PHARMACEUTICAL FORMULATIONS FOR THE ORAL DELIVERY OF PEPTIDE OR PROTEIN DRUGS
20170304195 · 2017-10-26
Inventors
Cpc classification
A61K47/18
HUMAN NECESSITIES
A61K47/186
HUMAN NECESSITIES
A61K47/20
HUMAN NECESSITIES
A61K47/26
HUMAN NECESSITIES
A61K47/44
HUMAN NECESSITIES
A61K38/29
HUMAN NECESSITIES
A61K38/14
HUMAN NECESSITIES
A61K9/0053
HUMAN NECESSITIES
A61K38/09
HUMAN NECESSITIES
International classification
A61K9/00
HUMAN NECESSITIES
A61K47/44
HUMAN NECESSITIES
A61K38/14
HUMAN NECESSITIES
A61K47/26
HUMAN NECESSITIES
A61K9/48
HUMAN NECESSITIES
A61K38/29
HUMAN NECESSITIES
A61K47/18
HUMAN NECESSITIES
A61K47/20
HUMAN NECESSITIES
Abstract
The present invention relates to improved pharmaceutical formulations, uses and methods for the oral delivery of peptide or protein drugs with advantageously high bioavailability, safety and cost-effectiveness. In particular, the invention provides a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa for use as a medicament, wherein said peptide or protein drug is to be administered orally in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex, and with a pharmaceutically acceptable reducing agent. The invention also provides a pharmaceutical composition comprising: a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa; a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex; and a pharmaceutically acceptable reducing agent.
Claims
1-4. (canceled)
5. A pharmaceutical composition comprising: a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa; a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex; and a pharmaceutically acceptable reducing agent.
6. A pharmaceutical dosage form comprising: a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa; a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex; and a pharmaceutically acceptable reducing agent; wherein the peptide or protein drug is physically separated from the pharmaceutically acceptable copper salt/complex and the pharmaceutically acceptable zinc salt/complex within the pharmaceutical dosage form.
7. The pharmaceutical composition of claim 5, wherein the peptide or protein drug has a molecular weight of about 500 Da to about 30 kDa.
8. The pharmaceutical composition of claim 5, wherein the peptide or protein drug has a molecular weight of about 1 kDa to about 10 kDa.
9. The pharmaceutical composition of claim 5, wherein the peptide or protein drug is selected from the group consisting of insulin, an insulin analog, 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)eicosanedioyl-γ-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, a GLP-1 analog, an acylated GLP-1 analog, a diacylated GLP-1 analog, a GLP-1 agonist, semaglutide, liraglutide, exenatide, exendin-4, lixisenatide, taspoglutide, albiglutide, dulaglutide, langlenatide, GLP-1(7-37), GLP-1(7-36)NH.sub.2, a dual agonist of the GLP-1 receptor and the glucagon receptor, oxyntomodulin, GLP-2, a GLP-2 analog, a GLP-2 agonist, teduglutide, elsiglutide, amylin, an amylin analog, pramlintide, a somatostatin analog, octreotide, lanreotide, pasireotide, goserelin, buserelin, leptin, a leptin analog, metreleptin, peptide YY, a peptide YY analog, glatiramer, leuprolide, desmopressin, osteocalcin, an osteocalcin analog or derivative, human growth hormone, a human growth hormone analog, a glycopeptide antibiotic, a glycosylated cyclic or polycyclic nonribosomal peptide antibiotic, vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, decaplanin, bortezomib, cosyntropin, chorionic gonadotropin, menotropin, sermorelin, luteinizing-hormone-releasing hormone, somatropin, calcitonin, calcitonin-salmon, pentagastrin, oxytocin, neseritide, anakinra, enfuvirtide, pegvisomant, dornase alfa, lepirudin, anidulafungin, eptifibatide, interferon alfacon-1, interferon alpha-2a, interferon alpha-2b, interferon beta-1a, interferon beta-1b, interferon gamma-1b, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon beta-1a, fibrinolysin, vasopressin, aldesleukin, epoetin alfa, darbepoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, filgrastim, interleukin-11, cyclosporine, glucagon, urokinase, viomycin, thyrotropin-releasing hormone, leucine-enkephalin, methionine-enkephalin, substance P, adrenocorticotropic hormone, parathyroid hormone, a parathyroid hormone fragment, teriparatide, PTH(1-31), PTH(2-34), parathyroid hormone-related protein, abaloparatide, linaclotide, carfilzomib, icatibant, ecallantide, cilengitide, a prostaglandin F2α receptor modulator, PDC31, and pharmaceutically acceptable salts thereof.
10-11. (canceled)
12. The pharmaceutical composition of claim 5, wherein said copper salt/complex is a copper(II) salt/complex selected from the group consisting of copper sulfate, copper carbonate, a copper(II) amino acid complex, copper(II) lysine complex, copper(II) glycinate, copper(II) EDTA complex, copper(II) chitosan complex, copper(II) citrate, copper(II) gluconate, copper(II) lactate, copper lactate gluconate, and copper(II) orotate.
13. The pharmaceutical composition of claim 5, wherein said copper salt/complex is a copper(I) salt/complex selected from the group consisting of copper(I) chloride and copper(I) acetate.
14-15. (canceled)
16. The pharmaceutical composition of claim 5, wherein said zinc salt/complex is a zinc(II) salt/complex selected from the group consisting of zinc sulfate, zinc chloride, zinc acetate, zinc oxide, zinc ascorbate, zinc caprylate, zinc gluconate, zinc stearate, zinc carbonate, zinc orotate, a zinc amino acid complex, zinc glycinate, zinc arginate, zinc picolinate, zinc pidolate, zinc carnosine, zinc undecanoate, zinc undecylenate, zinc methionine, zinc lactate, and zinc lactate gluconate.
17. The pharmaceutical composition of claim 5, wherein said reducing agent is selected from the group consisting of ascorbic acid, reduced glutathione, cysteine, N-acetylcysteine, histidine, glycine, arginine, gelatin, uric acid, a reducing sugar, glucose, glyceraldehyde, galactose, fructose, ribose, xylose, sorbose, lactose, maltose, cellobiose, a glucose polymer, starch, a starch derivative, glucose syrup, maltodextrin, dextrin, dextrose, dextran, cellulose, microcrystalline cellulose, mannitol, α-tocopherol, vitamin A, α-lipoic acid, dihydro-α-lipoic acid, oxalic acid, phytic acid, a tannin, propyl gallate, butylated hydroxy toluene, butylated hydroxy anisole, sodium metabisulfite, povidone, crospovidone, an aldehyde, formaldehyde, acetaldehyde, furfuraldehyde, a dialdehyde, glyoxal, a phenolic compound, phenol, a polyphenol, salicylic acid, a salicylic acid derivative, an iron(II) salt/complex, diphosphate, disodiumdiphosphate, tri sodiumdiphosphate, tetrasodiumdiphosphate, tetrapotassiumdiphosphate, dicalciumdiphosphate, calciumdihydrogendiphophate, phosphate, dipotassium hydrogen phosphate, calcium phosphate, calcium hydrogen phosphate, a thiol-bearing compound, a thiomer, and pharmaceutically acceptable salts thereof.
18. The pharmaceutical composition of claim 17, wherein said reducing agent is an iron(II) salt/complex selected from the group consisting of iron(II) gluconate, iron(II) orotate, iron(II) tartrate, iron(II) fumarate, iron(II) sulfate, iron(II) lactate, iron(II) lactate gluconate, iron(II) acetate, iron(II) carbonate, iron(II) citrate, iron(II) oxide, iron(II) hydroxide, iron(II) ascorbate, an iron(II) amino acid complex, and ferrous bis-glycinate.
19. The pharmaceutical composition of claim 5, wherein said pharmaceutical composition further comprises an absorption enhancer.
20. The pharmaceutical composition of claim 19, wherein said absorption enhancer is selected from the group consisting of C.sub.8-20 alkanoyl carnitine, salicylic acid, a salicylic acid derivative, 3-methoxysalicylic acid, 5-methoxysalicylic acid, homovanillic acid, a C.sub.8-20 alkanoic acid, citric acid, tartaric acid, a fatty acid acylated amino acid, a C.sub.8-20 alkanoyl sarcosinate, an alkylsaccharide, a C.sub.8-10 alkylpolysaccharide, 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 cocoate, sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose mono-tetradecanoate, a coco-glucoside, a cyclodextrine, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl β-cyclodextrin, sulfobutylether β-cyclodextrin, N-[8-(2-hydroxybenzoyl)amino]caprylic acid, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, a sodium N[8-(2-hydroxybenzoyl)amino]caprylate derivative, a thiomer, a mucoadhesive polymer having a vitamin B partial structure, a calcium chelating compound, ethylenediaminetetraacetic acid, ethylene glycol tetraacetic acid, polyacrylic acid, cremophor EL, chitosan, N,N,N-trimethyl chitosan, benzalkonium chloride, bestatin, cetylpyridinium chloride, cetyltrimethylammonium bromide, a C.sub.2-20 alkanol, a C.sub.8-20 alkenol, a C.sub.8-20 alkenoic acid, dextran sulfate, diethyleneglycol monoethyl ether, 1-dodecylazacyclo-heptan-2-one, caprylocaproyl polyoxylglycerides, ethyl caprylate, glyceryl monolaurate, lysophosphatidylcholine, menthol, a C.sub.8-20 alkylamine, a C.sub.8-20 alkenylamine, phosphatidylcholine, a poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, a polysorbate, cholic acid, a deoxycholate, sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate, sodium decyl sulfate, sodium octyl sulfate, sodium laureth sulfate, N-lauryl sarcosinate, decyltrimethyl ammonium bromide, benzyldimethyl dodecyl ammonium chloride, myristyltrimethyl ammonium chloride, dodecyl pyridinium chloride, decyldimethyl ammonio propane sulfonate, myristyldimethyl ammonio propane sulfonate, palmityldimethyl ammonio propane sulfonate, ChemBetaine CAS, ChemBetaine Oleyl, Nonylphenoxypolyoxyethylene, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, sorbitan monooleate, Triton X-100, hexanoic acid, heptanoic acid, methyl laurate, isopropyl myristate, isopropyl palmitate, methyl palmitate, diethyl sebaccate, sodium oleate, urea, lauryl amine, caprolactam, methyl pyrrolidone, octyl pyrrolidone, methyl piperazine, phenyl piperazine, Carbopol 934P, glyccyrhetinic acid, bromelain, pinene oxide, limonene, cineole, octyl dodecanol, fenchone, menthone, trimethoxy propylene methyl benzene, a cell-penetrating peptide, KLAKLAK, polyarginine, penetratin, HIV-1 Tat, macrogol-15-hydroxystearate, Solutol HS 15, CriticalSorb, a taurocholate, a taurodeoxycholate, a sulfoxide, decyl methyl sulfoxide, dimethyl sulfoxide, cyclopentadecalactone, 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid, N-(10-[2-hydroxybenzoyl]amino)decanoic acid, dodecyl-2-N,N-dimethylamino propionate, D-α-tocopheryl polyethylene glycol-1000 succinate, and pharmaceutically acceptable salts thereof.
21. The pharmaceutical composition of claim 20, wherein said absorption enhancer is a fatty acid acylated amino acid selected from the group consisting of sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteinate, 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 methioninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl prolinate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, sodium lauroyl sarcosinate, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N-decanoyl-L-aspartic acid, sodium capric cysteinate, N-decanoyl-L-cysteine, sodium capric glutamic acid, N-decanoyl-L-glutamic acid, sodium capric glutaminate, 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, sodium capric methioninate, N-decanoyl-L-methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric prolinate, N-decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophane, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, 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-decyl leucine, sodium cocoyl glycine, sodium cocoyl glutamate, sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteinate, 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 methinoninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl prolinate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N-decanoyl-L-aspartic acid, sodium capric cysteinate, N-decanoyl-L-cysteine, sodium capric glutamic acid, N-decanoyl-L-glutamic acid, sodium capric glutaminate, 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, sodium capric methioninate, N-decanoyl-L-methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric prolinate, N-decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophane, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, sodium oleoyl sarcosinate, and pharmaceutically acceptable salts thereof.
22. The pharmaceutical composition of claim 19, wherein said absorption enhancer is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate.
23. The pharmaceutical composition of claim 5, wherein said pharmaceutical composition is a solid composition or a liquid composition that contains less than about 5% (v/v) of water.
24. The pharmaceutical composition of claim 19, wherein said pharmaceutical composition comprises: the copper salt/complex in an amount of about 0.1 mg to about 5 mg per dosage unit, and/or the zinc salt/complex in an amount of about 0.1 mg to about 50 mg per dosage unit; the reducing agent in an amount of about 1 mg to about 1000 mg per dosage unit; and the absorption enhancer in an amount of about 10 mg to about 1000 mg per dosage unit.
25-29. (canceled)
30. A method of orally delivering a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa, the method comprising orally administering said peptide or protein drug in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and with a pharmaceutically acceptable reducing agent to a subject in need thereof.
31. The method of claim 30, wherein the peptide or protein drug has a molecular weight of about 500 Da to about 30 kDa.
32. The method of claim 30, wherein the peptide or protein drug has a molecular weight of about 1 kDa to about 10 kDa.
33. The method of claim 30, wherein the peptide or protein drug is selected from the group consisting of insulin, an insulin analog, 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)eicosanedioyl-γ-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, a GLP-1 analog, an acylated GLP-1 analog, a diacylated GLP-1 analog, a GLP-1 agonist, semaglutide, liraglutide, exenatide, exendin-4, lixisenatide, taspoglutide, albiglutide, dulaglutide, langlenatide, GLP-1(7-37), GLP-1(7-36)NH.sub.2, a dual agonist of the GLP-1 receptor and the glucagon receptor, oxyntomodulin, GLP-2, a GLP-2 analog, a GLP-2 agonist, teduglutide, elsiglutide, amylin, an amylin analog, pramlintide, a somatostatin analog, octreotide, lanreotide, pasireotide, goserelin, buserelin, leptin, a leptin analog, metreleptin, peptide YY, a peptide YY analog, glatiramer, leuprolide, desmopressin, osteocalcin, an osteocalcin analog or derivative, human growth hormone, a human growth hormone analog, a glycopeptide antibiotic, a glycosylated cyclic or polycyclic nonribosomal peptide antibiotic, vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, decaplanin, bortezomib, cosyntropin, chorionic gonadotropin, menotropin, sermorelin, luteinizing-hormone-releasing hormone, somatropin, calcitonin, calcitonin-salmon, pentagastrin, oxytocin, neseritide, anakinra, enfuvirtide, pegvisomant, dornase alfa, lepirudin, anidulafungin, eptifibatide, interferon alfacon-1, interferon alpha-2a, interferon alpha-2b, interferon beta-1a, interferon beta-1b, interferon gamma-1b, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon beta-1a, fibrinolysin, vasopressin, aldesleukin, epoetin alfa, darbepoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, filgrastim, interleukin-11, cyclosporine, glucagon, urokinase, viomycin, thyrotropin-releasing hormone, leucine-enkephalin, methionine-enkephalin, substance P, adrenocorticotropic hormone, parathyroid hormone, a parathyroid hormone fragment, teriparatide, PTH(1-31), PTH(2-34), parathyroid hormone-related protein, abaloparatide, linaclotide, carfilzomib, icatibant, ecallantide, cilengitide, a prostaglandin F2α receptor modulator, PDC31, and pharmaceutically acceptable salts thereof.
