WO2018065634A1

WO2018065634A1 - Pharmaceutical compositions for the nasal delivery of peptide or protein drugs

Info

Publication number: WO2018065634A1
Application number: PCT/EP2017/075703
Authority: WO
Inventors: Martin Werle; Florian FÖGER
Original assignee: Cyprumed Gmbh
Priority date: 2016-10-07
Filing date: 2017-10-09
Publication date: 2018-04-12

Abstract

The present invention relates to improved pharmaceutical formulations, uses and methods for the nasal 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 100 kDa for use as a medicament, wherein said peptide or protein drug is to be administered nasally in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex. The invention also provides a pharmaceutical composition for use by nasal administration, comprising: a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa; and a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex.

Description

Pharmaceutical compositions for the nasal delivery of peptide or protein drugs

The present invention relates to improved pharmaceutical formulations, uses and methods for the nasal 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 100 kDa for use as a medicament, wherein said peptide or protein drug is to be administered nasally in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex. The invention also provides a pharmaceutical composition for use by nasal administration, comprising; a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa; and a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex. A growing number of proteins and peptides have been made available as therapeutic agents. The systemic delivery of proteins and peptides via the nasal route has been investigated for many years, but obtaining sufficient bioavailability to result in a commercially viable and efficacious product has to date been challenging. Although nasal delivery avoids the hepatic first pass effect, the enzymatic barrier of the nasal mucosa creates a pseudo-first-pass effect. The efficient delivery of peptides and proteins has been hindered by the peptidase and protease activity in the nasal mucosa. The presence of a range of exopeptidases (such as different carboxy- and aminopeptidases, including dipeptidyl peptidase IV) in the nasal mucosa has been reported. In addition, specific endopeptidases present in the nasal mucosa (e.g.: neutral endopeptidase) as well as trypsin like endopeptidase activity have been reported (Na DH et al., J Pharm Sci. 2004; 93(2): 256-61 ; Morimoto K et al., Pharm Res. 1991 ; 8(9): 1 175-9).

The absorption of peptide drugs can be improved by using enzyme inhibitors or absorption enhancers. Presently, just very few nasal peptide products are on the market such as calcitonin (Novartis), desmopressin (Ferring) and buserelin (Sanofi, Ferring). These peptides show a very low bioavailability (less than 3%). None of the marketed products contain an efficient nasal absorption promoter, due to the poor nasal tolerability of most known absorption enhancers. Many absorption promoters have been evaluated over the years in animal models and have in general been found to have some degree of perturbing or even, for some, a detrimental effect on the nasal membrane that prevents them from being used for chronic nasal application. Thus, there is a need for safe but also efficient delivery systems for the delivery of peptides and proteins via the nasal route.

EP-A-1466610 discloses a pharmaceutical composition for nasal absorption, specifically in the form of a dry powder, which comprises a certain acidic polypeptide, a carrier that is insoluble or little soluble in water, and an additive for dispersing or embedding the polypeptide on the surface of the carrier. The acidic polypeptide and the carrier, which may be a polyvalent metal compound, are invariably and necessarily present in the same composition since the polypeptide must be dispersed or embedded on the surface of the carrier.

WO 01/52894 relates to nasaily administrable compositions comprising a cyclic peptide and particles of a specific powdery or crystalline carrier, which may contain a polyvalence metal, wherein the cyclic peptide is always dispersed in or adsorbed onto the powdery or crystalline carrier particles.

WO 2004/024226 discloses certain nasal membrane delivery systems. The composition to be delivered to the nasal membrane may contain an active substance which can be zinc. While zinc gluconate is mentioned as one specific example of zinc as the active substance, there is no teaching or suggestion in this document of using zinc gluconate (or any other zinc salt or complex) in combination with a peptide or protein drug. Indeed, this document mentions the use of a peptide or protein merely generically in a list of possible active substances, as an alternative to zinc as the active substance, and completely fails to teach the use of any actual, specific peptide or protein.

WO 2016/055550 describes the therapeutic use, by oral administration, of certain peptide or protein drugs in combination with copper salts/complexes and/or zinc salts/complexes as well as reducing agents, but it does not relate to the nasal administration of any such therapeutic combinations.

Wetterholm A et al., Arch Biochem Biophys. 1994; 31 1(2): 263-71 and Lind SE et a!., Blood. 1993; 82(5): 1522-31 relate to the inhibition of certain proteolytic enzymes. Hogarth G, Mini Rev Med Chem. 2012; 12(12): 1202-15 is concerned with specific metal-dithiocarbamate complexes. Sarkar MA, Pharm Res. 1992; 9(1 ): 1-9 and Harshad P et al., Int J Drug Dev & Res. 2010; 2(3): 565-72 describe nasal drug delivery techniques. In the context of the present invention, it has been found that the use of a copper salt/complex or a zinc sa!t/complex or an iron salt/complex in combination with a peptide or protein drug allows to obtain a surprisingly high systemic bioavailability of the peptide or protein drug after nasal administration, as also demonstrated in the examples (see, in particular, Examples 2 and 7 to 12).

Moreover, it has surprisingly been found that a particularly high bioavailability after nasal administration can be achieved by providing the peptide or protein drug physically separated from the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex, and by administering these components separately (either simultaneously or sequentially) or by combining them directly upon or immediately before administration, as also demonstrated in Examples 8 to 12.

A further significant advantage of the pharmaceutical compositions, methods and uses provided in accordance with the present invention is that the trace element copper is already approved and used in commercial pharmaceutical products such as, for example, in parenteral nutrition (Nutryelt™ from Baxter and Laboratoire Aguettant) and is further even recommended for daily intake, for example, during pregnancy. Moreover, the required amounts of the trace elements zinc and iron are also well below the corresponding recommended intake levels and can therefore likewise be regarded as safe.

The present invention thus solves the problem of providing improved pharmaceutical compositions, uses and methods for the nasal delivery of peptide or protein drugs, allowing the nasal administration of a wide range of different peptide or protein drugs with advantageously high bioavailability, safety, storage stability and cost-effectiveness.

Accordingly, in a first aspect, the present invention provides a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa for use as a medicament, wherein said peptide or protein drug is to be administered nasally in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex.

In accordance with this first aspect, the invention also relates to a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa for use in therapy, wherein said peptide or protein drug is to be administered nasally in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex. The invention likewise provides a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa for use in the treatment or prevention of a disease/disorder, wherein said peptide or protein drug is to be administered nasally and in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex. The invention further relates to a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa for use as a medicament (or for use in therapy, or for use in the treatment or prevention of a disease/disorder), wherein said peptide or protein drug is to be administered nasally in combination with a pharmaceutically acceptable copper salt/complex. The present invention also relates to a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa for use as a medicament (or for use in therapy, or for use in the treatment or prevention of a disease/disorder), wherein said peptide or protein drug is to be administered nasally in combination with a pharmaceutically acceptable zinc salt/complex. The invention furthermore relates to a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa for use as a medicament (or for use in therapy, or for use in the treatment or prevention of a disease/disorder), wherein said peptide or protein drug is to be administered nasally in combination with a pharmaceutically acceptable iron salt/complex. Moreover, the present invention also relates to the use of a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa in the preparation of a medicament which is to be administered nasally in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex. The invention likewise refers to the use of a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa in the preparation of a medicament for the treatment or prevention of a disease/disorder, which is to be administered nasally and in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/comple and/or a pharmaceutically acceptable iron salt/complex.

In a second aspect, the present invention relates to a pharmaceutically acceptable copper salt/complex for use as a medicament (or for use in therapy, or for use in the treatment or prevention of a disease/disorder), wherein said copper salt/complex is to be administered nasally in combination with a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa. In accordance with this second aspect, the invention also relates to the use of a pharmaceutically acceptable copper salt/complex in the preparation of a medicament which is to be administered nasally in combination with a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa. The invention further relates to the use of a pharmaceutically acceptable copper salt/complex in the preparation of a medicament for the treatment or prevention of a disease/disorder, which is to be administered nasally in combination with a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa.

In a third aspect, the invention provides a pharmaceutically acceptable zinc salt/complex for use as a medicament (or for use in therapy, or for use in the treatment or prevention of a disease/disorder), wherein said zinc salt/complex is to be administered nasally in combination with a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa.

In accordance with this third aspect, the invention further relates to the use of a pharmaceutically acceptable zinc salt/complex in the preparation of a medicament which is to be administered nasally in combination with a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa. The invention likewise relates to the use of a pharmaceutically acceptable zinc salt/complex in the preparation of a medicament for the treatment or prevention of a disease/disorder, which is to be administered nasally in combination with a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa.

In a fourth aspect, the invention provides a pharmaceutically acceptable iron salt/complex for use as a medicament (or for use in therapy, or for use in the treatment or prevention of a disease/disorder), wherein said iron salt/complex is to be administered nasally in combination with a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa.

In accordance with this fourth aspect, the invention further relates to the use of a pharmaceutically acceptable iron salt/complex in the preparation of a medicament which is to be administered nasally in combination with a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa. The invention likewise relates to the use of a pharmaceutically acceptable iron salt/complex in the preparation of a medicament for the treatment or prevention of a disease/disorder, which is to be administered nasally in combination with a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa. In a fifth aspect, the invention provides a pharmaceutical composition for use by nasal administration, comprising: a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa; and a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex.

In accordance with this fifth aspect, the invention also relates to a pharmaceutical composition for nasal administration, the composition comprising: a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa; and a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex. The invention further relates to a pharmaceutical composition for use as a medicament, the composition comprising: a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa; and a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex; wherein the pharmaceutical composition is to be administered nasally. Moreover, the invention likewise provides a pharmaceutical composition for use as a medicament by nasal administration, comprising: a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa; and a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex.

In a sixth aspect, the present invention provides a method of treating or preventing a disease/disorder, the method comprising nasally administering, to a subject in need thereof, a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex.

In accordance with this sixth aspect, the invention further relates to a method of nasally delivering a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa, the method comprising nasally administering said peptide or protein drug in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex to a subject in need thereof. The invention also provides a method of facilitating the nasal delivery of a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa, the method comprising nasally administering said peptide or protein drug in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex to a subject in need thereof. Furthermore, the invention relates to a method of administering a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa, the method comprising nasaily administering said peptide or protein drug in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex to a subject in need thereof.

The following detailed description applies to all embodiments of the present invention, including all embodiments according to each one of the first, second, third, fourth, fifth and sixth aspect as described herein above.

The peptide or protein drug to be administered in accordance with the invention has a molecular weight of equal to or less than about 100 kDa (such as, e.g., equal to or less than about 90 kDa, or equal to or less than about 80 kDa, or equal to or less than about 70 kDa, or equal to or less than about 60 kDa, or equal to or less than about 50 kDa, or equal to or less than about 40 kDa, or equal to or less than about 30 kDa, or equal to or less than about 20 kDa, or equal to or less than about 10 kDa, or equal to or less than about 5 kDa, or equal to or less than about 2 kDa, or equal to or less than about 1 kDa, or equal to or less than about 500 Da). It is preferred that the peptide or protein drug has a maximum molecular weight of equal to or less than about 90 kDa, more preferably equal to or less than about 50 kDa, even more preferably equal to or less than about 40 kDa, even more preferably equal to or less than about 30 kDa, even more preferably equal to or less than about 20 kDa, and yet even more preferably equal to or less than about 10 kDa. It is furthermore preferred that the peptide or protein drug has a minimum molecular weight of equal to or greater than about 300 Da, more preferably equal to or greater than about 500 Da, even more preferably equal to or greater than about 800 Da, and yet even more preferably equal to or greater than about 1 kDa. Accordingly, it is particularly preferred that the peptide or protein drug has a molecular weight of about 300 Da to about 40 kDa, more preferably about 500 Da to about 40 kDa, even more preferably about 500 Da to about 30 kDa, even more preferably about 800 Da to about 20 kDa, and yet even more preferably about 1 kDa to about 10 kDa.

The molecular weight of the peptide or protein drug is indicated herein in dalton (Da), which is an alternative name for the unified atomic mass unit (u). A molecular weight of, e.g., 500 Da is thus equivalent to 500 g/mol. The term "kDa" (kilodalton) refers to 1000 Da. The molecular weight of the peptide or protein drug can be determined using methods known in the art, such as, e.g., mass spectrometry (e.g., electrospray ionization mass spectrometry (ESI-MS) or matrix-assisted laser desorption/ionization mass spectrometry (MALDI- S)), gel electrophoresis (e.g., polyacrylamide gel electrophoresis using sodium dodecyl sulfate (SDS-PAGE)), hydrodynamic methods (e.g., gel filtration chromatography or gradient sedimentation), or static light scattering (e.g., multi-angle light scattering (MALS)). It is preferred that the molecular weight of the peptide or protein drug is determined using mass spectrometry.

The peptide or protein drug may be any peptide or protein that is suitable to be used as a medicament. For example, the peptide or protein drug may be a linear peptide or protein drug or a cyclic peptide or protein drug (e.g., a cyclic peptide or protein drug that is cyclized via at least one ester linkage and/or at least one amide linkage; such as, e.g., a cyclotide; cyciotides are disulfide rich peptides characterized by their head-to-tail cyclized peptide backbone and the interlocking arrangement of their disulfide bonds). It may also be a modified or derivatized peptide or protein drug, such as a PEGylated peptide or protein drug or a fatty acid acylated peptide or protein drug or a fatty diacid acylated peptide or protein drug. Moreover, the peptide or protein drug may be free of histidine residues and/or free of cysteine residues. It is generally preferred that the peptide or protein drug is water-soluble, particularly at neutral pH (i.e., at about pH 7). It is furthermore preferred that the peptide or protein drug has at least one serine protease cleavage site, i.e., that the peptide or protein drug comprises one or more amino acid residue(s) amenable or prone to cleavage by a serine protease; more preferably, the peptide or protein drug comprises one or more amino acid residue(s) amenable or prone to cleavage by aminopeptidase. The term "peptide or protein drug" is used herein synonymously with "therapeutic peptide or protein" and "therapeutic peptide or protein drug".

The peptide or protein drug is preferably selected from insulin (preferably human insulin), an insulin analog (e.g., a long acting basal insulin analog or a protease stabilized long acting basal insulin analog; exemplary insulin analogs include, without limitation, insulin lispro, insulin PEGIispro, the insulin derivative "A14E, B25H, B29K(N(eps)octadecanedioyl-gGlu-OEG-OEG), desB30 human insulin" (see, e.g., US 2014/0056953 A1 ), insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, insulin degludec, and the insulin analogs/derivatives described in US 2014/0056953 A1 , which is incorporated herein by reference, particularly each one of the insulin analogs/derivatives described in paragraphs [0225] to [0332] of US 2014/0056953 A1 ), GLP-1 , a GLP-1 analog (e.g., an acylated GLP-1 analog or a diacylated GLP-1 analog) or GLP-1 agonist (also referred to as "glucagon-like peptide- 1 receptor agonist" or "GLP-1 receptor agonist"), semaglutide, liraglutide, exenatide, exendin-4, lixisenatide, taspoglutide, a!biglutide, dulaglutide, langlenatide, GLP-1(7-37), GLP-1(7-36)NH₂, a dual agonist of the GLP- receptor and the glucagon receptor, oxyntomodulin, GLP-2, a GLP-2 agonist or analog (e.g., teduglutide or elsiglutide), glucose- dependent insulinotropic polypeptide (also referred to as "gastric inhibitory polypeptide" or GIP), amylin, an amylin analog, pramlintide, a somatostatin analog (e.g., octreotide, lanreotide, or pasireotide), goserelin (e.g., goserelin acetate), buserelin (e.g., buserelin acetate), leptin, a leptin analog (e.g., metreleptin), peptide YY (PYY), a PYY analog, glatiramer (e.g., glatiramer acetate), leuprolide (e.g., Ieuprolide acetate), desmopressin (e.g., desmopressin acetate, particularly desmopressin monoacetate tri hydrate), osteocalcin, an osteocalcin analog or derivative, human growth hormone (hGH), a human growth hormone analog, a long-acting human growth hormone (such as, e.g., somapacitan or hGH-CTP (human growth hormone derivatized with the C-terminal peptide (CTP) of the beta chain of human chorionic gonadotropin (hCG)), fibroblast growth factor 21 (FGF21 ), a glycopeptide antibiotic (e.g., a glycosylated cyclic or polycyclic nonribosomal peptide such as vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, or decaplanin), a cyclotide, bortezomib, cosyntropin, chorionic gonadotropin, menotropin, sermorelin, luteinizing-hormone-releasing hormone (LHRH; also referred to as "gonadotropin-releasing hormone"), somatropin, calcitonin (e.g., calcitonin-salmon), pentagastrin, oxytocin, neseritide, anakinra, enfuvirtide, pegvisomant, dornase alfa, lepirudin, anidulafungin, eptifibatide, interferon alfacon- , interferon alpha-2a, interferon alpha-2b, interferon beta-1 a, interferon beta-1 b, interferon gamma-l b, peginterferon alfa-2a (i.e., pegylated interferon alfa-2a), peginterferon alfa-2b (i.e., pegylated interferon alfa- 2b), peginterferon beta- 1a (i.e., pegylated interferon beta-1a), fibrinolysin, vasopressin, aldesleukin, an epoetin, epoetin alfa, darbepoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, epoetin theta, methoxy polyethylene glycol-epoetin beta, continuous erythropoietin receptor activator (CERA; a pegylated EPO derivative), peglyiated epo, albupoetin, an epo-dimer analogue, epo-Fc, carbamylated EPO (CEPO), synthetic erythropoese protein (SEP), low molecular epo analogue (PBI-1402), filgrastim, PEG- filgrastim, interleukin-11 , cyclosporine, glucagon, urokinase, viomycin, thyrotropin-releasing hormone (TRH), leucine-enkephalin, methionine-enkephalin, substance P (CAS no. 33507- 63-0), adrenocorticotropic hormone (ACTH), parathyroid hormone (PTH), a parathyroid hormone (PTH) fragment (e.g., teriparatide (also referred to as "PTH(1-34)"), PTH(1-31 ), or PTH(2-34)), parathyroid hormone-related protein (PTHrP), abaloparatide, linaclotide, carfilzomib, icatibant, ecallantide, cilengitide, a prostaglandin F2a receptor modulator (e.g., PDC31 ), abciximab (C7E3-Fab), ranibizumab, alefacept, romiplostim, anakinra, abatacept, be!atacept, and pharmaceutically acceptable salts thereof. If the subject/patient to be treated is a human and if the peptide or protein drug is an endogenous peptide or protein in human beings (i.e., occurs naturally in humans; such as, e.g., insulin or glucagon), it is furthermore preferred to use a human isoform of the corresponding peptide or protein (which may, e.g., be recombinantiy expressed or chemically synthesized). It is particularly preferred that the peptide or protein drug is selected from buserelin, human growth hormone (hGH), somapacitan, hGH- CTP, insulin (particularly human insulin), an insulin analog, fibroblast growth factor 21 (FGF21 ), filgrastim, PEG-filgrastim, an epoetin (e.g., epoetin alfa, darbepoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, or epoetin theta), and pharmaceutically acceptable salts thereof. It is even more preferred that the peptide or protein drug is selected from buserelin, human growth hormone (hGH), somapacitan, hGH-CTP and pharmaceutically acceptable salts thereof (e.g., buserelin acetate).

