Compositions comprising peptides or proteins and acylated amino acids

Abstract

The present invention relates to compositions, in particular solid compositions, comprising a penetration enhancer, which is an acylated amino acid substituted on the amine function, also referred to as AC-aa-NS, in particular peptides or proteins, said AC-aa-NS compounds, to processes for their preparation and their use in pharmaceuticals.

Description

Technical Field

[0001] The present invention relates to compositions comprising a penetration enhancer, which is an acylated amino acid substituted on the amine function (also called AC-aa-NS), in particular a peptide or a protein, and to AC-aa-NS compounds, processes for their preparation and their use in medicine. Background Art

[0002] Current peptide or protein therapeutics rely primarily on parenteral administration.

[0003] Although oral delivery is clearly necessary for therapeutic purposes, particularly with respect to ease of administration and improved compliance with treatment, the barriers to obtaining oral administration of peptides and proteins are numerous and very challenging.

[0004] Among these obstacles, low bioavailability, great variability in bioavailability, processability difficulties, slow dissolution of penetration enhancers and / or absorption sites that can be aggressive for the active ingredient may be mentioned.

[0005] Most of the peptides or proteins marketed in oral form are small cyclic non-acylated or non-PEGylated peptides. Small means a molecular weight less than or equal to 1200 Da. Among them we can mention Cyclosporin, Octreotide and Desmopressin.

[0006] However, when talking about peptides or proteins that do not fall into this category, we as marketed peptide products can only refer to It is a long-acting GLP-1RA (semaglutide) combined with a penetration enhancer (SNAC) to allow oral delivery.

[0007] Although this product is available on the market, it still has some disadvantages, such as low bioavailability, large variability in bioavailability between different administrations, slow dissolution of the permeation enhancer, and limitations on dosage regimens ( Do not eat or drink for at least 30 minutes after the dose). Summary of the invention

[0008] The present invention proposes a way to solve at least some of the above mentioned problems.

[0009] Specifically, the present invention aims to

[0010] - Improved bioavailability, and / or

[0011] — have a very short absorption window, and / or

[0012] - Reduces bioavailability variability between administrations.

[0013] In particular, this last property would allow the use of short-acting APIs, since the great variability in absorption of short-acting APIs would lead to great variability in API concentrations in the blood and thus the risk of the patient having too low or too high an API dose.

[0014] Surprisingly, the Applicant has found that the composition according to the invention solves at least one of the above-mentioned technical problems.

[0015] Also surprisingly, the Applicant has found that a solid composition comprising the composition according to the invention, in particular in oral dosage form, solves at least one of the technical problems mentioned above.

[0016] Furthermore, the applicants have discovered unexpected properties of the acylated amino acids AC-aa-NS or their salts, in that these compounds are protease inhibitors. DETAILED DESCRIPTION

[0017] The composition according to the present invention comprises AC-aa-NS having the following general formula I:

[0018] R3OOC-CHR4-(CH2)n-NR2-COR1

[0019] in

[0020] - n is an integer selected from 0, 1, 2, 3, 4 and 5,

[0021] - R1 is an alkyl group containing 5 to 15 carbon atoms, an alkyl group containing 7 to 17 carbon atoms and having a carboxylate functional group or an alkyl group containing 7 to 17 carbon atoms and having an alcohol functional group,

[0022] -R2 is an alkyl group containing 2 to 8 carbon atoms or -(CH2)m-Aro, wherein m is an integer selected from 1 to 4, and Aro is selected from the group consisting of phenyl, naphthyl, anthracenyl, indole, pyridinyl, optionally substituted with an alkyl group containing 1 to 3 carbon atoms, methoxy or halogen.

[0023] —R4 is the side chain of an amino acid,

[0024] or

[0025] -R2 and R4 together form -(CH2)o-Ar-(CH2)p-, -(CH2)o- is attached to the R2 position, and -(CH2)p- is attached to the R4 position, o is 0 or 1, p is 0, 1 or 2, the sum of o+p is 1 or 2, and Ar is a phenyl or indole group,

[0026] and

[0027] - R3 is hydrogen or a cation, in particular selected from sodium and potassium,

[0028] and

[0029] Peptide or protein.

[0030] In the present specification, the peptide or protein is an API (Active Principle Ingredient), which is intended to treat or cure a disease.

[0031] In an embodiment, R1 is a linear alkyl group.

[0032] In an embodiment, R1 is a branched alkyl group.

[0033] According to an embodiment, R1 is an alkyl group containing 5 to 10 carbon atoms.

[0034] According to an embodiment, R1 is an alkyl group containing 5 carbon atoms.

[0035] According to an embodiment, R1 is an alkyl group containing 6 carbon atoms.

[0036] According to an embodiment, R1 is an alkyl group containing 7 to 11 carbon atoms.

[0037] According to an embodiment, R1 is an alkyl group containing 7 carbon atoms.

[0038] According to an embodiment, R1 is an alkyl group containing 8 carbon atoms.

[0039] According to an embodiment, R1 is an alkyl group containing 9 carbon atoms.

[0040] According to an embodiment, R1 is an alkyl group comprising 10 carbon atoms.

[0041] According to an embodiment, R1 is an alkyl group comprising 11 carbon atoms.

[0042] According to an embodiment, R1 is an alkyl group containing 12 to 15 carbon atoms.

[0043] According to an embodiment, R1 is an alkyl group comprising 12 carbon atoms.

[0044] According to an embodiment, R1 is an alkyl group comprising 13 carbon atoms.

[0045] According to an embodiment, R1 is an alkyl group comprising 14 carbon atoms.

