-propanol, and Figure 11G shows the XRPD pattern of sodium caprate form D granulated with 2-propanol. [Figure 12] FIG. 12 relates to Example 8 and illustrates an exemplary process for direct compression tablet manufacture. [Figure 13] Figure 13 relates to Example 8. Figure 13 shows the tabletting ability of sodium caprate Form A wet granulated with ethanol, dried and milled, mixed with either microcrystalline cellulose (MCC) or hydroxypropyl cellulose (L-HPC), with or without sodium stearyl fumarate (PRUV). [Figure 14]FIG. 14 illustrates an exemplary process for tablet manufacture involving wet granulation of sodium caprate and other excipients for Examples 9, 10 and 13 (Formulation 2), in which the macromolecule, e.g., MALAT1 ASO or MEDI7219 peptide, is not subjected to wet granulation and drying. [Figure 15] Figure 15 relates to Example 10. Figure 15 shows the compactibility as measured by tablet tensile strength of sodium caprate and mannitol Form A, sodium caprate and mannitol Form B, sodium caprate and mannitol Form C, and sodium caprate and mannitol Form D after wet granulation with ethanol, and sodium caprate and mannitol Form A and sodium caprate and mannitol Form D after wet granulation with 2-propanol. [Figures 16A-16F] Figures 16A-16F relate to Example 10. Figure 16A shows the WAXS spectrum of sodium caprate form A and mannitol granulated with ethanol, Figure 16B shows the WAXS spectrum of sodium caprate form B and mannitol granulated with ethanol, Figure 16C shows the WAXS spectrum of sodium caprate form C and mannitol granulated with ethanol, Figure 16D shows the WAXS spectrum of sodium caprate form D and mannitol granulated with ethanol, Figure 16E shows the WAXS spectrum of sodium caprate form A and mannitol granulated with 2-propanol, and Figure 16F shows the WAXS spectrum of sodium caprate form D and mannitol granulated with 2-propanol. [Figures 17A-17F]Figures 17A-17F relate to Example 10. Figure 17A shows the XRPD pattern of sodium caprate and mannitol form A granulated with ethanol, Figure 17B shows the XRPD pattern of sodium caprate and mannitol form B granulated with ethanol, Figure 17C shows the XRPD pattern of sodium caprate and mannitol form C granulated with ethanol, Figure 17D shows the XRPD pattern of sodium caprate and mannitol form D granulated with ethanol, Figure 17E shows the XRPD pattern of sodium caprate and mannitol form A granulated with 2-propanol, and Figure 17F shows the XRPD pattern of sodium caprate and mannitol form D granulated with 2-propanol. [Figure 18] Figure 18 relates to Example 12 (Formulation 1). Figure 18 illustrates an exemplary process for tablet manufacture that includes wet granulation of sodium caprate, and no polymers or other excipients are wet granulated and dried. [Figure 19] FIG. 19 illustrates an exemplary process for tablet manufacture involving wet granulation of sodium caprate with exemplary polymers and other excipients. [Figure 20A-20B] Figures 20A-20B relate to Example 14. Figure 20A shows the dissolution profile of a tablet containing sodium caprate form A and MALAT1 ASO. Figure 20B shows the dissolution profile of a tablet containing sodium caprate form A and MEDI7219 peptide. [Figure 21] Figure 21 relates to Example 15. Figure 21 illustrates an exemplary process for the preparation of sodium caprate spherulites. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] The present disclosure relates to a method for making an oral tablet.

[0033] Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the method / device used to determine the value or the variation that exists between test subjects. Typically, the term "about" is intended to encompass a variability of approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% or less, depending on the context.

[0034] Use of the term "or" in the claims is used to mean "and / or" unless expressly stated to refer to alternatives only or the alternatives are not mutually exclusive, however, the present disclosure supports a definition that refers to alternatives only and "and / or."

[0035] As used herein, the terms "comprising" (and any variation or form of comprising, e.g., "comprise" and "comprises"), "having" (and any variation or form of having, e.g., "have" and "has"), "including" (and any variation or form of including, e.g., "includes" and "include"), or "containing" (and any variation or form of containing, e.g., "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed herein can be implemented with respect to any method, system, host cell, expression vector, and / or composition of the disclosure. Additionally, the disclosed compositions, systems, host cells, and / or vectors can be used to achieve the disclosed methods and proteins.

[0036] The use of the term "for example" and its corresponding abbreviation "eg" (whether italicized or not) means that, unless expressly stated otherwise, the particular term cited is representative of examples and embodiments of the present disclosure that are not intended to be limited to the specific examples referenced or described.

[0037] As used herein, "between" refers to a range that includes both ends of the range. For example, a number between x and y explicitly includes numbers x and y, and every number between x and y.

[0038] As used herein, the term "polymer" refers to a naturally occurring and / or synthetic molecule, typically a polymer, containing several thousand or more atoms. Polymers can include biopolymers, such as, for example, nucleic acids, proteins, carbohydrates, and polymeric lipids, as well as non-polymeric large molecules, such as, for example, lipids, macrocycles, and large molecule drugs, such as drug molecules conjugated to a polymer, such as, for example, a peptide or an antibody. In some embodiments, the polymer of the present disclosure is a therapeutic polymer. In some embodiments, the therapeutic polymer is a therapeutic peptide, protein, or antibody or a conjugate or derivative thereof, a therapeutic oligonucleotide, such as an antisense oligonucleotide, or a water-soluble polymer or polymer drug conjugate, such as those described in Yang et al., J Control Release 0:288-303(2014).

[0039] As used herein, the terms "nucleic acid," "nucleic acid molecule," "oligonucleotide," or "polynucleotide" refer to a polymeric compound comprising covalently linked nucleotides, each of which may be independently modified or unmodified. An oligonucleotide may include natural nucleobases, such as adenine (A), guanine (G), cytosine (C), uracil (U), or thymine (T), modified nucleobases, such as hypoxanthine, xanthine, or 5-methylcytosine, or synthetic nucleobases, such as d5SICS, dNaM, aminoallyl, isoguanine, isocytosine, or Hachimoji nucleobases as described in Hoshika et al., Science 363:884-887 (2019). Oligonucleotides may include RNA, DNA, XNA, and / or RNA-DNA hybrids, all of which may be single-stranded or double-stranded. In some embodiments, the oligonucleotides of the present disclosure are therapeutic oligonucleotides. In some embodiments, the oligonucleotides of the present disclosure are antisense oligonucleotides. In some embodiments, the antisense oligonucleotide is an antisense RNA.

[0040] The terms "peptide", "peptide" and "protein" are used interchangeably herein and refer to polymeric forms of amino acids of any length, and can include coded and non-coded amino acids, chemically or biochemically modified or derivatized amino acids, and peptides with modified peptide backbones. In some embodiments, the peptide or peptides of the disclosure are therapeutic peptides, such as those described in Marqus et al., J Biomed Sci 24:21 (2017). In some embodiments, the peptide or peptides of the disclosure are therapeutic proteins. Therapeutic proteins include, for example, antibodies or conjugates or derivatives thereof, Fc fusion proteins, anticoagulants, blood factors, bone morphogenetic factors, engineered protein scaffolds, enzymes, growth factors, hormones, interferons, interleukins, and thrombolytic agents. For further examples of therapeutic proteins, see, for example, Dimitrov, Methods Mol Biol 899:1-26 (2012).

[0041] The term "alpha-methyl functionalized amino acid" refers to an amino acid in which the first (alpha) carbon atom of the amino acid contains a methyl substituent (CH3) attached to the alpha carbon. Alpha-methyl functionalized amino acids include any of the 20 naturally occurring amino acids that contain such functionalization. An alpha-methyl functionalized amino acid can replace any native amino acid in a peptide. The term "native" amino acid refers to one of the standard 20 amino acids present in biologically produced proteins.

[0042] The term "synthetic peptide" or "synthetic peptide" refers to a polymer of amino acid residues produced by chemically coupling the carboxyl group or C-terminus of one amino acid to the amino group or N-terminus of another amino acid. Chemical peptide synthesis usually begins at the C-terminus and ends at the N-terminus of the peptide. Various methods for producing synthetic peptides are well known in the art.

[0043] The term "polyol" refers to a compound containing multiple hydroxyl groups, and is sometimes referred to as a "sugar alcohol." Non-limiting examples of polyols include mannitol, maltitol, sorbitol, xylitol, erythritol, and isomalt. In some embodiments, the polyol is a pharmaceutical excipient. In some embodiments, the polyol is included in the oral tablet described herein.