As noted above, the peptide or protein drug may be an insulin analog. The insulin analog is preferably selected from:

B29K(N(s)hexadecanedioyi-Y-L-Glu) A14E B25H desB30 human insulin;

B29K(N(£)octadecanedioyl-Y-L-Glu-OEG-OEG) desB30 human insulin;

B29K(N(e)octadecanedioyl-Y-L-Glu) A14E B25H desB30 human insulin;

B29K(N(e)eicosanedioyl-Y-L-Glu) A14E B25H desB30 human insulin;

B29K(N(£)octadecanedioyl-Y-L-Glu-OEG-OEG) A14E B25H desB30 human insulin;

B29K(N( )eicosanedioyl-Y-L-Glu-OEG-OEG) A14E B25H desB30 human insulin;

B29K(N( )eicosaned!oyl-Y-L-Glu-OEG-OEG) A14E B16H B25H desB30 human insulin;

B29K(N(e)hexadecanedioyl-Y-L-Glu) A14E B16H B25H desB30 human insulin;

B29K(N(s)eicosanedioyl-Y-L-Glu-OEG-OEG) A14E B16H B25H desB30 human insulin; and

B29K(N(£)octadecanedsoyl) A14E B25H desB30 human insulin.

These insulin analogs are described and characterized, e.g., in US 2014/0056953 A1. It is particularly preferred that the insulin analog is B29K(N(e)octadecanedioyl-Y-L-Glu-OEG-OEG) A14E B25H desB30 human insulin.

Moreover, as also described above, the peptide or protein drug may be a GLP-1 analog. The GLP-1 analog may be, in particular, a variant of the human Glucagon-Like Peptide-1 , preferably a variant of GLP-1 (7-37). The amino acid sequence of GLP-1 (7-37) is HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG. The aforementioned "variant" of human Glucagon-Like Peptide-1 or of GLP-1 (7-37) preferably refers to a compound differing by one or more amino acids from human Glucagon-Like Peptide-1 or from GLP-1 (7-37), respectively, wherein such difference is caused by the addition, substitution or deletion of at least one amino acid (e.g., 1 to 10 amino acids) or any combination of such addition(s), substitution(s) and/or deletion(s). A GLP-1 analog may, e.g., exhibit at least 60% (preferably at least 65%, more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90%) sequence identity to GLP-1 (7-37) over the entire length of said GLP-1 (7-37). As an example of a method for the determination of sequence identity between a GLP-1 analog and GLP-1 (7-37), the two peptides [Aib8]GLP-1(7-37) and GLP-1 (7-37) are aligned. [Aib8]GLP-1 (7-37) differs from GLP-1 (7-37) in that the alanine in position 8 is replaced by a-methyialanine (Aib, i.e. 2-aminoisobutyric acid). The sequence identity of [Aib8]GLP-1 (7-37) relative to GLP-1 (7-37) is given by the number of aligned identical residues minus the number of different residues divided by the total number of residues in GLP-1 (7-37). Accordingly, in this example the sequence identity is (31 -1 )/31. The C-terminus of the GLP-1 analog (including any one of the specific GLP-1 analogs described herein) may also be in the form of an amide. Moreover, the GLP-1 analog may be, e.g., GLP-1 (7-37) or GLP-1 (7-36)amide. The GLP-1 analog may also be, e.g., exendin-4, the amino acid sequence of which is HGEGTFITSDLSKQ EEEAVRLFIEWLKNGGPSSGAPPPS. The GLP-1 analog may further be a modified form of naturally occuring GLP-1 (particularly human GLP-1 ), which differs from the GLP-1 peptide in that it comprises one substituent which is covaientiy attached to the peptide. Said substituent may comprise a fatty acid (e.g., a C16, C18 or C20 fatty acid) or a fatty diacid (e.g., a C16, C18 or C20 fatty diacid). Said substituent may also comprise a group of the following formula:

wherein n is at least 13 (e.g., 13, 14, 15, 16, 17, 18 or 19; preferably 13 to 17; more preferably 13, 15 or 17). Said substituent may also comprise one or more 8-amino-3,6-dioxaoctanoic acid (OEG) groups, such as two OEG groups. In particular, said substituent may be selected from [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}eth- oxy)acetylamino]ethoxy}ethoxy)acetyl] and [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19- carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}eth- oxy)acetylamino]ethoxy}ethoxy)acetyl]. The GLP-1 analog may also be selected from one or more of the GLP-1 agonists disclosed in WO 93/19175, WO 96/29342, WO 98/08871 , WO 99/43707, WO 99/43706, WO 99/43341 , WO 99/43708, WO 2005/027978, WO 2005/058954, WO 2005/058958, WO 2006/005667, WO 2006/037810, WO 2006/037811 , WO 2006/097537, WO 2006/097538, WO 2008/023050, WO 2009/030738, WO 2009/030771 and WO 2009/030774.

The peptide or protein drug may also be, e.g., a dual GLP-1 analog, a dual agonist of the glucagon-like peptide 1 receptor and the glucagon receptor (a GLP-1 R/GCGR dual agonist), a GLP1/glucagon receptor co-agonist (such as, e.g., any one of the compounds referred to in WO 2015/185640), a dual agonist of the glucagon-like peptide 1 receptor and the gastric inhibitory polypeptide receptor (a GLP-1 R/GIPR dual agonist; such as, e.g., any one of the compounds referred to in WO 2013/164483), a GLP1/GIP receptor co-agonist, an exendin-4 peptide analog (particularly an exendin-4 peptide analog which is a GLP-1 R/GIPR dual agonist; such as, e.g., any one of the exendin-4 peptide analogs referred to in WO 2015/086728), an exendin-4 derivative (particularly an exendin-4 derivative which is a GLP-1 R/GCGR dual agonist; such as, e.g., any one of the exendin-4 derivatives referred to in WO 2015/155139 or in WO 2015/086733), or a pharmaceutically acceptable salt of any of these agents. The peptide or protein drug to be used in accordance with the invention can also be a mixture of two or more different peptide or protein drugs, including the above-mentioned specific peptide or protein drugs. For example, the peptide or protein drug may be a mixture of human insulin and a GLP-1 agonist (e.g. liraglutide, semagiutide, exenatide, lixisenatide, taspoglutide, albiglutide, or dulaglutide).

The above-described exemplary peptide or protein drugs have been proposed in the literature to be suitable for the treatment or prevention of various different diseases/disorders, and some of these peptide or protein drugs have already received marketing authorizations for specific therapeutic indications. The present invention also specifically relates to the combination of agents provided herein (i.e., the peptide or protein drug which is to be administered nasally in combination with (i) a pharmaceutically acceptable copper salt/complex and/or (ii) a pharmaceutically acceptable zinc salt/complex and/or (iii) a pharmaceutically acceptable iron salt/complex; and likewise the corresponding pharmaceutical composition or the corresponding nasal pharmaceutical delivery form) for use in the treatment or prevention of a disease/disorder that is amenable to be treated or prevented with the respective peptide or protein drug. Likewise, the invention relates to a method of treating or preventing a disease/disorder, the method comprising nasally administering, to a subject in need thereof, a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex, wherein said disease/disorder is a disease/disorder that is amenable to be treated or prevented with the respective peptide or protein drug. Preferred examples of diseases/disorders that are amenable to be treated or prevented with any particular peptide or protein drug in accordance with the present invention are disclosed in (and can be derived from) the medical literature, particularly from any one of: ROTE LISTE online edition (in the version as of the priority date or the filing date of the present specification); ROTE L!STE 2017 (print edition, Rote Liste Service GmbH, 2017, ISBN 978-3946057109); GELBE LISTE online edition (in the version as of the priority date or the filing date of the present specification); GELBE LISTE 2017 (print edition, AVOXA - Mediengruppe Deutscher Apotheker GmbH, 2017, ISBN 978-3774199149); Aktories K et al. (eds.), Aligemeine und spezielle Pharmakologie und Toxikologie, Urban & Fischer Ver!ag / Elsevier GmbH, 12^th edition, 2017, ISBN 978- 3437425257; Ammon HPT et al. (eds.), Hunnius Pharmazeutisches Worterbuch, De Gruyter, 1 1^th edition, 2014, ISBN 978-31 10309904; Otto HH et al., Arzneimittel - Ein Handbuch fur Arzte und Apotheker, Wissenschaftliche Verlagsgesellschaft, 2017, ISBN 978-3804737266; DrugBank (www.drugbank.ca, in the version as of the priority date or the filing date of the present specification); Drugs.com (www.drugs.com, in the version as of the priority date or the filing date of the present specification); Merck Manuals (www.merckmanuals.com, in the version as of the priority date or the filing date of the present specification); European Medicines Agency (EMA) database (www.ema.europa.eu, in the version as of the priority date or the filing date of the present specification); U.S. Food & Drug Administration (U.S. FDA) database (www.fda.gov, in the version as of the priority date or the filing date of the present specification); Japanese Pharmaceuticals and Medical Devices Agency database (www.pmda.go.jp, in the version as of the priority date or the filing date of the present specification); or electronic Medicines Compendium (eMC) database (www.medicines.org.uk/emc/, in the version as of the priority date or the filing date of the present specification). Examples of diseases/disorders that are amenable to be treated or prevented with an analog or derivative of any particular peptide or protein drug include the same diseases/disorders that are amenable to be treated or prevented with the corresponding (underivatized) peptide or protein drug. Moreover, preferred examples of diseases/disorders that are amenable to be treated or prevented with any of the above-mentioned insulin or insulin analogs include, in particular, diabetes (e.g., type 1 diabetes mellitus or type 2 diabetes mellitus); preferred examples of diseases/disorders that are amenable to be treated or prevented with any of the above-mentioned GLP-1 peptides or GLP-1 receptor agonists include, in particular, diabetes, obesity, or non-alcoholic fatty liver disease (NASH); preferred examples of diseases/disorders that are amenable to be treated or prevented with buserelin include, in particular, hormone-responsive cancer (such as, e.g., prostate cancer or breast cancer), or estrogen-dependent conditions (such as, e.g., endometriosis or uterine fibroids); buserelin can further be used, e.g., in assisted reproduction; preferred examples of diseases/disorders that are amenable to be treated or prevented with human growth hormone (hGH) or any of the above-mentioned hGH analogs or derivatives include, in particular, growth hormone deficiency; preferred examples of diseases/disorders that are amenable to be treated or prevented with fibroblast growth factor 21 (FGF21 ) include, in particular, cardiovascular disease, obesity, or diabetes (particularly type 2 diabetes); preferred examples of diseases/disorders that are amenable to be treated or prevented with any of the above- mentioned epoetin or any of its analogues or derivatives include, in particular, anemia, Alzheimer's disease (see, e.g., Maurice T et al., J Psychopharmacol. 2013; 27(1 1 ): 1044-57), Parkinson's disease (see, e.g., Alca!a-Barraza SR et al., J Drug Target. 2010; 18(3): 179-90), or multiple sclerosis; preferred examples of diseases/disorders that are amenable to be treated or prevented with the above-mentioned filgrastim or any derivatives thereof (e.g., PEG-fi!grastim) include, in particular, low blood neutrophils due to a number of causes such as, e.g., chemotherapy, radiation poisoning, HIV or AIDS, or unkown causes.

The pharmaceutically acceptable "copper salt/complex" to be used in accordance with the present invention refers to a pharmaceutically acceptable salt of copper or a pharmaceutically acceptable complex (e.g., a chelate complex) of copper. Likewise, the pharmaceutically acceptable "zinc salt/complex" to be employed in accordance with the invention refers to a pharmaceutically acceptable salt of zinc or a pharmaceutically acceptable complex (e.g., a chelate complex) of zinc; and the pharmaceutically acceptable "iron salt/complex" to be used in accordance with the invention refers to a pharmaceutically acceptable salt of iron or a pharmaceutically acceptable complex (e.g., a chelate complex) of iron. While the expression "pharmaceutically acceptable" is omitted when referring to the copper salt/complex, the zinc salt/complex or the iron salt/complex in the following, it will be understood that the corresponding salts or complexes to be used in accordance with the invention are pharmaceutically acceptable.

The copper salt/complex is preferably a copper(l) salt/complex or a copper(ll) salt/complex. Exemplary copper(l) salts/complexes include copper(l) chloride (CuCI) and copper(l) acetate (CuCH₃C0₂). Exemplary copper(ll) saits/complexes include copper sulfate (CuS0₄), copper carbonate (CuC0₃), a copper(ll) amino acid complex (such as, e.g., copper(ll) iysine complex, or copper(ll) glycinate), copper(ll) EDTA complex, copper(li) chitosan complex, copper chlorophyllin complex (particularly E141 , natural green, or natural green 3), copper(ll) citrate, copper(ll) gluconate, copper(ll) lactate, copper lactate gluconate (also referred to as ΈΖ- Copper"), copper(ll) o rotate, and copper(ll) tartrate. The copper salt/complex is more preferably a copper(ll) salt/complex. The use of a copper(ll) salt/complex is advantageous since it provides better aqueous solubility and better oxidation state stability than a copper(l) salt/complex. Even more preferably, the copper salt/complex to be used in accordance with the invention is a copper(ll) salt/complex selected from copper sulfate (CuS0₄), copper carbonate (CuC0₃), a copper(ll) amino acid complex (preferably a Cu²⁺ L-amino acid complex), copper(ll) Iysine complex (preferably Cu²⁺ L-lysine complex), copper(ll) citrate, copper(ll) gluconate (preferably copper(ll) D-gluconate), copper(ll) orotate, and copper(ll) tartrate. The zinc salt/complex is preferably a zinc(ll) salt/complex. Exemplary zinc(ll) salts/complexes include zinc sulfate (e.g., zinc sulfate pentahydrate), zinc chloride, zinc acetate, zinc oxide, zinc ascorbate, zinc caprylate, zinc gluconate, zinc stearate, zinc carbonate, zinc orotate, a zinc amino acid complex (preferably a zinc L-amino acid complex), zinc glycinate, zinc arginate, zinc picolinate, zinc pidolate, zinc carnosine, zinc undecanoate, zinc undecylenate (e.g., zinc 10-undecenoate), zinc methionine, zinc lactate, and zinc lactate gluconate (also referred to as "EZ-Zinc"). The zinc salt/complex is more preferably selected from zinc sulfate, zinc chloride, zinc acetate, zinc oxide, zinc ascorbate, zinc caprylate, zinc gluconate, zinc stearate, zinc carbonate, zinc orotate, and a zinc amino acid complex (particularly a zinc L-amino acid complex).

The iron salt/complex is preferably an iron(ll) salt/complex or an iron(lll) salt/complex. Exemplary iron(ll) salts/complexes include iron(ll) gluconate, iron(ll) orotate, iron(ll) tartrate, iron(ll) fumarate, iron(ll) sulfate, iron(ll) lactate, iron(ll) lactate gluconate (also referred to as ΈΖ-Ferrous"), iron(ll) acetate, iron(ll) carbonate, iron(ll) citrate, iron(ll) oxide, iron(ll) hydroxide, iron(ll) ascorbate, and an iron(il) amino acid complex (e.g., an iron(ll) chelate of any one of the 20 standard proteinogenic α-amino acids; preferably ferrous bis-glycinate or ferrous bis-glycinate hydrochloride). Exemplary iron(lll) salts/complexes include iron(lll) chloride (FeCI₃), iron(lll) sulfate, iron(lll) oxide, iron(lll)carbonate, iron(l!l) acetate, iron(lll) phosphate, iron(lli) hydroxide, iron(lll) tartrate, iron(ll!) lactate, iron(lll) glycinate, iron(lll) EDTA (i.e., Fe(lll)-EDTA complex (1 :1 )), iron(lll) ascorbate, and ammonium iron(lll) citrate (i.e., ammonium ferric citrate). The iron salt/complex is more preferably an iron(ll) salt/complex. The use of iron(ll) salts/complexes is advantageous as they are more water-soluble than iron(lll) salts/complexes. Even more preferably, the iron salt/complex is an iron(ll) salt/complex selected from iron(ll) gluconate, iron(ll) orotate, iron(ll) tartrate, iron(ll) fumarate, iron(ll) sulfate, iron(ll) lactate, iron(ll) lactate gluconate, iron(ll) acetate, iron(ll) carbonate, iron(ll) citrate, iron(ll) oxide, iron(ll) hydroxide, iron(ll) ascorbate, and an iron(ll) amino acid complex (e.g., an iron(ll) chelate of any one of the 20 standard proteinogenic a-amino acids; preferably ferrous bis-glycinate or ferrous bis-glycinate hydrochloride). Yet even more preferably, the iron salt/complex is an organic iron(ll) salt/complex, particularly an iron(ll) salt/complex selected from iron(ll) gluconate, iron(ll) orotate, iron(ll) tartrate, iron(ll) fumarate, iron(ll) lactate, iron(ll) lactate gluconate, iron(ll) citrate, iron(ll) ascorbate, and an iron(ll) amino acid complex, still more preferably iron(ll) orotate, iron(ll) gluconate, or iron(ll) glycinate (i.e., ferrous bis-glycinate).

While either a copper salt/complex or a zinc salt/complex or an iron salt/complex (or any two or all three of these) can be employed in accordance with the present invention, the use of a copper salt/complex is most preferred, i.e., is preferred over the use of a zinc salt/complex or an iron salt/complex. The use of an iron salt/complex (which is less preferred than the use of a copper sait/complex) is still more preferable than the use of a zinc salt/complex. Accordingly, it is preferred to use a copper sait/complex and/or an iron salt/complex, and it is most preferred to use a copper salt/complex in accordance with the present invention, particularly in each of the first, second, fifth and sixth embodiment of the invention.

In each one of the first to sixth aspects described herein, it is particularly preferred that the peptide or protein drug as well as the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex are nasally administered in combination with an absorption enhancer (also referred to herein as a "mucosal absorption enhancer"). The administration of an absorption enhancer improves or facilitates the absorption of the peptide or protein drug through the nasal mucosa and is advantageous particularly if the peptide or protein drug is a large molecule, e.g., a peptide or protein drug having a molecular weight of about 1 kDa or more.

The absorption enhancer is preferably selected to be compatible with the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex that is/are used, which can readily be tested, e.g., as described in Example 1. In particular, it is preferred that the absorption enhancer is soluble in an aqueous medium at a pH of about 7 in the presence of the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex that is/are being used. The occurrence of precipitation or f!occulation, as observed for certain combinations of a specific copper salt/complex and a specific absorption enhancer in an aqueous medium (see Example 1 ), is undesirable but does not rule out the use of a corresponding formulation in accordance with the invention.