[0046] According to an embodiment, R1 is an alkyl group comprising 15 carbon atoms.

[0047] According to an embodiment, R1 is a branched alkyl group containing 7 to 17 carbon atoms and having a carboxylate functional group, in particular the carboxylate is located at the end of the alkyl chain.

[0048] According to an embodiment, R1 is a branched alkyl group containing 7 to 12 carbon atoms and having a carboxylate functional group, in particular the carboxylate is located at the end of the alkyl chain.

[0049] According to an embodiment, R1 is an alkyl group comprising 7 carbon atoms and having a carboxylate functionality.

[0050] According to an embodiment, R1 is an alkyl group comprising 8 carbon atoms and having a carboxylate functionality.

[0051] According to an embodiment, R1 is an alkyl group comprising 9 carbon atoms and having a carboxylate functionality.

[0052] According to an embodiment, R1 is an alkyl group comprising 10 carbon atoms and having a carboxylate functionality.

[0053] According to an embodiment, R1 is an alkyl group comprising 11 carbon atoms and having a carboxylate functional group.

[0054] According to an embodiment, R1 is an alkyl group comprising 12 carbon atoms and having a carboxylate functionality.

[0055] According to an embodiment, R1 is a branched alkyl group containing 13 to 17 carbon atoms and having a carboxylate functional group, in particular the carboxylate is located at the end of the alkyl chain.

[0056] According to an embodiment, R1 is an alkyl group comprising 13 carbon atoms and having a carboxylate functionality.

[0057] According to an embodiment, R1 is an alkyl group comprising 14 carbon atoms and having a carboxylate functionality.

[0058] According to an embodiment, R1 is an alkyl group comprising 15 carbon atoms and having a carboxylate functionality.

[0059] According to an embodiment, R1 is an alkyl group comprising 16 carbon atoms and having a carboxylate functionality.

[0060] According to an embodiment, R1 is an alkyl group comprising 17 carbon atoms and having a carboxylate functionality.

[0061] According to an embodiment, R1 is a linear alkyl group containing 7 to 17 carbon atoms and having an alcohol functional group, in particular the alcohol functional group is located at the end of the alkyl chain.

[0062] According to an embodiment, R1 is a branched alkyl group containing 7 to 17 carbon atoms and having an alcohol functional group, in particular the alcohol functional group is located at the end of the alkyl chain.

[0063] According to an embodiment, R1 is a branched alkyl group containing 7 to 12 carbon atoms and having an alcohol functional group, in particular the alcohol functional group is located at the end of the alkyl chain.

[0064] According to an embodiment, R1 is an alkyl group comprising 7 carbon atoms and having an alcohol functionality.

[0065] According to an embodiment, R1 is an alkyl group comprising 8 carbon atoms and having an alcohol functionality.

[0066] According to an embodiment, R1 is an alkyl group comprising 9 carbon atoms and having an alcohol functionality.

[0067] According to an embodiment, R1 is an alkyl group comprising 10 carbon atoms and having an alcohol functionality.

[0068] According to an embodiment, R1 is an alkyl group comprising 11 carbon atoms and having an alcohol functionality.

[0069] According to an embodiment, R1 is an alkyl group comprising 12 carbon atoms and having an alcohol functionality.

[0070] According to an embodiment, R1 is a branched alkyl group containing 13 to 17 carbon atoms and having an alcohol functional group, in particular the alcohol functional group is located at the end of the alkyl chain.

[0071] According to an embodiment, R1 is an alkyl group comprising 13 carbon atoms and having an alcohol functionality.

[0072] According to an embodiment, R1 is an alkyl group comprising 14 carbon atoms and having an alcohol functionality.

[0073] According to an embodiment, R1 is an alkyl group comprising 15 carbon atoms and having an alcohol functionality.

[0074] According to an embodiment, R1 is an alkyl group comprising 16 carbon atoms and having an alcohol functionality.

[0075] According to an embodiment, R1 is an alkyl group comprising 17 carbon atoms and having an alcohol functionality.

[0076] According to an embodiment, R2 is an alkyl group containing 2 to 4 carbon atoms, in particular R2 is a straight chain alkyl group.

[0077] According to an embodiment, R2 is an alkyl group containing 2 carbon atoms.

[0078] According to an embodiment, R2 is an alkyl group containing 3 carbon atoms.

[0079] According to an embodiment, R2 is an alkyl group containing 4 carbon atoms.

[0080] According to an embodiment, R2 is an alkyl group containing 5 to 8 carbon atoms, in particular R2 is a straight chain alkyl group.

[0081] According to an embodiment, R2 is an alkyl group containing 5 carbon atoms.

[0082] According to an embodiment, R2 is an alkyl group containing 6 carbon atoms.

[0083] According to an embodiment, R2 is an alkyl group containing 7 carbon atoms.

[0084] According to an embodiment, R2 is an alkyl group containing 8 carbon atoms.

[0085] According to an embodiment, R2 is -(CH2)m-Aro, wherein m is an integer selected from 1 to 4, Aro is phenyl optionally substituted by alkyl containing 1 to 3 carbon atoms, methoxy or halogen, specifically Aro is unsubstituted phenyl.

[0086] According to an embodiment, R2 is -(CH2)m-Aro, wherein m is 1, and Aro is phenyl optionally substituted by alkyl containing 1 to 3 carbon atoms, methoxy or halogen, specifically Aro is unsubstituted phenyl.

