Oral delivery of therapeutic agents

Abstract

Provided herein are pharmaceutical compositions comprising one or more therapeutic agents and a functional excipient capable of enhancing the oral bioavailability of the one or more therapeutic agents. Also provided herein are methods of making the pharmaceutical compositions and methods of using the pharmaceutical compositions to treat various diseases or conditions, such as type 2 diabetes.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to International Application No. PCT / CN2021 / 125360, filed on October 21, 2021, the contents of which are incorporated herein by reference in their entirety for all purposes. Background Technology Technical Field

[0004] In various embodiments, the present invention generally relates to the oral delivery of therapeutic agents. Background Technology

[0006] Oral delivery is the preferred route for drug administration. Oral administration offers several advantages, including better patient compliance, ease of administration, and typically lower production, storage, and distribution costs.

[0007] However, for macromolecules, they are rarely administered orally for the following reasons: 1) pre-systemic degradation due to acidity in the stomach and enzymes in the gastrointestinal (GI) tract; 2) low absorption by epithelial cells across lining absorption surfaces (such as those in the gastrointestinal tract); and 3) post-absorption degradation, such as first-pass metabolism. Summary of the Invention

[0008] In various embodiments, this disclosure relates to the oral delivery of therapeutic agents, particularly molecules, such as those having high molecular weights or those difficult to absorb by oral administration, such as peptides. This disclosure is partly based on the unexpected discovery that combinations of certain fatty acids and oral absorption enhancers can achieve a synergistic effect in enhancing the overall oral absorption of the therapeutic agent.

[0009] In some embodiments, this disclosure relates to the use of mixtures of functional excipients combined with formulation methods to significantly enhance the gastrointestinal absorption of biological therapeutic agents as single or combined agents, thereby transforming methods of curing and alleviating diseases.

[0010] Biologics used herein are not particularly limited and include carbohydrates, peptides, proteins, enzymes, antibodies, drug conjugates, vaccines, nucleic acids, and nucleic acid-based gene therapies. For example, biologics include, but are not limited to, ungraded heparin, low molecular weight heparin, synthetic heparin, growth hormone, growth factors, insulin, insulinicodec, interferon, interleukin, follicle-stimulating hormone, gonadotropins, erythropoietin, glucagon, semaglutide, liraglutide, exenatide, telpoietin, PYY, gastrin, GLP-1, GLP-2, calcitonin, PTH and analogues, vancomycin, daptomycin, micafungin, anisofungin, caspofungin, leuprorelin, and monoclonal antibodies.

[0011] Functional excipients that may be used in this article include, but are not limited to, the following molecules and their analogues: sodium 8-(2-hydroxybenzoamide)octanoate (SNAC), sodium 10-((2-hydroxybenzoyl)amino)decanoate (SNAD), 8-(N-2-hydroxy-5-chlorobenzoyl)-amino-octanoate (5CNAC), sodium N-(4-chlorosalicylic acid)-4-aminobutyrate (4-CNAB), sodium N-[8-(2-hydroxy-4-methoxy)benzoyl]aminooctanoate (4-MOAC), and bis-3,6(4-fumarylaminobutyl)-2,5-diketopiramate. Furthermore, functional excipients that may be used in this article include, for example, straight-chain fatty acids and their salts with aliphatic chains having 2 to 20 carbon atoms in the chain.

[0012] In some illustrative embodiments, the drug is administered using an oral dosage form containing an active agent of an enterokinin therapeutic (“enterokinin”) such as a GLP-1 receptor agonist (GLP-1RA), a functional excipient such as a mixture of fatty acids and surfactants, and common excipients used in oral dosage forms (such as tablets and capsules). Functional excipients that may be used herein include, but are not limited to, sodium N-[8(-2-hydroxybenzoyl)amino]octanoate (SNAC), 8-(N-2-hydroxy-5-chlorobenzoyl)-amino-octanoic acid (5-CNAC), [bis-3,6(4-fumarylaminobutyl)-2,5-diketopiramate], salts of straight-chain fatty acids, and combinations thereof. In other embodiments, the oral dosage form may contain a combination of active agents such as, but not limited to, GLP-1RA and SGLT-2 inhibitors, GLP-1RA and DPP4 inhibitors, and GLP-1RA and insulin. Enteroglycemic agents that can be used in the embodiments described herein include, but are not limited to, GLP-1, GIP, and GLP-1 / GIP agonists. Enteroglycemic agents that can be used in the embodiments described herein also include GIP, GLP-1 / GIP agonists in clinical trials, GLP-1RAs, and GLP-1 analogs, including but not limited to semaglutide, liraglutide, dulaglutide, lixilatide, and exenatide. SGLT2 inhibitors that can be used in the embodiments described herein include, but are not limited to, empagliflozin, canagliflozin, dapagliflozin, and eleggliflozin. DPP4 inhibitors that can be used in the embodiments described herein include, but are not limited to, sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin. Insulin and insulin analogs that can be used in the embodiments described herein include, but are not limited to, icodec insulin. In other embodiments, this disclosure relates to methods for preparing oral dosage forms, such as tablets and capsules. In other embodiments, the mixtures of functional excipients and preparation methods described herein may also be applied to other routes of administration.

[0013] Exemplary embodiments of this disclosure are also shown in claims 1-43 as described herein.

[0014] It should be understood that the foregoing description of the invention and the following detailed description are merely exemplary and illustrative, and do not limit the scope of the invention herein. Attached Figure Description

[0015] Figure 1 The mean pharmacokinetics of semaglutide in plasma are compared on a linear scale after oral administration of (1) a formulation containing only 10 mg semaglutide and 300 mg SNAC or (2) a formulation containing 10 mg semaglutide, 300 mg SNAC, and 150 mg sodium decanoate. Error bars represent the standard deviation of semaglutide concentration at specified times.

[0016] Figure 2The graph shows the plasma semaglutide concentration over time on a log-linear scale after (1) oral administration of 10 mg semaglutide and 300 mg SNAC; or (2) oral administration of 10 mg semaglutide, 300 mg SNAC, and 150 mg sodium decanoate. The error bars represent the standard deviation of the semaglutide concentration at a specified time.

[0017] Figure 3 The curves of glucose concentration over time in the oral glucose test in healthy beagle dogs are shown in (1) negative control, (2) oral administration of 10 mg semaglutide and 300 mg SNAC; or (3) oral administration of 10 mg semaglutide, 300 mg SNAC and 150 mg sodium decanoate.

[0018] Figure 4 The graph shows the plasma concentration of semaglutide over time, comparing the oral administration of 7 mg semaglutide prepared by freeze-drying in 300 mg SNAC / 150 mg C10 with the oral administration of 7 mg semaglutide in commercial tablets (Rybelsus).

[0019] Figure 5 The graph shows the plasma concentration of semaglutide over time, compared by freeze-drying to oral administration of 10 mg semaglutide prepared by simple blending in 300 mg SNAC / 150 mg C10.

[0020] Figure 6 The graph shows the plasma concentration of semaglutide over time, comparing the oral administration of 10 mg semaglutide prepared by freeze-drying in 300 mg SNAC, 300 mg C10, or 300 mg SNAC / 150 mg C10. Detailed Implementation

[0021] This disclosure generally relates to the oral delivery of therapeutic agents. As detailed herein, the inventors have discovered that the combination of semaglutide with SNAC and sodium decanoate produces unexpectedly higher drug absorption and more effective glycemic control compared to formulations containing only semaglutide and SNAC. The effective enhancement of semaglutide plasma concentration is approximately 5-fold. Inter-individual variability is also significantly reduced. Furthermore, the combination of semaglutide with SNAC and sodium decanoate has also demonstrated superior pharmacological effects of semaglutide based on oral glucose tolerance tests (oGTT). Moreover, data here indicate that the use of a freeze-drying method in preparing the formulations herein is beneficial for achieving higher semaglutide exposure compared to equivalent formulations prepared using a simple blending method. Furthermore, data here indicate that the use of SNAC and sodium decanoate achieves a synergistic effect in enhancing oral exposure of semaglutide.

[0022] In a broad sense, this disclosure provides pharmaceutical compositions comprising a therapeutic agent (e.g., any of those described herein) and one or more, particularly two or more, functional excipients (e.g., any of those described herein). Unless otherwise stated in the context, a functional excipient as used herein refers to those excipients that enhance the oral bioavailability of the therapeutic agent. For example, in some embodiments, a functional excipient refers to those excipients that, upon oral administration, increase the bioavailability of a GLP-1 agonist in the composition.

[0023] Typically, pharmaceutical compositions comprise two or more functional excipients that synergistically enhance the oral absorption of the therapeutic agent. In some embodiments, one or more functional excipients comprise an aliphatic acid of formula I: RCOOH, wherein R represents an aliphatic group or a pharmaceutically acceptable salt thereof. In some embodiments, one or more functional excipients comprise a compound of formula II:

[0024]

[0025] Or its pharmaceutically acceptable salt, wherein:

[0026] n is an integer selected from 0, 1, 2, 3 or 4;

[0027] G 1 Each time it appears, it is independently OH, NH2, or NH(C). 1-4 Alkyl), N(C) 1-4 Alkyl)(C 1-4 Alkyl groups), halogens (e.g., Cl), C 1-4 Alkyl or C 1-4 Alkyl groups (e.g., OCH3); and

[0028] L 1 C2-C, whether substituted or unsubstituted 16 Alkylene, or substituted or unsubstituted C2-C 16 Imethylene group. Typically, the pharmaceutical composition is formulated for oral administration. Preferably, a therapeutically effective plasma concentration of the therapeutic agent can be achieved after oral administration of the pharmaceutical composition described herein.

[0029] In some embodiments, this disclosure provides pharmaceutical compositions comprising (a) a therapeutic agent (e.g., any of those described herein); (b) an aliphatic acid of formula I: RCOOH, wherein R represents an aliphatic group or a pharmaceutically acceptable salt thereof; and (c) a compound of formula II:

[0030]

[0031] Or its pharmaceutically acceptable salt, wherein:

[0032] n is an integer selected from 0, 1, 2, 3 or 4;

[0033] G 1 Each time it appears, it is independently OH, NH2, or NH(C). 1-4 Alkyl), N(C) 1-4 Alkyl)(C 1-4 Alkyl groups), halogens (e.g., Cl), C 1-4 Alkyl or C 1-4 Alkyl groups (e.g., OCH3); and

[0034] L 1 C2-C, whether substituted or unsubstituted 16 Alkylene, or substituted or unsubstituted C2-C 16 Alkenyl group.

[0035] Therapeutic agents

[0036] There are no particular limitations on the therapeutic agents that can be used in the pharmaceutical compositions described herein. For example, therapeutic agents may include carbohydrates, peptides, proteins, antibodies, vaccines, nucleic acids, etc. In some embodiments, the therapeutic agent may be a biological therapeutic agent as described herein. In some embodiments, the therapeutic agent may be a macromolecule, such as those with a molecular weight greater than 2,000 Daltons, greater than 3,000 Daltons, greater than 10,000 Daltons, or greater than 100,000 Daltons.

[0037] For example, in some implementations, the therapeutic agent may be a carbohydrate, such as heparin (e.g., ungraded heparin, low molecular weight heparin, synthetic heparin such as fondaparin) or glucosamine.

