Pharmaceutical compositions for transmucosal delivery of therapeutic peptides and therapeutic proteins

Abstract

To provide effective, shelf-stable and safe biological preparations such as peptides and proteins for non-invasive delivery.SOLUTION: The present invention relates to a pharmaceutical composition for transmucosal administration, comprising a peptide drug or a protein drug in combination with an excipient with a pKa value of 12 or higher.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention is a The present invention relates to a pharmaceutical composition for transmucosal administration comprising a peptide or protein drug in combination with an excipient having a value of 12 or greater (e.g., arginine free base, EDTA tetrazolium salt, trisodium phosphate, tris(hydroxymethyl)aminomethane, lysine, or calcium hydroxide). [Background technology]

[0002] There is a strong need for effective, shelf-stable, yet safe compositions for the noninvasive delivery of biologics such as peptides and proteins. In addition to poor permeability across mucosal membranes (e.g., gastrointestinal or nasal mucosa), enzymatic degradation of peptides and proteins is one of the most important barriers to the successful delivery of such therapeutic agents. It has long been reported that peptidases such as trypsin can be reversibly inactivated at alkaline pH levels (Kunitz M et al., J Gen Physiol. 1934, 17(4):591-615), and this also applies to bacterial peptidases in the intestinal tract. However, it has not yet been reported that this concept of enzyme inhibition can be applied to pharmaceutical formulations for transmucosal delivery of therapeutic peptides and proteins. A successful formulation must not only generate a pH high enough to reduce the enzymatic activity of proteolytic enzymes in the vicinity of the site where the dosage form releases the therapeutic peptide or protein, but also do so in highly safe excipients suitable for pharmaceutical administration. Furthermore, it is known that peptides and proteins are prone to chemical degradation at alkaline pH (Brange J et al., Acta Pharm Nord. 1992, 4(3):149-58), and therefore formulations with sufficient storage stability also need to be developed. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] US2014 / 0056953A1 [Patent Document 2] WO2015 / 185640 [Patent Document 3] WO2013 / 164483 [Patent Document 4] WO2015 / 086728 [Patent Document 5] WO2015 / 155139 [Patent Document 6] WO2015 / 086733 [Patent Document 7] WO93 / 19175 [Patent Document 8] WO96 / 29342 [Patent Document 9] WO98 / 08871 [Patent Document 10] WO99 / 43707 [Patent Document 11] WO99 / 43706 [Patent Document 12] WO99 / 43341 [Patent Document 13] WO99 / 43708 [Patent Document 14] WO2005 / 027978 [Patent Document 15] WO2005 / 058954 [Patent Document 16] WO2005 / 058958 [Patent Document 17] WO2006 / 005667 [Patent Document 18] WO2006 / 037810 [Patent Document 19] WO2006 / 037811 [Patent Document 20] WO2006 / 097537 [Patent Document 21] WO2006 / 097538 [Patent Document 22] WO2008 / 023050 [Patent Document 23] WO2009 / 030738 [Patent Document 24] WO2009 / 030771 [Patent Document 25] WO2009 / 030774 [Patent Document 26] US5,661,130 [Patent Document 27] WO2012 / 112319 [Patent Document 28] US8,980,238B2 [Patent Document 29] US2012 / 0065124 [Patent Document 30] US5,866,536 [Patent Document 31] US5,773,647 [Patent Document 32] WO2011 / 133198 [Patent Document 33] US2015 / 174076 [Patent Document 34] U.S. Patent No. 3,219,656 [Patent Document 35] U.S. Patent No. 3,839,318 [Patent Document 36] Australian Patent No. 382,381 [Patent Document 37] US8,927,497 [Patent Document 38] WO00 / 59863 [Patent Document 39] WO2013 / 139694 [Patent Document 40] US2015 / 0174076 [Patent Document 41] US2003 / 0017195 [Non-patent literature]

[0004] [Non-Patent Document 1] Kunitz M et al. J Gen Physiol. 1934, 17(4):591~615 [Non-patent document 2] Brange J et al., Acta Pharm Nord. 1992, 4(3):149~58 [Non-patent document 3] Rote Liste Service GmbH, 2017, ISBN 978-3946057109) [Non-patent document 4] AVOXA - Mediengruppe Deutscher Apotheker GmbH, 2017, ISBN 978-3774199149 [Non-Patent Document 5] Aktories K et al. (eds.), Allgemeine und spezielle Pharmakologie und Toxikologie, Urban & Fischer Verlag / Elsevier GmbH, 12th edition, 2017, ISBN 978-3437425257 [Non-patent document 6] Ammon HPT et al. (eds.), Hunnius Pharmazeutisches Worterbuch, De Gruyter, 11th edition, 2014, ISBN 978-3110309904 [Non-Patent Document 7] Otto HH et al., Arzneimittel-Ein Handbuch fur Arzte und Apotheker, Wissenschaftliche Verlagsgesellschaft, 2017, ISBN 978-3804737266 [Non-patent document 8] www.drugbank.ca [Non-Patent Document 9] www.drugs.com [Non-Patent Document 10] www.merckmanuals.com [Non-Patent Document 11] www.ema.europa.eu [Non-Patent Document 12] www.fda.gov [Non-Patent Document 13] www.pmda.go.jp [Non-Patent Document 14] www.medicines.org.uk / emc / [Non-Patent Document 15] Maurice T et al., J Psychopharmacol. 2013, 27(11): 1044~57 [Non-Patent Document 16] Alcala-Barraza SR et al., J Drug Target. 2010, 18(3): 179~90 [Non-Patent Document 17] Fitch CA et al., Protein Sci. 2015, 24(5):752-61 [Non-Patent Document 18] Laffleur F et al., Future Med Chem. 2012, 4(17):2205~16 (doi: 10.4155 / fmc.12.165) [Non-Patent Document 19] El-Sayed Khafagy et al., Eur J Pharm Biopharm. 2013, 85(3 Pt A):736~43 [Non-Patent Document 20] Illum L et al. J Control Release. 2012, 162(1):194~200 [Non-Patent Document 21] Whitehead K et al., Pharm Res. 2008 June, 25(6):1412-9 [Non-Patent Document 22] Torres-Lugo M et al., Biotechnol Prog. 2002, 18(3):612~6 [Non-Patent Document 23] Rosevear et al., Biochemistry 19:4108-4115 (1980) [Non-Patent Document 24] Koeltzow and Urfer, J. Am. Oil Chem. Soc., 61:1651~1655 (1984) [Non-licensed Document 25] Li ら, J. Biol. Chem., 266:10723~10726 (1991) [Non-licensed Document 26] Gopalan, J. Biol. Chem. 267:9629~9638 (1992) [Non-licensed Document 27] Defaye, J. and Pederson, C., "Hydrogen Fluoride, Solvent and Reagent for Carbohydrate Conversion Technology" in Carbohydrates as Organic Raw Materials, 247~265 (edited by FW Lichtenthaler) VCH Publishers, New York (1991) [Non-licensed Document 28] Ferenci, T., J. Bacteriol, 144:7~11 (1980) [Non-licensed Document 29] Saito, S. and Tsuchiya, T. Chem. Pharm. Bull. 33:503~508 (1985) [Non-licensed Document 30] Binder, TP and Robyt, JF, Carbohydr. Res. 140:9~20 (1985) [Non-licensed Document 31] Chem. Abstr., 108:114719 (1988) [Non-licensed Document 32] Gruber and Greber pp. 95~116 [Non-licensed Document 33] Kunz, M., "Sucrose-based Hydrophilic Building Blocks as Intermediates for the Synthesis of Surfactants and Polymers" in Carbohydrates as Organic Raw Materials, 127~153 [Non-licensed Document 34] Ugwoke MI et al. Adv Drug Deliv Rev. 2005, 57(11):1640~65 [Non-Patent Document 35] Remington's Pharmaceutical Sciences, 20th edition [Non-Patent Document 36] Kamble MS et al., International Journal of Pharmaceutical and Chemical Sciences. 2013, 2(1):516~25 [Non-Patent Document 37] Wuts PG & Greene TW, Greene's protective groups in organic synthesis, John Wiley & Sons, 2006 Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention addresses these shortcomings in the art and provides pharmaceutical compositions that are advantageously stable in the presence of proteolytic enzymes, thus allowing for particularly efficient delivery of therapeutic peptides or proteins via the mucosal route, in particular via the oral mucosal route, as also demonstrated in the accompanying examples. [Means for solving the problem]

[0006] Thus, the present invention provides a peptide or protein drug and a pK a A pharmaceutical composition for transmucosal administration is provided, which comprises an excipient having a value of 12 or more.

[0007] The present invention also provides a method for the preparation of a mucosally administered peptide or protein drug and a pK a The present invention also provides a pharmaceutical composition comprising an excipient having a pK value of 12 or greater, wherein the excipient has a pK value of 12 or greater. aIt relates to pharmaceutical compositions containing excipients with a value of 12 or more.

[0008] The present invention further relates to the use of a peptide or protein drug and a pK a Regarding the use of excipients with values ​​of 12 or greater.

[0009] Furthermore, the present invention relates to a peptide or protein drug and a pK a The present invention provides a method for treating or preventing a disease / disorder, comprising transmucosally administering to a subject (e.g., a human) in need thereof a pharmaceutical composition comprising an excipient having a value of at least 12. It will be understood that the disease / disorder being treated or prevented is one that is amenable to treatment or prevention with said peptide or protein drug.

[0010] The present invention also provides a method for the preparation of peptide or protein drugs and pK a The present invention relates to a method for transmucosally delivering a peptide or protein drug, comprising transmucosally administering to a subject (e.g., a human) in need thereof a pharmaceutical composition comprising an excipient having a value of 12 or more.

[0011] Peptide or protein drugs administered in accordance with the present invention preferably have a molecular weight of about 300 kDa or less (e.g., about 260 kDa or less, or 220 kDa or less, or about 180 kDa or less, or about 150 kDa or less, or about 120 kDa or less, or about 100 kDa or less, or about 90 kDa or less, or about 80 kDa or less, or about 70 kDa or less, or about 60 kDa or less, or about 50 kDa or less, or about 40 kDa or less, or about 30 kDa or less, or about 20 kDa or less, or about 10 kDa or less, or about 5 kDa or less, or about 2 kDa or less, or about 1 kDa or less, or about 500 Da or less, etc.). More preferably, the peptide or protein drug has a maximum molecular weight of about 200 kDa or less, more preferably about 150 kDa or less, more preferably about 100 kDa or less, more preferably about 50 kDa or less, more preferably about 40 kDa or less, more preferably about 30 kDa or less, more preferably about 20 kDa or less, and more preferably about 10 kDa or less. More preferably, the peptide or protein drug has a minimum molecular weight of about 300 Da or more, more preferably about 500 Da or more, more preferably about 800 Da or more, and even more preferably about 1 kDa or more. Thus, particularly preferably, the peptide or protein drug has a molecular weight of about 300 Da to about 150 kDa, more preferably about 300 Da to about 50 kDa, more preferably about 500 Da to about 30 kDa, more preferably about 500 Da to about 20 kDa, and even more preferably about 800 Da to about 10 kDa. For oral administration, peptide or protein drugs have particularly preferred molecular weights of about 1 kDa to about 6 kDa, and for nasal administration, molecular weights of about 1 kDa to about 10 kDa are particularly preferred.

[0012] The molecular weight of a peptide or protein drug is given herein in Daltons (Da), an alternative name for the unified atomic mass unit (u). For example, a molecular weight of 500 Da is therefore equivalent to 500 g / mol. The term "kDa" (kilodalton) refers to 1000 Da.

[0013] The molecular weight of a peptide or protein drug can be determined using methods known in the art, such as mass spectrometry (e.g., electrospray ionization mass spectrometry (ESI-MS) or matrix-assisted laser desorption / ionization mass spectrometry (MALDI-MS)), gel electrophoresis (e.g., polyacrylamide gel electrophoresis using sodium dodecyl sulfate (SDS-PAGE)), hydrodynamic methods (e.g., gel filtration chromatography or gradient sedimentation), or static light scattering methods (e.g., multi-angle light scattering (MALS)). Preferably, the molecular weight of a peptide or protein drug is determined using mass spectrometry.

[0014] The peptide or protein drug may be any peptide or protein suitable for use as a pharmaceutical. For example, the peptide or protein drug may be a linear peptide or protein drug or a cyclic peptide or protein drug (a cyclic peptide or protein drug cyclized via at least one ester bond and / or at least one amide bond; e.g., a cyclotide; a cyclotide is a disulfide-rich peptide characterized by its head-to-tail cyclized peptide backbone and its interlocked disulfide bond arrangement). It may also be a modified or derivatized peptide or protein drug, such as a pegylated peptide or protein drug, a fatty acid acylated peptide or protein drug, or a fatty diacid acylated peptide or protein drug. Furthermore, the peptide or protein drug may lack histidine residues and / or lack cysteine ​​residues. In general, it is preferred that the peptide or protein drug be water-soluble, particularly at a neutral pH (i.e., about pH 7). More preferably, the peptide or protein drug has at least one serine protease cleavage site, i.e., the peptide or protein drug contains one or more amino acid residues that can be or are prone to be cleaved by a serine protease, and even more preferably, the peptide or protein drug contains one or more amino acid residues that can be or are prone to be cleaved by a serine protease. The term "peptide or protein drug" is used interchangeably herein with "therapeutic peptide or therapeutic protein" and "therapeutic peptide or therapeutic protein drug."

[0015] The peptide or protein drug is preferably insulin (preferably human insulin), an insulin analog (e.g., a long-acting basal insulin analog, or a protease-stabilized long-acting basal insulin analog; exemplary insulin analogs include, but are not limited to, insulin lispro, insulin peglispro, insulin derivative "A14E, B25H, B29K (N(eps)octadecandioyl-gGlu-OEG-OEG), desB30 human insulin" (e.g., US2014 / 0056953A1 see US2014 / 0056953A1), insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, insulin degludec, and the insulin analogues / derivatives described in US2014 / 0056953A1, which is incorporated herein by reference, in particular each of the insulin analogues / derivatives described in US2014 / 0056953A1, paragraphs

[0225] to

[0332] ), GLP-1, GLP-1 analogues (e.g., acylated GLP-1 analogues, or diacylated GLP-1 analogues), or GLP-1 agonists (also called "glucagon-like peptide-1 receptor agonists" or "GLP-1 receptor agonists"), such as semaglutide, liraglutide, exenatide, exendin-4, lixisenatide, taspoglutide, albiglutide, dulaglutide, langrenatide, beinaglutide, ephegrenatide, GLP-1(7-37), GLP-1(7-36)NH2, dual agonists of the GLP-1 receptor and another receptor (e.g., GLP- dual agonists of the GLP-1 receptor and the glucagon receptor, or dual agonists of the GLP-1 receptor and the gastric inhibitory polypeptide (GIP) receptor), oxyntomodulin, GLP-2, GLP-2 agonists or analogs (e.g., teduglutide or elsiglutide), glucose-dependent insulinotropic polypeptide (also called "gastric inhibitory polypeptide" or GIP), dual GLP-1 analogs, dual agonists of the glucagon-like peptide 1 receptor and the glucagon receptor (GLP-1R / GCGR dual agonists),GLP1 / glucagon receptor co-agonists (e.g., any one of the compounds mentioned in WO2015 / 185640), glucagon-like peptide 1 receptor and gastric inhibitory polypeptide receptor dual agonists (GLP-1R / GIPR dual agonists; e.g., any one of the compounds mentioned in WO2013 / 164483), GLP1 / GIP receptor co-agonists, exendin-4 peptide analogs (particularly exendin-4, which is a GLP-1R / GIPR dual agonist), peptide analogs; such as any one of the exendin-4 peptide analogs mentioned in WO2015 / 086728), exendin-4 derivatives (particularly exendin-4 derivatives that are GLP-1R / GCGR dual agonists; such as any one of the exendin-4 derivatives mentioned in WO2015 / 155139 or WO2015 / 086733), elamipretide, cyclotides (i.e., cyclotides having at least two disulfide bonds, and preferably Preferably, a peptide characterized by its head-to-tail cyclized peptide backbone containing a cyclotide having three disulfide bonds and an interlocked arrangement of its disulfide bonds), recombinant factor VIIa (rFVIIa), eptacog alfa, amylin, amylin analogs, pramlintide, somatostatin analogs (e.g., octreotide, lanreotide, or pasireotide), goserelin (e.g., goserelin acetate), buserelin (e.g., buserelin acetate), leptin, leptin analogs (e.g., metreleptin), peptide YY (PYY), PYY analogs, glatiramer (e.g., glatiramer acetate), leuprolide (e.g., leuprolide acetate), desmopressin (e.g., desmopressin acetate, particularly desmopressin monoacetate trihydrate), desmopressin analogs, vasopressin receptor 2 (V2 receptor) agonist peptides, osteocalcin, osteocalcin analogs or derivatives, human growth hormone (hGH), human growth hormone analogs, long-acting human growth hormone (e.g.,somapsitan or hGH-CTP (human growth hormone derivatized with the C-terminal peptide (CTP) of the beta chain of human chorionic gonadotropin (hCG)), fibroblast growth factor 21 (FGF21), antibodies (e.g., any of the exemplary antibodies described herein below), glycopeptide antibiotics (e.g., glycosylated cyclic or polycyclic non-ribosomal peptides, e.g., vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, or decaplanin), cyclotide, bortezomib, cosyntropin, chorionic Gonadotropins, menotropins, sermorelin, luteinizing hormone-releasing hormone (LHRH, also known as "gonadotropin-releasing hormone"), somatropin, calcitonin (e.g., salmon calcitonin), pentagastrin, oxytocin, nesiritide, anakinra, enfuvirtide, pegvisomant, dornase alfa, lepirudin, anidulafungin, eptifibatide, interferon alfacon-1, interferon alfa-2a, interferon alfa-2b, interferon beta-1a, interferon beta-1 b, interferon gamma-1b, pegylated interferon alfa-2a (i.e., pegylated interferon alfa-2a), pegylated interferon alfa-2b (i.e., pegylated interferon alfa-2b), pegylated interferon beta-1a (i.e., pegylated interferon beta-1a), fibrinolysin, vasopressin, aldesleukin, epoetin, epoetin alfa, darbepoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, epoetin c ta, methoxypolyethylene glycol-epoetin beta, sustained-release erythropoietin receptor activator (CERA, PEGylated EPO derivative), PEGylated EPO, albupoetin, EPO-dimer analog, EPO-Fc, carbamylated EPO (CEPO), synthetic erythropoietic protein (SEP), small molecule EPO analog (PBI-1402), filgrastim, PEG-filgrastim, interleukin-11, cyclosporine, glucagon, urokinase, viomycin, thyrotropin-releasing hormone (TRH),The active ingredient is selected from leucine-enkephalin, methionine-enkephalin, substance P (CAS No. 33507-63-0), adrenocorticotropic hormone (ACTH), parathyroid hormone (PTH), parathyroid hormone (PTH) fragments (e.g., teriparatide (also referred to as "PTH(1-34)"), PTH(1-31), or PTH(2-34)), parathyroid hormone-related protein (PTHrP), abaloparatide, linaclotide, carfilzomib, icatibant, ecallantide, cilengitide, prostaglandin F2α receptor modulators (e.g., PDC31), abciximab (C7E3-Fab), ranibizumab, alefacept, romiplostim, anakinra, abatacept, belatacept, and pharmaceutically acceptable salts thereof. If the subject / patient being treated is a human, and if the peptide or protein agent is an endogenous peptide or protein in humans (i.e., occurring naturally in humans; e.g., insulin or glucagon), it is further preferred to use a human isoform of the corresponding peptide or protein (which may, e.g., be recombinantly expressed or chemically synthesized).