[0087] According to an embodiment, R2 is -(CH2)m-Aro, wherein m is an integer selected from 1 to 4, Aro is selected from the group consisting of naphthyl, anthracenyl, indole, pyridinyl optionally substituted with alkyl containing 1 to 3 carbon atoms, methoxy or halogen, specifically Aro is unsubstituted naphthyl, anthracenyl, indole or pyridinyl.

[0088] According to an embodiment, R2 is -(CH2)m-Aro, wherein m is 1, Aro is selected from the group consisting of naphthyl, anthracenyl, indole, pyridinyl optionally substituted with alkyl containing 1 to 3 carbon atoms, methoxy or halogen, specifically Aro is unsubstituted naphthyl, anthracenyl, indole or pyridinyl.

[0089] In an embodiment, R4 is an amino acid side chain selected from the side chains of the following amino acids,

[0090] - glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), N-methylphenylalanine (NMePhe), pipecolinic acid (Pip), phenylglycine (PGly), tryptophan (Trp), methionine (Met), proline (Pro), serine (Ser), threonine (Thr), cysteine ​​(Cys), tyrosine (Tyr), asparagine (Asn), glutamine (Gln), aspartic acid (Asp) and glutamic acid (Glu),

[0091] — hydroxyproline (Hyp) and phosphoserine, and

[0092] —α-aminoisobutyric acid (Aib), α-aminobutyric acid (Abu), tert-butyl-glycine.

[0093] In an embodiment, R4 is an amino acid side chain selected from the group consisting of the side chains of alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), N-methylphenylalanine (NMePhe), picolinic acid (Pip), phenylglycine (PGly), tryptophan (Trp), methionine (Met), proline (Pro) and sarcosine (Sarc).

[0094] In an embodiment, R4 is an amino acid side chain selected from the group consisting of the side chains of alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), N-methylphenylalanine (NMePhe), picolinic acid (Pip), phenylglycine (PGly), tryptophan (Trp), methionine (Met) and proline (Pro).

[0095] In an embodiment, R4 is an amino acid side chain selected from the group consisting of phenylalanine (Phe), N-methylphenylalanine (NMePhe), picolinic acid, phenylglycine (PGly), tryptophan (Trp) and proline (Pro).

[0096] In an embodiment, R4 is an amino acid side chain selected from the group consisting of serine (Ser), threonine (Thr), cysteine ​​(Cys), tyrosine (Tyr), asparagine (Asn), and glutamine (Gln).

[0097] In an embodiment, R4 is an amino acid side chain selected from the side chains of phenylalanine (Phe), N-methylphenylalanine (NMePhe), phenylglycine (PGly), tryptophan (Trp), and tyrosine (Tyr).

[0098] In an embodiment, R4 is an amino acid side chain selected from the side chains of alanine (Ala), valine (Val), leucine (Leu) and isoleucine (Ile).

[0099] In an embodiment, R4 is an amino acid side chain selected from the side chain of glycine (Gly).

[0100] In an embodiment, aa of AC-aa-NS is produced from an amino acid in the form of an L-isomer, a D-isomer, or a mixture of enantiomers.

[0101] In an embodiment, R4 is selected from the group consisting of: -H, -CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2-Ph (-Ph is -C6H5), -Ph, -CH2-Ph-OH (tyrosine side chain), -CH2-indole (-indole is C8H6N, tryptophan side chain), -CH2CH2SCH3, -CH2OH, -CH2SH, -CH2CONH2, -CH2CH2CONH2, -CH2COOH, -CH2CH2COOH and salts thereof.

[0102] In an embodiment, R4 is selected from the group consisting of: -H, -CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2-Ph (-Ph is -C6H5), -Ph.

[0103] In an embodiment, R4 is -H.

[0104] In an embodiment, n=0 or 1.

[0105] In an embodiment, n=0.

[0106] In an embodiment, n=1.

[0107] In an embodiment, n=2, 3, 4 or 5.

[0108] In an embodiment, n=2.

[0109] In an embodiment, n=3.

[0110] In an embodiment, n=4.

[0111] In an embodiment, n=5.

[0112] In an embodiment, AC-aa-NS corresponds to the following Formula Ia, wherein R1 and R3 are as disclosed in the specification:

[0113]

[0114] In an embodiment, AC-aa-NS corresponds to the following Formula Ib, wherein R1 and R3 are as disclosed in the specification:

[0115]

[0116] In an embodiment, AC-aa-NS corresponds to the following formula Ic, wherein R1 and R3 are as disclosed in the specification:

[0117]

[0118]

[0119] In an embodiment, AC-aa-NS corresponds to the following Formula Id, wherein R1 and R3 are as disclosed in the specification:

[0120]

[0121] In an embodiment, AC-aa-NS corresponds to the following formula le, wherein R1 and R3 are as disclosed in the specification:

[0122]

[0123] In an embodiment, AC-aa-NS corresponds to the following formula If, wherein R1 and R3 are as disclosed in this specification:

[0124]

[0125] In an embodiment, AC-aa-NS corresponds to the following formula Ig, wherein R1 and R3 are as disclosed in the specification:

[0126]

[0127] In an embodiment, AC-aa-NS corresponds to any one of Formulas Ia, Ib, Ic, Id, Ie, If, Ig, wherein R3 is H or Na, specifically Na.

[0128] In an embodiment, AC-aa-NS corresponds to any one of Formulas Ia, Ib, Ic, Id, Ie, If, Ig, wherein R1 is an alkyl group containing 6 to 9 carbon atoms, specifically 7 to 8 carbon atoms.