[0044] The term "particle size" as used herein refers to the median or average size of particles in a sample and can be based on the number of particles, the volume of particles, or the mass of particles, and can be obtained using any number of standard measurement techniques known in the art. Materials of the desired particle size range can be obtained directly from a synthesis process, or any known particle size reduction process can be used, such as, but not limited to, sieving, grinding, micronization, fluid energy milling, media milling, ball milling, high pressure homogenizer grinding, and air jet milling. Methods for determining particle size include analytical sieving and laser light diffraction, such as using instruments manufactured by Malvern Instruments Ltd. (Malvern, Worcestershire, UK).

[0045] As described herein, a macromolecule is typically a polymeric, natural and / or synthetic molecule, containing several thousand or more atoms. In some embodiments, the macromolecule is a nucleic acid, a protein, a carbohydrate, or a lipid. In some embodiments, the macromolecule is a peptide. In some embodiments, the macromolecule is a therapeutic peptide, protein, or antibody or a conjugate or derivative thereof.

[0046] In some embodiments, the polymer is an oligonucleotide. In some embodiments, the polymer is an RNA molecule. In some embodiments, the polymer is an antisense oligonucleotide. In some embodiments, the oligonucleotide can be 5-1000 nucleotides in length, 10-500 nucleotides in length, or 10-100 nucleotides in length. A variety of therapeutic oligonucleotides are known in the art and may be suitable for use within the disclosure herein.

[0047] In some embodiments, the oligonucleotide is an antisense oligonucleotide, an interfering RNA (e.g., small interfering RNA (siRNA), catalytic RNA, microRNA (miRNA), double-stranded RNA (dsRNA), non-coding RNA (ncRNA), mitochondrial RNA (mtDNA), or a ribozyme.

[0048] In some embodiments, the therapeutic oligonucleotide can be selected from the group consisting of, but not limited to, fomivirsen, mipomersen, eteplirsen, nusinersen, AP12009, AVI-6002, AVI-6003, voranesorsen, to name a few.

[0049] In some embodiments, the macromolecule is a compound comprising a modified oligonucleotide of SEQ ID NO:1.

[0050] In some embodiments, the polynucleotide encodes a peptide that is to be expressed in vivo in a subject.

[0051] In some embodiments, the polymer is a DNA molecule, for example, a double-stranded or single-stranded DNA molecule. In some embodiments, the DNA encodes a peptide to be expressed in vivo in a subject. For example, in some embodiments, the DNA molecule is a viral vector.

[0052] Those skilled in the art can understand that additional oligonucleotides can be used in the present disclosure, and the above list is for illustrative purposes only. In some embodiments, the oligonucleotide has a modified backbone to enhance stability and extend half-life. Furthermore, in some embodiments, the oligonucleotide is conjugated to another molecule to improve delivery, e.g., target protein, and / or stability of the oligonucleotide. Such modifications are contemplated by the present disclosure, and the term "oligonucleotide" encompasses such modifications.

[0053] In some embodiments, the polymer is a protein, i.e., a peptide. In some embodiments, the peptide can be 5-3000 amino acids long, 25-2000 amino acids long, or 100-1000 amino acids long. In other embodiments, the peptide can be 5-200 amino acids long, such as 10-150 amino acids long, such as 20-100 amino acids long, such as 30-75 amino acids long, such as about 20 amino acids long, about 30 amino acids long, about 40 amino acids long, about 50 amino acids long, about 60 amino acids long, about 70 amino acids long, about 80 amino acids long, about 90 amino acids long, or about 100 amino acids long.

[0054] In certain embodiments, the peptide is modified, for example, by lipid modification. In certain embodiments, the peptide is modified by lipidation, such as lactamization, disulfide bridge closure, palmitoylation, and / or PEGylation. In certain embodiments, the peptide comprises at least one lipidated amino acid residue. In certain embodiments, the lipidated peptide comprises at least two lipidated amino acid residues. In certain embodiments, the lipidated peptide contains only one lipidated amino acid residue. As used herein, a peptide with one lipid or lipid moiety attached is referred to as a mono-lipidated peptide. In other embodiments, the lipidated peptide contains two lipidated amino acid residues. As used herein, a peptide with two lipids or lipid moieties attached is referred to as a bis-lipidated peptide. In certain embodiments, the lipidated peptide is a synthetic peptide. In certain embodiments, the lipidated peptide is a synthetic peptide. In certain embodiments, the lipidated synthetic peptide comprises at least one substitution of an alpha-methyl functionalized amino acid for a native amino acid residue. In other embodiments, the lipidated synthetic peptide comprises at least two, three, four, five, six or more alpha-methyl functionalized amino acid substitutions for native amino acid residues.

[0055] In certain embodiments, the lipidated peptides described herein are derived from the sequence of GLP-1 and are referred to herein as lipidated GLP-1 peptide analogs. The native (wild type) peptide sequences of the various peptides and classes of peptides described herein that can be prepared to obtain synthetic peptides with the above-mentioned properties are well known in the art. The native amino acid sequence of GLP-1(7-36) is known in the art as shown below: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR (SEQ ID NO: 2) (Table 1).

[0056] In certain embodiments, the peptide comprises the amino acid sequence HAibEGS-(αMeF)TSDV-(αMeS)SX13LE-GEAA(αMeK)-E(αMeF)IAX25-VVEGG; wherein X13 is a lipid-modified K, X25 is a lipid-modified K, "αM" is an alpha-methyl functionalized amino acid, and the two lipid-modified K residues are the same or different and are selected from the group consisting of K(ε-(PEG)2-(PEG)2-γE-lauroyl), K(ε-(PEG)2-(PEG)2-γE-myristoyl), K(ε-(PEG)2-(PEG)2-γE-palmitoyl), K(ε-(PEG)2-(PEG)2-γE-stearoyl), and any combination thereof, e.g. as described in International Patent Application No. PCT / EP16 / 063206.

[0057] In certain embodiments, the peptide comprises a C-terminal amide. In certain embodiments, the peptide comprises a C-terminal acid.

[0058] In certain embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO:3 (Table 1), SEQ ID NO:4 (Table 1), SEQ ID NO:5 (Table 1), or SEQ ID NO:6 (Table 1).

[0059] [Table 1]

[0060] A variety of therapeutic proteins are known in the art and may be suitable for use within the disclosure herein. In some embodiments, the therapeutic protein may be selected from the group consisting of, but not limited to, an antigen, an antibody or antibody fragment, an enzyme, a cytokine, a therapeutic protein, a chemokine, a regulatory protein, a structural protein, a chimeric protein, a nuclear protein, a transcription factor, a viral protein, a TLR protein, an interferon regulatory factor, an angiogenesis inhibitory or angiogenic protein, an apoptotic protein, an Fc gamma receptor, a hematopoietic protein, a tumor suppressor, a cytokine receptor, or a chemokine receptor. In some embodiments, the protein is an enzyme or a hormone. In some embodiments, the protein is a clotting factor, a growth factor, or a cytokine.

[0061] Representative antigens include, but are not limited to, cholera toxoid, tetanus toxoid, diphtheria toxoid, hepatitis B surface antigen, hemagglutinin, neuraminidase, influenza M protein, PfHRP2, pLDH, aldolase, MSP1, MSP2, AMA1, Der-p-1, Der-f-1, adipophilin, AFP, AIM-2, ART-4, BAGE, alpha fetoprotein, BCL-2, Bcr-Abl, BING-4, CEA, CPSF, CT, cyclin D1, Ep-CAM, EphA2, EphA3. , ELF-2, FGF-5, G250, gonadotropin releasing hormone, HER-2, intestinal carboxylesterase (iCE), IL13R alpha 2, MAGE-1, MAGE-2, MAGE-3, MART-1, MART-2, M-CSF, MDM-2, MMP-2, MUC-1, NY-EOS-1, MUM-1, MUM-2, MUM-3, p53, PBF, PRAME, PSA, PSMA, RAGE-1, RNF43, RU1, RU2AS, SART-1, SART-2, SART-3, SAGE-1, SCRN1, SOX2, SOX 10, STEAP1, survivin, telomerase, TGF beta RII, TRAG-3, TRP-1, TRP-2, TERT, or WT1; derived from cowpox virus, vaccinia virus, pseudocowpox virus, human herpes virus 1, human herpes virus 2, cytomegalovirus, human adenovirus A-F, polyoma virus, human papilloma virus, parvovirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, human immunodeficiency virus, orthoreovirus, rotavirus, Ebola virus, parainfluenza virus, derived from viruses such as influenza A virus, influenza B virus, influenza C virus, measles virus, mumps virus, rubella virus, pneumovirus, human respiratory syncytial virus, rabies virus, California encephalitis virus, Japanese encephalitis virus, Hantaan virus, lymphocytic choriomeningitis virus, coronavirus, enterovirus, rhinovirus, poliovirus, norovirus, flavivirus, dengue virus, West Nile virus, yellow fever virus, and chickenpox;Bacillus anthracis, Brucella, Candida, Chlamydia pneumoniae, Chlamydia psittaci, Vibrio cholerae, Clostridium botulinum, Coccidioides immitis, Cryptococcus, Corynebacterium diphtheriae, Escherichia coli O157:H7, Enterohemorrhagic Escherichia coli, Enterotoxigenic Escherichia coli, Haemophilus influenzae, Helicobacter pylori pylori, Legionella, Leptospira, Listeria, Meningococcus, Mycoplasma pneumoniae, Mycobacterium, Bordetella pertussis, Pneumoniae, Salmonella, Shigella, Staphylococcus, Streptococcus pneumoniae and Yersinia enterocolitica; or protozoa, such as Plasmodium falciparum;