34. The method of claim 30, wherein the method comprises orally administering said peptide or protein drug in combination with a pharmaceutically acceptable copper salt/complex.
35. (canceled)
36. The method of claim 34, wherein said copper salt/complex is a copper(II) salt/complex which is selected from the group consisting of copper sulfate, copper carbonate, a copper(II) amino acid complex, copper(II) lysine complex, copper(II) glycinate, copper(II) EDTA complex, copper(II) chitosan complex, copper(II) citrate, copper(II) gluconate, copper(II) lactate, copper lactate gluconate, and copper(II) orotate.
37. The method of claim 34, wherein said copper salt/complex is a copper(I) salt/complex which is selected from the group consisting of copper(I) chloride and copper(I) acetate.
38. The method of claim 30, wherein the method comprises orally administering said peptide or protein drug in combination with a pharmaceutically acceptable zinc salt/complex.
39. (canceled)
40. The method of claim 38, wherein said zinc salt/complex is a zinc(II) salt/complex which is selected from the group consisting of zinc sulfate, zinc chloride, zinc acetate, zinc oxide, zinc ascorbate, zinc caprylate, zinc gluconate, zinc stearate, zinc carbonate, zinc orotate, a zinc amino acid complex, zinc glycinate, zinc arginate, zinc picolinate, zinc pidolate, zinc carnosine, zinc undecanoate, zinc undecylenate, zinc methionine, zinc lactate, and zinc lactate gluconate.
41. The method of claim 30, wherein said reducing agent is selected from the group consisting of ascorbic acid, reduced glutathione, cysteine, N-acetylcysteine, histidine, glycine, arginine, gelatin, uric acid, a reducing sugar, glucose, glyceraldehyde, galactose, fructose, ribose, xylose, sorbose, lactose, maltose, cellobiose, a glucose polymer, starch, a starch derivative, glucose syrup, maltodextrin, dextrin, dextrose, dextran, cellulose, microcrystalline cellulose, mannitol, α-tocopherol, vitamin A, α-lipoic acid, dihydro-α-lipoic acid, oxalic acid, phytic acid, a tannin, propyl gallate, butylated hydroxy toluene, butylated hydroxy anisole, sodium metabisulfite, povidone, crospovidone, an aldehyde, formaldehyde, acetaldehyde, furfuraldehyde, a dialdehyde, glyoxal, a phenolic compound, phenol, a polyphenol, salicylic acid, a salicylic acid derivative, an iron(II) salt/complex, diphosphate, disodiumdiphosphate, trisodiumdiphosphate, tetrasodiumdiphosphate, tetrapotassiumdiphosphate, dicalciumdiphosphate, calciumdihydrogendiphophate, phosphate, dipotassium hydrogen phosphate, calcium phosphate, calcium hydrogen phosphate, a thiol-bearing compound, a thiomer, and pharmaceutically acceptable salts thereof.
42. The method of claim 41, wherein said reducing agent is an iron(II) salt/complex selected from the group consisting of iron(II) gluconate, iron(II) orotate, iron(II) tartrate, iron(II) fumarate, iron(II) sulfate, iron(II) lactate, iron(II) lactate gluconate, iron(II) acetate, iron(II) carbonate, iron(II) citrate, iron(II) oxide, iron(II) hydroxide, iron(II) ascorbate, an iron(II) amino acid complex, and ferrous bis-glycinate.
43. The method of claim 30, wherein the method further comprises orally administering an absorption enhancer.
44. The method of claim 43, wherein said absorption enhancer is selected from the group consisting of C.sub.8-20 alkanoyl carnitine, salicylic acid, a salicylic acid derivative, 3-methoxysalicylic acid, 5-methoxysalicylic acid, homovanillic acid, a C.sub.8-20 alkanoic acid, citric acid, tartaric acid, a fatty acid acylated amino acid, a C.sub.8-20 alkanoyl sarcosinate, an alkylsaccharide, a C.sub.8-10 alkylpolysaccharide, 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 cocoate, sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose mono-tetradecanoate, a coco-glucoside, a cyclodextrine, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl β-cyclodextrin, sulfobutylether β-cyclodextrin, N-[8-(2-hydroxybenzoyl)amino]caprylic acid, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, a sodium N-[8-(2-hydroxybenzoyl)amino]caprylate derivative, a thiomer, a mucoadhesive polymer having a vitamin B partial structure, a calcium chelating compound, ethylenediaminetetraacetic acid, ethylene glycol tetraacetic acid, polyacrylic acid, cremophor EL, chitosan, N,N,N-trimethyl chitosan, benzalkonium chloride, bestatin, cetylpyridinium chloride, cetyltrimethylammonium bromide, a C.sub.2-20 alkanol, a C.sub.8-20 alkenol, a C.sub.8-20 alkenoic acid, dextran sulfate, diethyleneglycol monoethyl ether, 1-dodecylazacyclo-heptan-2-one, caprylocaproyl polyoxylglycerides, ethyl caprylate, glyceryl monolaurate, lysophosphatidylcholine, menthol, a C.sub.8-20 alkylamine, a C.sub.8-20 alkenylamine, phosphatidylcholine, a poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, a polysorbate, cholic acid, a deoxycholate, sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate, sodium decyl sulfate, sodium octyl sulfate, sodium laureth sulfate, N-lauryl sarcosinate, decyltrimethyl ammonium bromide, benzyldimethyl dodecyl ammonium chloride, myristyltrimethyl ammonium chloride, dodecyl pyridinium chloride, decyldimethyl ammonio propane sulfonate, myristyldimethyl ammonio propane sulfonate, palmityldimethyl ammonio propane sulfonate, ChemBetaine CAS, ChemBetaine Oleyl, Nonylphenoxypolyoxyethylene, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, sorbitan monooleate, Triton X-100, hexanoic acid, heptanoic acid, methyl laurate, isopropyl myristate, isopropyl palmitate, methyl palmitate, diethyl sebaccate, sodium oleate, urea, lauryl amine, caprolactam, methyl pyrrolidone, octyl pyrrolidone, methyl piperazine, phenyl piperazine, Carbopol 934P, glyccyrhetinic acid, bromelain, pinene oxide, limonene, cineole, octyl dodecanol, fenchone, menthone, trimethoxy propylene methyl benzene, a cell-penetrating peptide, KLAKLAK, polyarginine, penetratin, HIV-1 Tat, macrogol-15-hydroxystearate, Solutol HS 15, CriticalSorb, a taurocholate, a taurodeoxycholate, a sulfoxide, decyl methyl sulfoxide, dimethyl sulfoxide, cyclopentadecalactone, 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid, N-(10[2-hydroxybenzoyl]amino)decanoic acid, dodecyl-2-N,N-dimethylamino propionate, D-α-tocopheryl polyethylene glycol-1000 succinate, and pharmaceutically acceptable salts thereof.
45. The method of claim 44, wherein said absorption enhancer is a fatty acid acylated amino acid selected from the group consisting of sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteinate, 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 methioninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl prolinate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, sodium lauroyl sarcosinate, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N-decanoyl-L-aspartic acid, sodium capric cysteinate, N-decanoyl-L-cysteine, sodium capric glutamic acid, N-decanoyl-L-glutamic acid, sodium capric glutaminate, 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, sodium capric methioninate, N-decanoyl-L-methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric prolinate, N-decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophane, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, 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-decyl leucine, sodium cocoyl glycine, sodium cocoyl glutamate, sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteinate, 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 methinoninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl prolinate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N-decanoyl-L-aspartic acid, sodium capric cysteinate, N-decanoyl-L-cysteine, sodium capric glutamic acid, N-decanoyl-L-glutamic acid, sodium capric glutaminate, 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, sodium capric methioninate, N-decanoyl-L-methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric prolinate, N-decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophane, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, sodium oleoyl sarcosinate, and pharmaceutically acceptable salts thereof.
46. The method of claim 43, wherein said absorption enhancer is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate.
Description
[0094] The invention is also described by the following illustrative figures. The appended figures show:
[0095]
[0096]
[0097] The present invention particularly relates to the following items: [0098] 1. A peptide or protein drug having a molecular weight of equal to or less than about 50 kDa for use as a medicament, wherein said peptide or protein drug is to be administered orally in combination with: [0099] a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex; and [0100] a pharmaceutically acceptable reducing agent. [0101] 2. A pharmaceutically acceptable copper salt/complex for use in therapy, wherein said copper salt/complex is to be administered orally in combination with:
[0102] a pharmaceutically acceptable reducing agent; and [0103] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa. [0104] 3. A pharmaceutically acceptable zinc salt/complex for use in therapy, wherein said zinc salt/complex is to be administered orally in combination with: [0105] a pharmaceutically acceptable reducing agent; and [0106] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa. [0107] 4. A pharmaceutically acceptable reducing agent for use in therapy, wherein said reducing agent is to be administered orally in combination with: [0108] a pharmaceutically acceptable copper salt'complex and/or a pharmaceutically acceptable zinc salt/complex; and [0109] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa. [0110] 5. A pharmaceutical composition comprising: [0111] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa; [0112] a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex; and [0113] a pharmaceutically acceptable reducing agent. [0114] 6. The pharmaceutical composition of item 5, wherein said pharmaceutical composition is for oral administration. [0115] 7. A pharmaceutical dosage form comprising: [0116] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa; [0117] a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex; and [0118] a pharmaceutically acceptable reducing agent; [0119] wherein the peptide or protein drug is physically separated from the pharmaceutically acceptable copper salt/complex and the pharmaceutically acceptable zinc salt/complex within the pharmaceutical dosage form. [0120] 8. The pharmaceutical dosage form of item 7, which is a pharmaceutical dosage form comprising: [0121] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa, which is present in a first compartment of the pharmaceutical dosage form; [0122] a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex, which is/are present in a second compartment of the pharmaceutical dosage form; and [0123] a pharmaceutically acceptable reducing agent, which is present in the first compartment and/or the second compartment of the pharmaceutical dosage form. [0124] 9. The pharmaceutical dosage form of item 7 or 8, which is in the form of a double capsule. [0125] 10. The pharmaceutical dosage form of item 7, which is a pharmaceutical dosage form comprising: [0126] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa, which is present in a first compartment of the pharmaceutical dosage form; [0127] a pharmaceutically acceptable reducing agent, which is present in a second compartment of the pharmaceutical dosage form; and [0128] a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex, which is/are present in a third compartment of the pharmaceutical dosage form. [0129] 11. The pharmaceutical dosage form of item 7 or 10, which is in the form of a multi-particulate dosage form. [0130] 12. The pharmaceutical dosage form of any one of items 7 to 11, wherein said pharmaceutical dosage form is for oral administration. [0131] 13. The peptide or protein drug for use according to item 1 or the copper salt/complex for use according to item 2 or the zinc salt/complex for use according to item 3 or the reducing agent for use according to item 4 or the pharmaceutical composition of item 5 or 6 or the pharmaceutical dosage form of any one of items 7 to 12, wherein the peptide or protein drug has a molecular weight of about 500 Da to about 30 kDa. [0132] 14. The peptide or protein drug for use according to item 1 or 13 or the copper salt/complex for use according to item 2 or 13 or the zinc salt/complex for use according to item 3 or 13 or the reducing agent for use according to item 4 or 13 or the pharmaceutical composition of item 5, 6 or 13 or the pharmaceutical dosage form of any one of items 7 to 13, wherein the peptide or protein drug has a molecular weight of about 1 kDa to about 10 kDa. [0133] 15. The peptide or protein drug for use according to item 1 or the copper salt/complex for use according to item 2 or the zinc salt/complex for use according to item 3 or the reducing agent for use according to item 4 or the pharmaceutical composition of item 5 or 6 or the pharmaceutical dosage form of any one of items 7 to 12, wherein the peptide or protein drug is selected from insulin, an insulin analog, 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)eicosanedioyl-γ-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, a GLP-1 analog, an acylated GLP-1 analog, a diacylated GLP-1 analog, a GLP-1 agonist, semaglutide, liraglutide, exenatide, exendin-4, lixisenatide, taspoglutide, albiglutide, dulaglutide, langlenatide, GLP-1(7-37), GLP-1(7-36)NH.sub.2, a dual agonist of the GLP-1 receptor and the glucagon receptor, oxyntomodulin, GLP-2, a GLP-2 analog, a GLP-2 agonist, teduglutide, elsiglutide, amylin, an amylin analog, pramlintide, a somatostatin analog, octreotide, lanreotide, pasireotide, goserelin, buserelin, leptin, a leptin analog, metreleptin, peptide YY, a peptide YY analog, glatiramer, leuprolide, desmopressin, osteocalcin, an osteocalcin analog or derivative, human growth hormone, a human growth hormone analog, a glycopeptide antibiotic, a glycosylated cyclic or polycyclic nonribosomal peptide antibiotic, vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, decaplanin, bortezomib, cosyntropin, chorionic gonadotropin, menotropin, sermorelin, luteinizing-hormone-releasing hormone, somatropin, calcitonin, calcitonin-salmon, pentagastrin, oxytocin, neseritide, anakinra, enfuvirtide, pegvisomant, dornase alfa, lepirudin, anidulafungin, eptifibatide, interferon alfacon-1, interferon alpha-2a, interferon alpha-2b, interferon beta-1a, interferon beta-1b, interferon gamma-1b, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon beta-1a, fibrinolysin, vasopressin, aldesleukin, epoetin alfa, darbepoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, filgrastim, interleukin-11, cyclosporine, glucagon, urokinase, viomycin, thyrotropin-releasing hormone, leucine-enkephalin, methionine-enkephalin, substance P, adrenocorticotropic hormone, parathyroid hormone, a parathyroid hormone fragment, teriparatide, PTH(1-31), PTH(2-34), parathyroid hormone-related protein, abaloparatide, linaclotide, carfilzomib, icatibant, ecallantide, cilengitide, a prostaglandin F2α receptor modulator, PDC31, and pharmaceutically acceptable salts thereof. [0134] 16. The peptide or protein drug for use according to any one of items 1 or 13 to 15, wherein said peptide or protein drug is to be administered in combination with a pharmaceutically acceptable copper salt/complex. [0135] 17. The peptide or protein drug for use according to any one of items 1 or 13 to 16 or the copper salt/complex for use according to any one of items 2 or 13 to 15 or the reducing agent for use according to any one of items 4 or 13 to 15 or the pharmaceutical composition of any one of items 5, 6 or 13 to 15 or the pharmaceutical dosage form of any one of items 7 to 15, wherein said copper salt/complex is a copper(I) salt/complex or a copper(II) salt/complex. [0136] 18. The peptide or protein drug for use according to item 17 or the copper salt/complex for use according to item 17 or the reducing agent for use according to item 17 or the pharmaceutical composition of item 17 or the pharmaceutical dosage form of item 17, wherein said copper salt/complex is a copper(II) salt/complex which is selected from copper sulfate, copper carbonate, a copper(II) amino acid complex, copper(II) lysine complex, copper(II) glycinate, copper(II) EDTA complex, copper(II) chitosan complex, copper(II) citrate, copper(II) gluconate, copper(II) lactate, copper lactate gluconate, and copper(II) orotate. [0137] 19. The peptide or protein drug for use according to item 17 or the copper salt/complex for use according to item 17 or the reducing agent .sup.for use according to item 17 or the pharmaceutical composition of item 17 or the pharmaceutical dosage