[0038] In some embodiments, the therapeutic agent may be a polypeptide (or referred to herein as a peptide), including proteins and antibodies. Useful polypeptides for the embodiments herein are not particularly limited and include, for example, the following agents:

[0039] 1. GLP-1 and analogues

[0040] a)GLP-1

[0041] b) Semaglutide

[0042] c) Liraglutide

[0043] d) Exenatide

[0044] e) Thilborpeptide

[0045] f) Lixilatin

[0046] g) Efinopegdutide

[0047] h) Ketodextrin

[0048] 2. Tiduglutide

[0049] 3. Pramlinide

[0050] 4. PYY

[0051] 5. Gastric acid regulator

[0052] 6. Glucagon

[0053] 7. Calcitonin

[0054] 8. Octreotide

[0055] 9. PTH and similar substances

[0056] a) Teriparatide

[0057] 10. Vicosine

[0058] 11. Oxytocin

[0059] 12. Antibiotics

[0060] a) Vancomycin

[0061] b) Daptomycin

[0062] c) Dabawanxing

[0063] d) Orivan

[0064] e) Travan Star

[0065] 13. Antifungal drugs

[0066] a) Micafenicol

[0067] b) Anifenzin

[0068] c) Caspofungin

[0069] 14. Vasopressin

[0070] 15. Leuprorelin

[0071] 16.Nesiritide

[0072] 17. Enfuwedi

[0073] 18. Growth hormones and analogues

[0074] 19. Pevisomeng

[0075] 20. Mekaserine (rhIGF-1)

[0076] 21.GnRH

[0077] a) Histidine Relin

[0078] 22. Diotrimine-α

[0079] 23. Palifmin

[0080] 24. Beccalplem 2

[0081] 25. Adrenocorticotropic hormone (ACTH)

[0082] 26. Somatostatin

[0083] 27. Oxyoctreotide

[0084] 28. Paretaide

[0085] 29. Trypsin

[0086] 30. Insulin and analogues

[0087] a) Insulin

[0088] b) Ico insulin

[0089] c) Detemir insulin

[0090] d) Glargine insulin

[0091] e) Lispro insulin

[0092] f) Lysine insulin

[0093] g) Aspart insulin

[0094] 31. Interferon

[0095] a) Compound Interferon 1

[0096] b) Interferon-α2a

[0097] c) Interferon-α2b

[0098] d) Interferon-αn3

[0099] e) Interferon-β1a

[0100] f) Interferon-β1b

[0101] g) Interferon-γ1b

[0102] 32. Interleukins

[0103] a) Interleukin-1

[0104] h) Aldehyde interleukin

[0105] i) Dinylleukin

[0106] 33. Follicle-stimulating hormone

[0107] 34. Human chorionic gonadotropin

[0108] 35. Luteinizing hormone-alpha

[0109] 36. Erythropoietin

[0110] 37. Epoetin-α

[0111] 38. Dabepoetin-α

[0112] 39. Ferguson

[0113] 40. Pfeiffersky

[0114] 41. Shagstine

[0115] 42. Alteplase

[0116] 43. Reteplase

[0117] 44. Tenecteplase

[0118] 45. Urokinase

[0119] 46. ​​Factor VIIa

[0120] 47. Factor VIII

[0121] 48. Factor IX

[0122] 49. Antithrombin III

[0123] 50. Protein C

[0124] 51. Flexibility-α

[0125] 52. β-Glucocerebroside lipase

[0126] 53. Glucosidase-α

[0127] 54. Laronibacterium

[0128] 55. Idursulphase

[0129] 56. Galactosidase

[0130] 57. Agardase-β

[0131] 58. α-1-Protein Inhibitors

[0132] 59. Lactase 2

[0133] 60. Pancreatic enzymes

[0134] 61. Adenosine deaminase

[0135] 62. Immunoglobulins

[0136] 63. Albumin

[0137] 64. Lapirudin

[0138] 65. Bivaludin

[0139] 66. Streptokinase

[0140] 67. Anipase

[0141] 68. Lizalizumab

[0142] 69. Inasipu

[0143] 70. Adalimumab

[0144] 71. Infliximab

[0145] 72. Bevacizumab

[0146] 73. Trastuzumab

[0147] 74. Rituximab

[0148] 75. Kipson

[0149] 76. Pathezilan

[0150] 77. Givasiland

[0151] 78. Lumaasiran

[0152] In some implementations, the therapeutic agent may also include a vaccine. In some implementations, the therapeutic agent may also include nucleic acids.

[0153] In some preferred embodiments, the therapeutic agent may include an enterokinin therapeutic agent. For example, in some preferred embodiments, the therapeutic agent may include a glucagon-like peptide-1 (GLP-1) receptor agonist, such as any of those described herein, or any of those described in U.S. Patent Nos. 10,960,052, 8,129,343, 8,536,122, 9,278,123, 10,086,047, 10,278,923, and 10,933,120, the entire contents of each of which are incorporated herein by reference. In some preferred embodiments, the therapeutic agent may include semaglutide, liraglutide, dulaglutide, lixilatide, or exenatide. Other glucagons and peptides may include, but are not limited to, PYY and PYY analogs; GLP-1 / GIP receptor agonists, such as, but not limited to, telpolide, CT-388, SCO-094, etc.; and GLP-1 / GCGR receptor agonists, such as, but not limited to, ifenopeptide, IB1362, etc.

[0154] In some preferred embodiments, the pharmaceutical compositions herein may comprise a GLP-1 receptor agonist as the sole therapeutic agent. In some embodiments, the pharmaceutical compositions herein may comprise a combination of a GLP-1 receptor agonist as a therapeutic agent with one or more other therapeutic agents available for the treatment of diabetes (e.g., any of those known in the art). In some embodiments, one or more other therapeutic agents may comprise (1) an SGLT-2 inhibitor, such as empagliflozin, canagliflozin, dapagliflozin, or eleggliflozin; (2) a DPP-4 inhibitor, such as sitagliptin, vildagliptin, saxagliptin, linagliptin, or alogliptin; (3) insulin or an insulin analog (e.g., iprodione); (4) GIP, a glucose-dependent insulinotropic peptide; and / or (5) amylin or an amylin analog. In some embodiments, one or more other therapeutic agents may also comprise (1) biguanides; (2) thiazolidinediones; (3) DPP-4 inhibitors; (4) PYY; and (5) sulfonylureas.

[0155] In some embodiments, the pharmaceutical compositions herein may comprise a combination of a GLP-1 receptor agonist as a therapeutic agent and one or more other therapeutic agents that can be used to treat neurological disorders, such as Alzheimer's disease. For example, in some embodiments, the pharmaceutical compositions herein may comprise a combination of semaglutide as a therapeutic agent and (1) a cholinesterase inhibitor (e.g., Aricept, Exelon, Razadyne); (2) a glutamate modulator (e.g., Namenda); and / or (3) an orexin receptor antagonist (e.g., Belsomra).

[0156] In a more preferred embodiment, the therapeutic agent described herein may include semaglutide. Semaglutide as used herein is not limited to any particular form. For example, in some embodiments, semaglutide may be in the form of a pharmaceutically acceptable salt, such as a sodium salt. Semaglutide is marketed in the United States under several brand names, including oral. Tablet formulation for sale. See the FDA-approved Rybelsus Prescription Information, 2021 edition, the contents of which are incorporated herein by reference in their entirety. As described herein, the peptide backbone of semaglutide is produced by yeast fermentation. The primary elongation mechanism of semaglutide is albumin binding facilitated by modification of lysine at position 26 with a hydrophilic spacer and a C18 fatty diacid. Furthermore, semaglutide is modified at position 8 to provide stability against degradation by dipeptidyl peptidase 4 (DPP-4) enzymes. A minor modification is made at position 34 to ensure that only one fatty diacid is linked. The molecular formula is C187H291N45O59, and the molecular weight is 4113.58 g / mol. The structure is shown below:

[0157]

[0158] In some preferred embodiments, the pharmaceutical compositions herein may comprise semaglutide as the sole therapeutic agent. In some embodiments, the pharmaceutical compositions herein may comprise semaglutide as a therapeutic agent in combination with one or more other therapeutic agents that can be used to treat diabetes (e.g., any of those known in the art). In some embodiments, one or more other therapeutic agents may comprise (1) SGLT-2 inhibitors, such as empagliflozin, canagliflozin, dapagliflozin, or eleggliflozin; (2) DPP-4 inhibitors, such as sitagliptin, vildagliptin, saxagliptin, linagliptin, or alogliptin; (3) insulin or insulin analogs (e.g., iprodione); (4) GIP, glucose-dependent insulinotropic peptides; and / or (5) amylin or amylin analogs. In some embodiments, one or more other therapeutic agents may also comprise (1) biguanides; (2) thiazolidinediones; (3) DPP-4 inhibitors; (4) PYY; and (5) sulfonylureas. In some embodiments, one or more other therapeutic agents may include one or more selected from the following: biguanides, sulfonylureas and megglitinides, thiazolidinediones, alpha-glucosidase inhibitors, other glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP4) inhibitors, amylin analogs, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, dopamine agonists, and bile acid sequestrants. In some embodiments, one or more other therapeutic agents may include one or more selected from the following: metformin, glipizide, gliclazide, glibenclamide, glimepiride, nateglinide, repaglinide, pioglitazone, rosiglitazone, acarbose, miglitol, voglibose, exenatide, liraglutide, lixilamide, duraglutide, abiglutide, sitagliptin, vildagliptin, saxagliptin, liraglitin, giglitin, alagliptin, ticagliptin, alogliptin, tregliptin, ocagliptin, evogliptin, gogliptin, pramlintide, canagliflozin, dapagliflozin, empagliflozin, iogliptin, bromocriptine, and colesvelam.

[0159] In some embodiments, the pharmaceutical compositions herein may comprise semaglutide as a therapeutic agent in combination with one or more other therapeutic agents that can be used to treat neurological disorders, such as Alzheimer's disease. For example, in some embodiments, the pharmaceutical compositions herein may comprise semaglutide as a therapeutic agent in combination with (1) a cholinesterase inhibitor (e.g., Aricept, Exelon, Razadyne); (2) a glutamate modulator (e.g., Namenda); and / or (3) an orexin receptor antagonist (e.g., Belsomra).

[0160] Aliphatic acids of formula I

[0161] Typically, the pharmaceutical compositions described herein comprise an aliphatic acid of formula I: RCOOH, where R represents an aliphatic group or a pharmaceutically acceptable salt thereof.

[0162] There are no particular limitations on the useful aliphatic acids. For example, in some embodiments, the aliphatic acid has the formula I: RCOOH, where R represents an alkyl group having 1-30 carbon atoms. The alkyl group can be straight-chain or branched. For example, in some embodiments, R in Formula I can be -(CH2). 1-18 CH3. In some embodiments, R in Formula I may be an alkyl group having 3-20 carbon atoms. In some embodiments, R in Formula I may be an alkyl group having 5-16 carbon atoms. In some embodiments, the aliphatic acid of Formula I is a straight-chain aliphatic acid having 2 to 20 carbon atoms, such as octanoic acid, decanoic acid, or lauric acid. In any embodiment described herein, unless otherwise stated or contrary to the context, the aliphatic acid of Formula I may be decanoic acid.

[0163] The aliphatic acids of Formula I may be present in the pharmaceutical compositions herein as free acids or any pharmaceutically acceptable salt thereof (such as their alkali metal or basic salts, e.g., sodium or potassium salts). In some preferred embodiments, the pharmaceutical compositions herein comprise sodium decanoate.

[0164] Compound of Formula II

[0165] Typically, the pharmaceutical compositions described herein comprise compounds of formula II:

[0166]

[0167] Or its pharmaceutically acceptable salt, wherein the variable is defined in this document.

[0168] In some embodiments, the compound of formula II may not have a G on the benzene ring. 1 Substituents, i.e., n is 0.

[0169] In some embodiments, the compound of formula II may have a G substituted on the benzene ring. 1 That is, n is 1. In some implementations, in Equation II, n is 1, and G 1 Halogen, C 1-4 Alkyl or C 1-4 Alkyl group. In some embodiments, n is 1 in formula II, and G 1 For Cl. In some implementations, in Equation II, n is 1, and G 1 It is OCH3.

[0170] L in Formula II 1 Typically, it is either substituted or unsubstituted C2-C. 16 Alkylene. For example, in some embodiments, L1 For unreplaced C3-C 15 Alkylene. In some embodiments, L 1 For the unreplaced C5-C 13 Alkylene. Alkylenes can be straight-chain or branched. For example, in some embodiments, L 1 It is an unsubstituted straight-chain C5-C9 alkylene group.

[0171] In some preferred embodiments, the compound of formula II may be Its chemical name is 8-(2-hydroxybenzamido)octanoic acid (ChemDraw software, version 20.0). In a preferred embodiment, the pharmaceutical composition herein comprises a salt (preferably a sodium salt) of 8-(2-hydroxybenzamido)octanoic acid, which can be prepared using, for example, the methods described in WO96 / 030036, WO00 / 046182, WO01 / 092206 or WO2008 / 028859. The salt of 8-(2-hydroxybenzamido)octanoic acid (or N-(8-(2-hydroxybenzoyl)amino)octanoic acid) can be crystalline and / or amorphous. In some embodiments, the delivery agent comprises an anhydrous, monohydrate, dihydrate, trihydrate, solvate, or one-third hydrate of the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid, or combinations thereof. In some embodiments, the pharmaceutical compositions herein comprise a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid as described in WO2007 / 121318.

[0172] In a more preferred embodiment, the pharmaceutical composition comprises sodium N-(8-(2-hydroxybenzoyl)amino)octanoate (referred to herein as "SNAC").