The absorption enhancer may be, e.g., a zwitter-ionic absorption enhancer, a cationic absorption enhancer, an anionic absorption enhancer (e.g., an anionic absorption enhancer comprising one or more sulfonic acid groups (-S0₃H)), or a non-ionic absorption enhancer, particularly a zwitter-ionic absorption enhancer or a non-ionic absorption enhancer. It is preferred that the absorption enhancer is selected from C_8-20 alkanoyi carnitine (preferably iauroyl carnitine, myristoyl carnitine or palmitoyl carnitine; e.g., lauroyl carnitine chloride, myristoyl carnitine chloride or palmitoyl carnitine chloride), salicylic acid (preferably a salicylate, e.g., sodium salicylate), a salicylic acid derivative (such as, e.g., 3-methoxysalicylic acid, 5-methoxysalicylic acid, or homovanillic acid, a C_8-2o alkanoic acid (preferably a C₈.₂o alkanoate, more preferably a cap rate, a caprylate, a myristate, a palmitate, or a stearate, such as, e.g., sodium cap rate, sodium caprylate, sodium myristate, sodium palmitate, or sodium stearate), citric acid (preferably a citrate, e.g., sodium citrate), tartaric acid (preferably a tartrate), a fatty acid acylated amino acid (e.g., any of the fatty acid acylated amino acids described in US 2014/0056953 A1 which is incorporated herein by reference, including, without being limited thereto, sodium lauroyi alaninate, N-dodecanoyl-L-alanine, sodium lauroyi asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyi aspartic acid, N-dodecanoyl-L- aspartic acid, sodium lauroyi cysteinate, N-dodecanoyl-L-cysteine, sodium lauroyi glutamic acid, N-dodecanoy!-L-glutamic acid, sodium lauroyi glutaminate, N-dodecanoyl-L-glutamine, sodium lauroyi glycinate, N-dodecanoyl-L-glycine, sodium lauroyi histidinate, N-dodecanoyl-L- histidine, sodium lauroyi isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyi leucinate, N-dodecanoyl-L-leucine, sodium lauroyi methioninate, N-dodecanoy!-L-methionine, sodium lauroyi phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyi prolinate, N-dodecanoyl-L-proline, sodium lauroyi serinate, N-dodecanoyl-L-serine, sodium lauroyi threoninate, N-dodecanoyl-L-threonine, sodium lauroyi tryptophanate, N-dodecanoyl-L- tryptophane, sodium lauroyi tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyi valinate, N-dodecanoyl-L-valine, sodium lauroyi 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 (e.g., Amisoft HS-1 1 P), sodium myristoyl glutamate (e.g., Amisoft MS-11 ), sodium lauroyi glutamate (e.g., Amisoft LS-11 ), sodium cocoyl glutamate (e.g., Amisoft CS-11 ), sodium cocoyl glycinate (e.g., Amilite GCS-11 ), sodium N-decyl leucine, sodium cocoyl glycine, sodium cocoyl glutamate, sodium lauroyi alaninate, N-dodecanoyl-L-alanine, sodium lauroyi asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyi aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyi cysteinate, N-dodecanoyl-L-cysteine, sodium lauroyi glutamic acid, N-dodecanoyl-L-glutamic acid, sodium lauroyi glutaminate, N-dodecanoyl-L-glutamine, sodium lauroyi glycinate, N-dodecanoyl-L- glycine, sodium lauroyi histidinate, N-dodecanoyl-L-histidine, sodium lauroyi isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyi leucinate, N-dodecanoyl-L-leucine, sodium lauroyi methinoninate, N-dodecanoyl-L-methionine, sodium lauroyi phenylalaninate, N-dodecanoyl-L- phenylalanine, sodium lauroyi proiinate, N-dodecanoyl-L-proline, sodium lauroyi serinate, N-dodecanoyl-L-serine, sodium lauroyi threoninate, N-dodecanoyl-L-threonine, sodium lauroyi tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyi tyrosinate, N-dodecanoyl-L- tyrosine, sodium lauroyi 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 proiinate, 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 of any of the aforementioned compounds; or, e.g., C₈-2o alkanoyl sarcosinate (e.g., a lauroyi sarcosinate, such as sodium lauroyi sarcosinate) or one of the 20 standard proteinogenic a-amino acids that is acylated with a C₈.₂o alkanoic acid), an alkylsaccharide (e.g., a Ci 2₀ alkylsaccharide, such as, e.g., C_8-io alkylpolysaccharide like Multitrope™ 1620-LQ-(MV); or, e.g., n-octyl-beta-D-glucopyranoside, n-dodecyl-beta-D- maltoside, n-tetradecyl-beta-D-maltoside, tridecyl-beta-D-maltoside, sucrose laurate, sucrose myristate, sucrose pa Imitate, sucrose cocoate, sucrose mono-dodecanoate, sucrose mono- tridecanoate, sucrose mono-tetradecanoate, a coco-glucoside, or any of the alkylsaccharides described in US 5,661 ,130 or in WO 2012/112319 which are herein incorporated by reference), a cyclodextrine (e.g., a-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β- cyclodextrin, hydroxypropyl β-cyclodextrin, or sulfobutylether β-cyclodextrin), N-[8-(2- hydroxybenzoyl)amino]caprylic acid (preferably a N-[8-(2-hydroxybenzoyl)amino]caprylate, more preferably sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, also referred to as "SNAC"), a N-[8-(2-hydroxybenzoyl)amino]caprylate derivative (preferably a sodium N-[8-(2- hydroxybenzoyl)amino]caprylate derivative), a thiomer (also referred to as a thiolated polymer; may be synthesized, e.g., by immobilization of sulfhydryl bearing ligands on a polymeric backbone of well-established polymers such as, e.g., polyacrylic acid, carboxymethyiceliulose or chitosan; exemplary thiomers include the thiomers that are described in Laffleur F et a!., Future Med Chem. 2012, 4(17):2205-16 (doi; 10.4155/fmc.12.165) which is incorporated herein by reference), a mucoadhesive polymer having a vitamin B partial structure (e.g., any of the mucoadhesive polymers described in US 8,980,238 B2 which is incorporated herein by reference; including, in particular, any of the polymeric compounds as defined in any one of claims 1 to 3 of US 8,980,238 B2), a calcium chelating compound (e.g., ethylenediaminetetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), sodium citrate, or polyacrylic acid), cremophor EL (also referred to as "Kolliphor EL"; CAS no. 61791- 12-6), chitosan, Ν,Ν,Ν-trimethyl chitosan, benzalkonium chloride, bestatin, cetylpyridinium chloride, cetyltrimethylammonium bromide, a C_2-2o alkanol (e.g., ethanol, decanol, lauryl alcohol, myristyl alcohol, or palmityl alcohol), a C_8-2o alkenol (e.g., oleyl alcohol), a C₈-2o alkenoic acid (e.g., oleic acid), dextran sulfate, diethyleneglycol monoethyl ether (transcutol), 1 -dodecylazacyclo-heptan-2-one (Azone^®), caprylocaproyl polyoxylglycerides (such as, e.g., caprylocaproyl polyoxyl-8 glycerides; available, e.g., as Labrasol^® or ACCONON^® MC8-2), ethyl caprylate, glyceryl monolaurate, lysophosphatidy!choline, menthol, a C₈.₂₀ alkylamine, a C₈-2o alkenylamine (e.g., oleylamine), phosphatidylcholine, a poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, a polysorbate (e.g., polysorbate 20 or polysorbate 80), cholic acid (preferably a cholate, e.g., sodium chlolate), a deoxycholate (e.g., sodium deoxycholate), sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate (SDS), 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, decyldimethyi 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 (e.g., KLAKLAK, polyarginine or oiigoarginine (particularly octa-arginine), penetratin (particularly L-penetratin), a penetratin analog (particularly PenetraMax; see, e.g., El-Sayed Khafagy et al., Eur J Pharm Biopharm. 2013; 85(3 Pt A):736- 43), HIV-1 Tat, transportan, or any of the cell-penetrating peptides referred to in US 2012/0065124), macrogol-15-hydroxystearate (e.g., Solutol HS 15), CriticalSorb (see., e.g., Ilium L et al. J Control Release. 2012;162(1 ):194-200), a taurocholate (e.g., sodium taurocholate), a taurodeoxycholate (e.g., sodium taurodeoxycholate), a sulfoxide (e.g., a (C_1-10 alkyl)-(Ci_{- 0} alkyl)-sulfoxide, such as, e.g., decyl methyl sulfoxide, or dimethyl sulfoxide), cyciopentadecalactone, 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid (also referred to as "5-CNAC"), N-(10-[2-hydroxybenzoyl]amino)decanoic acid (also referred to as "SNAD"), dodecyl-2-N,N-dimethylamino propionate (also referred to as "DDAIP"), D-a-tocopheryl polyethylene glycol-1000 succinate (also referred to as "TPGS"), arginine, and pharmaceutically acceptable salts of the aforementioned compounds. Mixtures of two or more absorption enhancers, including any of the above-described absorption enhancers, can also be used. Moreover, any of the chemical permeation enhancers described in Whitehead K et al. Pharm Res. 2008 Jun;25(6):1412-9 (particularly any one of those described in Table I of this reference), any one of the modified amino acids disclosed in US 5,866,536 (particularly any one of compounds I to CXXII!, as disclosed in US 5,866,536 which is incorporated herein by reference, or a pharmaceutically acceptable salt or solvate thereof, such as a disodium salt, an ethanol solvate, or a hydrate of any one of these compounds), any one of the modified amino acids disclosed in US 5,773,647 (particularly any one of compounds 1 to 193, as disclosed in US 5,773,647 which is incorporated herein by reference, or a pharmaceutically acceptable salt or solvate thereof, such as a disodium salt, an ethanol solvate, or a hydrate of any one of these compounds), any of the nanoparticies described in WO 201 1/133198, any of the polymer preparations described in US 2015/174076 and/or a hydrogel (e.g., as described in Torres- Lugo M et al. Biotechnol Prog. 2002; 18(3):612-6) can likewise be used as absorption enhancer. Moreover, a complex lipoidal dispersion (e.g., a combination of an insoluble surfactant or oil with a soluble surfactant, and optionally with water or a co-solvent) can also be used as absorption enhancer; corresponding exemplary absorption enhancers include, in particular, mixed micelles, reversed micelles, a self emulsifying system (e.g., SEDDS, SMEDDS, or SNEDDS), a lipid dispersion, a course emulsion, or solid lipid nanoparticies (SLNs). A particularly preferred absorption enhancer is N-[8-(2- hydroxybenzoyl)amino]caprylate or a pharmaceutically acceptable salt thereof, in particular sodium N-[8-(2-hydroxybenzoyl)amino]caprylate. In accordance with the present invention, it is furthermore particularly preferred to use an organic copper salt/complex and/or an organic zinc salt/complex and/or an organic iron salt/complex (particularly an organic copper salt/complex), and to use sodium N-[8-(2-hydroxybenzoyl)amino]caprylate as an absorption enhancer.

Further preferred absorption enhancers are alky polysaccharides, arginine or CriticalSorb^® (Solutol^® HS15). In particular, the absorption enhancer may an a Iky I glycoside (or a combination of two or more a Iky I glycosides) which may be selected from any of the a Iky I glycosides described in the following.

Alkyl glycosides to be used as absorption enhancer in accordance with the present invention can be synthesized by known procedures, i.e., chemically, as described, e.g., in Rosevear et al., Biochemistry 19:4108-41 15 (1980) or Koeltzow and Urfer, J. Am. Oil Chem. Soc, 61 :1651 - 1655 (1984), U.S. Pat. No. 3,219,656 or U.S. Pat. No. 3,839,318 or enzymatically, as described, e.g., in Li et al., J. Biol. Chem., 266:10723-10726 (1991 ) or Gopalan et al., J. Biol. Chem. 267:9629-9638 (1992). AlkyI glycosides to be used as absorption enhancer in the present invention can include, but are not limited to: alkyl glycosides, such as octyl-, nonyl-, decyl-, undecyl-, dodecyi-, tridecyl-, tetradecyl-, pentadecyl-, hexadecyl-, heptadecyl-, and octadecyl-a- or β-D-maltoside, -glucoside or -sucroside (which may be synthesized according to Koeltzow and Urfer; Anatrace Inc., Maumee, Ohio; Calbiochem, San Diego, Calif.; Fluka Chemie, Switzerland); alkyl thiomaltosides, such as heptyi-, octyl-, dodecyl-, tridecyl-, and tetradecyl-p-D-thiomaltoside (which may be synthesized according to Defaye, J. and Pederson, C, "Hydrogen Fluoride, Solvent and Reagent for Carbohydrate Conversion Technology" in Carbohydrates as Organic Raw Materials, 247-265 (F. W. Lichtenthaler, ed.) VCH Publishers, New York (1991 ); Ferenci, T., J. Bacteriol, 144:7-1 1 (1980)); alkyl thioglucosides, such as heptyl- or octyl 1 -thio a- or β-D- glucopyranoside (Anatrace, Inc., Maumee, Ohio; see Saito, S. and Tsuchiya, T. Chem. Pharm. Bull. 33:503-508 (1985)); alkyl thiosucroses (which may be synthesized according to, for example, Binder, T. P. and Robyt, J. F., Carbohydr. Res. 140:9-20 (1985)); alkyl maltotriosides (which may be synthesized according to Koeltzow and Urfer); long chain aliphatic carbonic acid amides of sucrose β-amino-alkyl ethers (which may be synthesized according to Austrian Patent 382,381 (1987); Chem. Abstr., 108:114719 (1988) and Gruber and Greber pp. 95-1 16); derivatives of palatinose and isomaltamine linked by amide linkage to an alkyl chain (which may be synthesized according to Kunz, M., "Sucrose-based Hydrophilic Building Blocks as Intermediates for the Synthesis of Surfactants and Polymers" in Carbohydrates as Organic Raw Materials, 127-153); derivatives of isomaltamine linked by urea to an alkyl chain (which may be synthesized according to Kunz); long chain aliphatic carbonic acid ureides of sucrose β-amino-alkyi ethers (which may be synthesized according to Gruber and Greber, pp. 95-116); and long chain aliphatic carbonic acid amides of sucrose β-amino-aikyl ethers (which may be synthesized according to Austrian Patent 382,381 (1987), Chem. Abstr., 108:1 4719 (1988) and Gruber and Greber, pp. 95-116).

The absorption enhancer may also be selected from any of the enhancing agents referred to in US 8,927,497, including in particular any of alkyl glycosides, any of the saccharide alkyl esters, and/or any of the mucosal delivery-enhancing agents described in this document.

Moreover, the absorption enhancer may also be a compound of the following formula (I):

(I)

wherein:

R\ R², R³ and R⁴ are each independently selected from hydrogen, -OH, -NR⁶R⁷, halogen (e.g., -F, -CI, -Br or -I), d. alkyl or C_1- alkoxy;

R⁵ is a substituted or unsubstituted C_2-i₆ alkylene, substituted or unsubstituted C₂-16 alkenylene, substituted or unsubstituted C_1-12 alkyl(arylene) [e.g., substituted or unsubstituted C-M2 alkyl(phenylene)], or substituted or unsubstituted aryl(C_M2 alkylene) [e.g., substituted or unsubstituted phenyl(Ci_{- 2} alkylene)]; and

R⁶ and R⁷ are each independently hydrogen, oxygen, -OH or C_1-4 alkyl;

or a pharmaceutically acceptable salt or solvate thereof, particularly a disodium salt, an alcohol solvate (e.g., a methanol solvate, an ethanol solvate, a propanol solvate, or a propylene glycol solvate, or any such solvate of the disodium salt; particularly an ethanol solvate or an ethanol solvate of the disodium salt), or a hydrate thereof (e.g., a monohydrate of the disodium salt). The above-mentioned "substituted" groups comprised in formula (I) are preferably substituted with one or more (e.g., one, two, or three) substituent groups independently selected from halogen (e.g., -F, -CI, -Br or -I), -OH, Ci_₄ alkyl or C_1-4 alkoxy. Such compounds and methods for their preparation are described, e.g., in WO 00/59863 which is incorporated herein by reference. Accordingly, the absorption enhancer may also be a "delivery agent" as described in WO 00/59863. Preferred examples of the compounds of formula (I) include N-(5- chiorosaiicyloyl)-8-aminocaprylic acid, N-(10-[2-hydroxybenzoyl]amino)decanoic acid, N-(8-[2- hydroxybenzoyi]amino)caprylic acid, a monosodium or disodium salt of any one of the aforementioned compounds, an ethanol solvate of the sodium salt (e.g., monosodium or disodium salt) of any one of the aforementioned compounds, a monohydrate of the sodium salt (e.g., monosodium or disodium salt) of any one of the aforementioned compounds, and any combination thereof. A particularly preferred compound of formula (I) is the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid or the monohydrate thereof.