form of item 17, wherein said copper salt/complex is a copper(I) salt/complex which is selected from copper(I) chloride and copper(I) acetate. [0138] 20. The peptide or protein drug for use according to any one of items 1 or 13 to 15, wherein said peptide or protein drug is to be administered in combination with a pharmaceutically acceptable zinc salt/complex. [0139] 21. The peptide or protein drug for use according to any one of items 1, 13 to 15 or 20 or the zinc salt/complex for use according to any one of items 3 or 13 to 15 or the reducing agent for use according to any one of items 4 or 13 to 15 or the pharmaceutical composition of any one of items 5, 6 or 13 to 15 or the pharmaceutical dosage form of any one of items 7 to 15, wherein said zinc salt/complex is a zinc(II) salt/complex. [0140] 22. The peptide or protein drug for use according to item 21 or the zinc salt/complex for use according to item 21 or the reducing agent for use according to item 21 or the pharmaceutical composition of item 21 or the pharmaceutical dosage form of item 21, wherein said zinc salt/complex is a zinc(II) salt/complex which is selected from zinc sulfate, zinc chloride, zinc acetate, zinc oxide, zinc ascorbate, zinc caprylate, zinc gluconate, zinc stearate, zinc carbonate, zinc orotate, a zinc amino acid complex, zinc glycinate, zinc arginate, zinc picolinate, zinc pidolate, zinc carnosine, zinc undecanoate, zinc undecylenate, zinc methionine, zinc lactate, and zinc lactate gluconate. [0141] 23. The peptide or protein drug for use according to any one of items 1 or 13 to 22 or the copper salt/complex for use according to any one of items 2, 13 to 15 or 17 to 19 or the zinc salt/complex for use according to any one of items 3, 13 to 15, 21 or 22 or the reducing agent for use according to any one of items 4, 13 to 15, 17 to 19, 21 or 22 or the pharmaceutical composition of any one of items 5, 6, 13 to 15, 17 to 19, 21 or 22 or the pharmaceutical dosage form of any one of items 7 to 15, 17 to 19, 21 or 22, wherein said reducing agent is selected from ascorbic acid, reduced glutathione, cysteine, N-acetylcysteine, histidine, glycine, arginine, gelatin, uric acid, a reducing sugar, glucose, glyceraldehyde, galactose, fructose, ribose, xylose, sorbose, lactose, maltose, cellobiose, a glucose polymer, starch, a starch derivative, glucose syrup, maltodextrin, dextrin, dextrose, dextran, cellulose, microcrystalline cellulose, mannitol, α-tocopherol, vitamin A, α-lipoic acid, dihydro-α-lipoic acid, oxalic acid, phytic acid, a tannin, propyl gallate, butylated hydroxy toluene, butylated hydroxy anisole, sodium metabisulfite, povidone, crospovidone, an aldehyde, formaldehyde, acetaldehyde, furfuraldehyde, a dialdehyde, glyoxal, a phenolic compound, phenol, a polyphenol, salicylic acid, a salicylic acid derivative, an iron(II) salt/complex, diphosphate, disodiumdiphosphate, trisodiumdiphosphate, tetrasodiumdiphosphate, tetrapotassiumdiphosphate, dicalciumdiphosphate, calciumdihydrogendiphophate, phosphate, dipotassium hydrogen phosphate, calcium phosphate, calcium hydrogen phosphate, a thiol-bearing compound, a thiomer, and pharmaceutically acceptable salts thereof. [0142] 24. The peptide or protein drug for use according to item 23 or the copper salt/complex for use according to item 23 or the zinc salt/complex for use according to item 23 or the reducing agent for use according to item 23 or the pharmaceutical composition of item 23 or the pharmaceutical dosage form of item 23, wherein said reducing agent is an iron(II) salt/complex selected from iron(II) gluconate, iron(II) orotate, iron(II) tartrate, iron(II) fumarate, iron(II) sulfate, iron(II) lactate, iron(II) lactate gluconate, iron(II) acetate, iron(II) carbonate, iron(II) citrate, iron(II) oxide, iron(II) hydroxide, iron(II) ascorbate, an iron(II) amino acid complex, and ferrous bis-glycinate. [0143] 25. The peptide or protein drug for use according to any one of items 1 or 13 to 24 or the copper salt/complex for use according to any one of items 2, 13 to 15, 17 to 19, 23 or 24 or the zinc salt/complex for use according to any one of items 3, 13 to 15 or 21 to 24 or the reducing agent for use according to any one of items 4, 13 to 15, 17 to 19 or 21 to 24, wherein said peptide or protein drug or said copper salt/complex or said zinc salt/complex or said reducing agent is to be administered orally in combination with an absorption enhancer. [0144] 26. The pharmaceutical composition of any one of items 5, 6, 13 to 15, 17 to 19 or 21 to 24 or the pharmaceutical dosage form of any one of items 7 to 15, 17 to 19 or 21 to 24, wherein said pharmaceutical composition or said pharmaceutical dosage form further comprises an absorption enhancer. [0145] 27. The peptide or protein drug for use according to item 25 or the copper salt/complex for use according to item 25 or the zinc salt/complex for use according to item 25 or the reducing agent for use according to item 25 or the pharmaceutical composition of item [0146] 26 or the pharmaceutical dosage form of item 26, wherein said absorption enhancer is selected from C.sub.8-20 alkanoyl carnitine, salicylic acid, a salicylic acid derivative, 3-methoxysalicylic acid. 5-methoxysalicylic acid, homovanillic acid, a C.sub.8-20 alkanoic acid, citric acid, tartaric acid, a fatty acid acylated amino acid, a C.sub.8-20 alkanoyl sarcosinate, an alkylsaccharide, a C.sub.8-10 alkylpolysaccharide, 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 cocoate, sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose mono-tetradecanoate, a coco-glucoside, a cyclodextrine, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl β-cyclodextrin, sulfobutylether β-cyclodextrin, N-[8-(2-hydroxybenzoyl)amino]caprylic acid, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, a sodium N-[8-(2-hydroxybenzoyl)amino]caprylate derivative, a thiomer, a mucoadhesive polymer having a vitamin B partial structure, a calcium chelating compound, ethylenediaminetetraacetic acid, ethylene glycol tetraacetic acid, polyacrylic acid, cremophor EL, chitosan, N,N,N-trimethyl chitosan, benzalkonium chloride, bestatin, cetylpyridinium chloride, cetyltrimethylammonium bromide, a C.sub.2-20 alkanol, a C.sub.8-20 alkenol, a C.sub.8-20 alkenoic acid, dextran sulfate, diethyleneglycol monoethyl ether, 1-dodecylazacyclo-heptan-2-one, caprylocaproyl polyoxylglycerides, ethyl caprylate, glyceryl monolaurate, lysophosphatidylcholine, menthol, a C.sub.8-20 alkylamine, a C.sub.8-20 alkenylamine, phosphatidylcholine, a poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, a polysorbate, cholic acid, a deoxycholate, sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate, sodium decyl sulfate, sodium octyl sulfate, sodium laureth sulfate, N-lauryl sarcosinate, decyltrimethyl ammonium bromide, benzyldimethyl dodecyl ammonium chloride, myristyltrimethyl ammonium chloride, dodecyl pyridinium chloride, decyldimethyl ammonio propane sulfonate, myristyldimethyl ammonio propane sulfonate, palmityldimethyl ammonio propane sulfonate, ChemBetaine CAS, ChemBetaine Oleyl, Nonylphenoxypolyoxyethylene, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, sorbitan monooleate, Triton X-100, hexanoic acid, heptanoic acid, methyl laurate, isopropyl myristate, isopropyl palmitate, methyl palmitate, diethyl sebaccate, sodium oleate, urea, lauryl amine, caprolactam, methyl pyrrolidone, octyl pyrrolidone, methyl piperazine, phenyl piperazine, Carbopol 934P, glyccyrhetinic acid, bromelain, pinene oxide, limonene, cineole, octyl dodecanol, fenchone, menthone, trimethoxy propylene methyl benzene, a cell-penetrating peptide, KLAKLAK, polyarginine, penetratin, HIV-1 Tat, macrogol-15-hydroxystearate, Solutol HS 15, CriticalSorb, a taurocholate, a taurodeoxycholate, a sulfoxide, decyl methyl sulfoxide, dimethyl sulfoxide, cyclopentadecalactone, 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid, N-(10[2-hydroxybenzoyl]amino)decanoic acid, dodecyl-2-N,N-dimethylamino propionate, D-α-tocopheryl polyethylene glycol-1000 succinate, and pharmaceutically acceptable salts thereof. [0147] 28. The peptide or protein drug for use according to item 27 or the copper salt/complex for use according to item 27 or the zinc salt/complex for use according to item 27 or the reducing agent for use according to item 27 or the pharmaceutical composition of item 27 or the pharmaceutical dosage form of item 27, wherein said absorption enhancer is a fatty acid acylated amino acid selected from sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteinate, 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 methioninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl prolinate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, sodium lauroyl sarcosinate, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N-decanoyl-L-aspartic acid, sodium capric cysteinate, N-decanoyl-L-cysteine, sodium capric glutamic acid, N-decanoyl-L-glutamic acid, sodium capric glutaminate, 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, sodium capric methioninate, N-decanoyl-L-methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric prolinate, N-decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophane, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, 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-decyl leucine, sodium cocoyl glycine, sodium cocoyl glutamate, sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteinate, 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 methinoninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl prolinate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N-decanoyl-L-aspartic acid, Sodium capric cysteinate, N-decanoyl-L-cysteine, sodium capric glutamic acid, N-decanoyl-L-glutamic acid, sodium capric glutaminate, 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, sodium capric methioninate, N-decanoyl-L-methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric prolinate, N-decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophane, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, sodium oleoyl sarcosinate, and pharmaceutically acceptable salts thereof. [0148] 29. The peptide or protein drug for use according to item 25 or the copper salt/complex for use according to item 25 or the zinc salt/complex for use according to item 25 or the reducing agent for use according to item 25 or the pharmaceutical composition of item 26 or the pharmaceutical dosage form of item 26, wherein said absorption enhancer is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate. [0149] 30. The pharmaceutical composition of any one of items 5, 6, 13 to 15, 17 to 19, 21 to 24 or 26 to 29, wherein said pharmaceutical composition is a solid composition or a liquid composition that contains less than about 5% (v/v) of water. [0150] 31. The pharmaceutical composition of any one of items 5, 6, 13 to 15, 17 to 19, 21 to 24 or 26 to 30 or the pharmaceutical dosage form of any one of items 7 to 15, 17 to 19, 21 to 24 or 26 to 29, wherein said pharmaceutical composition or said pharmaceutical dosage form comprises: [0151] the copper salt/complex in an amount of about 0.1 mg to about 5 mg per dosage unit, and/or the zinc salt/complex in an amount of about 0.1 mg to about 50 mg per dosage unit; [0152] the reducing agent in an amount of about 1 mg to about 1000 mg per dosage unit; and [0153] the absorption enhancer in an amount of about 10 mg to about 1000 mg per dosage unit. [0154] 32. Use of a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa in the preparation of a medicament which is to be administered orally in combination with: [0155] a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex; and [0156] a pharmaceutically acceptable reducing agent. [0157] 33. Use of a pharmaceutically acceptable copper salt/complex in the preparation of a medicament which is to be administered orally in combination with: [0158] a pharmaceutically acceptable reducing agent; and [0159] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa. [0160] 34. Use of a pharmaceutically acceptable zinc salt/complex in the preparation of a medicament which is to be administered orally in combination with: [0161] a pharmaceutically acceptable reducing agent; and [0162] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa. [0163] 35. Use of a pharmaceutically acceptable reducing agent in the preparation of a medicament which is to be administered orally in combination with: [0164] a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex; and [0165] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa. [0166] 36. A method of treating or preventing a disease/disorder, the method comprising orally administering, to a subject in need thereof, a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa, a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex, and a pharmaceutically acceptable reducing agent. [0167] 37. A method of orally delivering a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa, the method comprising orally administering said peptide or protein drug in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and with a pharmaceutically acceptable reducing agent to a subject in need thereof. [0168] 38. The use of any one of items 32 to 35 or the method of item 36 or 37, wherein the peptide or protein drug has a molecular weight of about 500 Da to about 30 kDa. [0169] 39. The use of any one of items 32 to 35 or 38 or the method of any one of items 36 to 38, wherein the peptide or protein drug has a molecular weight of about 1 kDa to about 10 kDa. [0170] 40. The use of any one of items 32 to 35 or the method of item 36 or 37, wherein the peptide or protein drug is selected from insulin, an insulin analog, 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)eicosanedioyl-γ-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, a GLP-1 analog, an acylated GLP-1 analog, a diacylated GLP-1 analog, a GLP-1 agonist, semaglutide, liraglutide, exenatide, exendin-4, lixisenatide, taspoglutide, albiglutide, dulaglutide, langlenatide, GLP-1(7-37), GLP-1(7-36)NH.sub.2, a dual agonist of the GLP-1 receptor and the glucagon receptor, oxyntomodulin, GLP-2, a GLP-2 analog, a GLP-2 agonist, teduglutide, elsiglutide, amylin, an amylin analog, pramlintide, a somatostatin analog, octreotide, lanreotide, pasireotide, goserelin, buserelin, leptin, a leptin analog, metreleptin, peptide YY, a peptide YY analog, glatiramer, leuprolide, desmopressin, osteocalcin, an osteocalcin analog or derivative, human growth hormone, a human growth hormone analog, a glycopeptide antibiotic, a glycosylated cyclic or polycyclic nonribosomal peptide antibiotic, vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, decaplanin, bortezomib, cosyntropin, chorionic gonadotropin, menotropin, sermorelin, luteinizing-hormone-releasing hormone, somatropin, calcitonin, calcitonin-salmon, pentagastrin, oxytocin, neseritide, anakinra, enfuvirtide, pegvisomant, dornase alfa, lepirudin, anidulafungin, eptifibatide, interferon alfacon-1, interferon alpha-2a, interferon alpha-2b, interferon beta-1a, interferon beta-1 b, interferon gamma-1b, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon beta-1a, fibrinolysin, vasopressin, aldesleukin, epoetin alfa, darbepoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, filgrastim, interleukin-11, cyclosporine, glucagon, urokinase, viomycin, thyrotropin-releasing hormone, leucine-enkephalin, methionine-enkephalin, substance P, adrenocorticotropic hormone, parathyroid hormone, a parathyroid hormone fragment, teriparatide, PTH(1-31), PTH(2-34), parathyroid hormone-related protein, abaloparatide, linaclotide, carfilzomib, icatibant, ecallantide, cilengitide, a prostaglandin F2α receptor modulator, PDC31, and pharmaceutically acceptable salts thereof. [0171] 41. The use of any one of items 32 or 38 to 40 or the method of any of items 36 to 40, wherein said peptide or protein drug is to be administered in combination with a pharmaceutically acceptable copper salt/complex. [0172] 42. The use of any one of items 32 to 35 or 38 to 41 or the method of any one of items 36 to 41, wherein said copper salt/complex is a copper(I) salt/complex or a copper(II) salt/complex. [0173] 43. The use of item 42 or the method of item 42, wherein said copper salt/complex is a copper(II) salt/complex which is selected from copper sulfate, copper carbonate, a copper(II) amino acid complex, copper(II) lysine complex, copper(II) glycinate, copper(II) EDTA complex, copper(II) chitosan complex, copper(II) citrate, copper(II) gluconate, copper(ii) lactate, copper lactate gluconate, and copper(II) orotate. [0174] 44. The use of item 42 or the method of item 42, wherein said copper salt/complex is a copper(I) salt/complex which is selected from copper(I) chloride and