[0016] More preferably, the peptide drug or protein drug is GLP-1, a GLP-1 analogue (e.g., an acylated GLP-1 analogue, or a diacylated GLP-1 analogue, or a long-acting albumin-bound fatty acid-derivatised GLP-1 analogue), a GLP-1 agonist, semaglutide, liraglutide, exenatide, exendin-4, lixisenatide, taspoglutide, albiglutide, dulaglutide, langrenatide, veinaglutide, efegrenatide, GLP-1(7-37), GLP-1(7-36)NH2, a GLP-1 receptor agonist, dual agonists of one receptor and another receptor (e.g., dual agonists of the GLP-1 receptor and the glucagon receptor, or dual agonists of the GLP-1 receptor and the GIP receptor), oxyntomodulin, GLP-2, GLP-2 agonists or analogs (e.g., teduglutide or elsiglutide), recombinant factor VIIa (rFVIIa), eptacog alfa, amylin, amylin analogs, pramlintide, somatostatin analogs (e.g., octreotide, lanreotide, or pasireotide), goserelin (e.g., goserelin acetate), bronchodilator, Serelin, peptide YY (PYY), PYY analogs, glatiramer (e.g., glatiramer acetate), leuprolide (e.g., leuprolide acetate), desmopressin (e.g., desmopressin acetate, particularly desmopressin monoacetate trihydrate), desmopressin analogs, vasopressin receptor 2 (V2 receptor) agonist peptides, teicoplanin, telavancin, bleomycin, ramoplanin, decaplanin, bortezomib, cosyntropin, sermorelin, luteinizing hormone-releasing hormone (LHRH), calcitonin (e.g., salmon calcitonin), The anti-inflammatory drug is selected from the group consisting of steroids, steroids, steroid hormones, steroid hormones, steroid hormones (SHRH), ...

[0017] More preferably, the peptide drug or protein drug is a GLP-1 agonist, semaglutide, liraglutide, exenatide, exendin-4, lixisenatide, taspoglutide, albiglutide, dulaglutide, langrenatide, veinaglutide, efegrenatide, GLP-1(7-37), GLP-1(7-36)NH2, a dual agonist of the GLP-1 receptor and another receptor (e.g., a dual agonist of the GLP-1 receptor and the glucagon receptor, or a dual agonist of the GLP-1 receptor and the GIP receptor), or oxyntomodulin. , GLP-2, a GLP-2 agonist or analog (e.g., teduglutide or elsiglutide), a somatostatin analog (e.g., octreotide, lanreotide, or pasireotide), desmopressin (e.g., desmopressin acetate, particularly desmopressin monoacetate trihydrate), a desmopressin analog, a vasopressin receptor 2 (V2 receptor) agonist peptide, a parathyroid hormone (PTH) fragment (e.g., teriparatide (PTH(1-34)), PTH(1-31), or PTH(2-34)), and pharmaceutically acceptable salts thereof. For example, the peptide or protein drug can be a GLP-1 agonist (such as liraglutide), a PTH fragment (such as teriparatide, i.e., PTH(1-34)), a somatostatin analog (such as octreotide), or desmopressin (e.g., desmopressin acetate, particularly desmopressin monoacetate trihydrate).

[0018] More preferably, the peptide or protein drug is selected from GLP-1 agonists, semaglutide, liraglutide, exenatide, exendin-4, lixisenatide, taspoglutide, albiglutide, dulaglutide, langrenatide, veinaglutide, efegrenatide, GLP-1(7-37), GLP-1(7-36)NH2, dual agonists of the GLP-1 receptor and the glucagon receptor, oxyntomodulin, and pharmaceutically acceptable salts thereof.

[0019] As noted above, the peptide or protein drug may be an insulin analogue. The insulin analogue is preferably B29K(N(ε)hexadecandioyl-γ-L-Glu)A14E B25H desB30 human insulin, B29K(N(ε)octadecandioyl-γ-L-Glu-OEG-OEG)desB30 human insulin, B29K(N(ε)octadecandioyl-γ-L-Glu)A14E B25H desB30 human insulin, B29K(N(ε)eicosanedioylγ-L-Glu)A14E B25H desB30 human insulin, B29K(N(ε)octadecandioyl-γ-L-Glu-OEG-OEG)A14E B25H desB30 human insulin, B29K(N(ε)eicosanedioylγ-L-Glu-OEG-OEG)A14E B25H desB30 human insulin, B29K(N(ε)eicosanedioylγ-L-Glu-OEG-OEG)A14E B16H B25H desB30 human insulin, B29K(N(ε)hexadecandioyl-γ-L-Glu)A14E B16H B25H desB30 human insulin, B29K(N(ε)eicosanedioylγ-L-Glu-OEG-OEG)A14E B16H B25H desB30 human insulin, and B29K(N(ε)octadecandioyl)A14E B25H desB30 human insulin is selected from.

[0020] These insulin analogues are described and characterized, for example, in US 2014 / 0056953 A1. Particularly preferred is B29K(N(ε)octadecandioyl-γ-L-Glu-OEG-OEG)A14E B25H desB30 human insulin.

[0021] Furthermore, as described above, the peptide or protein drug may be a GLP-1 analog. The GLP-1 analog may be, in particular, a variant of human glucagon-like peptide-1, preferably a variant of GLP-1(7-37). The amino acid sequence of GLP-1(7-37) is HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG. The aforementioned "variant" of human glucagon-like peptide-1 or "variant" of GLP-1(7-37) preferably refers to a compound that differs from human glucagon-like peptide-1 or GLP-1(7-37), respectively, by one or more amino acids, where such difference occurs through the addition, substitution, or deletion of at least one amino acid (e.g., 1 to 10 amino acids), or any combination of such additions, substitutions, and / or deletions. A GLP-1 analog may, for example, exhibit at least 60% (preferably at least 65%, more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90%) sequence identity to GLP-1(7-37) over the entire length of GLP-1(7-37). As an example of a method for determining sequence identity between a GLP-1 analog and GLP-1(7-37), the two peptides [Aib8]GLP-1(7-37) and GLP-1(7-37) are aligned. [Aib8]GLP-1(7-37) differs from GLP-1(7-37) in that alanine at position 8 has been replaced by α-methylalanine (i.e., Aib is 2-aminoisobutyric acid). The sequence identity of [Aib8]GLP-1(7-37) to GLP-1(7-37) is obtained by subtracting the number of aligned identical residues from the number of different residues and dividing the result by the total number of residues in GLP-1(7-37). Thus, in this example, the sequence identity is (31-1) / 31. The C-terminus of a GLP-1 analog (including any one of the specific GLP-1 analogs described herein) can also be in the form of an amide. Furthermore, the GLP-1 analog can be, for example, GLP-1(7-37)amide or GLP-1(7-36)amide.A GLP-1 analog can also be, for example, exendin-4, which has the amino acid sequence HGEGTFITSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS. A GLP-1 analog can also be a modified form of natural GLP-1 (particularly human GLP-1) that differs from the GLP-1 peptide in that it contains a substituent covalently attached to the peptide. The substituent can include a fatty acid (e.g., a C16, C18, or C20 fatty acid) or a fatty diacid (e.g., a C16, C18, or C20 fatty diacid). The substituent can also be a group having the following formula:

[0022] [ka]

[0023] where n is at least 13 (e.g., 13, 14, 15, 16, 17, 18, or 19, preferably 13 to 17, more preferably 13, 15, or 17). The substituent may also include one or more 8-amino-3,6-dioxaoctanoic acid (OEG) groups, for example, two OEG groups. In particular, the substituents may be selected from [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] and [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl]. GLP-1 analogs are also disclosed in WO93 / 19175, WO96 / 29342, WO98 / 08871, WO99 / 43707, WO99 / 43706, WO99 / 43341, WO99 / 43708, WO2005 / 027978, WO2005 / 058954, WO2005 / 058958, WO2006 / 005667, WO The GLP-1 agonist may be selected from one or more of the GLP-1 agonists disclosed in WO2006 / 037810, WO2006 / 037811, WO2006 / 097537, WO2006 / 097538, WO2008 / 023050, WO2009 / 030738, WO2009 / 030771, and WO2009 / 030774.

[0024] The peptide or protein drug may also be an antibody, preferably a monoclonal antibody, and in particular a single-chain antibody or a single-domain antibody (e.g., a "nanobody"). Such therapeutic antibodies are preferably administered via the nasal route. An example of a nanobody that may be used as a peptide or protein drug according to the present invention is caplacizumab. Caplacizumab is a single-domain antibody that may be used, for example, in the treatment or prevention of thrombotic thrombocytopenic purpura or thrombosis.

[0025] In particular, the peptide or protein drug may be 3F8, 8H9, abagovomab, abciximab, abituzumab, abrezekimab, abrilumab, actoxumab, adalimumab, adecatumumab, atidortoxumab, aducanumab, afacevicumab, afelimomab, afutuzumab, alacizumab pegol, alemtuzumab, alirocumab, altumomab pentetate, amatuximab, anatumomab mafenatox, andecaliximab, anetumab ravtansine, anifrolumab, , anrukinzumab, apolizumab, ixadotin, arcitumomab, asclinicalbacumab, acelizumab, atezolizumab, atinumab, atorolimu-mab, avelumab, azintuximab vedotin, bapineuzumab, basiliximab, bavituximab, BCD-100, bectumomab, begelomab, belantamab mafodotin, belimumab, bemarituzumab, benralizumab, berlimatoxumab, bersanlimab, bertilimumab, besileso Mab, bevacizumab, bezlotoxumab, biciromab, bimagrumab, bimekizumab, viltamimab, bivatuzumab mertansine, BIVV009, bleselumab, blinatumomab, brontuzumab, brosozumab, bococizumab, brazikumab, brentuximab vedotin, briakinumab, brodalumab, brolucizumab, brontixutuzumab, burosumab, cabilalizumab, camidalumab tesirin, camrelizumab, canakinumab, cantuzumab mertansine, cantuzumab mertansine, caplacizumab, capromab pendetide, carlu Mab, carotuximab, catumaxomab, cbr96-doxorubicin immunoconjugate, cedelizumab, cemiplimab, sergituzumab amnaleukin, certolizumab pegol, cetrelimab, cetuximab, civisatamab, sitatuzumab bogatox, cixutumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, codrituzumab, cofetuzumab peridotin, coltuximab ravtansine, conatumumab, concizumab, cosfrobiximab, crenezumab, crizanlizumab, cloteduumab, CR6261,Cusatuzumab, dacetuzumab, daclizumab, dalotuzumab, dapirolizumab pegol, daratumumab, dectrecumab, demcizumab, denintuzumab mafodotin, denosumab, depatuxizumab mafodotin, delrotuximab biotin, detumomab, dezamizumab, dinutuximab, zilidabumab, domagrozumab, dorlimomab alitox, drozitumab, DS-8201, durigotuzumab, dupilumab, durvalumab, dusigitumab, duvortuxizumab, ecromeximab, eculizumab, edovaco Mab, edrecolomab, efalizumab, efungumab, eldelumab, elezanumab, elgemtumab, elotuzumab, ersilimomab, emactuzumab, emapalumab, emibetuzumab, emicizumab, enapotamab vedotin, enavatuzumab, enfortumab vedotin, enlimomab pegol, enobilituzumab, enokizumab, enoticumab, ensituximab, epitumomab cituxetan, epratuzumab, eptinezumab, erenumab, erlizumab, ertumaxomab, etaracizumab, etigilimab, etorolizumab, evinacumab, evo Rokumab, exbivirumab, fanolesomab, faralimomab, faricimab, farletuzumab, fasinumab, FBTA05, felvizumab, fezakinumab, fibatuzumab, ficlatuzumab, figitumumab, filibumab, flavotumab, fretikumab, flotetuzumab, fontolizumab, foralumab, foravirumab, fremanezumab, fresolimumab, furunevetumab, furanumab, futuximab, galcanezumab, galiximab, gancotamab, ganitumab, gantenerumab, gatipotuzumab, gavilimomab, gezivumab, Gemtuzumab ozogamicin, gevokizumab, zirvetomab, dimcirumab, dilentuximab, glenbatumumab vedotin, golimumab, gomiliximab, goslanemab, guselkumab, ianalumab, ibalizumab, IBI308, ibritumomab tiuxetan, icrucumab, idarucizumab, ifavotuzumab, igovomab, iradatuzumab vedotin, IMAB362, imalumab, imaprelimab, imciromab, imgatuzumab, inlacumab, indatuximab vedotin,Indusatumab vedotin, inebilizumab, infliximab, intetumumab, inolimomab, inotuzumab ozogamicin, ipilimumab, iomab-b, iratumumab, isatuximab, iscalimab, istiratumab, itolizumab, ixekizumab, keliximab, labetuzumab, lacnotuzumab, ladilatuzumab vedotin, lampalizumab, lanadelumab, landgrozumab, laprituximab emtansine, ralcabiximab, lebrikizumab, remaresomab, lendalizumab, lembervimab ervimab, lenzilumab, lerdelimumab, leronlimab, lesofabumab, letolizumab, lexatumumab, ribivirumab, rifastuzumab vedotin, ligelizumab, loncastuximab tesirin, rosatuxizumab vedotin, rilotumab satetraxetan, lintuzumab, lirilumab, roderucizumab, loxivetumab, lorvotuzumab mertansine, lucatumumab, lurizumab pegol, rumiliximab, lumletuzumab, rupartumab amadotin, rutikizumab, MABp1, mapatum Mab, margetuximab, marstakimab, maslimomab, mavrilimumab, matuzumab, mepolizumab, metelimumab, milatuzumab, minletumomab, mirikizumab, mirvetuximab soravtansine, mitumomab, modotuximab, mogamulizumab, monalizumab, morolimumab, mosunetuzumab, motavizumab, moxetumomab pasudotox, muromonab-CD3, nacolomab butafenatox, namilumab, naptumomab estafenatox, naratuximab emtansine, narutumab, natalizumab, navicixizumab, navicixizumab, naxix Citamab, nebacumab, necitumumab, nemolizumab, NEOD001, nerelimomab, nesbacumab, netakimab, nimotuzumab, nirsevimab, nivolumab, nofetumomab merpentan, obilutoxaximab, obinutuzumab, occaratuzumab, ocrelizumab, odulimomab, ofatumumab, olaratumab, oleculumab, orendalizumab, olokizumab, omalizumab, OMS721, onartuzumab, ontuxizumab, onvatilimab, opicinumab, oportuzumab monatox, oregovomab, olticumab, otelixizumab,Otilimab, otlertuzumab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, palivizumab, pamrevlumab, panitumumab, pancomab, panobacumab, palsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, patritumab, PDR001, pembrolizumab, pemtumomab bu, perakizumab, pertuzumab, pexelizumab, pidilizumab, pinatuzumab vedotin, pintumomab, placuramab, prosalizumab, pogalizumab, polatuzumab vedotin, ponezumab, polgabiximab, prasinezumab, prezalizumab, priliximab, pritoxaximab, pritumumab, PRO 140, Kirizumab, Racotumomab, Ladolezumab, Rafivirumab, Ralpancizumab, Ramucirumab, Ranevetomab, Ranibizumab, Raxibacumab, Rabagalimab, Ratobulizumab, Refanezumab, Regavirumab, Lemtolumab, Reslizumab, Rilotumumab, Linucumab, Risankizumab, Rituximab, Ribazumab pegol, Lobatumumab, Rmab, Loredumab, Romilkimab, Romo Sozumab, lontalizumab, rosmantuzumab, rovalpituzumab tesirin, rovelizumab, rozanolixizumab, ruplizumab, SA237, sacituzumab govitecan, samalizumab, samrotamab vedotin, sapelizumab, sarilumab, satralizumab, satumomab pendetide, secukinumab, selicrelumab, seribantumab, cetoxaximab, ceturusumab, se Virumab, sibrotuzumab, SGN-CD19A, SHP647, sifalimumab, siltuximab, simtuzumab, siplizumab, sirtratumab vedotin, sirkumab, sofituzumab vedotin, solanezumab, solitomab, sonepcizumab, sontuzumab, spartalizumab, stamulumab, sulesomab, sputabumab, stimulimab, suvizumab, subratox Mab, tabalumab, tacatuzumab tetraxetan, tadocizumab, talaxuzumab, talizumab, tamtubetumab, tanezumab, taplitumomab paptox, talectumab, tabolimab, tefibazumab, terimomab alitox, telisotuzumab vedotin, tenatumomab, teneliximab, teplizumab, tepoditamab, teprotumumab, tesidolumab, tetulomab,Tezepelumab, TGN1412, tiburizumab, tildrakizumab, tigatuzumab, timigituzumab, timolumab, tiragotumab, tislelizumab, tisotumab vedotin, TNX-650, tocilizumab, tomzotuximab, toralizumab, tosatoxumab, tositumomab, tobetumab, tralokinumab, trastuzumab, trastuzumab emtansine, TRBS07, tregalizumab, tremelimumab, trevoglumab, tucotuzumab-celmoleukin, tuvilumab, ublituximab, urocuplumab, urelumab, urtoxazumab, ustekinumab, utomilumab, vadastuximab The antibody may be selected from butariline, vanalimab, bundeltuzumab vedotin, vanticutumab, vanucizumab, bapaliximab, valisacumab, varlilumab, batelizumab, vedolizumab, veltuzumab, bepalimomab, besencumab, visilizumab, bovalilizumab, volociximab, bonlerolizumab, bopratelimab, borsetuzumab mafodotin, votumumab, bunakizumab, xentuzumab, XMAB-5574, zalutumumab, zanolimumab, zatuximab, zenocutuzumab, diralimumab, zolbetuicinab, and zolimomab alitox.