The (i) peptide or protein drug, (ii) the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex, and (iii) the optionally used absorption enhancer may be administered simultaneously/concomitantly or sequentially, in the case of sequential administration, the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex may be administered first, followed by the administration of the peptide or protein drug and the optionally used absorption enhancer (e.g., at least about 5 min after the first administration, preferably about 5 min to about 3 hours after the first administration, more preferably about 10 min to about 1 hour after the first administration), which is particularly advantageous if the peptide or protein drug is insulin (e.g., human insulin). Also, the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex as well as the optionally used absorption enhancer may be administered first, followed by the administration of the peptide or protein drug (e.g., at least about 5 min after the first administration, preferably about 5 min to about 3 hours after the first administration, more preferably about 10 min to about 1 hour after the first administration), which is likewise advantageous if the peptide or protein drug is insulin (e.g., human insulin). In the case of simultaneous administration, the (i) peptide or protein drug, (ii) the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex, and (iii) the optionally used absorption enhancer may be administered in the same pharmaceutical composition, or in two or more different/separate pharmaceutical compositions. In the context of the present invention it has surprisingly been found that a particularly improved nasal bioavailability and a particularly advantageous pharmacokinetic profile can be achieved by providing the peptide or protein drug physically separated from the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex (see Examples 8 to 12); these physically separated components can then be administered separately (either simultaneously or sequentially), or they can be combined directly upon or immediately before administration. Thus, (i) the peptide or protein drug on the one hand, and (ii) the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex on the other hand, can be provided, e.g., in separate pharmaceutical compositions, or in physically separated compartments of the same pharmaceutical delivery/dosage form or device (particularly of the same nasal pharmaceutical delivery/dosing form or device). The optional absorption enhancer (if an absorption enhancer is used) can be formulated/provided, e.g., together with the peptide or protein drug, or together with the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex, or in a further pharmaceutical composition or a further physically separated compartment; if an absorption enhancer is used, it is preferably provided together with (e.g., in the same composition/formulation/compartment as) the peptide or protein drug. In the case of using separate pharmaceutical compositions, e.g., a pharmaceutical composition comprising the peptide or protein drug (and optionally an absorption enhancer) and another pharmaceutical composition comprising the copper, salt/complex and/or the zinc salt/complex and/or the iron salt/complex (and optionally an absorption enhancer), the respective pharmaceutical compositions can be administered simultaneously or sequentially (e.g., by first administering the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex, followed by the administration of the peptide or protein drug, as also described herein above), or they can be combined directly upon or immediately before administration. Administration is preferably effected by using a delivery or dosing form/device (particularly a nasal pharmaceutical delivery/dosing form or device, such as, e.g., a nasal spray) comprising the peptide or protein drug (and optionally an absorption enhancer) in one compartment and the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex (and optionally an absorption enhancer) in another, physically separated compartment. An example of a corresponding preferred deliery form/device is a double-chamber nasal spray device as described in any one of Examples 9 to 12. Thus, administration can be effected, e.g., by using a nasal pharmaceutical delivery/dosing form or device (preferably a nasal spray) comprising at least two separated compartments/chambers, wherein the peptide or protein drug is provided in one compartment/chamber, and the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex is/are provided in another compartment/chamber, wherein the at least two compartments/chambers are connected to a mixing unit which allows the mixing of the respective components directly upon or immediately before administration; the optional absorption enhancer, if present, can be provided in the same compartment/chamber as the peptide or protein drug, or in the same compartment/chamber as the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex, or it can be provided in a further separated compartment/chamber. It is thus preferred that the peptide or protein drug is provided in physically separated form from the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex, and that these physically separated components are to be administered simultaneously or sequentially, or that they are to be combined directly upon or immediately before administration. Corresponding exemplary formulation approaches and delivery forms/devices have been described in the preceding paragraphs herein above. In this case (where the aforementioned components are provided in physically separated form), it is furthermore preferred that a zinc salt/complex and/or a copper salt/complex is used, and it is particularly preferred that a zinc salt/complex is used. The peptide or protein drug, the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex, and the optionally used absorption enhancer can be administered, e.g., in the form of a pharmaceutical composition as described in the fifth aspect of the invention. The following explanations concerning the pharmaceutical composition according to the fifth aspect of the invention analogously apply to the case that the peptide or protein drug is provided physically separated from the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex; for example, the peptide or protein drug (and optionally an absorption enhancer) can be provided in the form of a pharmaceutical composition which is as decribed in the following, and the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex (and optionally an absorption enhancer) can be provided in the form of another, physically separated pharmaceutical composition which is also as decribed in the following. Moreover, the explanations provided in the following also analogously apply to the above- described nasal pharmaceutical delivery/dosing forms and devices. It is preferred that the pharmaceutical composition according to the fifth aspect of the invention is a liquid composition. The liquid composition may, e.g., be based on water, an oil, an organic solvent, or a mixture thereof; accordingly, the liquid composition may comprise, for example, at least about 60% (v/v) (or, e.g., at least about 70, 80 or 90% (v/v)) of water, an oil or an organic solvent, with respect to the total volume of the corresponding liquid composition. The organic solvent is not particularly limited, and is preferably selected from glycerol, propylene glycol (particularly propane-1 ,2-diol), and ethanol. The liquid composition may be, e.g., a solution, a suspension or an emulsion (such as an oil-in-water emulsion or a water-in-oil emulsion). More preferably, the pharmaceutical composition is an aqueous composition (i.e., an aqueous liquid composition), and even more preferably it is an aqueous solution. The aqueous composition (or the aqueous solution) comprises water, preferably at least about 60% (v/v) water, more preferably at least about 70% (v/v) water, even more preferably at least about 80% (v/v) water, even more preferably at least about 90% (v/v) water, and yet even more preferably at least about 95% (v/v) water, with respect to the total volume of the corresponding (liquid) pharmaceutical composition.

The water in the aqueous composition (or the aqueous solution) is preferably water for injection (e.g., as defined in the European Pharmacopoeia (Ph. Eur.), 8^th Edition as of July 1 , 2015, including supplement 8.6). Water for injection (WFI) can be prepared using techniques known in the art, e.g., by distillation or by membrane technologies (such as reverse osmosis or ultrafiltration), as described, e.g., in Felton LA (ed.), Remington: Essentials of Pharmaceutics, Pharmaceutical Press, 2013. The aqueous composition may be, e.g., an aqueous solution, an aqueous suspension or an oil-in-water emulsion. In this regard, it is preferred that the aqueous composition has an oil content of less than about 5% (v/v), more preferably of less than about 3% (v/v), even more preferably of less than about 2% (v/v), even more preferably of less than about 1 % (v/v), even more preferably of less than about 0.5% (v/v), and yet even more preferably it does not contain any oil. Accordingly, it is preferred that the aqueous composition is an aqueous solution.

It is preferred that the aqueous composition (or the aqueous solution) has a pH of about 4.0 to about 8.0, preferably a pH of about 5.0 to about 7.5. It is furthermore preferred that the aqueous composition (or the aqueous solution) is isotonic with respect to human blood plasma. In particular, it is preferred that the aqueous composition (or the aqueous solution) has an osmolality of about 280 mOsm/kg to about 500 mOsm/kg, more preferably an osmolality of about 285 mOsm/kg to about 350 mOsm/kg, even more preferably an osmolality of about 290 mOsm/kg to about 300 mOsm/kg, and still more preferably an osmolality of about 296 mOsm/kg. The use of an aqueous composition (or aqueous solution) that is isotonic with respect to human blood plasma is particularly advantageous in the case of chronic administration, while an aqueous composition (or aqueous solution) having a higher osmolality (e.g., up to about 500 mOsm/kg) may be employed for emergency or single-application uses.

The pharmaceutical composition according to the fifth aspect of the present invention may also be in the form of a dry powder, particularly a lyophilized dry powder, for nasal administration. A corresponding dry powder formulation may, e.g., be administered directly as a dry powder (with or without a carrier) using a dry powder inhaler device, or may be provided for reconstitution as a liquid. For example, the dry powder may be reconstituted as a liquid composition (particularly as an aqueous liquid composition, as described above) prior to nasal administration; the dry powder and the liquid for reconstitution may, e.g., be stored in separate compartments of a delivery device (e.g., a spray delivery device), and may be mixed upon or directly before being emitted from the delivery device.

The pharmaceutical composition according to the fifth aspect of the present invention may also be in the form of a mucoadhesive product or device, such as a mucoadhesive patch or a liquid spray containing one or more mucoadhesive polymers, e.g., as described in US 2015/0174076, US 2003/0017195, or Ugwoke Ml et al., Adv Drug Deliv Rev. 2005; 57(11 ): 1640-65. In accordance with the above explanations, the pharmaceutical composition of the fifth aspect of the invention may thus be provided, e.g., as a nasal spray, as nasal drops, as an aerosol, or as a dry powder for nasal administration. Preferably, the pharmaceutical composition is an aqueous composition (particularly an aqueous solution) which is provided as a nasal spray. The pharmaceutical composition according to the fifth aspect of the invention preferably comprises the copper salt/complex in an amount of about 0.1 mg to about 20 mg (calculated as Cu⁺ or Cu²⁺) per dosage unit, more preferably about 0.1 mg to about 10 mg per dosage unit, and even more preferably about 0.1 mg to about 5 mg per dosage unit. Alternatively or in addition thereto, if the pharmaceutical composition comprises a zinc salt/complex and/or an iron salt/complex, it is preferred that the zinc salt/complex is present in an amount of about 0.1 mg to about 50 mg (calculated as Zn²⁺) per dosage unit (e.g., about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 20 mg, or about 50 mg of Zn²' per dosage unit), and/or that the iron salt/complex is present in an amount of about 1 mg to about 100 mg (calculated as Fe ⁺ or Fe³⁺) per dosage unit (particularly about 1 mg to about 50 mg of Fe²⁺ or Fe ⁺ per dosage unit). Moreover, if the pharmaceutical composition comprises an absorption enhancer, the absorption enhancer is preferably included in an amount of about 10 mg to about 1000 mg per dosage unit, more preferably about 50 mg to about 500 mg per dosage unit. The amounts specified in this paragraph are particularly suitable for administration to an adult human (and can be adjusted if the subject/patient to be treated is, e.g., a juvenile human or a non-human animal). The pharmaceutically acceptable salts referred to herein may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of a carboxylic acid group with a physiologically acceptable cation as they are well-known in the art. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as Ν,Ν-dibenzylethylenediamine salts, benzathine salts, benethamine salts: heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethy!ammonium saits, tetraethylammonium salts, benzyltrimethy!ammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts, nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts or perchlorate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, glycolate, nicotinate, benzoate, salicylate, ascorbate, or pamoate (embonate) salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; and acidic amino acid salts such as aspartate or glutamate salts. It is to be understood that the term "pharmaceutically acceptable salt" also embraces pharmaceutically acceptable salts of the corresponding compound in any solvated form. The peptide or protein drug, the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex, and the optionally used absorption enhancer (which are collectively referred to as the "compounds to be administered" in the following) may each be administered as compounds per se or may be formulated as medicaments, e.g., in the form of a pharmaceutical composition according to the fifth aspect of the invention. The medicaments/pharmaceutical compositions, including also the pharmaceutical composition according to the fifth aspect, may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, reducing agents, bioadhesive agents and/or solubility enhancers. In particular, they may comprise one or more additives selected from vitamin E, histidine, microcrystalline cellulose (MCC), mannitol, starch, sorbitol and/or lactose. The pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in Remington's Pharmaceutical Sciences, 20^th Edition.

As noted above, the pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., poly(ethylene glycol), including poly(ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da, ethylene glycol, propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 20, polysorbate 80, macrogol-15- hydroxystearate, phospholipids, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, cyclodextrins, a-cyclodextrin, β- cyclodextrin, γ-cyclodextrin, hydroxyethyl- -cyclodextrin, hydroxypropyl^-cyclodextrin, hydroxyethyl-y-cyclodextrin, hydroxypropyl-y-cyclodextrin, dihydroxypropyl- -cyclodextrin, suifobutylether-$-cyclodextrin, sulfobutylether-y-cyclodextrin, glucosyl-a-cyclodextrin, glucosyl- β-cyclodextrin, diglucosyl- -cyclodextrin, maltosyl-a-cyclodextrin, maltosyl- -cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl- -cyclodextrin, maltotriosyl-y-cyclodextrin, dimaltosyl-β- cyclodextrin, methyl-p-cyclodextrin, carboxyalkyl thioethers, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymers, vinyl pyrrolidone, sodium lauryl sulfate, dioctyi sodium sulfosuccinate, or any combination thereof. Preferably, the one or more solubility enhancers include at least one non-ionic surfactant, more preferably at least one non-ionic surfactant having a hydrophilic-lipophilic balance (HLB) of greater than 10 (i.e., HLB > 10). The pharmaceutical compositions may also comprise at least one non-ionic surfactant having an HLB > 10 and at least one non-ionic surfactant having an HLB < 10. It is thus preferred that the pharmaceutical compositions comprise at least one non-ionic surfactant. In particular, the pharmaceutical compositions may comprise a substance (preferably a detergent) that is capable of adsorbing at surfaces and/or interfaces (such as liquid to air, liquid to liquid, liquid to container, or liquid to any solid) and that has no charged groups in its hydrophilic group(s) (sometimes referred to as "heads"). The non-ionic surfactant may be a detergent and may, in particular, be selected from ethoxylated castor oil, a polyglycolyzed glyceride, an acetylated monoglyceride, a sorbitan-fatty-acid-ester, a polysorbate (such as, e.g., polysorbate-20, polysorbate-40, polysorbate-60, polysorbate-80, super-refined polysorbate 20, super-refined polysorbate 40, super-refined polysorbate 60, or super-refined polysorbate 80; including any of the corresponding Tween products, e.g., from the supplier Croda), a poloxamer (such as, e.g., poloxamer 188 or poloxamer 407), a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene derivative (such as, e.g., an alkylated and/or alkoxyiated polyoxyethylene derivative; particularly a Tween product like, e.g., Tween-20 or Tween-80), a block copolymer such as, e.g., a polyethyleneoxide/polypropyleneoxide block copolymer (e.g., Pluronics Tetronics, TritonX-100 and/or Synperonic PE/L44PEL), an ethoxylated sorbitan alkanoate (such as, e.g., Tween-20, Tween-40, Tween-80, or Brij-35), diglycerol laurate, diglycerol caprate, diglycerol caprylate, diglycerol monocaprylate, poiyglyceroi laurate, polyglyceroi caprate, polyglyceroi caprylate, or any combination thereof. Further examples of non-ionic surfactants that may be used as solubility enhancers in accordance with the invention include, but are not limited to: (1.) reaction products of a natural or hydrogenated castor oil and ethylene oxide (where the natural or hydrogenated castor oil may be reacted with ethyleneoxide in a molar ratio of from about 1 :35 to about 1 :60, with optional removal of the PEG component from the products; various such surfactants are commercially available, e.g., the CREMOPHOR series from BASF Corp. (Mt. Olive, N.J.), such as CREMOPHOR RH 40 which is PEG40 hydrogenated castor oil and an HLB of about 14-16); (2.) polyoxyethylene fatty acid esters, including in particular polyoxyethylene stearic acid esters (such as the MYRJ series from Uniqema, e.g., MYRJ 53 having a m.p. of about 47°C; particular compounds in the MYRJ series are, e.g., MYRJ 53 having a m.p. of about 47°C and PEG-40-stearate which is available, e.g., as MYRJ 52); (3.) sorbitan derivatives, including in particular the TWEEN series from Uniqema (e.g., TWEEN 60, Tween 20, Tween 80, or Tween 40); (4.) polyoxyethylene-polyoxypropylene co-polymers and/or block co-polymers and/or poloxamers (e.g., Pluronic P127 or Pluronic F68 from BASF or Synperonic PE/L from Croda); (5.) polyoxyethylenealkylethers (such as, e.g., polyoxyethylene glycol ethers of C12-C18 alcohols, like, e.g., polyoxyl 10- or 20-cetyiether or polyoxyl 23-laurylether, or 20-oleylether, or polyoxyl 10-.20- or 100-stearylether, e.g., as commercially available as the BRI series from Uniqema; particularly useful products from the BRIJ series include BRIJ 58, BRIJ 76, BRIJ 78, BRIJ 35 (or polyoxyl 23-laurylether), or BRIJ 98 (or polyoxyl 20 oleyl ether); these products may have a m.p. between about 32°C and about 43°C); (6.) water-soluble tocopheryi PEG succinic acid esters (e.g., as available from Eastman Chemical Co., with a m.p. of about 36°C, such as, e.g, TPGS, particularly vitamin E-TPGS); (7.) PEG sterol ethers (such as, e.g., SOLULAN C24 (Choleth-24 and Cetheth-24) from Chemron (Paso Robles, Calif.); similar products which may also be used are those which are known and commercially available as NIKKOL BPS-30 (poly ethoxylated 30 phytosterol) and NIKKOL BPSH-25 (poly ethoxylated 25 phytostanol) from Nikko Chemicals); (8.) polyglycerol fatty acid esters, e.g., having 4 to 10 glycerol units, such as 4, 6 or 10 glycerol units (e.g., particularly suitable are deca- hexa-/tetraglycerylmonostearate, e.g., DECAGLYN, HEXAGLYN or TETRAGLYN from Nikko Chemicals); (9.) alkylene polyolether or ester (e.g., lauroyl macrogol-32 glyce rides and/or stearoylmacrogol-32 glycerides, such as GELUCIRE 44/14 and/or GELUCIRE 50/13); (10.) polyoxyethylenemonoesters of a saturated C ₀-C₂2 (e.g., C ₈) hydroxy fatty acid (which may optionally be substituted), such as, e.g., 12-hydroxystearic acid PEG ester, e.g., of PEG 600, 900 or 660 (e.g., SOLUTOL HS 15 from BASF (Ludwigshafen, Germany); or a substance comprsining (or consisting of) about 70% polyethoxylated 12- hydroxystearate by weight and about 30% by weight unesterified polyethylene glycol component, having a hydrogenation value of 90 to 110, a saponine cation value of 53 to 63, an acid number of maximum 1 , and a maximum water content of 0.5% by weight); (11.) polyoxyethylene-polyoxypropylene-aikyl ethers (such as, e.g., polyoxyethylene- polyoxypropylene ethers of Ci₂-C₁₈ alcohols, e.g., poiyoxyethylen-20-polyoxypropylene-4- cetylether, which is commercially available as NIKKOL PBC 34 from Nikko Chemicals); or (12.) polyethoxylated distearates (e.g., as commercially available under the trade names ATLAS G 1821 from Uniqema and/or NIKKOCDS-6000P from Nikko Chemicals).

Moreover, as noted above, the pharmaceutical compositions may comprise one or more pharmaceutically acceptable carriers. The pharmaceutically acceptable carrier may be an aqueous or non-aqueous agent, for example alcoholic or oleaginous, or a mixture thereof, and may contain a surfactant, an emollient, a lubricant, a stabilizer, a dye, a perfume, a preservative, an acid or base for adjustment of pH, a solvent, an emulsifier, a gelling agent, a moisturizer, a stabilizer, a wetting agent, a time release agent, a humectant, or any other component commonly included in a particular form of pharmaceutical composition. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, and oils such as olive oil or injectable organic esters. A pharmaceutically acceptable carrier can contain physiologically acceptable compounds that act, for example, to stabilize or to increase the absorption of the corresponding peptide or protein drug, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. A pharmaceutically acceptable carrier can also be selected from substances such as distilled water, benzyl alcohol, lactose, starches, talc, magnesium s tea rate, polyvinylpyrrolidone, alginic acid, colloidal silica, titanium dioxide, and flavoring agents.

It is preferred that the pharmaceutical compositions comprise arginine, which is advantageous as it can increase the inhibitory activity of the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex against peptidases in the nasal mucosa, as also demonstrated in Example 4. Moreover, it is preferred that the pharmaceutical compositions do not comprise histidine, particularly since histidine can reduce the inhibitory activity of the aforementioned copper, zinc and/or iron salts/complexes against peptidases in the nasal mucosa (see Example 4); the pharmaceutical compositions are thus preferably free of (or essentially free of) histidine.

It is furthermore preferred that the pharmaceutical compositions are free of (i.e., do not comprise) reducing agents, or are essentially free of reducing agents. Examples of reducing agents that are preferably not contained in the pharmaceutical compositions include each of the pharmaceutically acceptable reducing agents disclosed in WO 20 6/055550.