[0129] In an embodiment, AC-aa-NC is according to Formula I, wherein

[0130] - R1 is an alkyl group containing 5 to 15 carbon atoms,

[0131] - R2 is -(CH2)m-Aro, wherein m is 1 to 4, and Aro is phenyl.

[0132] In an embodiment, AC-aa-NC is according to Formula I, wherein

[0133] - R1 is an alkyl group containing 6 to 9 carbon atoms,

[0134] - R2 is -(CH2)m-Aro, wherein m is 1 to 4, and Aro is phenyl.

[0135] In an embodiment, AC-aa-NC is according to Formula I, wherein

[0136] - R1 is an alkyl group containing 7 to 8 carbon atoms,

[0137] - R2 is -(CH2)m-Aro, wherein m is 1 to 4, and Aro is phenyl.

[0138] In an embodiment, AC-aa-NC is according to Formula I, wherein

[0139] - R1 is an alkyl group containing 7 to 17 carbon atoms and having a carboxylate functional group,

[0140] -R2 is -(CH2)m-Aro, wherein m is 1 to 4, and Aro is phenyl.

[0141] In an embodiment, AC-aa-NC is according to Formula I, wherein

[0142] - R1 is an alkyl group containing 7 to 11 carbon atoms and having a carboxylate functional group,

[0143] - R2 is -(CH2)m-Aro, wherein m is 1 to 4, and Aro is phenyl.

[0144] In an embodiment, AC-aa-NC is according to Formula I, wherein

[0145] - R1 is an alkyl group containing 7 to 17 carbon atoms and having an alcohol function,

[0146] - R2 is -(CH2)m-Aro, wherein m is 1 to 4, and Aro is phenyl.

[0147] In an embodiment, AC-aa-NC is according to Formula I, wherein

[0148] - R1 is an alkyl group containing 7 to 11 carbon atoms and having an alcohol function,

[0149] - R2 is -(CH2)m-Aro, wherein m is 1 to 4, and Aro is phenyl.

[0150] In an embodiment, the solid composition comprises at least 300 mg / g AC-aa-NS relative to the total weight of the composition.

[0151] In an embodiment, the solid composition comprises at least 400 mg / g AC-aa-NS relative to the total weight of the composition.

[0152] In an embodiment, the solid composition comprises at least 500 mg / g AC-aa-NS relative to the total weight of the composition.

[0153] In an embodiment, the solid composition comprises at least 600 mg / g AC-aa-NS relative to the total weight of the composition.

[0154] In an embodiment, the solid composition comprises at least 700 mg / g AC-aa-NS relative to the total weight of the composition.

[0155] In an embodiment, the solid composition comprises at least 800 mg / g AC-aa-NS relative to the total weight of the composition.

[0156] In an embodiment, the solid composition comprises at least 900 mg / g AC-aa-NS relative to the total weight of the composition.

[0157] In an embodiment, the solid composition comprises up to 990 mg / g AC-aa-NS relative to the total weight of the composition.

[0158] In an embodiment, the solid composition comprises up to 980 mg / g AC-aa-NS relative to the total weight of the composition.

[0159] In an embodiment, the solid composition comprises up to 950 mg / g AC-aa-NS relative to the total weight of the composition.

[0160] In an embodiment, the solid composition comprises up to 900 mg / g AC-aa-NS relative to the total weight of the composition.

[0161] In an embodiment, the solid composition comprises up to 800 mg / g AC-aa-NS relative to the total weight of the composition.

[0162] The composition according to the present invention relates to a solid composition comprising a peptide or protein, AC-aa-NS and a lubricant.

[0163] The composition according to the present invention relates to a solid composition comprising a peptide or protein, AC-aa-NS and a pH adjuster.

[0164] The present invention also relates to a unit solid dosage form comprising or consisting of the composition according to the present invention.

[0165] In an embodiment, the unit solid dosage form comprises a peptide or protein and at least 300 mg / g of AC-aa-NS.

[0166] The present invention also relates to a unit solid dosage form comprising a peptide or protein and at least 300 mg / g AC-aa-NS, the unit solid dosage form comprising at least 50 mg of AC-aa.

[0167] The present invention also relates to a pharmaceutical preparation comprising the solid composition as disclosed in the present specification.

[0168] The present invention also relates to a solid composition for oral delivery, comprising a peptide or protein and AC-aa-NS.

[0169] The present invention also relates to a method of treatment comprising the step of orally administering the solid composition disclosed in the present specification for preventing or treating a disease.

[0170] In this specification, AC-aa-NS is a penetration enhancer.

[0171] According to an embodiment, the composition is an oral composition.

[0172] "Peptide" refers to an amide derived from two or more aminocarboxylic acid molecules (the same or different) through the formation of a covalent bond between the carbonyl carbon of one aminocarboxylic acid molecule and the nitrogen atom of another aminocarboxylic acid molecule in a dehydrated form (formal loss of water). The term is usually applied to structures formed by α-amino acids, but it includes those derived from any aminocarboxylic acid. The definition is from the IUPAC gold book (https: / / goldbook.iupac.org / terms / view / P04479).

[0173] "Polypeptide" refers to a peptide containing 10 or more amino acid residues. Polypeptides are a specific type of peptide.

[0174] In this specification and unless otherwise specified, "peptides" and "polypeptides" have a molecular weight less than or equal to 10,000.

[0175] "Protein" refers to a naturally occurring or synthetic polypeptide with a molecular weight greater than about 10,000. This definition is from the IUPAC gold book.

[0176] In an embodiment, the critical micelle concentration (also referred to as CMC) of AC-aa-NS in solution in water in a biologically relevant FASSIF buffer at pH 6.5 and 25°C is at least 1 mM.