[0026] The peptide or protein drug used in accordance with the present invention may also be a mixture of two or more different peptide or protein drugs, including any of the specific peptide or protein drugs described above. For example, the peptide or protein drug may be a mixture of human insulin and a GLP-1 agonist (e.g., semaglutide, liraglutide, exenatide, exendin-4, lixisenatide, taspoglutide, albiglutide, dulaglutide, langrenatide, veinaglutide, or efegrenatide).

[0027] The above exemplary peptide or protein drugs have been proposed in the literature as being suitable for treating or preventing a variety of different diseases / disorders, and some of these peptide or protein drugs have already received marketing approval for specific therapeutic indications. The present invention also specifically relates to pharmaceutical compositions provided herein for use in the treatment or prevention of diseases / disorders that can be treated or prevented with the respective peptide or protein drugs. Similarly, the present invention relates to a peptide or protein drug and a pK aThe present invention relates to a method for treating or preventing a disease / disorder, comprising transmucosally administering to a subject in need thereof a pharmaceutical composition comprising an excipient with a value of 12 or more, wherein the disease / disorder is a disease / disorder that can be treated or prevented with a respective peptide or protein drug. Preferred examples of diseases / disorders that can be treated or prevented with any particular peptide or protein drug according to the present invention can be found in the medical literature, in particular in ROTE LISTE online edition (the version as of the priority date or filing date of this application); ROTE LISTE 2017 (print edition, Rote Liste Service GmbH, 2017, ISBN 978-3946057109); GELBE LISTE online edition (the version as of the priority date or filing date of this application); GELBE LISTE 2017 (print edition, AVOXA - Mediengruppe Deutscher Apotheker GmbH, 2017, ISBN 978-3774199149); Aktories K et al. (eds.), Allgemeine und spezielle Pharmakologie und Toxikologie, Urban & Fischer Verlag / Elsevier GmbH, 12th edition, 2017, ISBN 978-3437425257; Ammon HPT et al. (eds.), Hunnius Pharmazeutisches Worterbuch, De Gruyter, 11th ed., 2014, ISBN 978-3110309904; Otto HH et al., Arzneimittel-Ein Handbuch fur Arzte und Apotheker, Wissenschaftliche Verlagsgesellschaft, 2017, ISBN 978-3804737266; ​​DrugBank (www.drugbank.ca, version as of the priority date or filing date of the present specification); Drugs.com (www.drugs.com, version as of the priority date or filing date of the present specification); Merck Manuals (www.merckmanuals.com, version as of the priority date or filing date of the present specification); European Medicines Agency (EMA) database (www.ema.europa.eu, in the version of the priority date or filing date of this specification; the United States Food and Drug Administration (US FDA) database (www.fda.gov, in the version of the priority date or filing date of this specification); the Pharmaceuticals and Medical Devices Agency database (www.pmda.go.jp, in the version of the priority date or filing date of this specification); or the electronic Medicines Compendium (eMC) database (www.medicines.org.uk / emc / , in the version of the priority date or filing date of this specification). Examples of diseases / disorders that can be treated or prevented with analogs or derivatives of any particular peptide or protein drug include the same diseases / disorders that can be treated or prevented with the corresponding (underivatized) peptide or protein drug. Furthermore, preferred examples of diseases / disorders that can be treated or prevented with any of the above insulin or insulin analogs include, in particular, diabetes (e.g., type 1 diabetes or type 2 diabetes). Preferred examples of diseases / disorders that can be treated or prevented with any of the above-mentioned GLP-1 peptides or GLP-1 receptor agonists include, in particular, diabetes, obesity, or nonalcoholic fatty liver disease (NASH). Preferred examples of diseases / disorders that can be treated or prevented with buserelin include, in particular, hormone-responsive cancers (e.g., prostate cancer or breast cancer) or estrogen-dependent conditions (e.g., endometriosis or uterine fibroids). Buserelin may also be used, for example, in assisted reproduction. Preferred examples of diseases / disorders that can be treated or prevented with human growth hormone (hGH) or any of the above-mentioned hGH analogs or hGH derivatives include, in particular, growth hormone deficiency. Preferred examples of diseases / disorders that can be treated or prevented with fibroblast growth factor 21 (FGF21) include, in particular, cardiovascular disease, obesity, or diabetes (especially type 2 diabetes). Preferred examples of diseases / disorders that can be treated or prevented with any of the above epoetin or any of their analogs or derivatives include, inter alia, anemia, Alzheimer's disease (see, e.g., Maurice T et al., J Psychopharmacol.2013, 27(11): 1044-57), Parkinson's disease (see, e.g., Alcala-Barraza SR et al., J Drug Target. 2010, 18(3): 179-90), or multiple sclerosis. Preferred examples of diseases / disorders that can be treated or prevented with filgrastim or any derivative thereof (e.g., PEG-filgrastim) include, in particular, neutropenia resulting from many causes, such as chemotherapy, radiation poisoning, HIV or AIDS, or unknown causes. Preferred examples of diseases / disorders that can be treated or prevented with the antibody adalimumab include, in particular, inflammatory or autoimmune diseases / disorders, and more preferably, selected from rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis (e.g., chronic psoriasis), hidradenitis suppurativa, juvenile idiopathic arthritis, and shotcretinitis chorioretinitis. Preferred examples of diseases / disorders that can be treated or prevented with the antibody ustekinumab include, in particular, inflammatory or autoimmune diseases / disorders (e.g., intestinal inflammatory or intestinal autoimmune diseases / disorders), and more preferably, selected from Crohn's disease, ulcerative colitis, psoriasis (e.g., chronic psoriasis), and psoriatic arthritis.

[0028] The pharmaceutical composition according to the present invention can also be used to treat or prevent intestinal diseases / disorders, particularly inflammatory, infectious, or cancerous intestinal diseases / disorders, such as inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, colonic bacterial infection, or colorectal cancer. It will be understood that the peptide or protein drug contained in the pharmaceutical composition in this case should be a peptide or protein drug (particularly an antibody, e.g., adalimumab) that is effective against the respective intestinal disease / disorder. The corresponding pharmaceutical composition is preferably administered orally and is preferably formulated to release the peptide or protein drug in the ileum and / or colon. In particular, the pharmaceutical composition can be provided as a dosage form (e.g., capsule, multiparticulate, or tablet) with an enteric coating.

[0029] pKa There is no particular limitation on excipients with a pK value of 12 or greater. a pK values, e.g., 12 to 14 a , or a pK of 12 to 13 a etc. pK of excipient a The pK value can be determined, for example, by potentiometric titration, calorimetry (e.g., isothermal titration calorimetry), UV / VIS spectrophotometry, conductometry, or nuclear magnetic resonance (NMR). a Values ​​can be determined by the complementary use of potentiometry and NMR spectroscopy (e.g., as described in Fitch CA et al., Protein Sci. 2015, 24(5):752-61). It will further be understood that the excipients are pharmaceutically acceptable.

[0030] Preferably, pK a Excipients with a value of 12 or greater include arginine free base (i.e., the free base form of 2-amino-5-guanidinopentanoic acid, CAS 7200-25-1), EDTA tetrazolium salts (i.e., tetrazolium ethylenediaminetetraacetate, including, among others, anhydrous tetrazolium EDTA or tetrazolium EDTA hydrate), trisodium phosphate (i.e., Na3PO4, especially anhydrous trisodium phosphate (CAS 7601-54-9), partially hydrated trisodium phosphate (Na3PO4·xH2O, where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11), or fully hydrated trisodium phosphate (Na3PO4·12H2O; CAS 10101-89-0), tris(hydroxymethyl)aminomethane ("Tris", i.e., trometamol), lysine (e.g., L-lysine or D-lysine), or calcium hydroxide (i.e., Ca(OH)2). Arginine free base, trisodium phosphate, lysine, and calcium hydroxide are listed by the U.S. FDA as inactive ingredients in approved formulations and are therefore particularly suitable for pharmaceutical use. More preferably, the pK a The excipient with a pK value of 12 or greater is arginine free base, EDTA tetrazolium salt, or trisodium phosphate.a An excipient with a value of 12 or greater is arginine free base or trisodium phosphate. More preferably, the excipient is arginine free base, especially L-arginine free base (CAS 74-79-3).

[0031] In another embodiment, arginine hydrochloride (particularly L-arginine HCl) is added to a solution having a pK a The present invention therefore relates to a pharmaceutical composition for transmucosal administration comprising a peptide or protein drug and arginine hydrochloride, and a method for determining the pK of such a composition. a The present invention also relates to corresponding methods and uses as described herein for pharmaceutical compositions of the present invention (including excipients with a value of 12 or more). In this context, the present invention particularly relates to pharmaceutical compositions for nasal administration comprising a peptide or protein drug and arginine hydrochloride, and corresponding methods and uses of such compositions.

[0032] The pharmaceutical compositions according to the present invention (especially peptide or protein drugs and pK a A pharmaceutical composition for transmucosal administration containing an excipient with a pK a In addition to an excipient with a value of 12 or greater, the composition may contain arginine hydrochloride (particularly, L-arginine HCl). For example, the pharmaceutical composition may contain arginine free base and arginine hydrochloride (particularly, L-arginine free base and L-arginine HCl).

[0033] The pharmaceutical compositions according to the present invention (especially peptide or protein drugs and pK a A pharmaceutical composition for transmucosal administration containing an excipient with a pK a In addition to excipients with a value of 12 or greater, tyrosine (L-tyrosine or D-tyrosine) may be included. For example, the pharmaceutical composition may contain tyrosine and L-arginine free base.

[0034] Particularly preferred is a pharmaceutical composition according to the present invention (especially a peptide drug or a protein drug and a pK a A pharmaceutical composition for transmucosal administration containing an excipient with a value of 12 or greater further contains a permeation enhancer (also called an "absorption enhancer" or "mucosal absorption enhancer"). The administration of a permeation enhancer improves or accelerates mucosal absorption / permeation of a peptide or protein drug, and is particularly advantageous when the peptide or protein drug is a macromolecule, for example, when the peptide or protein drug has a molecular weight of about 1 kDa or greater.

[0035] The permeation enhancer can be, for example, a zwitterionic permeation enhancer, a cationic permeation enhancer, an anionic permeation enhancer (e.g., an anionic permeation enhancer containing one or more sulfonic acid groups (-SO3H)), or a non-ionic permeation enhancer. a When the excipient with a value of 12 or greater is arginine free base (e.g., comprising L-arginine free base), it is preferred to use an anionic permeation enhancer (e.g., any one or more of the specific anionic permeation enhancers described herein).

[0036] Preferably, the penetration enhancer is C 8~20 Alkanoylcarnitine (preferably lauroylcarnitine, myristoylcarnitine, or palmitoylcarnitine, for example, lauroylcarnitine chloride, myristoylcarnitine chloride, or palmitoylcarnitine chloride), salicylic acid (preferably a salicylate, for example, sodium salicylate), salicylic acid derivatives (for example, 3-methoxysalicylic acid, 5-methoxysalicylic acid, homovanillic acid, etc.), C 8~20 Alkanoic acid (preferably C 8~20Alkanoates, more preferably caprate, caprylate, myristate, palmitate, or stearate, such as sodium caprate, sodium caprylate, sodium myristate, sodium palmitate, or sodium stearate, citric acid (preferably a citrate, such as sodium citrate), tartaric acid (preferably a tartrate), fatty acid acylated amino acids (e.g., any of the fatty acid acylated amino acids described in US 2014 / 0056953 A1, which is incorporated herein by reference; including, but not limited to, sodium lauroyl alanine, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid acid), N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteine, N-dodecanoyl-L-cysteine, sodium lauroyl glutamic acid, N-dodecanoyl-L-glutamic acid, sodium lauroyl glutaminate, N-dodecanoyl-L-glutamine, sodium lauroyl glycinate, N-dodecanoyl-L-glycine, sodium lauroyl histidinate, N-dodecanoyl-L-histidine, sodium lauroyl isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyl leucinate, N-dodecanoyl-L-leucine, sodium lauroyl methionate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalanine , N-dodecanoyl-L-phenylalanine, sodium lauroylprophosphate, N-dodecanoyl-L-proline, sodium lauroylserate, N-dodecanoyl-L-serine, sodium lauroylthreonate, N-dodecanoyl-L-threonine, sodium lauroyltryptophanate, N-dodecanoyl-L-tryptophan, sodium lauroyltyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroylvalinate, N-dodecanoyl-L-valine,Sodium lauroyl sarcosinate, N-dodecanoyl-L-sarcosine, sodium capric alanate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N-decanoyl-L-aspartic acid, sodium capric cysteine, N-decanoyl-L-cysteine, sodium capric glutamate, N-decanoyl-L-glutamic acid, sodium capric glutamate glutaminate), N-decanoyl-L-glutamine, capric sodium glycinate, N-decanoyl-L-glycine, capric sodium histidinate, N-decanoyl-L-histidine, capric sodium isoleucinate, N-decanoyl-L-isoleucine, capric sodium leucinate, N-decanoyl-L-leucine, capric sodium methionate, N-decanoyl-L-methionine, capric sodium phenylalanine, N-decanoyl-L-phenylalanine, capric sodium prophosphate, N-decanoyl-L -Proline, sodium caprylic serine, N-decanoyl-L-serine, sodium caprylic threonine, N-decanoyl-L-threonine, sodium caprylic tryptophanate, N-decanoyl-L-tryptophan, sodium caprylic tyrosinate, N-decanoyl-L-tyrosine, sodium caprylic valine, N-decanoyl-L-valine, sodium caprylic sarcosinate, N-decanoyl-L-sarcosine, sodium oleoyl sarcosinate, sodium N-decyl leucine, sodium stearoyl glutamate (e.g., Amisoft HS-11 P), sodium myristoyl glutamate (e.g., Amisoft MS-11), sodium lauroyl glutamate (e.g., Amisoft LS-11), sodium cocoyl glutamate (e.g., Amisoft CS-11), sodium cocoyl glycinate (e.g., Amilite GCS-11), sodium N-decyl leucine,Sodium cocoyl glycinate, sodium cocoyl glutamate, sodium lauroyl alanine, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteine, N-dodecanoyl-L-cysteine, sodium lauroyl glutamic acid, N-dodecanoyl-L-glutamic acid, sodium lauroyl glutamate glutaminate), N-dodecanoyl-L-glutamine, sodium lauroyl glycinate, N-dodecanoyl-L-glycine, sodium lauroyl histidinate, N-dodecanoyl-L-histidine, sodium lauroyl isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyl leucinate, N-dodecanoyl-L-leucine, sodium lauroyl methionate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalanine, N-dodecanoyl-L-phenylalanine, sodium lauroyl prophosphate, N-dodecanoyl-L-proline, sodium lauroyl serine, N-dodecanoyl-L-serine, sodium lauroyl threonate, N-dodecanoyl-L-threonine, Sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophan, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, N-dodecanoyl-L-sarcosine, sodium capric alanate, N-decanoyl-L-alanine, sodium capric aspartate, N-decanoyl-L-asparagine, sodium capric aspartate, N-decanoyl-L-aspartic acid, sodium capric cysteine, N-decanoyl-L-cysteine, sodium capric glutamate, N-decanoyl-L-glutamic acid, sodium capric glutamate, N-decanoyl-L-glutamine, sodium capric glycinate,N-Decanoyl-L-glycine, Sodium capric histidinate, N-Decanoyl-L-histidine, Sodium capric isoleucinate, N-Decanoyl-L-isoleucine, Sodium capric leucinate, N-Decanoyl-L-leucine, Leucine, Sodium capric methionate, N-Decanoyl-L-methionine, Sodium capric phenylalanine, N-Decanoyl-L-phenylalanine, Sodium capric prophosphate, N-Decanoyl-L-proline, Caprylic acid sodium capric sarcosinate, N-decanoyl-L-serine, sodium caprylic threonate, N-decanoyl-L-threonine, sodium caprylic tryptophanate, N-decanoyl-L-tryptophan, sodium caprylic tyrosinate, N-decanoyl-L-tyrosine, sodium caprylic valine, N-decanoyl-L-valine, sodium caprylic sarcosinate, sodium oleoyl sarcosinate, and pharmaceutically acceptable salts of any of the foregoing compounds, or, for example, C, 8~20 Alkanoyl sarcosinates (e.g., lauroyl sarcosinates such as sodium lauroyl sarcosinate), or C 8~20 containing one of the 20 standard proteinogenic α-amino acids acylated with alkanoic acids), alkyl saccharides (e.g., C 1~20 Alkyl saccharides, e.g., C such as Multitrope™ 1620-LQ-(MV) 8~10Alkyl polysaccharides, such as, for example, n-octyl-beta-D-glucopyranoside, n-dodecyl-beta-D-maltoside, n-tetradecyl-beta-D-maltoside, tridecyl-beta-D-maltoside, sucrose laurate, sucrose stearate, sucrose myristate, sucrose palmitate, sucrose cocoate, sucrose monododecanoate, sucrose monotridecanoate, sucrose monotetradecanoate, cocoglucoside, or any of the alkyl saccharides described in U.S. Pat. No. 5,661,130 or WO 2012 / 112319, which are incorporated herein by reference), cyclodextrins (e.g., α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl β-cyclodextrin, phosphorus, or sulfobutyl ether β-cyclodextrin), N-[8-(2-hydroxybenzoyl)amino]caprylic acid (preferably N-[8-(2-hydroxybenzoyl)amino]caprylate, more preferably sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, also known as "SNAC"), N-[8-(2-hydroxybenzoyl)amino]caprylate derivatives (preferably sodium N-[8-(2-hydroxybenzoyl)amino]caprylate derivatives), thiomers (also known as thiolated polymers, which can be synthesized by immobilizing sulfhydryl-bearing ligands onto the polymer backbone of well-established polymers, such as polyacrylic acid, carboxymethylcellulose, or chitosan; exemplary thiomers include those described in Laffleur F et al., Future Med Chem. 2012, 4(17):2205-16 (doi: 10.4155 / fmc.12), which is incorporated herein by reference.165)), mucoadhesive polymers having a vitamin B moiety (e.g., any of the mucoadhesive polymers described in U.S. Pat. No. 8,980,238 B2, which is incorporated herein by reference; this includes, inter alia, any of the polymeric compounds set forth in any one of claims 1 to 3 of U.S. Pat. No. 8,980,238 B2), calcium chelating compounds (e.g., ethylenediaminetetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), sodium citrate, or polyacrylic acid), Cremophor EL (also known as "Coriphor EL"; CAS No. 61791-12-6), chitosan, N,N,N-trimethylchitosan, benzalkonium chloride, bestatin, cetylpyridinium chloride, cetyltrimethylammonium bromide, C. 2~20 Alkanols (e.g., ethanol, decanol, lauryl alcohol, myristyl alcohol, or palmityl alcohol), C 8~20 Alkenols (e.g., oleyl alcohol), C 8~20 Alkene acids (e.g., oleic acid), dextran sulfate, diethylene glycol monoethyl ether (Transcutol), 1-dodecylazacyclo-heptan-2-one (Azone®), caprylcaproyl polyoxylglycerides (e.g., caprylcaproyl polyoxyl-8 glycerides; available, for example, as Labrasol® or ACCONON® MC8-2), ethyl caprylate, glyceryl monolaurate, lysophosphatidylcholine, menthol, C 8~20 Alkylamines, C 8~20Alkenylamines (e.g., oleylamine), phosphatidylcholine, poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, polysorbate (e.g., polysorbate 20 or polysorbate 80), cholic acid (preferably cholate salts, e.g., sodium cholate), deoxycholate (e.g., sodium deoxycholate), chenodeoxycholate (e.g., sodium chenodeoxycholate), sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate (SDS), sodium decyl sulfate, sodium octyl sulfate, sodium laureth sulfate, N-lauryl sarcosinate, decyltrimethylamine Mononium bromide, benzyl dimethyl dodecyl ammonium chloride, myristyl trimethyl ammonium chloride, dodecyl pyridinium chloride, decyl dimethyl ammonio propane sulfonate, myristyl dimethyl ammonio propane sulfonate, palmityl dimethyl ammonio propane sulfonate, chembetaine CAS, chembetaine oleyl, nonylphenoxy polyoxyethylene, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, sorbitan monooleate, Triton X-100, hexanoic acid, heptanoic acid, methyl laurate, isopropyl myristate, iso palmitate Propyl, methyl palmitate, diethyl sebacate, sodium oleate, urea, laurylamine, caprolactam, methylpyrrolidone, octylpyrrolidone, methylpiperazine, phenylpiperazine, Carbopol 934P, glycyrrhetinic acid, bromelain, pinene oxide, limonene, cineole, octyldodecanol, fenchone, menthone, trimethoxypropylenemethylbenzene, cell membrane penetrating peptides (e.g., KLAKLAK, polyarginine, or oligoarginine (especially octaarginine)), penetratin (especially L-penetratin), penetratin analogs (especially PenetraMax; e.g., El-Sayed Khafagy et al., Eur J Pharm Biopharm. 2013, 85(3 Pt A):736-43), HIV-1 Tat, transportan, or any of the cell membrane penetrating peptides mentioned in US2012 / 0065124), macrogol-15-hydroxystearate (e.g., Solutol HS 15), CriticalSorb (see, e.g., Illum L et al., J Control Release. 2012, 162(1):194-200), taurocholate (e.g., sodium taurocholate), taurodeoxycholate (e.g., sodium taurodeoxycholate), sulfoxide (e.g., (C 1~10 alkyl)-(C 1~10The permeation enhancer may be selected from the group consisting of alkyl (N-alkyl)-sulfoxides, such as decylmethyl sulfoxide or dimethyl sulfoxide, cyclopentadecalactone, 8-(N-2-hydroxy-5-chlorobenzoyl)-amino-caprylic acid (also known as "5-CNAC"), N-(10-[2-hydroxybenzoyl]amino)decanoic acid (also known as "SNAD"), dodecyl-2-N,N-dimethylaminopropionate (also known as "DDAIP"), D-α-tocopheryl polyethylene glycol-1000 succinate (also known as "TPGS"), arginine, and pharmaceutically acceptable salts of the foregoing compounds. Mixtures of two or more permeation enhancers, including any of the permeation enhancers listed above, may also be used. Additionally, any of the chemical permeation enhancers described in Whitehead K et al., Pharm Res. 2008 June, 25(6):1412-9 (particularly Table 1 of this reference) may be used. I), any one of the modified amino acids disclosed in US 5,866,536 (particularly any one of compounds I to CXXIII disclosed in US 5,866,536, which is incorporated herein by reference, or a pharmaceutically acceptable salt or solvate thereof, such as the disodium salt, ethanol solvate, or hydrate of any one of these compounds), any one of the modified amino acids disclosed in US 5,773,647 (particularly any one of compounds 1 to 193 disclosed in US 5,773,647, which is incorporated herein by reference, or a pharmaceutically acceptable salt or solvate thereof, such as the disodium salt, ethanol solvate, or hydrate of any one of these compounds), any of the nanoparticles described in WO 2011 / 133198, any of the polymer preparations described in US 2015 / 174076, and / or hydrogels (e.g., Torres-Lugo M et al., Biotechnol Prog. 2002, 18(3):612-6) can also be used as penetration enhancers.In addition, complex lipid dispersions (e.g., a combination of an insoluble surfactant or oil with a soluble surfactant, and optionally with water or a cosolvent) can also be used as permeation enhancers. Corresponding typical permeation enhancers include, inter alia, mixed micelles, reverse micelles, self-emulsifying systems (e.g., SEDDS, SMEDDS, or SNEDDS), lipid dispersions, coarse emulsions, or solid lipid nanoparticles (SLN). Preferably, the permeation enhancer is selected from sodium caprylate, sodium caprate, sodium laurate, sucrose laurate, sucrose stearate, sodium stearate, EDTA, polyacrylic acid, and N-[8-(2-hydroxybenzoyl)amino]caprylic acid salts or pharmaceutically acceptable salts thereof (e.g., sodium N-[8-(2-hydroxybenzoyl)amino]caprylate). A particularly preferred permeation enhancer is N-[8-(2-hydroxybenzoyl)amino]caprylate or a pharmaceutically acceptable salt thereof, especially sodium N-[8-(2-hydroxybenzoyl)amino]caprylate. Furthermore, when the pharmaceutical composition is for oral administration, it is particularly preferred that the permeation enhancer is sodium caprate.