[0173] In some preferred embodiments, the compound of formula II may be Its chemical name is 8-(5-chloro-2-hydroxybenzamido)octanoic acid (ChemDraw software, version 20.0). In some embodiments, the pharmaceutical compositions herein comprise a salt of 8-(5-chloro-2-hydroxybenzamido)octanoic acid.

[0174] In some embodiments, the compound of formula II may be Its chemical name is 10-((2-hydroxybenzoyl)amino)decanoic acid. In some embodiments, the pharmaceutical compositions herein comprise a salt of 10-((2-hydroxybenzoyl)amino)decanoic acid, such as sodium 10-((2-hydroxybenzoyl)amino)decanoate.

[0175] In some embodiments, the compound of formula II may be Its chemical name is N-(4-chlorosalicyloyl)-4-aminobutyric acid. In some embodiments, the pharmaceutical compositions herein comprise a salt of N-(4-chlorosalicyloyl)-4-aminobutyric acid, such as sodium N-(4-chlorosalicyloyl)-4-aminobutyrate.

[0176] In some embodiments, the compound of formula II may be It has the chemical name N-[8-(2-hydroxy-4-methoxy)benzoyl]aminooctanoic acid. In some embodiments, the pharmaceutical compositions herein comprise a salt of N-[8-(2-hydroxy-4-methoxy)benzoyl]aminooctanoic acid, such as sodium N-[8-(2-hydroxy-4-methoxy)benzoyl]aminooctanoate.

[0177] There are no particular restrictions on the combination of therapeutic agents, aliphatic acids of formula I, and compounds of formula II.

[0178] In some preferred embodiments, the pharmaceutical compositions herein comprise (a) a polypeptide (e.g., any of those described herein, such as semaglutide); (b) decanoic acid or a pharmaceutically acceptable salt thereof; and (c) a compound of formula II or a pharmaceutically acceptable salt thereof.

[0179] In some preferred embodiments, the pharmaceutical compositions herein comprise (a) a polypeptide (e.g., any of those described herein, such as semaglutide); (b) a straight-chain aliphatic acid having 2 to 20 carbon atoms, such as caprylic acid, capric acid, or lauric acid, or a pharmaceutically acceptable salt thereof; and (c) SNAC.

[0180] In some preferred embodiments, the pharmaceutical compositions herein comprise (a) a polypeptide (e.g., any of those described herein, such as semaglutide); (b) decanoic acid or a pharmaceutically acceptable salt thereof; and (c) 8-(2-hydroxybenzoamide)octanoic acid or a pharmaceutically acceptable salt thereof.

[0181] In some preferred embodiments, the pharmaceutical compositions herein comprise (a) a polypeptide (e.g., any of those described herein, such as semaglutide); (b) sodium decanoate; and (c) SNAC.

[0182] In some preferred embodiments, the pharmaceutical compositions herein comprise (a) semaglutide; (b) sodium decanoate; and (c) SNAC.

[0183] Typically, in the pharmaceutical compositions described herein, if applicable, the weight ratio (b) / (c) of the aliphatic acid of formula I or a pharmaceutically acceptable salt thereof to the compound of formula II or a pharmaceutically acceptable salt thereof is in the range of about 20:1 to about 1:20, such as 5:1 to 1:5, such as about 3:1, about 2:1, about 1:1, about 1:1.5, about 1:2, about 1:2.5 or about 1:3 or any range between the listed values, for example, about 1:2. For example, in some embodiments, the pharmaceutical compositions described herein comprise (a) semaglutide; (b) sodium decanoate; and (c) SNAC, wherein the weight ratio of sodium decanoate to SNAC is about 5:1 to about 1:5, such as about 3:1, about 2:1, about 1:1, about 1:1.5, about 1:2, about 1:2.5 or about 1:3, or any range between the listed values.

[0184] Typically, for each unit dosage form, the combined amount of (b) the aliphatic acid of formula I or a pharmaceutically acceptable salt thereof and (c) the compound of formula II or a pharmaceutically acceptable salt thereof is in the range of about 100 mg to about 900 mg, such as about 300 mg, about 450 mg, about 600 mg, about 750 mg or about 900 mg, or any range or value between the listed values. For example, in some embodiments, the unit dosage form (such as a tablet or capsule) of the pharmaceutical composition herein may contain (a) a polypeptide (e.g., any of those described herein, such as semaglutide); (b) sodium decanoate and (c) SNAC, wherein the combined amount of sodium decanoate and SNAC is in the range of about 300-600 mg, such as about 450 mg. There is no particular limitation on the amount of therapeutic agent (e.g., peptides such as semaglutide in this article) used in each unit dosage form. For example, typically, the amount of therapeutic agent may be from about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the listed values).

[0185] In some embodiments, the pharmaceutical composition comprises an aliphatic acid of Formula I or a pharmaceutically acceptable salt thereof in an amount of about 50 mg to about 300 mg per unit dose, such as about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg per unit dose, or any range between the listed values. As used herein, unless otherwise stated or clearly contrary to the context, the weight of an aliphatic acid of Formula I or a pharmaceutically acceptable salt thereof shall be understood as an equivalent weight expressed as the weight of the free acid. However, when specifically referring to an amount of sodium decanoate, the amount shall be understood as the weight of the sodium salt itself, and not the equivalent weight of the decanoic acid. In some embodiments, the pharmaceutical composition comprises at least 0.6 mmol (millimoles) per unit dose, such as an amount selected from the group consisting of at least 0.65 mmol, at least 0.7 mmol, at least 0.75 mmol, at least 0.8 mmol, at least 0.8 mmol, at least 0.9 mmol, at least 0.95 mmol, and at least 1 mmol. In some embodiments, the pharmaceutical composition comprises an aliphatic acid of formula I or a pharmaceutically acceptable salt thereof in an amount of 0.6 mmol to 2 mmol, such as 0.8 mmol to 1.3 mmol, 0.9 mmol to 1.1 mmol, such as 0.95 mmol, 1.0 mmol, etc., per unit dose.

[0186] In some embodiments, the pharmaceutical composition comprises an amount of Formula II compound or a pharmaceutically acceptable salt thereof in the form of about 200 mg to about 400 mg per unit dose, such as about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg per unit dose, or any range between the listed values. As used herein, unless otherwise stated or clearly contrary to the context, the weight of Formula II compound or a pharmaceutically acceptable salt thereof should be understood as an equivalent weight expressed as the weight of Formula II compound. However, when specifically referring to an amount of SNAC, the amount should be understood as the weight of the sodium salt itself, and not the equivalent weight of the acid. In some embodiments, the pharmaceutical composition comprises at least 0.6 mmol per unit dose, such as an amount selected from the group consisting of at least 0.65 mmol, at least 0.7 mmol, at least 0.75 mmol, at least 0.8 mmol, at least 0.8 mmol, at least 0.9 mmol, at least 0.95 mmol, and at least 1 mmol of Formula II compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound of formula II or a pharmaceutically acceptable salt thereof in an amount of 0.6 mmol to 2 mmol, such as 0.8 mmol to 1.3 mmol or 0.9 mmol to 1.1 mmol, such as 1 mmol, per unit dose.

[0187] Typically, pharmaceutical compositions comprise a synergistic combination of an aliphatic acid of formula (b) or a pharmaceutically acceptable salt thereof and a compound of formula (c) or a pharmaceutically acceptable salt thereof to achieve enhanced oral delivery of a therapeutic agent, such as a peptide.

[0188] In some specific embodiments, the pharmaceutical composition comprises (a) a therapeutic agent (e.g., any of those described herein); (b) a sodium decanoate in an amount of about 50 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or any range between the listed values); and (c) a SNAC in an amount of about 200 mg to about 400 mg (e.g., about 200 mg, about 300 mg, about 400 mg, or any range between the listed values). There is no particular limitation on the amount of the therapeutic agent; for example, typically, the amount of the therapeutic agent may be about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the listed values).

[0189] In some specific embodiments, the pharmaceutical composition comprises (a) a therapeutic agent (e.g., any of those described herein); (b) a sodium decanoate in an amount of about 0.6 mmol to 2 mmol (e.g., 0.6 mmol, 0.8 mmol, 0.9 mmol, 1 mmol, 1.1 mmol, 1.3 mmol, 2 mmol, or any range between the listed values, such as 0.9-1.1 mmol); and (c) a SNAC in an amount of 0.6 mmol to 2 mmol (e.g., 0.6 mmol, 0.8 mmol, 0.9 mmol, 1 mmol, 1.1 mmol, 1.3 mmol, 2 mmol, or any range between the listed values, such as 0.9-1.3 mmol). There is no particular limitation on the amount of the therapeutic agent; for example, typically, the amount of the therapeutic agent may be from about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the listed values) or from about 0.1 μmol to about 2 μmol.

[0190] In some specific embodiments, the pharmaceutical composition comprises (a) a polypeptide (e.g., any of those described herein); (b) a sodium decanoate in an amount of about 50 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or any range between the listed values); and (c) an SNAC in an amount of about 200 mg to about 400 mg (e.g., about 200 mg, about 300 mg, about 400 mg, or any range between the listed values). There is no particular limitation on the amount of the polypeptide; for example, typically the amount of the polypeptide may be from about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the listed values).

[0191] In some specific embodiments, the pharmaceutical composition comprises (a) a polypeptide (e.g., any of those described herein); (b) sodium decanoate in an amount of about 0.6 mmol to 2 mmol (e.g., 0.6 mmol, 0.8 mmol, 0.9 mmol, 1 mmol, 1.1 mmol, 1.3 mmol, 2 mmol, or any range between the listed values, such as 0.9-1.1 mmol); and (c) SNAC in an amount of 0.6 mmol to 2 mmol (e.g., 0.6 mmol, 0.8 mmol, 0.9 mmol, 1 mmol, 1.1 mmol, 1.3 mmol, 2 mmol, or any range between the listed values, such as 0.9-1.3 mmol). There is no particular limitation on the amount of the polypeptide; for example, the amount of the polypeptide can typically be from about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the listed values).

[0192] In some specific embodiments, the pharmaceutical composition comprises (a) a GLP-1 agonist (e.g., any of those described herein); (b) a sodium decanoate in an amount of about 50 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or any range between the listed values); and (c) an SNAC in an amount of about 200 mg to about 400 mg (e.g., about 200 mg, about 300 mg, about 400 mg, or any range between the listed values). There is no particular limitation on the amount of the GLP-1 agonist; for example, the amount of the GLP-1 agonist can typically be from about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the listed values).

[0193] In some specific embodiments, the pharmaceutical composition comprises (a) a GLP-1 agonist (e.g., any of those described herein); (b) a sodium decanoate in an amount of about 0.6 mmol to 2 mmol (e.g., 0.6 mmol, 0.8 mmol, 0.9 mmol, 1 mmol, 1.1 mmol, 1.3 mmol, 2 mmol, or any range between the listed values, such as 0.9-1.1 mmol); and (c) a SNAC in an amount of 0.6 mmol to 2 mmol (e.g., 0.6 mmol, 0.8 mmol, 0.9 mmol, 1 mmol, 1.1 mmol, 1.3 mmol, 2 mmol, or any range between the listed values, such as 0.9-1.3 mmol). There is no particular limitation on the amount of the GLP-1 agonist; for example, the amount of the GLP-1 agonist can typically be from about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the listed values).

[0194] In some specific embodiments, the pharmaceutical composition comprises (a) semaglutide; (b) sodium decanoate in an amount of about 50 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or any range between the listed values); and (c) SNAC in an amount of about 200 mg to about 400 mg (e.g., about 200 mg, about 300 mg, about 400 mg, or any range between the listed values). There is no particular limitation on the amount of semaglutide; for example, typically the amount of semaglutide may be about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the listed values). In some embodiments, the amount of semaglutide may be about 0.1 μmol to about 2.5 μmol, such as about 0.5 μmol to about 2.5 μmol.

[0195] In some specific embodiments, the pharmaceutical composition comprises (a) semaglutide; (b) sodium decanoate in an amount of about 0.6 mmol to 2 mmol (e.g., 0.6 mmol, 0.8 mmol, 0.9 mmol, 1 mmol, 1.1 mmol, 1.3 mmol, 2 mmol, or any range between the listed values, such as 0.9-1.1 mmol); and (c) SNAC in an amount of 0.6 mmol to 2 mmol (e.g., 0.6 mmol, 0.8 mmol, 0.9 mmol, 1 mmol, 1.1 mmol, 1.3 mmol, 2 mmol, or any range between the listed values, such as 0.9-1.3 mmol). There is no particular limitation on the amount of semaglutide; for example, typically the amount of semaglutide can be from about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the listed values). In some implementations, the amount of semaglutide may be from about 0.1 micromoles to about 2.5 micromoles, such as from about 0.5 micromoles to about 2.5 micromoles.