[0062] Various means of modifying proteins are known in the art to increase (or possibly decrease) their stability and / or increase (or possibly decrease) their half-life. Similarly, methods are known for modifying proteins to increase their targeting and potency. In some embodiments, the protein is post-translationally modified. In some embodiments, the post-translational modification is glycosylation or phosphorylation. Such modifications are contemplated by the present disclosure, and the term "oligonucleotide" encompasses such modifications.

[0063] In some embodiments, the polymer is a therapeutic polymer suitable for treating a disease or disorder.

[0064] Sodium caprate, also known as sodium decanoate, has the chemical formula C 10 H 19 NaO2 and the following structure: [ka] It is a plant-derived compound having the formula:

[0065] The present disclosure discloses that the sodium caprate has two or more solid forms. A compound may have two or more solid forms due to the diversity of crystal lattices or structures, molecular packing, and / or the amount of solvent in the packed molecules, and / or a combination thereof. Several different forms of sodium caprate have been identified, including Form A, Form B, Form C, and Form D. Methods for identifying the forms of sodium caprate are described herein and include various analytical methods such as X-ray diffraction, X-ray scattering, and water content determination by Karl Fischer titration.

[0066] In some embodiments, the form of sodium caprate is identified by small angle X-ray scattering (SAXS). In some embodiments, the form of sodium caprate is identified by wide angle X-ray scattering (WAXS). SAXS and WAXS are scattering techniques in which X-rays are scattered by fluctuations in the electron density in a sample. Thus, in some embodiments, SAXS and WAXS are used to determine the crystal structure. SAXS typically diffracts at smaller angles than WAXS (i.e., the distance between the sample and the detector is longer for SAXS than for WAXS). Methods for setting up an experimental setup for SAXS or WAXS are known to those skilled in the art.

[0067] In some embodiments, sodium caprate forms A, B, C and D described herein have WAXS or SAXS patterns substantially as shown in Figures 3A-3D and 4A-4D. For example, the term "substantially as shown in" when referring to a WAXS or SAXS pattern refers to a pattern that is not necessarily identical to that shown herein, but falls within the limits of experimental error or deviation as considered by one of ordinary skill in the art. Various values ​​of WAXS and SAXS are described herein. As used throughout this disclosure (unless otherwise specified), all WAXS and SAXS peak position values ​​should be construed to be ±0.02. For simplicity, this difference will not be explicitly stated next to each peak value. For example, if the present disclosure states that Form A has a peak position of 0.12 Å, the peak position will be 0.12 Å. -1 This is 0.12±0.02 Å. -1 , i.e. 0.10 Å -1 ~0.14Å -1 Includes.

[0068] In some embodiments, SAXS and / or WAXS are used to determine the crystal structure of the compound. In some embodiments, Form A sodium caprate has a crystal structure of about 0.1 to about 0.15 Å. -1 In some embodiments, Form A sodium caprate comprises a WAXS peak in the region of about 0.12 to about 0.23 Å. -1In some embodiments, Form A sodium caprate comprises two or more WAXS peaks in the region of about 0.12 Å. -1 In some embodiments, Form A sodium caprate comprises a WAXS peak at about 0.23 Å. -1 Includes WAXS peaks.

[0069] In some embodiments, Form B sodium caprate has a pH of about 0.1 to about 0.2 Å. -1 In some embodiments, Form B sodium caprate comprises a WAXS peak in the region of about 0.17 Å. -1 In some embodiments, Form B sodium caprate comprises a WAXS peak at about 0.23 Å. -1 Contains WAXS peaks in the region.

[0070] In some embodiments, sodium caprate forms C and D have a viscosity of about 0.1 to about 0.3 Å. -1 In some embodiments, Forms C and D contain only one peak in the region of about 0.1 to about 0.2 Å. -1 In some embodiments, sodium caprate forms C and D do not contain a WAXS peak in the region of about 0.12 Å. -1 and 0.17 Å -1 In some embodiments, Forms C and D do not contain a WAXS peak at about 0.23 Å. -1 Includes WAXS peaks.

[0071] In some embodiments, Form A sodium caprate has a viscosity of about 0.1 to about 0.15 Å. -1 In some embodiments, Form A sodium caprate comprises a SAXS peak in the region of about 0.12 to about 0.23 Å. -1 In some embodiments, Form A sodium caprate comprises two or more SAXS peaks in the region of about 0.12 Å. -1 In some embodiments, Form A sodium caprate comprises a SAXS peak at about 0.23 Å. -1 Includes SAXS peaks.

[0072] In some embodiments, Form B sodium caprate has a pH of about 0.1 to about 0.2 Å. -1 In some embodiments, Form B sodium caprate comprises a SAXS peak in the region of about 0.17 Å. -1 In some embodiments, Form B sodium caprate comprises a SAXS peak at about 0.23 Å. -1 Contains SAXS peaks in the region.

[0073] In some embodiments, sodium caprate forms C and D have a viscosity of about 0.1 Å -1 ~about 0.3Å -1 In some embodiments, sodium caprate of forms C and D contains only one SAXS peak in the region of 0.12 Å. -1 does not contain any SAXS peaks.

[0074] In some embodiments, the form of sodium caprate is identified by X-ray powder diffraction (XRPD). XRPD is a diffraction method, i.e., scattering from atoms in planes in a regular crystal lattice. In general, XRPD can be used to detect the unique fingerprint of the crystallographic unit cell present in a crystalline substance, with each type of unit cell appearing as a peak at a specific position in the XRPD pattern. Thus, crystalline substances can be differentiated by their unit cells by identifying the peaks appearing in the diffraction pattern. Methods for setting up an XRPD experimental setup are known to those skilled in the art.

[0075] In some embodiments, the sodium caprate described herein has an XRPD pattern substantially as shown in Figures 1 and / or 2A-2D. For example, the term "substantially as shown in" when referring to an XRPD pattern refers to a pattern that is not necessarily identical to that shown herein, but falls within the limits of experimental error or variation as would be considered by one of ordinary skill in the art. Various values ​​of the XRPD are described herein. As used throughout this disclosure (unless otherwise specified), all XRPD peak position values ​​should be interpreted as being ±0.5° 2θ.

[0076] In some embodiments, Form A sodium caprate contains an XRPD peak at about 4° 2θ. In some embodiments, Form B, C, or D sodium caprate does not contain an XRPD peak at about 4° 2θ.

[0077] In some embodiments, the water content of sodium caprate is determined by Karl Fischer titration. Karl Fischer titration uses coulometric or quantitative titration to determine trace amounts of water in a sample. Methods for performing Karl Fischer titration are known to those of skill in the art. In some embodiments, sodium caprate in Form A or Form B has a reduced water content compared to the water content of Form C or Form D. In some embodiments, the sodium caprate is Form A sodium caprate characterized by a water content by Karl Fischer titration of less than 2%, less than 1.9%, less than 1.8%, less than 1.7%, less than 1.6%, less than 1.5%, or less than 1.4%. In some embodiments, sodium caprate in Form A has a water content of about 0.4% to about 1.7%. Sodium caprate in Form B has a water content of ≦1%. Form C sodium caprate has a moisture content of about 2% to about 3%, and Form D sodium caprate has a moisture content of about 2.5% to about 4%. In some embodiments, the sodium caprate used to make the oral tablet has a moisture content of less than about 2% as measured by Karl Fischer titration. In some embodiments, the sodium caprate has a moisture content of less than about 1.5%. In some embodiments, the sodium caprate has a moisture content of about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2.0%.