The pharmaceutical compositions are formulated as dosage forms for nasal administration, particularly for intranasal administration (including, e.g., for intranasal transmucosal administration, for local administration to the nasal cavity, or for nose brain delivery). Accordingly, the compounds to be administered or the above described pharmaceutical compositions, including also the pharmaceutical composition according to the fifth aspect, are administered to a subject/patient nasally, particularly intranasally. It is thus envisaged that the peptide or protein drug, the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex, and the optionally used absorption enhancer are all to be administered nasally. It will be understood that the nasal/intranasal administration of the compounds or the pharmaceutical compositions according to the invention can have systemic therapeutic effects (particularly via absorption of the peptide or protein drug through the nasal mucosa) and/or local therapeutic effects (particularly in the nasal cavity) and/or therapeutic effects in the brain (particularly via nose-to-brain delivery; see, e.g., Kamble MS et al., International Journal of Pharmaceutical and Chemical Sciences, 2013; 2(1 ):516-25), depending inter alia on the choice of the specific peptide or protein drug to be administered and the optional use of an absorption enhancer or mucoadhesive polymer. The compounds or the pharmaceutical compositions to be administered nasally/intranasally in accordance with the present invention may be provided, e.g., as a nasal spray, as nasal drops, as an aerosol, or as a dry powder for nasal administration, and are preferably provided as a nasal spray. Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific peptide or protein drug employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy. The precise dose will ultimately be at the discretion of the attendant physician or veterinarian. The subject or patient to be treated, such as the subject in need of treatment or prevention, may be an animal (e.g., a non-human animal), a vertebrate animal, a mammal, a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), a murine (e.g., a mouse), a canine (e.g., a dog), a feline (e.g., a cat), a porcine (e.g., a pig), an equine (e.g., a horse), a primate, a simian (e.g., a monkey or ape), a monkey (e.g., a marmoset, a baboon), an ape (e.g., a gorilla, chimpanzee, orang-utan, gibbon), or a human. In the context of this invention, it is also envisaged that animals are to be treated which are economically or agronomically important. Non-limiting examples of agronomically important animals are sheep, cattle and pigs, while, for example, cats and dogs may be considered as economically important animals. Preferably, the subject/patient is a mammal; more preferably, the subject/patient is a human or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orang-utan, a gibbon, a sheep, cattle, or a pig); most preferably, the subject/patient is a human.

The term "treatment" of a disorder or disease as used herein is well known in the art. "Treatment" of a disorder or disease implies that a disorder or disease is suspected or has been diagnosed in a patient/subject. A patient/subject suspected of suffering from a disorder or disease typically shows specific clinical and/or pathological symptoms which a skilled person can easily attribute to a specific pathological condition (i.e., diagnose a disorder or disease). The "treatment" of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (e.g., no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only). The "treatment" of a disorder or disease may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject/patient suffering from the disorder or disease. Accordingly, the "treatment" of a disorder or disease may also refer to an amelioration of the disorder or disease, which may, e.g., lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject/patient may experience a broad range of responses to a treatment (such as the exemplary responses as described herein above). The treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief).

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

The terms "peptide" and "protein", as in the expression "peptide or protein drug", are used herein interchangeably and refer to a polymer of two or more amino acids linked via amide bonds that are formed between an amino group of one amino acid and a carboxyl group of another amino acid. The amino acids comprised in the peptide or protein, which are also referred to as amino acid residues, may be selected from the 20 standard proteinogenic a-amino acids (i.e., Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) but also from non-proteinogenic and/or non-standard a-amino acids (such as, e.g., ornithine, citrulline, homolysine, pyrrolysine, 4-hydroxyproline, a-methylalanine (i.e., 2-aminoisobutyric acid), norvaline, norleucine, terleucine (tert-leucine), labionin, or an alanine or glycine that is substituted at the side chain with a cyclic group such as, e.g., cyclopentylalanine, cyclohexylalanine, phenylalanine, naphthylalanine, pyridylalanine, thienylalanine, cyclohexylg!ycine, or phenylglycine) as well as β-amino acids (e.g., β-alanine), γ-amino acids (e.g., γ-aminobutyric acid, isogiutamine, or statine) and δ-amino acids. Preferably, the amino acid residues comprised in the peptide or protein are selected from a-amino acids, more preferably from the 20 standard proteinogenic a-amino acids (which can be present as the L-isomer or the D-isomer, and are preferably all present as the L-isomer). The peptide or protein may be unmodified or may be modified, e.g., at its N-terminus, at its C-terminus and/or at a functional group in the side chain of any of its amino acid residues (particularly at the side chain functional group of one or more Lys, His, Ser, Thr, Tyr, Cys, Asp, Glu, and/or Arg residues). Such modifications may include, e.g., the attachment of any of the protecting groups described for the corresponding functional groups in: Wuts PG & Greene TW, Greene's protective groups in organic synthesis, John Wiley & Sons, 2006. Such modifications may also include the covalent attachment of one or more polyethylene glycol (PEG) chains (forming a PEGylated peptide or protein), the glycosylation and/or the acylation with one or more fatty acids (e.g., one or more C_{8 30} alkanoic or alkenoic acids; forming a fatty acid acyiated peptide or protein). Moreover, such modified peptides or proteins may also include peptidomimetics, provided that they contain at least two amino acids that are linked via an amide bond (formed between an amino group of one amino acid and a carboxyl group of another amino acid). The amino acid residues comprised in the peptide or protein may, e.g., be present as a linear molecular chain (forming a linear peptide or protein) or may form one or more rings (corresponding to a cyclic peptide or protein). The peptide or protein may also form oligomers consisting of two or more identical or different molecules.

The term "amino acid" refers, in particular, to any one of the 20 standard proteinogenic a-amino acids (i.e., Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) but also to non-proteinogenic and/or non-standard a-amino acids (such as, e.g., ornithine, citrulline, homolysine, pyrrolysine, 4-hydroxyproline, a-methylalanine (i.e., 2-aminoisobutyric acid), norvaline, norleucine, terleucine (tert-leucine), labionin, or an alanine or glycine that is substituted at the side chain with a cyclic group such as, e.g., cyc!opentylaianine, cyclohexylalanine, phenylalanine, naphthylalanine, pyridylalanine, thienylalanine, cyclohexylglycine, or phenylglycine) as well as β-amino acids (e.g., β-alanine), γ-amino acids (e.g., y-aminobutyric acid, isoglutamine, or statine) and/or δ-amino acids as well as any other compound comprising at ieast one carboxyl ic acid group and at least one amino group. Unless defined otherwise, an "amino acid" preferably refers to an a-amino acid, more preferably to any one of the 20 standard proteinogenic a-amino acids (which can be present as the L-isomer or the D-isomer, and are preferably present as the L-isomer).

As used herein, the term "complex" refers to a chelate complex (in which coordinate bonds are formed between a single central atom/ion and a polydentate ligand) or a coordination complex composed of monodentate ligands coordinating a single central atom/ion. As used herein, the terms "optional", "optionally" and "may" denote that the indicated feature may be present but can also be absent. Whenever the term "optional", "optionally" or "may" is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, if a component of a composition is indicated to be "optional", the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.

As used herein, the term "about" refers to ±10% of the indicated numerical value, preferably to ±5% of the indicated numerical value, and in particular to the exact numerical value indicated. For example, the expression "about 100" refers to the range of 90 to 1 10, in particular the range of 95 to 105, and preferably refers to the specific value of 100. If the term "about" is used in connection with the endpoints of a range, it refers to the range from the lower endpoint -10% of its indicated numerical value to the upper endpoint +10% of its indicated numerical value, in particular to the range from of the lower endpoint -5% to the upper endpoint +5%, and preferably to the range defined by the exact numerical values of the lower endpoint and the upper endpoint. Thus, the expression "about 10 to about 20" refers to the range of 9 to 22, in particular 9.5 to 21 , and preferably 10 to 20. If the term "about" is used in connection with the endpoint of an open-ended range, it refers to the corresponding range starting from the lower endpoint -10% or from the upper endpoint +10%, in particular to the range starting from the lower endpoint -5% or from the upper endpoint +5%, and preferably to the open-ended range defined by the exact numerical value of the corresponding endpoint. For example, the expression "at least about 10%" refers to at least 9%, particularly at least 9.5%, and preferably at least 10%.

Unless specifically indicated otherwise, all properties and parameters referred to herein (including, e.g., any amounts/concentrations indicated in "mg/ml" or in "% (v/v)", and any pH values) are preferably to be determined at standard ambient temperature and pressure conditions, particularly at a temperature of 25°C (298.15 K) and at an absolute pressure of 101.325 kPa (1 atm).

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

In this specification, a number of documents including patent applications and scientific literature are cited. The disclosure of these documents, while not considered relevant for the patentability of this invention, is herewith incorporated by reference in its entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

The present invention particularly relates to the following items:

1. A peptide or protein drug having a molecular weight of equal to or less than about 100 kDa for use as a medicament, wherein said peptide or protein drug is to be administered nasally in combination with: a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex.

2. A pharmaceutically acceptable copper salt/complex for use in therapy, wherein said copper salt/complex is to be administered nasally in combination with a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa.

3. A pharmaceutically acceptable zinc salt/complex for use in therapy, wherein said zinc salt/complex is to be administered nasally in combination with a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa.

4. A pharmaceutically acceptable iron salt/complex for use in therapy, wherein said iron salt/complex is to be administered nasally in combination with a peptide or protein drug having a molecular weight of equal to or less than about 00 kDa.

5. A pharmaceutical composition for use by nasal administration, comprising:

a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa; and

a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex.

6. 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 iron salt/complex for use according to item 4 or the pharmaceutical composition for use according to item 5, wherein the peptide or protein drug has a molecular weight of about 500 Da to about 30 kDa.

7. 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 iron salt/complex for use according to item 4 or the pharmaceutical composition for use according to item 5, wherein the peptide or protein drug has a molecular weight of about 1 kDa to about 10 kDa.

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 iron salt/complex for use according to item 4 or the pharmaceutical composition for use according to item 5, wherein the peptide or protein drug is selected from insulin, an insulin analog, insulin lispro, insulin PEGiispro, insulin aspart, insulin glulisine, insulin giargine, insulin detemir, NPH insulin, insulin degludec, B29K(N(e)hexadecanedioyl-Y-L- Glu) A14E B25H desB30 human insulin, B29K(N(e)octadecanedioyl-Y-L-Glu-OEG- OEG) desB30 human insulin, B29K(N(£)octadecanedioyl-Y-L-Glu) A14E B25H desB30 human insulin, B29K(N(£)eicosanedioyl-Y-L-Glu) A14E B25H desB30 human insulin, B29K(N(£)octadecanedioyl-Y-L-Glu-OEG-OEG) A14E B25H desB30 human insulin, B29K(N(£)eicosanedioyl-Y-L-Glu-OEG-OEG) A14E B25H desB30 human insulin, B29K(N(£)eicosanedioyl-Y-L-Glu-OEG-OEG) A14E B16H B25H desB30 human insulin, B29K(N(£)hexadecanedioyl-Y-L-Glu) A14E B16H B25H desB30 human insulin, B29K(N(£)eicosanedioyl-Y-L-Glu-OEG-OEG) A14E B16H B25H desB30 human insulin, B29K(N(£)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)NH₂, 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, glucose-dependent insulinotropic polypeptide, 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 long- acting human growth hormone, fibroblast growth factor 21 , somapacitan, hGH-CTP, a glycopeptide antibiotic, a glycosylated cyclic or polycyclic nonribosomal peptide antibiotic, vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, decaplanin, a cyclotide, 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-1 a, interferon beta- 1 b, interferon gamma-1 b, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon beta-1 a, fibrinolysin, vasopressin, aldesleukin, an epoetin, epoetin alfa, darbepoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, epoetin theta, methoxy polyethylene glycol-epoetin beta, continuous erythropoietin receptor activator, pegiylated epo, albupoetin, an epo-dimer analogue, epo-Fc, carbamylated EPO, synthetic erythropoese protein, the low molecular epo analogue PBI-1402, filgrastim, PEG-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 F2a receptor modulator, PDC31 , abciximab, ranibizumab, alefacept, romiplostim, anakinra, abatacept, belatacept, and pharmaceutically acceptable salts thereof. The peptide or protein drug for use according to any one of items 1 or 6 to 8, wherein said peptide or protein drug is to be administered in combination with a pharmaceutically acceptable copper salt/complex. The pharmaceutical composition for use according to any one of items 5 to 8, wherein said pharmaceutical composition comprises a pharmaceutically acceptable copper salt/complex. The peptide or protein drug for use according to any one of items 1 or 6 to 9 or the copper salt/complex for use according to any one of items 2 or 6 to 8 or the pharmaceutical composition for use according to any one of items 5 to 8 or 10, wherein said copper salt/complex is a copper(ll) salt/compiex selected from copper sulfate, copper carbonate, a copper(ll) amino acid complex, copper(ll) lysine complex, copper(ll) glycinate, copper(ll) EDTA complex, copper(ll) chitosan complex, copper chlorophyllin complex, copper(ll) citrate, copper(ll) gluconate, copper(il) lactate, copper lactate gluconate, copper(ll) orotate, and copper(ll) tartrate. The peptide or protein drug for use according to any one of items 1 or 6 to 9 or the copper salt/complex for use according to any one of items 2 or 6 to 8 or the pharmaceutical composition for use according to any one of items 5 to 8 or 10, wherein said copper salt/complex is a copper(l) salt/complex selected from copper(l) chloride and copper(l) acetate. 13. The peptide or protein drug for use according to any one of items 1 or 6 to 8, wherein said peptide or protein drug is to be administered in combination with a pharmaceutically acceptable zinc salt/complex. 14. The pharmaceutical composition for use according to any one of items 5 to 8, wherein said pharmaceutical composition comprises a pharmaceutically acceptable zinc salt/complex.

15. The peptide or protein drug for use according to any one of items 1 , 6 to 8 or 13 or the zinc salt/complex for use according to any one of items 3 or 6 to 8 or the pharmaceutical composition for use according to any one of items 5 to 8 or 14, wherein said zinc salt/complex is a zinc(ll) salt/complex 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.

16. The peptide or protein drug for use according to any one of items 1 or 6 to 8, wherein said peptide or protein drug is to be administered in combination with a pharmaceutically acceptable iron salt/complex.

17. The pharmaceutical composition for use according to any one of items 5 to 8, wherein said pharmaceutical composition comprises a pharmaceutically acceptable iron salt/complex.

18. The peptide or protein drug for use according to any one of items 1 , 6 to 8 or 16 or the iron salt/complex for use according to any one of items 4 or 6 to 8 or the pharmaceutical composition for use according to any one of items 5 to 8 or 17, wherein said iron salt/complex is an iron(ll) salt/complex selected from iron(ll) gluconate, iron(ll) orotate, iron(ll) tartrate, iron(ll) fumarate, iron(ll) sulfate, iron(ll) lactate, iron(ll) lactate gluconate, iron(ll) acetate, iron(ll) carbonate, iron(ll) citrate, iron(ll) oxide, iron(ll) hydroxide, iron(ll) ascorbate, an iron(ll) amino acid complex, and iron(ll) glycinate.

19. The peptide or protein drug for use according to any one of items 1 , 6 to 8 or 16 or the iron salt/complex for use according to any one of items 4 or 6 to 8 or the pharmaceutical composition for use according to any one of items 5 to 8 or 17, wherein said iron salt/complex is an iron(lll) salt/complex selected from iron(lll) chloride, iron(lll) sulfate, iron(lll) oxide, iron(lll)carbonate, iron(lll) acetate, iron(lll) phosphate, iron(lll) hydroxide, iron(lll) tartrate, iron(lll) lactate, iron(lll) glycinate, iron(lll) EDTA, iron(lll) ascorbate, and ammonium iron(lll) citrate.

The peptide or protein drug for use according to any one of items 1 , 6 to 9, 11 to 13, 15, 16, 18 or 19 or the copper salt/complex for use according to any one of items 2, 6 to 8, 1 1 or 12 or the zinc salt/complex for use according to any one of items 3, 6 to 8 or 15 or the iron salt/complex for use according to any one of items 4, 6 to 8, 18 or 19 or the pharmaceutical composition for use according to any one of items 5 to 8, 10 to 12, 14, 15 or 17 to 19, wherein said peptide or protein drug or said copper salt/complex or said zinc salt/complex or said iron salt/complex is to be administered nasally in combination with an absorption enhancer, or wherein said pharmaceutical composition further comprises an absorption enhancer.

The peptide or protein drug for use according to item 20 or the copper salt/complex for use according to item 20 or the zinc salt/complex for use according to item 20 or the iron salt/complex for use according to item 20 or the pharmaceutical composition for use according to item 20, wherein said absorption enhancer is selected from C_8-2o alkanoyl carnitine, salicylic acid, a salicylic acid derivative, 3-methoxysalicylic acid, 5- methoxysalicylic acid, homovanillic acid, a C_s.₂o alkanoic acid, citric acid, tartaric acid, a fatty acid acylated amino acid, a C₈.₂₀ alkanoyl sarcosinate, an alkylsaccharide, a C₈-io alkylpolysaccharide, n-octyl-beta-D-glucopyranoside, n-dodecyl-beta-D-maitoside, n- tetradecyl-beta-D-maltoside, tridecyi-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, a-cyclodextrin, β-cyclodextrin, γ-cyciodextrin, methyl- -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, Ν,Ν,Ν- trimethyl chitosan, benzalkonium chloride, bestatin, cetylpyridinium chloride, cetyltrimethylammonium bromide, a C_2-20 alkanol, a C₈.₂o alkenol, a C₈..₂₀ alkenoic acid, dextran sulfate, diethyleneglycol monoethyi ether, 1 -dodecylazacyclo-heptan-2-one, capryiocaproyl polyoxylg!ycerides, ethyl caprylate, glyceryl monolaurate, lysophosphatidylcholine, menthol, a C_a.₂o alkylamine, a C₈.₂₀ 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, poiyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopaimitate, sorbitan monooieate, Triton X-100, hexanoic acid, heptanoic acid, methyl laurate, isopropyl myristate, isopropyl pa Imitate, 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, octa-arginine, penetratin, a penetratin analog, PenetraMax, HIV-1 Tat, transportan, 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-a-tocopheryl polyethylene glycol-1000 succinate, arginine, and pharmaceutically acceptable salts thereof. The peptide or protein drug for use according to item 21 or the copper salt/complex for use according to item 21 or the zinc salt/complex for use according to item 21 or the iron salt/complex for use according to item 21 or the pharmaceutical composition for use according to item 21 , 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 lauroyi 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-dodecanoyi-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyi-L-tryptophane, sodium lauroyi tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyi valinate, N-dodecanoyl-L-valine, sodium lauroyi 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-proiine, 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 stearoyi glutamate, sodium myristoyl glutamate, sodium lauroyi glutamate, sodium cocoyi glutamate, sodium cocoyi glycinate, sodium N-decyl leucine, sodium cocoyi glycine, sodium cocoyi glutamate, sodium lauroyi alaninate, N-dodecanoyl-L-alanine, sodium lauroyi asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyi aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyi cysteinate, N-dodecanoyl-L-cysteine, sodium lauroyi glutamic acid, N-dodecanoyl-L-glutamic acid, sodium lauroyi glutaminate, N-dodecanoyl-L-glutamine, sodium lauroyi glycinate, N-dodecanoyl- L-glycine, sodium lauroyi histidinate, N-dodecanoyl-L-histidine, sodium lauroyi isoieucinate, N-dodecanoyl-L-isoleucine, sodium lauroyi leucinate, N-dodecanoyl- L-leucine, sodium lauroyi methinoninate, N-dodecanoyl-L-methionine, sodium lauroyi phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyi prolinate, N-dodecanoyl-L-proline, sodium lauroyi serinate, N-dodecanoyl-L-serine, sodium lauroyi threoninate, N-dodecanoyl-L-threonine, sodium lauroyi tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyi tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyi 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-phenyialanine, sodium capric prolinate, N-decanoyl-L-proiine, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl- L-threonine, sodium capric tryptophanate, N-decanoyi-L-tryptophane, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, sodium oieoyi sarcosinate, and pharmaceutically acceptable salts thereof. The peptide or protein drug for use according to item 20 or the copper salt/complex for use according to item 20 or the zinc salt/complex for use according to item 20 or the iron salt/complex for use according to item 20 or the pharmaceutical composition for use according to item 20, wherein said absorption enhancer is sodium N-[8-(2- hydroxybenzoyl)amino]caprylate. The pharmaceutical composition for use according to any one of items 5 to 8, 10 to 12, 14, 15 or 17 to 23, wherein said pharmaceutical composition comprises:

the copper salt/complex in an amount of about 0.1 mg to about 20 mg calculated as Cu^* or Cu ⁺ per dosage unit, and/or

the zinc salt/complex in an amount of about 0.1 mg to about 50 mg calculated as Zn²⁺ per dosage unit, and/or

the iron salt/complex in an amount of about 1 mg to about 100 mg calculated as Fe²⁺ or Fe³⁺ per dosage unit. The pharmaceutical composition for use according to any one of items 20 to 24, wherein said pharmaceutical composition comprises the absorption enhancer in an amount of about 10 mg to about 1000 mg per dosage unit. Use of a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa in the preparation of a medicament which is to be administered nasally in combination with: a pharmaceutically acceptable copper salt complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex.

