Solid composition comprising a GLP-1 agonist and histidine

Abstract

The present invention relates to a stabilized solid pharmaceutical composition comprising a GLP-1 agonist. The present invention further relates to a method for preparing such a composition and its use in medicine.

Description

Technical Field

[0001] The present invention relates to a solid pharmaceutical composition comprising a GLP-1 agonist and histidine, a method for preparing the same, and its use in medicine.

[0002] Incorporation by Reference of the Sequence Listing

[0003] A sequence listing entitled "SEQUENCE LISTING" is 4KB, created on April 22, 2021, and is incorporated herein by reference. Background Art

[0004] Human GLP-1 and its analogs have low oral bioavailability. After oral administration, the exposure and bioavailability of human GLP-1 and its analogs are extremely low. Human GLP-1 and its analogs can only achieve therapeutically relevant plasma concentrations after oral administration when formulated with specific amounts of certain absorption promoters.

[0005] Steinert et al. (Am J Clin Nutr, October 2010; 92:810–817) disclosed the oral administration of tablets containing GLP-1(7-36) amide and 150 mg of sodium N-(8-(2-hydroxybenzoyl)amino)octanoate (SNAC).

[0006] WO 2010 / 020978 disclosed an oral pharmaceutical composition comprising a protein and N-(8-(2-hydroxybenzoyl)amino)octanoate (SNAC). Patent applications for oral dosage forms of GLP-1 analogs containing N-(8-(2-hydroxybenzoyl)amino)octanoate include WO2012 / 080471, WO2013 / 189988, WO2013 / 139694, WO2013 / 139695, and WO2014 / 177683. Further improved formulations are described in WO2019 / 149880 and WO2019 / 215063.

[0007] Irrespective of the specific formulation, the stability of GLP-1 analogs is important for ensuring that the solid GLP-1 composition maintains its efficacy during storage and for further minimizing waste of the pharmaceutical composition by extending the product shelf life. In addition, the stability of GLP-1 analogs is also important because it affects the storage temperature that is feasible within the product shelf life, which is preferably ambient room temperature for solid oral dosage forms. Summary of the Invention

[0008] In one aspect, 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 promoter or delivery agent, and histidine.

[0009] The composition according to the invention comprises a balanced amount of a GLP-1 agonist and histidine.

[0010] The inventors surprisingly found that when the composition was prepared with a relatively small amount of histidine, an increase in the stability of the GLP-1 agonist was observed.

[0011] One aspect of the present invention relates to a solid composition comprising:

[0012] i) a GLP-1 agonist, and

[0013] ii) histidine.

[0014] One embodiment of the present invention relates to a solid pharmaceutical composition comprising:

[0015] i) a GLP-1 agonist,

[0016] ii) a delivery agent, and

[0017] iii) histidine.

[0018] One embodiment of the present invention relates to a solid pharmaceutical composition comprising:

[0019] i) a GLP-1 agonist,

[0020] ii) a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), and iii) histidine

[0021] wherein the number of moles of histidine is at least equal to half the number of moles of the GLP-1 agonist.

[0022] In one embodiment, the solid pharmaceutical composition comprises:

[0023] i) 0.5 - 100 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B, or GLP-1 agonist C,

[0024] ii) 50 - 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), such as the sodium salt of NAC (SNAC), and

[0025] iii) 0.01 - 200 mg of histidine.

[0026] Another aspect of the present invention relates to a method for preparing a solid pharmaceutical composition as described herein, which comprises the following steps:

[0027] i) Mixing a GLP-1 agonist with histidine, and

[0028] ii) Using the product of i) to prepare the solid pharmaceutical composition.

[0029] Another aspect of the present invention relates to a method for preparing a solid pharmaceutical composition as described herein, which comprises the following steps:

[0030] i) Co-processing a GLP-1 agonist and histidine, and

[0031] ii) Using the product of i) to prepare the solid pharmaceutical composition.

[0032] Another aspect relates to the medical use of the compositions described herein. One embodiment relates to the pharmaceutical use of the compositions described herein, such as compositions for oral administration. In a further embodiment, the composition is a pharmaceutical composition in a method for treating diabetes and / or obesity.

[0033] In another aspect, the present invention relates to a method for treating diabetes or obesity, which comprises administering to a patient in need a composition as defined herein. Description of the Drawings

[0034] Figure 1 Shows the amount of formaldehyde adduct in the tablets measured after 2, 4, and 6 weeks.

[0035] Figure 2 Shows the amount of acetaldehyde adduct in the tablets measured after 2, 4, and 6 weeks. Detailed Description

[0036] Aspects of the present invention described herein relate to solid compositions comprising a GLP-1 agonist and a stability enhancer such as histidine, such as compositions comprising a GLP-1 agonist and an absorption promoter or delivery agent and histidine. The composition is preferably in a form suitable for oral administration, such as a solid form exemplified by tablets, sachets or capsules. In one embodiment, the composition is a composition for oral administration, or a pharmaceutical composition, such as an oral pharmaceutical composition.

[0037] GLP-1 Agonist

[0038] As used herein, the term "GLP-1 agonist" refers to a compound that fully or partially activates the human GLP-1 receptor. Thus, the term is equivalent to the term "GLP-1 receptor agonist" used in other documents. The term GLP-1 agonist and the specific GLP-1 agonists described herein also cover their salt forms.

[0039] Thus, a GLP-1 agonist should exhibit "GLP-1 activity", which refers to the ability of the compound (i.e., a GLP-1 analogue or a compound comprising a GLP-1 analogue) to bind to the GLP-1 receptor and initiate a signal transduction pathway, resulting in insulinotropic effects or other physiological effects known in the art. In some embodiments, as measured by methods known in the art (see, e.g., WO 98 / 08871), a "GLP-1 agonist" binds to the GLP-1 receptor, for example, with an affinity constant (K D ), or activates the receptor with a potency (EC 50 ) of less than 1 μM, for example, less than 100 nM, and exhibits insulinotropic activity, where the insulinotropic activity can be measured by in vivo or in vitro assays known to those of ordinary skill in the art. For example, a GLP-1 agonist can be administered to an animal with elevated blood glucose (e.g., obtained using an intravenous glucose tolerance test (IVGTT)). Those skilled in the art will be able to determine an appropriate glucose dose and an appropriate blood sampling protocol, e.g., depending on the species of the animal, (for an IVGTT), and measure plasma insulin concentration over time. Suitable assays have been described, for example, in WO2015 / 155151.

[0040] The term half-maximal effective concentration (EC 50 ) generally refers to the concentration that induces a response halfway between the baseline and the maximum, with reference to a dose-response curve. EC 50 is used as a measure of the potency of a compound and represents the concentration at which 50% of its maximum effect is observed. Due to the albumin-binding effect of the GLP-1 agonists with substituents described herein, it is important to note whether the assay includes human serum albumin.

[0041] The in vitro potency of a GLP-1 agonist can be determined as described in Example 29 (without human serum albumin (HSA)) of 2015 / 155151, and the EC 50 can be determined. The lower the EC 50 value, the better the potency. In one embodiment, the measured potency (EC 50 ) (without HSA) is 5 - 1000 pM, such as 10 - 750 pM, 10 - 500 pM, or 10 - 200 pM. In one embodiment, EC 50 (without HSA) is at most 500 pM, such as at most 300 pM, such as at most 200 pM.

[0042] In one embodiment, EC 50 (without HSA) is comparable to that of human GLP-1 (7 - 37).

[0043] In one embodiment, EC 50(Without HSA) is at most 50 pM. In another such embodiment, EC 50 is at most 40 pM, such as at most 30 pM, such as at most 20 pM, such as at most 10 pM. In one embodiment, EC 50 is about 10 pM.

[0044] Alternatively, or optionally, the in vitro potency assay including HSA of Example 29 can be used to measure the binding of the GLP-1 agonist to albumin. In the presence of serum albumin, an increase in the in vitro potency EC 50 value reflects the affinity for serum albumin.

[0045] In one embodiment, the measured potency (EC 50 )(with 1% HSA) is 5 - 1000 pM, such as 100 - 750 pM, 200 - 500 pM or 100 - 400 pM. In one embodiment, EC 50 (with 1% HSA) is at most 750 pM, such as at most 500 pM, such as at most 400 pM, such as at most 300 pM, or such as at most 250 pM.

[0046] If desired, the fold change relative to a known GLP-1 receptor agonist can be calculated as EC 50 (test analog) / EC 50 (known analog), and if the ratio is, for example, 0.5 - 1.5 or 0.8 - 1.2, the potencies are considered equivalent.

[0047] In one embodiment, the potency - - EC 50 (without HSA), is equal to the potency of liraglutide.

[0048] In one embodiment, the potency - - EC 50 (without HSA), is equal to the potency of semaglutide.

[0049] In one embodiment, the potency - - EC 50 (without HSA), is equal to the potency of GLP-1 agonist B.

[0050] In one embodiment, the potency - - EC 50 (without HSA), is equal to the potency of GLP-1 agonist C.

[0051] In one embodiment, the potency - - EC 50 (with 1% HSA), is equal to the potency of liraglutide.

[0052] In one embodiment, the potency - - EC 50 (with 1% HSA), is equal to the potency of semaglutide.

[0053] In one embodiment, the potency - EC 50 (with 1% HSA), is equal to the potency of GLP-1 agonist B.

[0054] In one embodiment, the potency - EC 50 (with 1% HSA), is equal to the potency of GLP-1 agonist C.

[0055] In one embodiment, the GLP-1 agonist is a bifunctional molecule, such as a co-agonist or a tri-agonist.

[0056] 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.

[0057] In some embodiments, the GLP-1 agonist is a GLP-1 analogue, optionally comprising one substituent. As used herein, the term "analogue" with respect to a GLP-1 peptide (hereinafter referred to as "peptide") refers to such a peptide in which at least one amino acid residue of the peptide has been replaced by another amino acid residue, and / or in which at least one amino acid residue has been deleted from the peptide, and / or in which at least one amino acid residue has been added to the peptide, and / or in which at least one amino acid residue of the peptide has been modified. Such addition or deletion of amino acid residues may occur at the N-terminus of the peptide and / or at the C-terminus of the peptide. In some embodiments, GLP-1 agonists are described using a simple nomenclature. For example, [Aib8]GLP-1(7-37) represents an analogue of GLP-1(7-37) in which the naturally occurring Ala at position 8 has been replaced by Aib. In some embodiments, compared to, for example, GLP-1(7-37), the GLP-1 agonist has up to twelve, such as up to 10, 8, or 6 amino acids that have been altered, for example, by substitution, deletion, insertion, and / or modification. In some embodiments, compared to, for example, GLP-1(7-37), the analogue comprises at most 10 substitutions, deletions, additions, and / or insertions, such as at most 9 substitutions, deletions, additions, and / or insertions, at most 8 substitutions, deletions, additions, and / or insertions, at most 7 substitutions, deletions, additions, and / or insertions, at most 6 substitutions, deletions, additions, and / or insertions, at most 5 substitutions, deletions, additions, and / or insertions, at most 4 substitutions, deletions, additions, and / or insertions, or at most 3 substitutions, deletions, additions, and / or insertions. Unless otherwise specified, the GLP-1 only comprises L-amino acids.