[0037] More preferred permeation enhancers are alkyl polysaccharides, arginine, or CriticalSorb® (Solutol® HS15). In particular, the permeation enhancer can be an alkyl glycoside (or a combination of two or more alkyl glycosides), which can be selected from any of the alkyl glycosides described below.

[0038] Alkyl glycosides used as penetration enhancers according to the present invention can be synthesized by known procedures, i.e., chemically as described, for example, in Rosevear et al., Biochemistry 19:4108-4115 (1980), or Koeltzow and Urfer, J. Am. Oil Chem. Soc., 61:1651-1655 (1984), U.S. Pat. No. 3,219,656, or U.S. Pat. No. 3,839,318, or enzymatically as described, for example, in Li et al., J. Biol. Chem., 266:10723-10726 (1991), or Gopalan et al., J. Biol. Chem., 267:9629-9638 (1992).

[0039] Alkyl glycosides useful as permeation enhancers in the present invention include, but are not limited to, alkyl glycosides such as octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentadecyl-, hexadecyl-, heptadecyl-, and octadecyl-α- or β-D-maltoside, -glucoside, or -sucrose (which may be synthesized according to Koeltzow and Urfer, Anatrace Inc., Maumee, Ohio; Calbiochem, San Diego, Calif.; Fluka Chemie, Switzerland); alkyl thiomaltosides such as heptyl-, octyl-, dodecyl-, tridecyl-, and tetradecyl-β-D-thiomaltoside (which may be synthesized according to Defaye, J., and Pederson, C., "Hydrogen Fluoride, Solvent and Reagent for Carbohydrate Conversion" in J. Chem. Soc. 1999, 14, 131-135, 1999); "Technology" in Carbohydrates as Organic Raw Materials, pp. 247-265 (ed. F.W. Lichtenthaler), VCH Publishers, New York (1991); Ferenci, T., J. Bacteriol., 144:7-11 (1980); alkylthioglucosides, e.g., heptyl- or octyl 1-thio α- or β-D-glucopyranoside (Anatrace, Inc., Maumee, Ohio; Saito, S. and Tsuchiya, T. Chem. Pharm. Bull., 33:503-508 (1985)); alkylthiosucroses, which can be synthesized according to, e.g., Binder, TP and Robyt, JF, Carbohydr. Res., 140:9-20 (1985); alkyl maltotriosides, which can be synthesized according to Koeltzow and Urfer; long-chain aliphatic carbonic acid amides of sucrose β-amino-alkyl ethers, which can be synthesized according to Australian Patent No. 382,381 (1987); Chem. Abstr., 108:114719 (1988), and Gruber and Greber pp.95-116); derivatives of palatinose and isomaltamine linked to alkyl chains by amide bonds (which can be synthesized according to Kunz, M., "Sucrose-based Hydrophilic Building Blocks as Intermediates for the Synthesis of Surfactants and Polymers," in Carbohydrates as Organic Raw Materials, 127-153); derivatives of isomaltamine linked to alkyl chains by urea (which can be synthesized according to Kunz); long-chain aliphatic ureidocarbonates of sucrose β-amino-alkyl ethers (which can be synthesized according to Gruber and Greber, pp. 95-116); and long-chain aliphatic amide carbonates of sucrose β-amino-alkyl esters (which can be synthesized according to Australian Patent No. 382,381 (1987), Chem. Abstr., 108:114719 (1988), and Gruber and Greber, pp. 95-116).

[0040] The permeation enhancer may also be selected from any of the enhancers mentioned in US 8,927,497, including in particular any of the alkyl glycosides, any of the saccharide alkyl esters, and / or any of the mucosal delivery enhancers described in this document.

[0041] Additionally, the permeation enhancer may also During the ceremony, R 1 , R 2 , R 3 , and R 4 is hydrogen, -OH, -NR 6 R 7 , halogen (e.g., —F, —Cl, —Br, or —I), C 1~4 Alkyl or C 1~4 are each independently selected from alkoxy; R 5 substituted or unsubstituted C 2~16Alkylene, substituted or unsubstituted C 2~16 Alkenylene, substituted or unsubstituted C 1~12 Alkyl(arylene) [e.g., substituted or unsubstituted C 1~12 alkyl(phenylene)], or substituted or unsubstituted aryl (C 1~12 alkylene) [e.g., substituted or unsubstituted phenyl (C 1~12 alkylene)], and R 6 and R 7 are each independently hydrogen, oxygen, —OH, or C 1~4 is alkyl, Formula (I):

[0042] [ka]

[0043] or a pharmaceutically acceptable salt or solvate thereof, particularly a disodium salt, an alcohol solvate (e.g., a methanol solvate, an ethanol solvate, a propanol solvate, or a propylene glycol solvate, or any such solvate of the disodium salt; particularly an ethanol solvate or an ethanol solvate of the disodium salt), or a hydrate thereof (e.g., a monohydrate of the disodium salt). The above-mentioned "substituted" groups included in formula (I) can be halogen (e.g., -F, -Cl, -Br, or -I), -OH, C 1~4 Alkyl or C 1~4The compound of formula (I) is preferably substituted with one or more (e.g., one, two, or three) substituents independently selected from alkoxy. Such compounds and methods for preparing them are described, for example, in WO00 / 59863, which is incorporated herein by reference. Thus, the permeation enhancer may also be the "delivery substance" described in WO00 / 59863. Preferred examples of the compound of formula (I) include N-(5-chlorosalicyloyl)-8-aminocaprylic acid, N-(10-[2-hydroxybenzoyl]amino)decanoic acid, N-(8-[2-hydroxybenzoyl]amino)caprylic acid, the monosodium salt or disodium salt of any one of the aforementioned compounds, the ethanol solvate of the sodium salt (e.g., the monosodium salt or disodium salt) of any one of the aforementioned compounds, the monohydrate of the sodium salt (e.g., the monosodium salt or disodium salt) of any one of the aforementioned compounds, and any combination thereof. A particularly preferred compound of formula (I) is the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid or its monohydrate.

[0044] Furthermore, when the peptide or protein drug is GLP-1, a GLP-1 analog, a GLP-1 agonist, or a dual agonist of the GLP-1 receptor and another receptor (e.g., a dual agonist of the GLP-1 receptor and the glucagon receptor, or a dual agonist of the GLP-1 receptor and the gastric inhibitory polypeptide (GIP) receptor), it is particularly preferable to use a permeation enhancer selected from sucrose laurate, sodium caprate, sodium chenodeoxycholate, and SNAC. When the peptide or protein drug is desmopressin, a desmopressin analog, or a vasopressin receptor 2 agonist peptide, it is particularly preferable to use a permeation enhancer selected from SNAC, arginine, sucrose laurate, and sucrose stearate.

[0045] The pharmaceutical compositions of the present invention may be, for example, solid or liquid compositions. Solid compositions are preferably solid compositions (e.g., tablets or powders) that contain little to no water, for example, less than about 5% (w / w) water, preferably less than about 3% (w / w) water, more preferably less than about 1% (w / w) water, more preferably less than about 0.5% (w / w) water, even more preferably less than about 0.1% (w / w) water, and even more preferably no water. Liquid compositions may be, for example, liquid compositions that contain little to no water, such as less than about 5% (v / v) water, or less than about 3% (v / v) water, or less than about 1% (v / v) water, or less than about 0.5% (v / v) water, or less than about 0.1% (v / v) water, or no water. Alternatively, liquid compositions may be based on, for example, water, oil, organic solvents, or mixtures thereof. Thus, a liquid composition may contain, for example, at least about 60% (v / v) of water, oil, or organic solvent (or, for example, at least about 70, 80, or 90% (v / v)) relative to the total volume of the corresponding liquid composition. The organic solvent is not particularly limited and is preferably selected from glycerol, propylene glycol (particularly, propane-1,2-diol), and ethanol. The liquid composition may be, for example, a solution, suspension, or emulsion (such as an oil-in-water emulsion or a water-in-oil emulsion), and in particular, the pharmaceutical composition is an aqueous composition (i.e., an aqueous liquid composition) such as an aqueous solution. An aqueous composition (or aqueous solution) contains water, and preferably contains at least about 60% (v / v) of water, more preferably at least about 70% (v / v) of water, more preferably at least about 80% (v / v) of water, even more preferably at least about 90% (v / v) of water, and even more preferably at least about 95% (v / v) of water relative to the total volume of the corresponding (liquid) pharmaceutical composition. As explained above, the aqueous composition can be, for example, an aqueous solution, an aqueous suspension, or an oil-in-water emulsion.In this regard, preferably, the aqueous composition has an oil content of less than about 5% (v / v), more preferably less than about 3% (v / v), even more preferably less than about 2% (v / v), even more preferably less than about 1% (v / v), even more preferably less than about 0.5% (v / v), and even more preferably, the aqueous composition contains no oil. Thus, preferably, the aqueous composition is an aqueous solution. More preferably, the aqueous composition (or aqueous solution) is isotonic with human plasma. In particular, preferably, the aqueous composition (or aqueous solution) has an osmolality of about 280 mOsm / kg to about 500 mOsm / kg, more preferably about 285 mOsm / kg to about 350 mOsm / kg, even more preferably about 290 mOsm / kg to about 300 mOsm / kg, and even more preferably about 296 mOsm / kg.

[0046] The pharmaceutical composition according to the present invention may also be a composition of GLP-1 peptide, which is prepared as described in WO2013 / 139694, but with a pK a Preferably, the excipient further comprises a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a pK a The excipient having a pK value of 12 or greater is present in the first type of granules and the GLP-1 peptide is present in the second type of granules. Alternatively, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is present in the first type of granules and the pK a Excipients and GLP-1 peptides with values ​​of 12 or greater are present in the second type of granules.

[0047] Furthermore, the pharmaceutical composition may also be in the form of a mucoadhesive product or device, such as a mucoadhesive patch or liquid spray containing one or more mucoadhesive polymers, e.g. as described in US2015 / 0174076, US2003 / 0017195, or Ugwoke MI et al., Adv Drug Deliv Rev. 2005, 57(11):1640-65.

[0048] Furthermore, preferably, the peptide or protein drug has a pK a Therefore, preferably, the pharmaceutical composition according to the present invention is such that the peptide or protein drug is physically separated from the excipient having a pK a A pharmaceutical dosage form is a pharmaceutical dosage form in which the excipient has a pK value of 12 or more and is physically separated from the excipient. The corresponding pharmaceutical dosage form preferably comprises at least two distinct compartments that are physically separated from each other (e.g., via a physical separating layer). Thus, preferably, the pharmaceutical dosage form comprises (i) a peptide or protein drug and (ii) a pK a The peptide or protein drug is present only in the first compartment of the pharmaceutical dosage form and includes a physical separation layer between the excipient and the peptide or protein drug, and the excipient has a pK a Excipients with a value of 12 or greater are present only in the second compartment. The permeation enhancer, if present, may be present in either the first or second compartment of the pharmaceutical dosage form, or in both the first and second compartments, or in the third compartment. In one preferred embodiment, the present invention therefore relates to a peptide or protein drug present in the first compartment of the pharmaceutical dosage form, a pK a

[0010] In a further preferred embodiment, the present invention provides a pharmaceutical dosage form (e.g., a double capsule) comprising an excipient having a pK value of 12 or greater, and optionally a permeation enhancer (if present) in a first compartment and / or a second compartment of the pharmaceutical dosage form. In a further preferred embodiment, the present invention provides a pharmaceutical dosage form comprising a peptide or protein drug present in a first compartment of the pharmaceutical dosage form, a pK a The present invention provides a pharmaceutical dosage form (e.g., a multiparticulate dosage form) comprising an excipient with a pK value of 12 or greater, and optionally, a permeation enhancer (if present) in a third compartment of the pharmaceutical dosage form. Particularly preferably, the pharmaceutical dosage form is a capsule within a capsule (also called a double capsule) or a multiparticulate dosage form. In the case of a double capsule, preferably, the larger outer capsule (whose contents are released first) has a pK aIt contains excipients with a value of 12 or more, and optionally a permeation enhancer, and a smaller inner capsule (the contents of which are released in a delayed manner) contains the peptide or protein drug. The dosage form can also be a modified-release dosage form, for example, a dosage form (e.g., capsule, multiparticulate, or tablet) with an enteric coating, or a dosage form (e.g., capsule, multiparticulate, or tablet) coated with Eudragit L30D55 ​​or Eudragit FS30D, or an acid-resistant capsule such as HPMCP capsules (commercially known as AR Caps®).

[0049] More preferably, the pharmaceutical composition has a pK a and particles of an excipient having a pK a The pharmaceutical composition is preferably coated with a protective coating that separates the excipient having a solubility of 12 or greater from the peptide or protein drug. Particularly preferably, the pharmaceutical composition comprises particles of arginine free base, the particles being coated with a protective coating that separates the arginine free base from the peptide or protein drug. The protective coating may, for example, have a solubility in water of at least 1 gram per 100 ml of water at 20°C. Preferably, the protective coating is made of glucose, maltodextrin, or HPMC.

[0050] The peptide or protein drug may be first granulated with an inert pharmaceutical excipient, and then granulated with a pK of 12 or greater. a Preferably, the peptide or protein drug is first granulated with an inert pharmaceutical excipient, and the granules are then coated with additional pharmaceutical excipients to impart a pK affinity to the peptide or protein drug. a A physical separation between excipients with values ​​of 12 or greater is provided.