[0078] In some embodiments, sodium caprate has a particular particle size range before mixing with the polymer. The present disclosure has found that sodium caprate of various particle sizes can change tablet tensile strength and friability. In some embodiments, various particle sizes can affect the amount of mixture sticking to equipment during the tableting process, for example, mixtures containing sodium caprate and polymer stick to tableting dies and presses or leave residues. In some embodiments, sodium caprate is milled to a desired particle size. In some embodiments, sodium caprate is sieved to a desired particle size. In some embodiments, sodium caprate is sieved or milled to a desired particle size before direct compression to form a tablet. In some embodiments, mixtures containing sodium caprate and polymer are sieved or milled to a desired particle size before direct compression to form a tablet. Thus, in some embodiments, the present disclosure provides a method for reducing mixture sticking during the tableting process by providing sodium caprate of a particular particle size.

[0079] In some embodiments, the sodium caprate has a particle size of about 35 μm to about 1300 μm. In some embodiments, the sodium caprate has a particle size of about 100 μm to about 850 μm. In some embodiments, the sodium caprate has a particle size of about 250 μm to about 700 μm.

[0080] In some embodiments, the method of making oral tablets provided by the present disclosure includes forming a coating on the tablet after compression. Various coating agents and processes for applying coatings are known in the art. In some embodiments, the coating can mask the odor, color or taste of the tablet, provide physical and / or chemical protection to the drug, provide controlled and / or sustained release of the drug, increase the mechanical strength of the tablet, or protect the drug from the gastric environment.

[0081] The disclosure described herein provides a method of making oral tablets that does not require wet granulation. Thus, in some embodiments, the disclosure described herein provides a method of making oral tablets that does not include a drying step after mixing the polymer with sodium caprate. In some embodiments, the disclosure described herein provides a method of making oral tablets that does not include a milling step after the wet granulation process. Thus, the mixture of polymer and sodium caprate of the present disclosure can be directly compressed into tablets without the need for wet granulation, drying, and / or additional milling steps, resulting in a simplified tablet manufacturing process. The simplified process can achieve greater efficiencies, including lower operating costs, less product loss, increased production rates, and reduced use of specialized equipment required to manufacture tablets. In some embodiments, tablets made by a process that does not include wet granulation have reduced sticking of the mixture containing polymer and sodium caprate to tablet press equipment.

[0082] The tablets described in the present disclosure can be made by compressing a mixture comprising sodium caprate and a polymer. In some embodiments, the compression is carried out at more than 10 MPa. In some embodiments, the compression is carried out at 15 MPa to 500 MPa. In some embodiments, the compression is carried out at 25 MPa to 300 MPa. In some embodiments, the compression is carried out at 50 MPa to 200 MPa. In some embodiments, the present disclosure has found that compression below 50 MPa increases the sticking of the mixture to the tablet press.

[0083] Sodium caprate provided herein can be used as a permeation enhancer to increase the uptake of macromolecules by a subject. In some embodiments, the amount of sodium caprate is greatest in the tablet. In some embodiments, sodium caprate is about 30% to about 99% by weight of the tablet. In some embodiments, sodium caprate is about 50% to about 85% by weight or about 60% to about 80% by weight of the tablet. In some embodiments, sodium caprate is about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% by weight of the tablet. In some embodiments, sodium caprate is greater than 80%, greater than 85%, greater than 90%, or greater than 95% by weight of the tablet. For inspectors, in some embodiments, sodium caprate is about 90%, about 92%, about 94% or about 96% by weight of the tablet.

[0084] A variety of additives are known in the art and may be included in the tablets described herein. Additives may include, but are not limited to, carriers, additives, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonicity agents, solvents, and / or emulsifiers, or combinations thereof. In some embodiments, the additives are pharmaceutically acceptable. "Pharmaceutically acceptable" includes compounds approved by the United States Food and Drug Administration as acceptable for use in humans or domestic animals. In some embodiments, the mixture of polymer and sodium caprate further includes a polyol. In some embodiments, the polyol is sorbitol, mannitol, maltitol, xylitol, or a combination thereof. In some embodiments, the polyol is mannitol.

[0085] Various amounts of additives can be used according to the present disclosure. In some embodiments, the additive is about 0.001% to about 50% by weight of the tablet. In some embodiments, the additive is about 0.01% to about 45% by weight or about 0.1% to about 40% by weight of the tablet. In some embodiments, the additive is about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, or about 50% by weight of the tablet. In some embodiments, the additive is less than 10%, less than 5%, less than 20%, or less than 1% by weight of the tablet. For example, in some embodiments, the additive is about 0.1%, about 0.5%, about 1%, or about 2% by weight of the tablet. In some embodiments, there are no additives in the tablet (sodium caprate being the exception).

[0086] Various amounts of polyol can be used according to the present disclosure. In some embodiments, the polyol is about 0.001% to about 50% by weight of the tablet. In some embodiments, the polyol is about 0.01% to about 45% by weight or about 0.1% to about 40% by weight of the tablet. In some embodiments, the polyol is about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, or about 50% by weight of the tablet. In some embodiments, the polyol is less than 10%, less than 5%, less than 20%, or less than 1% by weight of the tablet. For example, in some embodiments, the polyol is about 0.1%, about 0.5%, about 1%, or about 2% by weight of the tablet. In some embodiments, the tablet does not contain a polyol (sodium caprate is the exception).

[0087] The methods provided herein can provide a tablet comprising an effective amount of a therapeutic polymer. An "effective amount" or "therapeutically effective amount" refers to an amount of a polymer sufficient to treat a disease state, condition, or disorder for which the polymer has utility when administered to a patient in need of treatment. Such an amount will be sufficient to induce a biological or medical response in a tissue system or patient as desired by a researcher or clinician. The amount of a polymer according to the present disclosure that constitutes a therapeutically effective amount will vary depending on the polymer and its biological activity, the formulation used for administration, the time of administration, the half-life of the polymer, the rate of excretion of the polymer, the duration of treatment, the type of disease state or disorder being treated and its severity, drugs used in conjunction or incidentally together with the polymer of the present disclosure, and factors such as the age, weight, general health, sex, and diet of the patient. Such a therapeutically effective amount can be routinely determined by one of ordinary skill in the art having regard to his or her knowledge, the current state of the art, and the present disclosure. In some embodiments, the polymer is from about 0.1% to about 12% by weight of the tablet, from about 0.2% to about 10% by weight of the tablet, from about 0.3% to about 8% by weight of the tablet, from about 0.4% to about 5% by weight of the tablet, or from about 0.5% to about 4% by weight of the tablet.

[0088] The term "treat," as used herein, unless otherwise indicated, means to ameliorate, alleviate, inhibit the progression of, or prevent the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment," as used herein, refers to the act of treating, as "treat" is defined immediately above.

[0089] The tablet according to the present disclosure is suitable for oral administration to a subject or patient. The term "subject" or "patient" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal (or patient). In some embodiments, the subject (or patient) is a human, a domestic animal (e.g., dogs and cats), a farm animal (e.g., cows, horses, sheep, goats, and pigs), and / or a laboratory animal (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys). In some embodiments, the subject (or patient) is a human. "A human (or patient) in need thereof" refers to a human who may have or is suspected of having a disease or condition that would benefit from a particular treatment, e.g., treatment with a compound disclosed herein by the present application.

[0090] Tablets as described herein include solid compressed dosage forms of a size and shape suitable for oral administration, for example, caplets, are embodied by the term "tablet" as described herein. In some embodiments, the tablet is 5 mm to 25 mm in diameter, or 8 mm to 20 mm in diameter. In some embodiments, the tablet is circular in shape. In some embodiments, the tablet is oval in shape. In some embodiments, the tablet is elongated, e.g., capsule-like in shape. Tablets may be conveniently provided in individual dosage units, as appropriate, and may be prepared by any of the methods well known in the art of pharmacy.

[0091] Compressed tablets can be prepared by compressing in a suitable machine the active compound into a form such as a powder or granules, optionally mixed with sodium caprate as described herein, and optionally further comprising additives such as lubricants, inert diluents, lubricants, stabilizers, emulsifiers, disintegrants, surfactants or dispersing agents, etc. In some embodiments, the tablets can also include a coating.

[0092] The tablets of the present disclosure can be prepared using pharmaceutical processes, i.e., by direct compression or by granulation and final tableting, which may include first forming a core containing the active agent and then surrounding the core with one or more layers.

[0093] The tensile strength of the tablets of the present disclosure (measured using a tablet hardness tester) should be sufficient for table storage and administration. In some embodiments, the tablets have a tablet hardness tensile strength of more than 0.5 MPa. In some embodiments, the oral tablets have a tablet hardness tensile strength in the range of about 0.5 MPa to about 5 MPa, for example, in the range of about 0.75 MPa to about 3.0 MPa.