[0058] 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 HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (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.

[0059] In one embodiment, the GLP-1 agonist exhibits at least 60%, 65%, 70%, 80%, or 90% sequence identity with GLP-1(7-37) over the entire length of GLP-1(7-37). As an example of a method for determining sequence identity between two analogs, align the two peptides [Aib8]GLP-1(7-37) and GLP-1(7-37). The sequence identity of [Aib8]GLP-1(7-37) relative to GLP-1(7-37) is determined by subtracting the number of different residues from the number of aligned residues and dividing by the total number of residues in GLP-1(7-37). Thus, in this example, the sequence identity is (31 - 1) / 31.

[0060] In one embodiment, the C-terminus of the GLP-1 agonist is an amide.

[0061] 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, which has the sequence HGEGTFITSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ ID No:2). In one embodiment, the GLP-1 agonist is an exendin-4 analog or an engineered peptide thereof, as disclosed in WO2013009545 and its references.

[0062] To prolong the action of the GLP-1 agonist, it is preferred that the GLP-1 agonist has an extended half-life. The half-life can be determined in a suitable model by methods known in the art, such as in male Sprague Dawley rats or minipigs described in WO2012 / 140117. The half-life in rats can be determined as in Example 39, and the half-life in minipigs can be determined as in Example 37 therein.

[0063] In one embodiment, the half-life of the GLP-1 agonist according to the present invention in rats is more than 2 hours. In one embodiment, the half-life of the GLP-1 agonist according to the present invention in rats is more than 4 hours, such as more than 6 hours, such as more than 8 hours, such as more than 10 hours, such as more than 12 hours, or for example more than 15 hours.

[0064] In one embodiment, the half-life of the GLP-1 agonist according to the present invention in minipigs is more than 24 hours. In one embodiment, the half-life of the GLP-1 agonist according to the present invention in minipigs is more than 30 hours, such as more than 36 hours, such as more than 42 hours, such as more than 48 hours, such as more than 54 hours, or for example more than 60 hours.

[0065] In one embodiment, the molecular weight of the GLP-1 agonist is at most 50,000 Da, such as at most 40,000 Da, such as at most 30,000 Da.

[0066] In one embodiment, the molecular weight of the GLP-1 agonist is at most 20,000, such as at most 10,000 Da, such as at most 7,500 Da, such as at most 5,000 Da.

[0067] In one embodiment, the molar mass of the GLP-1 agonist is at most 50,000 g / mol, such as at most 40,000 g / mol, such as at most 30,000 g / mol.

[0068] In one embodiment, the molar mass of the GLP-1 agonist is at most 10,000 g / mol, such as at most 8,000 g / mol, such as at most 6,000 g / mol.

[0069] In some embodiments, the GLP-1 agonist comprises a substituent covalently linked 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.

[0070] In some embodiments, the substituent comprises formula (X)

[0071] Where n is at least 13, for example n is 13, 14, 15, 16, 17, 18 or 19. In some embodiments, the substituent comprises formula (X), where n ranges from 13 to 19, for example in the range from 13 to 17. In some embodiments, the substituent comprises formula (X), where n is 13, 15 or 17. In some embodiments, the substituent comprises formula (X), where n is 13. In some embodiments, the substituent comprises formula (X), where n is 15. In some embodiments, the substituent comprises formula (X), where n is 17.

[0072] In some embodiments, the substituent comprises formula (XIa)

[0073] HOOC-(C 6 H 4 )-O-(CH 2 ) m -CO-*(XIa), where m is an integer in the range of 6 - 14.

[0074] In some embodiments, the substituent comprises formula (XIb)

[0075] where the carboxyl group is at the 2, 3 or 4 position of the (C 6 H 4 ) group, and where m is an integer in the range of 8 - 11.

[0076] In some embodiments, the substituent comprises formula (XIa) or formula (XIb), where m ranges from 6 to 14, for example in the range from 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.

[0077] In some embodiments, the substituent comprises one or more 8-amino-3,6-dioxaoctanoic acid (OEG), such as two OEGs.

[0078] In some embodiments, the substituent is [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl].

[0079] In some embodiments, the substituent is [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoyl amino)methyl]cyclohexanecarbonyl}amino)butanoyl amino]ethoxy}ethoxy)acetyl amino]ethoxy}ethoxy)acetyl].

[0080] In some embodiments, the GLP-1 agonist is semaglutide, also known as N-ε26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoyl amino)butanoyl amino]ethoxy}ethoxy)acetyl amino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37) (SEQ ID NO.4), which can be prepared as described in Example 4 of WO2006 / 097537 and has the following structure:

[0081]

[0082] In one embodiment, the GLP-1 agonist is GLP-1 agonist B, which is diacylated [Aib8,Arg34,Lys37]GLP-1(7-37) (SEQ ID NO.5), as shown in Example 2 of WO2011 / 080103 and is named N ε26 {2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoyl amino]butanoyl amino}-ethoxy)ethoxy]acetyl amino}ethoxy)ethoxy]acetyl},N ε37 -{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoyl amino]butanoyl amino}ethoxy)ethoxy]acetyl amino}ethoxy)ethoxy]-acetyl}-[Aib 8 ,Arg 34 ,Lys 37 GLP-1(7-37)–peptide, which has the following structure.

[0083]

[0084] In one embodiment, the GLP-1 agonist is GLP-1 agonist C, which is diacylated [Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly (SEQ ID NO.6), as shown in Example 31 of WO2012 / 140117 and is named N ε27-[2-[2-[2-[[2-[2-[2-[[(4S)-4-Carboxy-4-[10-(4-carboxyphenoxy)decanoyl amino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]-acetyl],N ε36 -[2-[2-[2-[[2-[2-[2-[[(4S)-4-Carboxy-4-[10-(4-carboxyphenoxy)decanoyl amino]-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly, which has the following structure:

[0085]

[0086] Generally, the term GLP-1 agonist is intended to include GLP-1 agonists 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.

[0087] In some embodiments, the GLP-1 agonist is selected from one or more GLP-1 agonists mentioned in WO93 / 19175, WO96 / 29342, WO98 / 08871, WO99 / 43707, WO99 / 43706, WO99 / 43341, WO99 / 43708, WO2005 / 027978, WO2005 / 058954, WO2005 / 058958, WO2006 / 005667, WO2006 / 037810, WO2006 / 037811, WO2006 / 097537, WO2006 / 097538, WO2008 / 023050, WO2009 / 030738, WO2009 / 030771 and WO2009 / 030774.