[0051] The pharmaceutical composition (or the pharmaceutical dosage form described above) may be aThe pharmaceutical composition may include excipients with values ​​of 12 or more (especially including any one or more of the exemplary excipients listed above), for example, in an amount of about 1 mg to about 1000 mg per dosage unit, preferably about 50 mg to about 500 mg per dosage unit. Furthermore, if the pharmaceutical composition includes a permeation enhancer, the permeation enhancer is preferably included in an amount of about 10 mg to about 1000 mg per dosage unit, more preferably about 50 mg to about 500 mg per dosage unit.

[0052] More preferably, the pharmaceutical composition (or pharmaceutical dosage form) is configured such that when the pharmaceutical composition is added to 10 ml of 0.1 M aqueous sodium bicarbonate (NaHCO3) solution, the pH of the solution is greater than pH 9, more preferably greater than pH 10, more preferably greater than pH 11, or even more preferably greater than pH 12. Such configurations of pharmaceutical compositions resulting in the aforementioned pHs are advantageous because they allow for very effective inactivation of proteases, as also demonstrated in Examples 1 and 2. In particular, pK a The amount of excipient (and optionally the amount of peptide or protein drug, and / or the amount of any further components included in the pharmaceutical composition) having a value of 12 or greater may be selected so that when the pharmaceutical composition is added to 10 ml of 0.1 M aqueous sodium bicarbonate solution, the pH of the solution is greater than pH 9, more preferably greater than pH 10, more preferably greater than pH 11, or even more preferably greater than pH 12.

[0053] Pharmaceutically acceptable salts referred to herein can be formed, for example, by protonation of an atom having a lone pair of electrons susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as salts of carboxylic acid groups with physiologically acceptable cations as are well known in the art. Typical base addition salts include, for example, alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkylamine salts such as N,N-dibenzylethylenediamine salts, benzathine salts, benethamine salts, and the like; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts, or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts, or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts.Typical acid addition salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate (e.g., phosphate, hydrogen phosphate, or dihydrogen phosphate), carbonate, bicarbonate, or perchlorate; acetate, propionate, butyrate, valerate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, glycolate, glycerol, hydroxybenzoate ... Organic acid salts such as cholate, nicotinate, benzoate, salicylate, ascorbate, or pamoate (embonate); sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate; and acidic amino acid salts such as aspartate or glutamate. The term "pharmaceutically acceptable salt" should also be understood to encompass pharmaceutically acceptable salts of the corresponding compound in any solvated form.

[0054] Peptide or protein drugs, pK a The excipients with a value of 12 or greater, and optionally the permeation enhancer, can be formulated as a medicament, for example, in the form of a pharmaceutical composition. The medicament or pharmaceutical composition can optionally contain one or more additional pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants, amino acids, reducing agents, bioadhesives, and / or solubility enhancers. In particular, it can contain one or more additives selected from vitamin E, histidine, microcrystalline cellulose (MCC), mannitol, starch, sorbitol, and / or lactose. The pharmaceutical composition can be formulated by techniques known to those skilled in the art, such as those published in Remington's Pharmaceutical Sciences, 20th Edition.

[0055] As noted above, the pharmaceutical compositions may include one or more solubility enhancers, such as poly(ethylene glycol), including poly(ethylene glycol) having a molecular weight ranging from about 200 to about 5000 Da, ethylene glycol, propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 20, polysorbate 80, macrogol-15-hydroxystearate, phospholipids, lecithin, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl Examples of suitable cyclodextrins include hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioethers, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof. Preferably, the one or more solubility enhancers include at least one nonionic surfactant, more preferably at least one nonionic surfactant having a hydrophilic-lipophilic balance (HLB) of greater than 10 (i.e., HLB>10). The pharmaceutical composition may also include at least one nonionic surfactant having an HLB>10 and at least one nonionic surfactant having an HLB<10.

[0056] Therefore, preferably, the pharmaceutical composition comprises at least one non-ionic surfactant. In particular, the pharmaceutical composition may comprise a substance (preferably a detergent) that can adsorb at a surface and / or interface (e.g., liquid to air, liquid to liquid, liquid to container, or liquid to any solid) and that does not have a charged group in its hydrophilic group (sometimes called "head"). The non-ionic surfactant may be a detergent, and may also comprise, in particular, ethoxylated castor oil, polyglycolized glycerides, acetylated monoglycerides, sorbitan fatty acid esters, polysorbates (e.g., polysorbate-20, polysorbate-40, polysorbate-60, polysorbate-80, super-refined polysorbate 20, super-refined polysorbate 40, super-refined polysorbate 60, or super-refined polysorbate 80, etc.; any of the corresponding Tween products available, for example, from the supplier Croda. Examples of suitable ethylene glycol monoacrylates include ethylene glycol monoacrylates (e.g., ethylene glycol monoacrylates), poloxamers (e.g., poloxamer 188 or poloxamer 407), polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives (e.g., alkylated and / or alkoxylated polyoxyethylene derivatives; in particular, Tween products such as Tween-20 or Tween-80), block copolymers, e.g., polyethylene oxide / polypropylene oxide block copolymers (e.g., Pluronics / Tetronics, Triton X-100, and / or Synperonic PE / L44PEL), ethoxylated sorbitan alkanoates (e.g., Tween-20, Tween-40, Tween-80, or Brij-35, etc.), diglycerol laurate, diglycerol caprate, diglycerol caprylate, diglycerol monocaprate, polyglycerol laurate, polyglycerol caprate, polyglycerol caprylate, or any combination thereof. Further examples of nonionic surfactants that may be used as solubility enhancers in accordance with the present invention include, but are not limited to, (1.) reaction products of natural or hydrogenated castor oil with ethylene oxide (wherein the natural or hydrogenated castor oil can be reacted with ethylene oxide in a molar ratio of about 1:35 to about 1:60, with the PEG component optionally being removed from the product; various such surfactants are commercially available, e.g., the CREMOPHOR series from BASF Corp. (Mt. Olive, NJ), e.g., CREMOPHOR RH 40, which is a PEG 40 hydrogenated castor oil with an HLB of about 14-16); (2.) polyoxyethylene fatty acid esters, particularly including polyoxyethylene stearates (such as the MYRJ series from Uniqema, e.g., MYRJ 53, which has an mp of about 47°C; a specific compound in the MYRJ series is MYRJ 53, which has an mp of about 47°C, and PEG-40-stearate, available as MYRJ 52); (3.) the TWEEN series from Uniqema, particularly (e.g., TWEEN 60, Tween 20, Tween 80, or Tween 40), (4.) polyoxyethylene-polyoxypropylene copolymers and / or block copolymers and / or poloxamers (e.g., Pluronic P127 or Pluronic F68 from BASF, or Synperonic PE / L from Croda), (5.) polyoxyethylene alkyl ethers (e.g., polyoxyethylene glycol ethers of C12 to C18 alcohols, such as polyoxyl 10- or 20-cetyl ether, polyoxyl 23-lauryl ether, polyoxyl 20-oleyl ether, or polyoxyl 10-, 20-, or 100-stearyl ether, commercially available from Uniqema as the BRI series; particularly useful products of the BRIJ series include BRIJ 58, BRIJ 76, BRIJ 78, BRIJ 35 (or polyoxyl 23-lauryl ether), or BRIJ 98 (or polyoxyl 20 oleyl ether; these products may have an mp between about 32°C and about 43°C), (6.) water-soluble tocopheryl PEG succinate (e.g., Eastman Chemical Co.(7) PEG sterol ethers (e.g., SOLULAN C24 (Choleth-24 and Cetheth-24) from Chemron (Paso Robles, Calif.); similar products that can also be used include NIKKOL BPS-30 (polyethoxylated 30 phytosterols) and NIKKOL BPS-30 from Nikko Chemicals Co., Ltd. (BPSH-25 (polyethoxylated 25 phytostanol) and is commercially available), (8.) polyglycerol fatty acid esters, for example, having 4 to 10 glycerol units, for example, 4, 6, or 10 glycerol units (e.g., particularly suitable are deca- / hexa- / tetraglyceryl monostearate, for example, DECAGLYN, HEXAGLYN, or TETRAGLYN from Nikko Chemicals Co., Ltd.), (9.) alkylene polyol ethers or esters (e.g., lauroyl macrogol-32 glyceride and / or stearoyl macrogol-32 glyceride, for example, GELUCIRE 44 / 14 and / or GELUCIRE 50 / 13), (10.) saturated C. 10 ~C 22 (For example, C 18 ) polyoxyethylene monoesters of hydroxy fatty acids, which may be optionally substituted, such as PEG 12-hydroxystearic acid esters of PEG 600, 900, or 660 (e.g., SOLUTOL HS 15 from BASF, Ludwigshafen, Germany, or substances comprising (or consisting of) about 70% by weight of polyethoxylated 12-hydroxystearic acid salts and about 30% by weight of unesterified polyethylene glycol components, with a hydrogenation value of 90 to 110, a saponin cation value of 53 to 63, an acid value of up to 1, and a maximum moisture content of 0.5% by weight); (11.) polyoxyethylene-polyoxypropylene-alkyl ethers (e.g., C 12 ~C 18Polyoxyethylene-polyoxypropylene ethers of alcohols, such as polyoxyethylene-20-polyoxypropylene-4-cetyl ether, commercially available as NIKKOL PBC 34 from Nikko Chemicals Co., Ltd., or (12.) polyethoxylated distearate (such as those commercially available under the tradename ATLAS G 1821 from Uniqema and / or NIKKOCDS-6000P from Nikko Chemicals Co., Ltd.).

[0057] Furthermore, as mentioned above, pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers.Pharmaceutically acceptable carriers may be aqueous or non-aqueous agents, such as alcoholic or oily agents or their mixtures, and may contain surfactants, emollients, lubricants, stabilizers, dyes, fragrances, preservatives, acids or bases for adjusting pH, solvents, emulsifiers, gelling agents, moisturizing agents, stabilizers, humectants, time-release agents, humectants, or any other components that are generally included in certain forms of pharmaceutical compositions.Pharmaceutically acceptable carriers are well known in the art, and include, for example, aqueous solutions such as water, buffered saline, or other solvents, or vehicles such as glycols, glycerol, and oils such as olive oil or injectable organic esters. Pharmaceutically acceptable carriers may contain, for example, physiologically acceptable compounds that act to stabilize or increase the absorption of the corresponding peptide or protein drug, for example, carbohydrates such as glucose, sucrose, or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low-molecular-weight proteins, or other stabilizers or excipients. Pharmaceutically acceptable carriers may also be selected from substances such as distilled water, benzyl alcohol, lactose, starch, talc, magnesium stearate, polyvinylpyrrolidone, alginic acid, colloidal silica, titanium dioxide, and flavoring agents.

[0058] More preferably, the pharmaceutical composition according to the present invention does not have any copper, zinc, or iron salts or complexes. Thus, preferably, the pharmaceutical composition does not contain any copper salts or complexes, any zinc salts or complexes, or any iron salts or complexes.

[0059] The pharmaceutical composition is formulated as a dosage form for transmucosal administration, preferably for oral administration, oral mucosal administration, or nasal administration.Therefore, preferably, the pharmaceutical composition is administered to the subject / patient transmucosally, particularly orally, to the oral mucosa, or nasally.Preferably, the pharmaceutical composition is formulated as an oral dosage form, and therefore preferably administered orally.

[0060] In oral administration, the pharmaceutical composition is administered by oral ingestion, particularly by swallowing. The pharmaceutical composition can therefore be administered into the digestive tract via the mouth, which is also called "oral-gastrointestinal" administration. In this case, the peptide or protein drug contained in the pharmaceutical composition can be absorbed through the mucous membranes of the stomach and / or intestine. Oral administration also specifically includes oral-intestinal administration and / or oral-gastric administration.

[0061] Dosage forms for oral administration include, for example, tablets (e.g., coated or uncoated tablets), capsules (e.g., HPMC capsules or HPMCP capsules), capsules within capsules, mini-patch systems within capsules, lozenges, troches, vaginal tablets, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewable tablets, effervescent tablets, and multiparticulate dosage forms.

[0062] Tablets may contain excipients such as non-reducing sugars, microcrystalline cellulose, sodium citrate, calcium carbonate, dibasic calcium phosphate, and glycine; disintegrants such as starch (preferably corn starch, potato starch, or tapioca starch), sodium starch glycolate, croscarmellose sodium, and certain complex silicas; and granulating binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, and acacia. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc may be included. Solid compositions of a similar type may also be utilized as fillers in hard capsules. Preferred excipients in this regard include non-reducing sugars, starches, celluloses, or high molecular weight polyethylene glycols. In aqueous suspensions and / or elixirs, the agents may be combined with various sweeteners or flavoring agents, coloring agents or dyes, emulsifying and / or suspending agents, and diluents such as water, ethanol, propylene glycol, and glycerin, as well as combinations thereof.

[0063] The pharmaceutical composition may thus be provided in the form of a tablet, for example, a slow-disintegrating tablet or a slow-eroding tablet. In particular, the pharmaceutical composition may be provided as a dosage form (e.g., a tablet) having an enteric coating, preferably an enteric coating that dissolves at a pH above 7.

[0064] For nasal administration, the pharmaceutical composition may be provided, for example, as a nasal spray, nasal drops, aerosol, or dry powder for nasal administration, particularly as a nasal spray. Nasal administration includes, among others, intranasal transmucosal administration, local administration to the nasal cavity, or nose-to-brain delivery. Thus, nasal administration of the pharmaceutical composition of the present invention may have a systemic therapeutic effect (particularly via absorption of the peptide or protein drug through the nasal mucosa), and / or a local therapeutic effect (particularly in the nasal cavity), and / or a therapeutic effect in the brain (particularly via nose-to-brain delivery; see, for example, Kamble MS et al., International Journal of Pharmaceutical and Chemical Sciences. 2013, 2(1):516-25), depending, inter alia, on the selection of the specific peptide or protein drug to be administered and the optional use of a permeation enhancer or mucoadhesive polymer.

[0065] The pharmaceutical composition of the present invention can also be administered to the oral mucosa.Therefore, the pharmaceutical composition can be formulated as a dosage form for oral mucosa administration.Oral mucosal administration refers to the attachment or application of the pharmaceutical composition to the mucosal epithelium in the oral cavity of a subject / patient, for example, the mucosal epithelium of the oral cavity, the gingiva, the sublingual, the palate, the sublip, or the oropharynx.Oral mucosal administration therefore particularly includes oral administration, gingiva administration, sublingual administration, palate administration, sublip, or the oropharynx administration.Therefore, the pharmaceutical composition can be administered, for example, to the oral cavity, sublingually, the gingiva, the sublip, or the oropharynx.

[0066] For oral mucosal administration, the pharmaceutical compositions of the present invention can be administered using any suitable oral mucosal dosage form, for example, in the form of drops, as a spray, or by a dispensing device (e.g., a spray device, a dropper device, a unit dose device / dispenser, a multi-dose device / dispenser or ampule, a dispensing pen, or a dispensing pipette). The dispensing device may be equipped with an actuator and / or an outlet orifice to enable the patient or caregiver to deposit the desired dose accurately in the oral cavity. The dispensing device may be adapted to dispense a predetermined volume (corresponding to a unit dose) of the pharmaceutical composition upon actuation, for example, in the form of a spray or in the form of one or more drops. The dispensing device may also be a dispensing pen that delivers a metered volume containing a metered dose of a peptide or protein drug.

[0067] Typically, a physician will determine the actual dosage that will be most appropriate for an individual subject. The specific dose level and dosage frequency for any particular individual subject may vary and depend on a variety of factors, including the activity of the specific peptide or protein drug utilized, the metabolic stability and length of action of the compound, age, body weight, overall health, sex, diet, mode and time of administration, excretion rate, drug combination, the severity of the particular condition, and the individual subject being treated. The exact dosage is ultimately at the discretion of the attending physician or veterinarian.

[0068] The subject or patient treated according to the present invention can be an animal (e.g., a non-human animal). Preferably, the subject / patient is a mammal. More preferably, the subject / patient is a human (e.g., male or female) or a non-human mammal (e.g., a guinea pig, hamster, rat, mouse, rabbit, dog, cat, horse, monkey, ape, marmoset, baboon, gorilla, chimpanzee, orangutan, gibbon, sheep, cow, or pig, etc.). Most preferably, the subject / patient treated according to the present invention is a human.

[0069] As used herein, the term "treatment" of a disorder or disease is well known in the art. "Treatment" of a disorder or disease implies that the disorder or disease has been suspected or diagnosed in a patient / subject. A patient / subject suspected of suffering from a disorder or disease typically exhibits specific clinical and / or pathological symptoms that allow one skilled in the art to easily identify the specific underlying pathological condition (i.e., diagnose the disorder or disease).

[0070] "Treatment" of a disorder or disease may, for example, result in the cessation of the progression of the disorder or disease (e.g., no worsening of symptoms) or a slowing of the progression of the disorder or disease (in cases where the cessation of progression is only temporary). "Treatment" of a disorder or disease may also result in a partial response (e.g., improvement of symptoms) or a complete response (e.g., disappearance of symptoms) in a subject / patient afflicted with a disorder or disease. Thus, "treatment" of a disorder or disease may also refer to an improvement of the disorder or disease, which may, for example, result in the cessation of the progression of the disorder or disease or a slowing of the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It should be understood that a subject / patient may show a wide range of responses to treatment (such as the typical responses described herein above). Treatment of a disorder or disease may include, inter alia, curative treatment (preferably resulting in a complete response, ultimately resulting in a cure of the disorder or disease) and palliative treatment (including alleviation of symptoms).

[0071] The term "prevention" of a disorder or disease, as used herein, is also well known in the art. For example, a patient / subject suspected of being predisposed to a disorder or disease may particularly benefit from prevention of the disorder or disease. The subject / patient may have a susceptibility or predisposition to the disorder or disease, including but not limited to a genetic predisposition. Such predisposition can be determined by standard methods or assays, for example, using genetic markers or phenotypic indicators. It should be understood that the disorder or disease prevented in accordance with the present invention has not been or cannot be diagnosed in the patient / subject (e.g., the patient / subject does not exhibit any clinical or pathological symptoms). Thus, the term "prevention" includes the use of a peptide or protein agent in accordance with the present invention before any clinical and / or pathological symptoms have been or can be diagnosed or determined by the attending physician.