[0094] In some embodiments, the present disclosure provides a method of making an oral tablet comprising the steps of: a) sieving sodium caprate to obtain sodium caprate particles having a particle size of about 35 μm to about 1100 μm; b) mixing the sodium caprate particles with a polymer to form a mixture; and c) directly compressing the mixture to form a tablet, wherein the sodium caprate has a particle size of about 0.1 to about 0.15 Å. -1 It contains peaks in the region of 0.12 and 0.23 Å. -1 and wherein the process does not include any wet granulation, drying or milling steps after the mixing of step (a).

[0095] In some embodiments, the present disclosure provides that converting any form of sodium caprate to sodium caprate Form A is accomplished by introducing a wet granulation step of sodium caprate with a non-aqueous solvent during the tablet manufacturing process, where Form A sodium caprate has an X-ray powder diffraction (XRPD) spectrum containing peaks at 4° 2θ and / or a peak between 0.1 and 0.15 Å. -1 It contains peaks in the region of 0.12 and 0.23 Å. -1 The present invention relates to a method for making an oral tablet, the tablet being characterized by a wide angle X-ray scattering (WAXS) spectrum having a peak at

[0096] In some embodiments, the present disclosure is directed to a method of making an oral tablet comprising: a) mixing sodium caprate particles with additional additives to form a mixture; b) granulating the mixture with an organic non-aqueous solvent to form granules; c) drying the granules; d) sieving or milling the granules to obtain granules having a particle size of about 100 μm to 2000 μm; e) blending with a polymer and / or additional additives; and f) compressing the mixture to form a tablet, wherein the sodium caprate after step c) is sodium caprate Form A. In some embodiments, sodium caprate Form A is characterized by an X-ray powder diffraction (XRPD) spectrum comprising a peak at 4° 2θ. In some embodiments, the organic solvent is selected from methanol (MeOH), ethanol (EtOH), 2-propanol (IPA), toluene, cyclohexane, dioxane, dimethylformamide (DMF), acetonitrile (ACN), tetrahydrofuran (THF), methyl isobutyl ketone (MIBK), ethyl acetate (EtOAc), and diethyl ether. In at least one embodiment, the organic solvent is ethanol. In some embodiments, the additional additive is a polyol. In some embodiments, the polyol is mannitol.

[0097] In some embodiments, the present disclosure is directed to a method of making an oral tablet comprising the steps of: a) granulating sodium caprate particles with an organic non-aqueous solvent to form granules, b) drying the granules, c) sieving or milling the granules to obtain granules having a particle size of about 100 μm to 2000 μm, d) blending the granules with a polymer and / or additional excipients to form a mixture, and e) compressing the mixture to form a tablet, wherein the sodium caprate after step (b) is sodium caprate Form A. In some embodiments, sodium caprate Form A has an X-ray powder diffraction (XRPD) spectrum comprising a peak at 4° 2θ and / or a peak between 0.1 and 0.15 Å. -1It contains peaks in the region of 0.12 and 0.23 Å. -1 The composition is characterized by a wide angle X-ray scattering (WAXS) spectrum with a peak at 1000 nm. In some embodiments, the organic solvent is selected from methanol (MeOH), ethanol (EtOH), 2-propanol (IPA), toluene, cyclohexane, dioxane, dimethylformamide (DMF), acetonitrile (ACN), tetrahydrofuran (THF), methyl isobutyl ketone (MIBK), ethyl acetate (EtOAc), and diethyl ether. In at least one embodiment, the organic solvent is ethanol. In some embodiments, the additional additive is a polyol. In some embodiments, the polyol is mannitol. An exemplary process for tablet manufacture involving wet granulation of sodium caprate, without any polymer or other additive being wet granulated and dried, is illustrated in FIG. 17.

[0098] In some embodiments, the present disclosure is directed to a method of making an oral tablet comprising the steps of: a) mixing sodium caprate particles with additional additives and a polymer to form a mixture; b) granulating the mixture with an organic non-aqueous solvent to form granules; c) drying the granules; d) sieving or milling the granules to obtain granules having a particle size of about 100 μm to 2000 μm; e) blending the granules with additional additives to form a mixture; and f) compressing the mixture to form a tablet, wherein the sodium caprate after step c) is Form A sodium caprate. In some embodiments, the sodium caprate is characterized by an X-ray powder diffraction (XRPD) spectrum comprising a peak at 4° 2θ. In some embodiments, the organic non-aqueous solvent is selected from methanol (MeOH), ethanol (EtOH), 2-propanol (IPA), toluene, cyclohexane, dioxane, dimethylformamide (DMF), acetonitrile (ACN), tetrahydrofuran (THF), methyl isobutyl ketone (MIBK), ethyl acetate (EtOAc), and diethyl ether and isopropyl alcohol (IPOH). In at least one embodiment, the organic non-aqueous solvent is ethanol. In at least one embodiment, the organic non-aqueous solvent is isopropyl alcohol. An exemplary process for tablet manufacture comprising wet granulation of sodium caprate with polymer and other additives is illustrated in FIG. 18.

[0099] In some embodiments, the present disclosure is directed to a tablet made by the methods described herein.

[0100] In some embodiments, the composition further comprises a polyol. In some embodiments, the polyol is mannitol. In some embodiments, the polymer is about 0.1% to about 12% by weight of the tablet. In some embodiments, the sodium caprate is about 45% to about 90% by weight of the tablet. In some embodiments, the polyol is about 0.001% to about 50% by weight of the tablet.

[0101] In some embodiments, the polymer is a peptide or an oligonucleotide. In some embodiments, the polymer is an antisense oligonucleotide. In some embodiments, the composition comprises an oligonucleotide of SEQ ID NO: 1. In some embodiments, the composition comprises a peptide of SEQ ID NO: 3-6.

[0102] All references cited herein, such as patents, patent applications, articles, textbooks, and the like, and the references cited therein, are incorporated herein by reference in their entirety to the same extent as if they had not already been cited. EXAMPLES

[0103] Example 1. X-ray powder diffraction analysis of various forms of sodium caprate A preliminary X-ray powder diffraction (XRPD) experiment was used to screen sodium caprate from five different suppliers. The results in Figure 1 show that sodium caprate from all five suppliers had different XRPD patterns. The different diffraction patterns may be due to different forms of sodium caprate and / or different mixtures of different forms of sodium caprate.

[0104] Various forms of sodium caprate were prepared according to Table 1 and measured by XRPD.

[0105] [Table 2]

[0106] 2A-2D show the XRPD spectra of the various forms of sodium caprate listed in Table 1.

[0107] Example 2. Wide angle X-ray scattering of various forms of sodium caprate The various forms of sodium caprate were further characterized using wide angle X-ray scattering (WAXS). The results are shown in Figures 3A-3D. Sodium caprate form A has an average crystallinity of about 0.12 to about 0.23 Å. -1Sodium caprate form A contains two or more WAXS peaks in the region of about 0.12 Å. -1 Sodium caprate form A contains a WAXS peak at approximately 0.23 Å. -1 Sodium caprate form B contains a WAXS peak at about 0.1 to about 0.2 Å. -1 Sodium caprate form B contains a WAXS peak in the region of approximately 0.17 Å. -1 Sodium caprate form B contains a WAXS peak at approximately 0.23 Å. -1 Sodium caprate forms C and D contain WAXS peaks in the region of about 0.1 to about 0.3 Å. -1 Sodium caprate forms C and D contain only one peak in the region of about 0.1 to about 0.2 Å. -1 Sodium caprate forms C and D do not contain a WAXS peak in the region of about 0.12 Å. -1 and 0.17 Å -1 Sodium caprate forms C and D contain no WAXS peak at about 0.23 Å. -1 Includes WAXS peaks.

[0108] Example 3. Small angle X-ray scattering of various forms of sodium caprate The various forms of sodium caprate were further characterized using small angle X-ray scattering (SAXS). The results are shown in Figures 4A-4D. Form A sodium caprate has an average particle size ranging from about 0.1 to about 0.15 Å. -1 Form A sodium caprate contains a SAXS peak in the region of about 0.12 to about 0.23 Å. -1 Form A sodium caprate contains two or more SAXS peaks in the region of about 0.12 Å. -1 Form A sodium caprate contains a SAXS peak at approximately 0.23 Å. -1 Sodium caprate form B contains a SAXS peak at about 0.1 to about 0.2 Å. -1 Sodium caprate form B contains a SAXS peak in the region of approximately 0.17 Å. -1 Sodium caprate form B contains a SAXS peak at approximately 0.23 Å. -1Forms C and D of sodium caprate contain a SAXS peak in the region of about 0.1 Å. -1 ~about 0.3Å -1 Forms C and D of sodium caprate contain only one peak in the region of 0.12 Å. -1 does not contain any SAXS peaks.