copper(I) acetate. [0175] 45. The use of any one of items 32 or 38 to 40 or the method of any of items 36 to 40, wherein said peptide or protein drug is to be administered in combination with a pharmaceutically acceptable zinc salt/complex. [0176] 46. The use of any one of items 32, 38 to 40 or 45 or the method of any of items 36 to 40 or 45, wherein said zinc salt/complex is a zinc(II) salt/complex. [0177] 47. The use of item 46 or the method of item 46, wherein said zinc salt/complex is a zinc(II) salt/complex which is selected from zinc sulfate, zinc chloride, zinc acetate, zinc oxide, zinc ascorbate, zinc caprylate, zinc gluconate, zinc stearate, zinc carbonate, zinc orotate, a zinc amino acid complex, zinc glycinate, zinc arginate, zinc picolinate, zinc pidolate, zinc carnosine, zinc undecanoate, zinc undecylenate, zinc methionine, zinc lactate, and zinc lactate gluconate. [0178] 48. The use of any one of items 32 to 35 or 38 to 47 or the method of any of items 36 to 47, wherein said reducing agent is selected from ascorbic acid, reduced glutathione, cysteine, N-acetylcysteine, histidine, glycine, arginine, gelatin, uric acid, a reducing sugar, glucose, glyceraldehyde, galactose, fructose, ribose, xylose, sorbose, lactose, maltose, cellobiose, a glucose polymer, starch, a starch derivative, glucose syrup, maltodextrin, dextrin, dextrose, dextran, cellulose, microcrystalline cellulose, mannitol, α-tocopherol, vitamin A, α-lipoic acid, dihydro-α-lipoic acid, oxalic acid, phytic acid, a tannin, propyl gallate, butylated hydroxy toluene, butylated hydroxy anisole, sodium metabisulfite, povidone, crospovidone, an aldehyde, formaldehyde, acetaldehyde, furfuraldehyde, a dialdehyde, glyoxal, a phenolic compound, phenol, a polyphenol, salicylic acid, a salicylic acid derivative, an iron(II) salt/complex, diphosphate, disodiumdiphosphate, trisodiumdiphosphate, tetrasodiumdiphosphate, tetrapotassiumdiphosphate, dicalciumdiphosphate, calciumdihydrogendiphophate, phosphate, dipotassium hydrogen phosphate, calcium phosphate, calcium hydrogen phosphate, a thiol-bearing compound, a thiomer, and pharmaceutically acceptable salts thereof. [0179] 49. The use of item 48 or the method of item 48, wherein said reducing agent is an iron(II) salt/complex selected from iron(II) gluconate, iron(II) orotate, iron(II) tartrate, iron(II) fumarate, iron(II) sulfate, iron(II) lactate, iron(II) lactate gluconate, iron(II) acetate, iron(II) carbonate, iron(II) citrate, iron(II) oxide, iron(II) hydroxide, iron(II) ascorbate, an iron(II) amino acid complex, and ferrous bis-glycinate. [0180] 50. The use of any one of items 32 to 35 or 38 to 49 or the method of any of items 36 to 49, wherein an absorption enhancer is further to be administered orally. [0181] 51. The use of item 50 or the method of item 50, wherein said absorption enhancer is selected from C.sub.8-20 alkanoyl carnitine, salicylic acid, a salicylic acid derivative, 3-methoxysalicylic acid, 5-methoxysalicylic acid, homovanillic acid, a C.sub.8-20 alkanoic acid, citric acid, tartaric acid, a fatty acid acylated amino acid, a C.sub.8-20 alkanoyl sarcosinate, an alkylsaccharide, a C.sub.8-10 alkylpolysaccharide, 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 cocoate, sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose mono-tetradecanoate, a coco-glucoside, a cyclodextrine, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl β-cyclodextrin, sulfobutylether β-cyclodextrin, N-[8-(2-hydroxybenzoyl)amino]caprylic acid, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, a sodium N-[8-(2-hydroxybenzoyl)amino]caprylate derivative, a thiomer, a mucoadhesive polymer having a vitamin B partial structure, a calcium chelating compound, ethylenediaminetetraacetic acid, ethylene glycol tetraacetic acid, polyacrylic acid, cremophor EL, chitosan, N,N,N-trimethyl chitosan, benzalkonium chloride, bestatin, cetylpyridinium chloride, cetyltrimethylammonium bromide, a C.sub.2-20 alkanol, a C.sub.8-20 alkenol, a C.sub.8-20 alkenoic acid, dextran sulfate, diethyleneglycol monoethyl ether, 1-dodecylazacyclo-heptan-2-one, caprylocaproyl polyoxylglycerides, ethyl caprylate, glyceryl monolaurate, lysophosphatidylcholine, menthol, a C.sub.8-20 alkylamine, a C.sub.8-20 alkenylamine, phosphatidylcholine, a poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, a polysorbate, cholic acid, a deoxycholate, sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate, sodium decyl sulfate, sodium octyl sulfate, sodium laureth sulfate, N-lauryl sarcosinate, decyltrimethyl ammonium bromide, benzyldimethyl dodecyl ammonium chloride, myristyltrimethyl ammonium chloride, dodecyl pyridinium chloride, decyldimethyl ammonio propane sulfonate, myristyldimethyl ammonio propane sulfonate, palmityidimethyl ammonio propane sulfonate, ChemBetaine CAS, ChemBetaine Oleyl, Nonylphenoxypolyoxyethylene, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, sorbitan monooleate, Triton X-100, hexanoic acid, heptanoic acid, methyl laurate, isopropyl myristate, isopropyl palmitate, methyl palmitate, diethyl sebaccate, sodium oleate, urea, lauryl amine, caprolactam, methyl pyrrolidone, octyl pyrrolidone, methyl piperazine, phenyl piperazine, Carbopol 934P, glyccyrhetinic acid, bromelain, pinene oxide, limonene, cineole, octyl dodecanol, fenchone, menthone, trimethoxy propylene methyl benzene, a cell-penetrating peptide, KLAKLAK, polyarginine, penetratin, HIV-1 Tat, macrogol-15-hydroxystearate, Solutol HS 15, CriticalSorb, a taurocholate, a taurodeoxycholate, a sulfoxide, decyl methyl sulfoxide, dimethyl sulfoxide, cyclopentadecalactone, 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid, N-(10-[2-hydroxybenzoyl]amino)decanoic acid, dodecyl-2-N,N-dimethylamino propionate, D-α-tocopheryl polyethylene glycol-1000 succinate, and pharmaceutically acceptable salts thereof. [0182] 52. The use of item 51 or the method of item 51, wherein said absorption enhancer is a fatty acid acylated amino acid selected from sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteinate, 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 methioninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl prolinate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, sodium lauroyl sarcosinate, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N-decanoyl-L-aspartic acid, sodium capric cysteinate, N-decanoyl-L-cysteine, sodium capric glutamic acid, N-decanoyl-L-glutamic acid, sodium capric glutaminate, 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, sodium capric methioninate, N-decanoyl-L-methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric prolinate, N-decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophane, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, 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 glycine, sodium cocoyl glutamate, sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteinate, 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 methinoninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl prolinate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N-decanoyl-L-aspartic acid, Sodium capric cysteinate, N-decanoyl-L-cysteine, sodium capric glutamic acid, N-decanoyl-L-glutamic acid, sodium capric glutaminate, 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, sodium capric methioninate, N-decanoyl-L-methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric prolinate, N-decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophane, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, sodium oleoyl sarcosinate, and pharmaceutically acceptable salts thereof. [0183] 53. The use of item 50 or the method of item 50, wherein said absorption enhancer is sodium N48-(2-hydroxybenzoyl)amino]caprylate.
[0184] The invention furthermore relates to the following embodiments: [0185] 1. A peptide or protein drug having a molecular weight of equal to or less than about 50 kDa for use as a medicament, wherein said peptide or protein drug is to be administered orally in combination with: [0186] a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex; and [0187] a pharmaceutically acceptable reducing agent. [0188] 2. A pharmaceutically acceptable copper salt/complex for use in therapy, wherein said copper salt/complex is to be administered orally in combination with: [0189] a pharmaceutically acceptable reducing agent; and [0190] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa. [0191] 3. A pharmaceutically acceptable zinc salt/complex for use in therapy, wherein said zinc salt/complex is to be administered orally in combination with: [0192] a pharmaceutically acceptable reducing agent; and [0193] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa. [0194] 4. A pharmaceutically acceptable reducing agent for use in therapy, wherein said reducing agent is to be administered orally in combination with: [0195] a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex; and [0196] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa. [0197] 5. A pharmaceutical composition comprising: [0198] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa; [0199] a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex; and [0200] a pharmaceutically acceptable reducing agent. [0201] 6. The pharmaceutical composition of embodiment 5, wherein said pharmaceutical composition is for oral administration. [0202] 7. A pharmaceutical dosage form comprising: [0203] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa; [0204] a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex; and [0205] a pharmaceutically acceptable reducing agent; [0206] wherein the peptide or protein drug is physically separated from the pharmaceutically acceptable copper salt/complex and the pharmaceutically acceptable zinc salt/complex within the pharmaceutical dosage form. [0207] 8. The pharmaceutical dosage form of embodiment 7, which is a pharmaceutical dosage form comprising: [0208] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa, which is present in a first compartment of the pharmaceutical dosage form; [0209] a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex, which is/are present in a second compartment of the pharmaceutical dosage form; and [0210] a pharmaceutically acceptable reducing agent, which is present in the first compartment and/or the second compartment of the pharmaceutical dosage form. [0211] 9. The pharmaceutical dosage form of embodiment 7 or 8, which is in the form of a double capsule. [0212] 10. The pharmaceutical dosage form of embodiment 7, which is a pharmaceutical dosage form comprising: [0213] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa, which is present in a first compartment of the pharmaceutical dosage form; [0214] a pharmaceutically acceptable reducing agent, which is present in a second compartment of the pharmaceutical dosage form; and [0215] a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex, which is/are present in a third compartment of the pharmaceutical dosage form. [0216] 11. The pharmaceutical dosage form of embodiment 7 or 10, which is in the form of a multi-particulate dosage form. [0217] 12. The pharmaceutical dosage form of any one of embodiments 7 to 11, wherein said pharmaceutical dosage form is for oral administration. [0218] 13. The peptide or protein drug for use according to embodiment 1 or the copper salt/complex for use according to embodiment 2 or the zinc salt/complex for use according to embodiment 3 or the reducing agent for use according to embodiment 4 or the pharmaceutical composition of embodiment 5 or 6 or the pharmaceutical dosage form of any one of embodiments 7 to 12, wherein the peptide or protein drug has a molecular weight of about 500 Da to about 30 kDa. [0219] 14. The peptide or protein drug for use according to embodiment 1 or 13 or the copper salt/complex for use according to embodiment 2 or 13 or the zinc salt/complex for use according to embodiment 3 or 13 or the reducing agent for use according to embodiment 4 or 13 or the pharmaceutical composition of embodiment 5, 6 or 13 or the pharmaceutical dosage form of any one of embodiments 7 to 13, wherein the peptide or protein drug has a molecular weight of about 1 kDa to about 10 kDa. [0220] 15. The peptide or protein drug for use according to embodiment 1 or the copper salt/complex for use according to embodiment 2 or the zinc salt/complex for use according to embodiment 3 or the reducing agent for use according to embodiment 4 or the pharmaceutical composition of embodiment 5 or 6 or the pharmaceutical dosage form of any one of embodiments 7 to 12, wherein the peptide or protein drug is selected from insulin, an insulin analog, 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)eicosanedioyl-γ-L-Glu) A14E B25H desB30 human insulin, B29K(N(ε)octadecanedioyl-γ-L-Glu-OEG-OEG) Al 4E 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, a GLP-1 analog, an acylated GLP-1 analog, a diacylated GLP-1 analog, semaglutide, liraglutide, exenatide, lixizenatide, a dual agonist of the GLP-1 receptor and the glucagon receptor, amylin, an amylin analog, pramlintide, a somatostatin analog, octreotide, lanreotide, pasireotide, goserelin, buserelin, leptin, a leptin analog, metreleptin, peptide YY, a peptide YY analog, glatiramer, leuprolide, teriparatide, desmopressin, human growth hormone, a human growth hormone analog, a glycopeptide antibiotic, a glycosylated cyclic or polycyclic nonribosomal peptide antibiotic, vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, decaplanin, bortezomib, cosyntropin, chorionic gonadotropin, menotropin, sermorelin, luteinizing-hormone-releasing hormone, somatropin, calcitonin, calcitonin-salmon, pentagastrin, oxytocin, neseritide, anakinra, enfuvirtide, pegvisomant, dornase alfa, lepirudin, anidulafungin, eptifibatide, interferon alfacon-1, interferon alpha-2a, interferon alpha-2b, interferon beta-1a, interferon beta-1b, interferon gamma-1b, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon beta-1 a, fibrinolysin, vasopressin, aldesleukin, epoetin alfa, darbepoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, filgrastim, interleukin-11, cyclosporine, glucagon, urokinase, viomycin, thyrotropin-releasing hormone, leucine-enkephalin, methionine-enkephalin, substance P, adrenocorticotropic hormone, parathyroid hormone, and pharmaceutically acceptable salts thereof. [0221] 16. The peptide or protein drug for use according to any one of embodiments 1 or 13 to 15, wherein said peptide or protein drug is to be administered in combination with a pharmaceutically acceptable copper salt/complex. [0222] 17. The peptide or protein drug for use according to any one of embodiments 1 or 13 to 16 or the copper salt/complex for use according to any one of embodiments 2 or 13 to 15 or the reducing agent for use according to any one of embodiments 4 or 13 to 15 or the pharmaceutical composition of any one of embodiments 5, 6 or 13 to 15 or the pharmaceutical dosage form of any one of embodiments 7 to 15, wherein said copper salt/complex is a copper(I) salt/complex or a copper(II) salt/complex. [0223] 18. The peptide or protein drug for use according to embodiment 17 or the copper salt/complex for use according to embodiment 17 or the reducing agent for use according to embodiment 17 or the pharmaceutical composition of embodiment 17 or the pharmaceutical dosage form of embodiment 17, wherein said copper salt/complex is a copper(II) salt/complex which is selected from copper sulfate, copper carbonate, copper(II) lysine complex, copper(II) citrate, and copper(II) gluconate. [0224] 19. The peptide or protein drug for use according to embodiment 17 or the copper salt/complex for use according to embodiment 17 or the reducing agent for use according to embodiment 17 or the pharmaceutical composition of embodiment 17 or the pharmaceutical dosage form of embodiment 17, wherein said copper salt/complex is a copper(I) salt/complex which is selected from copper(I) chloride and copper(I) acetate. [0225] 20. The peptide or protein drug for use according to any one of embodiments 1 or 13 to 15, wherein said peptide or protein drug is to be administered in combination with a pharmaceutically acceptable zinc salt/complex. [0226] 21. The peptide or protein drug for use according to any one of embodiments 1, 13 to 15 or 20 or the zinc salt/complex for use according to any one of embodiments 3 or 13 to 15 or the reducing agent for use according to any one of embodiments 4 or 13 to 15 or the pharmaceutical composition of any one of embodiments 5, 6 or 13 to 15 or the pharmaceutical dosage form of any one of embodiments 7 to 15, wherein said zinc salt/complex is a zinc(II) salt/complex. [0227] 22. The peptide or protein drug for use according to embodiment 21 or the zinc salt/complex for use according to embodiment 