Solid composition comprising a GLP-1 agonist and histidine

Abstract

The present invention relates to stabilized solid pharmaceutical compositions comprising a GLP-1 agonist. The present invention further relates to processes for the preparation of such compositions and their use in medicines.

Description

[Technical Field]

[0001] The present invention relates to solid pharmaceutical compositions comprising a GLP-1 agonist and histidine, to processes for their preparation and to their use in medicines.

[0002] Incorporation by reference of sequence listing The sequence listing entitled "SEQUENCE LISTING" is 4KB, was created on April 22, 2021, and is incorporated herein by reference. [Background technology]

[0003] Human GLP-1 and its analogs have low oral bioavailability. The exposure and bioavailability of human GLP-1 and its analogs after oral administration are very low. Human GLP-1 and its analogs can only reach therapeutically relevant plasma concentrations after oral administration when formulated with a specific absorption enhancer in a specific amount.

[0004] [Non-Patent Document 1] discloses oral administration of a tablet containing GLP-1(7-36) amide and 150 mg of sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC).

[0005] [Patent Document 1] discloses an oral pharmaceutical composition comprising a protein and N-(8-[2-hydroxybenzoyl)amino)caprylate (SNAC). Patent applications disclosing oral dosage forms of GLP-1 analogs containing salts of N-(8-(2-hydroxybenzoyl)amino)caprylate include [Patent Document 2], [Patent Document 3], [Patent Document 4], [Patent Document 5], and [Patent Document 6]. Further improved formulations are described in [Patent Document 7] and [Patent Document 8].

[0006] Regardless of the particular formulation, the stability of the GLP-1 analog is very important to ensure that the solid GLP-1 composition maintains its efficacy during storage and also minimizes waste of the pharmaceutical composition by extending the shelf life of the product. Furthermore, the stability of the GLP-1 analog is very important because it affects the viable storage temperature during the shelf life of the product, which is preferably the ambient room temperature of the solid oral dosage form. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2010 / 020978 [Patent Document 2] International Publication No. 2012 / 080471 [Patent Document 3] International Publication No. 2013 / 189988 [Patent Document 4] International Publication No. 2013 / 139694 [Patent Document 5] International Publication No. 2013 / 139695 [Patent Document 6] International Publication No. 2014 / 177683 [Patent Document 7] International Publication No. 2019 / 149880 [Patent Document 8] International Publication No. 2019 / 215063 [Non-patent literature]

[0008] [Non-Patent Document 1] Steinert et al. (Am J Clin Nutr, Oct 2010;92:810-817) Summary of the Invention

[0009] The present invention relates to a solid composition comprising a GLP-1 agonist and histidine. In one embodiment, the present invention relates to a solid composition comprising a GLP-1 agonist, an absorption enhancer or delivery agent, and histidine.

[0010] The composition according to the present invention comprises balanced amounts of a GLP-1 agonist and histidine.

[0011] Surprisingly, the inventors have discovered that when compositions are prepared with relatively low amounts of histidine, increased stability of GLP-1 agonists is observed.

[0012] One aspect of the present invention is a solid composition comprising: i) a GLP-1 agonist; and ii) histidine.

[0013] One embodiment of the present invention is a solid pharmaceutical composition comprising: i) a GLP-1 agonist; and ii) a delivery agent; and iii) histidine.

[0014] One embodiment of the present invention is a solid pharmaceutical composition comprising: i) a GLP-1 agonist; and ii) a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC); iii) histidine, The solid pharmaceutical composition relates to a solid pharmaceutical composition in which the moles of histidine are at least equal to half the moles of the GLP-1 agonist.

[0015] In one embodiment, the solid pharmaceutical composition comprises: i) 0.5 to 100 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B, or GLP-1 agonist C; ii) 50 to 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), for example, the sodium salt of NAC (SNAC); iii) 0.01 to 200 mg of histidine.

[0016] A further aspect of the present invention is a method for producing a solid pharmaceutical composition as described herein, comprising the steps of: i) mixing a GLP-1 agonist and histidine; ii) using the product of i) to prepare the solid pharmaceutical composition.

[0017] A further aspect of the present invention is a method for producing a solid pharmaceutical composition as described herein, comprising the steps of: i) co-processing a GLP-1 agonist and histidine; ii) using the product of i) to prepare the solid pharmaceutical composition.

[0018] Further aspects relate to medical uses of the compositions described herein. One embodiment relates to pharmaceutical uses of the compositions described herein, such as compositions for oral administration. In a further embodiment, the composition is a pharmaceutical composition for use in a method for treating diabetes and / or obesity.

[0019] In a further aspect, the present invention relates to a method for treating diabetes or obesity, comprising administering to a patient in need thereof a composition as defined herein. [Brief explanation of the drawings]

[0020] [Figure 1] Figure 1 shows the amount of formaldehyde adduct in the tablets measured after 2, 4, and 6 weeks. [Figure 2] FIG. 2 shows the amount of acetaldehyde adducts in the tablets measured after 2, 4, and 6 weeks. DETAILED DESCRIPTION OF THE INVENTION

[0021] Aspects of the invention described herein relate to compositions comprising a GLP-1 agonist and a stability enhancer, e.g., histidine, e.g., a composition comprising a GLP-1 agonist, an absorption enhancer or delivery agent, and histidine. Preferably, the composition can be in a form suitable for oral administration, such as a solid form exemplified by a tablet, a sachet, or a capsule. In one embodiment, the composition is a pharmaceutical composition, e.g., a composition for oral administration or an oral pharmaceutical composition.

[0022] GLP-1 agonists As used herein, the term "GLP-1 agonist" refers to a compound that fully or partially activates human GLP-1 receptor.Therefore, this term is equivalent to the term "GLP-1 receptor agonist" used in other documents.The term GLP-1 agonist, as well as the specific GLP-1 agonist described herein, also includes its salt form.

[0023] It follows that a GLP-1 agonist should exhibit "GLP-1 activity," which refers to the ability of a compound, i.e., a GLP-1 analog or a compound comprising a GLP-1 analog, to bind to a GLP-1 receptor, initiate a signal transduction pathway, and produce an insulinotropic effect or other physiological effect as known in the art. In some embodiments, a "GLP-1 agonist" is one that exhibits, for example, an affinity constant (K D ) or its potency (EC ) of less than 1 μM, e.g., less than 100 nM, as measured by methods known in the art (see, e.g., WO 98 / 08871 ). 50) and exhibit insulinotropic activity, which can be measured by in vivo or in vitro assays known to those skilled in the art. For example, GLP-1 agonists can be administered to animals with increased blood glucose (e.g., obtained using an intravenous glucose tolerance test (IVGTT)). Those skilled in the art can determine the appropriate glucose dosage and the appropriate blood sample collection method depending on, for example, the animal species involved in the IVGTT, and measure plasma insulin concentration over time. Suitable assays are described in, for example, WO2015 / 155151.

[0024] 50% effective concentration (EC 50 The term EC generally refers to the concentration that elicits a response halfway between baseline and maximum by reference to a dose-response curve. 50 is used as a measure of a compound's potency and represents the concentration at which 50% of its maximal effect is observed. Due to the albumin binding effect of GLP-1 agonists containing substituents as described herein, it is important to pay attention to whether the assay includes human serum albumin.

[0025] In vitro potency of GLP-1 agonists may be determined as described in Example 29 of 2015 / 155151, without human serum albumin (HSA), and EC 50 may be determined. 50 The lower the value, the better the potency. In one embodiment, the potency (EC50) determined (without HSA) is 5 to 1000 pM, for example, 10 to 750 pM, 10 to 500 pM, or 10 to 200 pM. In one embodiment, the EC50 (without HSA) is up to 500 pM, for example, up to 300 pM, for example, up to 200 pM.

[0026] In one embodiment, the EC50 (without HSA) is equivalent to human GLP-1(7-37).

[0027] In one embodiment, the EC50 (without HSA) is at most 50 pM. In further such embodiments, the EC50 is at most 40 pM, such as at most 30 pM, such as at most 20 pM, for example at most 10 pM. In one embodiment, the EC50 is about 10 pM.

[0028] Similarly, or alternatively, the binding of GLP-1 agonists to albumin may be measured using the in vitro potency assay of Example 29, which includes HSA. In vitro potency in the presence of serum albumin, EC 50 Increasing values ​​reflect affinity for serum albumin.

[0029] In one embodiment, the potency (EC50) determined (with 1% HSA) is between 5 and 1000 pM, e.g., between 100 and 750 pM, 200 and 500 pM, or 100 and 400 pM. In one embodiment, the EC50 (with 1% HSA) is up to 750 pM, e.g., up to 500 pM, e.g., up to 400 pM, e.g., up to 300, or e.g., up to 250 pM.

[0030] If necessary, the fold change with respect to a known GLP-1 receptor agonist can be calculated as EC50(test analog) / EC50(known analog), and the potencies are considered equivalent if this ratio is 0.5-1.5 or 0.8-1.2, etc.

[0031] In one embodiment, the potency, EC50 (without HSA), is equivalent to that of liraglutide.

[0032] In one embodiment, the potency, EC50 (without HSA) is equivalent to that of semaglutide.

[0033] In one embodiment, the potency, EC50 (without HSA) is equivalent to that of GLP-1 agonist B.

[0034] In one embodiment, the potency, EC50 (without HSA) is equivalent to that of GLP-1 agonist C.

[0035] In one embodiment, the potency, EC50 (with 1% HSA) is equivalent to that of liraglutide.

[0036] In one embodiment, the potency, EC50 (with 1% HSA) is equivalent to that of semaglutide.

[0037] In one embodiment, the potency, EC50 (with 1% HSA) is equivalent to that of GLP-1 agonist B.

[0038] In one embodiment, the potency, EC50 (with 1% HSA) is equivalent to that of GLP-1 agonist C.

[0039] In one embodiment, the GLP-1 agonist is a bifunctional molecule, such as a co-agonist or a tri-agonist.

[0040] In one embodiment, the GLP-1 agonist is also a gastric inhibitory polypeptide receptor agonist (GIP agonist). In one embodiment, the GLP-1 agonist is tirzepatide.