[0088] In some embodiments, the GLP-1 agonist is selected from N-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propanoyl)amino]ethoxy}ethoxy)acetyl]amino}ethoxy]ethoxy}acetyl[desamino His7, Glu22, Arg26, Arg34, Lys37]GLP-1(7-37) amide; N-epsilon26{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propanoyl)amino]ethoxy}ethoxy)acetyl]amino}ethoxy]ethoxy}acetyl[desamino His7, Arg34]GLP-1-(7-37); N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propanoyl)amino]ethoxy}ethoxy)acetyl]amino}ethoxy]ethoxy}acetyl[Aib8, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37) amide; N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxy-heptadecanoyl)piperidine-4-ylcarbonylamino]3-carboxypropanoyl)amino]ethoxy)ethoxy)acetyl]amino}ethoxy]ethoxy)acetyl][, desamino His7, Glu22 Arg26, Arg 34, Phe(m-CF3)28]GLP-1-(7-37) amide; N-epsilon26-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butanoyl][Aib8, Arg34]GLP-1-(7-37); N-epsilon26-{4-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butanoyl]amino}butanoyl}[Aib8, Arg34]GLP-1-(7-37); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butanoyl]amino}ethoxy)ethoxy]acetyl][Aib8, Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoyl amino)methyl]cyclohexanecarbonyl}amino)butanoyl amino]ethoxy}ethoxy)acetyl amino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37) amide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoyl amino)methyl]cyclohexanecarbonyl}amino)butanoyl amino]ethoxy}ethoxy)acetyl amino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37) amide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoyl amino)methyl]cyclohexanecarbonyl}amino)butanoyl amino]ethoxy}ethoxy)acetyl amino]ethoxy}ethoxy)acetyl][deaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37) amide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(trans-19-carboxy-nonadecanoyl amino)methyl]cyclohexanecarbonyl}amino)butanoyl amino]ethoxy}ethoxy)acetyl amino]ethoxy}ethoxy)acetyl][deaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37) amide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoyl amino)methyl]cyclohexanecarbonyl}amino)butanoyl amino]ethoxy}ethoxy)acetyl amino]ethoxy}ethoxy)acetyl][deaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37); N-epsilon26[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(19-carboxy-nonadecanoyl amino)methyl]cyclohexanecarbonyl}amino)butanoyl amino]ethoxy}ethoxy)acetyl amino]ethoxy}ethoxy)acetyl[Aib8,Lys 26]GLP-1(7-37) amide;N-epsilon26[2-(2-[2-(2-[2-(2-((S)-2-[trans-4-((9-carboxy-nonadecanoyl-amino]methyl)cyclohexylcarbonylamino]-4-carboxybutyrylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Lys26]GLP-1(7-37) amide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoyl-amino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37); N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoyl-amino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)-hexadecanesulfonylamino)butyrylamino]-butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanesulfonyl-amino)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanesulfonyl-amino)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)hexadecanesulfonylamino)butyrylamino]butyrylamino}butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanecarbonylsulfamoyl)butyrylamino]-dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanecarbonylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanecarbonyl-sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanecarbonylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanecarbonylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-36) amide; N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanecarbonylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanecarbonyl-sulfamoyl)butyrylamino]dodecanoylamino}butyryl-amino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Lys33,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanecarbonylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-36) amide; N-epsilon26-[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)hexadecanecarbonylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Lys26,Arg34]GLP-1-(7-36) amide; N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanecarbonylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37) amide; N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanecarbonylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37) amide; N-epsilon37{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-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propanoyl)amino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37) amide; N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxy-heptadecanoyl)piperidine-4-ylcarbonylamino]-3-carboxy-propionyl)amino]ethoxy)ethoxy)acetylamino]ethoxy)ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Phe(m-CF3)28]GLP-1-(7-37) amide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butanoyl]amino}ethoxy)ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37) amide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butanoyl]amino}ethoxy)ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37) amide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butanoyl]amino}ethoxy)ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37); N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butanoyl]amino}ethoxy)ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-aminosulfonyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37) amide; N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylaminosulfonyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][deaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37) amide; N-epsilon37-(3-((2-(2-(2-(2-(2-hexyldecyloxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy))propionyl)[deaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide; N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxybutyryl-amino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl}-[deaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37) amide; N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxy-butyryl-amino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl}-[deaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37) amide; N-epsilon37-(2-(2-(2-(2-(2-(2-(2-(2-(2-(octadecanoyl-amino)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetyl)[deaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37) amide; N-epsilon37-[4-(16-(1H-tetrazol-5-yl)hexadecanoylaminosulfonyl)butyryl][deaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37) amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxy nonadecanoylamino) butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desamino His7, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37); N-epsilon37-(2-{2-[2-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino) butyrylamino] butyrylamino} butyrylamino)ethoxy]ethoxy}acetyl)[desamino His7, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37); N-epsilon37-{2-[2-(2-{(S)-4-[(S)-4-(12-{4-[16-(2-tert-butyl-2H-tetrazol-5-yl)-hexadecanesulfonylamino] dodecanoylamino}-4-carboxy butyrylamino]-4-carboxy butyrylamino}ethoxy)ethoxy]acetyl}[desamino His7, Glu22, Arg26, Arg34, Lys37]GLP-1(7-37); N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)- butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][Aib8, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37); N-alpha37-[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][desamino His7, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37);N-epsilon36-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxypentadecanoyl amino)-butyryl amino]-ethoxy}-ethoxy)-acetyl amino]-ethoxy}-ethoxy)-acetyl][deamino His7,Glu22,Arg26,Glu30,Arg34,Lys36]GLP-1-(7-37)-Glu-Lys peptide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoyl amino)methyl]cyclohexanecarbonyl}amino)butyryl-amino]ethoxy}ethoxy)acetyl amino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37); N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoyl amino)-butyryl amino]-ethoxy}-ethoxy)-acetyl amino]-ethoxy}-ethoxy)-acetyl]-[Aib8,Glu22,Arg26,Arg34,Aib35,Lys37]GLP-1-(7-37); N-epsilon37-[(S)-4-carboxy-4-(2-{2-[2-(2-{2-[2-(17-carboxyheptadecanoyl amino)ethoxy]ethoxy}acetyl amino)ethoxy]ethoxy}acetyl amino)butyryl][Aib8,Glu22,Arg26,34,Lys37]GLP-1(7-37); N-epsilon37-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoyl amino)-4(S)-carboxybutyryl amino]ethoxy)ethoxy]acetyl amino)ethoxy]ethoxy)acetyl][ImPr7,Glu22,Arg26,34,Lys37],GLP-1-(7-37); N-epsilon26-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoyl amino]butyryl amino}ethoxy)ethoxy]acetyl amino}ethoxy)ethoxy]acetyl},N-epsilon37-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy-phenoxy)decanoyl amino]butyryl amino}ethoxy)ethoxy]acetyl amino}ethoxy)ethoxy]acetyl}-[Aib8,Arg34,Lys37]GLP-1(7-37)-OH; N-epsilon26(17-carboxyheptadecanoyl)-[Aib8,Arg34]GLP-1-(7-37)-peptide;N-epsilon26-(19-Carboxy-nonadecanoyl)-[Aib8,Arg34]GLP-1-(7-37); N-epsilon26-(4-{[N-(2-Carboxyethyl)-N-(15-carboxypentadecanoyl)amino]methyl}benzoyl)[Arg34]GLP-1-(7-37); N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-Carboxyheptadecanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37); N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(19-Carboxynonadecanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37); N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-Carboxyheptadecanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][3-(4-Imidazolyl)propionyl7,Arg34]GLP-1-(7-37); N-epsilon26-[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-epsilon26-[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-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-Carboxyheptadecanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37); N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-Carboxyheptadecanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)-amide;N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxybutanoyl-amino]ethoxy)ethoxy]acetyl-amino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37) amide; Aib8,Lys26(N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(pentadecanoyl-amino)-4-carboxybutanoyl-amino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}),Arg34)GLP-1H(7-37)-OH; N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxyheptadecanoyl)amino]methyl}benzoyl)amino]ethoxy)ethoxy]acetyl-amino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37); N-alpha7-formyl,N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxy-butanoyl-amino]ethoxy)ethoxy]acetyl-amino)ethoxy]ethoxy)acetyl][Arg34]GLP-1-(7-37); N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxy-butanoyl-amino]ethoxy)ethoxy]acetyl-amino)ethoxy]ethoxy)acetyl][Aib8,Glu22,Arg34]GLP-1-(7-37); N-epsilon26{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(15-(N-((S)-1,3-dicarboxypropyl)aminocarbonyl)pentadecanoyl-amino)-(S)-4-carboxybutanoyl-amino]ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)propionyl}[Aib8,Arg34]GLP-1-(7-37); N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxy-heptadecanoyl)amino]methyl}benzoyl)amino](4(S)-carboxybutanoyl-amino)ethoxy)ethoxy]acetyl-amino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37);N-epsilon26-{(S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butanoylamino)butanoylamino)butanoylamino)butanoylamino}[Aib8,Arg34]GLP-1-(7-37); N-epsilon26-4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutanoyl-[Aib8,Arg34]GLP-1-(7-37); N-epsilon26-{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1-(7-37); N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(17-carboxyheptadecanoylamino)-4-carboxybutanoylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[Aib8,22,27,30,35,Arg34,Pro37,Lys26]GLP-1(7-37) amide; N-epsilon26-[2-(2-[2-[4-(21-carboxyhenicosoylamino)-4(S)-carboxybutanoylamino]ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37); and N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37).;

[0089] Delivery Agent

[0090] For the present invention, a delivery agent or absorption enhancer is an excipient capable of increasing the oral exposure of a GLP-1 agonist.

[0091] Salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid

[0092] The delivery agent used in the examples herein is a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (also referred to herein as "NAC") which contains the anion N-(8-(2-hydroxybenzoyl)amino)octanoate. The structural formula of N-(8-(2-hydroxybenzoyl)amino)octanoate is shown in formula (I).

[0093]

[0094] In some embodiments, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid comprises one monovalent cation, two monovalent cations or one divalent cation. In one embodiment, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from the sodium, potassium and / or calcium salts of N-(8-(2-hydroxybenzoyl)amino)octanoic acid.

[0095] In further embodiments, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from the sodium, potassium and / or ammonium salts. In further embodiments, the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is the sodium or potassium salt. The salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid can be prepared using, for example, the methods described in WO96 / 030036, WO00 / 046182, WO01 / 092206 or WO2008 / 028859. The salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid can be crystalline and / or amorphous. In some embodiments, the delivery agent comprises the anhydrate, monohydrate, dihydrate, trihydrate, solvate or hemihydrate of the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid, and combinations thereof. In some embodiments, the delivery agent is the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid as described in WO2007 / 121318.

[0096] In further embodiments, the delivery agent is sodium N-(8-(2-hydroxybenzoyl)amino)octanoate (referred to herein as "SNAC"), also known as sodium 8-(salicylamino)octanoate.

[0097] Composition

[0098] The composition or pharmaceutical composition of the invention is a solid or dry composition suitable for oral administration, as further described below.

[0099] In some embodiments, the composition comprises at least one pharmaceutically acceptable excipient. As used herein, the term "excipient" generally refers to any component other than the active therapeutic ingredient or active pharmaceutical ingredient (API). Excipients can be pharmaceutically inert substances, inactive substances and / or therapeutically or medically inactive substances.

[0100] Excipients can be used for a variety of purposes, such as carriers, vehicles, fillers, binders, lubricants, glidants, disintegrants, flow control agents, crystallization inhibitors, solubilizers, stabilizers, colorants, flavorants, surfactants, emulsifiers, or combinations thereof, and / or for improving the administration of the therapeutically active substance or active pharmaceutical ingredient and / or improving its absorption. The amount of each excipient used can vary within the conventional ranges in the art. Techniques and excipients that can be used to formulate oral dosage forms are described in Handbook of Pharmaceutical Excipients, 8th Edition, edited by Sheskey et al., American Pharmaceuticals Association and the Pharmaceutical Press, Publishing Division of the Royal Pharmaceutical Society of Great Britain (2017); and Remington: the Science and Practice of Pharmacy, 22nd Edition, edited by Remington and Allen, Pharmaceutical Press (2013).

[0101] In some embodiments, the excipients may be selected from binders such as polyvinylpyrrolidone (povidone), etc.; fillers such as cellulose powder, microcrystalline cellulose (MCC), cellulose derivatives such as hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, calcium hydrogen phosphate, corn starch, pregelatinized starch, etc.; disintegrants such as cellulose powder, microcrystalline cellulose, sodium starch glycolate, potassium polacrilin, crospovidone, crosslinked carboxymethylcellulose, sodium carboxymethylcellulose, dried corn starch, etc.; lubricants and / or glidants such as stearic acid, magnesium stearate, sodium stearyl fumarate, glyceryl behenate, etc.; flow control agents such as colloidal silica, talc, etc.; crystallization inhibitors such as povidone, etc.; solubilizers such as Pluronic, povidone, etc.; colorants including dyes and pigments such as iron oxide red or iron oxide yellow, titanium dioxide, talc, etc.; pH control agents such as citric acid, tartaric acid, fumaric acid, sodium citrate, calcium hydrogen phosphate, disodium hydrogen phosphate, etc.; surfactants and emulsifiers such as Pluronic, polyethylene glycol, sodium carboxymethylcellulose, polyethoxylated and hydrogenated castor oil, etc.; and mixtures of two or more of these excipients and / or adjuvants; hydrotropes such as Nipecotamide, niacinamide, sodium p-hydroxybenzoate, N,N-dimethylurea, N,N-dimethylbenzamide, N,N-diethylnicotinamide, sodium salicylate, resorcinol, sodium benzoate, sodium xylenesulfonate, sodium p-toluenesulfonate, 1-methylnicotinamide, pyrogallol, catechol, epigallocatechin gallate, tannic acid, and sodium gentisate hydrate.

[0102] The composition may comprise a binder such as povidone; starch; cellulose and its derivatives such as microcrystalline cellulose, such as Avicel PH, hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxypropyl methylcellulose, sucrose, dextrose, corn syrup, polysaccharides, and gelatin. The binder may be selected from dry granulation binders and / or wet granulation binders. Suitable dry granulation binders are, for example, cellulose powder and microcrystalline cellulose, such as Avicel. In some embodiments, the composition comprises Avicel, such as AavicelPH 101. Suitable binders for wet granulation or dry granulation are corn starch, polyvinylpyrrolidone (povidone), vinylpyrrolidone-vinyl acetate copolymer (copovidone), and cellulose derivatives such as hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. In some embodiments, the composition comprises povidone.

[0103] In some embodiments, the composition comprises a filler, which may be selected from lactose, mannitol, erythritol, sucrose, sorbitol, calcium phosphate such as dicalcium phosphate, microcrystalline cellulose (MCC), powdered cellulose, confectioner's sugar, compressible sugar, glucose binder, dextrin, and dextrose. In some embodiments, the composition comprises microcrystalline cellulose, such as Avicel PH 101 or Avicel PH 200.

[0104] In some embodiments, the composition comprises a lubricant and / or a glidant. In some embodiments, the composition comprises a lubricant and / or a glidant such as talc, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, diglyceryl behenate, behenoyl polyoxyl-8 glyceride, polyethylene oxide polymer, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, silica, and / or polyethylene glycol, etc. In some embodiments, the composition comprises magnesium stearate.