[0177] The CMC is determined by surface tension measurements of aqueous solutions.

[0178] In an embodiment, AC-aa-NS has a CMC of at least 2.5 mM.

[0179] In an embodiment, AC-aa-NS has a CMC of at least 5 mM.

[0180] In an embodiment, AC-aa-NS has a CMC of at least 10 mM.

[0181] In an embodiment, AC-aa-NS has a CMC of at least 15 mM.

[0182] In an embodiment, AC-aa-NS has a CMC of at least 20 mM.

[0183] In an embodiment, AC-aa-NS has a CMC of at least 25 mM.

[0184] In an embodiment, AC-aa-NS has a CMC of at least 30 mM.

[0185] In an embodiment, AC-aa-NS has a CMC of at most 200 mM.

[0186] In an embodiment, AC-aa-NS has a CMC in the range of 5 to 50 mM.

[0187] In an embodiment, AC-aa-NS has a CMC in the range of 10 to 30 mM.

[0188] In an embodiment, the composition comprises at least 300 mg / g AC-aa-NS relative to the total weight of the composition.

[0189] In an embodiment, the composition comprises at least 400 mg / g AC-aa-NS relative to the total weight of the composition.

[0190] In an embodiment, the composition comprises at least 500 mg / g AC-aa-NS relative to the total weight of the composition.

[0191] In an embodiment, the composition comprises at least 600 mg / g AC-aa-NS relative to the total weight of the composition.

[0192] In an embodiment, the composition comprises at least 700 mg / g AC-aa-NS relative to the total weight of the composition.

[0193] In an embodiment, the composition comprises at least 800 mg / g AC-aa-NS relative to the total weight of the composition.

[0194] In an embodiment, the composition comprises at least 900 mg / g AC-aa-NS relative to the total weight of the composition.

[0195] In an embodiment, the composition comprises up to 980 mg / g AC-aa-NS relative to the total weight of the composition.

[0196] In an embodiment, the composition comprises up to 950 mg / g AC-aa-NS relative to the total weight of the composition.

[0197] In an embodiment, the composition comprises up to 900 mg / g AC-aa-NS relative to the total weight of the composition.

[0198] In an embodiment, the composition comprises up to 800 mg / g AC-aa-NS relative to the total weight of the composition.

[0199] In an embodiment, the composition according to the invention comprises at least one further penetration enhancer besides AC-aa-NS.

[0200] In an embodiment, the other penetration enhancer is selected from the group consisting of: decanoate, specifically sodium decanoate, octanoate, specifically sodium octanoate, bile salts, 8-(2-hydroxybenzamido) octanoate (salcaprozate), specifically sodium 8-(2-hydroxybenzamido) octanoate (SNAC), glycocholate, ursodeoxycholic acid, glycochenodeoxycholate, glycodeoxycholate and pharmaceutically acceptable salts thereof and mixtures thereof.

[0201] In an embodiment, the composition comprises a bile salt.According to an embodiment, the composition comprises only one bile salt.

[0202] According to an embodiment, the composition comprises a mixture of bile salts.

[0203] In an embodiment, the bile salt is selected from the group consisting of glycocholate, ursodeoxycholic acid, glycochenodeoxycholate, glycodeoxycholate, and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0204] According to an embodiment, the bile salt is glycocholate, in particular sodium glycocholate.

[0205] In an embodiment, the further penetration enhancer is selected from the group consisting of caprate, in particular sodium caprate, caprylate, in particular sodium caprylate, bile salts, 8-(2-hydroxybenzamido)caprylate and mixtures thereof, in particular sodium 8-(2-hydroxybenzamido)caprylate (SNAC).

[0206] In an embodiment, the further penetration enhancer is selected from the group consisting of: a decanoate, in particular sodium decanoate, a octanoate, in particular sodium octanoate.

[0207] In an embodiment, the further penetration enhancer is selected from the group consisting of: caprates, in particular sodium caprate.

[0208] In an embodiment, the composition comprises at least 300 mg / g of penetration enhancer relative to the total weight of the composition.

[0209] In an embodiment, the composition comprises at least 400 mg / g of penetration enhancer relative to the total weight of the composition.

[0210] In an embodiment, the composition comprises at least 500 mg / g of penetration enhancer relative to the total weight of the composition.

[0211] In an embodiment, the composition comprises at least 600 mg / g of penetration enhancer relative to the total weight of the composition.

[0212] In an embodiment, the composition comprises at least 700 mg / g of penetration enhancer relative to the total weight of the composition.

[0213] In an embodiment, the composition comprises at least 800 mg / g of penetration enhancer relative to the total weight of the composition.

[0214] In an embodiment, the composition comprises at least 900 mg / g of penetration enhancer relative to the total weight of the composition.

[0215] In an embodiment, the composition comprises up to 990 mg / g of penetration enhancer relative to the total weight of the composition.

[0216] In an embodiment, the composition comprises up to 980 mg / g of penetration enhancer relative to the total weight of the composition.

[0217] In an embodiment, the composition comprises up to 950 mg / g of penetration enhancer relative to the total weight of the composition.

[0218] In an embodiment, the composition comprises up to 900 mg / g of penetration enhancer relative to the total weight of the composition.

[0219] In an embodiment, the composition comprises up to 800 mg / g of penetration enhancer relative to the total weight of the composition.

[0220] In an embodiment, the composition comprises a protease inhibitor other than AC-aa-NS.