[0041] In some embodiments, the GLP-1 agonist is a GLP-1 analog, optionally containing one substituent. The term "analog," as used herein with reference to a GLP-1 peptide (hereinafter "peptide"), refers to a peptide in which at least one amino acid residue of the peptide has been replaced with another amino acid residue, and / or at least one amino acid residue has been deleted from the peptide, and / or at least one amino acid residue has been added to the peptide, and / or at least one amino acid residue of the peptide has been modified. Such addition or deletion of amino acid residues can occur at the N-terminus and / or C-terminus of the peptide. In some embodiments, a simple nomenclature is used to describe GLP-1 agonists; for example, [Aib8]GLP-1(7-37) refers to an analog of GLP-1(7-37), in which the naturally occurring Ala at position 8 is replaced with Aib. In some embodiments, the GLP-1 agonist includes up to 12 amino acids, e.g., up to 10, 8, or 6, that have been altered, e.g., by substitution, deletion, insertion, and / or modification, e.g., compared to GLP-1(7-37). In some embodiments, the analog includes up to 10 substitutions, deletions, additions, and / or insertions, e.g., up to 9 substitutions, deletions, additions, and / or insertions, up to 8 substitutions, deletions, additions, and / or insertions, up to 7 substitutions, deletions, additions, and / or insertions, up to 6 substitutions, deletions, additions, and / or insertions, up to 5 substitutions, deletions, additions, and / or insertions, up to 4 substitutions, deletions, additions, and / or insertions, or up to 3 substitutions, deletions, additions, and / or insertions, e.g., compared to GLP-1(7-37). Unless otherwise specified, GLP-1 includes only L-amino acids.

[0042] In some embodiments, the term "GLP-1 analog" or "analog of GLP-1," as used herein, refers to a peptide or compound that is a variant of human glucagon-like peptide-1 (GLP-1(7-37)). GLP-1(7-37) has the sequence HAEGTFTSDV SSYLEGQAAKEFIAWLVKGRG (SEQ ID NO: 1). In some embodiments, the term "variant" refers to a compound that contains one or more amino acid substitutions, deletions, additions, and / or insertions.

[0043] In one embodiment, the GLP-1 agonist shows at least 60%, 65%, 70%, 80%, or 90% sequence identity to GLP-1(7-37) over the entire length of GLP-1(7-37).As an example of a method for determining the sequence identity between two analogs, two peptides [Aib8]GLP-1(7-37) and GLP-1(7-37) are aligned.The sequence identity of [Aib8]GLP-1(7-37) to GLP-1(7-37) is obtained by subtracting the number of different residues from the number of aligned identical residues and dividing by the total number of residues in GLP-1(7-37).Therefore, in this example, the sequence identity is (31-1) / 31.

[0044] In one embodiment, the C-terminus of the GLP-1 agonist is an amide.

[0045] In some embodiments, the GLP-1 agonist is GLP-1(7-37) or GLP-1(7-36)amide. In some embodiments, the GLP-1 agonist is exendin-4, the sequence of which is HGEGTFITSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ ID NO: 2). In one embodiment, the GLP-1 agonist is an exendin-4 analog or modified peptide thereof, as disclosed in WO2013009545 and references therein.

[0046] In order to prolong the effect of GLP-1 agonist, it is preferred that GLP-1 agonist has a prolonged half-life.Half-life can be determined by methods known in the art in suitable models such as male Sprague Dawley rats or minipigs, as described in WO2012 / 140117.The half-life of rats can be determined as in Example 39 therein, and the half-life of minipigs can be determined as in Example 37 therein.

[0047] In one embodiment, the GLP-1 agonist according to the invention has a half-life in rats of more than 2 hours, hi one embodiment, the GLP-1 agonist according to the invention has a half-life in rats of more than 4 hours, such as more than 6 hours, for example more than 8 hours, such as more than 10 hours, for example more than 12 hours, or such as more than 15 hours.

[0048] In one embodiment, the GLP-1 agonist according to the invention has a half-life in minipigs of more than 24 hours, hi one embodiment, the GLP-1 agonist according to the invention has a half-life in minipigs of more than 30 hours, such as more than 36 hours, for example more than 42 hours, such as more than 48 hours, for example more than 54 hours, or such as more than 60 hours.

[0049] In one embodiment the GLP-1 agonist has a molecular weight of at most 50,000 Da, such as at most 40,000 Da, such as at most 30,000 Da.

[0050] In one embodiment the GLP-1 agonist has a molecular weight of at most 20000 Da, such as at most 10000 Da, such as at most 7500 Da, such as at most 5000 Da.

[0051] In one embodiment the GLP-1 agonist has a molar mass of at most 50000 g / mol, such as at most 40000 g / mol, such as at most 30000 g / mol.

[0052] In one embodiment the GLP-1 agonist has a molar mass of at most 10000 g / mol, such as at most 8000 g / mol, such as at most 6000 g / mol.

[0053] In some embodiments, the GLP-1 agonist comprises a substituent covalently attached to the peptide. In some embodiments, the substituent comprises a fatty acid or a fatty diacid. In some embodiments, the substituent comprises a C16, C18, or C20 fatty acid. In some embodiments, the substituent comprises a C16, C18, or C20 fatty diacid.

[0054] In some embodiments, the substituent is a group of formula (X): [ka] wherein n is at least 13, e.g., n is 13, 14, 15, 16, 17, 18, or 19. In some embodiments, the substituent comprises formula (X) wherein n is in the range of 13 to 19, e.g., in the range of 13 to 17. In some embodiments, the substituent comprises formula (X) wherein n is 13, 15, or 17. In some embodiments, the substituent comprises formula (X) wherein n is 13. In some embodiments, the substituent comprises formula (X) wherein n is 15. In some embodiments, the substituent comprises formula (X) wherein n is 17.

[0055] In some embodiments, the substituent is a group of formula (XIa)HOOC-(C6H4)-O-(CH2) m -CO-*(XIa) (wherein m is an integer ranging from 6 to 14).

[0056] In some embodiments, the substituent is a group of formula (XIb): [ka] wherein the carboxy group is at position 2, 3, or 4 of the (C6H4) group, and m is an integer ranging from 8 to 11.

[0057] In some embodiments, the substituent comprises formula (XIa) or formula (XIb) where m is in the range of 6 to 14, for example, in the range of 8 to 11. In some embodiments, the substituent comprises formula (XIa) or formula (XIb) where m is 8, 10, or 12. In some embodiments, the substituent comprises formula (XIa) or formula (XIb) where m is 9. In some embodiments, the substituent comprises formula (XIa) or formula (XIb) where m is 11.

[0058] In some embodiments, the substituent comprises one or more 8-amino-3,6-dioxaoctanoic acids (OEGs), such as two OEGs.

[0059] In some embodiments, the substituent is [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl].

[0060] In some embodiments, the substituent is [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl].

[0061] In some embodiments, the GLP-1 agonist is semaglutide, also known as N-epsilon 26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37), (SEQ ID NO: 4), which has the following structure and can be prepared as described in Example 4 of WO2006 / 097537: [ka] .

[0062] In one embodiment, the GLP-1 agonist is GLP-1 agonist B, which is shown in Example 2 of WO2011 / 080103 and is ε26 diacylated [Aib8,Arg34,Lys37]GLP-1(7-37) (SEQ ID NO: 5), designated {2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}-ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}, N ε37 -{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]-acetyl}-[Aib 8 ,Arg 34 ,Lys 37 ]GLP-1(7-37)-peptide. [ka] .

[0063] In one embodiment, the GLP-1 agonist is GLP-1 agonist C, which is shown in Example 31 of WO2012 / 140117, and ε27 diacylated [Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly (SEQ ID NO: 6), referred to as N-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]-acetyl]; ε36-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly. [ka] .

[0064] In general, the term GLP-1 agonist is intended to encompass a GLP-1 agonist and any pharmaceutically acceptable salts, amides, or esters thereof. In some embodiments, the composition comprises a GLP-1 agonist or a pharmaceutically acceptable salt, amide, or ester thereof. In some embodiments, the composition comprises a GLP-1 agonist and one or more pharmaceutically acceptable counterions.

[0065] In some embodiments, the GLP-1 agonist is any of the compounds described in WO93 / 19175, WO96 / 29342, WO98 / 08871, WO99 / 43707, WO99 / 43706, WO99 / 43341, WO99 / 43708, WO2005 / 027978, WO2005 / 058954, WO2005 / 058958, WO2006 / 0 05667, WO2006 / 037810, WO2006 / 037811, WO2006 / 097537, WO2006 / 097538, WO2008 / 023050, WO2009 / 030738, WO2009 / 030771, and WO2009 / 030774.