[0105] In some embodiments, the composition comprises a disintegrant such as sodium starch glycolate, polacrilin potassium, sodium starch glycolate, crospovidone, cross-linked carboxymethyl cellulose, sodium carboxymethyl cellulose, or dried corn starch, or a solubilizer such as niacinamide or resorcinol. The composition may comprise one or more surfactants, for example, one surfactant, at least one surfactant, or two different surfactants. The term "surfactant" refers to any molecule or ion composed of a water-soluble (hydrophilic) part and a lipid-soluble (lipophilic) part. The surfactant may be selected, for example, from anionic surfactants, cationic surfactants, nonionic surfactants, and / or zwitterionic surfactants.

[0106] In a broad aspect, the present invention relates to a solid pharmaceutical composition comprising a GLP-1 agonist and a stability enhancer. As demonstrated herein, histidine has been found to act as a stability enhancer because it is an effective aldehyde scavenger in compositions containing a GLP-1 agonist sensitive to aldehyde-mediated degradation (resulting in the accumulation of impurities over time). Alternative aldehyde scavengers may be selected from a large group of chemical compounds suitable as excipients in pharmaceutical compositions.

[0107] The description hereinafter also relates to a composition comprising or consisting of specific components, namely a GLP-1 agonist, a delivery agent, and histidine, and optionally one or more excipients such as a filler, a binder, a disintegrant, or a solubilizer, and / or a lubricant. The term "consisting of" should be understood to potentially include trace amounts of any substance that does not affect the function of the composition. Such substances may be impurities remaining from the preparation of the GLP-1 agonist, the production of the NAC salt, or the preparation of histidine, or any pharmaceutically acceptable excipient in the minimal amount (less than 1%) that does not affect the quality of the formulation.

[0108] In one embodiment, the pharmaceutical composition comprises histidine in an amount balanced relative to the amount of the GLP-1 agonist. The effect of histidine has been observed within a certain concentration range.

[0109] In one embodiment, the number of moles of histidine is at least equal to half the number of moles of the GLP-1 agonist; in other words, the molar ratio of histidine to the GLP-1 agonist is at least 0.5. In one embodiment, the molar ratio of histidine to the GLP-1 agonist is at least 0.6, or at least 0.7, or at least 0.8, or at least 0.9, or at least 1.

[0110] In one embodiment, the number of moles of histidine is at most 100 times the number of moles of the GLP-1 agonist; in other words, the molar ratio of histidine to the GLP-1 agonist is at most 100. In one embodiment, the molar ratio of histidine to the GLP-1 agonist is at most 80, or at most 60, or at most 40 or 30.

[0111] In one embodiment, the molar ratio of histidine to the GLP-1 agonist is 0.5 - 100, such as 0.6 - 80, such as 0.7 - 60, such as 0.75 - 50, such as 0.8 - 40, or such as 0.9 - 30.

[0112] In an embodiment where the GLP-1 agonist has a molar mass of about 4000 g / mol, the mass ratio of histidine to the GLP-1 agonist is at least 0.02, such as at least 0.03 or 0.04. In another such embodiment, the mass ratio of histidine to the GLP-1 agonist is at most 4, such as at most 3, such as at most 2 or 1.

[0113] In one embodiment, the mass ratio of histidine to a GLP-1 agonist having a molecular weight of about 4000 g / mol is 0.02 - 4, such as 0.02 - 3, such as 0.02 - 2, such as 0.03 - 1, such as 0.04 - 1, or such as 0.05 - 1.

[0114] The pharmaceutical composition according to the present invention is preferably in a dosage form suitable for oral administration as described hereinafter. Hereinafter, the absolute amounts of the components of the composition of the present invention are provided with reference to the dose unit, i.e., the content in each tablet, capsule or sachet.

[0115] In a further embodiment, the pharmaceutical composition of the present invention may comprise at most 1000 mg of the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) in each dose unit. In one embodiment, the present invention relates to a composition wherein the dose unit comprises at most 600 mg of said salt.

[0116] In some embodiments, the amount of N-(8-(2-hydroxybenzoyl)amino)octanoate in each dosage unit is at least 0.15 mmol, such as 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.

[0117] In some embodiments, the amount of N-(8-(2-hydroxybenzoyl)amino)octanoate in each dosage unit of the composition is at most 2.5 mmol, such as at most 2.0 mmol, such as 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.

[0118] In some embodiments, the amount of N-(8-(2-hydroxybenzoyl)amino)octanoate in each dosage unit of the composition ranges from 0.20–2.5 mmol, 0.25-1.5 mmol.

[0119] In some embodiments, the amount of N-(8-(2-hydroxybenzoyl)amino)octanoate in each dosage unit of the composition ranges from 0.2-0.6 mmol, 0.8-1.4 mmol or 1.4-2.0 mmol.

[0120] In some embodiments, the delivery agent is sodium N-(8-(2-hydroxybenzoyl)amino)octanoate (“SNAC”).

[0121] In some embodiments, the amount of SNAC in each dosage unit of the composition is at least 50 mg, such as 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.

[0122] In some embodiments, the amount of SNAC in each dosage unit of the composition is at most 750 mg per dosage unit, such as at most 700 mg, such as at most 650 mg, such as at most 600 mg, such as at most 550 mg, at most 525 mg, at most 500 mg, at most 475 mg, at most 450 mg, at most 425 mg, at most 400 mg, at most 375 mg, at most 350 mg, at most 300 mg, at most 250 mg, at most 200 mg, or at most 150 mg.

[0123] In some embodiments, the amount of SNAC in each dosage unit of the composition is in the range of 50 - 750 mg, 65 - 600 mg, such as 80 - 550 mg.

[0124] In some embodiments, the amount of SNAC in each dosage unit of the composition is in the range of 50 - 150 mg, 150 - 500 mg, such as 200 - 400 mg, such as 300 - 700 mg, or such as 400 - 600 mg.

[0125] In one embodiment, the dosage unit of the pharmaceutical composition of the present invention comprises 0.5 - 100 mg, such as 0.5 - 75 mg, such as 0.5 - 60 mg of a GLP-1 agonist.

[0126] In some embodiments, the amount of the GLP-1 agonist comprised in the dosage unit of the composition is in the range of 0.5–50 mg, 1 to 50 mg, 2 to 50 mg, or 4 to 40 mg.

[0127] In some embodiments, the amount of the GLP-1 agonist comprised in the dosage unit of the composition is in the range of 0.5–50 mg, 0.5–40 mg, 0.5–30 mg, or 0.5–20 mg.

[0128] In some embodiments, the dosage unit comprises 0.5 - 10 mg of a GLP-1 agonist, such as 0.75 - 4 1 / 2 mg per dosage unit, such as 1, 1 1 / 2, 2, 2 1 / 2, or 3 mg, or 3 1 / 2, 4, 4 1 / 2 mg, such as 1 - 3 or 3 - 5 mg of a GLP-1 agonist.

[0129] In some embodiments, the dosage unit comprises 2 to 20 mg of a GLP-1 agonist, such as 2 - 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 a GLP-1 agonist.

[0130] In some embodiments, the dosage unit comprises 5 to 75 mg of a GLP-1 agonist, such as 10 - 60 mg, such as 20, 30, 40 or 50 mg, or such as 25, 35 or 45 mg, or such as 30 - 50 mg, or such as 20 - 40 mg of a GLP-1 agonist.

[0131] As described above, the amount of histidine will be balanced with the amount of the GLP-1 agonist, but generally the dosage unit of the compositions of the present invention comprises 0.01 - 400 mg of histidine. In one embodiment, the dosage unit comprises 0.01 - 300 mg, such as 0.02 - 300 mg, such as 0.05 - 200 mg, such as 0.02 - 100 mg or such as 1 - 50 mg of histidine.

[0132] In one embodiment, the dosage unit of the composition according to the present invention comprises:

[0133] i) 0.5 - 100 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B or GLP-1 agonist C,

[0134] ii) 50 - 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), such as the sodium salt of NAC (SNAC), and

[0135] iii) 0.01 - 200 mg of histidine.

[0136] In one embodiment, the dosage unit of the composition according to the present invention comprises:

[0137] i) 1 - 100 mg of semaglutide

[0138] ii) 50 - 150 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), such as the sodium salt of NAC (SNAC), and

[0139] iii) 0.02 - 100 mg, such as 1 - 50 mg of histidine.

[0140] In one embodiment, the dosage unit of the composition according to the present invention comprises:

[0141] i) 1 - 100 mg of semaglutide

[0142] ii) 150 - 500 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), such as the sodium salt of NAC (SNAC), and

[0143] iii) 0.02 - 100 mg, such as 1 - 50 mg of histidine.

[0144] In one embodiment, a dosage unit of the composition according to the invention comprises:

[0145] i) 1 - 100 mg semaglutide

[0146] ii) 350 - 600 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), such as the sodium salt of NAC (SNAC), and

[0147] iii) 0.02 - 100 mg, such as 1 - 50 mg histidine.

[0148] As described above, the composition may further comprise pharmaceutical excipients such as lubricants, binders, disintegrants or solubilizers and / or fillers.

[0149] In one embodiment, a dosage unit of the composition according to the invention comprises:

[0150] i) 0.5 - 100 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B or GLP-1 agonist C,

[0151] ii) 50 - 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), such as the sodium salt of NAC (SNAC),

[0152] iii) 0.01 - 200 mg histidine, and

[0153] iv) Optionally, other pharmaceutical excipients.

[0154] In one embodiment, a dosage unit of the composition according to the invention comprises:

[0155] i) 0.5 - 100 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B or GLP-1 agonist C,

[0156] ii) 50 - 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), such as the sodium salt of NAC (SNAC),

[0157] iii) 0.01 - 200 mg histidine

[0158] iv) A lubricant, and

[0159] v) Optionally, other pharmaceutical excipients.

[0160] In one embodiment, a dosage unit of the composition according to the invention comprises:

[0161] i) 0.5 - 100 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B, or GLP-1 agonist C,

[0162] ii) 50 - 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), such as the sodium salt of NAC (SNAC),

[0163] iii) 0.01 - 200 mg of histidine,

[0164] iv) A lubricant,

[0165] v) A disintegrant or solubilizer, and

[0166] vi) Optionally, other pharmaceutical excipients.

[0167] In one embodiment, the dosage unit of the composition according to the invention comprises:

[0168] i) 0.5 - 100 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B, or GLP-1 agonist C,

[0169] ii) 50 - 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), such as the sodium salt of NAC (SNAC),

[0170] iii) 0.01 - 200 mg of histidine,

[0171] iv) A lubricant,

[0172] v) A disintegrant or solubilizer,

[0173] vi) A filler, and

[0174] vii) Optionally, other pharmaceutical excipients.

[0175] In one embodiment, the dosage unit of the composition according to the invention comprises:

[0176] i) 0.5 - 100 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B, or GLP-1 agonist C,

[0177] ii) 50 - 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), such as the sodium salt of NAC (SNAC),

[0178] iii) 0.01 - 200 mg of histidine,

[0179] iv) A lubricant,

[0180] v) A disintegrant or solubilizer,

[0181] vi) Filler,

[0182] vii) Binder, and

[0183] viii) Optionally, other pharmaceutical excipients.