[0196] In any of the embodiments described herein, unless otherwise stated or contrary to the context, the pharmaceutical composition may be in the form of a solid oral dosage form. For example, the pharmaceutical compositions described herein may typically be capsules or tablets. In some embodiments, the pharmaceutical compositions described herein may be present in discrete units (referred herein to as “unit dosage forms” or “dose units”), such as capsules, pills, sachets, lozenges, or tablets, each containing a predetermined amount of the active compound. In any of the embodiments described herein, unless otherwise stated or contrary to the context, the pharmaceutical composition may be in the form of a unit dosage form. It should be understood that the pharmaceutical compositions described herein may include one or more dose units. For example, the pharmaceutical compositions described herein may typically be capsules or tablets, wherein each capsule or tablet constitutes a dose unit. As used herein, each “unit dose” of a pharmaceutical composition refers to a dose of the pharmaceutical composition administered each time, which may contain one or more unit dosage forms or dose units; when more than one dose unit is used to satisfy a unit dose, the dose units may be the same or different. In a preferred embodiment, each unit dose contains a single dose unit.

[0197] The pharmaceutical compositions described herein may optionally contain one or more additional excipients, such as those suitable for oral administration. For example, in some embodiments, the pharmaceutical compositions described herein contain at least one pharmaceutically acceptable excipient. As used herein, the term "excipient" broadly refers to any component other than the active therapeutic ingredient. Excipients may be inert, inactive, and / or non-pharmaceutical active substances. Excipients can be used for a variety of purposes, such as acting as carriers, mediators, fillers, binders, lubricants, flow aids, disintegrants, flow control agents, crystallization inhibitors, solubilizers, stabilizers, colorants, flavoring agents, surfactants, enzyme inhibitors, alkalizing agents, acidifying agents, emulsifiers, and / or to improve the administration and / or absorption of the active ingredient, or as tablet coatings to control the dissolution rate of the solid dosage form according to the pH in the gastrointestinal tract. Those skilled in the art can select one or more of the above-described excipients by routine experimentation and without any undue burden, based on the specific desired properties of the solid oral dosage form. The amount of each excipient used may vary within the range conventionally practiced in the art. The techniques and excipients that can be used to formulate oral dosage forms are described in Handbook of Pharmaceutical Excipients, 6th edition, Rowe et al., editors, American Pharmaceutical Association and the Pharmaceutical Press, publications department of the Royal Pharmaceutical Society of Great Britain (2009); and Remington: the Science and Practice of Pharmacy, 21st edition, Gennaro, editors, Lippincott Williams & Wilkins (2005).In some embodiments, the excipients may be selected from binders, such as polyvinylpyrrolidone (Povidone); fillers, such as cellulose powder, microcrystalline cellulose, cellulose derivatives such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose, dicalcium phosphate, corn starch, pregelatinized starch, etc.; lubricants and / or flow aids, such as stearic acid, magnesium stearate, sodium stearoyl fumarate, glyceryl tris(oxalate) ester, etc.; and flow control agents, such as colloidal silica, talc, etc. Crystallization inhibitors, such as povidone; solubilizers, such as Pluronic acid, povidone; colorants, including dyes and pigments, such as iron oxide red or iron oxide yellow, titanium dioxide, talc; pH control agents, such as citric acid, tartaric acid, fumaric acid, sodium citrate, calcium hydrogen phosphate, sodium dihydrogen phosphate; surfactants and emulsifiers, such as Pluronic acid, polyethylene glycol, sodium carboxymethyl cellulose, polyethoxylated and hydrogenated castor oil; and mixtures of two or more of these excipients and / or adjuvants.

[0198] In some embodiments, the pharmaceutical compositions herein may contain lubricants, binders, fillers, and / or chelating agents (e.g., ethylenediaminetetraacetic acid (EDTA)). However, in some embodiments, the pharmaceutical compositions herein may also be free of or substantially free of lubricants, such as lubricants present in amounts of less than 0.1 wt%, less than 0.05 wt%, less than 0.01 wt%, or undetectable amounts. In some embodiments, the pharmaceutical compositions herein may be free of magnesium stearate. In some embodiments, the pharmaceutical compositions herein may also be free of or substantially free of binders, such as binders present in amounts of less than 0.1 wt%, less than 0.05 wt%, less than 0.01 wt%, or undetectable amounts. In some embodiments, the pharmaceutical compositions herein may also be free of or substantially free of fillers, such as fillers present in amounts of less than 0.1 wt%, less than 0.05 wt%, less than 0.01 wt%, or undetectable amounts. In some embodiments, the pharmaceutical compositions herein may also be free of or substantially free of chelating agents, such as chelating agents present in amounts of less than 0.1 wt%, less than 0.05 wt%, less than 0.01 wt%, or undetectable amounts.

[0199] In some implementations, the pharmaceutical composition is in the form of a unit dosage form.

[0200] Preparation method

[0201] Pharmaceutical compositions can be prepared by those skilled in the art based on this disclosure. In some preferred embodiments, the preparation method may include the steps of freeze-drying the therapeutic agent, the aliphatic acid of formula I described herein or a pharmaceutically acceptable salt thereof, and the compound of formula II described herein or a pharmaceutically acceptable salt thereof, which may be advantageous in achieving superior PK characteristics compared to simply blending these components together, as shown in the Examples section.

[0202] In some embodiments, this disclosure also provides a method for preparing a pharmaceutical composition, the method comprising: (a) mixing a therapeutic agent (e.g., any of those described herein, such as a polypeptide) with a compound of formula II described herein or a pharmaceutically acceptable salt thereof and an aliphatic acid of formula I described herein or a pharmaceutically acceptable salt thereof to form a mixture; (b) freeze-drying the mixture formed in (a) to form a freeze-dried mixture; and optionally (c) mixing the freeze-dried mixture with a pharmaceutically acceptable excipient.

[0203] In some embodiments, the therapeutic agent is first mixed with a compound of formula II described herein or a pharmaceutically acceptable salt thereof, and then an aliphatic acid of formula I described herein or a pharmaceutically acceptable salt thereof is added to form a mixture.

[0204] In some embodiments, this disclosure also provides a method for preparing a composition comprising a polypeptide (e.g., any of those described herein, such as semaglutide), said method comprising:

[0205] (a) The polypeptide is reacted with a compound of formula II:

[0206]

[0207] Or a pharmaceutically acceptable mixture of its salts, wherein:

[0208] n is an integer selected from 0, 1, 2, 3 or 4;

[0209] G 1 Each time it appears, it is independently OH, NH2, or NH(C). 1-4 Alkyl), N(C) 1-4 Alkyl)(C 1-4 Alkyl groups), halogens (e.g., Cl), C 1-4 Alkyl or C 1-4 Alkyl groups (e.g., OCH3); and

[0210] L 1 C2-C, whether substituted or unsubstituted 16 Alkylene, or substituted or unsubstituted C2-C 16 alkenyl groups; and

[0211] (b) The mixture formed in (a) by freeze drying.

[0212] In some embodiments, the mixing in (a) further comprises mixing the polypeptide, the compound of Formula II, or a pharmaceutically acceptable salt thereof with an aliphatic acid of Formula I: RCOOH (where R represents an aliphatic group) or a pharmaceutically acceptable salt thereof. In some embodiments, the aliphatic acid of Formula I is a straight-chain aliphatic acid having 2 to 20 carbon atoms, such as caprylic acid, capric acid, or lauric acid. In some embodiments, the weight ratio (i) / (ii) of the aliphatic acid of Formula I or a pharmaceutically acceptable salt thereof to (ii) the compound of Formula II or a pharmaceutically acceptable salt thereof is in the range of about 20:1 to about 1:20, such as 5:1 to 1:5, such as about 3:1, about 2:1, about 1:1, about 1:1.5, about 1:2, about 1:2.5, or about 1:3, or any range between the listed values, such as about 1:2. In some embodiments, the amount of the aliphatic acid of Formula I or a pharmaceutically acceptable salt thereof is about 50 mg to about 300 mg. In some embodiments, the amount of the compound of formula II or a pharmaceutically acceptable salt thereof is from about 200 mg to about 400 mg.

[0213] In some specific embodiments, in the applicable methods described above, (a) the amount of the therapeutic agent (e.g., any of those described herein) is from about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the listed values); (b) the aliphatic acid of Formula I or a pharmaceutically acceptable salt thereof is sodium decanoate, in an amount from about 50 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or any range between the listed values); and / or (c) the compound of Formula II or a pharmaceutically acceptable salt thereof is SNAC, in an amount from about 200 mg to about 400 mg (e.g., about 200 mg, about 300 mg, about 400 mg, or any range between the listed values).

[0214] In some specific embodiments, in the applicable methods described above, (a) the amount of the therapeutic agent (e.g., any of those described herein) is from about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the listed values); (b) the aliphatic acid of Formula I or a pharmaceutically acceptable salt thereof is sodium decanoate, in an amount from about 0.6 mmol to 2 mmol (e.g., 0.6 mmol, 0.8 mmol, 0.9 mmol, 1 mmol, 1.1 mmol, 1.3 mmol, 2 mmol, or any range between the listed values, such as 0.9-1.1 mmol); and / or (c) the compound of Formula II or a pharmaceutically acceptable salt thereof is SNAC, in an amount from 0.6 mmol to 2 mmol (e.g., 0.6 mmol, 0.8 mmol, 0.9 mmol, 1 mmol, 1.1 mmol, 1.3 mmol, 2 mmol, or any range between the listed values, such as 0.9-1.3 mmol).

[0215] In some specific embodiments, in the applicable methods described above, (a) the therapeutic agent (e.g., any of those described herein) is a polypeptide described herein, for example, in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the listed values); (b) the aliphatic acid of Formula I or a pharmaceutically acceptable salt thereof is sodium decanoate, in an amount of about 50 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or any range between the listed values); and / or (c) the compound of Formula II or a pharmaceutically acceptable salt thereof is SNAC, in an amount of about 200 mg to about 400 mg (e.g., about 200 mg, about 300 mg, about 400 mg, or any range between the listed values).

[0216] In some specific embodiments, in the applicable methods described above, (a) the therapeutic agent (e.g., any of those described herein) is a polypeptide described herein, for example, in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the listed values); (b) the aliphatic acid of Formula I or a pharmaceutically acceptable salt thereof is sodium decanoate, in an amount of about 0.6 mmol to 2 mmol (e.g., 0.6 mmol, 0.8 mmol, 0.9 mmol, 1 mmol, 1.1 mmol, 1.3 mmol, 2 mmol, or any range between the listed values, such as 0.9-1.1 mmol); and / or (c) the compound of Formula II or a pharmaceutically acceptable salt thereof is SNAC, in an amount of 0.6 mmol to 2 mmol (e.g., 0.6 mmol, 0.8 mmol, 0.9 mmol, 1 mmol, 1.1 mmol, 1.3 mmol, 2 mmol, or any range between the listed values, such as 0.9-1.3 mmol).

[0217] In some specific embodiments, in the applicable methods described above, (a) the therapeutic agent is a GLP-1 agonist (e.g., any of those described herein), for example, in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the listed values); (b) the aliphatic acid of Formula I or a pharmaceutically acceptable salt thereof is sodium decanoate, in an amount of about 50 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or any range between the listed values); and / or (c) the compound of Formula II or a pharmaceutically acceptable salt thereof is SNAC, in an amount of about 200 mg to about 400 mg (e.g., about 200 mg, about 300 mg, about 400 mg, or any range between the listed values).

[0218] In some specific embodiments, in the applicable methods described above, (a) the therapeutic agent is a GLP-1 agonist (e.g., any of those described herein), for example, in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the listed values); (b) the aliphatic acid of Formula I or a pharmaceutically acceptable salt thereof is sodium decanoate, in an amount of about 0.6 mmol to 2 mmol (e.g., 0.6 mmol, 0.8 mmol, 0.9 mmol, 1 mmol, 1.1 mmol, 1.3 mmol, 2 mmol, or any range between the listed values, such as 0.9-1.1 mmol); and / or (c) the compound of Formula II or a pharmaceutically acceptable salt thereof is SNAC, in an amount of 0.6 mmol to 2 mmol (e.g., 0.6 mmol, 0.8 mmol, 0.9 mmol, 1 mmol, 1.1 mmol, 1.3 mmol, 2 mmol, or any range between the listed values, such as 0.9-1.3 mmol).