[0066] In some embodiments, the GLP-1 agonist is N-epsilon 37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide; N-epsilon 26{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[desaminoHis7,A rg34]GLP-1-(7-37);N-epsilon 37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon 37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyheptadecanoyl)piperidin-4-ylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][,desaminoHis7,Glu22 Arg26,Arg34,Phe(m-CF3)28]GLP-1-(7-37)amide; N-26-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl][Aib8,Arg34]GLP-1-(7-37); N-epsilon 26-{4-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]butyryl}[Aib8,Arg34]GLP-1-(7-37);N-epsilon 26-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon 26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl] cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)amide;N-epsilon 37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy} ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon 37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg 26,Arg34,Lys37]GLP-1-(7-37)amide; N-epsilon 37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(trans-19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon 37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon 26[2-(2-{2-[2-(2-{2-[(S)-4 -carboxy-4-({4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl[Aib8,Lys26]GLP-1(7-37)amide; N-epsilon 26 [2-(2-[2-(2-[2-(2-((S)-2-[trans-4-((9-carboxynonadecanoylamino]methyl)cyclohexylcarbonylamino]-4-carboxybutanoyl N-epsilon 37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Arg2 6,Arg34,Lys37]GLP-1-(7-37);N-epsilon 37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37);N-epsilon 26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)-hexadecanoylsulfamoyl)butyrylamino]-butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37); N-epsilon 26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl N-epsilon 26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37); N-epsilon 26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37 );N-epsilon 26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);N-epsilon 26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl N-epsilon 26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);N-epsilon 26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35); N-epsilon 26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy N-epsilon 26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35); N-epsilon 26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfa N-epsilon 26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-36)amide;N-epsilon 26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);N-epsilon 26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyryl-amino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Lys33,Arg34]GLP-1-(7-34);N-epsilon 26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-36) Amide;N-epsilon 26-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamine N-(2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-; 37)amide;N-epsilon 37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon 37{2-[2-(2-{2-[2-(( R)-3-Carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide; N-epsilon 37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetyl onylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon 37-[2-(2-[2-(2-[2-(2-(2-((R)-3-[1-(17-carboxyheptadecanoyl)piperidin-4-ylcarbonylamino]3-carboxy-propionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][desaminoHis7,Glu 22,Arg26,Arg34,Phe(m-CF3)28]GLP-1-(7-37)amide; N-epsilon 37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon 37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide; N-epsilon 37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans N-epsilon 37-[2-(2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37); N-epsilon 37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl N-epsilon 37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][A ib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide; N-epsilon 37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon 37-(3-((2-(2-(2-(2-(2-(2-hexadecyloxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy)propionyl)[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide; N-epsilon 37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxybutyryl-amino)ethoxy)ethoxy]acet N-epsilon 37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxy-butyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[desaminoHis7,Glu22,Arg26,Arg34,Lys37]G LP-1-(7-37)amide; N-epsilon 37-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(octadecanoyl-amino)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetyl)[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide; N-epsilon 37-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfa N-epsilon 37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxynonadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon 37-(2-{2-[2-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyrylamino]butyrylamino}butyrylamino)ethoxy]ethoxy}acetyl)[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37); N-epsilon 37-{2-[2-(2-{(S)-4-[(S)-4-(12-{4-[ 16-(2-tert-butyl-2H-tetrazol-5-yl)-hexadecanoylsulfamoyl]butyrylamino}dodecanoylamino)-4-carboxybutyrylamino]-4-carboxybutyrylamino}ethoxy)ethoxy]acetyl}[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37); N-epsilon 37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptyl) N-alpha 37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl] [Aib8,Glu22,Arg26,Arg34,epsilon-Lys37]GLP-1-(7-37) peptide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon 36-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxy-pentadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][desaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys36]GLP-1-(7-37)-Glu-Lys peptide; N-epsilon 37-[2-(2-{2-[2-( 2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl-amino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon 37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17- carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl]-[Aib8,Glu22,Arg26,Arg34,Aib35,Lys37]GLP-1-(7-37);N-epsilon 37-[(S)-4-carboxy-4-(2-{2-[2-(2-{2-[2-(17-carboxyheptadecanoylamino)ethoxy]ethoxy}acetylamino)ethoxy] ethoxy}acetylamino)butyryl][Aib8,Glu22,Arg26,34,Lys37]GLP-1(7-37);N-epsilon37-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][ImPr7,Glu22,Arg26,34,Lys37],GLP-1-(7-37);N-epsilon 26-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}, N-epsilon 37-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetyl}}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}-[Aib8,Arg34,Lys37]GLP-1(7-37)-OH; N-epsilon 26(17-carboxyheptadecanoyl)-[Aib8,Arg34]GLP-1-(7-37)-peptide; N-epsilon 26-(19-carboxynonadecanoyl)-[Aib8,Arg34]GLP-1-(7-37); N-epsilon 26-( 4-{[N-(2-carboxyethyl)-N-(15-carboxypentadecanoyl)amino]methyl}benzoyl[Arg34]GLP-1-(7-37); N-epsilon 26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GL P-1-(7-37);N-epsilon 26-[2-(2-[2-(2-[2-(2-[4-(19-carboxynonadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon 26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino; )-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][3-(4-imidazolyl)propionyl 17,Arg34]GLP-1-(7-37);N-epsilon 26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-(carboxymethyl-amino)acetylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-( 7-37;N-epsilon 26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-3(S)-sulfopropionylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon 26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetyl N-epsilon 26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)-amide; N-epsilon 26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)-amide decanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34,Pro37]GLP-1-(7-37)amide;Aib8,Lys26(N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(pentadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}),Arg34)GLP-1H(7-37)-OH;N-epsilon 26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxyheptadecanoyl)amino]methyl}benzoyl)amino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37);N-alpha 7-formyl,N-epsilon 26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxy-butyrylamino]ethoxy)ethoxy]acetylamino )ethoxy]ethoxy)acetyl][Arg34]GLP-1-(7-37);N-epsilon 2626-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxy-butyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Glu22,Arg34]GLP-1-(7-37);N-epsilon 26{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(15-(N-((S)-1,3-dicarboxypropyl)carbamoyl N-epsilon 26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxy-heptadecanoyl)amino]methyl}benzoyl)amino](4(S)-carboxybutyrylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][ Aib8,Arg34]GLP-1(7-37);N-epsilon 26-{(S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyrylamino)butyrylamino)butyrylamino}[Aib8,Arg34]GLP-1-(7-37);N-epsilon 26-4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxybutyryl-[Aib8,Arg34]GLP-1-(7-37);N-epsilon 26-{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1-(7-37);N-epsilon 26-{2-(2-(2-(2-[2-(2-(4-(17-carboxyheptadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[Aib8,22,27,30,35,A N-epsilon 26-[2-(2-[2-[4-(21-carboxyuneicosanoylamino)-4(S)-carboxybutyrylamino]ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37); and N-epsilon 26-[2-(2-[2-(2-[2-(2-[4-(21-carboxyuneicosanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37).

[0067] Delivery Agent A delivery agent or absorption enhancer, in the context of the present invention, is an excipient that can increase the oral exposure of a GLP-1 agonist.

[0068] Salts of N-(8-(2-hydroxybenzoyl)amino)caprylic acid The delivery agent used in the examples herein is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (also referred to herein as a salt of NAC), including the anion N-(8-(2-hydroxybenzoyl)amino)caprylate. The structural formula of N-(8-(2-hydroxybenzoyl)amino)caprylate is shown in Formula (I). [ka]

[0069] In some embodiments, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid includes one monovalent cation, two monovalent cations, or one divalent cation. In embodiments, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is selected from the group consisting of sodium, potassium, and / or calcium salts of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.

[0070] In a further embodiment, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is selected from the group consisting of sodium salts, potassium salts, and / or ammonium salts. In a further embodiment, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is a sodium salt or a potassium salt. Salts of N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt may be prepared using, for example, the methods described in WO 96 / 030036, WO 00 / 046182, WO 01 / 092206, or WO 2008 / 028859. Salts of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be crystalline and / or amorphous. In some embodiments, the delivery agent comprises an anhydrate, monohydrate, dihydrate, trihydrate, solvate, or one-third hydrate of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, as well as combinations thereof. In some embodiments, the delivery agent is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, as described in WO2007 / 121318.

[0071] In a further embodiment, the delivery agent is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (referred to herein as "SNAC"), also known as sodium 8-(salicyloylamino)octanoate.

[0072] composition The compositions or pharmaceutical compositions of the present invention are solid or dry compositions suitable for administration by the oral route, as further described herein below.

[0073] In some embodiments, the composition comprises at least one pharmaceutically acceptable excipient. As used herein, the term "excipient" broadly refers to any component other than the active therapeutic ingredient or active pharmaceutical ingredient (API). An excipient can be an inactive substance, a non-active substance, and / or a substance that is not therapeutically or pharmaceutically active.

[0074] Excipients can serve various purposes, such as carriers, vehicles, fillers, binders, lubricants, disintegrants, flow control agents, crystallization inhibitors, solubilizers, stabilizers, colorants, flavoring agents, surfactants, emulsifiers, or combinations thereof, and / or to improve the administration and / or absorption of therapeutically active substances or active pharmaceutical ingredients.The amount of each excipient used can vary within the conventional range in the art.The techniques and excipients that can be used to formulate oral dosage forms are described in Handbook of Pharmaceutical Excipients, 8th edition, Sheskey et al., Eds., American Pharmaceuticals Association and the Pharmaceutical Press, publications department of the Royal Pharmaceutical Society of Great Britain (2017), and Remington: the Science and Practice of Pharmacy, 22nd edition, Remington and Allen, Eds., Pharmaceutical Press (2013).

[0075] In some embodiments, the excipient is a binder such as polyvinylpyrrolidone (povidone), a cellulose derivative such as cellulose powder, microcrystalline cellulose (MCC), hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, a filler such as dibasic calcium phosphate, cornstarch, pregelatinized starch, a disintegrant such as cellulose powder, microcrystalline cellulose, sodium starch glycolate, polacrilin potassium, crospovidone, croscarmellose, sodium carboxymethylcellulose, dry cornstarch, a lubricant and / or glidant such as stearic acid, magnesium stearate, sodium stearyl fumarate, glycerol tribehenate, a flow control agent such as colloidal silica, talc, a crystallization inhibitor such as povidone, a solubilizer such as pluronic, povidone, red or yellow iron oxide, colorants, including dyes and pigments such as titanium dioxide, talc, pH adjusters such as citric acid, tartaric acid, fumaric acid, sodium citrate, dibasic calcium phosphate, dibasic sodium phosphate, surfactants and emulsifiers such as pluronic, polyethylene glycol, sodium carboxymethylcellulose, polyethoxylated and hydrogenated castor oil, mixtures of two or more of these excipients and / or adjuvants, hydrotropes such as nipecotamide, nicotinamide, sodium p-hydroxybenzoate, N,N dimethyl urea, N,N dimethyl benzamide, N,N diethyl nicotinamide, sodium salicylate, resorcinol, sodium benzoate, sodium xylene sulfonate, sodium p-toluene sulfonate, 1-methyl nicotinamide, pyrogallol, pyrocatechol, epigallocatechin gallate, tannic acid, and gentisic acid sodium salt hydrate.

[0076] The composition may contain binders such as povidone, starch, cellulose, and derivatives thereof, such as microcrystalline cellulose, e.g., Avicel PH, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, sucrose, dextrose, corn syrup, polysaccharides, and gelatin. The binder may be selected from the group consisting of dry binders and / or wet granulation binders. Suitable dry binders are, for example, cellulose powder and microcrystalline cellulose, such as Avicel. In some embodiments, the composition contains Avicel, e.g., Aavicel PH 101. Suitable binders for wet or dry granulation are corn starch, polyvinylpyrrolidone (povidone), vinylpyrrolidone-vinyl acetate copolymer (copovidone), and cellulose derivatives, e.g., hydroxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. In some embodiments, the composition contains povidone.