[0184] In one embodiment, the dosage unit of the composition according to the present invention comprises:

[0185] i) 0.5 - 100 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B or GLP-1 agonist C,

[0186] ii) 50 - 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), such as the sodium salt of NAC (SNAC),

[0187] iii) 0.01 - 200 mg of histidine,

[0188] iv) Lubricant, such as magnesium stearate,

[0189] v) Filler, such as MCC,

[0190] vi) Disintegrant or solubilizer, such as nicotinamide,

[0191] vii) Binder, such as povidone, and

[0192] viii) Optionally, other pharmaceutical excipients.

[0193] In a further embodiment, the amounts of the various pharmaceutical excipients can be adjusted according to the dosage unit or relative to one or more other components.

[0194] In one embodiment, the composition comprises less than 5% w / w of a lubricant based on the total amount of excipients.

[0195] In one embodiment, the composition comprises less than 5% w / w of a lubricant based on the amount of the delivery agent. In one embodiment, the composition comprises 0.25 - 5% w / w, such as 1 - 4% w / w of a lubricant based on the amount of the delivery agent. In a further embodiment, the composition comprises 0.25 - 5% w / w, such as 1 - 4% w / w of a lubricant based on the amount of a salt of NAC such as SNAC.

[0196] In one embodiment, the dosage unit of the composition comprises 0.1 - 20 mg or 1 - 15 mg of a lubricant, such as magnesium stearate.

[0197] In one embodiment, a dosage unit of the composition according to the present invention contains 20 - 150 mg of a filler or 40 - 100 mg of a filler, such as MCC.

[0198] In one embodiment, the dosage unit of the composition contains 10 - 600 mg, such as 10 - 500 mg of a disintegrant or solubilizer. In one embodiment, the dosage unit of the composition contains 10 - 600 mg, such as 10 - 500 mg, such as 10 - 400 mg, such as 20 - 300 mg, or such as 25 - 250 mg of niacinamide.

[0199] In one embodiment, a dosage unit of the composition according to the present invention contains 1 - 30 mg of a binder, 1 - 25 mg of a binder, or 1 - 20 mg of a binder, such as povidone.

[0200] Dosage Form

[0201] The composition can be administered in several dosage forms, for example, as tablets, coated tablets, sachets or capsules such as hard or soft capsules, and all such compositions are considered solid oral dosage forms.

[0202] The composition can be in the form of a dosage unit, such as a tablet. In some embodiments, the weight of the dosage unit is in the range of 50 mg to 1000 mg, such as in the range of 50 - 750 mg, or such as in the range of 100 - 600 mg.

[0203] In some embodiments, the weight of the dosage unit is in the range of 50 mg to 400 mg, such as in the range of 75 - 350 mg or 100 - 300 mg.

[0204] In some embodiments, the weight of the dosage unit is in the range of 200 mg to 600 mg, such as in the range of 250 - 550 mg or 300 - 500 mg.

[0205] In some embodiments, the weight of the dosage unit is in the range of 300 mg to 700 mg, such as in the range of 350 - 650 mg or 400 - 600 mg.

[0206] In some embodiments, the weight of the dosage unit is in the range of 400 mg to 1000 mg, such as in the range of 450 - 850 mg or 500 - 700 mg.

[0207] In some embodiments, the composition, or some components of the composition, can be granulated before being compressed into tablets or filled into capsules or sachets.

[0208] The composition may comprise a particulate portion and / or an extra-particulate portion, wherein the particulate portion has been granulated and the extra-particulate portion has been added after granulation.

[0209] The particulate portion may comprise one or more types of particles, which comprise different subsets of the composition ingredients.

[0210] The particulate portion may comprise a GLP-1 agonist, a delivery agent, and / or histidine. In one embodiment, the particulate portion may comprise one or more additional excipients, such as a lubricant, a filler, a disintegrant, a solubilizer, and / or a binder.

[0211] In one embodiment, the particulate portion comprises a delivery agent and a lubricant. In one embodiment, the particulate portion comprises SNAC and magnesium stearate.

[0212] In one embodiment, histidine is included in the particulate portion or the extra-particulate portion.

[0213] In one embodiment, the GLP-1 agonist is included in the extra-particulate portion. In one embodiment, the extra-particulate portion comprises a GLP-1 agonist. In one embodiment, the extra-particulate portion may further comprise histidine. In one embodiment, the extra-particulate portion further comprises a lubricant, such as magnesium stearate.

[0214] Preparation of the Composition

[0215] The preparation of the composition according to the present invention can be carried out according to methods known in the art.

[0216] To prepare a dry blend of the materials, the various components are weighed, optionally delumped or sieved, and then combined. The mixing of the components can be carried out until a uniform blend is obtained.

[0217] The term "particle" generally refers to drug ingredients in the form of fine particles, granules, and aggregates used for preparing solid dosage forms. Generally, particles are obtained as follows: processing powders or blends to obtain new combined fine particles of the desired size.

[0218] If the granules are to be used for further processing into tablets, capsules or sachets, the granules can be produced in a manner known to those skilled in the art, for example using wet granulation methods known for producing "built-up" granules or "broken-down" granules. The method of forming built-up granules can be operated continuously and includes, for example, simultaneously spraying the granulating material with a granulating solution and drying, for example in a drum granulator, in a pan granulator, in a disk granulator, in a fluidized bed, by spray drying or spray solidification, or can be operated discontinuously, for example in a fluidized bed, in a rotary fluidized bed, in a batch mixer such as a high-shear mixer or a low-shear mixer, or in a spray drying drum such as equipment from Loedige, Glatt, Diosna, Fielder and Collette companies. The method of producing broken-down granules can be carried out discontinuously, where the granulating material is first formed into wet aggregates with a granulating solution, which are then comminuted or otherwise formed into granules of the desired size, and the granules can then be dried. Equipment suitable for the granulation step is planetary mixers, low-shear mixers, high-shear mixers, extruders and spheronizers, such as equipment from Loedige, Glatt, Diosna, Fielder, Collette, Aeschbach, Alexanderwerk, Ytron, Wyss&Probst, Werner&Pfleiderer, HKD, Loser, Fuji, Nica, Caleva and Gabler companies. Granules can also be formed by dry granulation techniques, where one or more excipients and / or active pharmaceutical ingredients are compressed to form relatively large moldings, such as bars or ribbons, which are comminuted by grinding into granules of the desired size, and the ground material is used as the material for further processing into tablets, capsules or sachets. Equipment suitable for dry granulation is equipment from Gerteis, Alexanderwerk and Freund-Vector companies.

[0219] Other methods of obtaining granules can include hot melt extrusion, spray drying, spray granulation and / or ball milling.

[0220] In one embodiment, the invention relates to a composition comprising

[0221] i. a GLP-1 agonist,

[0222] ii. a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC),

[0223] iii. histidine, and

[0224] iv. a lubricant such as magnesium stearate.

[0225] Wherein the composition comprises the particles of ii) and iv).

[0226] In embodiments where the particle portion comprises a delivery agent and a lubricant, these excipients can be co-processed before or during the preparation of the particles.

[0227] Granulation can be achieved by the various methods described above, wherein ii) and iv) are first mixed in powder form or by preparing a solution comprising these two components.

[0228] The particles of ii) and iv) can be obtained by wet granulation or dry granulation of a solution or blend.

[0229] In one embodiment, i) and iii) are co-processed before tableting.

[0230] In one embodiment, a solution or suspension of i) and iii) is prepared and spray-dried or spray granulated, whereby their powder or granules are directly obtained. In one embodiment, spray drying can be employed, followed by dry granulation / roller compaction to obtain granules. Alternatively, i) and iii) can be prepared as a mixture.

[0231] To obtain a homogeneous product, one or more sieving steps can be included before the final dry granulation step / roller compaction or tableting.

[0232] To compact the material into a solid oral dosage form, such as a tablet, a tableting machine can be used. In the tableting machine, the tableting material is filled (e.g., pressure-fed or gravity-fed) into the die cavity. Then the tableting material is compacted with a set of punches applying pressure. Subsequently, the resulting tablets are ejected from the tableting machine. The above tableting process is hereinafter referred to as the "compression process". Suitable tableting machines include, but are not limited to, rotary tableting machines and eccentric tableting machines. Equipment suitable for tableting is equipment from companies such as Fette, Korsch, GEA Courtouy, and Manesty.

[0233] In some embodiments, the present invention relates to a method for preparing a composition according to the present invention, such as a tablet. In one embodiment, the method for preparing a tablet comprises:

[0234] a) granulating the delivery agent and an optional lubricant

[0235] b) blending the granules of a) with a GLP-1 agonist and histidine, and

[0236] c) compressing the blend into a tablet.

[0237] The granulation can be wet or dry granulation. As described above, the lubricant can be magnesium stearate, which can also be included in one or more of steps b) and c) in addition to step a).

[0238] In one embodiment, the present invention relates to a method for preparing a solid pharmaceutical composition, which comprises the following steps:

[0239] i) obtaining an admixture comprising a GLP-1 agonist and histidine,

[0240] ii) co-processing the admixture of i), and

[0241] iii) using the product of ii) to prepare the solid pharmaceutical composition.

[0242] In one embodiment, the method is for preparing a solid pharmaceutical composition, which comprises the following steps:

[0243] i) obtaining a solution or suspension comprising a GLP-1 agonist and histidine,

[0244] ii) spray-drying i), and

[0245] iii) using the product of ii) to prepare the solid pharmaceutical composition.

[0246] In all of the above embodiments, the method may further comprise preparing the solid pharmaceutical composition using one or more pharmaceutical excipients, such as lubricants, binders, disintegrants or solubilizers and / or fillers as described above.