[0109] Example 4. Karl Fischer titration analysis of various forms of sodium caprate Karl Fischer titration was used to determine the water content in various forms of sodium caprate prepared as described in Example 1. The results are summarized in Table 3. Different solid state forms contain different amounts of water. The results show that Form D sodium caprate has the highest water content, followed by Form C. Form A has a water content of less than 2%.

[0110] [Table 3]

[0111] Example 5. Compaction properties of various forms of sodium caprate The tableting ability of sodium caprate with various particle sizes and morphologies was obtained by measuring the tensile strength of compressed tablets using a compaction simulator. Figures 5A-5C show the tableting ability results for laboratory-scale amounts of sodium caprate with particle sizes of about 37-53 μm, about 150-300 μm, and about 600-710 μm, respectively.

[0112] Tablets were prepared for each of the sodium caprate forms and evaluated for compaction. Form A exhibited the best compaction, e.g., pressure-dependent sticking, with no sticking observed at high pressures (above approximately 50 MPa). Forms B, C, and D exhibited poor tableting ability and a high tendency to stick. Forms C and D exhibited the poorest tableting ability, with no possibility of producing intact compacted tablets at most of the applied compaction pressures.

[0113] Example 6. Preparation of various forms of sodium caprate Sodium caprate was treated with various solvents and subjected to XRPD. The results in Figure 6 show that when sodium caprate was treated with water, Form C sodium caprate was formed, whereas when sodium caprate was treated with non-aqueous solvents such as methanol (MeOH), ethanol (EtOH), toluene, cyclohexane, dioxane, dimethylformamide (DMF), acetonitrile (ACN), tetrahydrofuran (THF), methyl isobutyl ketone (MIBK), ethyl acetate (EtOAc) and diethyl ether, predominantly Form A sodium caprate was formed. Sodium caprate treated with dimethyl sulfoxide (DMSO) produced an amorphous form with a small amount of crystalline material.

[0114] Further experiments were performed with a smaller panel of solvents, and as shown in Figure 7, treatment with solvents containing water yielded Form C sodium caprate, whereas treatment with solvents alone (e.g., ethanol, acetonitrile, acetone, or toluene) yielded predominantly Form A sodium caprate.

[0115] Example 7. Wet granulation of sodium caprate using alcohol or water Sodium caprate was wet granulated with water and with ethanol, dried, milled and sieved. As shown in Figure 8, sieved granules containing Form A sodium caprate granulated with ethanol had superior compaction properties compared to sieved granules prepared using water granulation. The water granulated material showed extensive sticking to the punches and dies of the tablet press. No sticking was observed for granules granulated in ethanol, regardless of the compaction pressure applied.

[0116] Sodium caprate forms A, B, C and D were each wet granulated with ethanol. Sodium caprate forms A, C and D were each wet granulated with 2-propanol. The wet granulated sodium caprate materials were then dried and milled. As shown in FIG. 9, after granulation with ethanol or 2-propanol, no sticking or picking was observed for all granulated sodium caprate materials, and tablet compacts with improved compactability could be formed. As shown in FIG. 10A-10G, WAXS analysis of the wet granulated, dried and milled sodium caprate materials showed the presence of sodium caprate form A. As shown in FIG. 11A-11G, XRPD analysis of the wet granulated, dried and milled sodium caprate materials showed the presence of sodium caprate form A.

[0117] Example 8. Preparation of tablets containing sodium caprate form A by direct compression The required amount of sodium caprate form A and mannitol were weighed into a bin blender. The ingredients were blended. Optionally, sodium stearyl fumarate was screened and added to the above dry mix and blended. The final blend was compressed into tablets using a 10 station rotary tablet press. The flow chart of this process is shown diagrammatically in Figure 12.

[0118] FIG. 13 shows the tabletting ability of sodium caprate Form A wet granulated with ethanol, dried and milled, and mixed with either microcrystalline cellulose (MCC) or hydroxypropyl cellulose (L-HPC), with and without sodium stearyl fumarate (PRUV).

[0119] Example 9. Preparation of tablets containing polymer and Form A sodium caprate wet granulated with mannitol The required amount of sodium caprate form A and mannitol will be weighed into a 60L high shear mixer. The two components will be dry mixed in the high shear mixer for 1 minute at an impeller speed of 140 rpm. During continuous mixing in the high shear mixer, ethanol will be added until the appropriate granulation is reached. After granulation, the wet granules will be transferred into a fluid bed dryer and dried at an inlet temperature of 70°C until the desired loss on drying of the granules is reached (<1.8%). The dried granules will then be milled in a cone mill with a screen size of 1.27 mm. The milled granules will then be blended with polymer (passed through a screen size of 0.25 mm), hydrous colloidal silica (passed through a screen size of 0.5 mm) and microcrystalline cellulose in an 80L diffusion mixer at a rotation speed of 30 rpm for 11 minutes. Sodium stearyl fumarate (passed through a 0.5 mm screen size) will be added to the blend and mixed for an additional 3 minutes at 30 rpm. The final blended granules will be compressed into uncoated core tablets using an 8-station rotary tablet press. The uncoated tablets will then be coated with a gastro-resistant coating (passed through a 0.25 mm screen size) in a pan coater (drum size 5 kg) at an inlet temperature of 50° C. to 70° C. The flow chart of this process is shown diagrammatically in FIG. 14.

[0120] Example 10: Wet granulation of sodium caprate and mannitol using alcohol Placebo formulations of sodium caprate with mannitol in Forms A, B, C and D were each subjected to wet granulation with ethanol. Sodium caprate in Forms A, C and D were each subjected to wet granulation with 2-propanol. The granulated materials were then dried and milled. The process flow chart for the entire process is shown diagrammatically in FIG. 14. As shown in FIG. 15, sodium caprate combined with mannitol after granulation with ethanol or 2-propanol improved compactability. WAXS analysis of the granulated (dried and milled) material showed the presence of sodium caprate Form A, as shown in FIG. 16A-16F. XRPD analysis of the granulated (dried and milled) material showed the presence of sodium caprate Form A, as shown in FIG. 17A-17F.

[0121] Example 11. Preparation of sodium caprate forms A, B, C and D [ka] Preparation of Sodium Caprate Form A, Method 1. Methanol (234 L) and water (12.3 L) were added to pre-melted capric acid (24.6 kg, 143 mol) and sodium bicarbonate (11.0 kg, 131 mol). The reaction mixture was heated at 65±5° C. and stirred for at least 16 hours. Upon completion of the reaction (capric acid≦3 mg / mL), the reaction solution was filtered through a polished filter. The temperature was adjusted to 50±5° C., the mixture was cooled (at 5° C. / hour) to 27±3° C., and tert-butyl methyl ether (TBME, 492 L) was added. The temperature was adjusted to 25±5° C. and stirred for at least 12 hours. The solid was collected by centrifugation and washed with TMBE (123 L). The solid was dried under reduced pressure at 50±5° C. for at least 12 hours (loss on drying, LoD≦2.0%) to give 20.99 kg of the desired product. Yield 81.3%, LoD 0.6%.

[0122] Preparation of Sodium Caprate Form A, Method 2 Charge ethanol (400 L, 8.0 v) to reactor A and start stirring. Charge capric acid (50.0 Kg, 1.0 eq.) to reactor A. Transfer capric acid / ethanol solution through microporous filter to reactor B. Charge ethanol (1100 L, 22.0 v) through microporous filter to reactor B. Heat to 65 ± 5 °C. Charge EtONa in ethanol (concentration: 20.5% w / w, 94.1 Kg, 0.96 eq.) through microporous filter to reactor B. Heat to reflux (85 ± 3 °C). Stir for at least 3 hours. Take a sample for GC (IPC). Capric acid concentration ≤ 0.5%. Cool to 55 ± 5 °C over 2 hours and stir for at least 6 hours. Cool the mixture to 45 ± 5 °C by controlling the cooling rate at 3-5 °C / hour and stir continuously for at least 6 hours. Cool the mixture to 30±5°C by controlling the cooling rate at 3-5°C / hr and keep stirring continuously for at least 10 hours. Isolation; centrifuge under nitrogen atmosphere and wash the cake once with ethanol (3.0v). Dry the cake under vacuum at 50±5°C for at least 12 hours. (Mix material every 2-4 hours). Sample every 4-6 hours until LoD≦2.0%. Collect crude product: 44.50 kg, LoD: 1.1%. Sift material through 20 mesh (800um) sieve. 43.32 kg product was obtained.