[0077] In some embodiments, the composition comprises a filler that may be selected from lactose, mannitol, erythritol, sucrose, sorbitol, calcium phosphate, e.g., calcium hydrogen phosphate, microcrystalline cellulose (MCC), powdered cellulose, powdered sugar, compressible sugar, dextrates, dextrin, and dextrose. In some embodiments, the composition comprises microcrystalline cellulose, such as Avicel PH 101 or Avicel PH 200.

[0078] In some embodiments, the composition comprises a lubricant and / or glidant, such as talc, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, glyceryl debehenate, behenoyl polyoxyl-8 glyceride, polyethylene oxide polymer, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, hydrogenated vegetable oil, silicon dioxide, and / or polyethylene glycol. In some embodiments, the composition comprises magnesium stearate.

[0079] In some embodiments, the composition includes a disintegrant, such as sodium starch glycolate, polacrilin potassium, sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethylcellulose, or dried cornstarch, or a hydrotrope, such as nicotinamide or resorcinol. The composition may include one or more surfactants, such as a surfactant, at least one surfactant, or two different surfactants. The term "surfactant" refers to any molecule or ion consisting of a water-soluble (hydrophilic) portion and a fat-soluble (lipophilic) portion. The surfactant may be selected from the group consisting of, for example, anionic surfactants, cationic surfactants, nonionic surfactants, and / or zwitterionic surfactants.

[0080] In a broad aspect, the present invention relates to a solid pharmaceutical composition comprising a GLP-1 agonist and a stability promoter.As shown herein, it has been found that histidine is an efficient aldehyde scavenger in compositions comprising GLP-1 agonists that are susceptible to aldehyde-mediated degradation, which leads to the accumulation of impurities over time, and therefore serves as a stability promoter.Alternative aldehyde scavengers can be selected from a larger group of compounds that are suitable as excipients in pharmaceutical compositions.

[0081] The following description also refers to compositions that contain or consist of specific ingredients, namely, a GLP-1 agonist, a delivery agent, and histidine, and optionally one or more excipients, such as a filler, binder, disintegrant, or hydrotrope, and / or lubricant. The term "consisting of" should be understood to encompass any substance, even in trace amounts, that does not affect the function of the composition. Such substances may be impurities from the preparation of the GLP-1 agonist, the manufacture of a salt of NAC, the histidine preparation, or minimal amounts (less than 1%) of any pharmaceutically acceptable excipient that do not affect the quality or absorption of the formulation.

[0082] In one embodiment, the pharmaceutical composition comprises an amount of histidine balanced relative to the amount of the GLP-1 agonist. The effect of histidine has been observed over a range of concentrations.

[0083] In one embodiment, the moles of histidine are at least half the moles of the GLP-1 agonist, in other words, the molar ratio of histidine to GLP-1 agonist is at least 0.5. In one embodiment, the molar ratio of histidine to GLP-1 agonist is at least 0.6, or such as at least 0.7, or such as at least 0.8, or such as at least 0.9, or such as at least 1.

[0084] In one embodiment, the moles of histidine are at most 100 times greater than the moles of GLP-1 agonist, in other words, the molar ratio of histidine to GLP-1 agonist is at most 100. In one embodiment, the molar ratio of histidine to GLP-1 agonist is at most 80, or such as at most 60, or such as at most 40 or 30.

[0085] In one embodiment, the molar ratio of histidine to GLP-1 agonist is 0.5-100, for example, 0.6-80, for example, 0.7-60, for example, 0.75-50, for example, 0.8-40, or for example, 0.9-30.

[0086] In embodiments in which the GLP-1 agonist has a molar mass of about 4000 g / mol, the mass ratio of histidine to GLP-1 agonist is at least 0.02, such as at least 0.03, or 0.04. In further such embodiments, the mass ratio of histidine to GLP-1 agonist is at most 4, such as at most 3, for example at most 2, or 1.

[0087] In one embodiment, the mass ratio of histidine to a GLP-1 agonist having a Mw of about 4000 g / mol is 0.02-4, such as 0.02-3, for example, 0.02-2, such as 0.03-1, for example, 0.04-1, or such as 0.05-1.

[0088] The pharmaceutical compositions according to the invention are preferably in a dosage form suitable for oral administration as described herein below. Hereinafter, absolute amounts of the components of the compositions of the invention are provided with reference to the content per dosage unit, i.e., per tablet, capsule or sachet.

[0089] In further embodiments, the pharmaceutical composition of the invention may contain up to 1000 mg of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) per dosage unit. In one embodiment, the invention relates to a composition wherein the dosage unit contains up to 600 mg of the salt.

[0090] In some embodiments, the amount of salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid per dosage unit is at least 0.15 mmol, e.g., at least 0.20 mmol, at least 0.25 mmol, at least 0.30 mmol, at least 0.35 mmol, at least 0.40 mmol, at least 0.45 mmol, at least 0.50 mmol, at least 0.55 mmol, at least 0.60 mmol, at least 0.65 mmol, at least 0.75 mmol, or at least 0.8 mmol.

[0091] In some embodiments, the amount of salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid per dosage unit of the composition is at most 2.5 mmol, e.g., at most 2.0 mmol, e.g., at most 1.5 mmol, at most 1 mmol, at most 0.75 mmol, at most 0.6 mmol, at most 0.5 mmol, at most 0.4 mmol, at most 0.3 mmol, or at most 0.2 mmol.

[0092] In some embodiments, the amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid per dosage unit of the composition is in the range of 0.20 to 2.5 mmol, 0.25 to 1.5 mmol.

[0093] In some embodiments, the amount of salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid per dosage unit of the composition is in the range of 0.2 to 0.6 mmol, 0.8 to 1.4 mmol, or 1.4 to 2.0 mmol.

[0094] In some embodiments, the delivery agent is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC'').

[0095] In some embodiments, the amount of SNAC per dosage unit of the composition is at least 50 mg, e.g., at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 350 mg, at least 450 mg, or at least 500 mg.

[0096] In some embodiments, the amount of SNAC per dose unit of the composition is up to 750 mg, e.g., up to 700 mg, e.g., up to 650 mg, e.g., up to 600 mg, e.g., up to 550 mg, up to 525 mg, up to 500 mg, up to 475 mg, up to 450 mg, up to 425 mg, up to 400 mg, up to 375 mg, up to 350 mg, up to 300 mg, up to 250 mg, up to 200 mg, or up to 150 mg per dose unit.

[0097] In some embodiments, the amount of SNAC per dosage unit of the composition is in the range of 50-750 mg, 65-600 mg, for example, 80-550 mg.

[0098] In some embodiments, the amount of SNAC per dosage unit of the composition is in the range of 50-150 mg, 150-500 mg, e.g., 200-400 mg, e.g., 300-700, or e.g., 400-600 mg.

[0099] In one embodiment, a dosage unit of the pharmaceutical composition of the present invention contains 0.5 to 100 mg, for example, 0.5 to 75 mg, for example, 0.5 to 60 mg, of the GLP-1 agonist.

[0100] In some embodiments, a dosage unit of the composition comprises an amount of GLP-1 agonist in the range of 0.5 to 50 mg, 1 to 50 mg, 2 to 50 mg, or 4 to 40 mg.

[0101] In some embodiments, a dosage unit of the composition comprises an amount of GLP-1 agonist in the range of 0.5 to 50 mg, 0.5 to 40 mg, 0.5 to 30 mg, or 0.5 to 20 mg.

[0102] In some embodiments, the dosage units contain 0.5 to 10 mg of GLP-1 agonist, 0.75 to 4 mg of GLP-1 agonist, or 1 / 2mg, e.g., 1, 1 1 / 2, 2, 2 1 / 2, or 3 mg, 3 1 / 2, 4, 4 1 / 2 mg, e.g., 1 to 3 or 3 to 5 mg of a GLP-1 agonist.

[0103] In some embodiments, the dose unit contains 2 to 20 mg of GLP-1 agonist, such as 2 to 15 mg, such as 2, 3, 4, or 5 mg, or such as 8, 10, 12, or 14 mg, such as 15 mg, or such as 20 mg of GLP-1 agonist.

[0104] In some embodiments, the dose unit contains 5 to 75 mg of GLP-1 agonist, such as 10 to 60 mg, such as 20, 30, 40, or 50 mg, or such as 25, 35, or 45 mg, or such as 30 to 50 mg, or such as 20 to 40 mg of GLP-1 agonist.

[0105] As described above, the amount of histidine is balanced with the amount of GLP-1 agonist, but typically a dosage unit of the composition of the present invention contains 0.01 to 400 mg of histidine. In one embodiment, the dosage unit contains 0.01 to 300 mg, e.g., 0.02 to 300 mg, e.g., 0.05 to 200 mg, e.g., 0.02 to 100 mg, or 1 to 50 mg of histidine.

[0106] In one embodiment, the dosage unit of the composition according to the invention comprises: i) 0.5 to 100 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B, or GLP-1 agonist C; ii) 50 to 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), for example, the sodium salt of NAC (SNAC); iii) 0.01 to 200 mg of histidine.

[0107] In one embodiment, the dosage unit of the composition according to the invention comprises: i) 1 to 100 mg of semaglutide; ii) 50 to 150 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), for example, the sodium salt of NAC (SNAC); iii) 0.02 to 100 mg, for example, 1 to 50 mg, of histidine.

[0108] In one embodiment, the dosage unit of the composition according to the invention comprises: i) 1 to 100 mg of semaglutide; ii) 150 to 500 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), for example, the sodium salt of NAC (SNAC); iii) 0.02 to 100 mg, for example, 1 to 50 mg, of histidine.

[0109] In one embodiment, the dosage unit of the composition according to the invention comprises: i) 1 to 100 mg of semaglutide; ii) 350 to 600 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), for example, the sodium salt of NAC (SNAC); iii) 0.02 to 100 mg, for example, 1 to 50 mg, of histidine.