[0219] In some specific embodiments, in the applicable methods described above, (a) the therapeutic agent is semaglutide, for example, in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the listed values), or in an amount of about 0.1 μmol to about 2.5 μmol, such as about 0.5 μmol to about 2.5 μmol; (b) the aliphatic acid of formula I or a pharmaceutically acceptable salt thereof is sodium decanoate, in an amount of about 50 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or any range between the listed values); and / or (c) the compound of formula II or a pharmaceutically acceptable salt thereof is SNAC, in an amount of about 200 mg to about 400 mg (e.g., about 200 mg, about 300 mg, about 400 mg, or any range between the listed values).

[0220] In some specific embodiments, in the applicable methods described above, (a) the therapeutic agent is semaglutide, for example, in an amount from about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the listed values), or in an amount from about 0.1 μmol to about 2.5 μmol, such as about 0.5 μmol to about 2.5 μmol; (b) the aliphatic acid of formula I or a pharmaceutically acceptable salt thereof is sodium decanoate, in an amount from about 0.6 mmol to 2 mmol (e.g., 0.6 mmol, 0.8 mmol, 0.9 mmol). 1 mmol, 1 mmol, 1.1 mmol, 1.3 mmol, 2 mmol, or any range between the listed values, such as 0.9-1.1 mmol); and / or the compound of formula II or its pharmaceutically acceptable salt is SNAC, in an amount of 0.6 mmol to 2 mmol (e.g., 0.6 mmol, 0.8 mmol, 0.9 mmol, 1 mmol, 1.1 mmol, 1.3 mmol, 2 mmol, or any range between the listed values, such as 0.9-1.3 mmol).

[0221] Compositions comprising therapeutic agents prepared by the methods described herein are also novel compositions of this disclosure.

[0222] In some embodiments, this disclosure further provides a method for preparing a pharmaceutical composition, the method comprising mixing a composition comprising a therapeutic agent prepared by the methods herein with a pharmaceutically acceptable excipient (e.g., any of those described herein).

[0223] Treatment

[0224] The pharmaceutical compositions described herein can be used to treat a disease or condition in a subject in need, said disease or condition being any of those known to be treatable with the therapeutic agents disclosed herein. Enhanced oral delivery of the therapeutic agents as shown in this disclosure can provide an alternative and advantageous treatment option for using these therapeutic agents.

[0225] For example, in some embodiments, this disclosure provides a method for treating type 2 diabetes or obesity in a subject in need, the method comprising orally administering to the subject a pharmaceutical composition described herein to deliver a therapeutically effective amount of a therapeutic agent (e.g., a GLP-1 agonist described herein).

[0226] Type 2 diabetes (T2D) is a serious global public health problem with a huge burden associated with complications resulting from microvascular and macrovascular disease. The pathogenesis of diabetes involves changes in multiple organs, typically accompanied by elevated blood glucose levels and loss or reduction of glycemic control. Glycemic control of T2D through different mechanisms of action has been shown to reduce the incidence of microvascular diseases such as diabetic nephropathy and diabetic retinopathy. (Chatterjee S, Khunti K, Davies MJ. Type 2diabetes. Lancet. 2017; 389(10085):2239–2251.)

[0227] Glucose-lowering peptides are an important class of drugs used to treat diabetes and obesity, including GLP-1, GIP, PYY, etc. GLP-1 receptor agonists have become important and essential drugs that are widely prescribed. GLP-1 is mainly expressed in intestinal L cells and brainstem. GLP-1 receptor (GLP-1R) is a G protein-coupled receptor that is expressed in a variety of tissues, including the pancreas, gastrointestinal tract, lung, cardiovascular system, kidney, tuberous ganglion neurons of the vagus nerve, hypothalamus in CNS and brainstem (Thorens B. Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci US A. 1992; 89(18):8641–8645.). GLP-1, expressed by intestinal L cells, can circulate and bind directly to typical receptors in the pancreas, or indirectly signal to the hepatic vagal branches in the portal vein, thereby enhancing glucose-induced insulin secretion and most postprandial insulin secretion (Pais R, Gribble FM, Reimann F. Stimulation of incretinsecreting cells. Ther Adv Endocrinol Metab. 2016; 7(1):24–42.). These signals are sent to the hypothalamus to reduce appetite, stimulate gluconeogenesis, reduce hepatic glucose output, amplify glucose-dependent insulin release, inhibit glucagon release, increase cardiac output and provide cardioprotection and reduce hypertension (Muller TD, Finan B, Bloom SR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019; 30:72–130.). In type 2 diabetes mellitus (T2D) with insufficient GLP-1 production or interrupted GLP-1 action, the function of the intestinal glucagon axis is impaired. Therefore, GLP-1 and GLP-1 analogues have been developed as drugs for the treatment of T2D (Aulinger BA, Vahl TP, Prigeon RL, D'Alessio DA, Elder DA. The increase effect in obese adolescents with and without type 2 diabetes: impairedor intact? Am J Physiol Endocrinol Metab. 2016; 310(9):E774–781).

[0228] Natural GLP-1 is rapidly degraded by dipeptidyl peptidase-IV (DPP-IV), with a half-life of less than 2 minutes. Therefore, many GLP-1 receptor agonist analogs (GLP-1RAs) have been developed in an attempt to prolong this half-life. These GLP-1 analogs include: seraphim exopeptide-4, liraglutide, dulaglutide, lixilamide, and semaglutide, which are approved by the U.S. Food and Drug Administration (FDA) for the regulation of T2D. Seraphim exopeptide-4 is a 53% homologous peptide extracted from the venom of the seraphim. It is resistant to DPP4 degradation. Structural modifications (such as replacing certain amino acids and / or adding certain fatty acids) are applied to prolong the half-life, thereby allowing for weekly administration of GLP-1 analogs instead of daily administration; said analogs include dulaglutide, abiglutide, liraglutide, lixilatide, semaglutide (Romera I, Cebria′n-Cuenca A, A′lvarez-Guisasola F, Gomez-Peralta F, Reviriego JA review of practical issues on the use of glucagon-like peptide-1 receptor agonists for the management of type 2 diabetess. Diabetes Ther. 2019; 10(1):5–19.).

[0229] GLP-1 RAs in type 2 diabetes mellitus (T2D) have been shown to significantly reduce A1C and have a beneficial effect on weight control with minimal risk of hypoglycemia (Trujillo JM. Glucagon-like peptide-1 receptor agonists. In: White JR (ed.) Guide to medications for the treatment of diabetes mellitus. Arlington County, VA: American Diabetes Association, 2020, pp. 190–210.). Furthermore, three GLP-1 RAs have been shown to have cardiovascular benefits: dulaglutide, liraglutide, and semaglutide (Matza LS, Boye KS, Sterward DK, et al. Crossover clinical trial assessing patient preference between thedulaglutide pen and the semaglutide pen (PREFER). Diabetes Met Obes 2020; 22:355–364). The use of GLP-1 RAs is associated with adverse reactions, primarily glucagon-related adverse events (GI AEs) and injection site-related AEs. The use of GLP-RAs may also be limited by the injection delivery route, leading to adherence issues. Head-to-head studies have shown that long-acting agents result in a greater reduction in A1C compared to short-acting agents, with semaglutide causing the largest reduction in A1C. Among long-acting agents, exenatide XR appears to have the least effect on A1C, although it still produces a greater reduction in A1C compared to short-acting agents. Regarding weight, the differences between agents are more ambiguous.Compared to short-acting agents, long-acting agents tend to produce more significant weight loss, with semaglutide again leading in maximum weight loss (Pratley RE, Aroda VR, Lingvay I, et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): arandomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol 2018; 6:275–286.)(Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): arandomised, double-blind, phase 3a trial. Lancet 2019; 394:39–50.). Short-acting agents and subcutaneous semaglutide appear to have the highest glycemic index (GI) adverse reactions, while exenatide XR appears to have the lowest GI adverse reactions. Injection site reactions may be more common with long-acting agents, especially weekly exenatide, which can cause transient small nodules at the injection site. Patient satisfaction data suggest that weekly injections result in higher patient satisfaction compared to twice-daily injections. Discontinuation rates due to adverse events vary by agent and study, but are generally low, with less than 10% of patients discontinuing GLP-1RA treatment due to adverse events in studies (Wilke T, Mueller S, Groth A, et al. Nonpersistence and non-adherence of patients with type 2 diabetes mellitus in therapy with GLP-1 receptor agonists: atrospective analysis. Diabetes Ther 2016; 7:105–124.). The risk of hypoglycemia with GLP-1RAs is low, and the risk rate is similar across all GLP-1RA treatment groups. Importantly, current guidelines prioritize the use of GLP-1RAs (dulaglutide, liraglutide, and semaglutide) with significant CV benefits in patients with atherosclerotic CV disease (ASCVD) and at risk of ASCVD, regardless of baseline A1C.

[0230] GLP-1 and GLP-1 analogs are peptides with high molecular weight and very low transmembrane permeability, readily degraded by intestinal enzymes. Therefore, oral delivery of GLP-1 analogs typically results in very low oral bioavailability. Consequently, all GLP-1 RA therapies are injectable, leading to difficulties in use and needle phobia, thus resulting in poor acceptance and adherence (Wilke T, Mueller S, Groth A, et al. Nonpersistence and non-adherence of patients with type 2 diabetes mellitus in therapy with GLP-1 receptor agonists: a spectral analysis. Diabetes Ther 2016; 7:105–124.).

[0231] The first orally delivered GLP-1 analogue is semaglutide, which is co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl]amino)octanoate (SNAC) (Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OKH, Jabbour S, Rosenstock J. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA. 2017; 318(15):1460–70.290). Although the mechanism by which SNAC promotes the oral absorption of semaglutide is unclear, it is preliminarily thought that one or more of the following MOAs may be involved: reducing enzymatic degradation, optimizing the physicochemical properties of the drug for membrane transport, and enhancing the transport fluidity of biological membranes. In the PIONEER trial, oral semaglutide co-formulated with SNAC has shown efficacy and safety in hospitalized patients, and the product It received FDA approval on September 20, 2019 (Bucheit J, Pamulapati LG, Carter N, Malloy K, Dixon DL, Sisson EM. Oral semaglutide: a review of the first oral glucagon-like peptide-1 receptor agonist. Diabetes Technol Ther. 2020; 1:10–8). However, although SNAC has been shown to enhance the absorption of semaglutide, its oral bioavailability (BA%) remains very low, approximately 0.5%–1% in humans (FDA Clinical Pharmacology Review; https: / / www.accessdata.fda.gov / drugsatfda_docs / nda / 2019 / 213051Orig1s000ClinPharmR.pdf ).

[0232] Low bioavailability leads to high variability in drug exposure throughout the systemic circulation. Furthermore, low bioavailability can significantly increase costs, potentially deterring payers, especially since higher doses would be required to control obesity. For example, semaglutide (Ozempic) is administered as an injectable drug at a weekly dose of 0.5 to 1 mg for diabetes control; while obesity control requires a weekly dose of 2.4 mg (FDA approved Wegovy in 2021). In the oral form of semaglutide (Rybelsus), the daily dose is up to 14 mg (FDA labels for Rybelsus and Wegovy). The oral dose required for obesity can be as high as 50 mg or more. The chemical or semi-biological synthesis of semaglutide as a modified peptide is expensive; currently, the cost of semaglutide as an active ingredient (API) is approximately $0.8 per milligram (mg). Therefore, the cost of goods and services (COG) for Rybelsus at 14 mg daily for diabetes indications is approximately USD 336 per month, which is close to the cost of commercial products (priced at $770 per month by Novo Nodisk) https: / / www.goodrx.com / rybelsus. For 50 mg daily, for potential indications such as obesity, the COG is approximately USD 1200 per month, exceeding the payer's acceptable pricing. Therefore, developing oral formulations of semaglutide with improved BA%, reduced variability, and controlled COG to allow for extended treatment of obesity, thereby realizing the medical value of GLP-1 therapeutics and benefiting healthcare for patients with type 2 diabetes and obesity, as well as alleviating the financial burden on the healthcare system, is crucial.