[0221] In an embodiment, the composition comprises a protease inhibitor selected from the group consisting of serine protease inhibitors, metalloprotease inhibitors, and mixtures thereof.

[0222] In an embodiment, the composition comprises a serine protease inhibitor.

[0223] In an embodiment, the composition comprises a serine protease inhibitor selected from the group consisting of proteins, peptides, serine protease inhibitors, chemical agents, and mixtures thereof, as listed in the following paragraphs.

[0224] In an embodiment, the composition comprises a serine protease inhibitor, which is a protein or peptide selected from the group consisting of Aprotinin, Bacitracin, Lima bean trypsin inhibitor, Ovomucoid, soybean trypsin inhibitor (SBTI), KTI (Kunitz Trypsine Inhibitor), BBI (Bowman-Birk Inhibitor), SFTI (Sunflower Trypsin Inhibitor) and mixtures thereof.

[0225] In an embodiment, the composition comprises a serine protease inhibitor, which is a serine protease inhibitor selected from the group consisting of alpha-1-antitrypsin, alpha 1-antichymotrypsin, alpha 2-macroglobulin, antithrombin, centromeric protein (Centerin), kallistatin, neuroserpin, pancpin, plasminogen activator inhibitor-2, protein C inhibitor, secretory leukocyte protease inhibitor, squamous cell carcinoma antigen-1, squamous cell carcinoma antigen-2, ulinastatin, visceral fat-specific serine protease inhibitor (Vaspin) and a mixture thereof.

[0226] In an embodiment, the composition comprises a serine protease inhibitor, which is a chemical agent selected from the group consisting of: AEBSF-hydrochloride (4-(2-aminoethyl)benzenesulfonyl fluoride), aminobenzamidine dihydrochloride, ε-aminocaproic acid, APMSF-hydrochloride, benzamidine-hydrochloride, camostat mesylate, chymosin inhibitor, FK448, leupeptin, PEFABLOC SC, PMSF (phenylmethylsulfonyl fluoride), TLCK (Nα-tosyl-Lys-chloromethyl ketone), TPCK (6-(1-tosylamino-2-phenyl)ethyl chloromethyl ketone) and mixtures thereof.

[0227] In an embodiment, the composition comprises a serine protease inhibitor selected from the group consisting of SBTI, KTI, BBI, aprotinin, SFTI, ovomucoid, and mixtures thereof.

[0228] In an embodiment, the composition comprises a serine protease inhibitor selected from the group consisting of SBTI, KTI, BBI and mixtures thereof, specifically SBTI.

[0229] According to an embodiment, the composition comprises only one serine protease inhibitor.

[0230] According to an embodiment, the composition comprises SBTI.

[0231] According to an embodiment, the composition comprises KTI.

[0232] According to an embodiment, the composition comprises BBI.

[0233] According to an embodiment, the composition comprises SFTI.

[0234] According to an embodiment, the composition comprises at least 90% w / w, in particular at least 95% w / w, SBTI as a protease inhibitor.

[0235] According to an embodiment, the composition comprises at least 90% w / w, in particular at least 95% w / w, of KTI as a protease inhibitor.

[0236] According to an embodiment, the composition comprises at least 90% w / w, specifically at least 95% w / w, of BBI as a protease inhibitor.

[0237] According to an embodiment, the composition comprises at least 90% w / w, specifically at least 95% w / w, of BBI and KTI as protease inhibitors.

[0238] According to an embodiment, the composition comprises at least 90% w / w, in particular at least 95% w / w, SFTI as protease inhibitor.

[0239] According to an embodiment, the composition comprises only SBTI as protease inhibitor.

[0240] According to an embodiment, the composition comprises only KTI as protease inhibitor.

[0241] According to an embodiment, the composition comprises only BBI as protease inhibitor.

[0242] According to an embodiment, the composition comprises only BBI and KTI as protease inhibitors.

[0243] According to an embodiment, the composition comprises only SFTI as protease inhibitor.

[0244] According to an embodiment, the composition comprises a mixture of serine protease inhibitors.

[0245] According to an embodiment, the composition comprises a mixture of serine protease inhibitors selected from the group consisting of SBTI and aprotinin, KTI and aprotinin, BBI and aprotinin, SFTI and aprotinin, ovomucoid and aprotinin, SBTI and ovomucoid, KTI and ovomucoid, BBI and ovomucoid, SFTI and ovomucoid.

[0246] In an embodiment, the composition comprises a metalloproteinase inhibitor.

[0247] In an embodiment, the composition comprises as metalloproteinase inhibitor a CPB (carboxypeptidase) inhibitor from potato tubers.

[0248] According to an embodiment, the composition comprises only one metalloproteinase inhibitor.

[0249] According to an embodiment, the composition comprises a mixture of metalloproteinase inhibitors.

[0250] According to an embodiment, the composition comprises a mixture of a serine protease inhibitor and a metalloprotease inhibitor.

[0251] According to an embodiment, the composition comprises a mixture of serine protease inhibitors and metalloprotease inhibitors selected from the group consisting of SBTI and CPB inhibitor, BBI and CPB inhibitor, KTI and CPB inhibitor, aprotinin and CPB inhibitor, ovomucoid and CPB inhibitor.

[0252] According to an embodiment, the composition comprises a mixture of a serine protease inhibitor and a metalloprotease inhibitor.

[0253] According to an embodiment, the composition comprises a mixture of serine protease inhibitors and metalloprotease inhibitors selected from the group consisting of SBTI and sodium glycocholate, aprotinin and sodium glycocholate, ovomucoid and sodium glycocholate.