[0110] As described herein above, the composition may further comprise pharmaceutical excipients such as lubricants, binders, disintegrants, or hydrotropes, and / or fillers.

[0111] In one embodiment, the dosage unit of the composition according to the invention comprises: i) 0.5 to 100 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B, or GLP-1 agonist C; ii) 50 to 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), e.g., the sodium salt of NAC (SNAC); iii) 0.01 to 200 mg of histidine, and iv) optionally containing further pharmaceutical excipients.

[0112] In one embodiment, the dosage unit of the composition according to the invention comprises: i) 0.5 to 100 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B, or GLP-1 agonist C; ii) 50 to 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), e.g., the sodium salt of NAC (SNAC); iii) 0.01 to 200 mg of histidine; iv) a lubricant, and v) optionally containing additional pharmaceutical excipients.

[0113] In one embodiment, the dosage unit of the composition according to the invention comprises: i) 0.5 to 100 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B, or GLP-1 agonist C; ii) 50 to 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), e.g., the sodium salt of NAC (SNAC); iii) 0.01 to 200 mg of histidine; iv) lubricants, v) a disintegrant or hydrotrope, and vi) optionally containing further pharmaceutical excipients.

[0114] In one embodiment, the dosage unit of the composition according to the invention comprises: i) 0.5 to 100 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B, or GLP-1 agonist C; ii) 50 to 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), e.g., the sodium salt of NAC (SNAC); iii) 0.01 to 200 mg of histidine; iv) lubricants, v) disintegrants or hydrotropes; vi) fillers, and vii) optionally containing further pharmaceutical excipients.

[0115] In one embodiment, the dosage unit of the composition according to the invention comprises: viii) 0.5 to 100 mg of a GLP-1 agonist, e.g., semaglutide, GLP-1 agonist B, or GLP-1 agonist C; ix) 50 to 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), e.g., the sodium salt of NAC (SNAC); x) 0.01 to 200 mg of histidine, xi) lubricants, xii) disintegrants or hydrotropes; xiii) fillers; xiv) a binder, and xv) optionally containing further pharmaceutical excipients.

[0116] In one embodiment, the dosage unit of the composition according to the invention comprises: i) 0.5 to 100 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B, or GLP-1 agonist C; ii) 50 to 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), e.g., the sodium salt of NAC (SNAC); iii) 0.01 to 200 mg of histidine; iv) lubricants, such as magnesium stearate; v) fillers, e.g., MCC; vi) disintegrants or hydrotropes, e.g., nicotinamide; vii) a binder, such as povidone, and viii) optionally containing further pharmaceutical excipients.

[0117] In further embodiments, the amounts of various pharmaceutical excipients may be adjusted per dosage unit or relative to one or more other ingredients.

[0118] In one embodiment, the composition comprises less than 5% w / w of lubricant by total amount of excipients.

[0119] In one embodiment, the composition comprises less than 5% w / w of the lubricant by weight of the delivery agent. In one embodiment, the composition comprises 0.25-5% w / w, e.g., 1-4% w / w, of the lubricant by weight of the delivery agent. In a further embodiment, the composition comprises 0.25-5% w / w, e.g., 1-4% w / w, of the lubricant by weight of the NAC salt, such as SNAC.

[0120] In one embodiment, a unit dose of the composition comprises 0.1 to 20 mg of a lubricant, or 1 to 15 mg of a lubricant such as magnesium stearate.

[0121] In one embodiment, a unit dose of a composition according to the invention comprises 20-150 mg of filler, or 40-100 mg of filler, such as MCC.

[0122] In one embodiment, a dosage unit of the composition comprises 10 to 600 mg, for example, 10 to 500 mg, of disintegrant or hydrotrope. In one embodiment, a dosage unit of the composition comprises 10 to 600 mg, for example, 10 to 500 mg, for example, 10 to 400 mg, for example, 20 to 300 mg, or for example, 25 to 250 mg, of nicotinamide.

[0123] In one embodiment, a unit dose of a composition according to the invention comprises 1 to 30 mg of a binder, 1 to 25 mg of a binder, or 1 to 20 mg of a binder, such as povidone.

[0124] Dosage form The composition may be administered in several dosage forms, for example, as a tablet, a coated tablet, a sachet, or a capsule, such as a hard or soft capsule, all such compositions being considered solid oral dosage forms.

[0125] The composition may be in the form of a dosage unit, such as a tablet, hi some embodiments, the weight of the dosage unit is in the range of 50 mg to 1000 mg, e.g., in the range of 50 to 750 mg, or, e.g., in the range of about 100 to 600 mg.

[0126] In some embodiments, the weight of the dosage unit is in the range of 50 mg to 400 mg, for example, in the range of 75 to 350 mg or 100 to 300 mg.

[0127] In some embodiments, the weight of the dosage unit is in the range of 200 mg to 600 mg, for example, in the range of 250 to 550 mg or 300 to 500 mg.

[0128] In some embodiments, the weight of the dosage unit is in the range of 300 mg to 700 mg, for example, in the range of 350 to 650 mg or 400 to 600 mg.

[0129] In some embodiments, the weight of the dosage unit is in the range of 400 mg to 1000 mg, for example, in the range of 450 to 850 mg or 500 to 700 mg.

[0130] In some embodiments, the composition, or some of the ingredients of the composition, may be granulated before being compressed into a tablet or filled into a capsule or sachet.

[0131] The composition may comprise a granulated portion and / or an extragranulated portion, where the granulated portion has been granulated and the extragranulated portion has been added after granulation.

[0132] The granulation portion may include one or more types of granulation containing different subsets of the components of the composition.

[0133] The granulation portion may include a GLP-1 agonist, a delivery agent, and / or histidine. In one embodiment, the granulation portion may include one or more additional excipients, such as a lubricant, a filler, a disintegrant, a hydrotrope, and / or a binder.

[0134] In one embodiment, the granulation portion comprises a delivery agent and a lubricant, hi one embodiment, the granulation portion comprises SNAC and magnesium stearate.

[0135] In one embodiment, the histidine is included in the granulate portion or the extragranulate portion.

[0136] In one embodiment, the GLP-1 agonist is included in the extragranular portion. In one embodiment, the extragranular portion comprises a GLP-1 agonist. In one embodiment, the extragranular portion may further comprise histidine. In one embodiment, the extragranular portion further comprises a lubricant such as magnesium stearate.

[0137] Preparation of the Composition The preparation of the compositions according to the invention can be carried out according to methods known in the art.

[0138] To prepare a dry blend of materials, the various components are weighed, optionally de-lumped or sieved, and then combined. Mixing of the components may be carried out until a homogeneous blend is obtained.

[0139] The term "granulation" refers broadly to pharmaceutical ingredients in the form of particles, granules, and agglomerates used in the preparation of solid dosage formulations. Generally, granulations are obtained by processing powders or blends to obtain new composite particles of a desired size.

[0140] If the granulation is to be used for further processing into tablets, capsules, or sachets, the granulation can be produced in a manner known to those skilled in the art, for example, using wet granulation methods known for producing "built-up" or "broken-down" granulations. Methods for forming built-up granulations can operate continuously, such as with equipment from Loedige, Glatt, Diosna, Fielder, and Collette, and can involve, for example, simultaneously spraying the granulation mass with a granulating solution and drying by spray drying or spray congealing, for example, in a drum granulator, pan granulator, disk granulator, fluidized bed, or can operate discontinuously, for example, in a fluidized bed, rotary fluidized bed, batch mixer such as a high-shear mixer or low-shear mixer, or in a spray-drying drum. The process for producing disintegrated granules can be carried out discontinuously, where the granulation mass first forms a wet agglomerate with the granulating solution, which is subsequently milled or formed by other means into granules of the desired size, and then the granules can be dried. Suitable equipment for the granulation step are planetary mixers, low shear mixers, high shear mixers, extruders, and spheronizers, such as those manufactured by companies Loedige, Glatt, Diosna, Fielder, Collette, Aeschbach, Alexanderwerk, Ytron, Wyss & Probst, Werner & Pfleiderer, HKD, Loser, Fuji, Nica, Caleva, and Gabler. Granules can also be formed by dry granulation techniques in which one or more of the excipients and / or active pharmaceutical ingredients are compressed to form relatively large bodies, such as slugs or ribbons, which are then broken down by milling to the desired size of the granules, and the milled material serves as material for further processing into tablets, capsules, or sachets. Suitable equipment for dry granulation is from Gerteis, Alexanderwerk, and Freund-Vector.

[0141] Further methods for obtaining granulation may include hot melt extrusion, spray drying, spray granulation, and / or ball milling.

[0142] In one embodiment, the present invention provides i. GLP-1 agonists, ii. Salts of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC); iii. histidine, and iv. For compositions optionally comprising a lubricant, e.g., magnesium stearate, The composition comprises the granulations of ii) and iv).

[0143] In embodiments where the granulation portion includes a delivery agent and a lubricant, these excipients may be co-processed prior to or during preparation of the granulation.

[0144] Granulation can be obtained by the various methods mentioned above, whereby ii) and iv) are initially mixed either as powders or by preparing a solution containing both components.

[0145] The granulations of ii) and iv) can be obtained by wet granulation or dry granulation of a solution or blend.

[0146] In one embodiment, i) and iii) are co-processed prior to tablet compression.

[0147] In one embodiment, a solution of i) and iii) is prepared and subjected to spray drying or spray granulation, thereby directly obtaining the powder or granules. In one embodiment, spray drying followed by dry granulation / roller compaction can be used to obtain the granules. Alternatively, i) and iii) can be prepared as a mixture.

[0148] To obtain a homogeneous product, one or more sieving steps may be included before the final dry granulation step / roller compaction or tablet compression.

[0149] Tablet presses may be used to compact materials into solid oral dosage forms, such as tablets. In tablet presses, tableting materials are loaded (e.g., force-fed or gravity-fed) into die cavities. The tableting materials are then compressed by a set of punches that apply pressure. The resulting tablets are then ejected from the tablet press. The above-described tableting process is hereinafter referred to as the "compression process." Suitable tablet presses include, but are not limited to, rotary tablet presses and eccentric tablet presses. Suitable equipment for tablet compression is equipment from Fette, Korsch, GEA Courtouy, and Manesty.