[0233] As discussed herein, the combination of an aliphatic acid of Formula I with a compound of Formula II or their respective salts (more specifically, sodium decanoate and SNAC) achieves significantly higher oral bioavailability of GLP-1 agonists (particularly semaglutide) compared to using SNAC alone as an enhancer. Therefore, the methods described herein can be advantageously used with the pharmaceutical compositions of this invention for the oral administration of GLP-1 agonists to treat a variety of diseases or conditions to which GLP-1 agonists can benefit, such as type 2 diabetes or obesity.

[0234] Combination therapy

[0235] The pharmaceutical compositions described herein can be used as monotherapy or in combination therapy. For example, in some embodiments, the pharmaceutical composition may be a fixed-dose combination of two or more active therapeutic agents. Intended non-limiting combination therapies include the following.

[0236] Combination of GLP-RA with SGLT2 inhibitors: Cardiovascular benefits. Sodium-glucose cotransporter (SGLT) proteins function independently of insulin in glucose regulation. Sodium-glucose cotransporter 1 (SGLT1) is a high-affinity, low-volume glucose transporter expressed in the small intestine and the proximal tubules of the kidney. SGLT1 protein in the proximal tubules of the kidney is responsible for less than 10% of filtered glucose reabsorption. Sodium-glucose cotransporter 2 (SGLT2) protein is expressed in the proximal convoluted tubules of the kidney and is responsible for approximately 90% of filtered glucose reabsorption (Scheen AJ. Pharmacodynamics, efficiency and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. Jan 2015; 75(1):33–59.). The FDA has approved several selective SGLT2 inhibitors, including canagliflozin, dapagliflozin, and empagliflozin. Of the three FDA-approved drugs, empagliflozin has the highest selectivity for SGLT2 compared to SGLT1 inhibitors, while canagliflozin has the lowest selectivity (Shubrook JH, Bokaie BB, Adkins SE. Empagliflozin in the treatment of type 2 diabetes: evidence to date. Drug design, development and therapy. 2015; 9:5793–803.). SGLT2 inhibitors have shown clinical benefits in weight control and antihypertensive effects. Compared to insulin and sulfonylureas, SGLT2 inhibitors carry a lower risk of hypoglycemia (Desouza CV, Gupta N, Patel A. Cardiometabolic Effects of a New Class of Antidiabetic Agents. Clin Ther. 2015 1 June; 37(6):1178–94.).

[0237] Recent studies have shown that GLP-RAs (such as dapagliflozin and empagliflozin) do not increase the risk of major adverse cardiovascular events. More importantly, studies have shown that SGLT2 inhibition has demonstrated significant cardiovascular benefits in patients with type 2 diabetes (T2D) at high risk of cardiovascular events, such as a 38% reduction in the relative risk of death from cardiovascular causes in the empagliflozin group compared to the placebo group (Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. The New England Journal of Medicine. 26 Nov 2015; 373(22):2117–28. This is a pivotal cardiovascular outcome trial for empagliflozin.)

[0238] GLP-1RAs and SGLT-2 inhibitors have shown evidence of improved clinical outcomes in diabetic patients with cardiovascular disease. New guidelines for T2D drug therapy recommend the use of GLP-1RAs for the prevention and treatment of obese patients at risk of atherosclerotic cardiovascular disease, while SGLT-2 inhibitors are recommended for patients at risk of chronic heart failure. However, given the different mechanisms of action of the two classes of drugs in treating T2D and diabetes, no systematic studies, particularly clinical trials, have been conducted to further evaluate the potential additive or synergistic effects of these two classes of drugs on cardiovascular benefits.

[0239] A key reason for the lack of robust clinical studies on combinations of GLP-RAs and SGLT2i can be explained on a commercial or financial basis: GLP-RAs are also injectable peptides administered once daily or weekly (except for oral semaglutide), while SGLT2i are all once-daily oral tablets. Developing an economically viable combination is not feasible because such an injectable and oral combination may not be well-received by patients in practice, and more importantly, such a direct combination of two commercially available drugs would not be possible with intellectual property rights.

[0240] Commercially, the only available oral GLP-RA is Rybelsus; however, its BA% is too low, making its combination economically challenging. Technically, oral semaglutide is absorbed in the stomach via the carrier SNAC, while SGLT is formulated as a coated tablet that targets absorption in the small intestine, where the absorption surface area is large and endothelial cell villi are abundant, allowing for much higher permeability than in the stomach.

[0241] In some embodiments, the present invention enables the formulation of GLP-RA and SGLTi into identical tablets, which, compared to formulations containing only SNAC, not only have improved oral bioavailability of GLP-RA but also allow for the absorption of SGLTi from the stomach. This fixed-dose combination of GLP-RA and SGLT in a single tablet offers significant medical value, is convenient to use, and is cost-effective.

[0242] definition

[0243] As used herein, the singular forms “a”, “an”, and “the” include plural indicators unless explicitly stated or clearly apparent from the context that this is not intended.

[0244] The phrases used herein, such as “A and / or B”, and the term “and / or” as used, are intended to include both A and B; A or B; A (alone); and B (alone). Similarly, the phrases used herein, such as “A, B and / or C”, and the term “and / or” are intended to cover each of the following embodiments: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0245] Titles and subtitles are used for convenience and / or formal compliance only, do not limit the subject matter, and are not associated with an interpretation of the description of the subject matter. In various embodiments, features described under one title or subtitle disclosed in this subject matter may be combined with features described under other titles or subtitles. Furthermore, all features under a single title or subtitle are not necessarily used together in all embodiments.

[0246] As used herein, the term "about" modifying quantities relating to this invention refers to variations in numerical quantities that may occur, for example, through routine testing and processing; through negligence or errors in such testing and processing; through differences in the manufacture, origin, or purity of the ingredients used in this invention, etc. As used herein, "about" also includes specific values, for example, about 10% includes 10%. Whether or not modified by the term "about," the claims include equivalent values ​​of the listed quantities. In one embodiment, the term "about" means within 20% of the reported value.

[0247] As used herein, the terms “polypeptide” and “peptide” refer to compounds consisting of at least five constituent amino acids linked by peptide bonds. The constituent amino acids can be derived from the amino acid set encoded by the genetic code, and they can be natural amino acids not encoded by the genetic code, as well as synthetic amino acids.

[0248] As used herein with respect to peptides, the term "analyte" means a modified peptide in which one or more amino acid residues of the peptide have been replaced by other amino acid residues and / or one or more amino acid residues have been removed from the peptide and / or one or more amino acid residues have been removed from the peptide and / or one or more amino acid residues have been added to the peptide.

[0249] As used herein, the term "derivative" refers to a chemically modified peptide or its analogue in which at least one substituent is not present in the unmodified peptide or its analogue, i.e., a covalently modified peptide. Typical modifications include amides, carbohydrates, alkyl groups, acyl groups, esters, etc. An example of a GLP-1(7-37) derivative is NE26-((4S)-4-(hexadecylamino)-carboxy-butyryl)[Arg34,Lys26]GLP-1-(7-37).

[0250] In some embodiments, the term "GLP-1 analogue" 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 comprising one or more amino acid substitutions, deletions, additions, and / or insertions.

[0251] In some embodiments, the GLP-1 agonist exhibits at least 60%, 65%, 70%, 80%, or 90% sequence identity with GLP-1(7-37) across the entire length of GLP-1(7-37). As an example of a method for determining sequence identity between two analogues, two peptides, [Aib8]GLP-1(7-37) and GLP-1(7-37), are aligned. The sequence identity of [Aib8]GLP-1(7-37) relative to GLP-1(7-37) is obtained by subtracting the number of different residues from the number of identical residues in the alignment and dividing by the total number of residues in GLP-1(7-37). Thus, in this example, the sequence identity is (31-1) / 31.

[0252] As used herein, the term "GLP-1 agonist" refers to a compound that fully or partially activates the human GLP-1 receptor. In some embodiments, the GLP-1 agonist is a GLP-1 analog that optionally contains a substituent. In some embodiments, the GLP-1 agonist is salicornic exopeptide-4, the sequence of which is HGEGTFITSDL SKQMEEEAVR-LFIEWLKNGGPSSGAPPPS (SEQ ID No:2). In some embodiments, the GLP-1 agonist contains a substituent covalently linked to the peptide. In some embodiments, the substituent comprises a fatty acid or a fatty acid 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 acid. Examples of GLP-1 RAs include, but are not limited to, semaglutide, liraglutide, dulaglutide, lixilaglutide, exenatide, etc.

[0253] In some embodiments, the GLP-1 agonist is selected from one or more of the following: WO93 / 19175, WO96 / 29342, WO98 / 08871, WO99 / 43707, WO99 / 43706, WO99 / 43341, WO99 / 43708, WO2005 / 027978, WO2005 / 058954, WO2005 / 05895. 8. One or more of the GLP-1 agonists disclosed in WO2006 / 005667, WO2006 / 037810, WO2006 / 037811, WO2006 / 097537, WO2006 / 097538, WO2008 / 023050, WO2009 / 030738, WO2009 / 030771 and WO2009 / 030774.