[0072] The terms "peptide" and "protein," as in the expression "peptide drug or protein drug," are used interchangeably herein and refer to a polymer of two or more amino acids linked via an amide bond formed between the amino group of one amino acid and the carboxyl group of another amino acid. The amino acids contained in a peptide or protein, also referred to as amino acid residues, can be selected from the 20 standard proteinogenic α-amino acids (i.e., Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val), but can also include non-proteinogenic and / or non-standard α-amino acids (e.g., ornithine, citrulline, homolysine, pyrrolysine, 4-hydroxyproline, α-methylalanine (i.e., 2-amino acid, α ... The amino acid residues contained in the peptide or protein may also be selected from α-amino acids, more preferably from the 20 standard proteinogenic α-amino acids (which may exist as L- or D-isomers, preferably all L-isomers). A peptide or protein may be unmodified or modified, for example, at its N-terminus, at its C-terminus, and / or at functional groups in the side chains of any of its amino acid residues (in particular at the side chain functional groups of one or more Lys, His, Ser, Thr, Tyr, Cys, Asp, Glu, and / or Arg residues).Such modifications include, for example, the attachment of any of the protecting groups described for the corresponding functional groups in Wuts PG & Greene TW, Greene's protective groups in organic synthesis, John Wiley & Sons, 2006. Such modifications also include the covalent attachment of one or more polyethylene glycol (PEG) chains (forming a PEGylated peptide or protein), one or more fatty acids (e.g., one or more C. 8~30 The modified peptide or protein may include glycosylation and / or acylation with alkanoic or alkenoic acids (forming a fatty acid-acylated peptide or protein). Furthermore, such modified peptides or proteins may also include peptidomimetics, so long as they contain at least two amino acids linked via an amide bond (formed between the amino group of one amino acid and the carboxyl group of another amino acid). The amino acid residues contained in the peptide or protein may, for example, exist as a linear molecular chain (forming a linear peptide or protein) or may form one or more rings (corresponding to a cyclic peptide or protein). The peptide or protein may also form an oligomer consisting of two or more identical or different molecules.

[0073] The term "amino acid" specifically refers to any one of the 20 standard proteinogenic α-amino acids (i.e., Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val), but also to non-proteinogenic and / or non-standard α-amino acids (e.g., ornithine, citrulline, homolysine, pyrrolysine, 4-hydroxyproline, α-methylalanine (i.e., 2-aminoisobutyric acid), norvaline, norleucine, tellureucine (ter), and the like. The term also refers to amino acids such as t-leucine, rabionin, or alanine or glycine substituted in the side chain with a cyclic group, such as cyclopentylalanine, cyclohexylalanine, phenylalanine, naphthylalanine, pyridylalanine, thienylalanine, cyclohexylglycine, or phenylglycine, as well as β-amino acids (e.g., β-alanine), γ-amino acids (e.g., γ-aminobutyric acid, isoglutamine, or statins), and / or δ-amino acids, and any other compounds containing at least one carboxylic acid group and at least one amino group. Unless otherwise specified, "amino acid" preferably refers to an α-amino acid, and more preferably to any one of the 20 standard proteinogenic α-amino acids (which can exist as L- or D-isomers, preferably as the L-isomer).

[0074] The term "antibody" refers to any immunoglobulin molecule that specifically binds to (or is immunologically reactive with) a particular antigen. An antibody can be, for example, a monoclonal or polyclonal antibody, and is preferably a monoclonal antibody. Furthermore, an antibody (e.g., a monoclonal antibody) can be a whole antibody (e.g., IgA, IgD, IgE, IgM, or IgG, including, inter alia, IgG1, IgG2, IgG3, or IgG4), a chimeric antibody, a humanized antibody, a human antibody, a heteroconjugate antibody (e.g., a bispecific antibody), or it can be an antigen-binding fragment of any of the aforementioned types of antibodies (e.g., Fab, Fab', F(ab')2, Fv, or scFv, etc.). An antibody can also be a single-chain antibody (scAb) or a single-domain antibody (sdAb, e.g., a "nanobody").

[0075] The term "complex" refers to either a chelate complex (in which coordinate bonds are formed between a single central atom / ion and a multidentate ligand) or a coordination complex composed of a monodentate ligand coordinating a single central atom / ion.

[0076] As used herein, the terms "optional," "optionally," and "may" indicate that the indicated feature may be present or may be absent. Whenever the terms "optional," "optionally," or "may" are used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present, or alternatively, that the corresponding feature is absent. For example, when a component of a composition is indicated as "optional," the present invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition), or that the corresponding component is absent from the composition.

[0077] As used herein, the term "about" refers to ±10% of the indicated numerical value, preferably ±5% of the indicated numerical value, particularly the exact indicated numerical value. For example, the expression "about 100" refers to a range of 90 to 110, particularly a range of 95 to 105, preferably the specific value 100. When the term "about" is used in connection with the end points of a range, it refers to a range from the lower end point of the indicated numerical value minus 10% to the upper end point of the indicated numerical value plus 10%, particularly a range from the lower end point minus 5% to the upper end point plus 5%, preferably the range defined by the exact numerical values ​​of the lower and upper end points. Thus, the expression "about 10 to about 20" refers to a range of 9 to 22, particularly 9.5 to 21, preferably 10 to 20. When the term "about" is used in reference to an end point of an open-ended range, it refers to the corresponding range starting from the lower endpoint -10% or the upper endpoint +10%, particularly a range starting from the lower endpoint -5% or the upper endpoint +5%, preferably an open-ended range defined exactly by the numerical value of the corresponding endpoint. For example, the phrase "at least about 10%" refers to at least 9%, particularly at least 9.5%, and preferably at least 10%.

[0078] Unless specifically indicated otherwise, all properties and parameters referred to herein (including, for example, any amounts / concentrations expressed in "mg / ml" or "% (v / v)", and any pH values) are preferably determined at standard room temperature and pressure conditions, in particular at a temperature of 25°C (298.15 K) and an absolute pressure of 101.325 kPa (1 atm).

[0079] Furthermore, it should be understood that the present invention specifically relates to each and every combination of features and embodiments described herein, including any combination of general and / or preferred features / embodiments. In particular, the present invention specifically relates to all combinations of preferred features described herein.

[0080] Many documents, including patents, patent applications, and scientific literature, have been cited herein. The disclosures of these documents, while not considered relevant to the patentability of this invention, are hereby incorporated by reference in their entireties. More specifically, all references are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

[0081] The invention is also illustrated by the following exemplary drawings, in which: [Brief explanation of the drawings]

[0082] [Figure 1] Figure 1 shows pharmacokinetic profiles of PTH(1-34) formulations after enteral administration in pigs (see Example 4). The formulations included: -●- L-arginine free base and sodium caprate ("ARG+C10", n=3), -■- L-arginine free base and sodium dodecyl sulfate ("ARG+SDS", n=3), -Δ- L-arginine free base and sucrose laurate ("ARG+SL", n=1), -□- sodium dodecyl sulfate ("SDS", n=4), -O- sodium caprate ("C10", n=3). [Figure 2] Figure 1 shows plasma octreotide concentrations after intestinal injection in rats (see Example 11). OCT005 (-●-), OCT006 (-◯-). Each data point represents the mean of at least n=3±SE. [Figure 3] Figure 1 shows plasma PTH(1-34) concentrations after intestinal application in pigs (see Example 12). Matrix tablets with sodium caprate (-●-, n=3±SE), L-arginine free base, sodium caprylate, and polyacrylate in solution (-◯-, n=1). [Figure 4A] FIG. 1 shows the pharmacokinetic profile of PTH(1-34) formulations after oral administration to non-human primates (see Example 15). [Figure 4B]FIG. 1 shows the individual pharmacokinetic profiles of PTH(1-34) formulations after oral administration to non-human primates. [Figure 5] Figure 1 shows the permeation of semaglutide through the human nasal cell line RPMI 2650 (see Example 21). [Figure 6] FIG. 1 shows a cell proliferation cytotoxicity assay (MTS) (see Example 22). [Figure 7] FIG. 1 shows TEER measurements in MDCK cells in the presence of arginine hydrochloride (see Example 23). DETAILED DESCRIPTION OF THE INVENTION

[0083] The invention will now be described by reference to the following examples, which are illustrative only and should not be construed as limiting the scope of the invention. [Example]

[0084] Example 1 Stability of PTH(1-34) formulations in simulated gastric fluid containing pepsin (SGFP) PTH(1–34) formulations were incubated for 20 minutes at 37°C in simulated gastric fluid containing pepsin at a final concentration of 1.6 mg / ml. Intact PTH(1–34) was analyzed by HPLC. The results are shown in Table 1.

[0085] [Table 1]

[0086] Conclusions: Formulations containing L-arginine free base were shown to protect PTH(1-34) from pepsin degradation in simulated gastric fluid. L-arginine HCl, however, did not prevent peptide degradation in SGFP. Addition of zinc arginate chelate provided partial protection against pepsin degradation.

[0087] Example 2 Stability of PTH(1-34) formulations in the presence of trypsin. PTH(1–34) preparations were incubated for 15 minutes at 37°C in a solution containing trypsin at a final concentration of 0.05 mg / ml. Intact PTH(1–34) was analyzed by HPLC. The results are shown in Table 2.

[0088] [Table 2]

[0089] Conclusions: Formulations containing L-arginine free base were shown to protect PTH(1-34) from trypsin-mediated degradation. L-arginine HCl prevented, to a lesser extent, degradation of the peptide in the presence of trypsin.

[0090] Example 3 Stability of PTH(1-34) formulations in the presence of porcine nasal mucosa. Preparations containing PTH(1-34): PTH-NAS-001 0.5 mg / ml of PTH(1-34) was dissolved in 0.5 M phosphate buffer (pH 7.4). PTH-NAS-002 0.5 mg / ml of PTH(1-34) and 100 mg / ml of L-arginine free base were dissolved in 0.5 M phosphate buffer (pH 7.4). PTH-NAS-003 0.5 mg / ml of PTH(1-34) and 100 mg / ml of L-arginine HCl were dissolved in 0.5 M phosphate buffer (pH 7.4).

[0091] PTH(1-34) preparations were incubated with excised porcine nasal mucosa (50 mg / ml) for 4 hours at 37°C. Intact PTH(1-34) was analyzed by HPLC. The results are shown in Table 3.

[0092] [Table 3]

[0093] Conclusions: Nasal formulations containing L-arginine substantially improved the enzymatic stability of PTH(1-34) in the presence of nasal mucosa.

[0094] Example 4 Pharmacokinetic profile of PTH(1-34) formulations after enteral administration to pigs Preparations containing PTH(1-34): PTH-PIG-001 2 mg of PTH (1-34) 200mg SDS PTH-PIG-002 2 mg of PTH (1-34) 200mg SDS 200mg L-arginine PTH-PIG-003 2 mg of PTH (1-34) 200mg sodium caprate PTH-PIG-004 2 mg of PTH (1-34) 200mg sodium caprate 200mg L-arginine PTH-PIG-005 2 mg of PTH (1-34) 200mg sucrose laurate 200mg L-arginine

[0095] The formulations were prepared as dry powders and dissolved in 2 ml of HO 5 minutes before administration. PTH(1–34) formulations were administered to anesthetized pigs via the distal jejunum in a volume of 2 ml per pig (final concentration 1 mg / ml). Blood samples were collected at 0 minutes before administration and at 10, 20, 30, 60, 90, and 120 minutes after administration. Blood was drawn into Vacuette EDTA aprotinin tubes (Greiner Bio-One). Blood samples were centrifuged (4 minutes, 10,000 g, 4°C), and plasma concentrations of PTH(1–34) were determined using a commercially available High Sensitivity Human PTH(1–34) ELISA kit (Immundiagnostik AG, Germany, KI603900). Data are presented as mean ± SE. Results are shown in Figure 1.

[0096] Conclusion: Oral formulations containing L-arginine and a permeation enhancer improved the intestinal absorption of PTH(1-34). In particular, the combination of L-arginine free base and sodium caprate surprisingly improved the intestinal absorption of PTH(1-34). Such formulations improved the AUC by more than 20-fold compared to compositions without L-arginine free base.

[0097] Example 5 Pharmacokinetic profile of liraglutide in rats after enteral administration Formulations containing liraglutide: LIRA-INT-001 6mg / ml liraglutide 60mg / ml L-arginine 10mg / ml Fe(II) gluconate 4mg / ml Cu(II) gluconate Final pH=9.7

[0098] The formulations were prepared as dry powders and dissolved 5 minutes before administration. Liraglutide formulations were administered to anesthetized rats via the ileum at a volume of 0.4 ml / kg (final concentration 6 mg / ml). Blood was collected from the tail vein at 0, 30, 60, 90, 120, 180, and 240 minutes after administration. Blood was drawn from the tail tip into Microtainer Microgard EDTA tubes (Becton Dickinson, USA). Blood samples were centrifuged (4 minutes, 10,000 g, 4°C), and liraglutide plasma concentrations were determined using a commercially available liraglutide EIA kit (Peninsula Laboratories International, USA, catalog number S-1502.0001). Data are presented as mean ± SE. The mean pharmacokinetic parameters are summarized in Table 4.

[0099] [Table 4]

[0100] Conclusions: The formulation containing L-arginine resulted in a distinct PK-profile of liraglutide after administration to the ileum of rats.

[0101] Example 6 In vitro permeation of desmopressin across Caco-2 cell monolayers Permeability experiments were performed using a ready-to-use Caco-2 cell kit (CacoReady™, Readycell). The kit consists of a 24-insert permeable support seeded with differentiated, polarized Caco-2 barrier cells on a polycarbonate microporous filter. Cells were treated according to the instructions provided by the supplier. A desmopressin stock solution containing 2.83 mg of desmopressin per ml of simulated intestinal fluid (SIF pH 7, USP) was prepared. Additional stock solutions were arginine HCl, 1% in SIF pH 7, arginine base, 1% in SIF pH 7, and trisodium phosphate, 1% in SIF pH 7. 0.75 ml of SIF pH 7, USP was added to each basolateral compartment. Four groups (n=3 each) were tested. The following combinations were added to the apical side of the permeabilization device: (1) 0.125 ml of desmopressin stock solution + 0.125 ml of SIF, pH 7, USP; (2) 0.125 ml of desmopressin stock solution + 0.125 ml of 1% arginine HCl stock solution; (3) 0.125 ml of desmopressin stock solution + 0.125 ml of 1% arginine free base stock solution; and (4) 0.125 ml of desmopressin stock solution + 0.125 ml of 1% trisodium phosphate stock solution. After adding desmopressin to the apical side, the cells were incubated for 2 hours at 37°C, 5% CO2, and high relative humidity. After incubation, the contents of the apical and basolateral sides of each experiment were collected and stored at -20°C before analysis. Desmopressin concentrations in the basolateral compartment were analyzed via a gradient HPLC method based on H2O containing 0.1% trifluoroacetic acid and acetonitrile containing 0.1% trifluoroacetic acid.

[0102] Results: At 0.5% (m / v), arginine HCl was shown not to increase the transport of desmopressin across Caco-2 monolayers compared to desmopressin in buffer alone. However, the presence of 0.5% (m / v) arginine free base or trisodium phosphate resulted in a significant increase in desmopressin permeation compared to the buffer-only control. The corresponding results are detailed in Table 5.

[0103] [Table 5]

[0104] Conclusion: L-arginine free base and trisodium phosphate (Na3PO4) exhibit permeation-enhancing effects in Caco-2 monolayers.

[0105] Example 7 In vitro enzymatic degradation of desmopressin by chymotrypsin. The enzymatic degradation of desmopressin by chymotrypsin was investigated in the presence and absence of L-arginine free base, and the results are shown in Table 6 below.

[0106] Stock solution: Desmopressin: 1 mg / ml in 50 mM phosphate buffer pH 6.5 Buffer pH 9: 0.2M phosphate buffer pH=9.2 L-Arginine (free base): 200 mg / ml in 0.2 M phosphate buffer pH=9.2 Chymotrypsin: 1 mg / ml in 0.2 M phosphate buffer pH=9.2 Incubation at 37°C and 400 rpm, 5 hours incubation Stop solution: 300 μl of 1.25% HCl, analysis via HPLC

[0107] [Table 6]

[0108] Conclusion: The above results indicate that L-arginine free base reduces the enzymatic degradation of desmopressin by chymotrypsin.

[0109] Example 8 Inhibition of intestinal proteases by a combination of trisodium phosphate and sodium decanoate Simulated intestinal fluid (SIF), pH 7, and enzymatically active simulated intestinal fluid containing pancreatin (SIF-P), pH 7, were prepared according to USP guidelines. Stock solutions of peptide PTH(1–34) in SIF, pH 7, with a concentration of 1 mg PTH(1–34) per ml, were prepared. PTH(1–34) stock solutions were incubated in the absence and presence of sodium decanoate (C10), trisodium phosphate (Na3PO4), and mixtures thereof dissolved in SIF-P (see Table 7 for compositions). After the specified incubation times at 37°C and 250 rpm, samples were directly injected into an HPLC system and analyzed for PTH(1–34) content using a gradient method based on HO containing 0.1% trifluoroacetic acid and acetonitrile containing 0.1% trifluoroacetic acid.

[0110] The results are shown in Table 7. PTH(1–34) was completely degraded within 10 minutes in the presence of SIF-P. Furthermore, PTH(1–34) was completely degraded in the presence of C10 and Na3PO4. However, no degradation of PTH(1–34) was observed when incubated in the presence of a mixture of C10 and Na3PO4.

[0111] [Table 7]

[0112] Conclusion: The combination of Na3PO4 and sodium decanoate shows surprisingly good inhibition of intestinal proteases.

[0113] Example 9 Pharmacokinetic profile of desmopressin formulations after intraileal administration in rats Desmopressin formulations were administered into the ileum of anesthetized rats (n = 5) at a volume of 0.4 ml / kg and a final desmopressin concentration of 0.08 mg / kg. Anesthesia was induced with a solution of Hypnorm and Dormicum mixed in a 3:1 ratio. After checking the depth of anesthesia, a 3-5 cm incision was made in the abdominal skin. The cecum was exposed, and the distal portion of the small intestine was withdrawn from the abdominal cavity. The catheter tip was pierced through the intestine, and the catheter was inserted downstream into the ileal lumen, 5 cm from the cecum, outside the lymphoid tissue accumulation area and outside the blood vessels, in a fecal-free spot, and secured with a ligature. A prepared syringe filled with the administration solution was gradually attached to the inserted catheter. Administration was performed slowly. Blood samples were collected from the tail vein at 0, 30, 60, 120, and 240 minutes after administration. Plasma concentrations of desmopressin were determined using a commercially available desmopressin EIA kit (Peninsula Laboratories International, USA, Cat. No. S-1365.0001), and the results are shown in Table 8.

[0114] Composition: DESMO-A (= reference product, desmopressin only) 0.2 mg / ml desmopressin DESMO-B 0.2 mg / ml desmopressin 1mg / ml aprotinin DESMO-C 0.2 mg / ml desmopressin 100mg / ml trisodium phosphate (Na3PO4)

[0115] [Table 8]

[0116] Conclusion: Trisodium phosphate (Na3PO4) improved the absorption of desmopressin from the rat ileum several-fold.