[0123] Preparation of Sodium Caprate Form A, Method 3 Capric acid (15 g) was dissolved in 150 ml of EtOH / water (12%-vol) at 65° C. with stirring (500 rpm) until dissolution occurred. Sodium ethoxide in EtOH (77 ml, 1.1 M, 1.0 eq) was added and stirred for 30 min (final water content 8%). A seed suspension was made by suspending sodium caprate form A (500 mg, 3%-wt) in TBME (225 ml) with stirring (450 rpm) at 50° C. The capric acid solution was added dropwise to the seed suspension at the midpoint between the impeller and the wall over 2.5 h. After addition, further sodium ethoxide in EtOH (1.1 M, 0.3 eq) was added for 1 h and stirred for 30 min. The sample was then cooled at 0.1 °C / min to 25 °C and then temperature cycled (25-40 °C; 2 cycles, cooling rate 0.1 °C / min, heating rate 2 °C / min) to a final temperature of 25 °C. Isolation was performed by filtration under suction under a nitrogen cone, followed by washing with chilled TBME (75 ml). The sample was dried in a vacuum oven at 40 °C overnight.

[0124] Preparation of Sodium Caprate Form B The sodium caprate powder was transferred into a reactor and the powder was heated to 280° C. under a flow of nitrogen gas. The resulting melt was continuously stirred. When all the material became liquid, the heating was stopped. The liquid in the reactor was cooled to room temperature under a flow of nitrogen gas overnight. The resulting solid sodium caprate Form B was collected from the sealed reactor.

[0125] Preparation of Sodium Caprate Form C Capric acid (1516.5g, 8.80mol, 1.0eq) was dissolved in ethanol (26 litres) and heated to 75-80°C. At temperature, sodium hydroxide solution (3683g, 9.46% w / w, 8.71mol, 0.99eq) was charged to the vessel over approximately 30 minutes while maintaining the temperature within the range of 70-80°C. After addition was complete, the mixture was stirred for 15 minutes, then cooled to 60°C, polish filtered into a second vessel at 60°C, then cooled to 52°C. TBME (15 litres) was then charged into it while maintaining the reaction mixture at a temperature within the range of 45-52°C. After addition, the batch was cooled to 37.5°C and then seeded (1.5g, sodium caprate). The batch was cooled to 36°C and then stirred for 1 hour between 34-36°C. During this time the reaction mixture became translucent, indicating further precipitation of product. The batch was cooled to 7-14° C. for 15-17 hours, collected by filtration and dried at 50° C. under reduced pressure to constant weight (1330 g, 77.8% yield, 1.69% LoD).

[0126] Preparation of Sodium Caprate Form D Charge THF (7 L, 4.5v) to reactor A and start stirring. Charge sodium caprate (Form A, 1.56Kg, 1.0eq.) to reactor A. Charge water (936ml, 0.6v / w.) to reactor A at 20-30°C. Heat to 65°C and stir for 2 hours (clear solution is observed). Cool to 20°C in 5 hours. Stir at 20°C for 38 hours. Take a sample for XRPD (Form D) filter and wash the cake once with THF (780ml, 0.5v). Dry the cake under vacuum at 45±5°C for at least 16 hours. Collect crude product. 952g, Yield: 61%.

[0127] Example 12. Preparation of Formulation 1, a tablet containing MEDI7219 peptide or MALAT1 ASO or placebo and wet granulated Form A sodium caprate 1200 g of sodium caprylate Form A was added to a powerful blending device and dry mixed for 1 minute at an impeller speed of 250 rpm and a chopper speed of 1500 rpm, after which 600 g of absolute ethanol was added (30 mL / min). After the addition was complete, the resulting material was mixed for an additional 1 minute. The material was dried overnight at ambient temperature in a fume hood until <LoD 1.5%. The dried material was milled using a Quadro Comil equipped with a 0.061’ grater screen and an angled impeller at 2000 rpm.

[0128] MEDI7219 Peptide - Sodium caprylate Form A (93 g) wet granulated as described in Example 12, microcrystalline cellulose (Avicel PH-102, 5.0 g), and MEDI7219 peptide (10 mg) were passed through a 500 μm sieve and manually pre-blended for 1 minute using a spoon in a metal container. Further blending was carried out in a turbula mixer for 8 minutes. Sodium stearyl fumarate (PRUV®, 2 g) was passed through a 250 μm sieve and manually pre-blended for 1 minute using a spoon. Further blending was carried out in a turbula mixer for 2 minutes. The material was put into a tableting machine and compacted.

[0129] MALAT1 ASO - Sodium caprylate Form A (93 g) wet granulated as described in Example 12, microcrystalline cellulose (Avicel PH-102, 5 g), and MALAT1 ASO (20 mg) were passed through a 500 um sieve and manually pre-blended for 1 minute using a spoon in a 1 L metal container. Further blending was carried out in a turbula mixer for 8 minutes. Sodium stearyl fumarate (PRUV®, 2 g) was passed through a 250 μm sieve and manually pre-blended for 1 minute using a spoon. Further blending was carried out in a turbula mixer for 2 minutes. The material was put into a tableting machine and compacted.

[0130] Placebo - Sodium caprate form A (93 g) and microcrystalline cellulose (Avicel PH-102, 5 g), wet granulated as described in Example 12, were passed through a 500um sieve and pre-blended manually with a spoon in a 1L metal container for 1 minute. Further blending was carried out in a turbula mixer for 8 minutes. Sodium stearyl fumarate (PRUV®, 2 g) was passed through a 250μm sieve and pre-blended manually with a spoon for 1 minute. Further blending was carried out in a turbula mixer for 2 minutes. The material was compacted to obtain a tablet tensile strength of 0.8MPa using a single punch machine equipped with a long and narrow punch (16×8 mm).

[0131] Placebo - Sodium caprate form A (87 g), microcrystalline cellulose (Avicel PH-102, 10 g) and silicon dioxide (Syloid 244FP, 1 g), wet granulated as described in Example 12, were passed through a 500um sieve and pre-blended manually with a spoon for 1 minute in a 1L metal container. Further blending was carried out in a turbula mixer for 8 minutes. Sodium stearyl fumarate (PRUV®, 2 g) was passed through a 250μm sieve and pre-blended manually with a spoon for 1 minute. Further blending was carried out in a turbula mixer for 2 minutes. The material was compacted to a tablet tensile strength of 1.4MPa using a single punch machine equipped with a long and narrow punch (16×8 mm).

[0132] Placebo - Sodium caprate form A (92 g), microcrystalline cellulose (Avicel PH-102, 5 g) and silicon dioxide (Syloid 244FP, 1 g), wet granulated as described in Example 12, were passed through a 500um sieve and pre-blended manually with a spoon for 1 minute in a 1L metal container. Further blending was carried out in a turbula mixer for 8 minutes. Sodium stearyl fumarate (PRUV®, 2 g) was passed through a 250μm sieve and pre-blended manually with a spoon for 1 minute. Further blending was carried out in a turbula mixer for 2 minutes. The material was compacted to a tablet tensile strength of 1.2MPa using a single punch machine equipped with a long and narrow punch (16×8 mm).

[0133] Example 13. Preparation of Formulation 2, a placebo tablet containing Form A sodium caprate wet granulated with mannitol Sodium caprate form A (7700 g) and mannitol (Pearlitol 100SD, 3300 g) were weighed into a 60 L high shear mixer. The two components were dry mixed for 3 minutes at an impeller speed of 140 rpm. During continuous mixing, ethanol (4050 g) was added until the appropriate granulation was reached. After granulation, the wet granules were transferred into a fluid bed dryer and dried at an inlet temperature of 70° C. until the desired loss on drying of the granules was reached (<1.8%). The dried granules were milled in a cone mill with a screen size of 1.27 mm. The LoD after milling was 0.5%-w / w.

[0134] The above dried granules (47.8 g), microcrystalline cellulose (Avicel PH-102, 2.5 g), silicon dioxide (Syloid 244FP, 0.5 g) were passed through a 250 um sieve and pre-blended manually with a spoon in a 1 L metal container for 1 minute, and further blended in a turbula mixer for 10 minutes. Sodium stearyl fumarate (1.0 g) was added to about 10 g of the above mixture and pre-blended manually with a spoon for 1 minute, the remaining amount of the above mixture was added and further blended manually with a spoon for 2 minutes. The material was put into a tablet press "as is" and compacted to obtain a tensile strength of 2.0 MPa.