[0254] In some embodiments, the GLP-1 agonist is selected from the group consisting of: N-ε37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[deaminHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide; N-ε26{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[deaminHis7 ,Arg34]GLP-1-(7-37); N-ε37{2-[2-(2-{2-[2-((S)-3-carboxyl-3-{[1-(19-carboxynodecanoyl)piperidin-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide; N-ε37-[2-(2-(2-[2-(2-((R)-3-[1-(17-carboxyheptadecanoyl)piperidin-4-carbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy]acetyl][,deaminationHis7,Glu22 Arg26,Arg 34,Phe(m-CF3)28]GLP-1-(7-37)amide; N-ε26-[(S)-4-carboxy-4-({trans-4-[(19-carboxynodecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl][Aib8,Arg34]GLP-1-(7-37); N-ε26-{4-[(S)-4-carboxy-4-({trans-4-[(19-carboxynodecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]butyryl}[Aib8,Arg34]GLP-1-(7-37); N-ε2 6-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetyl][Ai b8,Arg34]GLP-1-(7-37)amide; N-ε26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino]butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Ai b8,Arg34]GLP-1-(7-37)amide;N-ε37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide; N-ε37-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino]butyrylamino]ethoxy}ethoxy)acetyl] Carbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deamin His7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide; N-ε37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxyl-4-({4-[(trans-19-carboxyl-nonadecanylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deamin His7,Arg26,Arg34,Lys 37]GLP-1-(7-37)amide; N-ε37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deaminated His7,Glu22,Arg26,Arg 34,Lys37]GLP-1-(7-37); N-ε26[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl[Aib8,Lys 26]GLP-1(7-37)amide; N-ε26[2-(2-[2-(2-(2-((S)-2-[trans-4-((9-carboxynodecanoylamino]methyl)cyclohexylcarbonylamino]-4-carboxybutyrylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Lys26]GLP-1(7-37)amide; N -ε37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deaminHis7,Arg26,Arg34,Lys37]GLP-1-(7-37);N-ε37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deaminHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37); N-ε26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)-hexadecylaminosulfonyl)butyrylamino]-butyrylamino] [Aib8,Arg34]GLP-1-(7-37); N-ε26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecyl-aminosulfonyl)butyrylamino]dodecylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37); N-ε26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H- ... -tetrazol-5-yl)hexadecyl-sulfamyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37); N-ε26-[2-(2-{2-[(S)-4-carboxyl-4-((S)-4-carboxyl-4-{4-[4-(16-(1H-tetrazol-5-yl)hexadecyl-sulfamyl)butyrylamino]butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34); N-ε26-[2-(2-{2-[(S)-4-carboxyl-4- ((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylaminosulfonyl)butyrylamino]-dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34); N-ε26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylaminosulfonyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);N-ε26-[2-(2-{2-[(S)-4-carboxyl-4-((S)-4-carboxyl-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecyl-aminosulfonyl)butyrylamino]dodecylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35); N-ε26-[2-(2-{2-[(S)-4-carboxyl-4-((S)-4-carboxyl-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecyl-aminosulfonyl]dodecylamino}butyrylamino]butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35); N-ε26-[2-(2-{2-[(S)-4-carboxyl-4-((S)-4-carboxyl-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecyl-aminosulfonyl]butyrylamino ... Acyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35); N-ε26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecylaminosulfonyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-36)amide; N-ε2 6-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecylaminosulfonyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);N-ε26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecylaminosulfonyl)butyryl] [Amino] dodecylamino}butyryl-amino)butyrylamino] ethoxy} ethoxy)acetyl][Aib8,Lys33,Arg34]GLP-1-(7-34); N-ε26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecylaminosulfonyl)butyrylamino] dodecylamino}butyrylamino)butyrylamino] ethoxy} ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-36)amide;N-ε26-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxyl-4-((S)-4-carboxyl-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecylaminosulfonyl)butyrylamino]dodecylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]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-ε37-[2-(2-{2-[(S)-4-carboxyl-4-((S)-4-carboxyl-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecylaminosulfonyl)butyrylamino]dodecylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide; N-ε37-[2-(2-{2-[(S)-4-carboxyl-4-((S)-4-carboxyl-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecylaminosulfonyl)butyrylamino]dodecylamino} Butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][deamin His7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide; N-ε37{2-[2-(2-{2-[2-((R)-3-carboxyl-3-{[1-(19-carboxyl-nonadecanyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[deamin His7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide; N-ε37{2-[2-(2-{2-[2-((S)-3-carboxyl-3-{[1- (19-Carboxynodecanoyl)piperidin-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide; N-ε37-[2-(2-[2-(2-(2-((R)-3-[1-(17-Carboxyheptadecanoyl)piperidin-4-carbonylamino]3-carboxy-propionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy]acetyl][deaminoHis7,Glu22,Arg26,Arg34,Phe(m-CF3)28]GLP-1-(7-37)amide;N-ε37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide; N-ε37-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy]}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deamin His7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide; N-ε37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deamin His7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37); N-ε37-[2 -(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deamin His7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37);N-ε37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylaminosulfonyl)butyrylamino]dodecanoyl] [Amino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide; N-ε37-[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-ε37-(3-((2-(2-(2-(2-(2-hexadecyloxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy)propionyl)[deaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide; N-ε37-{2-(2-(2-(2-[2-(2-(4-(hexadecylamino)-4-carboxybutyryl-amino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[deaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37)amide; N-ε37-{2-( ... -[2-(2-(4-(hexadecylamino)-4-carboxybutyryl-amino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[deaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide; N-ε37-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(octadecylamino)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetyl)[deaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide; N-ε37-[4-(16-(1 H-Tetrazol-5-yl)hexadecylaminosulfonyl)butyryl][deaminated His7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide; N-ε37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deaminated His7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37); N-ε37-(2-{2-[2-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4- (19-Carboxy-Ninetaacylamino)Butyrylamino]Butyrylamino}Butyrylamino)Ethoxy]Ethoxy}Acetyl)[DeaminatedHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-ε37-{2-[2-(2-{(S)-4-[(S)-4-(12-{4-[16-(2-tert-butyl-2H-tetrazole-5-yl)-hexadecanoylaminosulfonyl]Butyrylamino}Dodecanoylamino)-4-Carboxybutyrylamino]-4-Carboxybutyrylamino}Ethoxy)Ethoxy]Acetyl}[DeaminatedHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37);N-ε37-[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-α37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetyl][Aib8,Glu22,Arg26]GLP-1-(7-37]N-α37 ...{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetyl]GLP-1-(7-37]GLP-1-(7-37]GLP-1-(7-37]GLP-1-(7-37]GLP [Arg34,ε-Lys37]GLP-1-(7-37) peptide; N-ε37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-pentadecanylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][deaminated His7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37); N-ε36-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxy-pentadecanylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]- Ethoxy}-ethoxy)-acetyl][deaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys36]GLP-1-(7-37)-Glu-Lys peptide; N-ε37-[2-(2-{2-[2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynodecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37); N-ε37-[2-(2-{2-[2-( 2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl]-[Aib8,Glu22,Arg26,Arg34,Aib35,Lys37]GLP-1-(7-37); N-ε37-[(S)-4-carboxy-4-(2-{2-[2-(2-{2-[2-(17-carboxyheptadecanoylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetylamino)butyryl][Aib8,Glu22,Arg26,34,Lys37]GLP-1(7-37);N-ε37-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][ImPr7,Glu22,Arg26,34,Lys37],GLP-1-(7-37); N-ε26-{2-[2-(2-{2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}; N-ε37-{2-[2-(2-{2- [2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}-[Aib8,Arg34,Lys37]GLP-1(7-37)-OH;N-ε26(17-carboxyheptadecanoyl)-[Aib8,Arg34]GLP-1-(7-37)-peptide;N-ε26-(19-carboxynonadecanoyl)-[Aib8,Arg34]GLP-1-(7-37);N-ε26-(4-{[N-(2-carboxyethyl)-N-(15-carboxypentadecanoyl)amino] Methyl benzoyl [Arg34]GLP-1-(7-37); N-ε26-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37); N-ε26-[2-(2-[2-(2-[2-(2-[4-(19-carboxynodecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP- 1-(7-37); N-ε26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][3-(4-imidazolyl)propionyl7,Arg34]GLP-1-(7-37); N-ε26-[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-ε26-[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-ε26-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37); N-ε26-[2- (2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)-amide; N-ε26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34,Pro37]GLP-1-(7-37)-amide; Aib8,Lys 26(N-ε26-{2-(2-(2-(2-[2-(2-(4-(pentadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}),Arg34)GLP-1-(7-37)-OH;N-ε26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyl and)-N-(17-carboxyheptadecanoyl)amino]methyl}benzoyl)amino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37;N-α7- Formicyl, N-ε26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxy-butyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Arg34]GLP-1-(7-37); N-ε2626-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxy-butyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Glu22,Arg34]GLP-1-(7-37);N-ε26{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(15-(N-((S)-1,3-dicarboxypropyl)carbamoyl)pentadecanoylamino)-(S)-4-carboxybutyrylamino]ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1-(7-37;N-ε26-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxy-heptadecanoyl)amino]methyl}benzoyl)amino](4(S)-carboxybutyryl] [Aib8,Arg34]GLP-1(7-37); N-ε26-{(S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-(19-carboxy-nonadecanylamino)butyrylamino)butyrylamino)butyrylamino)butyrylamino}[Aib8,Arg34]GLP-1-(7-37); N-ε26-4-(17-carboxy-heptadecyl-amino)-4(S)-carboxy-butyryl-[Aib8,Arg34]GLP-1- (7-37); N-ε26-{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1-(7-37); N-ε26-{2-(2-(2-(2-[2-(2-(4-(17-carboxyheptadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[Aib8,22,27,30,3 5,Arg34,Pro37,Lys26]GLP-1(7-37)amide; N-ε26-[2-(2-[2-[4-(21-carboxycoteicoacylamino)-4(S)-carboxybutyrylamino]ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37); and N-ε26-[2-(2-[2-(2-[4-(21-carboxycoteicoacylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37). ;

[0255] The term solid dosage form can refer to tablets, capsules filled with solids, or capsules filled with solutions.

[0256] As used herein, the terms “treat,” “treating,” “treatment,” etc., refer to the elimination, reduction, or improvement of a disease or ailment and / or its associated symptoms. Although not excluded, treating a disease or ailment does not require the complete elimination of the disease, ailment, or its associated symptoms.

[0257] As used herein, the term “therapeutic effective amount” refers to an amount of a therapeutic agent (e.g., semaglutide) sufficient to improve one or more symptoms of a condition or disease (e.g., type 2 diabetes) or prevent the onset or progression of a condition or disease or cause its remission or cure.

[0258] As used herein, the term "subject" (or "patient") refers to an animal, preferably a mammal, and most preferably a human, that is the object of treatment, observation or experimentation.

[0259] Example

[0260] Example 1.

[0261] This example demonstrates that, compared to SNAC alone, the combination of semaglutide with SNAC and sodium decanoate produces unexpectedly higher drug absorption and more effective glycemic control. The effective enhancement of semaglutide plasma concentration is approximately 5-fold. Furthermore, the combination of semaglutide with SNAC and sodium decanoate also demonstrates superior pharmacological effects of semaglutide based on the oral glucose tolerance test (oGTT).

[0262] Preparation of formulation

[0263] An appropriate amount of the drug (e.g., semaglutide sodium) and excipients such as SNAC or SNAC and sodium decanoate (“C10”) and other optional excipients (if present) are mixed in water to form a solution. The solution is then freeze-dried to provide the formulation.

[0264] A representative procedure for preparing a formulation containing semaglutide, SNAC, and C10 is as follows: Weigh semaglutide sodium and add it to a glass vial. Add approximately 15 ml of water to dissolve 65 mg of semaglutide sodium. Then weigh SNAC and add it to the above semaglutide aqueous solution. Stir using a stir bar. Next, add sodium decanoate (and other excipients, if necessary) to the solution and stir to dissolve all excipients. Then freeze-dry the solution.

[0265] Formulation 1 prepared according to this procedure contains 10 mg semaglutide and 300 mg SNAC. Formulation 2 prepared according to this procedure contains 10 mg semaglutide, 300 mg SNAC, and 150 mg sodium decanoate.

[0266] The freeze-dried powder was then processed into tablet form, as described in the embodiments herein. Tablets were formed using a circular tablet mold with a diameter of 12 mm and a manual compressor with an arc on the mold surface.

[0267] Example 2A. Pharmacokinetic Studies and Oral Glucose Tolerance Test

[0268] This example describes a pharmacokinetic ("PK") study of an oral semaglutide formulation. An oGTT study will also be performed on day one of each PK study.

[0269] The dogs were housed in individual cages. Prior to the experiment, they were fed twice daily, at approximately 3 PM and 7 AM. The food consisted of kibble with water in a bowl. The day before the experiment, after feeding at 3 PM, the dogs were fasted overnight for approximately 18 hours. They were allowed to drink water overnight, but this water was removed one hour before administration. Before administration, the dogs were placed in a sling, and 0.8 ml of blood was collected from a leg vein of each dog using a sterile, disposable syringe.

[0270] Oral administration of tablets: Open the cage and allow the dog to climb onto the cage using its front legs. Hold their mouth open with your hand. The staff will keep the dog's mouth open and place the tablet down the dog's throat with their fingers. Then close the dog's mouth and hold it closed for about ten seconds. The dog will swallow the tablet naturally without needing to drink water.

[0271] Following drug administration, 0.8 ml blood samples were collected from the dog's foreleg vein into EDTA anticoagulant tubes at the following time points: 15 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, and 168 hours. After mixing by inversion several times, the blood samples were centrifuged at 3500 rpm for 10 minutes. The supernatant plasma sample was collected to clean the tubes and stored at -60°C before measurement. After sample collection at the 8-hour time point, the dog was released and immediately given food and water.

[0272] LC-MS in MRM mode was used to measure the plasma concentration of semaglutide. 150 μL of acetonitrile containing internal standards was added to 50 μL of plasma to precipitate the protein. After vortexing for 30 seconds, the sample was sonicated for two minutes. The sample was then centrifuged at 15400 G for 10 minutes. The supernatant was then collected for analysis. The mass spectrometer was an AB (Triple Quad 6400+), SHIMADZU. A Sepax Bio-C18 (4.6*150 mm, 5 μm) was used. The LC-MS parameters are summarized below:

[0273] Mobile phase: A: H₂O (0.1% formic acid and 5mM ammonium acetate); B: ACN (0.2% formic acid)

[0274] Flow rate: 1 ml / min

[0275] Column temperature: 40℃

[0276] CAD (psi): 12

[0277] Gas 1 (psi): 60

[0278] IS(V): 5500

[0279] CUR (psi): 40

[0280] Gas 2 (psi): 55

[0281] TEM (°C): 600

[0282] Mode: ESI / +

[0283] Semaglutide ion pair: 1029.2 m / z to 136.1 m / z, collision energy 100 V.

[0284] As described above, in each PK study, an oGTT study was also conducted on day 1 of the experiment. Blood glucose levels were measured starting 3.5 hours after semaglutide administration, at t = -30 minutes. Blood samples were collected at t = -15 minutes and 0 minutes for glucose measurement. After measuring background blood glucose levels, a glucose solution (0.3 mg / ml) was injected into the dogs' mouths using a disposable needle-free syringe at a dose of 1.5 g glucose / kg. The dogs' mouths were then closed to ensure they swallowed the solution. This procedure may need to be repeated five to six times, as only about 10 ml of solution can be injected into the dogs at a time. After glucose administration, the glucose concentration of blood samples was measured using a blood glucose meter at the following time points: t = 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, and 3 hours.