21 or the reducing agent for use according to embodiment 21 or the pharmaceutical composition of embodiment 21 or the pharmaceutical dosage form of embodiment 21, wherein said zinc salt/complex is a zinc(II) salt/complex which is selected from zinc sulfate, zinc chloride, zinc acetate, zinc oxide, zinc ascorbate, zinc caprylate, zinc gluconate, zinc stearate, and zinc carbonate. [0228] 23. The peptide or protein drug for use according to any one of embodiments 1 or 13 to 22 or the copper salt/complex for use according to any one of embodiments 2, 13 to 15 or 17 to 19 or the zinc salt/complex for use according to any one of embodiments 3, 13 to 15, 21 or 22 or the reducing agent for use according to any one of embodiments 4, 13 to 15, 17 to 19, 21 or 22 or the pharmaceutical composition of any one of embodiments 5, 6, 13 to 15, 17 to 19, 21 or 22 or the pharmaceutical dosage form of any one of embodiments 7 to 15, 17 to 19, 21 or 22, wherein said reducing agent is selected from ascorbic acid, reduced glutathione, cysteine, uric acid, a reducing sugar, glucose, glyceraldehyde, galactose, lactose, maltose, mannitol, α-tocopherol, vitamin A, α-lipoic acid, dihydro-α-lipoic acid, a thiol-bearing compound, a thiomer, and pharmaceutically acceptable salts thereof. [0229] 24. The peptide or protein drug for use according to any one of embodiments 1 or 13 to 23 or the copper salt/complex for use according to any one of embodiments 2, 13 to 15, 17 to 19 or 23 or the zinc salt/complex for use according to any one of embodiments 3, 13 to 15 or 21 to 23 or the reducing agent for use according to any one of embodiments 4, 13 to 15, 17 to 19 or 21 to 23, wherein said peptide or protein drug or said copper salt/complex or said zinc salt/complex or said reducing agent is to be administered orally in combination with an absorption enhancer. [0230] 25. The pharmaceutical composition of any one of embodiments 5, 6, 13 to 15, 17 to 19 or 21 to 23 or the pharmaceutical dosage form of any one of embodiments 7 to 15, 17 to 19 or 21 to 23, wherein said pharmaceutical composition or said pharmaceutical dosage form further comprises an absorption enhancer. [0231] 26. The peptide or protein drug for use according to embodiment 24 or the copper salt/complex for use according to embodiment 24 or the zinc salt/complex for use according to embodiment 24 or the reducing agent for use according to embodiment 24 or the pharmaceutical composition of embodiment 25 or the pharmaceutical dosage form of embodiment 25, wherein said absorption enhancer is selected from C.sub.8-20 alkanoyl carnitine, salicylic acid, a salicylic acid derivative, 3-methoxysalicylic acid, 5-methoxysalicylic acid, homovanillic acid, a C.sub.8-20 alkanoic acid, citric acid, a fatty acid acylated amino acid, a C.sub.8-20 alkanoyl sarcosinate, an alkylsaccharide, a C.sub.8-10 alkylpolysaccharide, n-octyl-beta-D-glucopyranoside, n-dodecyl-beta-D-maltoside, a cyclodextrine, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl β-cyclodextrin, sulfobutylether β-cyclodextrin, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, a thiomer, a calcium chelating compound, ethylenediaminetetraacetic acid, ethylene glycol tetraacetic acid, polyacrylic acid, cremophor EL, chitosan, N,N,N-trimethyl chitosan, benzalkonium chloride, bestatin, cetylpyridinium chloride, cetyltrimethylammonium bromide, a C.sub.2-20 alkanol, a C.sub.8-20 alkenol, a C.sub.8-20 alkenoic acid, dextran sulfate, diethyleneglycol monoethyl ether, 1-dodecylazacyclo-heptan-2-one, ethyl caprylate, glyceryl monolaurate, lysophosphatidylcholine, menthol, a C.sub.8-20 alkylamine, a C.sub.8-20 alkenylamine, phosphatidylcholine, a poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, a polysorbate, a deoxycholate, sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate, a taurocholate, a taurodeoxycholate, sucrose laurate, a sulfoxide, decyl methyl sulfoxide, dimethyl sulfoxide, cyclopentadecalactone, 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid, dodecyl-2-N,N-dimethylamino propionate, D-α-tocopheryl polyethylene glycol-1000 succinate, and pharmaceutically acceptable salts thereof. [0232] 27. The peptide or protein drug for use according to embodiment 26 or the copper salt/complex for use according to embodiment 26 or the zinc salt/complex for use according to embodiment 26 or the reducing agent for use according to embodiment 26 or the pharmaceutical composition of embodiment 26 or the pharmaceutical dosage form of embodiment 26, wherein said absorption enhancer is a fatty acid acylated amino acid selected from sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteinate, 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 methioninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl prolinate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, sodium lauroyl sarcosinate, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N-decanoyl-L-aspartic acid, sodium capric cysteinate, N-decanoyl-L-cysteine, sodium capric glutamic acid, N-decanoyl-L-glutamic acid, sodium capric glutaminate, 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, sodium capric methioninate, N-decanoyl-L-methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric prolinate, N-decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophane, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, 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-decyl leucine, sodium cocoyl glycine, sodium cocoyl glutamate, sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteinate, 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 methinoninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl prolinate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N-decanoyl-L-aspartic acid, Sodium capric cysteinate, N-decanoyl-L-cysteine, sodium capric glutamic acid, N-decanoyl-L-glutamic acid, sodium capric glutaminate, 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, sodium capric methioninate, N-decanoyl-L-methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric prolinate, N-decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophane, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, sodium oleoyl sarcosinate, and pharmaceutically acceptable salts thereof. [0233] 28. The pharmaceutical composition of any one of embodiments 5, 6, 13 to 15, 17 to 19, 21 to 23 or 25 to 27, wherein said pharmaceutical composition is a solid composition or a liquid composition that contains less than about 5% (v/v) of water. [0234] 29. The pharmaceutical composition of any one of embodiments 5, 6, 13 to 15, 17 to 19, 21 to 23 or 25 to 28 or the pharmaceutical dosage form of any one of embodiments 7 to 15, 17 to 19, 21 to 23 or 25 to 27, wherein said pharmaceutical composition or said pharmaceutical dosage form comprises: [0235] the copper salt/complex in an amount of about 0.1 mg to about 5 mg per dosage unit, and/or the zinc salt/complex in an amount of about 0.1 mg to about 50 mg per dosage unit; [0236] the reducing agent in an amount of about 1 mg to about 1000 mg per dosage unit; and the absorption enhancer in an amount of about 10 mg to about 1000 mg per dosage unit. [0237] 30. Use of a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa in the preparation of a medicament which is to be administered orally in combination with: [0238] a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex; and [0239] a pharmaceutically acceptable reducing agent. [0240] 31. Use of a pharmaceutically acceptable copper salt/complex in the preparation of a medicament which is to be administered orally in combination with: [0241] a pharmaceutically acceptable reducing agent; and [0242] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa. [0243] 32. Use of a pharmaceutically acceptable zinc salt/complex in the preparation of a medicament which is to be administered orally in combination with: [0244] a pharmaceutically acceptable reducing agent; and [0245] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa. [0246] 33. Use of a pharmaceutically acceptable reducing agent in the preparation of a medicament which is to be administered orally in combination with: [0247] a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex; and [0248] a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa. [0249] 34. A method of treating or preventing a disease/disorder, the method comprising orally administering, to a subject in need thereof, a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa, a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex, and a pharmaceutically acceptable reducing agent. [0250] 35. A method of orally delivering a peptide or protein drug having a molecular weight of equal to or less than about 50 kDa, the method comprising orally administering said peptide or protein drug in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and with a pharmaceutically acceptable reducing agent to a subject in need thereof. [0251] 36. The use of any one of embodiments 30 to 33 or the method of embodiment 34 or 35, wherein the peptide or protein drug has a molecular weight of about 500 Da to about 30 kDa. [0252] 37. The use of any one of embodiments 30 to 33 or 36 or the method of any one of embodiments 34 to 36, wherein the peptide or protein drug has a molecular weight of about 1 kDa to about 10 kDa. [0253] 38. The use of any one of embodiments 30 to 33 or the method of embodiment 34 or 35, wherein the peptide or protein drug is selected from insulin, an insulin analog, 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)eicosanedioyl-γ-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, a GLP-1 analog, an acylated GLP-1 analog, a diacylated GLP-1 analog, semaglutide, liraglutide, exenatide, lixizenatide, a dual agonist of the GLP-1 receptor and the glucagon receptor, amylin, an amylin analog, pramlintide, a somatostatin analog, octreotide, lanreotide, pasireotide, goserelin, buserelin, leptin, a leptin analog, metreleptin, peptide YY, a peptide YY analog, glatiramer, leuprolide, teriparatide, desmopressin, human growth hormone, a human growth hormone analog, a glycopeptide antibiotic, a glycosylated cyclic or polycyclic nonribosomal peptide antibiotic, vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, decaplanin, bortezomib, cosyntropin, chorionic gonadotropin, menotropin, sermorelin, luteinizing-hormone-releasing hormone, somatropin, calcitonin, calcitonin-salmon, pentagastrin, oxytocin, neseritide, anakinra, enfuvirtide, pegvisomant, dornase alfa, lepirudin, anidulafungin, eptifibatide, interferon alfacon-1, interferon alpha-2a, interferon alpha-2b, interferon beta-1a, interferon beta-1b, interferon gamma-1b, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon beta-1 a, fibrinolysin, vasopressin, aldesleukin, epoetin alfa, darbepoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, filgrastim, interleukin-11, cyclosporine, glucagon, urokinase, viomycin, thyrotropin-releasing hormone, leucine-enkephalin, methionine-enkephalin, substance P, adrenocorticotropic hormone, parathyroid hormone, and pharmaceutically acceptable salts thereof. [0254] 39. The use of any one of embodiments 30 or 36 to 38 or the method of any of embodiments 34 to 38, wherein said peptide or protein drug is to be administered in combination with a pharmaceutically acceptable copper salt/complex. [0255] 40. The use of any one of embodiments 30 to 33 or 36 to 39 or the method of any one of embodiments 34 to 39, wherein said copper salt/complex is a copper(I) salt/complex or a copper(II) salt/complex. [0256] 41. The use of embodiment 40 or the method of embodiment 40, wherein said copper salt/complex is a copper(II) salt/complex which is selected from copper sulfate, copper carbonate, copper(II) lysine complex, copper(II) citrate, and copper(II) gluconate. [0257] 42. The use of embodiment 40 or the method of embodiment 40, wherein said copper salt/complex is a copper(I) salt/complex which is selected from copper(I) chloride and copper(I) acetate. [0258] 43. The use of any one of embodiments 30 or 36 to 38 or the method of any of embodiments 34 to 38, wherein said peptide or protein drug is to be administered in combination with a pharmaceutically acceptable zinc salt/complex. [0259] 44. The use of any one of embodiments 30, 36 to 38 or 43 or the method of any of embodiments 34 to 38 or 43, wherein said zinc salt/complex is a zinc(II) salt/complex. [0260] 45. The use of embodiment 44 or the method of embodiment 44, wherein said zinc salt/complex is a zinc(II) salt/complex which is selected from zinc sulfate, zinc chloride, zinc acetate, zinc oxide, zinc ascorbate, zinc caprylate, zinc gluconate, zinc stearate, and zinc carbonate. [0261] 46. The use of any one of embodiments 30 to 33 or 36 to 45 or the method of any of embodiments 34 to 45, wherein said reducing agent is selected from ascorbic acid, reduced glutathione, cysteine, uric acid, a reducing sugar, glucose, glyceraldehyde, galactose, lactose, maltose, mannitol, α-tocopherol, vitamin A, α-lipoic acid, dihydro-α-lipoic acid, a thiol-bearing compound, a thiomer, and pharmaceutically acceptable salts thereof. [0262] 47. The use of any one of embodiments 30 to 33 or 36 to 46 or the method of any of embodiments 34 to 46, wherein an absorption enhancer is further to be administered orally. [0263] 48. The use of embodiment 47 or the method of embodiment 47, wherein said absorption enhancer is selected from C.sub.8-20 alkanoyl carnitine, salicylic acid, a salicylic acid derivative, 3-methoxysalicylic acid, 5-methoxysalicylic acid, homovanillic acid, a C.sub.8-20 alkanoic acid, citric acid, a fatty acid acylated amino acid, a C.sub.8-20 alkanoyl sarcosinate, an alkylsaccharide, a C.sub.8-10 alkylpolysaccharide, n-octyl-beta-D-glucopyranoside, n-dodecyl-beta-D-maltoside, a cyclodextrine, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl β-cyclodextrin, sulfobutylether β-cyclodextrin, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, a thiomer, a calcium chelating compound, ethylenediaminetetraacetic acid, ethylene glycol tetraacetic acid, polyacrylic acid, cremophor EL, chitosan, N,N,N-trimethyl chitosan, benzalkonium chloride, bestatin, cetylpyridinium chloride, cetyltrimethylammonium bromide, a C.sub.2-20 alkanol, a C.sub.8-20 alkenol, a C.sub.8-20 alkenoic acid, dextran sulfate, diethyleneglycol monoethyl ether, 1-dodecylazacyclo-heptan-2-one, ethyl caprylate, glyceryl monolaurate, lysophosphatidylcholine, menthol, a C.sub.8-20 alkylamine, a C.sub.8-20 alkenylamine, phosphatidylcholine, a poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, a polysorbate, a deoxycholate, sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate, a taurocholate, a taurodeoxycholate, sucrose laurate, a sulfoxide, decyl methyl sulfoxide, dimethyl sulfoxide, cyclopentadecalactone, 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid, dodecyl-2-N,N-dimethylamino propionate, D-α-tocopheryl polyethylene glycol-1000 succinate, and pharmaceutically acceptable salts thereof. [0264] 49. The use of embodiment 48 or the method of embodiment 48, wherein said absorption enhancer is a fatty acid acylated amino acid selected from sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteinate, 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 methioninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl prolinate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, sodium lauroyl sarcosinate, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N-decanoyl-L-aspartic acid, sodium capric cysteinate, N-decanoyl-L-cysteine, sodium capric glutamic acid, N-decanoyl-L-glutamic acid, sodium capric glutaminate, 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, sodium capric methioninate, N-decanoyl-L-methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric prolinate, N-decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophane, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, 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-decyl leucine, sodium cocoyl glycine, sodium cocoyl glutamate, sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteinate, 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 methinoninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl prolinate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N-decanoyl-L-aspartic acid, Sodium capric cysteinate, N-decanoyl-L-cysteine, sodium capric glutamic acid, N-decanoyl-L-glutamic acid, sodium capric glutaminate, 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, sodium capric methioninate, N-decanoyl-L-methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric prolinate, N-decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophane, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, sodium oleoyl sarcosinate, and pharmaceutically acceptable salts thereof.