[0247] Drug Indication

[0248] The present invention also relates to the composition of the present invention for use as a medicament. In certain embodiments, the composition of the present invention can be used for the following medical treatments, all of which are preferably always related to diabetes:

[0249] (i) preventing and / or treating all forms of diabetes, such as 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 for reducing HbA1C;

[0250] (ii) delaying or preventing the progression of diabetes, such as the progression of type 2 diabetes, delaying the progression of impaired glucose tolerance (IGT) to insulin-requiring type 2 diabetes, and / or delaying the progression of non-insulin-requiring type 2 diabetes to insulin-requiring type 2 diabetes;

[0251] (iii) improving β-cell function, such as reducing β-cell apoptosis, enhancing β-cell function and / or β-cell mass, and / or restoring the glucose sensitivity of β-cells;

[0252] (iv) preventing and / or treating cognitive impairment;

[0253] (v) Preventing and / or treating eating disorders, such as obesity, by, for example, reducing food intake, losing weight, suppressing appetite, and inducing satiety; treating or preventing binge eating disorder, bulimia nervosa, and / or obesity induced by antipsychotic or steroid administration; reducing gastric motility; and / or delaying gastric emptying;

[0254] (vi) Preventing and / or treating diabetic complications, such as neuropathy, including peripheral neuropathy; nephropathy; or retinopathy;

[0255] (vii) Improving lipid parameters, such as preventing and / or treating dyslipidemia, reducing total serum lipids; reducing HDL; reducing small, dense LDL; reducing VLDL; reducing triglycerides; reducing cholesterol; increasing HDL; reducing the plasma level of human lipoprotein a (Lp(a)); inhibiting the production of apolipoprotein a (apo(a)) in vitro and / or in vivo;

[0256] (iix) Preventing and / or treating cardiovascular diseases, such as syndrome X; atherosclerosis; myocardial infarction; coronary heart disease; stroke; cerebral ischemia; early heart disease or early cardiovascular disease, such as left ventricular hypertrophy; coronary artery disease; essential hypertension; acute hypertensive emergency; cardiomyopathy; cardiac insufficiency; exercise tolerance; chronic heart failure; arrhythmia; cardiac arrhythmia; syncope; atherosclerosis; mild chronic heart failure; angina pectoris; cardiac bypass reocclusion; intermittent claudication (obstructive atherosclerosis); diastolic dysfunction; and / or systolic dysfunction;

[0257] (ix) Preventing and / or treating gastrointestinal diseases, such as inflammatory bowel syndrome; small bowel syndrome or Crohn's disease; indigestion; and / or gastric ulcer;

[0258] (x) Preventing and / or treating critical illness, such as treating critically ill patients, patients with critical illness polynephropathy (CIPNP), and / or potential CIPNP patients; preventing the progression of critical illness or CIPNP; preventing, treating, and / or curing a patient's systemic inflammatory response syndrome (SIRS); and / or preventing or reducing the likelihood of a patient developing bacteremia, sepsis, and / or septic shock during hospitalization; and / or

[0259] (xi) Preventing and / or treating polycystic ovary syndrome (PCOS).

[0260] In one embodiment, the indication is selected from (i)-(iii) and (v)-(iix), such as 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 a still further embodiment, the indication is (iix). In some embodiments, the indication is type 2 diabetes and / or obesity.

[0261] The present invention further relates to a method of treating an individual in need thereof, which comprises administering to the individual a therapeutically active amount of a composition according to the present invention. In another such embodiment, one or more dosage units may be administered to the individual in need thereof.

[0262] Treatment Method

[0263] The present invention further relates to a method of treating a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a composition according to the present invention. In one embodiment, the treatment method is used to treat diabetes or obesity and / or other indications specified above.

[0264] In some embodiments, a method of treating diabetes is described, which comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a GLP-1 agonist, a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), histidine and optionally excipients such as fillers, binders, disintegrants and / or lubricants.

[0265] In some embodiments, a method of treating diabetes is described, which comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising:

[0266] i) 0.5-100 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B or GLP-1 agonist C,

[0267] ii) 50-750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), such as the sodium salt of NAC (SNAC), and

[0268] iii) 0.01-200 mg of histidine, and

[0269] iv) 0-10 mg of a lubricant.

[0270] In some embodiments, the GLP-1 agonist is semaglutide having the formula N-ε26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoyl-amino)butanoyl-amino]ethoxy}ethoxy)acetyl-amino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37).

[0271] In some embodiments, the GLP-1 agonist is N ε26 {2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoyl-amino]butanoyl-amino}-ethoxy)ethoxy]acetyl-amino}ethoxy)ethoxy]acetyl}, N ε37 -{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoyl-amino]butanoyl-amino}ethoxy)ethoxy]acetyl-amino}ethoxy)ethoxy]-acetyl}-[Aib 8 , Arg 34 Lys 37 GLP-1(7-37) (GLP-1 agonist B).

[0272] In some embodiments, the GLP-1 peptide is N ε27 -[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoyl-amino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl], N ε36 -[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoyl-amino]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).

[0273] In one embodiment, the composition is administered orally and is in the form of a tablet, capsule or sachet.

[0274] In another such embodiment, one or more dosage units may be administered to the subject in need thereof.

[0275] Combined therapy

[0276] Treatment with the composition according to the invention can also be combined with one or more additional active pharmaceutical ingredients selected, for example, from antidiabetic agents, anti-obesity agents, appetite regulators, antihypertensive agents, agents for the treatment and / or prevention of complications caused by or associated with diabetes, and agents for the treatment and / or prevention of complications and conditions caused by or associated with obesity.Examples of such pharmacologically active substances are: insulin, sulfonylureas, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists, DPP-IV (dipeptidyl peptidase-IV) inhibitors, sodium glucose co-transporter 2 (SGLT2) inhibitors; canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, tofogliflozin, luseogliflozin, bexagliflozin, ertugliflozin etabonate, and sotagliflozin, in particular dapagliflozin and empagliflozin, inhibitors of liver enzymes involved in stimulating gluconeogenesis and / or glycogenolysis, glucose uptake regulators, compounds that alter lipid metabolism such as antihyperlipidemics such as HMG-CoA inhibitors (statins), gastric inhibitory polypeptide (GIP analogs), compounds that reduce food intake, RXR agonists, and agents that act on the ATP-dependent potassium channels of β-cells; cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol, dextrothyroxine, nateglinide, repaglinide; β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol, and metoprolol, ACE (angiotensin-converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, fasidotril, quinapril, and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem, and verapamil, and α-blockers such as doxazosin, urapidil, prazosin, and terazosin; CART (cocaine- and 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, β3 agonists, oxyntomodulin and analogs, MSH (melanocyte-stimulating hormone) agonists, MCH (melanin-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin reuptake inhibitors, serotonin and norepinephrine 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) regulators, leptin agonists, DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors, RXR (retinoid X receptor) regulators, TRβ agonists; histamine H3 antagonists, gastric inhibitory polypeptide agonists or antagonists (GIP analogs), gastrin, and gastrin analogs.

[0277] The invention described herein is further defined by the embodiments described below and the claims of this document, but is not limited thereto.

[0278] Embodiment

[0279] 1. A solid pharmaceutical composition comprising a GLP-1 agonist and histidine.

[0280] 2. The composition according to embodiment 1, further comprising a delivery agent.

[0281] 3. The composition according to embodiment 2, wherein the delivery agent is a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC).

[0282] 4. The composition according to embodiment 1, comprising

[0283] i) a GLP-1 agonist,

[0284] ii) a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), and

[0285] iii) histidine.

[0286] 5. The composition according to any one of the foregoing embodiments, wherein the molar ratio of histidine to the GLP-1 agonist is at least 0.5.

[0287] 6. The composition according to any one of the foregoing embodiments, wherein the molar ratio of histidine to the GLP-1 agonist is at most 100.

[0288] 7. The composition according to any one of the foregoing embodiments, wherein the molar ratio of histidine to the GLP-1 agonist is 0.5 - 100, such as 0.6 - 80, such as 0.7 - 60, such as 0.8 - 40, or such as 0.9 - 30.

[0289] 8. The composition according to embodiment 3, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) is selected from the sodium salt, potassium salt, and / or calcium salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid.

[0290] 9. The composition according to any one of the foregoing embodiments, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) is sodium N-(8-(2-hydroxybenzoyl)amino)octanoate (SNAC).

[0291] 10. The composition according to any one of the foregoing embodiments, wherein the composition further comprises one or more pharmaceutical excipients, such as fillers, binders, disintegrants, or solubilizers, and / or lubricants.

[0292] 11. The composition according to any one of the foregoing embodiments, wherein the composition comprises a lubricant.

[0293] 12. The composition according to any one of the foregoing embodiments, wherein the composition comprises a lubricant in an amount of 0.25 - 5 w / w% of the total amount of excipients.

[0294] 13. The composition according to any one of the foregoing embodiments, wherein the composition comprises a lubricant in an amount of 0.25 - 5 w / w% of the amount of the delivery agent.

[0295] 14. The composition according to any one of the foregoing embodiments, wherein the composition comprises a lubricant, such as magnesium stearate.

[0296] 15. The composition according to any one of the foregoing embodiments, wherein the lubricant is magnesium stearate.

[0297] 16. The composition according to any one of the foregoing 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.

[0298] 17. The composition according to any one of the foregoing embodiments, wherein the T1 / 2 of the GLP-1 agonist in minipigs is at least 24 hours.

[0299] 18. The composition according to any one of the foregoing embodiments, wherein the T1 / 2 of the GLP-1 agonist in rats is at least 2 hours.

[0300] 19. The composition according to any one of the foregoing embodiments, wherein the EC 50 (without HSA) of the GLP-1 agonist is at most 100 pM, such as at most 50.

[0301] 20. The composition according to any one of the foregoing embodiments, wherein the EC 50 (with 1% HSA) of the GLP-1 agonist is at most 100 pM, such as at most 50.

[0302] 21. The composition according to any one of the foregoing embodiments, wherein the molar mass of the GLP-1 agonist is at most 50000 g / mol.

[0303] 22. The composition according to any one of the foregoing embodiments, wherein the GLP-1 agonist comprises an albumin-binding substituent.

[0304] 23. The composition according to any one of the foregoing embodiments, wherein the GLP-1 agonist comprises a fatty acid or a fatty diacid.

[0305] 24. A composition according to any one of the foregoing embodiments, wherein the GLP-1 agonist comprises a C16, C18 or C20 fatty acid or a C16, C18 or C20 fatty diacid.

[0306] 25. A composition according to any one of the foregoing embodiments, wherein the GLP-1 agonist is selected from: liraglutide, semaglutide, GLP-1 agonist B and GLP-1 agonist C.

[0307] 26. A composition according to any one of the foregoing embodiments, wherein the GLP-1 agonist is semaglutide.

[0308] 27. A composition according to any one of the foregoing embodiments, wherein the dosage unit comprises 0.1 - 100 mg of the GLP-1 agonist.

[0309] 28. A composition according to any one of the foregoing embodiments, wherein the mass ratio of histidine to semaglutide is at least 0.02.

[0310] 29. A composition according to any one of the foregoing embodiments, wherein the mass ratio of histidine to semaglutide is at most 4.

[0311] 30. A composition according to any one of the foregoing embodiments, wherein the mass ratio of histidine to semaglutide is 0.02 - 4, such as 0.02 - 3, such as 0.02 - 2, such as 0.03 - 1, or such as 0.05 - 1.

[0312] 31. A composition according to any one of the foregoing embodiments, which comprises or consists of the following substances:

[0313] i) A GLP-1 agonist, such as semaglutide, GLP-1 agonist B or GLP-1 agonist C,

[0314] ii) A salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), such as SNAC,

[0315] iii) Histidine, and

[0316] iμ) A lubricant.

[0317] 32. A composition according to any one of the foregoing embodiments, wherein the dosage unit comprises at most 1000 mg of NAC / SNAC.

[0318] 33. A composition according to any one of the foregoing embodiments, wherein the dosage unit comprises

[0319] i) 0.5 - 100 mg, such as 1 - 75 mg of a GLP-1 agonist, such as semaglutide, GLP-1 agonist B, or GLP-1 agonist C,

[0320] ii) 50 - 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), such as SNAC,

[0321] iii) 0.01 - 200 mg of histidine, and

[0322] iv) 0 - 15 mg of a lubricant.