[0254] According to an embodiment, the composition comprises 10 to 500 mg of a protease inhibitor.

[0255] According to an embodiment, the composition comprises 10 to 200 mg of a protease inhibitor.

[0256] According to an embodiment, the composition comprises 10 to 150 mg of a protease inhibitor.

[0257] According to an embodiment, the composition comprises 10 to 100 mg of a protease inhibitor.

[0258] According to an embodiment, the composition comprises 20 to 600 mg / g of the protease inhibitor.

[0259] According to an embodiment, the composition comprises 20 to 400 mg / g of the protease inhibitor.

[0260] According to an embodiment, the composition comprises 20 to 250 mg of a protease inhibitor.

[0261] According to an embodiment, the composition comprises 20 to 150 mg of a protease inhibitor.

[0262] In an embodiment, the composition comprises 100 to 400 mg / g of SBTI, KTI, BBI and mixtures thereof, and specifically SBTI.

[0263] In an embodiment, the composition comprises 120 to 300 mg / g of SBTI, KTI, BBI and mixtures thereof, and specifically SBTI.

[0264] In an embodiment, the composition comprises 140 to 250 mg / g of SBTI, KTI, BBI and mixtures thereof, and specifically SBTI.

[0265] In an embodiment, the composition comprises 150 to 200 mg / g of SBTI, KTI, BBI and mixtures thereof, and specifically SBTI.

[0266] In an embodiment, the composition comprises 100 to 400 mg / g of SBTI, KTI, BBI, SFTI and mixtures thereof, and specifically SBTI.

[0267] In an embodiment, the composition comprises 120 to 300 mg / g of SBTI, KTI, BBI, SFTI and mixtures thereof, and specifically SBTI.

[0268] In an embodiment, the composition comprises 140 to 250 mg / g of SBTI, KTI, BBI, SFTI and mixtures thereof, and specifically SBTI.

[0269] In an embodiment, the composition comprises 150 to 200 mg / g of SBTI, KTI, BBI, SFTI and mixtures thereof, and specifically SBTI.

[0270] In an embodiment, the composition comprises at least 500 mg / g of a penetration enhancer and a protease inhibitor, in particular a serine protease inhibitor, relative to the total weight of the composition.

[0271] In an embodiment, the composition comprises at least 600 mg / g of a penetration enhancer and a protease inhibitor, in particular a serine protease inhibitor, relative to the total weight of the composition.

[0272] In an embodiment, the composition comprises at least 700 mg / g of a penetration enhancer and a protease inhibitor, in particular a serine protease inhibitor, relative to the total weight of the composition.

[0273] In an embodiment, the composition comprises at least 800 mg / g of a penetration enhancer and a protease inhibitor, in particular a serine protease inhibitor, relative to the total weight of the composition.

[0274] In an embodiment, the composition comprises at least 900 mg / g of a penetration enhancer and a protease inhibitor, in particular a serine protease inhibitor, relative to the total weight of the composition.

[0275] In an embodiment, the composition comprises at least 950 mg / g of a penetration enhancer and a protease inhibitor, in particular a serine protease inhibitor, relative to the total weight of the composition.

[0276] In an embodiment, the composition comprises up to 990 mg / g of penetration enhancer relative to the total weight of the composition.

[0277] In an embodiment, the composition comprises a divalent cation chelator.

[0278] In an embodiment, the chelator is a physiologically acceptable compound having a high affinity for at least one of calcium, magnesium, and manganese ions.

[0279] In another embodiment, the chelating agent is selected from the group consisting of: ethylenediaminetetraacetic acid (EDTA) or its salts (e.g., disodium EDTA and calcium disodium EDTA); EGTA (ethylene glycol tetraacetic acid) or its salts; diethylenetriaminepentaacetic acid (DTPA) or its salts; BAPTA (l,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid) or its salts; and mixtures thereof.

[0280] In another embodiment, only one of the above listed chelating agents is present in the composition.

[0281] In another embodiment, the chelating agent is EDTA.

[0282] In an embodiment, the composition comprises 1 to 50% w / w of a divalent cation chelator, in particular EDTA.

[0283] In an embodiment, the composition comprises 2 to 30% w / w of a divalent cation chelator, in particular EDTA.

[0284] In an embodiment, the composition comprises 5 to 25% w / w of a divalent cation chelator, in particular EDTA.

[0285] In an embodiment, the peptide or protein is a therapeutic peptide or protein.

[0286] In an embodiment, the peptide or protein is long-acting.

[0287] "Long-acting" means a plasma half-life of at least 1 day.

[0288] In an embodiment, the long-acting peptide or protein has a plasma half-life of at least 2 days.

[0289] In an embodiment, the long-acting peptide or protein has a plasma half-life of at least 3 days.

[0290] In an embodiment, the long-acting peptide or protein has a plasma half-life of at least 5 days.

[0291] In an embodiment, the long-acting peptide or protein has a plasma half-life of at least 7 days.

[0292] In an embodiment, the long-acting peptide or protein has a plasma half-life of at least 10 days.

[0293] In an embodiment, the long-acting peptide or protein has a plasma half-life of at least 15 days.

[0294] In an embodiment, the peptide or protein is short-acting.

[0295] "Short-acting" means a plasma half-life of less than 1 day.

[0296] In an embodiment, the short-acting peptide or protein has a plasma half-life of up to 18 hours.

[0297] In an embodiment, the short-acting peptide or protein has a plasma half-life of up to 12 hours.

[0298] In an embodiment, the short-acting peptide or protein has a plasma half-life of up to 6 hours.