[0135] Example 14. Dissolution profiles of MALAT1 ASO and MEDI7219 peptides The dissolution profile of Formulation 1, a tablet containing sodium caprate form A and ASO, prepared according to Example 12, is shown in Figure 20A. The graph shows that the release (dissolution) of the ASO (in this example, MALAT1) and sodium caprate form A from the tablet occurs rapidly and simultaneously in pH 6.8 phosphate buffer (simulating small intestinal conditions) at 37°C, allowing for maximum absorption enhancement. The dissolution profile of a tablet containing sodium caprate form A and MEDI7219 peptide is shown in Figure 20B. The graph shows that the release (dissolution) of the polypeptide (in this example, MEDI7219) from the tablet occurs rapidly in pH 6.8 phosphate buffer (simulating small intestinal conditions) at 37°C.

[0136] Example 15. Preparation of spherical agglomerates from sodium caprate form A Sodium caprate Form A particles prepared by Example 11, Method 3 were pre-wetted with acetonitrile (dispersion, liquid to solid ratio: 1:20) with stirring at 500 rpm for approximately 15 minutes to ensure a homogenous slurry. The slurry was wet milled (8000, 12000, 15000 rpm) at 10°C for 15 minutes to reduce particle size using an IKA Magic Lab mill. The cross-linking liquid, cyclohexane (liquid to solid ratio 1:3.5 to 1:3.8), was added over 60 minutes. After addition was complete, high shear mixing was continued for an additional 30 minutes, followed by overhead stirring for 30 minutes. Spherical agglomerates are collected by filtration with drying in a vacuum oven at 40°C overnight. Variation in the amount of cross-linking liquid and high shear wet milling rotor speed produces agglomerates with average sizes (D(50)) between 230μm and 1330μm. A process flow chart of the entire process is shown generally in FIG.

Claims

1. a) mixing a polymer with sodium caprate to form a mixture; b) directly compressing the mixture to form a tablet; 5. A method for making an oral tablet comprising the steps of: －１ wherein the form A sodium caprate is characterized by a wide angle X-ray scattering (WAXS) spectrum containing a peak in the region of

2. The sodium caprate has a viscosity of 0.12 and 0.23 Å. －１ 2. The method of claim 1, wherein the sodium caprate form A is characterized by a wide angle X-ray scattering (WAXS) spectrum comprising a peak at

3. The sodium caprate has a viscosity of 0.12 and 0.23 Å. －１ 3. The method of claim 1 or 2, wherein the sodium caprate form A is characterized by a small angle X-ray scattering (SAXS) spectrum comprising a peak at

4. 4. The method of any one of claims 1 to 3, wherein the sodium caprate is Form A sodium caprate characterized by an X-ray powder diffraction (XRPD) spectrum including a peak at 4° 2θ.

5. 5. The method of claim 1, wherein the sodium caprate has a water content of less than about 3.5% as measured by Karl Fischer titration.

6. 6. The method of any one of claims 1 to 5, wherein the sodium caprate has a water content of less than about 2.0% as measured by Karl Fischer titration.

7. 7. The method of any one of claims 1 to 6, wherein the sodium caprate has a water content of less than about 1.5% as measured by Karl Fischer titration.

8. 8. The method of any one of claims 1 to 7, wherein the sodium caprate of step (a) is sieved or milled to obtain a desired particle size prior to (b) direct compression to form a tablet.

9. 9. The method of any one of claims 1 to 8, wherein the mixture of step (a) is sieved or milled to obtain a desired particle size prior to (b) direct compression to form a tablet.

10. 10. The method of any one of claims 1 to 9, wherein the sodium caprate has a particle size in the range of about 35 μm to about 1300 μm prior to step (b).

11. The method of claim 10, wherein the sodium caprate has a particle size ranging from about 100 μm to about 850 μm.

12. The method of claim 11, wherein the sodium caprate has a particle size ranging from about 250 μm to about 750 μm.

13. The method according to any one of claims 1 to 12, wherein a coating is formed on the tablet after (b) tablet compression.

14. a) wet granulating sodium caprate in a non-aqueous organic solvent to form granules; b) drying and grinding the granules; c) mixing the resulting granules with polymers and other additives; d) compressing the mixture to form a tablet. wherein the sodium caprate after step b) has a pH of 0.1-0.15 Å. －１ and / or an X-ray powder diffraction (XRPD) spectrum containing a peak at 4° 2θ.

15. a) wet granulating sodium caprate along with other excipients in a non-aqueous organic solvent to form granules; b) drying and grinding the granules; c) mixing the resulting granules with a polymer and optionally additional additives; d) compressing the mixture to form a tablet. wherein after step b) the sodium caprate is Form A sodium caprate characterized by an X-ray powder diffraction (XRPD) spectrum comprising a peak at 4° 2θ.

16. a) wet granulating sodium caprate together with a polymer and optionally other excipients in a non-aqueous organic solvent to form granules; b) drying and grinding the granules; c) mixing the resulting granules with other additives; d) compressing the mixture to form a tablet. wherein after step b) the sodium caprate is Form A sodium caprate characterized by an X-ray powder diffraction (XRPD) spectrum comprising a peak at 4° 2θ.

17. The method according to any one of the preceding claims, wherein the compressing step is carried out at more than 10 MPa.

18. The method according to any one of the preceding claims, wherein the compressing step is carried out at between 15 MPa and 500 MPa.

19. The method according to any one of the preceding claims, wherein the compressing step is carried out at between 25 MPa and 300 MPa.

20. The method according to any one of the preceding claims, wherein the compressing step is carried out at between 50 MPa and 200 MPa.

21. The method of any one of claims 1 to 20, wherein the mixing step of (a) further comprises a polyol.

22. The method according to any one of claims 1 to 21, wherein the polyol is selected from sorbitol, mannitol, maltitol, xylitol and combinations thereof.

23. 23. The method according to any one of claims 1 to 22, wherein the polyol is mannitol.

24. 24. The method of any one of claims 1 to 23, wherein the polymer is about 0.1% to about 12% by weight of the tablet.

25. 25. The method of any one of claims 1 to 24, wherein the sodium caprate is about 30% to about 99% by weight of the tablet.

26. 26. The method of any one of claims 1 to 25, wherein the polyol is from about 0.001% to about 50% by weight of the tablet.

27. The method according to any one of claims 1 to 26, wherein the macromolecule is a peptide or an oligonucleotide.

28. The method of any one of claims 1 to 27, wherein the macromolecule is an oligonucleotide.

29. The method of any one of claims 1 to 28, wherein the macromolecule is an oligonucleotide of SEQ ID NO:

1.

30. 30. The method according to any one of claims 1 to 29, wherein the oral tablet has a tablet hardness tensile strength of about 0.5 MPa to about 5 MPa.

31. The method according to any one of claims 1 to 30, wherein the oral tablet has a tablet hardness tensile strength of about 0.75 MPa to about 3 MPa.

32. 32. The method according to any one of claims 1 to 31, wherein the oral tablet has a tablet hardness tensile strength of about 1.0 MPa to about 2.5 MPa.

33. a) sieving sodium caprate to obtain sodium caprate particles having a particle size of about 35 μm to about 1100 μm; b) mixing the sodium caprate particles with a polymer to form a mixture; c) directly compressing the mixture to form a tablet; 5. A method for making an oral tablet comprising the steps of: －１ and / or an X-ray powder diffraction (XRPD) spectrum containing a peak at 4° 2θ, wherein the process does not include a wet granulation, drying or milling step after the mixing of step (a).

34. A tablet made by the method of any one of claims 1 to 33.

35. A composition comprising a polymer and sodium caprate, wherein the sodium caprate has a viscosity of 0.1 to 0.15 Å. －１ and / or an X-ray powder diffraction (XRPD) spectrum containing a peak at 4° 2θ.

36. 36. The composition of claim 35 further comprising a polyol.

37. 37. The composition of claim 36, wherein the polyol is mannitol.

38. 38. The composition of any one of claims 35 to 37, wherein the polymer is about 0.1% to about 12% by weight of the tablet.

39. 39. The composition of any one of claims 35 to 38, wherein the sodium caprate is about 30% to about 99% by weight of the tablet.

40. 40. The composition of any one of claims 35 to 39, wherein the polyol is from about 0.001% to about 50% by weight of the tablet.

41. The composition according to any one of claims 35 to 40, wherein the macromolecule is a peptide or an oligonucleotide.

42. The composition of any one of claims 35 to 41, wherein the polymer is an oligonucleotide.

43. The composition of any one of claims 35 to 42, wherein the macromolecule is an oligonucleotide of SEQ ID NO:

1.

44. 46. ​​The composition of any one of claims 35 to 45, wherein the composition is in the form of an oral tablet, the oral tablet having a tablet hardness tensile strength of greater than 0.5 MPa.

45. 45. The composition of claim 44, wherein the oral tablet has a tablet hardness tensile strength of about 0.5 MPa to about 5 MPa.

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