Use of a pharmaceutically acceptable copper salt/complex in the preparation of medicament which is to be administered nasally in combination with a peptide protein drug having a molecular weight of equal to or less than about 100 kDa. Use of a pharmaceutically acceptable zinc salt/complex in the preparation of medicament which is to be administered nasally in combination with a peptide protein drug having a molecular weight of equal to or less than about 100 kDa.

Use of a pharmaceutically acceptable iron salt/complex in the preparation of medicament which is to be administered nasally In combination with a peptide protein drug having a molecular weight of equal to or less than about 100 kDa.

Use of a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex in the preparation of a medicament which is to be administered nasally.

A method of treating or preventing a disease/disorder, the method comprising nasally administering, to a subject in need thereof, a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex.

A method of nasally delivering a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa, the method comprising nasally administering said peptide or protein drug in combination with a pharmaceutically acceptable copper salt/complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex to a subject in need thereof.

The use of any one of items 26 to 30 or the method of item 31 or 32, wherein the peptide or protein drug has a molecular weight of about 500 Da to about 30 kDa.

The use of any one of items 26 to 30 or the method of item 31 or 32, wherein the peptide or protein drug has a molecular weight of about 1 kDa to about 10 kDa.

The use of any one of items 26 to 30 or the method of item 31 or 32, wherein the peptide or protein drug is selected from insulin, an insulin analog, insulin lispro, insulin PEGIispro, insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, insulin degludec, B29K(N(e)hexadecanedioyl-y-L-Glu) A14E B25H desB30 human insulin, B29K(N(E)octadecanedioyl-y-L-Glu-OEG-OEG) desB30 human insulin, B29K(N(£)octadecanedioyl-Y-L-G!u) A14E B25H desB30 human insulin, B29K(N(e)eicosanedioyl-Y-L-Glu) A14E B25H desB30 human insulin, B29K(N(e)octadecanedioyl-Y-L-Glu-OEG-OEG) A14E B25H desB30 human insulin, B29K(N(e)eicosanedioyl-Y-L-Glu-OEG-OEG) A14E B25H desB30 human insulin, B29K(N(£)eicosanedioyl-Y-L-Glu-OEG-OEG) A14E B16H B25H desB30 human insulin, B29K(N(£)hexadecanedioyl-Y-L-Glu) A14E B16H B25H desB30 human insulin, B29K(N(e)eicosanedioyl-Y-L-Glu-OEG-OEG) A14E B16H B25H desB30 human insulin, B29K(N(e)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)NH₂, 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, glucose-dependent insulinotropic polypeptide, 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 long- acting human growth hormone, fibroblast growth factor 21 , somapacitan, hGH-CTP, a glycopeptide antibiotic, a glycosylated cyclic or polycyclic nonribosomal peptide antibiotic, vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, decaplanin, a cyclotide, bortezomib, cosyn tropin, 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-lb, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon beta- a, fibrinolysin, vasopressin, aldesleukin, an epoetin, epoetin alfa, darbepoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, epoetin theta, methoxy polyethylene glycol-epoetin beta, continuous erythropoietin receptor activator, pegiylated epo, albupoetin, an epo-dimer analogue, epo-Fc, carbamylated EPO, synthetic erythropoese protein, the low molecular epo analogue PBI-1402, filgrastim, PEG-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 F2a receptor modulator, PDC31 , abciximab, ranibizumab, alefacept, romiplostim, anakinra, abatacept, belatacept, and pharmaceutically acceptable salts thereof.

The use of any one of items 26, 27, 30 or 33 to 35 or the method of any one of items 31 to 35, wherein said copper salt/complex is a copper(ll) salt/complex selected from copper sulfate, copper carbonate, a copper(ll) amino acid complex, copper(ll) lysine complex, copper(ll) glycinate, copper(ll) EDTA complex, copper(ll) chitosan complex, copper chlorophyllin complex, copper(ll) citrate, copper(ll) gluconate, copper(ll) lactate, copper lactate gluconate, copper(ll) orotate, and copper(ll) tartrate.

The use of any one of items 26, 27, 30 or 33 to 35 or the method of any one of items 31 to 35, wherein said copper salt/complex is a copper(l) salt/complex selected from copper(l) chloride and copper(l) acetate.

The use of any one of items 26, 28, 30 or 33 to 35 or the method of any one of items 31 to 35, wherein said zinc salt/complex is a zinc(ll) salt/complex 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.

The use of any one of items 26, 29, 30 or 33 to 35 or the method of any one of items 31 to 35, wherein said iron salt/complex is an iron(ll) salt/complex selected from iron(ll) gluconate, iron(ll) orotate, iron(ll) tartrate, iron(ll) fumarate, iron(ll) sulfate, iron(ll) lactate, iron(ll) lactate gluconate, iron(ll) acetate, iron(ll) carbonate, iron(l!) citrate, iron(ll) oxide, iron(ll) hydroxide, iron(ll) ascorbate, an iron(ll) amino acid complex, and iron(ll) glycinate.

The use of any one of items 26, 29, 30 or 33 to 35 or the method of any one of items 31 to 35, wherein said iron salt/complex is an iron(lll) salt/complex selected from iron(lll) chloride, iron(lll) sulfate, iron(lll) oxide, iron(lll)carbonate, iron(lll) acetate, iron(lll) phosphate, iron(lll) hydroxide, iron(lll) tartrate, iron(lll) lactate, iron(lll) glycinate, iron(lll) EDTA, iron(lll) ascorbate, and ammonium iron(lll) citrate.

The use of any one of items 26 to 30 or 33 to 40 or the method of any one of items 31 to 40, wherein an absorption enhancer is further to be administered nasally. The use of item 41 or the method of item 41 , wherein said absorption enhancer is selected from C₈.₂o alkanoyl carnitine, salicylic acid, a salicylic acid derivative, 3-methoxysalicylic acid, 5-methoxysalicylic acid, homovaniilic acid, a C₈.₂₀ alkanoic acid, citric acid, tartaric acid, a fatty acid acylated amino acid, a C_{8 2}o alkanoyl sarcosinate, an alkylsaccharide, a C_8-io alkylpolysaccharide, n-octyl-beta-

D-glucopyranoside, n-dodecyl-beta-D-maltoside, n-tetradecyl-beta-D-maitoside, tridecyl-beta-D-maltoside, sucrose la urate, sucrose myristate, sucrose palmitate, sucrose cocoate, sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose mono-tetradecanoate, a coco-glucoside, a cyclodextrine, a-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-p-cyclodextrin, hydroxypropyl β-cyclodextrin, sulfobutylether β-cyclodextrin, N-[8-(2-hydroxybenzoyl)amino]caprylic acid, sodium N-[8-(2- hyd roxybenzoyl )ami no]ca prylate , 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, Ν,Ν,Ν-trimethyl chitosan, benzalkonium chloride, bestatin, cetylpyridinium chloride, cetyltrimethylammonium bromide, a C2-20 alkanol, a C_8-2o alkenol, a C₈.₂₀ alkenoic acid, d extra n sulfate, diethyleneglycol monoethyl ether, 1 -dodecylazacyclo-heptan-2-one, caprylocaproyl polyoxylglycerides, ethyl caprylate, glyceryl monolaurate, lysophosphatidylcholine, menthol, a C₈.₂o alkylamine, a C₈.₂₀ 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 chioride, myristyltrimethyl ammonium chloride, dodecyl pyridinium chloride, decyldimethyl ammonio propane sulfonate, myristyldimethyl ammonio propane sulfonate, paimityidimethyl ammonio propane sulfonate, ChemBetaine CAS, ChemBetaine Oleyl, Nonyiphenoxypolyoxyethylene, 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, caproiactam, methyl pyrrolidone, octyl pyrrolidone, methyl piperazine, phenyl piperazine, Carbopoi 934P, glyccyrhetinic acid, bromelain, pinene oxide, limonene, cineoie, octyl dodecanol, fenchone, menthone, trimethoxy propylene methyl benzene, a cell-penetrating peptide, KLAKLAK, polyarginine, octa-arginine, penetratin, a penetratin analog, Penetra ax, H!V-1 Tat, transportan, 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-a-tocopheryl polyethylene glycol-1000 succinate, arginine, and pharmaceutically acceptable salts thereof. The use of item 42 or the method of item 42, wherein said absorption enhancer is a fatty acid acylated amino acid selected from sodium lauroyi alaninate, N-dodecanoyl-L- alanine, sodium lauroyi asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyi aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyi cysteinate, N-dodecanoyl- L-cysteine, sodium lauroyi glutamic acid, N-dodecanoyl-L-glutamic acid, sodium lauroyi glutaminate, N-dodecanoyl-L-glutamine, sodium lauroyi glycinate, N-dodecanoyl-L- glycine, sodium lauroyi histidinate, N-dodecanoyl-L-histidine, sodium lauroyi isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyi leucinate, N-dodecanoyl-L- leucine, sodium lauroyi methioninate, N-dodecanoyl-L-methionine, sodium lauroyi phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyi prolinate, N-dodecanoyl-L-proline, sodium lauroyi serinate, N-dodecanoyl-L-serine, sodium lauroyi threoninate, N-dodecanoyl-L-threonine, sodium lauroyi tryptophanate, N- dodecanoyl-L-tryptophane, sodium lauroyi tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyi valinate, N-dodecanoyl-L-vaiine, sodium lauroyi 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 lauroyi glutamate, sodium cocoyl glutamate, sodium cocoyl glycinate, sodium N-decyl leucine, sodium cocoyl glycine, sodium cocoyl glutamate, sodium lauroyi alaninate, N-dodecanoyl-L-alanine, sodium lauroyi asparaginate, N- dodecanoyl-L-asparagine, sodium lauroyi aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyi cysteinate, N-dodecanoyl-L-cysteine, sodium lauroyi glutamic acid, N- dodecanoyi-L-g!utamic acid, sodium lauroyi glutaminate, N-dodecanoyl-L-glutamine, sodium lauroyi glycinate, N-dodecanoyl-L-glycine, sodium lauroyi histidinate, N- dodecanoyl-L-histidine, sodium lauroyi isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyi leucinate, N-dodecanoyl-L-leucine, sodium lauroyi methinoninate, N- dodecanoyl-L-methionine, sodium lauroyi phenylalaninate, N-dodecanoyl-L- phenyla!anine, sodium lauroyi prolinate, N-dodecanoyl-L-proiine, sodium lauroyi serinate, N-dodecanoyl-L-serine, sodium lauroyi threoninate, N-dodecanoyl-L- threonine, sodium lauroyi tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyi tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyi 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-decanoyi-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-decanoyi-L-leucine, sodium capric methioninate, N-decanoyl-L-methionine, sodium capric phenylalaninate, N-decanoyl-L-phenyialanine, 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. 44. The use of item 41 or the method of item 41 , wherein said absorption enhancer is sodium N-[8-(2-hydroxybenzoyi)amino]caprylate.

The invention is also described by the following illustrative figures. The appended figures show:

Figure 1 : PK plasma profile of BUS002 (-■-) and BUS001 (-o-); 30 pg Buserelin / rat; n=4 ± S.E. (see Example 2).

Figure 2: Pharmacokinetic profile of three human growth hormone (hGH) formulations: intranasally administered formulation hGH009 (-·-), intranasally administered formulation hGH010 (-A-) and subcutaneously administered formulation hGH011 (-o-); each point represents the mean of n=3 ± S.E. (see Example 9). Figure 3: Pharmacokinetic profile of two formulations with epoetin alfa: intranasally administered formulation EPO001 (-A-) and subcutaneously administered formulation (-o-); both formulations with n=1 (see Example 10).

Figure 4: Pharmakokinetic profile of two formulations with filgrastim: intranasally administered formulation FIL001 (-X-) and subcutaneously administered formulation (-o-); each point represents the mean of n=3 ± S.D. (see Example 11 ). 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 Example 1: Compatibility of absorption enhancers with the trace element copper

Various absorption enhancers were screened regarding their compatibility with the trace element copper in the two main oxidation states as Cu²⁺ and Cu^*. The results of this test are shown in the following Table 1 :

Absorption enhancer Copper salt Reducing agent Dissolution in aqueous {10 mg/ml) (1 mg/m!) (10 mg/ml) medium (2 ml)

Sodium cap rate CuS0₄ Sodium ascorbate Precipitation

Sodium caprylate CuS0₄ Sodium ascorbate Precipitation

Sodium lauroyl CuS0₄ Sodium ascorbate Precipitation

sarcosinate

Lauroyl carnitine CuS0₄ Sodium ascorbate Clear solution

Lauroyl carnitine CuS0₄ Glutathione Clear solution

Sodium dodecyl sulfate CuS0₄ Sodium ascorbate Clear solution

Multitrope 1620 LQ CuS0₄ Sodium ascorbate Clear solution

(alkylsaccharide)

n-Octyl-beta-D- CuS0₄ Sodium ascorbate Clear solution

glucopyranoside

n-Dodecyl-beta-D- CuS0₄ Sodium ascorbate Clear solution

maltoside

Cremophor EL CuS0₄ Sodium ascorbate Clear solution Sodium salicylate CuS0₄ Sodium ascorbate Clear solution

EDTA CuS0₄ Sodium ascorbate Clear solution

Sodium citrate CuS0₄ Sodium ascorbate Clear solution

Methyl-beta- CuS0₄ Sodium ascorbate Clear solution

cyclodextrin

Sodium caprylate Copper (I) Sodium ascorbate Clear solution

acetate

Sodium caprate Copper (!) Sodium ascorbate Clear solution

acetate

Sodium caprate Cu(l)CI Sodium ascorbate Clear solution

Sodium caprylate Cu(l)CI ' Sodium ascorbate Clear solution

Table 1: Compatibility of various absorption enhancers with Cu²⁺ and Cu⁺ salts.

The term "clear solution" as used in this table indicates 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.

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⁺ oxidation state in aqueous solutions. The monovalent copper salt Cu(l)CI, on the other hand, has aqueous solubility and oxidation state stability.

Example 2: Pharmacokinetic profile of buserelin formulations after nasal administration

Buserelin formulations (concentration 750 pg/ml) were dosed into both the nostrils in volume of 20 μΙ per nostril to conscious rats. The habituated awake rats were firmly immobilized in horizontal supine position. The solutions were instilled into nostril using automatic pipette. The application was performed slowly to minimize sneezing. Blood was taken from tail vessels at the time points 0, 15, 30, 60, 90, 120 and 180 min after dosing into Multivette 600 EDTA tubes (Sarstedt, Germany). Blood samples were centrifuged (4 min, 10,000 g, 4°C) and approximately 200 μΙ of plasma were collected. The buserelin plasma concentrations were determined using commercial buserelin EIA kit (Peninsula Laboratories International, Inc., USA, cat.number S-1303.0001).

BUS001

For BUS001 , a commercially available nasal spray solution containing 0.1575 mg buserelin acetate (corresponding to 0.15 mg buserelin) per 100 mg as well as benzalkonium chloride, citric acid monohydrate, sodium citrate, sodium chloride and water was used. Before nasal application, the formulation was diluted 1 :1 (v/v) with destilled water. BUS002

For BUS002, a commercially available nasal spray solution containing 0.1575 mg buserelin acetate (corresponding to 0.15 mg buserelin) per 100 mg as well as benzalkonium chloride, citric acid monohydrate, sodium citrate, sodium chloride and water was used. Before nasal application, the formulation was diluted 1 :1 (v/v) with a solution containing 20 mg/ml CuS0₄ (to achieve a dose of 100 pg of CuS0₄ per nostril).

Results

The PK data obtained for BUS001 and BUS002 are summarized in the following Table 2, and the PK plasma profile of BUS001 and BUS002 is furthermore illustrated in Figure 1 (30 pg buserelin / rat; n = 4 ± S.E.).

Table 2: Summary of PK data for BUS001 and BUS002

Conclusion

The addition of copper results in a more than 11 -fold improved in vivo nasal absorption of the peptide drug buserelin. It has thus been demonstrated that the nasal administration of a peptide or protein drug in combination with a copper salt/complex allows to achieve an advantageously improved nasal absorption and, thus, also an improved bioavailability of the peptide or protein drug.

Example 3: Peptidase inhibition by copper gluconate, iron gluconate and zinc- bisglycinate

Stock solutions:

0.1 mg/ml Trypsin in 50 mM TRIS pH 7

0.5 mg/mL Benzoyl-Arginine p-nitroanilid (BAPNA) in 50 mM TRIS pH 7

0.1 mg/ml Chymotrypsin in 50 mM TRIS pH 7

0.5 mg/mL Benzoyl-Tyrosine p-nitroanilid (BTPNA) in Acetone

1 mg/ml copper(ll)gluconate in 50 mM TRIS pH 7

1 mg/ml iron(fl)g!uconate in 50 mM TRIS pH 7

10 mg/ml zinc(ll)bisglycinate in 50 mM TRIS pH 7

Trypsin inhibition study:

120 μΙ 50 mM TRIS pH 7 + 50 μΙ_ Trypsin Stock + 50 pl_ BAPNA Stock

40 μΙ copper gluconate + 80 μΙ 50 mM TRIS pH 7 + 50 μΙ_ Trypsin Stock + 50 μΙ_ BAPNA Stock 40 μΙ zinc-bisglycinate + 80 μΙ 50 mM TRIS pH 7 + 50 μί. Trypsin Stock + 50 μ1_ BAPNA Stock 40 μΙ iron gluconate + 80 μΙ 50 mM TRIS pH 7 + 50 μί. Trypsin Stock + 50 μΐ_ BAPNA Stock Absorption was measured after 15 minutes at 405 nm

Chymotrypsin inhibition study:

120 μΙ 50 mM TRIS pH 7 + 50 μί Chymotrypsin Stock + 50 μΙ_ BTPNA Stock

40 μΙ copper gluconate + 80 μΙ 50 mM TRIS pH 7 + 50 μΐ_ Chymotrypsin Stock + 50 μΙ_ BTPNA Stock

40 μΙ zinc-bisglycinate + 80 μΙ 50 mM TRIS pH 7 + 50 μΙ_ Chymotrypsin Stock + 50 μΙ_ BTPNA Stock

40 μΙ iron gluconate + 80 μΙ 50 mM TRIS pH 7 + 50 μί Chymotrypsin Stock + 50 μ!_ BTPNA Stock

Absorption was measured after 30 minutes at 405 nm

Results: Salt Salt concentration Trypsin inhibition Salt concentration Chymotrypsin inhibition

Cu(II)gIuconate 12.5 mg/m! i 97% 0.18 mg/ml 68%

Fe(II)gluconate 5.0 mg/ml 76% 0.18 mg/ml 44%

Zn(li)bssgiycinate 12.5 mg/ml 16% 1.80 mg/ml 11%

Conclusion: Copper, iron or zinc salts/complexes as described in the present invention reduce the enzymatic activity of various proteolytic enzymes, which have been reported to be found in the nasal mucosa (Na DH et a!., J Pharm Sci. 2004; 93(2): 256-61 ; Morimoto K et al., Pharm Res. 1991 ; 8(9): 1 175-9).