[0323] 34. The composition according to any one of the foregoing embodiments, wherein the dosage unit comprises

[0324] i) 1 - 75 mg, such as 1 - 60 mg of semaglutide,

[0325] ii) 50 - 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), such as SNAC,

[0326] iii) 0.02 - 100 mg of histidine, and

[0327] iv) 0 - 15 mg of a lubricant.

[0328] 35. The composition according to any one of the foregoing embodiments, wherein the composition comprises other pharmaceutically excipients.

[0329] 36. The composition according to any one of the foregoing embodiments, wherein the dosage unit comprises

[0330] i) 0.5 - 100 mg, such as 1 - 75 mg of a GLP-1 agonist, such as semaglutide

[0331] ii) 50 - 750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), such as SNAC,

[0332] iii) 0.01 - 200 mg of histidine,

[0333] iv) 1 - 15 mg of a lubricant,

[0334] v) 20 - 100 mg of a filler, such as MCC,

[0335] vi) 30 - 500 mg of a disintegrant, such as nicotinamide, and

[0336] vii) 1 - 20 mg of a binder, such as povidone.

[0337] 37. A composition according to any one of the foregoing embodiments, wherein the composition is a solid oral dosage form.

[0338] 38. A composition according to any one of the foregoing embodiments, wherein the composition is a tablet.

[0339] 39. A composition according to embodiment 36, wherein i) and iii) are co-processed before tableting.

[0340] 40. A composition according to embodiment 36, wherein i) and iii) are co-processed by blending.

[0341] 41. A composition according to embodiment 36, wherein i) and iii) are co-processed by spray drying.

[0342] 42. A composition according to any one of the foregoing embodiments, wherein the composition comprises particles containing ii).

[0343] 43. A composition according to any one of the foregoing embodiments, wherein the composition comprises particles containing ii) and iv).

[0344] 44. A composition according to embodiment 43, wherein ii) and iv) are blended before granulation.

[0345] 45. A composition according to any one of embodiments 42 - 44, wherein the particles are obtained by roller compaction.

[0346] 46. A composition according to any one of embodiments 36 - 45, wherein the composition comprises an extragranular portion.

[0347] 47. A composition according to any one of the foregoing embodiments, wherein the composition is produced by a method comprising the steps of:

[0348] a) granulating a mixture comprising a delivery agent,

[0349] b) blending the particles of a) with a GLP-1 agonist and histidine, and

[0350] c) preparing a composition using the blend of b).

[0351] 48. A composition according to any one of the foregoing embodiments, wherein the composition is for use in a method of treating diabetes and / or obesity.

[0352] 49. A method of preparing a solid pharmaceutical composition, comprising the steps of:

[0353] i) obtaining a blend comprising a GLP-1 peptide and histidine,

[0354] ii) co-process the admixture of i), and

[0355] iii) prepare the solid pharmaceutical composition using the product of ii).

[0356] 50. The method according to embodiment 49, wherein the co-processing in step ii) is carried out by spray drying.

[0357] 51. The method according to embodiment 49, wherein the method comprises one or more additional steps of preparing the solid pharmaceutical composition using one or more other pharmaceutical excipients.

[0358] 52. A method for treating diabetes or obesity, which comprises administering to a subject in need thereof a therapeutically effective amount of the solid pharmaceutical composition according to embodiments 1-48 or the solid pharmaceutical composition produced by any of the methods of embodiments 49-51.

[0359] 53. The method according to embodiment 52, wherein the solid pharmaceutical composition is administered once daily or at a lower frequency.

[0360] Examples

[0361] Materials and Methods

[0362] Method 1 - Co-spray drying of semaglutide and histidine

[0363] Aqueous solutions or ethanol-aqueous solutions (1:9) were prepared by dissolving semaglutide and histidine at 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 produce a concentration of approximately 2-2.5% w / w. The solution was spray dried (Büchi Mini Spray Drier) with the aspirator set to 100%, an inlet temperature of approximately 120 or 155 °C, an outlet temperature of approximately 45 or 78 °C, and a solution feed flow rate of approximately 6 or 12 g / min.

[0364] Method 2 - Dry granulation of SNAC and magnesium stearate

[0365] Before dry granulation, SNAC and magnesium stearate were mixed for 50 min at 25 rpm using a Pharmatech Mb blender. Dry granulation was carried out by roller compressing on a Gerteis MINI-PACTOR using smooth rollers, a 0.63 or 0.80 mm screen, and a granulator speed of 30-120 rpm. The roller speed was set to 3-6 rpm, and a roller compression force of 6-9 kN / em was applied at a gap of 1-2 mm. After dry granulation, the molded product was crushed into granules.

[0366] Assay I: Analysis of Semaglutide Related Impurities - RP-UHPLC Method

[0367] Samples were prepared by dissolving tablets using phosphate buffer pH 7.4 (50 mM KH PO 2 PO 4 , 380 mM potassium chloride) mixed with 20% (v / v) acetonitrile and optionally with 0.1% (w / v) 4 )(polyoxyethylene lauryl ether) as the extraction buffer. The sample content of semaglutide related impurities was determined using the RP-UHPLC method. This UHPLC method was based on gradient elution on a C18 column. The eluent system was an aqueous solution of 0.09 M (NH 2 HPO 4 )(pH 3.6), acetonitrile, and 2-propanol, with UV detection at 215 nm.

[0368] Group 1 hydrophobic impurities were calculated as the percentage of the area of all semaglutide related peaks eluting after the end of the semaglutide peak up to the start of the second linear gradient relative to the total area of all semaglutide related peaks in the chromatogram.

[0369] Group 2 hydrophobic impurities were calculated as the percentage of the area of all semaglutide related peaks eluting in the second linear gradient relative to the total area of all semaglutide related peaks in the chromatogram.

[0370] Assay II: Analysis of Semaglutide Aldehyde Adducts - LC-MS Method

[0371] Samples were prepared by dissolving the mixture or tablets using phosphate buffer pH 7.4 (50 mM KH 2 PO 4 ) 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. This UHPLC method was based on gradient elution on a C18 column. The eluent system was an aqueous solution of 0.06% TFA, 90% acetonitrile, with UV detection at 214 nm.

[0372] The reconstructed ion chromatograms (RICs) of the triple-charged monoisotopic peaks of semaglutide and the +12 and +26 impurities (i.e., semaglutide formaldehyde adduct and semaglutide acetaldehyde adduct) were extracted separately from the total ion chromatogram (TIC). The RIC peaks were integrated, and the +12 and +26 levels relative to semaglutide were calculated using the areas.

[0373] Assay III: Analysis of Semaglutide Aldehyde Adducts - RP-UHPLC Method

[0374] By using phosphate buffer pH 7.4 (50 mM KH (polyoxyethylene lauryl ether) mixed with 20% (V / v) acetonitrile and optionally with 0.1% (w / v) 2 PO 4 , 380 mM potassium chloride) as the extraction buffer to dissolve the tablets to prepare the samples. The sample content of semaglutide aldehyde adduct was determined using the RP-UHPLC method. The UHPLC method was based on gradient elution on a C18 column. The eluent system was an aqueous solution of 0.09 M (NH 4 ) 2 HPO 4 (pH 3.2), acetonitrile and 2-propanol, and ultraviolet detection was carried out at 215 nm.

[0375] The semaglutide formaldehyde adduct was calculated as the % based on the peak area of the semaglutide formaldehyde adduct relative to the peak area of semaglutide in the chromatogram.

[0376] The semaglutide acetaldehyde adduct was calculated as the % based on the peak area of the semaglutide acetaldehyde adduct relative to the peak area of semaglutide in the chromatogram.

[0377] Example 1 - Stability of GLP-1 in Compositions with and without Histidine

[0378] Compositions of semaglutide and SNAC mixtures with and without histidine were prepared according to Table 1.1 below. The compositions were prepared using semaglutide or co-spray-dried semaglutide and histidine, each weighed into a container and mixed with SNAC. The co-spray-dried semaglutide and histidine were prepared according to Method 1.

[0379] Table 1.1 - Compositions of semaglutide and SNAC mixtures with and without histidine.

[0380]

[0381] The compositions were stored in an equilibration desiccator prepared with saturated NaCl suspension at 60 °C and 75% RH. Before storage, a certain volume of 1 mg / mL formaldehyde solution was additionally added to one desiccator, corresponding to a molar ratio of approximately 1:1 between formaldehyde and semaglutide.

[0382] 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 was significantly lower for the composition containing histidine (Mixture Y).

[0383] Table 1.2 - Levels of Semaglutide Formaldehyde Adduct in the Mixture Composition over Storage Time at 60 °C and 75% RH Level

[0384]

[0385] Example 2 - Stability of GLP - 1 in Tablet Compositions with and without Histidine

[0386] A series of tablet compositions containing semaglutide with and without histidine were prepared according to Table 2.1 below. The compositions were prepared using semaglutide or co - spray - dried semaglutide and histidine as described in Method 1, and granules of SNAC and magnesium stearate prepared according to Method 2. Pre - mixed semaglutide and histidine were prepared by alternately mixing and grinding equal amounts of semaglutide and histidine in a mortar with a pestle.

[0387] The granules of SNAC and magnesium stearate for one tablet were weighed onto a weighing pan. Semaglutide for one tablet, semaglutide and histidine, pre - mixed semaglutide and histidine, or co - spray - dried semaglutide and histidine were then weighed on top of the granules in the weighing pan. In all tablets, the molar ratio of semaglutide to histidine was 1:32.

[0388] The components were then manually mixed and directly transferred to the die cavities of an instrumented rotary tablet press (Fette 102i). The mixture in the die cavities was compressed into round convex tablets with a diameter of 7 mm at a turret speed of 20 rpm and a compression force of approximately 6.5 kN.

[0389] Table 2.1 - Tablet Compositions A - D with the Amounts of Components Given in mg / Tablet

[0390]

[0391] The compositions were stored in an equilibration desiccator prepared with a saturated NaCl suspension at 60 °C and 75% RH. After storage times of 2, 4, and 6 weeks, the tablets were removed from the desiccator and the levels of semaglutide aldehyde adducts were measured according to Assay II. The results are included in Tables 2.2 and 2.3 below and Figure 1 and Figure 2 show that the levels of semaglutide aldehyde adducts increase over time. In the compositions containing histidine (Tablets B, C, and D), the levels of semaglutide aldehyde adducts, especially the semaglutide formaldehyde adducts, are significantly lower.

[0392] Table 2.2 - Levels of Semaglutide Formaldehyde Adduct in Tablet Compositions A - D over Storage Time at 60 °C and 75% RH Level

[0393]

[0394] Table 2.3 - Levels of Semaglutide Acetaldehyde Adduct in Tablet Compositions A - D over Storage Time at 60 °C and 75% RH Level

[0395]

[0396]

[0397] Example 3 - Stability of GLP - 1 in Tablet Compositions Containing Different Amounts of Histidine

[0398] Prepare another series of semaglutide - containing tablet compositions with and without histidine according to Table 3.1 below. The compositions are prepared using semaglutide or co - spray - dried semaglutide and histidine according to Method 1.