[0285] The blood glucose meter was purchased from Yuyue Medicals (https: / / www.yuwell.com / index_en.php / Group / read / id / 3). Whole-body blood glucose was measured by collecting approximately 0.05 ml of blood from a vein in the dog's foreleg. A drop of blood was then pushed onto the needle tip and allowed to remain for a few seconds. A glucose test strip, pre-inserted into the meter, was used to draw the blood drop from the needle tip. The meter then automatically began the measurement, and the result was obtained in approximately 8 seconds. The measured glucose level was immediately recorded, and the test strip was removed.

[0286] Experimental results:

[0287] The pharmacokinetics of semaglutide and the corresponding pharmacodynamics from oGTT measurements were summarized in experimental results in beagle dogs.

[0288] The terminal half-life of semaglutide was determined based on the terminal logarithmic linear phase. The area under concentration-time (AUC) of semaglutide was calculated using the linear trapezoidal rule. Inter-individual variability was assessed using the coefficient of variation (CV), calculated by dividing the standard deviation by the mean.

[0289] Semaglutide + SNAC In this experiment, dogs were administered oral formulations containing 10 mg of semaglutide and 300 mg of SNAC, as shown above. The concentration-time curve for semaglutide is shown in the figure. Figure 1 and Figure 2 The mean pharmacokinetic parameters (N = 6 dogs) are summarized in Table 1. The mean Tmax was at approximately 1 hour, indicating that SNAC, as a carrier, facilitated rapid absorption. In dogs, the terminal half-life was approximately 43 hours. The mean Cmax and AUC infinity were approximately 16 nM and 647 h·nM, respectively. (The corresponding inter-individual variability (IIV) was measured using the coefficient of variation.)

[0290] Semaglutide + SNAC + Sodium decanoate In this experiment, oral formulations containing 10 mg, 300 mg, and 150 mg of semaglutide, SNAC, and sodium decanoate, respectively, were administered to dogs, as shown above. The concentration-time curve for semaglutide is shown in the figure. Figure 1 and Figure 2 The mean pharmacokinetic parameters are summarized in Table 1. The mean Tmax is at approximately 1 hour, indicating that SNAC and sodium decanoate act as carriers to facilitate rapid absorption. In dogs, the terminal half-life is approximately 43 hours. The mean Cmax and AUC_infinity are approximately 90 nM and 3125 nM, respectively.

[0291] Table 1: Summary of pharmacokinetic results

[0292]

[0293] Compared to formulations containing only SNAC, formulations containing both SNAC and sodium decanoate showed significant improvements in AUC and Cmax, approximately 4.8-fold and 5.9-fold higher, respectively. Furthermore, the CVs for Cmax and AUC were significantly reduced, which is clinically important because smaller inter-individual variability implies safer and more effective treatment for patients (a smaller proportion of patients receive unnecessary high exposure) and (a smaller proportion of patients receive subtherapeutic exposure).

[0294] Oral glucose tolerance test (oGTT): The oral glucose dose used in the study was 1.5 g glucose / kg. Glucose concentration-time curves from formulations containing 10 mg semaglutide with SNAC 300 mg alone, and 10 mg semaglutide with SNAC 300 mg and sodium decanoate 150 mg are shown in the figures. Figure 3The oGTT reflects the pharmacodynamic regulation of glucose uptake and disposal by GLP-1 receptor agonists (Courtney Moore, et al., Am J Physiol Endocrinol Metab. 2013 Dec 15; 305(12):E1473–E1482). Compared with the control group (without semaglutide), 10 mg semaglutide with SNAC alone showed a slight improvement in glycemic control (particularly in the early 0.25 hours). In contrast, 10 mg semaglutide with SNAC plus sodium decanoate showed more significant glycemic control compared with 10 mg semaglutide with SNAC alone, suggesting that the measured semaglutide concentration was pharmacodynamically effective and consistent with the improved plasma pharmacokinetics of the formulation derived from SNAC plus sodium decanoate.

[0295] Example 3.

[0296] This example compares (1) the effect of using SNAC alone, C10 alone, or a combination of SNAC and C10 on the bioavailability of semaglutide; (2) the effect of using freeze-drying and simple blending on the bioavailability of semaglutide; and (3) a representative formulation of this application versus a commercial tablet (Rybelsus 7 mg).

[0297] Preparation of formulation

[0298] For samples using freeze-drying as a blending process, the preparation procedure can be as follows: An appropriate amount of the drug (e.g., semaglutide sodium) and excipients such as SNAC alone or sodium decanoate alone (“C10”) or SNAC and C10 together, along with other optional excipients (if present), are mixed in water to form a solution. The solution is then freeze-dried to provide the formulation.

[0299] A representative procedure for preparing a formulation containing semaglutide, SNAC, and C10 is as follows: Weigh semaglutide sodium and add it to a glass vial. Add approximately 15 ml of water to dissolve 65 mg of semaglutide sodium. Then weigh C10 and add it to the above semaglutide aqueous solution. Stir using a stir bar. Next, add SNAC (and other excipients, if desired) to the solution and stir to dissolve all excipients. Then freeze-dry the solution to obtain a dry mixture.

[0300] For samples using simple blending as the blending process, the preparation procedure can be as follows: Appropriate amounts of the drug (e.g., semaglutide sodium) and excipients such as SNAC and sodium decanoate (“C10”), along with other optional excipients (if present), are mixed in a mortar or by shaking in a plastic bag for at least 20 minutes. The mixture is then obtained by simple blending.

[0301] The powder, prepared by freeze-drying or simple blending, is then processed into tablet form, as described in the examples herein. Tablets are formed using a circular tablet mold with a diameter of 10 mm and a manual compressor with an arc on the mold surface.

[0302] Pharmacokinetic studies and LC / MS determination

[0303] This example describes a pharmacokinetic ("PK") study of an oral semaglutide formulation.

[0304] The dogs were housed in individual cages. Prior to the experiment, they were fed twice daily, at approximately 3 PM and 7 AM. The food consisted of kibble with water in a bowl. The day before the experiment, after feeding at 3 PM, the dogs were fasted overnight for approximately 18 hours. They were allowed to drink water overnight, but this water was removed one hour before administration. Before administration, the dogs were placed in a sling, and 0.8 ml of blood was collected from a leg vein of each dog using a sterile, disposable syringe.

[0305] Oral administration of tablets: Open the cage and allow the dog to climb onto the cage using its front legs. Hold their mouth open with your hand. The staff will keep the dog's mouth open and place the tablet down the dog's throat with their fingers. Then close the dog's mouth and hold it closed for about ten seconds. The dog will swallow the tablet naturally without needing to drink water.

[0306] Following drug administration, 0.6 ml blood samples were collected from the dog's foreleg vein into EDTA anticoagulant tubes at the following time points: before administration, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, and 48 hours. After mixing by inversion several times, the blood samples were centrifuged at 3500 rpm for 10 minutes. The supernatant plasma sample was collected to clean the tubes and stored at -60°C before measurement. After sample collection at the 6-hour time point, the dog was released and immediately given food and water.

[0307] The plasma concentration of semaglutide was measured using LC-MS in MRM mode. 150 μL of acetonitrile containing internal standards was added to 50 μL of plasma to precipitate the protein. After vortexing for 30 seconds, the sample was sonicated for two minutes. The sample was then centrifuged at 15400 G for 10 minutes. The supernatant was then collected for analysis. The mass spectrometer used was an AB (Triple Quad 6400+), SHIMADZU. A Sepax Bio-C18 (4.6*150 mm, 5 mm) was used. The LC-MS parameters are summarized below:

[0308] • Mobile phase: A: H₂O (0.1% formic acid and 5mM ammonium acetate); B: ACN (0.2% formic acid)

[0309] • Flow rate: 1 ml / min

[0310] Column temperature: 40℃

[0311] • Mode: ESI / +

[0312] Semaglutide ion pair: 1029.2 m / z to 136.1 m / z.

[0313] result:

[0314] like Figure 4 As shown, compared with the commercial tablet Rybelsus, the combination of SNAC (300 mg) / C10 (150 mg) significantly improved the bioavailability / PK characteristics of semaglutide. Detailed PK parameters are also shown in Table 2 below, with an AUC enhancement of approximately 10-fold and a Cmax enhancement of nearly 14-fold.

[0315] Table 2: 7 mg semaglutide formulated by freeze-drying in 300 mg SNAC / 150 mg C10 compared with commercial tablets Pharmacokinetic comparison of 7 mg semaglutide (Rybelsus)

[0316]

[0317]

[0318] like Figure 5 As shown, compared with formulations prepared by simple blending, preparation of the formulation using freeze-drying is beneficial for enhancing the bioavailability of semaglutide and producing better PK characteristics. Detailed PK parameters are also shown in Table 3 below, with an AUC increase of approximately 4-fold and a Cmax increase of approximately 4-fold.

[0319] Table 3: Comparison of 10 mg serotonin prepared by freeze-drying with simple blending in 300 mg SNAC / 150 mg C10 by freeze-drying Pharmacokinetics of Marutide

[0320]

[0321] like Figure 6 As shown, the combined use of SNAC and C10 achieved a synergistic effect and yielded better PK characteristics compared to using SNAC or C10 alone. Detailed PK parameters are also shown in Table 4 below. As shown in Table 4, the additive effect of 300 mg SNAC and 300 mg C10 is smaller in both AUC and Cmax than the additive effect observed in the combination of SNAC / C10 (even with a lower C10 concentration).

[0322] Table 4: Preparations of 300 mg SNAC, 300 mg C10, and 300 mg SNAC / 150 mg C10 by freeze-drying Pharmacokinetics of 10 mg semaglutide

[0323]

[0324] It should be understood that the claims are intended to be interpreted using the detailed description section rather than the summary and abstract sections. The summary and abstract sections illustrate one or more, but not all, exemplary embodiments of the invention as contemplated by the inventors, and therefore are not intended to limit the invention and the appended claims in any way.

[0325] This invention has been described above using functional building blocks that illustrate the implementation of specific functions and their relationships. For ease of description, the boundaries of these functional building blocks have been arbitrarily defined herein. Alternative boundaries can be defined as long as the specific functions and their relationships are properly executed.

[0326] Regarding aspects of the invention described as belonging to the genus, all individual species are considered separately as independent aspects of the invention. If an aspect of the invention is described as "comprising" a certain feature, the embodiment is also contemplated as "consisting of said feature" or "substantially consisting of said feature".

[0327] The foregoing description of the specific embodiments will fully reveal the general nature of the invention, enabling others to readily modify and / or alter such specific embodiments for various applications by applying knowledge in the art, without excessive experimentation and without departing from the general concept of the invention. Therefore, based on the teachings and guidance presented herein, such adaptations and modifications are intended within the meaning and scope of equivalents of the disclosed embodiments. It should be understood that the wording or terminology herein is intended to be illustrative rather than limiting, and those skilled in the art will interpret the terminology or terminology in accordance with the teachings and guidance.

[0328] The breadth and scope of this invention should not be limited to any of the exemplary embodiments described above, but should be defined only by the appended claims and their equivalents.

[0329] All the various aspects, implementation schemes, and options described in this article can be combined in any and all variations.

[0330] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated by reference. If any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in any document incorporated by reference, the meaning or definition given to that term in this document shall prevail.

Claims

1. A pharmaceutical composition comprising the following components: (a) Semaglutide; (b) Sodium decanoate; and (c) sodium salt, The weight ratio of component (b) to component (c) (b) / (c) is in the range of 1:1 to 1:

3. The pharmaceutical composition is formulated for oral administration.

2. The pharmaceutical composition of claim 1, wherein the weight ratio (b) / (c) of component (b) to component (c) is 1:1, 1:1.5, 1:2, 1:2.5 or 1:

3.

3. The pharmaceutical composition of claim 1, wherein the weight ratio of component (b) to component (c) is 1:

2.

4. The pharmaceutical composition of claim 1, wherein the amount of component (b) is from 50 mg to 300 mg per unit dose, and wherein the amount of component (c) is from 200 mg to 400 mg per unit dose.

5. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in the form of a solid oral dosage form.

6. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in the form of a capsule or a tablet.

7. A method for preparing a pharmaceutical composition according to any one of claims 1-6, the method comprising (1) mixing the component (a) with the component (c) and the component (b) to form a mixture; and (2) freeze-drying the mixture formed in (1) to form a freeze-dried mixture.

8. The method of claim 7, further comprising (3) mixing the freeze-dried mixture with a pharmaceutically acceptable excipient.

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