[0265] The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.
EXAMPLES
[0266] General Description of Methods
[0267] Administration into Mid-Jejunum in Rats:
[0268] After checking of the depth of anesthesia the animal was placed on its back and a 3-5 cm long midline incision was made in the skin of abdomen. The wound margins were released from the base. The muscle layer of the abdominal wall was carefully cut in the middle line (linea alba).
[0269] The caecum was exposed and the small intestine was gradually pulled out of the abdominal cavity and the position of the spot convenient for introduction of catheter was measured using a PE tubing with marks at a distance of 40, 50, and 60 cm. Pulling the intestine was performed very carefully to avoid injury of blood vessels and mesentery. The intestine was penetrated by the catheter tip and the catheter was inserted downstream into the jejunal lumen at a distance of 50 (35-65) cm from caecum in a spot without feces, outside the area with accumulated lymphatic tissue and outside the blood vessels and fixed with ligature. The distance of the spot from caecum was measured and recorded.
[0270] The pulled loops of small intestine were replaced into the abdominal cavity, 2 ml of sterile saline were flushed over the intestine and the abdominal cavity was closed with metal wound clips in two layers. The prepared syringes filled with the formulations were gradually attached to the inserted catheters. Dosing was performed slowly. The syringes with peptide or protein drug were attached to the inserted cannula until the end of the experiment.
[0271] Correctness of the application was checked. The abdominal cavity was opened by cutting next to the surgical wound to see if the catheter was still in place. About 1 ml of air was flushed into the lumen of the intestine with a syringe to reveal possible penetration of intestinal wall. The site of application was inspected and possible changes were identified.
Example 1
Compatibility of Absorption Enhancers with the Trace Element Copper
[0272] Various absorption enhancers were screened regarding their compatibility with the trace element copper in the two main oxidation states as Cu.sup.2+ and Cu.sup.+. The results of this test are shown in the following Table 1:
TABLE-US-00001 TABLE 1 Compatibility of various absorption enhancers with Cu.sup.2+ and Cu.sup.+ salts. Dissolution Absorption enhancer Copper salt Reducing agent in aqueous (10 mg/ml) (1 mg/ml) (10 mg/ml) medium (2 ml) Sodium caprate CuSO.sub.4 Sodium ascorbate Precipitation Sodium caprylate CuSO.sub.4 Sodium ascorbate Precipitation Sodium lauroyl CuSO.sub.4 Sodium ascorbate Precipitation sarcosinate Lauroyl carnitine CuSO.sub.4 Sodium ascorbate Clear solution Lauroyl carnitine CuSO.sub.4 Glutathione Clear solution Sodium dodecyl CuSO.sub.4 Sodium ascorbate Clear solution sulfate Multitrope 1620 LQ CuSO.sub.4 Sodium ascorbate Clear solution (alkylsaccharide) n-Octyl-beta-D- CuSO.sub.4 Sodium ascorbate Clear solution glucopyranoside n-Dodecyl-beta-D- CuSO.sub.4 Sodium ascorbate Clear solution maltoside Cremophor EL CuSO.sub.4 Sodium ascorbate Clear solution Sodium salicylate CuSO.sub.4 Sodium ascorbate Clear solution EDTA CuSO.sub.4 Sodium ascorbate Clear solution Sodium citrate CuSO.sub.4 Sodium ascorbate Clear solution Methyl-beta- CuSO.sub.4 Sodium ascorbate Clear solution cyclodextrin Sodium caprylate Copper (I) Sodium ascorbate Clear solution acetate Sodium caprate Copper (I) Sodium ascorbate Clear solution acetate Sodium caprate Cu(I)Cl Sodium ascorbate Clear solution Sodium caprylate Cu(I)Cl Sodium ascorbate Clear solution
[0273] The term clear solution as used in this table refers to that no clear visible precipitation or flocculation has been observed. The term clear solution also includes slightly colored clear solutions such as yellowish or orange solutions.
[0274] Conclusion: Certain absorption enhancers such as medium chain fatty acid salts and derivatives are not well compatible with divalent copper salts. However, zwitter-ionic as well as non-ionic surfactants showed good compatibility with copper salts. Moreover, monovalent copper also showed compatibility with sodium caprate and caprylate. A disadvantage of monovalent copper salts is their low aqueous solubility and the instability of the Cu.sup.+ oxidation state in aqueous solutions. The monovalent copper salt Cu(I)Cl, on the other hand, has aqueous solubility and oxidation state stability.
Example 2
The Pharmacodynamic and Pharmacokinetic Profiles of Human Insulin Formulations After Administration into Mid-Jejunum of Sprague Dawley Rats
[0275] Method—Administration into rat jejunum: The direct application of peptide or protein drugs and their formulations into mid-jejunum (the middle part of the small intestine-jejunum) enables to study their ability to pass through the intestinal barrier and to resist the degradation caused by the digestive enzymes. Sprague-Dawley rats, males, weighing 250-300 g were used. The studies were preformed under anesthesia. The results obtained are indicated in the following Table 2:
TABLE-US-00002 TABLE 2 Pharmacokinetic profiles of human insulin formulations. Absorption Trace AUC.sub.(0-t) Human enhancer element Reducing (pmol/ C.sub.max insulin (10 mg/ml) (1 mg/ml) agent l × min) (pmol/l) 22 IU/kg Sodium — — 2093 ± 1759 28 ± 24 caprate 22 IU/kg Sodium CuSO.sub.4 Ascorbate 2505 ± 2921 37 ± 54 caprate
[0276] Conclusion: A simple physical blend of human insulin and the classical absorption enhancer sodium caprate in the presence of the trace element copper with ascorbate as a reducing agent moderately improved the oral bioavailability of human insulin. A more pronounced improvement of the oral bioavailability was not observed in this experiment because of the poor aqueous solubility of both sodium caprate and insulin in the presence of 1 mg/ml Cu.sup.2+.
Example 3
The Pharmacodynamic and Pharmacokinetic Profiles of Human Insulin Formulations After Administration into Mid-Jejunum of Sprague Dawley Rats
[0277] In order to improve insulin solubility, Cu.sup.2+ and insulin were dosed separately. Experimental design—10 minutes predosing of the trace element copper with sodium ascorbate followed by dosing of an insulin solution comprising one of various absorption enhancers. In such a setup, insulin was found to retain good aqueous solubility.
[0278] Predosing solution: 1 mg/ml CuSO.sub.4and 10 mg/ml sodium ascorbate
[0279] The respective insulin solutions: 22 IU/kg human insulin, and absorption enhancer [0280] a) 22 IU/kg human insulin and 50 mg/ml sodium caprate [0281] b) 22 IU/kg human insulin and 100 mg/ml Cremophor EL and 10 mg/ml Na.sub.2HPO.sub.4 [0282] c) 22 IU/kg human insulin and 50 mg/ml lauroyl-DL-carnitine-chloride and 40 mg/ml Na.sub.2HPO.sub.4
TABLE-US-00003 TABLE 3 Pharmacokinetic profiles of human insulin formulations comprising different absorption enhancers after pre-dosing of copper sulfate and sodium ascorbate. Predosing Human Absorption AUC.sub.(0-t) C.sub.max solution insulin enhancer Buffer agent (pmol/l × min) (pmol/l) CuSO.sub.4 and 22 IU/kg Sodium caprate — 5351 ± 2289 72 ± 26 ascorbate CuSO.sub.4 and 22 IU/kg Cremophor EL Na.sub.2HPO.sub.4 2340 ± 899 48 ± 23 ascorbate CuSO.sub.4 and 22 IU/kg Lauroyl Na.sub.2HPO.sub.4 145896 ± 89530 1850 ± 1117 ascorbate carnitine chloride
[0283] Conclusion: The results show that compositions comprising the zwitter-ionic absorption enhancer lauroyl-carnitine resulted in 27 to 62-fold improved insulin absorption (AUC.sub.(o-t)) as compared with compositions comprising absorption enhancers such as sodium caprate or Cremophor EL, respectively. Moreover, the predosing of CuSO.sub.4 and sodium ascorbate prior to the administration of insulin and sodium caprate was found to provide a more favorable insulin absorption than the simultaneous administration of these agents, as tested in Example 2.
Example 4
Pharmacodynamics in Non Human Primates After Oral Administration of Solid Oral Compositions of Human Insulin
[0284] Composition A:
[0285] Double capsule formulations providing a physical barrier between insulin and Cu.sup.2+ and the reducing agent sodium ascorbate are described. A small size 4 capsule is placed into a larger size 1 capsule. In such a solid oral dosage form the therapeutic polypeptide drug is not in intimate contact with the trace element copper and the reducing agent. Further, copper and ascorbate will be released in vivo prior to insulin. Such a composition will also improve insulin solubility.
[0286] The composition comprises 4 mg human insulin and 50 mg sodium salicylate in size 4 hard capsule and 100 mg sodium ascorbate, 1 mg CuSO.sub.4 and 100 mg sodium salicylate in size 1 capsule. The size 4 capsule is placed into the size 1 capsule. The capsule was dosed per oral to a female cynomolgus monkey with additional 5 ml of tap water.
[0287] As control, a capsule comprising 4 mg of human insulin and 200 mg of the known absorption enhancer sodium caprylate was used.
TABLE-US-00004 TABLE 4 % Glucose reduction in non human primate after oral administration of composition A 4 mg Insulin 0 min 20 min 40 min 60 min 120 min 150 min Control: 200 mg sodium caprylate 0 +16 +20 +47 1 0 150 mg sodium salicylate, 100 mg 0 +59 −14 −19 −14 −1 sodium ascorbate, 1 mg CuSO.sub.4
[0288] Conclusion: A solid oral insulin composition according to the invention comprising the absorption enhancer sodium salicylate in the presence of the trace element copper and the reducing agent sodium ascorbate resulted in a clear pharmacodynamic effect (reduction of the blood glucose levels). The control formulation did not show any reduction of the blood glucose levels.
[0289] Composition B:
[0290] Double capsule:
[0291] Double capsule formulations providing a physical barrier between insulin and Cu.sup.2+ and the reducing agent sodium ascorbate are described. A small size 4 capsule is placed into a larger size 1 capsule. In such a solid oral dosage form the therapeutic polypeptide drug is not in intimate contact with the trace element copper and the reducing agent. Further, copper and ascorbate will be released in vivo prior to insulin.
[0292] The composition comprises 4 mg human insulin and 200 mg Multitrope 1620 LQ-(MV) which is a C8 and 010 fatty acid acylated polysaccharide and 5 mg sodium citrate in size 4 hard capsule and 180 mg sodium ascorbate, 0.5 mg CuSO.sub.4 in size 1 hard capsule. The size 4 capsule is placed into the size 1 capsule. In addition, 5 ml of TRIS (4 mg/ml) were dosed per oral to a female cynomolgus monkey.
TABLE-US-00005 TABLE 5 % Glucose reduction in non human primate after oral administration of composition B 4 mg Insulin 0 min 20 min 40 min 60 min 90 min 120 min 150 min Control: 200 mg sodium caprylate 0 +16 +20 +47 +16 1 0 200 mg Multitrope 1620 LQ-(MV), 0 −33 −21 −12 −15 −15 −19 180 mg sodium ascorbate, 0.5 mg CuSO.sub.4, 5 mg sodium citrate
[0293] Conclusion: An oral insulin composition according to the invention comprising the non-ionic absorption enhancer Multitrope 1620 LQ which is an alkylsaccharide in the presence of the trace element copper and the reducing agent sodium ascorbate resulted in a substantial pharmacodynamic effect (reduction of the blood glucose levels).