[0150] In some embodiments, the present invention relates to a method for preparing a composition such as a tablet according to the present invention. In one embodiment, the method for preparing a tablet comprises: a) granulating a delivery agent and optionally a lubricant; b) blending the granules of a) with a GLP-1 agonist and histidine; c) compressing the blend into tablets.

[0151] The granulation can be wet granulation or dry granulation. As mentioned above, the lubricant can be magnesium stearate, which can be included in step a, as well as in one or more of steps b) and c).

[0152] In one embodiment, the present invention provides a method for producing a solid pharmaceutical composition, comprising: i) obtaining a blend comprising a GLP-1 agonist and histidine; ii) co-processing the blend of i); iii) using the product of ii) to prepare a solid pharmaceutical composition.

[0153] In one embodiment, the method is for producing a solid pharmaceutical composition, i) obtaining a solution or suspension comprising a GLP-1 agonist and histidine; ii) spray drying i); iii) using the product of ii) to prepare the solid pharmaceutical composition.

[0154] In all of the above embodiments, the method may further comprise preparing the solid pharmaceutical composition using one or more pharmaceutical excipients, such as a lubricant, a binder, a disintegrant or hydrotrope, and / or a filler, as described above.

[0155] Drug indications The present invention also relates to the compositions of the present invention for use as a medicament. In certain embodiments, the compositions of the present invention may be used for the following medical treatments, all of which preferably relate in some way to diabetes: (i) prevention and / or treatment of all forms of diabetes, including hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin dependent diabetes, MODY (maturity-onset diabetes of the young), gestational diabetes, and / or reduction of HbA1C; (ii) delaying or preventing the progression of diabetic disease, such as the progression of type 2 diabetes, delaying the progression from impaired glucose tolerance (IGT) to insulin-requiring type 2 diabetes, and / or delaying the progression from insulin-nonrequiring type 2 diabetes to insulin-requiring type 2 diabetes; (iii) improved beta cell function, such as reduced beta cell apoptosis, increased beta cell function and / or beta cell mass, and / or restored glucose sensitivity to beta cells; (iv) prevention and / or treatment of cognitive impairment; (v) prevention and / or treatment of eating disorders such as obesity (e.g., by reducing food intake, weight loss, suppressing appetite, inducing satiety), treatment or prevention of antipsychotic or steroid-induced binge eating disorder, bulimia nervosa, and / or obesity, reducing gastric motility and / or delaying gastric emptying; (vi) prevention and / or treatment of diabetic complications such as neuropathy, including peripheral neuropathy, nephropathy, or retinopathy; (vii) improvement of lipid parameters (such as prevention and / or treatment of dyslipidemia, lowering total serum lipids, lowering HDL, lowering small dense LDL, lowering VLDL, lowering triglycerides, lowering cholesterol, increasing HDL, reducing plasma levels of lipoprotein a (Lp(a)) in humans, or inhibiting the production of apolipoprotein a (apo(a)) in vitro and / or in vitro); (iix) prevention and / or treatment of cardiovascular disease (including syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, stroke, cerebral ischemia, premature heart or premature cardiovascular disease (such as left ventricular hypertrophy), ischemic heart disease, essential hypertension, acute hypertensive attack, cardiomyopathy, cardiac dysfunction, exercise tolerance, chronic heart failure, arrhythmias, cardiac rhythm disorders, syncope, atherosclerosis, mild chronic heart failure, angina pectoris, cardiac bypass re-occlusion, intermittent claudication (arteriosclerosis obliterans), diastolic dysfunction, and / or systolic dysfunction; (ix) prevention and / or treatment of gastrointestinal disorders such as inflammatory bowel syndrome, small bowel syndrome, Crohn's disease, dyspepsia, and / or gastric ulcers; (x) prevention and / or treatment of critical illness (such as treating critically ill patients, critical illness polyneuropathy (CIPNP) patients, and / or potential CIPNP patients, preventing the onset of critical illness or CIPNP, preventing, treating, and / or curing systemic inflammatory response syndrome (SIRS) in patients, and / or preventing or reducing the likelihood that a patient will suffer from bacteremia, sepsis, and / or septic shock during hospitalization), and / or (xi) prevention and / or treatment of polycystic ovary syndrome (PCOS).

[0156] In embodiments, the indication is selected from the group consisting of (i)-(iii) and (v)-(iix), e.g., indication (i), (ii), and / or (iii); or indication (v), indication (vi), indication (vii), and / or indication (iix). In another embodiment, the indication is (i). In a further embodiment, the indication is (v). In yet a further embodiment, the indication is (iix). In some embodiments, the indication is type 2 diabetes and / or obesity.

[0157] The present invention further relates to a method of treating an individual in need thereof, the method comprising administering to the individual a therapeutically active amount of a composition according to the present invention. In further such embodiments, one or more dosage units may be administered to the individual in need thereof.

[0158] Treatment method The present invention further relates to a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition according to the present invention. In one embodiment, the method of treatment is for the treatment of diabetes or obesity and / or the further indications identified above.

[0159] In some embodiments, a method for treating diabetes is described that includes administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition that includes a GLP-1 agonist, a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), histidine, and optionally excipients such as fillers, binders, disintegrants, and / or lubricants.

[0160] In some embodiments, there is provided a method of treating diabetes, comprising administering to a subject in need thereof: i) 0.5 to 100 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B, or GLP-1 agonist C; ii) 50 to 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), for example, the sodium salt of NAC (SNAC); iii) 0.01 to 200 mg of histidine; and iv) 0 to 10 mg of a lubricant.

[0161] In some embodiments, the GLP-1 agonist is semaglutide, which has the formula N-epsilon 26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37).

[0162] In some embodiments, the GLP-1 agonist is N ε26 {2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}-ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl},N ε37 -{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]-acetyl}-[Aib 8 ,Arg 34 ,Lys 37 ]GLP-1(7-37) (GLP-1 agonist B).

[0163] In some embodiments, the GLP-1 agonist is N ε27 -[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]-acetyl, N ε36 -[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly (GLP-1 agonist C).

[0164] In one embodiment, the composition is administered orally and is in the form of a tablet, capsule, or sachet.

[0165] In further such embodiments, one or more dosage units may be administered to the subject in need thereof.

[0166] Combination therapy Treatment with the compositions according to the invention may also be combined with one or more additional active pharmaceutical ingredients selected from antidiabetic agents, antiobesity agents, appetite regulators, antihypertensive agents, agents for the treatment and / or prevention of complications resulting from or associated with diabetes, and agents for the treatment and / or prevention of complications and disorders resulting from or associated with obesity. Examples of these pharmacologically active substances include insulin, sulfonylureas, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists, DPP-IV (dipeptidyl peptidase-IV) inhibitors, sodium glucose transporter 2 (SGLT2) inhibitors; canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, tofogliflozin, luseogliflozin, bexagliflozin, remogliflozin etabonate, and sotagliflozin, in particular dapagliflozin and empagliflozin; inhibitors of hepatic enzymes involved in stimulating gluconeogenesis and / or glycogenolysis; glucose uptake regulators; HMG Compounds that modify lipid metabolism, such as hypolipidemic drugs (statins) as CoA inhibitors, gastrointestinal inhibitory polypeptides (GIP analogues), compounds that reduce food intake, RXR agonists, and drugs that act on the ATP-dependent potassium channel of beta-cells; cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol, dextrothyroxine, neteglinide, repaglinide; beta-blockers, such as alprenolol, atenolol, Timolol, pindolol, propranolol, and metoprolol, ACE (angiotensin-converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, alatriopryl, quinapril, and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem, and verapamil, and alpha-blockers such as doxazosin, urapidil, prazosin, and terazosin;CART (cocaine amphetamine-regulated transcript) agonists, NPY (neuropeptide Y) antagonists, PYY agonists, Y2 receptor agonists, Y4 receptor agonists, mixed Y2 / Y4 receptor agonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin-releasing factor) agonists, CRF BP (corticotropin-releasing factor binding protein) antagonists, urocortin agonists, beta3 agonists, oxyntomodulin and analogs, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone-releasing compounds, TRH (thyrotropin-releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptine, doplexin), lipase / amylase inhibitors, RXR (retinoid X receptor) modulators, TR Beta-agonists; histamine H3 antagonists, gastrointestinal inhibitory polypeptide agonists or antagonists (GIP analogs), gastrin and gastrin analogs;

[0167] The invention described herein is further defined, but not limited to, by the embodiments described herein below and the claims of this document.