Example 4: Inhibition of proteolytic enzymes from porcine nasal homogenate In the presence of various buffering agents

The stability of the leucine aminopeptidase substrate L-leucine-p-nitroanilide in the presence of enzymatically active, porcine nasal homogenate was assessed. The nasal homogenate was prepared by excising 8 g of porcine nasal mucosa, suspending it in 50 ml of 25 mM TRIS pH 7 solution and homogenizing it with a high-shear homogenizer. Aliquots of the homogenate were stored at -20°C. Prior to the experiments, aliquots were thawed and centrifuged for 10 min at 3 ^'500 rpm. The supernatant was diluted 1 :5 with 50 mM phosphate buffer pH 7 (NHP) or aqua destillata (NHA) and used as a stock solution for the experiments. Further stock solutions were: buffer solution (50 mM phosphate buffer pH 7; buffer), 1 mg of L-leucine-p-nitroanilide in 1 ml of acetone (SUB), 10 mg/ml of zinc bisglycinate (in 50 mM phosphate buffer pH 7; ZnBG), 10 mg/ml of zinc gluconate (in aqua dest.; ZnGLUC), 10 mg/ml of zinc sulfate pentahydrate (in aqua dest.; ZnSULF), 15 mg/ml of histidine (in aqua dest.; HIS) and a mixture of zinc gluconate and arginine (10 mg/ml in aqua dest., each; ZnGLUC+ARG). Different combinations of excipients and nasal homogenate were prepared and incubated for 3 hours in the dark at room temperature (see the following table).

Sample NHP NHA Buffer Aqua ZnBG ZnGLUC ZnSULF ZnGLUC HIS SUB

No. dest. +A G

1 200 μΙ - 100 μΙ - - - - - - 50 μΙ

2 200 μΙ - 150 μΙ - - - - - - -

3 200 μΙ - 50 μΙ - 50 μΙ - - - - 50 μ!

4 200 μΙ 50 μΙ 50 50 μΙ μΙ 5 - 200 μΙ 50 μΙ - - - - - 50 μΙ

6 - 200 μ! - 100 μΙ - - - - - -

7 - 200 μΙ - - - 50 μΙ - - - 50 μΙ

8 - 200 μΙ - - - - 50 μΙ - - 50 μΙ

9 - 200 μΙ - - - - - 50 μΙ - 50 μ!

Results:

Experiments of samples 1 , 2, 3 and 4 were performed in triplicate. Immediately after starting the incubation period, the pH of all incubation mixture was measured with pH test strips. After incubation, samples 1 , 2, 3 and 4 were diluted 1 : 1 with 0.2 M NaOH prior to the spectrophotometric analysis. Samples 5, 6, 7, 8 and 9 were directly measured. All samples were analysed at 405 nm with a spectrophotometer. The blank value (sample no. 2 in the case of sample 1 , 2, 3 and 4; sample 6 in the case of sample 5, 6, 7, 8 and 9) was subtracted from the respective samples. The corrected value of the positive control (sample no. 1 for samples 2, 3 and 4, sample no. 5 for samples 6, 7, 8 and 9) was set as the 100% absorbance increase value and percentages of absorbance increases of the corresponding samples were calculated relative to the 100% values (see the following table).

Conclusion:

The presence of various zinc salts resulted in lower absorbance values in comparison to the positive control. This indicates an inhibition of aminopeptidases present in porcine nasal homogenate, leading to a less intense conversion of the aminopeptidase substrate L-leucine- p-nitroanilide to nitroaniline, which is spectrophotometricaliy detectable at 405 nm. In addition it was shown that the presence of histidine reduced the inhibitory activity of zinc bisglycinate, whereas the presence of arginine further increased the inhibitory activity of zinc gluconate. Example 5: Solubility of proteins in presence of Zn^z* and Cu²⁺ compounds.

Various proteins have been tested regarding their solubility in presence of divalent cations (copper or zinc).

Protein Molecular weight Protease inhibitor Buffer Appearance

(10 mg ml) (5 mg/ml)

Human Insulin 5.8 kDa Zinc(ll)gluconate TRIS Unclear suspension (1 mg/ml)

Human Insulin 5.8 kDa Copper(l ^gluconate TRIS Unclear bluish (1 mg/ml) suspension

Filgrastim 18.8 kDa Zinc(ll)giuconate Slightly unclear (600 Mg/ml) suspension

Filgrastim 18.8 kDa Copper(ll)gluconate Clear bluish (600 Mg/ml) solution

Human growth 22.1 kDa Zinc(ll)gluconate Unclear suspension hormone

(2 mg/ml)

Human growth 22.1 kDa Zinc(ll)arginate Unclear suspension hormone

(2 mg/ml)

Human growth 22.1 kDa Zinc(l!)bisglycinate Unclear suspension hormone

(2 mg/ml)

Human growth 22.1 kDa Copper(ll)gluconate Clear bluish hormone solution

(2 mg/ml)

Epoetin alfa 30.4 kDa Zinc(ll)gluconate Unclear suspension (336 ug/mi)

Epoetin alfa 30.4 kDa Copper(ll)bisglycinate Unclear suspension (336 Mg/ml)

Epoetin alfa 30.4 kDa Copper(ll)gluconate Clear bluish (336 Mg/ml) solution

Epoetin alfa 30.4 kDa Ferrous(ll)gluconate Unclear suspension (336 Mg/ml)

Conclusion: All the proteins except FGF21 tested in this experiment showed unfavorable solubility in presence of zinc. Therefore, it would be an advantage to formulate such proteins separately from the zinc compounds.

Example 6: Differential Scanning Calorimetry (DSC) studies of human growth hormone (hGH) with and without copper(li)bisglycinate The transition enthalpies of hGH (20% w/v) in TRIS buffer pH 7.4 formulated with and without copper( 11 )bisglycinate (1 % w/v) were analyzed with a DSC 1 ettler Toledo with the samples placed in Al cells. The approximate mass of each sample was 30 mg. Measurements were performed at a scan rate of 10 °C/min for all samples. The TRIS buffer was used as reference.

Conclusion: The presence of 1 % w/v copper( 11 )bisg lycinate resulted in a slight enthalpy change of hGH indicating a minor conformational change of the protein which could affect storage stability or activity of this protein. Therefore, it would be favourable to formulate hGH separately from copper.

Example 7: Pharmacokinetic Profile of Human Growth Hormone Formulations after Nasal Administration to rats Formulations with human growth hormone (hGH) were prepared as solutions with a final concentration of 2.2 mg/ml. To 0.5 ml of a commercial formulation (Norditropin NordiFlex 5 mg/1.5 ml; 3.3 mg/ml hGH further comprising mannitol, histidin, poloxamer 188 and phenol), either 0.25 mi of 50 mM TRIS pH 7 (hGH002) or 0.25 ml of a 10 mg/ml copper( 11 gluconate solution in 50 mM TRIS pH 7.0 (hGH003) was added (see the following table). Group Formulation Dose (hGH) Appearance

hGH002 hGH in buffer 132 ug/rat slightly cloudy

hGH003 hGH and 3.3 mg/mi copper{N)gluconate in 132 pg/rat homogenic suspension

TRIS buffer pH 7

The formulations were dosed into both the nostrils in volume of 30 pi per nostril to conscious rats. The habituated awake rats were firmly immobilized in horizontal supine position. The liquid formulations were instilled into nostril using automatic pipette. The application was performed slowly to minimize sneezing. Blood was taken from tail vessels at the time points 0, 15, 30, 45, 60, 90, 120 and 180 min after dosing. 450 pi of blood were drawn from the tail tip into Multivette 600 EDTA tubes (Sarstedt, Germany). Blood samples were centrifuged (4 min, 10,000 g, 4 °C) and approximately 200 μΙ of plasma were collected. The plasma samples were kept at -20 °C until the human growth hormone analysis. The human growth hormone plasma concentrations were determined using commercial growth hormone ELISA kit (BioVendor, EU, cat.number. RMEE022).

Results:

The instillation of the human growth hormone formulations hGH002 and hGH003 resulted in similar maximal hGH plasma concentrations exceeding 2 ng/ml and similar elimination half life. Both the formulations were completely cleared within 2 hours. The formulation hGH003 showed mildly higher relative bioavailability reaching 2.5% and T_max in range of 15-30 min after dosing. The formulation hGH002 was absorbed in most of the rats in 2 phases with mean lower peak at 15 min and higher peak at 45 min after dosing. The human growth hormone data are summarized in the following table.

AUC, Δ AUC, Crnax, F and Half-life were expressed as mean ± SE, ^" as range, N=4-5.

Compound Human grow h hormone

AUCe ΔΑΙΚν,». Cmax Tm . F Half-fife

(ng/ml x min) (ng ml x min) (ng/ml) (min) (%> (min) hGH002 95.591 ± 30.179 88.923 ± 29.443 2.900 ± 1.584 15 - 45 1.6 ± 0.5 46.8 ± 10.9 hGH003 153.296 ± 50.092 143.815 ± 49.990 2.259 ± 0.737 15 - 30 2.5 ± 0.8 38.9 ± 3.6 Example 8: Pharmacokinetic Profile of Human Growth Hormone Formulations after Nasal Administration to rats with and without pre-dosing.

The formulations HGH006 and hGH007 were prepared as ready-to-use solutions (concentration 2.5 mg/ml) approximately one week before in vivo dosing. The formulations hGHOOA hGH005, hGH006 and hGH007 were dosed into both the nostrils in volume of 20 μΙ per nostril to conscious rats. To prepare the final formulation hGH004, 100 μΙ of 50 mM TRIS pH 7 was added to 100 μ! of a 8 mg/ml hGH solution in 50 mM TRIS pH 7 to obtain a final concentration of 4 mg/ml. The formulation was administered within 10 min after the mixing. The formulation hGH005 was prepared by adding 180 μΙ of a solution containing 10 mg/ml copper gluconate in a mixture of 50 mM TRIS pH 7 (60%) and glycerol 85% (40%) to 180 μΙ of a 8 mg/ml hGH solution in 50 mM TRIS pH 7. The formulation was administered within 10 min after the mixing. The conscious rats from the group hGH008 were pretreated nasally with 10 μΙ per nostril of a solution containing 10 mg/ml copper gluconate in a mixture of 50 mM TRIS pH 7 (60%) and glycerol 85% (40%) and were dosed after 10 min with 10 μΙ per nostril of a 8 mg/ml hGH solution in 50 mM TRIS pH 7. All the vials were inverted several times before each dosing to ensure homogeneity of the solutions. The habituated awake rats were firmly immobilized in horizontal supine position. The solutions were instilled into nostril using automatic pipette. The application was performed slowly to minimize sneezing. Blood was taken from tail vessels at the time points 0, 15, 30, 45, 60, 90, 120 and 180 min after dosing. 450 μΙ of blood were drawn from the tail tip into Multivette 600 EDTA tubes (Sarstedt, Germany). Blood samples were centrifuged (4 min, 10,000 g, 4 °C) and approximately 200 μΙ of plasma were collected. The plasma samples were kept at -20 °C until the human growth hormone analysis. The human growth hormone plasma concentrations were determined using commercial growth hormone ELISA kit (BioVendor, EU, cat.number. RMEE022).

Results:

The instillation of the human growth hormone formulations hGH006 and hGH007 resulted in relatively poor pharmacokinetic profile. The pharmacokinetic parameters of the formulation hGH006 were more favorable with the mean maximal plasma concentration of 2.5 ng/mi and the relative bioavailability of 1.7%. Similarly the simultaneous administration of the formulations hGH004 (hGH in buffer only) and hGH005 with the corresponding excipients did not increase the bioavailability of human growth hormone markedly. However, the separate administration of a solution comprising 10 mg/ml copper gluconate to each nostril 10 minutes prior to dosing of hGH improved the pharmacokinetic profile dramatically. The mean maximal concentration exceeded 30 ng/ml and relative bioavailability reached 1.6 %. The human growth hormone data are summarized in the following table.

AUC, Δ AUC, C_n«x, F and Half-life were expressed as mean + SE, Τ™_» as range, N=4.

Conclusion:

The simple co-formulation of hGH with essential trace elements such as Zn²⁺ or Cu²⁺ as enzyme inhibitors results in mildly improved bioavailability. However, separate administration of the essential trace elements from the hGH led to surprisingly high bioavailability. Accordingly, it is particularly advantageous to administer a peptide or protein drug that is poorly soluble in the presence of the copper salt/complex or the zinc sait/complex or the iron salt/complex (such as, e.g., human growth hormone, insulin, epoetin, or filgrastim) separately from the respective metal salt/complex. Example 9: Pharmacokinetic profile of human growth hormone (hGH) after nasal administration with a double chamber nasal spray device to non-human primates

A special nasal spray device was used. The device comprised two separated chambers (chamber A and chamber B) which were connected with tubes to a mixing unit, which was then connected to the spray nozzle. With this device it was possible to physically separate the solution comprising the essential trace elements from the solution comprising the protein drug. Experiments in Cynomolgus macaques (Macaca fascicularis, female, 3.5-5 kg) were conducted to compare the bioavailability of two nasal formulations with subcutaneously administered hGH. Pre-dose blood collection and administration of formulations was carried out on a small desk placed in the experimental room. Weil-trained monkey care takers were holding the monkey on the desk, and the veterinarian administered the solutions by nasal spray (1.0 mg hGH per monkey) or subcutaneous injection (0.1 mg hGH per monkey). Blood collection for hGH analysis was performed at the following time points: 1 time pre-dose (0 minute), 15, 30, 45, 60, 90, 120, 180 and 240 minutes post-dose. Blood volume was 1 mL per time point with heparinized syringe (heparin:blood; 0.1 :5) and 23 gauge needle. Each sample was collected from a peripheral vein. After each tube of blood was drawn, it was inverted gently several times to ensure the mixing with the anticoagulant. Then the tubes were placed immediately on ice until centrifugation. Within 15 min, the samples were centrifuged at between 3-5 °C for 10 minutes at approximately 3,000 g. Plasma was transferred to a labeled polypropylene screw- cap tube and frozen at < -20°C immediately after centrifugation. Samples were analyzed with a high sensitivity hGH ELISA Kit.

Results:

A relative bioavailability of 9.4% (versus s.c. administration) was obtained with the formulation comprising zinc(ll)gluconate administered with a double chamber nasal spray device. A relative bioavailability of 8.9% (versus s.c. administration) was obtained with the formulation comprising copper(ll)gluconate administered with a double chamber nasal spray device. The corresponding pharmacokinetic profiles are shown in Figure 2.

Conclusion:

Surprisingly high nasal bioavailability was obtained by dosing essential trace elements and hGH via a double chamber nasal spray device where the copper or zinc compounds are physically separated from the protein drug but mixed in a mixing unit just in the moment of application.

Example 10: Pharmacokinetic profile of epoetin alfa after nasal administration with a double chamber nasal spray device to non-human primates

A special nasal spray device was used. The device comprised two separated chambers (chamber A and chamber B) which were connected with tubes to a mixing unit, which was then connected to the spray nozzle. With this device it was possible to physically separate the solution comprising the protease inhibitor from the solution comprising the protein drug. Experiments in Cynomolgus macaques (Macaca fascicularis, female, 3.5-5 kg) were conducted to compare the bioavailability of one nasal formulation with subcutaneously administered epoetin alfa. 100 μΙ of epoetin alfa 336 Mg/ml were dosed subcutaneously to one monkey resulting in a total dose of 33.6 pg. 100 μΙ of the nasal formulations in a final concentration of 168 pg/ml (after mixing in the mixing unit) were dosed with a double chamber nasal spray into each nostril of another monkey resulting also in a total amount of 33.6 pg. Blood collection for epoetin alfa analysis was performed at the following time points: 1 time pre-dose (0 minute), 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes and 180 minutes post- dose. Blood volume was 1 niL per time point with heparinized syringe (heparin:blood; 0.1 :5) and 23 gauge needle. Each sample was collected from a peripheral vein. After each tube of blood was drawn, it was inverted gently several times to ensure the mixing with the anticoagulant. Then the tubes were placed immediately on ice until centrifugation. Within 15 min, the samples were centrifuged at between 3-5 °C for 10 minutes at approximately 3,000 g. Plasma was transferred to a labeled polypropylene screw-cap tube and frozen at < -20°C immediately after centrifugation. Samples were analyzed with a high sensitivity epoetin a If a ELISA Kit (from Abeam). Results:

A relative bioavailability of 21.8 % (versus s.c. administration) was obtained with the formulation comprising zinc(ll)gluconate and arginine administered with a double chamber nasal spray device. The corresponding pharmacokinetic profiles are shown in Figure 3.

Example 11 : Pharmacokinetic profile of filgrastim after nasal administration with double chamber nasal spray device to non-human primates

A special nasal spray device was used. The device comprised two separated chambers (chamber A and chamber B) which were connected with tubes to a mixing unit, which was then connected to the spray nozzle. With this device it was possible to physically separate the solution comprising the essential trace elements from the solution comprising the protein drug. Experiments in Cynomolgus macaques (Macaca fascicuiaris, female, 3.5-5 kg) were conducted to compare the bioavailability of one nasal formulation with subcutaneously administered filgrastim. 100 μΙ of filgrastim 600 Mg/ml were dosed subcutaneously to 3 monkeys resulting in a total dose of 60 pg per monkey. 100 μΙ of the nasal formulation in a final concentration of 300 Mg/ml (after mixing in the mixing unit) were dosed with a double chamber nasal spray into each nostril resulting also in a total amount of 60 M9 per monkey. Blood collection for filgrastim analysis was performed at the following time points: 1 time pre-dose (0 minute), 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes and 80 minutes post-dose. Blood volume was 1 mL per time point with heparinized syringe (heparin:blood; 0.1 :5) and 23 gauge needle. Each sample was collected from a peripheral vein. After each tube of blood was drawn, it was inverted gently several times to ensure the mixing with the anticoagulant. Then the tubes were placed immediately on ice until centrifugation. Within 15 min, the samples were centrifuged at between 3-5 °C for 10 minutes at approximately 3,000 g. Plasma was transferred to a labeled polypropylene screw-cap tube and frozen at < -20 °C immediately after centrifugation. Samples were analyzed with a high sensitivity filgrastim ELISA Kit (from Abeam).