Example 5
Pharmacokinetic Profile of the Glycopeptide Vancomycin After Administration into Ileum of Sprague Dawley Rats
[0294] Vancomycin hydrochloride is a glycopeptide antibiotic with an negligible oral bioavailability in the 0.1% range but usually under detection limit. [0295] a) Vancomycin was administered i.v. in dosing volume of 1 ml/kg (final concentration of 5 mg/ml) to anesthetized rats. [0296] b) Vancomycin was dosed into ileum in volume of 0.4 ml/kg (final concentration of 50 mg/ml) to anesthetized rats.
[0297] The vancomycin plasma concentrations were determined on biochemical autoanalyser Hitachi 912 using commercial vancomycin kit VANC2 (Roche Diagnostics GmbH, Germany). The absolute bioavailability (F) was calculated using equation F (%)=(AUC.sub.ileum/AUC.sub.i.v.)×(Dose.sub.i.v./Dose.sub.ileum)×100.
TABLE-US-00006 TABLE 6 Pharmacokinetic profile of vancomycin formulation. Reducing Trace agent Lauroyl element sodium AUC.sub.(0-t) C.sub.max Vancomycin carnitine CuSO.sub.4 ascorbate (μg/ml × min) (μg/ml) F (%) 5 mg/kg i.v. — — — 662 ± 60 8.8 ± 0.3 100 ± 7 20 mg/kg 50 mg/ml 1 mg/ml 250 mg/ml 180 ± 45 2.4 ± 0.2 8 ± 0.4 ileum
[0298] Conclusion: An oral vancomycin formulation according to the invention increased markedly its bioavailability in comparison with published F values after oral administration (Prasad Y V et al., Int J Pharm. 2003, 250(1):181-90; Van Bambeke F, Curr Opin Investig Drugs. 2006, 7(8):740-9).
Example 6
Pharmacokinetic Profiles of Liraglutide After Administration into Mid-Jejunum of Sprague Dawley Rats
[0299] 2.4 mg/kg of the polypeptide liraglutide were dosed into the mid-jejunum of anesthetized Sprague Dawley rats in the presence of the zwitter-ionic absorption enhancer lauroyl carnitine chloride (“LCC”) (20 mg/ml) with and without the addition of (i) the trace element CuSO.sub.4 (1 mg/ml) and the reducing agent sodium ascorbate (40 mg/ml) or (ii) the trace element ZnSO.sub.4 (1 mg/ml) and the reducing agent glutathione (40 mg/ml). All formulations further comprised Na.sub.2HPO.sub.4 to result in a neutral pH between 7 to 8. The results of these experiments are shown in
[0300] Conclusion: The combination of the zwitter-ionic absorption enhancer lauroyl carnitine (LCC) in the presence of the trace element copper and the reducing agent sodium ascorbate substantially increased the intestinal absorption of the polypeptide drug liraglutide. The reducing agent glutathione (GSH) in the presence of Zn.sup.2+ also showed improved liraglutide absorption albeit less pronounced than the composition comprising Cu.sup.2+.
Example 7
Pharmacokinetic Profiles of Liraglutide After Administration into Mid-Jejunum of Sprague Dawley Rats
[0301] 2.4 mg/kg of the polypeptide liraglutide were dosed into the mid-jejunum of anesthetized Sprague Dawley rats in the presence of the anionic absorption enhancer sodium dodecyl sulfate (SDS) (20 mg/ml) and the trace element CuSO.sub.4 (1 mg/ml) with and without the reducing agent reduced glutathione (40 mg/ml).
TABLE-US-00007 TABLE 7 Pharmacokinetic profiles of liraglutide formulations. Reducing Enhancer: agent: Sodium Trace Reduced AUC.sub.(0-t) dodecyl element: glutathione (μg/ C.sub.max Liraglutide sulfate CuSO.sub.4 (GSH) ml × min) (ng/ml) 2.4 mg/kg 20 mg/ml 1 mg/ml — 5504 ± 32 into jejunum 5729 2.4 mg/kg 20 mg/ml 1 mg/ml 40 mg/ml 49090 ± 416 into jejunum 23073
[0302] Conclusion: The combination of an absorption enhancer in the presence of the trace element copper and the reducing agent glutathione substantially increased the intestinal absorption of the polypeptide drug liraglutide.
Example 8
Pharmacodynamic Profiles After Insulin and Liraglutide Administration into Mid-Jejunum of Sprague Dailey Rats
[0303] A combination of human insulin (22 IU/kg) and liraglutide (2.4 mg/kg) was dosed together into the mid-jejunum of Sprague Dawley rats in the presence of the absorption enhancer lauroyl carnitine chloride (“LCC”) (50 mg/ml) and Na.sub.2HPO.sub.4 (40 mg/ml). A solution of the trace element copper as CuSO.sub.4 (1 mg/ml) and sodium ascorbate (10 mg/ml) was dosed 10 minutes prior to insulin and liraglutide into the mid-jejunum of rats. The results of this experiment are shown in
[0304] Conclusion: A combination of insulin and the GLP-1 receptor agonist liraglutide in the presence of lauroyl carnitine after predosing of Cu.sup.2+ and sodium ascorbate resulted in a substantial reduction of the blood glucose levels.
Example 9
Pharmacokinetic Profile of the Somatostatin Analog Octreotide After Administration into Ileum of Sprague Dawley Rats
[0305] Octreotide is an octapeptide with very low oral bioavailability of less than 1%. [0306] a) Octreotide was administered s.c. at a concentration of 1 mg/kg body weight to anesthetized rats (n=3). [0307] b) Octreotide was dosed into distal small intestine (ileum) at a concentration of 0.92 mg/kg body weight to anesthetized rats (n=8). TRIS buffer was used to generate a neutral pH.
[0308] The octreotide plasma concentrations were determined using a commercial octreotide kit (AB Biolabs, USA, cat. number CEK 0110-01).
TABLE-US-00008 TABLE 8 Pharmacokinetic profiles of octreotide formulations. Enhancer: Reducing Lauroyl Trace agent: Buffering carnitine element: Sodium agent: AUC.sub.(0-90) C.sub.max Octreotide chloride CuSO.sub.4 ascorbate TRIS (ng/ml × min) (ng/ml) F (%) 1 mg/kg — — — — 10045 ± 1837 153.7 ± 29.8 100 ± 18.3 s.c. (n = 3) 0.92 mg/kg 30 mg/ml 1 mg/ml 30 mg/ml 22.5 mg/ml 1504 ± 725 25.8 ± 14.2 16.3 ± 7.8 ileum (n = 8)
[0309] Conclusion: An oral octreotide formulation according to the invention, comprising a copper(II) salt, sodium ascorbate as reducing agent and lauroyl carnitine chloride as an exemplary absorption enhancer, showed a markedly increased bioavailability.
Example 10
Pharmacokinetic Profiles of Leuprolide Formulations After Intestinal Administration to Sprague Dawley Rats
[0310] Leuprolide was dosed subcutaneously in volume of 1 ml/kg (final concentration 0.1 mg/ml leuprolide) to anaesthetized rats (n=3). Two formulations of leuprolide (final concentration 0.4 mg/kg) according to the invention were dosed into ileum of Sprague Dawley rats (n=5-6). Blood was taken from tail vessels at the time points 0, 10, 20, 40, 60, 90, 120 and 180 min after dosing. The leuprolide plasma concentrations were determined using commercial leuprolide kit (AB Biolabs, USA, cat. number CEK 0100-01).
[0311] Composition:
[0312] LEU001
[0313] 1 mg/ml Leuprolide
[0314] 30 mg/ml Lauroylcarnitine HCl
[0315] 21 mg/ml TRIS
[0316] 1 mg/ml CuSO.sub.4
[0317] 40 mg/ml Sodium ascorbate
[0318] Composition:
[0319] LEU002
[0320] 1 mg/ml Leuprolide
[0321] 30 mg/ml Sodium dodecyl sulfate
[0322] 22 mg/ml TRIS
[0323] 1 mg/ml CuSO.sub.4
[0324] 40 mg/ml reduced glutathione
[0325] Results: The maximal plasma concentrations of leuprolide in dose of 0.1 mg/kg s.c. reached 50-100 ng/ml with peak within 20-40 min. The application of leuprolide formulations in dose of 0.4 mg/kg into ileum resulted in relatively high leuprolide plasma concentrations in range of 40-500 ng/ml and peak within 10-60 min. The high plasma concentrations persisted up to 120 min after dosing. The mean relative bioavailability was 70% for LEU001 and 47% for LEU002 in comparison with s.c. administration.
TABLE-US-00009 AUC.sub.(0-t) Cmax Tmax F (ng/ml × min) (ng/ml) (min) (%) Leuprolide s.c. 7771 ± 1514 78.9 ± 14.7 20-40 100 ± 19.5 LEU001 ileum 21840 ± 6735 202 ± 61.0 10-40 70 ± 21.7 LEU002 ileum 14695 ± 4251 133.2 ± 46.1 10-60 47 ± 13.7
[0326] Conclusion: Formulations according to the present invention comprising the peptide drug leuprolide, the trace element copper, a reducing agent and an absorption enhancer result in very high relative bioavailability.
Example 11
Pharmacokinetic Profile of Liraglutide Formulations After Intestinal Administration to Sprague Dawley Rats
[0327] Liraglutide formulations comprising different reducing agents in presence of the essential trace element copper (1 mg/ml) or increased amounts of zinc (5 mg/ml) and an absorption enhancer were dissolved in distilled water and dosed into ileum in volume of 0.4 ml/kg (final concentration 6 mg/ml) to anaesthetized rats. Blood was taken from tail vessels at the time points 0, 30, 60, 90, 120, 180 and 240 min after dosing. The liraglutide plasma concentrations were determined using commercial liraglutide kit (AB Biolabs, USA, cat. number CEK 0130-03). A formulation comprising liraglutide and sodium dodecyl sulfate without trace element and reducing agent served as control (LIRA-SDS).
[0328] Composition:
[0329] LIRA-SDS (control formulation)
[0330] 6 mg/ml Liraglutide
[0331] 20 mg/ml SDS
[0332] Composition:
[0333] LIRA001
[0334] 6 mg/ml Liraglutide
[0335] 40 mg/ml Sodium ascorbate
[0336] 1 mg/ml CuSO.sub.4
[0337] 20 mg/ml SDS
[0338] Composition:
[0339] LIRA002
[0340] 6 mg/ml Liraglutide
[0341] 40 mg/ml reduced glutathione
[0342] 40 mg/ml TRIS
[0343] 1 mg/ml CuSO.sub.4
[0344] 20 mg/ml SDS
[0345] Composition:
[0346] LIRA003
[0347] 6 mg/ml Liraglutide
[0348] 40 mg/ml Cysteine
[0349] 40 mg/ml TRIS
[0350] 1 mg/ml CuSO.sub.4
[0351] 20 mg/ml SDS
[0352] Composition:
[0353] LIRA004
[0354] 6 mg/ml Liraglutide
[0355] 40 mg/ml N-Acetylcysteine
[0356] 40 mg/ml TRIS
[0357] 1 mg/ml CuSO.sub.4
[0358] 20 mg/ml SDS
[0359] Composition:
[0360] LIRA005
[0361] 6 mg/ml Liraglutide
[0362] 40 mg/ml alpha-Lipoic acid
[0363] 80 mg/ml Chremophor EL
[0364] 40 mg/ml TRIS
[0365] 1 mg/ml CuSO.sub.4
[0366] 20 mg/ml SDS
[0367] Composition:
[0368] LIRA006
[0369] 6 mg/ml Liraglutide
[0370] 10 mg/ml Fe(2)gluconate
[0371] 10 mg/ml TRIS
[0372] 1 mg/ml CuSO.sub.4
[0373] 20 mg/ml SDS
[0374] Composition:
[0375] LIRA007
[0376] 6 mg/ml Liraglutide
[0377] 10 mg/ml TRIS
[0378] 5 mg/ml Fe(2)gluconate
[0379] 5 mg/ml ZnSO.sub.4
[0380] 20 mg/ml SDS
[0381] Composition:
[0382] LIRA008
[0383] 6 mg/ml Liraglutide
[0384] 40 mg/ml Lactose (reducing sugar)
[0385] 5 mg/ml TRIS
[0386] 5 mg/ml ZnSO.sub.4
[0387] 20 mg/ml SDS
[0388] Results:
TABLE-US-00010 AUC.sub.(0-t) Cmax Tmax (ng/ml × min) (ng/ml) (min) LIRA-SDS 1304 ± 298 12 ± 1 40-90 LIRA001 11198 ± 2389 62.1 ± 15.3 60-120 LIRA002 19256 ± 8762 137.9 ± 67.2 60-120 LIRA003 10153 ± 4026 120.2 ± 87.3 60-240 LIRA004 29891 ± 22388 170.3 ± 132 90-120 LIRA005 2134 ± 489 19.8 ± 10.3 30-120 LIRA006 16368 ± 3365 87.5 ± 18.4 60-120 LIRA007 55671 ± 9189 441.7 ± 112.1 60-180 LIRA008 14481 ± 4324 80.3 ± 25.7 90-120
[0389] Conclusion: Compositions with a GLP-1 peptide drug, the trace element copper, an absorption enhancer and various reducing agents showed up to 23-fold increased oral bioavailability (shown as AUC) compared with a control formulation only comprising an absorption enhancer and the GLP-1 peptide. Reducing agents with a functional thiol group such reduced glutathione or N-acetyl cysteine showed especially high efficacy in presence of copper. A composition comprising 5 mg/ml zinc, the reducing agent Fe(2)gluconate and an absorption enhancer increased AUC 42-fold compared to control.
Example 12
Pharmacokinetic Profiles of PTH(1-34) Formulations After Intestinal Administration to Sprague Dawley Rats.
[0390] Teriparatide (PTH1-34) was dosed subcutaneously in volume of 1 ml/kg (final concentration 0.024 mg/ml teriparatide) to anaesthetized rats. TER001, TER002, TER003, TER004, TER007, TER008, TER009 and TER010 were dosed into ileum in volume of 0.4 ml/kg (final concentration 0.24 mg/ml teriparatide) to anaesthetized rats. Blood was taken from tail vessels at the time points 0, 10, 20, 40, 60, 90, 120 and 180 min after dosing. The teriparatide plasma concentrations were determined using commercial pTH (1-34) human ELISA kit (Biovendor, EU, cat. number RS-1163.0001).