[0168] Embodiment 1. A solid pharmaceutical composition comprising a GLP-1 agonist and histidine. 2. The composition of embodiment 1, further comprising a delivery agent. 3. The composition of embodiment 2, wherein the delivery agent is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC). 4.i) a GLP-1 agonist; ii) a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC); iii) histidine. 5. The composition of any of the preceding embodiments, wherein the molar ratio of histidine to GLP-1 agonist is at least 0.5. 6. The composition of any of the preceding embodiments, wherein the molar ratio of histidine to GLP-1 agonist is at most 100. 7. The composition of any of the preceding embodiments, wherein the molar ratio of histidine to GLP-1 agonist is 0.5 to 100, such as 0.6 to 80, for example, 0.7 to 60, such as 0.8 to 40, or such as 0.9 to 30. 8. The composition of embodiment 3, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) is selected from the group consisting of sodium, potassium, and / or calcium salts of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. 9. The composition of any of the preceding embodiments, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC). 10. The composition of any of the preceding embodiments, wherein the composition further comprises one or more pharmaceutical excipients, such as a filler, binder, disintegrant, or hydrotrope, and / or a lubricant. 11. The composition of any of the preceding embodiments, wherein the composition comprises a lubricant. 12. The composition of any of the preceding embodiments, wherein the composition comprises 0.25-5 w / w% of a lubricant of the total amount of excipients. 13. The composition of any of the preceding embodiments, wherein the composition comprises 0.25-5 w / w% of a lubricant by weight of the delivery agent. 14. The composition of any of the previous embodiments, wherein the composition comprises a lubricant, for example, magnesium stearate. 15. The composition of any of the previous embodiments, wherein the lubricant is magnesium stearate. 16. The composition of any of embodiments 3-15, wherein the composition comprises magnesium stearate in an amount of 0.25-5% w / w of the amount of NAC or SNAC. 17. GLP-1 agonists demonstrate a T of at least 24 hours in minipigs. 1 10. The composition of any preceding embodiment, wherein the .DELTA..times ... 18. GLP-1 agonists have a T of at least 2 hours in minipigs. 1 10. The composition of any preceding embodiment, wherein the .DELTA..times ... 19. The composition of any of the preceding embodiments, wherein the GLP-1 agonist has an EC50 (without HSA) of up to 100 pM, such as up to 50. 20. The composition of any of the preceding embodiments, wherein the GLP-1 agonist has an EC50 (without 1% HSA) of up to 100 pM, such as up to 50. 21. The composition according to any of the preceding embodiments, wherein the GLP-1 agonist has a molar mass of up to 50000 g / mol. 22. The composition of any of the preceding embodiments, wherein the GLP-1 agonist comprises an albumin binding substituent. 23. The composition of any of the preceding embodiments, wherein the GLP-1 agonist comprises a fatty acid or a fatty diacid. 24. The composition of any of the preceding embodiments, wherein the GLP-1 agonist comprises a C16, C18, or C20 fatty acid, or a C16, C18, or C20 fatty diacid. 25. The composition of any of the preceding embodiments, wherein the GLP-1 agonist is selected from the group consisting of liraglutide, semaglutide, GLP-1 agonist B, and GLP-1 agonist C. 26. The composition of any of the preceding embodiments, wherein the GLP-1 agonist is semaglutide. 27. The composition of any of the preceding embodiments, wherein the dosage unit comprises 0.1 to 100 mg of the GLP-1 agonist. 28. The composition of any of the preceding embodiments, wherein the mass ratio of histidine to semaglutide is at least 0.02. 29. The composition of any of the preceding embodiments, wherein the mass ratio of histidine to semaglutide is at most 4. 30. The composition of any of the preceding embodiments, wherein the mass ratio of histidine to semaglutide is 0.02 to 4, for example, 0.02 to 3, 0.02 to 2, 0.03 to 1, or 0.05 to 1. 31.i) a GLP-1 agonist, e.g., semaglutide, GLP-1 agonist B, or GLP-1 agonist C; ii) a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), for example SNAC; iii) histidine, and iv) a lubricant. 32. The composition of any of the preceding embodiments, wherein the dosage unit contains up to 1000 mg of NAC / SNAC. 33. The dosage unit is i) 0.5 to 100 mg, for example, 1 to 75 mg, of a GLP-1 agonist, for example, semaglutide, GLP-1 agonist B, or GLP-1 agonist C; ii) 50 to 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), e.g., SNAC; iii) 0.01 to 200 mg of histidine; iv) 0-15 mg of a lubricant. 34. The dosage unit is i) 1 to 75 mg, for example 1 to 60 mg, of semaglutide; ii) 50 to 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), e.g., SNAC; iii) 0.02 to 100 mg of histidine; iv) 0-15 mg of a lubricant. 35. The composition of any of the preceding embodiments, wherein the composition further comprises a pharmaceutical excipient. 36. The dosage unit is i) 0.5 to 100 mg, for example, 1 to 75 mg, of a GLP-1 agonist, for example, semaglutide; ii) 50 to 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), e.g., SNAC; iii) 0.01 to 200 mg of histidine; iv) 1 to 15 mg of a lubricant; and v) 20 to 100 mg of a filler, for example, MCC; vi) 30 to 500 mg of a disintegrant, such as nicotinamide; vii) 1 to 20 mg of a binder, such as povidone. 37. The composition of any of the preceding embodiments, wherein the composition is a solid oral dosage form. 38. The composition of any of the preceding embodiments, wherein the composition is a tablet. 39. The composition of embodiment 36, wherein i) and iii) are co-processed prior to tableting. 40. The composition of embodiment 36, wherein i) and iii) are co-processed by blending. 41. The composition of embodiment 36, wherein i) and iii) are co-processed by spray drying. 42. The composition of any of the previous embodiments, wherein the composition comprises a granulation comprising ii). 43. The composition of any of the previous embodiments, wherein the composition comprises a granulation comprising ii) and iv). 44. The composition of embodiment 43, wherein ii) and iv) are blended before granulation. 45. The composition according to any of embodiments 42 to 44, wherein the granulation is obtained by roller compaction. 46. ​​The composition of any of embodiments 36-45, wherein the composition comprises an extragranular portion. 47. The composition comprises: a) granulating a mixture containing a delivery agent; b) blending the granulated product of a) with a GLP-1 agonist and histidine; c) preparing the composition using the blend of b). 48. The composition of any of the preceding embodiments, wherein the composition is for use in a method for treating diabetes and / or obesity. 49. A method for producing a solid pharmaceutical composition, comprising: i) obtaining a blend comprising a GLP-1 peptide and histidine; ii) co-processing the blend of i); iii) using the product of ii) to prepare the solid pharmaceutical composition. 50. The method of embodiment 49, wherein in step ii), the co-processing is carried out by spray drying. 51. The method according to embodiment 49, wherein the method comprises one or more further steps of preparing said solid pharmaceutical composition using one or more additional pharmaceutical excipients. 52. A method for the treatment of diabetes or obesity, comprising administering to a subject in need thereof a therapeutically effective amount of a solid pharmaceutical composition according to any of embodiments 1 to 48, or a solid pharmaceutical composition prepared by the method of any of embodiments 49 to 51. 53. The method according to embodiment 52, wherein the solid pharmaceutical composition is administered once a day or less frequently. [Example]

[0169] material and method Method 1 - Co-spray drying of semaglutide and histidine Aqueous or ethanol-water solutions (1:9) were prepared by dissolving semaglutide and histidine in molar ratios of approximately 1:1, 1:2, 1:3.75, 1:7.5, 1:15, 1:30, 1:32, and 1:100, respectively, to give concentrations of approximately 2-2.5% w / w. The solutions were spray-dried (Buchi Mini Spray Drier) with the aspirator set at 100%, an inlet temperature of approximately 120 or 155°C, an outlet temperature of approximately 45 or 78°C, and a solution feed rate of approximately 6 or 12 g / min.

[0170] Method 2 – Dry granulation of SNAC and magnesium stearate SNAC and magnesium stearate were mixed for 50 minutes at 25 rpm using a Pharmatech MB blender prior to dry granulation. Dry granulation was performed by roller compaction on a Gerteis MINI-PACTOR using a smooth roll, a 0.63 or 0.80 mm screen, and a granulator speed of 30 to 120 rpm. The roll speed was set at 3 to 6 rpm, and a roller compaction force of 6 to 9 kN / cm was applied at intervals of 1 to 2 mm. Following dry granulation, the extrusions were milled into granules.

[0171] Assay I: Analysis of semaglutide-related impurities - RP-UHPLC method Samples were prepared by dissolving tablets using phosphate buffer pH 7.4 (50 mM KH2PO4, 380 mM potassium chloride) mixed with 20% (v / v) acetonitrile and optionally 0.1% (w / v) Brij® 35 (polyoxyethylene lauryl ether) as extraction buffer. The sample content of semaglutide-related impurities was determined using an RP-UHPLC method. The UHPLC method was based on gradient elution on a C18 column. The eluent system was 0.09 M (NH4)2HPO4 in water (pH 3.6), acetonitrile, and 2-propanol, with UV detection at 215 nm.

[0172] Hydrophobic impurity group 1 was calculated as a percentage based on the area of ​​all semaglutide-related peaks eluted from the end of the semaglutide peak to the start of the second linear gradient relative to the total area of ​​all semaglutide-related peaks in the chromatogram.

[0173] Hydrophobic impurity group 2 was calculated as a % based on the area of ​​all semaglutide-related peaks eluted in the second linear gradient relative to the total area of ​​all semaglutide-related peaks in the chromatogram.

[0174] Assay II: Analysis of semaglutide aldehyde adducts - LC-MS method Samples were prepared by dissolving the mixture or tablets using phosphate buffer pH 7.4 (50 mM KH2PO4) mixed with 20% (v / v) acetonitrile. The sample content of semaglutide aldehyde adducts was determined using a high-resolution mass spectrometer equipped with RP-UHPLC. The UHPLC method was based on gradient elution on a C18 column. The eluent system was 0.06% TFA, 90% acetonitrile in water with UV detection at 214 nm.

[0175] From the total ion chromatogram (TIC), reconstructed ion chromatograms (RIC) were extracted from the triply charged monoisotopic peaks of semaglutide and the +12 and +26 impurities, namely the semaglutide formaldehyde adduct and semaglutide acetaldehyde adduct, respectively. The RIC peaks were integrated and the areas used to calculate the +12 and +26 levels relative to semaglutide.

[0176] Assay III: Analysis of semaglutide aldehyde adducts - RP-UHPLC method Samples were prepared by dissolving tablets using phosphate buffer pH 7.4 (50 mM KH2PO4, 380 mM potassium chloride) mixed with 20% (v / v) acetonitrile and optionally 0.1% (w / v) Brij® 35 (polyoxyethylene lauryl ether) as extraction buffer. The sample content of semaglutide aldehyde adducts was determined using an RP-UHPLC method. The UHPLC method was based on gradient elution on a C18 column. The eluent system was 0.09 M (NH4)2HPO4 in water (pH 3.2), acetonitrile, and 2-propanol, with UV detection at 215 nm.

[0177] Semaglutide formaldehyde adduct was calculated as a % based on the area of ​​the semaglutide formaldehyde adduct peak relative to the area of ​​the semaglutide peak in the chromatogram.

[0178] Semaglutide acetaldehyde adduct was calculated as a % based on the area of ​​the semaglutide acetaldehyde adduct peak relative to the area of ​​the semaglutide peak in the chromatogram.