[0117] Example 10 Pharmacokinetic profile of desmopressin formulations after administration to the rat ileum Desmopressin formulations were administered into the ileum of anesthetized rats (n = 5) at a volume of 0.4 ml / kg and a final desmopressin concentration of 0.092 mg / kg. Anesthesia was induced with a solution of Hypnorm and Dormicum mixed in a 3:1 ratio. After checking the depth of anesthesia, a 3-5 cm incision was made in the abdominal skin. The cecum was exposed, and the distal portion of the small intestine was withdrawn from the abdominal cavity. The catheter tip was pierced through the intestine, and the catheter was inserted downstream into the ileal lumen, 5 cm from the cecum, outside the lymphatic tissue accumulation area and outside the blood vessels, in a fecal-free spot, and secured with a ligature. A prepared syringe filled with the administration solution was gradually attached to the inserted catheter. Administration was performed slowly. Blood samples were collected from the tail vein at 0, 30, 60, 120, and 240 minutes after administration. Plasma concentrations of desmopressin were determined using a commercially available desmopressin EIA kit (Peninsula Laboratories International, USA, Cat. No. S-1365.0001), and the results are shown in Table 9.

[0118] Composition: DESMO-A (= reference product, desmopressin only) 0.23 mg / ml desmopressin DESMO-B 0.23 mg / ml desmopressin 100mg / ml monosodium phosphate DESMO-C 0.23 mg / ml desmopressin 100mg / ml disodium phosphate DESMO-D 0.23 mg / ml desmopressin 100mg / ml trisodium phosphate (Na3PO4) DESMO-E 0.23 mg / ml desmopressin 100mg / ml trisodium phosphate (Na3PO4) 10mg / ml sodium caprate (sodium decanoate) DESMO-F 0.23 mg / ml desmopressin 100mg / ml trisodium phosphate (Na3PO4) 50mg / ml sucrose laurate

[0119] [Table 9]

[0120] Conclusion: Trisodium phosphate significantly improved the absorption of desmopressin from the rat ileum, whereas monosodium phosphate and disodium phosphate did not produce any improvement.

[0121] Example 11 Pharmacokinetic profile of octreotide formulations after intrajejunal administration in rats Octreotide formulations were administered into the proximal jejunum of anesthetized rats (n = 4) at a volume of 0.4 ml / kg and a final octreotide concentration of 0.4 mg / kg. Anesthesia was induced with a solution of Hypnorm and Dormicum mixed in a 3:1 ratio. After checking the depth of anesthesia, a 3-5 cm incision was made in the abdominal skin. The cecum was exposed, and the small intestine was withdrawn from the abdominal cavity up to the duodenal flexure. The catheter tip was pierced through the intestine, and the catheter was inserted downstream into the jejunal lumen at a distance of 10 ± 5 cm from the cecum in a fecal-free spot outside the lymphoid tissue accumulation area and outside the blood vessels, and secured with a ligature. A prepared syringe filled with the administration solution was gradually attached to the inserted catheter. Administration was performed slowly. Blood samples were collected from the tail vein at 0, 10, 20, 60, and 120 minutes after administration. The plasma concentrations of octreotide were determined using a commercially available octreotide kit (Peninsula Laboratories International, Inc., USA, Catalog No. S-1342.0001). The results are shown in Table 10 and Figure 2.

[0122] Composition: OCT005 1mg / ml octreotide OCT006 1mg / ml octreotide 100mg / ml trisodium phosphate (Na3PO4)

[0123] [Table 10]

[0124] Example 12 Pharmacokinetic profile of PTH(1-34) preparations after intraileal administration in pigs An in situ gelling matrix tablet containing 2 mg of PTH(1-34), 200 mg of L-arginine free base, 10 mg of polyacrylate (Carbopol), and sodium caprylate was administered directly to the ileum of pigs. Plasma PTH(1-34) levels were analyzed using a commercially available high-sensitivity PTH(1-34) ELISA kit.

[0125] Results: The combination of polyacrylate (Carbopol) and arginine results in an in situ gelling matrix system that results in prolonged absorption of PTH(1-34), as also shown in FIG.

[0126] Example 13 In vitro enzymatic degradation of adalimumab by trypsin The enzymatic degradation of the antibody adalimumab in simulated intestinal fluid (SIF) containing trypsin at 37°C was investigated in the presence and absence of the inhibitor L-arginine free base.

[0127] [Table 11]

[0128] Conclusion: The above results indicate that adalimumab is degraded by trypsin but is fully protected in the presence of L-arginine base.

[0129] Example 14 Pharmacokinetic profile of PTH(1-34) preparations after intrajejunal administration in rats Similar to the procedure described in Example 11 above, the PTH(1-34) formulations described below can be administered to the jejunum of anesthetized rats, and plasma PTH(1-34) concentrations can be determined. The improved pharmacokinetic properties of exemplary formulations according to the present invention containing PTH(1-34) in combination with trisodium phosphate and sodium caprate can thus be demonstrated.

[0130] Composition: PTH(1-34)-A 0.2 mg / ml PTH(1-34) 20mg / ml sodium caprate PTH(1-34)-B 0.2 mg / ml PTH(1-34) 20mg / ml sodium caprate 100mg / ml trisodium phosphate (Na3PO4)

[0131] Example 15 Pharmacokinetic profile of PTH(1-34) preparations after oral administration to non-human primates Solid oral dosage forms containing PTH(1-34) were prepared for in vivo testing in non-human monkeys. The solid oral dosage forms were orally administered to cynomolgus monkeys weighing between 5 and 6 kg. Blood samples were collected at 0, 15, 30, 60, 120, and 180 minutes after oral administration. Plasma PTH(1-34) concentrations were analyzed using an Immutopics High Sensitivity Human PTH(1-34) ELISA kit. The pharmacokinetic profile is shown in Figure 4.

[0132] Composition: Reference (1) Size 4 gelatin capsules 2 mg of PTH (1-34) 50mg mannitol Formulation 2 Size 4 gelatin capsules 2 mg of PTH (1-34) 100mg L-arginine Formulation 3 Tablets compressed at a compression force of 5.4 kN 2 mg of PTH (1-34) 100mg L-arginine 100mg sucrose laurate Formulation 4 Tablets compressed at a compression force of 5.8 kN 2 mg of PTH (1-34) 100mg L-arginine 100mg sucrose stearate Formulation 5 Tablets compressed at a compression force of 6.9 kN 2 mg of PTH (1-34) 100mg of SNAC 50mg L-arginine 50mg sucrose stearate Formulation 6 Tablets compressed at a compression force of 7.8 kN 2 mg of PTH (1-34) 100mg L-arginine 90mg mannitol 2.5mg Carbopol 974P SNAC Gelatin capsules 2.5 mg of PTH (1-34) 100mg of SNAC

[0133] Conclusion: Formulations according to the present invention containing arginine provided significant oral bioavailability of PTH(1-34), whereas the control formulation without arginine had little bioavailability. Formulations containing arginine also showed improved bioavailability of PTH(1-34) compared with formulations containing only SNAC.

[0134] Example 16 Development of a delayed-eroding tablet formulation with semaglutide and L-arginine Semaglutide tablets were prepared on a Korsch EKO tablet press and their disintegration time in simulated gastric fluid (SGF) at 37°C was analysed in a disintegration tester according to USP.

[0135] Composition SEMA-A: 5 mg of semaglutide 300mg L-arginine 300mg sorbitol 50mg of Avicel The tablets were compressed at a compression force of 10.4 kN. The tablets disintegrated immediately within a few seconds.

[0136] Composition SEMA-B: 5 mg of semaglutide 300mg L-arginine 250mg sorbitol 50mg sucrose stearate was compressed at a compression force of 5.5 kN. The tablets showed an extended disintegration profile of 5.2 minutes.

[0137] Composition SEMA-C: 5 mg of semaglutide 300mg L-arginine 250mg sorbitol 100mg sucrose stearate was compressed at a compression force of 8.6 kN. The tablets showed an extended disintegration profile of 15.3 minutes.

[0138] Conclusion: Tablets with delayed disintegration profile can be prepared by combining arginine and sucrose stearate.

[0139] Example 17 Pharmacokinetic profile of semaglutide after oral administration in beagle dogs Formulation SEMA-D: Acid-resistant hard capsules containing 1.7 mg of semaglutide, 150 mg of sodium caprate, and 150 mg of L-arginine free base were orally administered to overnight-fasted beagle dogs (n=3). Intact capsules were orally administered. Immediately after administration of the formulation, 10 mL of water was administered to facilitate swallowing. As a reference, 0.1 mg of semaglutide (volume 0.1 mL per dog) was intravenously administered to beagle dogs (n=3). Approximately 2 mL of blood samples from each dog at 0, 1, 2, 4, and 6 hours for oral administration were collected from the jugular, brachiocephalic, or saphenous vein into pre-labeled vacutainer centrifuge tubes containing K2EDTA. Plasma was obtained by centrifugation of the blood samples at 5000 g for 5 minutes at 4°C within 0.5 hours after sampling. The resulting plasma samples were divided into two aliquots, transferred to pre-labeled microcentrifuge tubes of approximately 500 μL each, and stored at temperatures below -70 ± 10°C. Semaglutide content was analyzed using a commercially available semaglutide Elisa kit.

[0140] Results: A complete oral bioavailability of 3.1% was achieved.

[0141] Example 18 Pharmacokinetic profile of semaglutide formulations after administration to the rat ileum The formulation SEMA-E (50.5 mg / ml chenodeoxycholic acid sodium salt and 5.0 mg / ml Na3PO4) was administered into the ileum of anesthetized rats (n=5) at a volume of 0.4 ml / kg (final semaglutide concentration 2.02 mg / ml). Anesthesia was induced with a hypnorm / dormicum mixture. The cecum was exposed, and the distal portion of the small intestine was withdrawn from the abdominal cavity. The intestine was pierced with a catheter tip, and the catheter was inserted downstream into the ileal lumen 5 cm from the cecum. The withdrawn portion of the small intestine was transferred into the abdominal cavity, 2 ml of sterile saline was flushed over the intestine, and the abdominal cavity was closed with a metal wound clip. The prepared syringe filled with the dosing solution was gradually attached to the inserted catheter. The administration was gradual. Blood samples were collected from the tail vein at 0, 30, 60, 120, and 240 minutes after administration. 450 μl of blood was drawn from the tail tip into a Microtainer Microgard EDTA tube (Becton Dickinson, USA). Blood samples were centrifuged (4 min, 10000 g, 4°C) and approximately 200 μl of plasma was collected. Plasma samples were kept at -20°C until semaglutide analysis. Plasma semaglutide concentrations were determined using a commercially available semaglutide EIA kit (Peninsula Laboratories International, USA, catalog number S-1530.0001).

[0142] Results: Administration of the formulation SEMA-E resulted in a ΔC max This resulted in high plasma semaglutide concentrations of 787±263ng / ml and ΔAUC(0-t) of 134910±47574 (ng / ml×min).

[0143] Example 19 In vitro enzymatic degradation of desmopressin in the presence of L-lysine A stock solution of desmopressin (1 mg / ml) in water was prepared. Pancreatin-containing simulated intestinal fluid (SIF-P), pH 7, was prepared according to USP, containing 1 g of pancreatin per 100 ml of simulated intestinal fluid. The desmopressin stock solution was used to dissolve lysine salts, i.e., L-lysine base (1) and D-lysine base (2), each containing 100 mg of lysine and 1 mg / ml of desmopressin per ml in water. For the actual degradation experiments, 0.5 ml of different desmopressin-containing stock solutions was incubated with 0.5 ml of SIF-P (and one control omitting pancreatin) for 1 hour at 37°C and 300 rpm. After the incubation period, the enzyme reaction was stopped by adding 1.0 ml of 3.125% HCl in 50% acetonitrile. Samples were analyzed via HPLC. The desmopressin concentration in the sample omitting pancreatin was used as the 100% value, and the desmopressin concentrations measured in the other samples were calculated as a percentage of intact desmopressin based on the 100% value. The results are summarized in the table below.

[0144] [Table 12]

[0145] Conclusion: The results show that lysine can partially protect the peptide desmopressin from enzymatic degradation.

[0146] Example 20 Oral formulations containing the antibody infliximab Oral formulations with the antibody infliximab were prepared and the final pH measured as detailed in the table below: L-Arginine improves the solubility of L-Tyrosine.

[0147] [Table 13]

[0148] Example 21 Semaglutide penetration through human nasal cells All permeation studies were performed in RPMI 2650 model after 3 weeks of culture. Furthermore, the entire equipment was pre-warmed to 37°C. All steps were performed at 37°C. Prior to permeation, TEER values ​​were measured using an EVOM® in combination with an Endohm® chamber from World Precision Instruments (WPI, Sarasota, Florida, US).

[0149] The medium of the RPMI model was then replaced with Krebs-Ringer buffer (KRB) from the basolateral side (1500 μL) and apical side (500 μL) to remove the compounds in the medium and adapt the tissue to the experimental conditions. The RPMI model was incubated in KRB for 60 minutes. During this time, sample solutions containing excipients and active pharmaceutical ingredients were prepared. After the incubation period, the TEER value was determined again.

[0150] Before permeation, KRB was removed from both sides of the RPMI model, and 1200 μL of KRB was added as the acceptor volume. Then, 200 μL of formulations (each containing 0.5 mg / ml semaglutide; a reference formulation in KRB alone, and a sample formulation in KRB containing 5% arginine HCl) were applied to the apical surface of each RPMI model. This step marked the start of the permeation period. After 2 hours of exposure, the entire acceptor was removed, transferred to an Eppendorf tube, and replaced with 1200 μL of pre-warmed KRB. 4 hours after the start of the experiment, the entire amount of acceptor was recovered again. During permeation, the cell culture plate was shaken horizontally at 200 U / min at 37°C. The results are shown in Figure 5.

[0151] Conclusions: Arginine improves the permeation of semaglutide through human nasal cells.

[0152] Example 22 CellTiter 96® AQueous One Solution Cell Proliferation Cytotoxicity Assay (MTS) with Arginine HCl The CellTiter 96® AQueous One Solution Cell Proliferation Assay from Promega (Mannheim, Germany) is a colorimetric method for determining the number of viable cells in a cytotoxicity assay. The tetrazolium compound of MTS is bioreduced by viable cells to a colored formazan product. The amount of formazan is directly proportional to the number of viable cells and can be measured by absorbance at 490 nm. This assay was performed to determine the cytotoxic effect of arginine HCl at concentrations of 2.5% and 5.0% (m / V) on RPMI 2650 cells.

[0153] RPMI 2650 cells were seeded into 96-well tissue culture test plates at a density of 60,000 cells per well for 24 hours. Arginine HCl was dissolved in KRB. The medium was removed from the cells and replaced with 100 μL of excipient solution per well. The cells were incubated with the excipient solution for 0, 15, 30, 60, and 120 minutes. Additionally, cells were incubated with KRB, 1.0% Triton-X solution (V / V) for the same incubation time as negative and positive controls, respectively. Bacitracin (BAC) was used as a reference.

[0154] The CellTiter 96® AQueous One Solution cell proliferation assay was performed according to the manufacturer's protocol. Therefore, the CellTiter 96® AQueous One Solution reagent was completely thawed. After the incubation period, 20 μL of CellTiter 96® AQueous One Solution reagent was pipetted into each well of a 96-well assay plate containing 100 μL of excipient solution. The plate was incubated at 37° C. for 3 hours in a humidified 5% CO atmosphere.

[0155] After the incubation period, the samples were analyzed immediately. The absorbance was recorded at 490 nm and measured using the microplate reader Infinite® M Plex (Tecan, Switzerland). The results are shown in Figure 6.

[0156] Conclusion: In this cell assay, only a slight decrease in cell viability was observed in the presence of arginine HCl, with significantly lower cytotoxicity compared to the reference with bacitracin (BAC). Therefore, arginine HCl can be considered a safe excipient for nasal application, even at high concentrations such as 5%.

[0157] Example 23 Measurement of transepithelial electrical resistance (TEER) in the presence of arginine hydrochloride A cellZscope® from nanoAnalytics (Munster, Germany) was used for continuous assessment of TEER as a surrogate parameter for tight junction functionality. MDCK cells were grown in a 1.12 cm 2 Cells were grown on 1.0 μm transparent filter inserts (ThinCerts™, Greiner Bio-One, Frickenhausen, Germany) at a seeding density of 100,000 cells per well. Medium was changed on days 3, 4, and 5 of culture. Cells were grown at a resistivity of approximately 3500 Ω cm starting with replacement of growth medium with an equal volume of KRB, pH 7.4 (500 μL apically, 1500 μL basolaterally) and incubation of the cells for 60 min. 2 TEER measurements were performed on day 5, the day the resistance reached 100 kHz. After this pre-incubation, 250 μL of KRB was removed from the insert, and an equal volume of doubly concentrated sample solution (arginine HCl in KRB) was added to the 250 μL of KRB in the insert to achieve the desired concentration. Impedance measurements were then performed for 180 minutes in a 37°C, 5% CO2 incubator over a frequency range of 1 Hz to 100 kHz.

[0158] The cells were then carefully washed with fresh KRB, incubated in medium, and TEER was monitored at 30-minute intervals for up to 24 hours after the start of the experiment to assess TEER recovery. Results (shown in Figure 7) are presented as relative TEER reduction, defined as the percentage change from the starting value, corrected by the baseline value.

[0159] Conclusions: A significant decrease in TEER was observed in the presence of arginine, which may be related to the opening of tight junctions. It has been demonstrated that tight junction opening increases the apical-to-basolateral transport of hydrophilic drugs, such as peptides and proteins. Furthermore, tight junction opening was fully reversible at both 2.5% and 5%, leading to the conclusion that this effect is not cytotoxic and that the concentrations tested are safe to use.

[0160] Example 24 Adalimumab penetration through human nasal cells All permeation studies were performed in RPMI 2650 model after 3 weeks of culture. Furthermore, the entire equipment was pre-warmed to 37°C. All steps were performed at 37°C. Prior to permeation, TEER values ​​were measured using an EVOM® in combination with an Endohm® chamber from World Precision Instruments (WPI, Sarasota, Florida, US).

[0161] The medium of the RPMI model was then replaced with Krebs-Ringer buffer (KRB) from the basolateral side (1500 μL) and apical side (500 μL) to remove the compounds in the medium and adapt the tissue to the experimental conditions. The RPMI model was incubated in KRB for 60 minutes. During this time, sample solutions containing excipients and active pharmaceutical ingredients were prepared. After the incubation period, the TEER value was determined again.