[0391] Composition:
[0392] TER001
[0393] 0.24 mg/ml PTH(1-34)
[0394] 30 mg/ml Lauroylcarnitine HCl
[0395] 21 mg/ml TRIS
[0396] 1 mg/ml CuSO.sub.4
[0397] 40 mg/ml Sodium ascorbate
[0398] Composition:
[0399] TER002
[0400] 0.24 mg/ml PTH(1-34)
[0401] 30 mg/ml Sodium dodecyl sulfate
[0402] 22 mg/ml TRIS
[0403] 5 mg/ml ZnSO.sub.4
[0404] 40 mg/ml reduced glutathione
[0405] Composition:
[0406] TER003
[0407] 0.38 mg/ml PTH(1-34)
[0408] 30 mg/ml Lauroylcarnitine HCl
[0409] 7.5 mg/ml TRIS
[0410] 5 mg/ml Mannitol
[0411] 1 mg/ml CuSO.sub.4
[0412] 40 mg/ml Sodium ascorbate
[0413] (Final pH=5.8)
[0414] Composition:
[0415] TER004
[0416] 0.38 mg/ml PTH(1-34)
[0417] 30 mg/ml Lauroylcarnitine HCl
[0418] 30 mg/ml TRIS
[0419] 5 mg/ml Mannitol
[0420] 1 mg/ml CuSO.sub.4
[0421] 40 mg/ml Sodium ascorbate
[0422] (Final pH=8.0)
[0423] Composition:
[0424] TER007
[0425] 0.38 mg/ml PTH(1-34)
[0426] 30 mg/ml Lauroylcarnitine HCl
[0427] 7.5 mg/ml TRIS
[0428] 5 mg/ml Mannitol
[0429] 5 mg/ml ZnSO.sub.4
[0430] 6 mg/ml Fe(2)gluconate
[0431] (Final pH=5.1)
[0432] Composition:
[0433] TER008
[0434] 0.38 mg/ml PTH(1-34)
[0435] 30 mg/ml Lauroylcarnitine HCl
[0436] 30 mg/ml TRIS
[0437] 5 mg/ml Mannitol
[0438] 5 mg/ml ZnSO.sub.4
[0439] 6 mg/ml Fe(2)gluconate
[0440] (Final pH=8.3)
[0441] Composition:
[0442] TER009
[0443] 0.375 mg/ml PTH(1-34)
[0444] 30 mg/ml Lauroylcarnitine HCl
[0445] 40 mg/ml reduced glutathione
[0446] 1 mg/ml CuSO.sub.4
[0447] (Final pH=2.5)
[0448] Composition:
[0449] TER010
[0450] 0.375 mg/ml PTH(1-34)
[0451] 35 mg/ml Sucrose laurate
[0452] 5 mg/ml ZnSO.sub.4
[0453] 5 mg/ml Fe(2)gluconate
[0454] (Final pH=4.9)
[0455] Results: The maximal plasma concentrations of teriparatide in dose of 0.024 mg/kg s.c. reached 0.67-4.04 ng/ml with peak at 10 min. The application of TER001 formulation in dose of 0.096 mg/kg into ileum resulted in variable teriparatide plasma concentrations in range of 0.07-10.01 ng/ml and peak at 10 min in most of animals. The teriparatide plasma concentrations after TER002 administration were lower, but less variable, with peak 10 min in most of rats. The mean relative bioavailability was 34% for TER001 and 12% for TER002 in comparison with s.c. administration. The results for these formulations as well as the further tested formulations TER003, TER004 and TER007 to TER010 are summarized in the following table:
TABLE-US-00011 AUC.sub.(0-t) Cmax Tmax F Half-life (ng/ml × min) (ng/ml) (min) (%) (min) PTH(1-34) 136 ± 32 2.8 ± 0.8 10 100 ± 23 44 ± 8 s.c. TER001 184 ± 136 2.8 ± 1.9 10-90 34 ± 25 — TER002 64 ± 16 0.9 ± 0.1 10-90 12 ± 3 — TER003 302 ± 120 3.5 ± 1.1 10-90 35 ± 14 90 ± 8 TER004 145 ± 20 2.4 ± 0.5 10-20 17 ± 2 67 ± 6 TER007 79 ± 16 1.0 ± 0.2 10-40 9 ± 2 63 ± 14 TER008 46 ± 16 0.6 ± 0.2 10-40 5 ± 2 153 ± 84 TER009 178 ± 67 3.8 ± 1.0 10 21 ± 8 45 ± 6 TFR010 87 ± 23 1.2 ± 0.4 34 10 ± 3 77 ± 5
[0456] Conclusion: Significant oral bioavailability could be achieved with formulations according to the invention at different pH values ranging from 2.5 to 8.0. Further, the presence of trace elements resulted in increased plasma half-life of PTH(1-34) compared to s.c. administration, most likely due to a prolonged gastro-intestinal absorption phase.
Example 13
Pharmacokinetic Profile of Human Growth Hormone Formulation After Intestinal Administration to Sprague Dawley Rats
[0457] Human growth hormone was dosed subcutaneously in volume of 1 ml/kg (final concentration 0.2 mg/ml human growth hormone) to anaesthetized rats. HGH001 was dosed into ileum in volume of 0.4 ml/kg (final concentration 2 mg/ml human growth hormone) to anaesthetized rats. Blood was taken from tail vessels at the time points 0, 15, 30, 60, 90, 120, 180 and 240 min after dosing. The human growth hormone plasma concentrations were determined using commercial growth hormone sensitive human ELISA kit (Biovendor, EU, cat. number RMEE022).
[0458] Composition:
[0459] HGH001
[0460] 2 mg/ml hGH
[0461] 30 mg/ml Sodium dodecyl sulfate
[0462] 1 mg/ml CuSO.sub.4
[0463] 40 mg/ml Sodium ascorbate
[0464] Results: The mean maximal human growth hormone plasma concentration after s.c. treatment reached 44 ng/ml with peak 30 min after dosing. The mean plasma human growth hormone level after administration of HGH001 formulation into ileum was 4 ng/ml with the peak 15 min after application. The relative bioavailability of the formulation was 1%.
TABLE-US-00012 AUC.sub.(0-t) Cmax Tmax F (ng/ml × min) (ng/ml) (min) (%) hGH s.c. 7630 ± 471 44.0 ± 2.5 30 100 ± 6 HGH001 256 ± 177 4.0 ± 2.0 15 1 ± 0.6
Example 14
Pharmacokinetic Profiles of Desmopressin Acetate Formulations After Administration to Duodenum of Sprague Dawley Rats
[0465] Desmopressin formulations were dissolved in distilled water and dosed into duodenum in volume of 0.4 ml/kg (final concentration 0.2 mg/ml desmopressin) to anaesthetized rats. Blood was taken from tail vessels at the time points 0, 30, 60, 90, 120, 180 and 240 min after dosing. The desmopressin plasma concentrations were determined using commercial desmopressin EIA kit (AB Biolabs, USA, cat. number CEK 0120-01).
[0466] Composition:
[0467] DES001
[0468] 0.2 mg/ml Desmopressin acetate
[0469] Composition:
[0470] DES002
[0471] 0.2 mg/ml Desmopressin acetate
[0472] 50 mg/ml Sodium ascorbate
[0473] 1 mg/ml CuSO.sub.4
[0474] Composition:
[0475] DES003
[0476] 0.2 mg/ml Desmopressin acetate
[0477] 50 mg/ml Sodium ascorbate
[0478] 1 mg/ml CuSO.sub.4
[0479] 40 mg/ml TRIS
[0480] 50 mg/ml Lauroyl carnitine HCl
[0481] Composition:
[0482] DES004
[0483] 0.2 mg/ml Desmopressin acetate
[0484] 50 mg/ml Sodium ascorbate
[0485] 1 mg/ml CuSO.sub.4
[0486] 2 mg/ml TRIS
[0487] 25 mg/ml n-Dodecyl-b-D-maltoside
[0488] 25 mg/ml n-Octyl-b-D-glucopyranoside
[0489] Composition:
[0490] DES005
[0491] 0.2 mg/ml Desmopressin acetate
[0492] 50 mg/ml Sodium ascorbate
[0493] 1 mg/ml CuSO.sub.4
[0494] 50 mg/ml SNAC
[0495] Composition:
[0496] DES006
[0497] 0.2 mg/ml Desmopressin acetate
[0498] 10 mg/ml TRIS
[0499] 5 mg/ml ZnSO.sub.4
[0500] 5 mg/ml Fe(2)gluconate
[0501] Composition:
[0502] DES007
[0503] 0.2 mg/ml Desmopressin acetate
[0504] 50 mg/ml Sodium ascorbate
[0505] 1 mg/ml CuSO.sub.4
[0506] 50 mg/ml Methyl-b-cyclodextrin
[0507] Results:
TABLE-US-00013 Delta AUC.sub.(0-t) Cmax Tmax (ng/ml × min) (ng/ml) (min) DES001 98 ± 43 2.0 ± 0.4 60-90 DES002 215 ± 52 2.7 ± 0.4 30-120 DES003 1536 ± 422 12.3 ± 3.3 30-60 DES004 1676 ± 576 12.2 ± 4.0 30-60 DES005 221 ± 66 3.0 ± 0.6 60-90 DES006 109 ± 26 2.0 ± 0.5 30-240 DES007 124 ± 20 2.9 ± 0.6 60-240
[0508] Conclusion: The addition of essential trace elements and a reducing agent to oral desmopressin formulations increased its oral bioavailability and also reduced variability. Further addition of absorption enhancers increased AUC levels up to 17 fold compared to unformulated desmopressin.
Example 15
Pharmacokinetic Profile of Exenatide Formulations After Oral Administration to Beagle Dogs
[0509] Exenatide was dosed subcutaneously in volume of 2×40 μl/dog (2×10 μg/dog) to two injection sites in the area of shoulder blade. EXE001 capsules were dosed orally (n=3) directly on the root of the tongue. Administered capsule was washed down by 5 ml of water via a syringe to ensure that the drug was correctly swallowed and to ensure complete oesophageal clearance. The swallowing of the whole administered dose was checked. Blood was taken by venepuncture from v. cephalica antebrachii at the time points 0, 30, 60, 90, 120, 150, 180, 240, 300 and 360 min after oral dosing. The exenatide plasma concentrations were determined using commercial exenatide kit (AB Biolabs, USA, cat. number SEK 0130-01).
[0510] Composition (per capsule):
[0511] EXE001
[0512] HPMCP ARCaps (CapsCanada) size 0
[0513] 0.57 mg Exenatide
[0514] 50 mg Mannitol
[0515] 160 mg Lauroyl carnitine HCl
[0516] 210 mg TRIS
[0517] 100 mg Sodium ascorbate
[0518] 2 mg CuSO.sub.4
[0519] Results:
TABLE-US-00014 AUC.sub.(0-t) Cmax Tmax F (ng/ml × min) (ng/ml) (min) (%) EXE s.c. 1001 ± 59 6.2 ± 1.0 30-240 100 ± 5.9 EXE001 1140 ± 625 3.4 ± 1.9 120-180 4.0 ± 2.2
[0520] Conclusion: A solid gastric resistant oral dosage form comprising a GLP-1 peptide agonist, the trace element copper, a reducing agent and an absorption enhancer resulted in significant oral bioavailability.
Example 16
In vitro Compatibility of Different Absorption Enhancers and Trace Elements
[0521] Solid dry powder mixtures of desmopressin acetate, zinc sulfate and different absorption enhancers were prepared and dissolved in 2 ml aqua purificata. Visual examination was performed to observe either a clear solution or visible precipitation. The results of these experiments are summarized in the following table:
TABLE-US-00015 Trace Dissolution in element Absorption enhancer aqueous medium Polypeptide (5 mg/ml) (10 mg/ml) (2 ml) Desmopressin ZnSO.sub.4 Sodium caprate Precipitation Desmopressin ZnSO.sub.4 Sodium caprylate Precipitation Desmopressin ZnSO.sub.4 Lauroyl sarcosinate Precipitation Desmopressin ZnSO.sub.4 Cholic acid Precipitation Desmopressin ZnSO.sub.4 Sodium cholate Precipitation Desmopressin ZnSO.sub.4 Chitosan Precipitation Desmopressin ZnSO.sub.4 Sodium dodecyl sulfate Clear solution Desmopressin ZnSO.sub.4 Lauroyl carnitine HCl Clear solution Desmopressin ZnSO.sub.4 Sucrose laurate Clear solution Desmopressin ZnSO.sub.4 n-Dodecyl-b-D-maltoside Clear solution Desmopressin ZnSO.sub.4 n-Octyl-b-D- Clear solution glucopyranoside Desmopressin ZnSO.sub.4 Labrasol Clear solution Desmopressin ZnSO.sub.4 EDTA Clear solution
Example 17
Solid Compositions Comprising a Polypeptide, the Trace Element Zinc or Copper, a Reducing Agent and Optionally an Absorption Enhancer
[0522] Solid dry powder mixtures of PTH(1-34), a zinc or copper salt, different reducing agents and different absorption enhancers were prepared and dissolved in 5 ml aqua purificata. The pH of the solutions was measured immediately at RT. The results of these experiments are summarized in the following table:
TABLE-US-00016 Dissolution Absorption pH in 5 ml Trace element enhancer Reducing agent Aqua Polypeptide (10 mg) (10 mg) (50 mg) Buffer purificata PTH(1-34) ZnSO.sub.4 Lauroyl carnitine Lactose — 3.1 PTH(1-34) ZnSO.sub.4 Lauroyl carnitine Lactose 10 mg 7.5 TRIS PTH(1-34) ZnSO.sub.4 Sucrose laurate Lactose — 6.5 PTH(1-34) ZnCl.sub.2 Lauroyl carnitine Lactose 2.9 PTH(1-34) ZnCl.sub.2 Lauroyl carnitine Lactose 10 mg 7.1 TRIS PTH(1-34) ZnCl.sub.2 Lauroyl carnitine Gelatin capsule — 4.3 PTH(1-34) ZnCl.sub.2 Lauroyl carnitine Gelatin capsule 10 mg 6.8 TRIS PTH(1-34) ZnCl.sub.2 Lauroyl carnitine MCC — 3.5 PTH(1-34) ZnCl.sub.2 Lauroyl carnitine MCC 5 mg 6.3 TRIS PTH(1-34) CuSO.sub.4 Lauroyl carnitine MCC — 3.6 PTH(1-34) CuSO.sub.4 Lauroyl carnitine Gelatin capsule — 4.4 PTH(1-34) CuSO.sub.4 Lauroyl carnitine Lactose 3.2 PTH(1-34) CuSO.sub.4 Lauroyl carnitine Lactose 10 mg 6.5 TRIS PTH(1-34) CuSO.sub.4 Sucrose laurate Lactose — 5.0 Desmopressin ZnSO.sub.4 Citric acid Lactose — 2.7 Desmopressin ZnSO.sub.4 — Lactose — 5.5 Desmopressin CuSO.sub.4 Citric acid Lactose — 2.6 Desmopressin CuSO.sub.4 — Lactose — 4.7