[0179] Example 1 - Stability of GLP-1 in compositions with and without histidine The compositions of mixtures between semaglutide and SNAC, with and without histidine, were prepared according to Table 1.1 below. Compositions prepared using semaglutide or co-spray-dried semaglutide and histidine were each weighed into a container and mixed with SNAC. Co-spray-dried semaglutide and histidine were prepared according to method 1. [Table A]

[0180] The compositions were stored at 60°C and 75% RH in equilibrated desiccators prepared with saturated NaCl suspension. Prior to storage, an additional volume of 1 mg / mL formaldehyde solution was added to one desiccator, corresponding to an approximately 1:1 molar ratio between formaldehyde and semaglutide.

[0181] The levels of semaglutide formaldehyde adduct in the compositions before and after storage were measured according to Assay II. The results are shown in Table 1.2 below and show an increase in the level of semaglutide formaldehyde adduct after 19 days, which is significantly lower for the composition containing histidine (mixture Y). [Table B]

[0182] Example 2 - Stability of GLP-1 in tablet compositions with and without histidine A range of tablet compositions containing semaglutide with and without histidine were prepared according to Table 2.1 below. Compositions were prepared using semaglutide or co-spray dried semaglutide and histidine as described in method 1, and a granulation of SNAC and magnesium stearate was prepared according to method 2. Pre-mixed semaglutide and histidine was prepared by alternately mixing and grinding equal amounts of semaglutide and histidine in a mortar and pestle.

[0183] One tablet of SNAC and magnesium stearate granulation was weighed onto a weighing pan. One tablet of semaglutide, semaglutide and histidine, pre-mixed semaglutide and histidine, or spray-dried semaglutide and histidine was then weighed onto the granulation into the weighing pan. The molar ratio of semaglutide to histidine in all tablets was 1:32.

[0184] The ingredients were then mixed by hand and transferred directly into the tablet die cavities of an instrumented rotary tablet press (Fette 102i). The mixture in the die cavities was compressed into round convex tablets measuring 7 mm at a die table rotation speed of 20 rpm and a compression force of approximately 6.5 kN. [Table C]

[0185] The compositions were stored at 60°C and 75% RH in equilibrated desiccators prepared with saturated NaCl suspension. After storage periods of 2, 4, and 6 weeks, the tablets were removed from the desiccators and the levels of aldehyde adducts of semaglutide were measured according to Assay II. The results are contained in Tables 2.2 and 2.3 below and Figures 1 and 2, and show the increase in the levels of semaglutide aldehyde adducts over time. The levels of semaglutide aldehyde adducts, particularly semaglutide formaldehyde adducts, were significantly lower in the compositions containing histidine (Tablets B, C, and D). [Table D] [Table E]

[0186] Example 3 - Stability of GLP-1 in tablet compositions containing different amounts of histidine A further series of tablet compositions containing semaglutide with and without histidine were prepared according to Table 3.1 below. Compositions were prepared according to method 1 with semaglutide, or co-spray dried semaglutide and histidine.

[0187] For tablet compositions I-IV, a granulation of SNAC and magnesium stearate was prepared according to method 2, and one tablet of the granulation was weighed onto a weighing pan. One tablet of semaglutide, or spray-dried semaglutide and histidine, was then weighed onto the granulation in the weighing pan. The ingredients were then mixed by hand and transferred directly into the tablet die cavities of an instrumented rotary tablet press (Fette 102i). The mixture in the die cavities was compressed into round, convex tablets measuring 6.5 mm at a die table rotation speed of 20 rpm and a compression force of approximately 7.5 kN.

[0188] For tablet compositions V-VIII, the SNAC, microcrystalline cellulose, and magnesium stearate granulation and the microcrystalline cellulose and povidone granulation were generally prepared as described in WO 2013 / 139695, but using slightly different equipment and parameter settings. The microcrystalline cellulose and povidone granulation was premixed with magnesium stearate using a Turbula mixer at 25 rpm for 30 minutes. One tablet of the SNAC, microcrystalline cellulose, and magnesium stearate granulation was weighed onto a weighing pan. One tablet of the microcrystalline cellulose and povidone granulation premixed with magnesium stearate was weighed on top of it. Finally, one tablet of semaglutide or spray-dried semaglutide and histidine was weighed onto the other ingredients in the weighing pan. The ingredients were then mixed by hand and transferred directly to the cavity of the tablet die of an instrumented rotary tablet press (Fette 102i). The mixture in the die cavities was compressed into oval convex tablets measuring 7.5 x 13 mm at a die table rotation speed of 20 rpm and a compression force of approximately 9 kN.

[0189] Table 3.1 - Tablet compositions I-VIII. The compositions are provided as the total amount of each component in mg / tablet. Tablets I and V are prepared without histidine, while Tablets II-IV and VI-VIII contain different amounts of histidine, with the molar ratio of semglutide to histidine ranging from 1:1 to 1:30, as indicated.

[0190] For magnesium stearate, the number in parentheses is the amount of magnesium stearate outside the granules. For microcrystalline cellulose, the number in parentheses indicates the amount in the granules containing SNAC and magnesium stearate, and in the granules containing povidone, respectively. [Table F]

[0191] Tablet compositions I and V were stored at 60°C, 40°C, and 30°C and 75% RH in equilibrated desiccators prepared with saturated NaCl suspension. Similarly, tablet compositions II-IV and VI-VIII were stored at 60°C, 40°C, and 30°C and 75% RH, but also in separate equilibrated desiccators prepared with saturated NaCl suspension. Prior to storage, 0.012% w / w formaldehyde solution, corresponding to an approximate 1:20 molar ratio between formaldehyde and semaglutide, was added to the desiccators.

[0192] After a storage period of at least 1 month, the tablets were removed from the desiccator and the levels of hydrophobic impurities groups 1 and 2 were measured according to Assay I, and the level of semaglutide aldehyde adducts was measured according to Assay III. Prior to further storage of the remaining tablets in the desiccator, another volume of 0.012% w / w formaldehyde solution was added to the desiccator, corresponding to an approximate 1:20 molar ratio between formaldehyde and semaglutide in the desiccator.

[0193] The results of Assay I are contained in Tables 3.2 and 3.3 below and show that the levels of hydrophobic impurities Groups 1 and 2 increased over time. The levels of hydrophobic impurities Groups 1 and 2 were significantly lower in compositions containing histidine (Tablets II-IV and VI-VIII). Furthermore, it is particularly surprising that the level of hydrophobic impurity Group 1 decreased significantly even at the lowest molar ratio between semaglutide and histidine of 1:1, with relatively less decrease occurring with increasing molar ratios of semaglutide to histidine. [Table G] [Table H]

[0194] The results of Assay III are contained in Tables 3.4.1-3.4.3 and 3.5.1-3.5-3 below and show that the levels of semaglutide aldehyde adducts increased over time. The levels of semaglutide aldehyde adducts were significantly lower in compositions containing histidine (Tablets II-IV and VI-VIII). Furthermore, it is particularly surprising that the levels of semaglutide aldehyde adducts were reduced so significantly, i.e., by more than 50% even at the lowest amount of histidine, where the molar ratio of histidine to semaglutide was 1:1, and that the further reduction obtained when the molar ratio of semaglutide to histidine was increased was relatively small. [Table I] [Table J] [Table K] [Table L] [Table M] [Table N]

[0195] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those skilled in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes that fall within the true spirit of the invention.

Claims

1. A solid pharmaceutical composition comprising: i) a GLP-1 agonist; and ii) a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC); and iii) histidine, A solid pharmaceutical composition wherein the GLP-1 agonist is semaglutide.

2. 2. The composition of claim 1, wherein the molar ratio of histidine to the GLP-1 agonist is at least 0.

5.

3. The composition of claim 1 or 2, wherein the composition further comprises one or more pharmaceutical excipients.

4. 4. The composition of claim 1, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC).

5. The composition according to any one of claims 1 to 4, wherein the composition is a pharmaceutical composition for oral administration.

6. The composition according to any one of claims 1 to 5, wherein the composition is a tablet.

7. i) the GLP-1 agonist; ii) Salts of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), for example, sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC); iii) histidine, iv) a lubricant, and v) A composition according to any one of claims 1 to 6, optionally comprising or consisting of further pharmaceutical excipients.

8. The dosage unit is i) 0.5 to 100 mg, for example 0.5 to 50 mg, of the GLP-1 agonist; ii) 50-750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), for example, sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC); iii) 0.01 to 200 mg of histidine; and iv) 1 to 15 mg of a lubricant; and v) optionally 1-20 mg of a binder, e.g., povidone; vi) optionally 30-500 mg of a disintegrant, for example nicotinamide; vii) optionally, 20-100 mg of a filler, for example MCC.

9. The composition according to any one of claims 1 to 8, wherein the composition is a pharmaceutical composition for use in a method for treating diabetes and / or obesity.

10. 1. A method for producing a solid pharmaceutical composition, comprising: i) obtaining a blend comprising a GLP-1 agonist and histidine; ii) co-processing the blend of i); iii) using the product of ii) to prepare said solid pharmaceutical composition; The method, wherein the GLP-1 agonist is semaglutide.

11. 1. A method for producing a solid pharmaceutical composition, comprising: i) obtaining a solution comprising a GLP-1 agonist and histidine; ii) spray drying the solution of i); iii) using the product of ii) to prepare said solid pharmaceutical composition; The method, wherein the GLP-1 agonist is semaglutide.

12. 1. A method for producing a solid pharmaceutical composition, comprising: i) obtaining a blend comprising a salt of NAC and a lubricant; ii) granulating the blend of i) by dry granulation; iii) mixing the granulation of ii) with a GLP-1 agonist and histidine, and optionally with further excipients; iv) preparing the solid pharmaceutical composition using the mixture of iii), The method, wherein the GLP-1 agonist is semaglutide.

13. 1. A method for producing a solid pharmaceutical composition, comprising: i) obtaining a blend comprising a salt of NAC and a lubricant; ii) granulating the blend of i) by dry granulation; iii) obtaining a solution comprising a GLP-1 agonist and histidine; iv) spray drying the solution of iii); v) mixing the granulation of ii) with the product of iii) and optionally with further excipients; vi) preparing said solid pharmaceutical composition using the mixture of iii), The method, wherein the GLP-1 agonist is semaglutide.

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