[0399] For tablet compositions I - IV, prepare granules of SNAC and magnesium stearate according to Method 2, and weigh the granules for one tablet onto a weighing pan. Subsequently, weigh semaglutide or co - spray - dried semaglutide and histidine for one tablet on top of the granules in the weighing pan. Then manually mix the components and directly transfer them into the tablet - die cavities of an instrumented rotary tablet press (Fette 102i). Compress the mixture in the die cavities into circular tablets with a diameter of 6.5 mm at a turret speed of 20 rpm and a compression force of approximately 7.5 kN.

[0400] For tablet compositions V - VIII, granules of SNAC, microcrystalline cellulose, and magnesium stearate, and granules of microcrystalline cellulose and povidone are generally prepared as described in WO2013 / 139695, but with slightly different equipment and parameter settings. Pre - mix the granules of microcrystalline cellulose and povidone with magnesium stearate using a Turbula mixer at 25 rpm for 30 minutes. Weigh the granules of SNAC, microcrystalline cellulose, and magnesium stearate for one tablet onto a weighing pan. On top of it, weigh the granules of microcrystalline cellulose and povidone pre - mixed with magnesium stearate for one tablet. Finally, weigh semaglutide or co - spray - dried semaglutide and histidine for one tablet on top of the other components in the weighing pan. Then manually mix the components and directly transfer them into the tablet - die cavities of an instrumented rotary tablet press (Fette 102i). Compress the mixture in the die cavities into oval tablets with dimensions of 7.5 x 13 mm at a turret speed of 20 rpm and a compression force of approximately 9 kN.

[0401] Table 3.1 - Tablet Compositions I - VIII

[0402] The compositions are provided in 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, where the molar ratio of semaglutide to histidine ranges from 1:1 to 1:30, as shown in the table.

[0403] For magnesium stearate, the numbers in parentheses are the amounts of magnesium stearate outside the granules. For microcrystalline cellulose, the numbers in parentheses provide the amounts in the granules containing SNAC and magnesium stearate and in the granules containing povidone, respectively.

[0404]

[0405] Tablet compositions I and V were stored at 60 °C, 40 °C, and 30 °C and 75% RH in an equilibration dryer prepared with a 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 in another equilibration dryer also prepared with a saturated NaCl suspension. Prior to storage, a volume of 0.012% w / w formaldehyde solution was added to the dryer, corresponding to a molar ratio of formaldehyde to semaglutide of approximately 1:20.

[0406] After at least 1 month of storage, the tablets were removed from the dryer, and the levels of Group 1 and Group 2 hydrophobic impurities were measured according to Assay I, and the level of the semaglutide aldehyde adduct was measured according to Assay III. Prior to further storage of the remaining tablets in the dryer, another volume of 0.012% w / w formaldehyde solution was added to the dryer, corresponding to a molar ratio of formaldehyde to semaglutide of approximately 1:20 within the dryer.

[0407] The results of Assay I are included in Tables 3.2 and 3.3 below and show that the levels of Group 1 and Group 2 hydrophobic impurities increased over time. In the compositions containing histidine (tablet compositions II-IV and VI-VIII), the levels of Group 1 and Group 2 hydrophobic impurities were significantly lower. Additionally, and particularly surprisingly, even at the lowest molar ratio of semaglutide to histidine of 1:1, the level of Group 1 hydrophobic impurities was significantly reduced, and this reduction became relatively smaller as the molar ratio of histidine to semaglutide was increased.

[0408] Table 3.2 - Levels of Group 1 Hydrophobic Impurities in Tablet Compositions I - VIII over Storage Time at 60 °C and 75% RH Level

[0409]

[0410]

[0411] Table 3.3 - Levels of Group 2 Hydrophobic Impurities in Tablet Compositions I - VIII over Storage Time at 60 °C and 75% RH Level

[0412]

[0413]

[0414] The results of Determination III are included in Tables 3.4.1 - 3.4.3 and 3.5.1 - 3.5.3 below and show that the levels of semaglutide aldehyde adduct increase over time. In the compositions containing histidine (Tablets II - IV and VI - VIII), the levels of semaglutide aldehyde adduct are significantly lower. Additionally, and surprisingly, even at the lowest histidine content (representing a 1:1 molar ratio between semaglutide and histidine), the levels of semaglutide aldehyde adduct are significantly reduced, i.e., by more than 50%, and the further reduction obtained when increasing the molar ratio of histidine to semaglutide is relatively small.

[0415] Table 3.4.1 - Levels of Semaglutide Formaldehyde Adduct in Tablet Compositions I - VIII over Storage Time at 60 °C and 75% RH Level

[0416]

[0417]

[0418] Table 3.4.2 - Levels of Semaglutide Formaldehyde Adduct in Tablet Compositions I - VIII over Storage Time at 40 °C and 75% RH Level

[0419]

[0420]

[0421] Table 3.4.3 - Levels of Semaglutide Formaldehyde Adduct in Tablet Compositions I - VIII over Storage Time at 30 °C and 75% RH Level

[0422]

[0423] Table 3.5.1 - Levels of Semaglutide Acetaldehyde Adduct in Tablet Compositions I - VIII over Storage Time at 60 °C and 75% RH Level

[0424]

[0425] Table 3.5.2 - Levels of Semaglutide Acetaldehyde Adduct in Tablet Compositions I - VIII over Storage Time at 40 °C and 75% RH Level

[0426]

[0427]

[0428] Table 3.5.3 - Levels of Semaglutide Acetaldehyde Adduct in Tablet Compositions I - VIII over Storage Time at 30 °C and 75% RH Level

[0429]

[0430]

[0431] Although certain features of the invention have been set forth and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. Accordingly, it is to be understood that the intention is to cover all such modifications and changes that fall within the true scope of the invention in the appended claims.

Claims

1. A solid pharmaceutical composition comprising i) a GLP-1 agonist, ii) a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid, and iii) histidine wherein the molar ratio of histidine to the GLP-1 agonist is 0.5 - 100, wherein the GLP-1 agonist is semaglutide.

2. The composition according to claim 1, wherein the molar ratio of histidine to the GLP-1 agonist is 0.8 - 40.

3. The composition according to claim 2, wherein the molar ratio of histidine to the GLP-1 agonist is 0.9 - 30.

4. The composition according to any one of the preceding claims 1 - 3, wherein the composition further comprises one or more pharmaceutical excipients.

5. The composition according to claim 4, wherein the one or more pharmaceutical excipients are fillers, binders, disintegrants or solubilizers, and / or lubricants.

6. The composition according to claim 5, wherein the composition comprises a lubricant and the lubricant is magnesium stearate.

7. The composition according to claim 5, wherein the composition comprises 0.25 - 5% w / w of the lubricant based on the amount of the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid.

8. The composition according to claim 7, wherein the composition comprises 1 - 4% w / w of the lubricant based on the amount of the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid.

9. The composition according to any one of the preceding claims 1 - 3 and 5 - 8, wherein the mass ratio of histidine to semaglutide is 0.02 - 4.

10. The composition according to any one of the preceding claims 1 - 3 and 5 - 8, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is sodium N-(8-(2-hydroxybenzoyl)amino)octanoate.

11. The composition according to claim 9, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is sodium N-(8-(2-hydroxybenzoyl)amino)octanoate.

12. The composition according to any one of the preceding claims 1 - 3, 5 - 8 and 11, wherein the composition is a pharmaceutical composition for oral administration.

13. The composition according to claim 10, wherein the composition is a pharmaceutical composition for oral administration.

14. The composition according to any one of the preceding claims 1 - 3, 5 - 8, 11 and 13, wherein the composition is a tablet.

15. The composition according to any one of the preceding claims 1 - 3, 5 - 8, 11 and 13, comprising the following substances: i) a GLP-1 agonist, ii) a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid, iii) histidine, iv) a lubricant, and v) optionally, other pharmaceutical excipients.

16. The composition according to claim 15, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is sodium N-(8-(2-hydroxybenzoyl)amino)octanoate.

17. A composition according to any one of the preceding claims 1-3, 5-8, 11 and 13, which consists of the following substances consisting of: i) a GLP-1 agonist, ii) a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid, iii) histidine, iv) a lubricant, and v) optionally, other pharmaceutical excipients.

18. A composition according to claim 17 above, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is sodium N-(8-(2-hydroxybenzoyl)amino)octanoate.

19. A composition according to any one of the preceding claims 1-3, 5-8, 11, 13, 16 and 18, wherein the dosage unit contains i) 0.5-100 mg of a GLP-1 agonist, ii) 50-750 mg of a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid, iii) 0.01-200 mg of histidine, iv) 1-15 mg of a lubricant, v) optionally, 1-20 mg of a binder, vi) optionally, 30-500 mg of a disintegrant, and vii) optionally, 20-100 mg of a filler.

20. A composition according to claim 19 above, wherein the dosage unit contains 0.5-50 mg of a GLP-1 agonist.

21. A composition according to claim 19 above, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is sodium N-(8-(2-hydroxybenzoyl)amino)octanoate.

22. A composition according to claim 19 above, wherein the binder is povidone.

23. A composition according to claim 19 above, wherein the disintegrant is nicotinamide.

24. A composition according to claim 19 above, wherein the filler is microcrystalline cellulose.

25. A composition according to any one of the preceding claims 1-3, 5-8, 11, 13, 16, 18 and 20-24, wherein the composition is a pharmaceutical composition in a method for treating diabetes and / or obesity.

26. A composition according to claim 25, wherein the diabetes is hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin-dependent diabetes, maturity-onset diabetes of the young, gestational diabetes, and / or for reducing HbA1C.

27. A method for preparing a solid pharmaceutical composition according to any one of the preceding claims 1-26, which comprises the following steps: i) obtaining an admixture comprising a GLP1 agonist and histidine, ii) co-processing the admixture of i), and iii) using the product of ii) to prepare the solid pharmaceutical composition.

28. A method for preparing a solid pharmaceutical composition according to any one of the preceding claims 1-26, which comprises the following steps: i) obtaining a solution comprising a GLP1 agonist and histidine, ii) spray-drying the solution of i), iii) using the product of ii) to prepare the solid pharmaceutical composition.

29. A method for preparing a solid pharmaceutical composition according to any one of the preceding claims 1-26, which comprising the following steps: i) obtaining an admixture comprising a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid and a lubricant, ii) granulating the admixture of i) by dry granulation, iii) mixing the granules of ii) with a GLP-1 agonist and histidine and any optional additional excipients, and iv) preparing the solid pharmaceutical composition using the mixture of iii).

30. A method for preparing a solid pharmaceutical composition according to any one of the preceding claims 1-26, which comprises the following steps: i) obtaining an admixture comprising a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid and a lubricant, ii) granulating the admixture 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 granules of ii) with the product of iii) and any optional additional excipients, and vi) preparing the solid pharmaceutical composition using the mixture of v).

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