[0162] Before permeabilization, KRB was removed from both sides of the RPMI model, and 1200 μL of KRB was added as the acceptor volume. Then, 200 μL of formulations (each containing 2.0 mg / ml of adalimumab; a reference formulation in KRB alone, and a sample formulation in KRB containing 5% arginine HCl) were applied to the apical surface of each RPMI model. This step marked the start of the permeabilization period. After 2 hours of exposure, the entire acceptor was removed, transferred to an Eppendorf tube, and replaced with 1200 μL of pre-warmed KRB. Four hours after the start of the experiment, the entire acceptor volume was recovered again. During permeabilization, the cell culture plate was shaken horizontally at 200 U / min at 37 °C.

[0163] The results thus obtained are summarized in the table below.

[0164] [Table 14]

[0165] CONCLUSIONS: The presence of 5% arginine HCl increased the mean apical-to-basolateral penetration of the antibody adalimumab through human nasal cells.

Claims

1. Peptide drugs or protein drugs and pK a A pharmaceutical composition for transmucosal administration comprising an excipient with a value of 12 or higher, wherein the composition is such that when the pharmaceutical composition is added to 10 ml of a 0.1 M aqueous sodium bicarbonate solution, the pH of the solution becomes greater than pH 9.

2. Peptide drugs or protein drugs and pK a A pharmaceutical composition for treating or preventing a disease / disorder, comprising an excipient with a value of 12 or higher, wherein the composition is such that when the pharmaceutical composition is added to 10 ml of a 0.1 M aqueous sodium bicarbonate solution, the pH of the solution becomes greater than pH 9.

3. Peptide drugs or protein drugs and pK a A pharmaceutical composition for transmucosal delivery of a peptide drug or protein drug, comprising an excipient with a pH value of 12 or higher, wherein the composition is such that when the pharmaceutical composition is added to 10 ml of a 0.1 M aqueous sodium bicarbonate solution, the pH of the solution becomes greater than pH 9.

4. pK a The pharmaceutical composition according to any one of claims 1 to 3, wherein the excipient with a value of 12 or more is selected from arginine free base, EDTA tetrazolium salt, trisodium phosphate, tris(hydroxymethyl)aminomethane, lysine, and calcium hydroxide.

5. pK a The pharmaceutical composition according to any one of claims 1 to 3, wherein the excipient with a value of 12 or more is arginine free base or trisodium phosphate.

6. pK a The pharmaceutical composition according to any one of claims 1 to 3, wherein the excipient with a value of 12 or more is a free arginine base.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the peptide agent or protein agent has a molecular weight of about 50 kDa or less, preferably about 1 kDa to about 6 kDa.

8. Peptide drugs or protein drugs include insulin, insulin analogues, insulin lispro, insulin peglispro, insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, insulin degludec, B29K(N(ε)hexadecanedioyl-γ-L-Glu)A14E B25H desB30 human insulin, B29K(N(ε)octadecanedioyl-γ-L-Glu-OEG-OEG)desB30 human insulin, B29K(N(ε)octadecanedioyl-γ-L-Glu)A14E B25H desB30 human insulin, B29K(N(ε)eicosanedioylγ-L-Glu)A14E B25H desB30 human insulin, B29K(N(ε)octadecanedioyl-γ-L-Glu-OEG-OEG)A14E B25H desB30 human insulin, B29K(N(ε)eicosanedioyl γ-L-Glu-OEG-OEG)A14E B25H desB30 human insulin, B29K(N(ε)eicosanedioyl γ-L-Glu-OEG-OEG)A14E B16H B25H desB30 human insulin, B29K(N(ε)hexadecanedioyl-γ-L-Glu)A14E B16H B25H desB30 human insulin, B29K(N(ε)eicosanedioyl γ-L-Glu-OEG-OEG)A14E B16H B25H desB30 human insulin, B29K(N(ε)octadecanedioyl)A14E B25H desB30 human insulin, GLP-1, GLP-1 analogs, acylated GLP-1 analogs, diacylated GLP-1 analogs, GLP-1 agonists, semaglutide, liraglutide, exenatide, exendin-4, lixisenatide, taspoglutide, albiglutide, dulaglutide, langlenatide, veinaglutide, epheglenatide, GLP-1(7-37), GLP-1(7-36)NH 2 Dual agonists of the GLP-1 receptor and another receptor, dual agonists of the GLP-1 receptor and glucagon receptor, dual agonists of the GLP-1 receptor and gastric suppressor polypeptide receptor, oxytomodulin, GLP-2, GLP-2 analogs, GLP-2 agonists, teduglutide, elsiglutide, glucose-dependent insulin secretion-stimulating polypeptide, dual GLP-1 analogs, GLP-1R / GCGR dual agonists, GLP1 / glucagon receptor coagonists, GLP-1R / GIPR dual agonists, GLP1 / GIP Receptor coagonists, exendin-4 peptide analogs, exendin-4 derivatives, ellamypretide, cyclotide, recombinant factor VIIa, eptacog alfa, amyrin, amyrin analogs, plumrintide, somatostatin analogs, octreotide, lanreotide, pasireotide, gosererin, buserelin, leptin, leptin analogs, metreleptin, peptide YY, peptide YY analogs, glatiramer, leuprolide, desmopressin, desmopressin analogs, vasopressin receptor 2 agonist peptides, osteocalcin, osteocalcin Analogues or derivatives, human growth hormone, human growth hormone analogues, long-acting human growth hormone, fibroblast growth factor 21, somapacitan, hGH-CTP, antibodies, glycopeptide antibiotics, glycosylated cyclic or polycyclic non-ribosomal peptide antibiotics, vancomycin, teicoplanin, teravancin, bleomycin, lamopranin, decaplanin, cyclotide, bortezomib, cosyntropin, chorionic gonadotropin, menotropin, cermorelin, luteinizing hormone-releasing hormone, somatropin, calcitonin, salmon calcitonin, pe Ntagastrinn, oxytocin, nesiritide, anakinra, enfuvirtide, pegvisomant, dorunase alfa, repiridine, anidurafungin, eptifibatide, interferon alpha-1, interferon alpha-2a, interferon alpha-2b, interferon beta-1a, interferon beta-1b, interferon gamma-1b, peginterferon alpha-2a, peginterferon alpha-2b, peginterferon beta-1a, fibrinolysin, vasopressin, aldesleukin,Epoetin, epoetin alfa, darbepoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, epoetin theta, methoxypolyethylene glycol-epoetin beta, sustained-release erythropoietin receptor activator, pegylated epo, albupoietin, epo-dimer analog, epo-Fc, carbamylated epo, synthetic erythropoiesis protein, low molecular weight epo analog PBI-1402, filgrastim, PEG-filgrastim, intaleukin-11, cyclosporine, glucagon, urokinase, biomycin, thyrotropin-releasing hormone, leucine - A pharmaceutical composition according to any one of claims 1 to 6, selected from enkephalin, methionine-enkephalin, substance P, adrenocorticotropic hormone, parathyroid hormone, parathyroid hormone fragments, teriparatide, PTH(1-31), PTH(2-34), parathyroid hormone-related proteins, abaloparatide, linaclotide, carfilzomib, icatibant, ecalantide, sirengitide, prostaglandin F2α receptor modulators, PDC31, absiximab, ranibizumab, alefacept, romiprostin, anakinra, abatacept, beratacept, and pharmaceutically acceptable salts thereof.

9. Peptide or protein drugs include GLP-1 agonists, semaglutide, liraglutide, exenatide, exendin-4, lixisenatide, taspoglutide, albiglutide, dulaglutide, langlenatide, veinaglutide, epheglenatide, GLP-1(7-37), GLP-1(7-36)NH 2 A pharmaceutical composition according to any one of claims 1 to 6, selected from a dual agonist of the GLP-1 receptor and another receptor, a dual agonist of the GLP-1 receptor and a glucagon receptor, a dual agonist of the GLP-1 receptor and a gastric suppressor polypeptide receptor, oxytomodulin, GLP-2, a GLP-2 agonist, teduglutide, elsiglutide, somatostatin analog, octreotide, lanreotide, pasireotide, desmopressin, desmopressin analog, vasopressin receptor 2 agonist peptide, parathyroid hormone fragment, teriparatide, PTH(1-31), PTH(2-34), and pharmaceutically acceptable salts thereof.

10. The peptide agent or protein agent is selected from GLP-1 agonists, semaglutide, liraglutide, exenatide, exendin-4, lixisenatide, taspoglutide, albiglutide, dulaglutide, langlenatide, bairaglutide, efeglenatide, GLP-1(7-37), GLP-1(7-36)NH 2 The pharmaceutical composition according to any one of claims 1 to 6, which is selected from dual agonists of GLP-1 receptor and glucagon receptor, oxyntomodulin, and pharmaceutically acceptable salts thereof.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition further comprises a permeation enhancer.

12. The permeation enhancer is C 8～20 Alkanoyl carnitine, salicylic acid, salicylic acid derivatives, 3-methoxysalicylic acid, 5-methoxysalicylic acid, homovanillic acid, C 8～20 Alkanic acid, citric acid, tartaric acid, fatty acid acylated amino acids, C 8～20 Alkanoyl sarcosinate, alkyl saccharide, C 8～10 Alkyl polysaccharides, n-octyl-beta-D-glucopyranoside, n-dodecyl-beta-D-maltoside, n-tetradecyl-beta-D-maltoside, tridecyl-beta-D-maltoside, sucrose laurate, sucrose myristate, sucrose palmitate, sucrose coconutate, sucrose monododecanoate, sucrose monotridecanoate, sucrose monotetradecanoate, cocoglucoside, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl β-cyclodextrin, s β-cyclodextrin, N-[8-(2-hydroxybenzoyl)amino]caprylic acid, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate derivative, thiomer, mucosal adhesive polymer having a vitamin B substructure, calcium chelated compound, ethylenediaminetetraacetic acid, ethylene glycol tetraacetic acid, polyacrylic acid, Cremofor EL, chitosan, N,N,N-trimethylchitosan, benzalkonium chloride, bestatin, cetylpyridinium chloride, cetyltrimethylammonium bromide, C 2～20 Alkanol, C 8～20 Alkenol, C 8～20 Alkenic acid, dextran sulfate, diethylene glycol monoethyl ether, 1-dodecyl azacycloheptan-2-one, caprylcaproyl polyoxylglyceride, ethyl caprylate, glyceryl monolaurate, lysophosphatidylcholine, menthol, C 8～20 Alkylamine, C 8～20 Alkenylamine, phosphatidylcholine, poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, polysorbate, cholic acid, deoxycholate, chenodeoxycholate, sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate, sodium decyl sulfate, sodium octyl sulfate, sodium laureth sulfate, N-lauryl sarcosinate, decyltrimethylammonium bromide, benzyldimethyldodecylammonium chloride, myristyltrimethylammonium chloride, dodecylpyridinium chloride, decyldimethylammonium propanesulfonate, myristyldimethylammonium propanesulfonate, palmityldimethylammonium propanesulfonate, chembetaine CAS, chembetaine oleyl, nonyl phosphate Polyoxyethylene, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, sorbitan monoeolate, Triton X-100, hexanoic acid, heptanoic acid, methyl laurate, isopropyl myristate, isopropyl palmitate, methyl palmitate, diethyl sebacate, sodium oleate, urea, laurylamine, caprolactam, methylpyrrolidone, octylpyrrolidone, methylpiperazine, phenylpiperazine, Carbopol 934P, glycyrrhetinic acid, bromelain, pinene oxide, limonene, cineole, octyldodecanol, fencon, menthone, trimethoxypropylene methylbenzene, cell membrane permeable peptide, KLAKLAK, polyarginine, oligoarginine, octaarginine, penetratin, penetratin analog, PenetraMax, HIV-1 Tat, Transportan, Macrogol-15-hydroxystearate, Solutol HS 15, CriticalSorb, Taurocholate, Taurodeoxycholate, Sulfoxide, Decylmethylsulfoxide, Dimethylsulfoxide, Cyclopentadecalactone, 8-(N-2-hydroxy-5-chlorobenzoyl)-aminocaprylic acid, N-(10-[2-hydroxybenzoyl]amino)decanoic acid, Dodecyl-2-N,Selected from N-dimethylaminopropionate, D-α-tocopheryl polyethylene glycol-1000 succinate, arginine, and pharmaceutically acceptable salts thereof, Furthermore, the fatty acid acylated amino acids are preferably sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl aspartate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartate, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteine, N-dodecanoyl-L-cysteine, sodium lauroyl glutamate, N-dodecanoyl-L-glutamic acid, sodium lauroyl glutamate, N-dodecanoyl-L-glutamine, sodium lauroyl glycinate Lium, N-dodecanoyl-L-glycine, sodium lauroyl histidate, N-dodecanoyl-L-histidine, sodium lauroyl isoleucine, N-dodecanoyl-L-isoleucine, sodium lauroyl leucine, N-dodecanoyl-L-leucine, sodium lauroyl methionine, N-dodecanoyl-L-methionine, sodium lauroyl phenylalanate, N-dodecanoyl-L-phenylalanine, sodium lauroyl prophosphate, N-dodecanoyl-L-proline, sodium lauroyl serate, N-dodecanoyl Noyl-L-serine, sodium lauroyl threonate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophan, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valate, N-dodecanoyl-L-valine, sodium lauroyl sarcosinate, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric aspartate, N-decanoyl-L-asparagine, capric Capric sodium aspartate, N-decanoyl-L-aspartic acid, Capric sodium cysteine, N-decanoyl-L-cysteine, Capric sodium glutamate, N-decanoyl-L-glutamic acid, Capric sodium glutamate, N-decanoyl-L-glutamine, Capric sodium glycinate, N-decanoyl-L-glycine, Capric sodium histidate, N-decanoyl-L-histidine, Capric sodium isoleucine, N-decanoyl-L-isoleucine, Capric sodium leucine,N-decanoyl-L-leucine, Capric methionine sodium, N-decanoyl-L-methionine, Capric phenylalaninate sodium, N-decanoyl-L-phenylalanine, Capric prophosphate sodium, N-decanoyl-L-proline, Capric serate sodium, N-decanoyl-L-serine, Capric rheonate sodium, N-decanoyl-L-threonine, Capric tryptophanate sodium, N-decanoyl-L-tryptophan, Capric tyrosinate sodium, N-decanoyl-L-tyrosine, Capric Sodium licvarate, N-decanoyl-L-valine, sodium caprisarcosinate, N-decanoyl-L-sarcosine, sodium oleoyl sarcosinate, sodium N-decylleucine, sodium stearoyl glutamate, sodium myristoyl glutamate, sodium lauroyl glutamate, sodium cocoyl glutamate, sodium cocoyl glycinate, sodium N-decylleucine, sodium cocoyl glycinate, sodium cocoyl glutamate, sodium lauroyl alaninate, N-dodecanoyl-L-alanine Sodium lauroyl aspartate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartate, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteine, N-dodecanoyl-L-cysteine, sodium lauroyl glutamate, N-dodecanoyl-L-glutamic acid, sodium lauroyl glutamate, N-dodecanoyl-L-glutamine, sodium lauroyl glycinate, N-dodecanoyl-L-glycine, sodium lauroyl histidate, N-dodecanoyl-L-histidine, lauroyl iso Sodium leucate, N-dodecanoyl-L-isoleucine, sodium lauroyl leucate, N-dodecanoyl-L-leucine, sodium lauroyl methionine, N-dodecanoyl-L-methionine, sodium lauroyl phenylalanate, N-dodecanoyl-L-phenylalanine, sodium lauroyl prophosphate, N-dodecanoyl-L-proline, sodium lauroyl serate, N-dodecanoyl-L-serine, sodium lauroyl threonate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate,N-dodecanoyl-L-tryptophan, sodium lauroyltyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valate, N-dodecanoyl-L-valine, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric aspartate, N-decanoyl-L-asparagine, sodium capric aspartate, N-decanoyl-L- Aspartic acid, sodium capric cysteine, N-decanoyl-L-cysteine, sodium capric glutamate, N-decanoyl-L-glutamic acid, sodium capric glutamate, N-decanoyl-L-glutamine, sodium capric glycinate, N-decanoyl-L-glycine, sodium capric histidate, N-decanoyl-L-histidine, sodium capric isoleucinate, N- A pharmaceutical composition according to claim 11, selected from decanoyl-L-isoleucine, sodium capric leucine, N-decanoyl-L-leucine, leucine, sodium capric methionine, N-decanoyl-L-methionine, sodium capric phenylalanate, N-decanoyl-L-phenylalanine, sodium capric prophosphate, N-decanoyl-L-proline, sodium capric serate, N-decanoyl-L-serine, sodium capric leonate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophan, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valine, N-decanoyl-L-valine, sodium capric sarcosinate, sodium oleoyl sarcosinate, and pharmaceutically acceptable salts thereof.

13. The pharmaceutical composition according to claim 11, wherein the permeation enhancer is selected from sodium caprylate, sodium caprate, sodium laurate, sucrose laurate, sodium stearate, EDTA, polyacrylic acid, and sodium N-[8-(2-hydroxybenzoyl)amino]caprylate.

14. The pharmaceutical composition is pK a A pharmaceutical composition according to any one of claims 1 to 13, comprising an excipient with a value of 12 or higher in an amount of about 1 mg to about 1000 mg per drug unit, preferably in an amount of about 50 mg to about 500 mg per drug unit.

15. Peptide drugs or protein drugs have pK in their pharmaceutical composition. a A pharmaceutical composition according to any one of claims 1 to 14, wherein the excipients have a value of 12 or higher and are physically separated from them.

16. The pharmaceutical composition is pK a The particles contain excipient particles with a value of 12 or higher, and the particles are pK a A pharmaceutical composition according to any one of claims 1 to 15, wherein an excipient with a value of 12 or higher is coated with a protective coating that separates it from a peptide agent or protein agent, and the protective coating is preferably made of glucose, maltodextrin, or HPMC.

17. A pharmaceutical composition according to any one of claims 1 to 16, for use as a pharmaceutical, to be administered via the mucous membrane.

18. A pharmaceutical composition according to any one of claims 1 to 16, to be administered transmucosally for use in the treatment or prevention of a disease / disorder.

19. The pharmaceutical composition according to claim 10, for use in the treatment or prevention of diabetes, obesity, or non-alcoholic fatty liver disease, administered via mucosal administration.

20. The pharmaceutical composition according to any one of claims 17 to 19, wherein the pharmaceutical composition is administered orally.

21. The pharmaceutical composition according to any one of claims 17 to 19, wherein the pharmaceutical composition is administered to the oral mucosa.

22. The pharmaceutical composition according to any one of claims 17 to 19, wherein the pharmaceutical composition is administered intranasally.

23. A pharmaceutical composition according to any one of claims 1 to 16, to be administered orally for use in the treatment or prevention of intestinal diseases / disorders.

24. The pharmaceutical composition according to claim 22 or 23, wherein the pharmaceutical composition is a solid composition.

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