Results:

A relative bioavailability of 4.3 % (versus s.c. administration) was obtained with the formulation comprising zinc(ll)gluconate administered with a double chamber nasal spray device. The corresponding pharmacokinetic profiles are shown in Figure 4.

Example 12: Formulations with FGF21 protein in a single and double chamber nasal spray device

Overall conclusion: As demonstrated in the examples above, it has been found that the essential trace elements copper and zinc are able to reduce the enzymatic activity of proteolytic enzymes present in the nasal mucosa. However, at concentrations required for enzyme inhibition these compounds negatively impact the solubility of proteins. This results in relatively low bioavailability. It has been found, however, that if the essential trace element (i.e., the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex) is administered separately from the peptide or protein drug, surprisingly high bioavailability can be achieved, even for proteins with a high molecular weight like epoetin alfa.

Claims

4. A pharmaceutically acceptable iron salt/complex for use in therapy, wherein said iron salt/complex is to be administered nasally in combination with a peptide or protein drug having a molecular weight of equal to or less than about 100 kDa.

5. A pharmaceutical composition for use by nasal administration, comprising:

6. A nasal pharmaceutical delivery form, comprising:

7. The peptide or protein drug for use according to claim 1 or the copper salt/complex for use according to claim 2 or the zinc salt/complex for use according to claim 3 or the iron salt/complex for use according to claim 4 or the pharmaceutical composition for use according to claim 5 or the nasal pharmaceutical delivery form of claim 6, wherein the peptide or protein drug has a molecular weight of equal to or less than about 50 kDa.

8. The peptide or protein drug for use according to claim 1 or the copper salt/complex for use according to claim 2 or the zinc salt/complex for use according to claim 3 or the iron salt/complex for use according to claim 4 or the pharmaceutical composition for use according to claim 5 or the nasal pharmaceutical delivery form of claim 6, wherein the peptide or protein drug has a molecular weight of about 500 Da to about 40 kDa.

9. The peptide or protein drug for use according to claim 1 or the copper salt/complex for use according to claim 2 or the zinc salt/complex for use according to claim 3 or the iron salt/complex for use according to claim 4 or the pharmaceutical composition for use according to claim 5 or the nasal pharmaceutical delivery form of claim 6, wherein the peptide or protein drug is selected from insulin, an insulin analog, insulin lispro, insulin PEGIispro, insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, insulin degludec, B29K(N(E)hexadecanedioyl-y-L-Glu) A14E B25H desB30 human insulin, B29K(N(e)octadecanedioyl-Y-L-Glu-OEG-OEG) desB30 human insulin, B29K(N(e)octadecanedioyl-y-L-Glu) A14E B25H desB30 human insulin, B29K(N(£)eicosanedioyl-y-L-Glu) A14E B25H desB30 human insulin, B29K(N( )octadecanedioyl-y-L-Glu-OEG-OEG) A14E B25H desB30 human insulin, B29K(N(£)eicosanedioyl-Y-L-Glu-OEG-OEG) A14E B25H desB30 human insulin, B29K(N(e)eicosanedioyl-y-L-Glu-OEG-OEG) A14E B16H B25H desB30 human insulin, B29K(N(e)hexadecanedioyl-y-L-Glu) A14E B16H B25H desB30 human insulin, B29K(N(£)eicosanedioyl-Y-L-Glu-OEG-OEG) A14E B16H B25H desB30 human insulin, B29K(N(£)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, Ianglenatide, GLP-1 (7-37), GLP-1 (7-36)NH₂, 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, glucose-dependent insulinotropic polypeptide, 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 long- acting human growth hormone, fibroblast growth factor 21 , somapacitan, hGH-CTP, a glycopeptide antibiotic, a glycosylated cyclic or poiycyclic nonribosomal peptide antibiotic, vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, decaplanin, a cyclotide, 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-1 b, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon beta-l a, fibrinolysin, vasopressin, aldesleukin, an epoetin, epoetin alfa, darbepoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, epoetin theta, methoxy polyethylene glycol-epoetin beta, continuous erythropoietin receptor activator, pegiyiated epo, aibupoetin, an epo-dimer analogue, epo-Fc, carbamylated EPO, synthetic erythropoese protein, the low molecular epo analogue PB!-1402, filgrastim, PEG-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 F2a receptor modulator, PDC3 , abciximab, ranibizumab, alefacept, romiplostim, anakinra, abatacept, belatacept, and pharmaceutically acceptable salts thereof.

10. The peptide or protein drug for use according to claim 9 or the copper salt/complex for use according to claim 9 or the zinc salt/complex for use according to claim 9 or the iron salt/complex for use according to claim 9 or the pharmaceutical composition for use according to claim 9 or the nasal pharmaceutical delivery form of claim 9, wherein the peptide or protein drug is selected from buserelin, human growth hormone, somapacitan, hGH-CTP, insulin, an insulin analog, fibroblast growth factor 21 , filgrastim, PEG-filgrastim, an epoetin, epoetin alfa, darbepoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, epoetin theta, and pharmaceutically acceptable salts thereof.

11. The peptide or protein drug for use according to any one of claims 1 or 7 to 10 or the copper salt/complex for use according to any one of claims 2 or 7 to 10 or the pharmaceutical composition for use according to any one of claims 5 or 7 to 10 or the nasal pharmaceutical delivery form of any one of claims 6 to 10, wherein said copper salt/complex is a copper(ll) salt/complex selected from copper sulfate, copper carbonate, a copper(ll) amino acid complex, copper(ll) lysine complex, copper(ll) glycinate, copper(ll) EDTA complex, copper(ll) chitosan complex, copper chlorophyllin complex, copper(ll) citrate, copper(ll) gluconate, copper(ll) lactate, copper lactate gluconate, copper(ll) orotate, and copper(ll) tartrate.

12. The peptide or protein drug for use according to any one of claims 1 or 7 to 10 or the copper salt/complex for use according to any one of claims 2 or 7 to 10 or the pharmaceutical composition for use according to any one of claims 5 or 7 to 10 or the nasal pharmaceutical delivery form of any one of claims 6 to 10, wherein said copper salt/complex is a copper(l) salt/complex selected from copper(l) chloride and copper(l) acetate.

13. The peptide or protein drug for use according to any one of claims 1 or 7 to 10 or the zinc salt/complex for use according to any one of claims 3 or 7 to 10 or the pharmaceutical composition for use according to any one of claims 5 or 7 to 10 or the nasal pharmaceutical delivery form of any one of claims 6 to 10, wherein said zinc salt/complex is a zinc(ll) salt/complex 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.

14. The peptide or protein drug for use according to any one of claims 1 or 7 to 10 or the iron salt/complex for use according to any one of claims 4 or 7 to 10 or the pharmaceutical composition for use according to any one of claims 5 or 7 to 10 or the nasal pharmaceutical delivery form of any one of claims 6 to 10, wherein said iron salt/complex is an iron(ll) salt/complex selected from iron(ll) gluconate, iron(ll) orotate, iron(ll) tartrate, iron(!l) fumarate, iron(ll) sulfate, iron(ll) lactate, iron(li) lactate gluconate, iron(ll) acetate, iron(ll) carbonate, iron(ll) citrate, iron(ll) oxide, iron(ll) hydroxide, iron(ll) ascorbate, an iron(ll) amino acid complex, and iron(ll) glycinate.

15. The peptide or protein drug for use according to any one of claims 1 or 7 to 10 or the iron salt/complex for use according to any one of claims 4 or 7 to 10 or the pharmaceutical composition for use according to any one of claims 5 or 7 to 10 or the nasal pharmaceutical delivery form of any one of claims 6 to 10, wherein said iron salt/complex is an iron(lll) salt/complex selected from iron(lll) chloride, iron(lll) sulfate, iron(lll) oxide, iron(ill)carbonate, iron(lll) acetate, iron(lll) phosphate, iron(lll) hydroxide, iron(lll) tartrate, iron(lll) lactate, iron(lll) glycinate, iron(lll) EDTA, iron(lll) ascorbate, and ammonium iron(ill) citrate.

16. The peptide or protein drug for use according to any one of claims 1 or 7 to 15 or the copper salt/complex for use according to any one of claims 2 or 7 to 12 or the zinc salt/complex for use according to any one of claims 3, 7 to 10 or 13 or the iron salt/complex for use according to any one of claims 4, 7 to 10, 14 or 15, wherein the agents to be administered are provided in the form of a nasal spray, nasal drops, an aerosol, or a dry powder for nasal administration.

17. The pharmaceutical composition for use according to any one of claims 5 or 7 to 5 or the nasal pharmaceutical delivery form of any one of claims 6 to 15, wherein the pharmaceutical composition or the nasal pharmaceutical delivery form is provided in the form of a nasal spray, nasal drops, an aerosol, or a dry powder for nasal administration.

18. The peptide or protein drug for use according to any one of claims 1 or 7 to 16 or the copper salt/complex for use according to any one of claims 2, 7 to 12 or 16 or the zinc salt/complex for use according to any one of claims 3, 7 to 10, 13 or 16 or the iron salt/complex for use according to any one of claims 4, 7 to 10 or 14 to 16 or the nasal pharmaceutical delivery form of any one of claims 6 to 15 or 17, wherein the peptide or protein drug is provided in physically separated form from the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex.

19. The peptide or protein drug for use according to claim 18 or the copper salt/complex for use according to claim 18 or the zinc salt/complex for use according to claim 18 or the iron salt/complex for use according to claim 18, wherein (i) the peptide or protein drug on the one hand, and (ii) the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex on the other hand, are provided in separate pharmaceutical compositions, or in physically separated compartments of a nasal pharmaceutical delivery form.

20. The nasal pharmaceutical delivery form of claim 18, wherein (i) the peptide or protein drug on the one hand, and (ii) the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex on the other hand, are provided in physically separated compartments of the nasal pharmaceutical delivery form.

21 The peptide or protein drug for use according to claim 18 or 19 or the copper salt/complex for use according to claim 18 or 19 or the zinc salt/complex for use according to claim 18 or 19 or the iron salt/complex for use according to claim 18 or 19 or the nasal pharmaceutical delivery form of claim 18 or 20, wherein (i) the peptide or protein drug on the one hand, and (ii) the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex on the other hand, are to be administered simultaneously or sequentially, or are to be combined directly upon or immediately before administration.

22. The peptide or protein drug for use according to claim 19 or the copper salt/complex for use according to claim 19 or the zinc salt/complex for use according to claim 19 or the iron salt/complex for use according to claim 19, wherein the administration of the peptide or protein drug and of the copper salt/complex and/or the zinc salt/complex and/or the iron salt/complex is to be effected by using a nasal pharmaceutical delivery form comprising at least two separated compartments, wherein the peptide or protein drug is provided in one compartment, wherein the copper salt/complex and/or the zinc sa it/complex and/or the iron salt/complex is/are provided in another compartment, and wherein the at least two compartments are connected to a mixing unit which allows the mixing of the respective components directly upon or immediately before administration.

23. The nasal pharmaceutical delivery form of claim 20, wherein the nasal pharmaceutical delivery form comprises at least two separated compartments, wherein the peptide or protein drug is provided in one compartment, wherein the copper salt complex and/or the zinc salt/complex and/or the iron salt/complex is/are provided in another compartment, and wherein the at least two compartments are connected to a mixing unit which allows the mixing of the respective components directly upon or immediately before administration.

24. The peptide or protein drug for use according to any one of claims 1 , 7 to 16, 18, 19, 21 or 22 or the copper salt/complex for use according to any one of claims 2, 7 to 12, 16, 18, 19, 21 or 22 or the zinc salt/complex for use according to any one of claims 3, 7 to 10, 13, 16, 18, 19, 21 or 22 or the iron salt/complex for use according to any one of claims 4, 7 to 10, 14 to 16, 18, 19, 21 or 22 or the pharmaceutical composition for use according to any one of claims 5, 7 to 15 or 17 or the nasal pharmaceutical delivery form of any one of claims 6 to 15, 17, 18, 20, 21 or 23, wherein said peptide or protein drug or said copper salt/complex or said zinc salt/complex or said iron salt/complex is to be administered nasally in combination with an absorption enhancer, or wherein said pharmaceutical composition or said nasal pharmaceutical delivery form further comprises an absorption enhancer.

25. The peptide or protein drug for use according to claim 24 or the copper salt/complex for use according to claim 24 or the zinc salt/complex for use according to claim 24 or the iron salt/complex for use according to claim 24 or the pharmaceutical composition for use according to claim 24 or the nasal pharmaceutical delivery form of claim 24, wherein said absorption enhancer is selected from C₈.2o alkanoyl carnitine, salicylic acid, a salicylic acid derivative, 3-methoxysalicylic acid, 5-methoxysalicylic acid, homovaniliic acid, a C₈.₂₀ alkanoic acid, citric acid, tartaric acid, a fatty acid acy!ated amino acid, a C_8-20 alkanoyl sarcosinate, an alkylsaccharide, a C_8-io alkyl polysaccharide, n-octyl-beta-D-glucopyranoside, n-dodecyl-beta-D-maltoside, n- tetradecyl-beta-D-maltoside, tridecyl-beta-D-ma!toside, sucrose laurate, sucrose myristate, sucrose palmitate, sucrose cocoate, sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose mono-tetradeca noate , a coco-glucoside, a cyclodextrine, a-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-p-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, Ν,Ν,Ν- trimethyl chitosan, benzalkonium chloride, bestatin, cetylpyridinium chloride, cetyltrimethylammonium bromide, a C_2-2o alkanol, a C_8-2o alkenol, a C₈.₂₀ alkenoic acid, d extra n sulfate, diethyleneglycoi monoethyl ether, 1 -dodecylazacyclo-heptan-2-one, capryiocaproyl polyoxylglycerides, ethyi ca pry late, glyceryl monolaurate, lysophosphatidylcholine, menthol, a C₈.₂₀ alkylamine, a C_8-2o alkenylamine, phosphatidylcholine, a poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, a poiysorbate, 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, myristyltrimethy! 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 iaurate, isopropyl myristate, isopropyi 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, oligoarginine, octa-arginine, penetratin, a penetratin analog, Penetra ax, HIV-1 Tat, transportan, macrogol-15- hydroxys tea rate, Solutol HS 15, CriticalSorb, a taurocholate, a taurodeoxycholate, a sulfoxide, decyl methyl sulfoxide, dimethyl sulfoxide, cyciopentadecalactone, 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid, N-(10-[2-hydroxybenzoyl]amino)decanoic acid, dodecyl-2-N,N-dimethylamino propionate, D-a-tocopheryl polyethylene glycol- 1000 succinate, arginine, and pharmaceutically acceptable salts thereof;

and further wherein said fatty acid acylated amino acid is preferably selected from sodium lauroyi alaninate, N-dodecanoyl-L-alanine, sodium lauroyi asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyi aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyi cysteinate, N-dodecanoyl-L-cysteine, sodium lauroyi glutamic acid, N-dodecanoyl-L-glutamic acid, sodium lauroyi glutaminate, N-dodecanoyl-L-glutamine, sodium lauroyi glycinate, N-dodecanoyl-L-glycine, sodium lauroyi histidinate, N- dodecanoyl-L-histidine, sodium lauroyi isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyi leucinate, N-dodecanoyl-L-leucine, sodium lauroyi methioninate, N-dodecanoyl- L-methionine, sodium lauroyi phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyi prolinate, N-dodecanoyl-L-proline, sodium lauroyi serinate, N-dodecanoyl-L- serine, sodium lauroyi threoninate, N-dodecanoyl-L-threonine, sodium lauroyi tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyi tyrosinate, N-dodecanoyl- L-tyrosine, sodium lauroyi valinate, N-dodecanoyl-L-valine, sodium lauroyi sarcosinate, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-a!anine, 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-decanoy!-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-decanoyi- L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, N-decanoyl-L-sarcosine, sodium oieoyi sarcosinate, sodium N-decylleucine, sodium stearoyi glutamate, sodium myristoyi glutamate, sodium lauroyi glutamate, sodium cocoyl glutamate, sodium cocoyl glycinate, sodium N-decyl leucine, sodium cocoyl glycine, sodium cocoyl glutamate, sodium lauroyi alaninate, N-dodecanoyl-L-alanine, sodium lauroyi asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyi aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyi cysteinate, N-dodecanoyl-L-cysteine, sodium lauroyi glutamic acid, N-dodecanoyl-L-glutamic acid, sodium lauroyi glutaminate, N-dodecanoyl-L-glutamine, sodium lauroyi glycinate, N-dodecanoyi- L-glycine, sodium lauroyi histidinate, N-dodecanoyl-L-histidine, sodium lauroyi isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyi leucinate, N-dodecanoyl- L-leucine, sodium lauroyi methinoninate, N-dodecanoyl-L-methionine, sodium lauroyi phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyi prolinate, N-dodecanoyl-L-proiine, sodium lauroyi serinate, N-dodecanoyl-L-serine, sodium lauroyi threoninate, N-dodecanoyl-L-threonine, sodium lauroyi tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyi tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyi 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-decanoyi-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-d eca n oy I- L-ty ros i ne , sodium capric valinate, N-decanoyi-L-valine, sodium capric sarcosinate, sodium oleoyl sarcosinate, and pharmaceutically acceptable salts thereof.

26. The peptide or protein drug for use according to claim 24 or the copper salt/complex for use according to claim 24 or the zinc salt/complex for use according to claim 24 or the iron salt/complex for use according to claim 24 or the pharmaceutical composition for use according to claim 24 or the nasal pharmaceutical delivery form of claim 24, wherein said absorption enhancer is arginine or oligoarginine.

27. The pharmaceutical composition for use according to any one of claims 5, 7 to 15, 17 or 24 to 26 or the nasal pharmaceutical delivery form of any one of claims 6 to 15, 17, 18, 20, 21 or 23 to 26, wherein said pharmaceutical composition or said nasal pharmaceutical delivery form comprises:

the copper salt/complex in an amount of about 0.1 mg to about 20 mg calculated as Cu⁺ or Cu²⁺ per dosage unit, and/or

the iron salt/complex in an amount of about 1 mg to about 100 mg calculated as Fe²⁺ or Fe³⁺ per dosage unit.

28. The pharmaceutical composition for use according to any one of claims 24 to 27 or the nasal pharmaceutical delivery form of any one of claims 24 to 27, wherein said pharmaceutical composition or said nasal pharmaceutical delivery form comprises the absorption enhancer in an amount of about 10 mg to about 1000 mg per dosage unit.

29. The pharmaceutical composition for use according to any one of claims 5, 7 to 15, 17 or 24 to 28, wherein said pharmaceutical composition is a liquid composition, preferably an aqueous composition.