[0299] In an embodiment, the short-acting peptide or protein has a plasma half-life of at most 4 hours.

[0300] In an embodiment, the short-acting peptide or protein has a plasma half-life of at most 2 hours.

[0301] In an embodiment, the peptide or protein has a solubility in water at or above 25°C of at least 10 mg / ml.

[0302] In an embodiment, the peptide or protein has a solubility in water at or above 25°C of at least 20 mg / ml.

[0303] In an embodiment, the peptide or protein has a solubility in water at or above 25°C of at least 30 mg / ml.

[0304] In an embodiment, the peptide or protein has a solubility in water at or above 25°C of at least 40 mg / ml.

[0305] In an embodiment, the peptide or protein has a solubility in water at or above 25°C of at least 50 mg / ml.

[0306] In an embodiment, the peptide or protein has a solubility in water at or above 25°C of up to 40 mg / ml.

[0307] In an embodiment, the peptide or protein has a solubility in water at or above 25°C of at most 30 mg / ml.

[0308] In an embodiment, the peptide or protein has a solubility in water at or above 25°C of at most 20 mg / ml.

[0309] In an embodiment, the peptide or protein has a solubility in water at or above 25°C of at most 10 mg / ml.

[0310] In an embodiment, the peptide or protein has a molecular weight of at least 1500 Da.

[0311] In an embodiment, the peptide or protein has a molecular weight of at least 2000 Da.

[0312] In an embodiment, the peptide or protein has a molecular weight of at least 2500 Da.

[0313] In an embodiment, the peptide or protein has a molecular weight of at least 3000 Da.

[0314] In an embodiment, the peptide or protein has a molecular weight of at least 3500 Da.

[0315] In an embodiment, the peptide or protein has a molecular weight of at least 4000 Da.

[0316] In an embodiment, the peptide or protein has a molecular weight of at most 20,000 Da.

[0317] In an embodiment, the peptide or protein has a molecular weight of at most 15000 Da.

[0318] In an embodiment, the peptide or protein has a molecular weight of at most 10000 Da.

[0319] In an embodiment, the peptide or protein has a molecular weight of at most 5000 Da.

[0320] In an embodiment, the composition comprises 0.25 to 20 wt% peptide or protein.

[0321] In an embodiment, the composition comprises 0.5 to 20 wt% of the peptide or protein.

[0322] In an embodiment, the composition comprises 1 to 20 wt% of the peptide or protein.

[0323] In an embodiment, the composition comprises 2 to 20 wt% peptide or protein.

[0324] In an embodiment, the composition comprises 5 to 20 wt% peptide or protein.

[0325] In an embodiment, the composition comprises 1 to 15 wt% peptide or protein.

[0326] In an embodiment, the composition comprises 2 to 15 wt% peptide or protein.

[0327] In an embodiment, the composition comprises 5 to 15 wt% peptide or protein.

[0328] In an embodiment, the peptide or protein is selected from the group consisting of: GLP-1RA, GLP-2RA, insulin and insulin analogs, amylin RA, GIP RA, pancreatic polypeptide RA, also known as PP RA, neuropeptide Y RA, also known as NPYRA, peptide tyrosine tyrosine, also known as PYY RA, dual agonist PP / PYY, dual agonist GIP / GLP-1, dual agonist GLP-1 / glucagon, dual agonist GLP-1 / GLP-2, triple agonist glucagon / GIP / GLP-1, also known as GGG, parathyroid hormone (PTH) and PTH analogs, interleukins (IL) and IL analogs, growth hormone (GH) and GH analogs, insulin growth factor (IGF) and IGF analogs, interferon (IFN) and IFN analogs, MC4 RA (melanocortin 4 receptor agonist), leptin and leptin analogs, ghrelin antagonists, ghrelin agonists, fibroblast growth factor (FGF) and FGF analogs, cholecystokinin (CCK) and CCK analogs, gastrin and gastrin analogs, apelin and apelin analogs, xelin and xelin analogs, growth differentiation factor 15 (GDF 15) and GDF 15 analogs.

[0329] In an embodiment, the peptide or protein is octreotide

[0330] In an embodiment, the peptide or protein is a GLP-1RA selected from the group consisting of semaglutide.

[0331] In an embodiment, the peptide or protein is a GLP-1RA selected from the group consisting of dulaglutide.

[0332] In an embodiment, the peptide or protein is a GLP-2RA selected from the group consisting of teduglutide and glepaglutide.

[0333] In an embodiment, the peptide or protein is insulin or an insulin analog. Specifically, the insulin analog is selected from the group consisting of insulin degludec and insulin detemir.

[0334] In an embodiment, the peptide or protein is amylin RA or an amylin analog, specifically selected from the group consisting of pramlintide, mimylin, canagliflozin, davalintide, KBP-042, KBP 089 (from KeyBioscience) and acylated forms thereof.

[0335] In an embodiment, the peptide or protein is a GIP RA selected from the group consisting of GIP RA disclosed in WO2021021877, WO16066744 and WO2018181864.

[0336] In an embodiment, the GIP RA is selected from the group consisting of GIP(Lys16PAL), GIP(Lys37PAL) and ZP4165 (from Zealand).

[0337] In an embodiment, the peptide or protein is PYY RA selected from the group consisting of PYY(1-36), PYY(3-36) and PYY RA disclosed in WO2021023817, WO19147650 and WO2016198682.

[0338] In an embodiment, the peptide or protein is pancreatic polypeptide RA, also known as PP RA. In a specific embodiment, it is pancreatic polypeptide.

[0339] In an embodiment, the peptide or protein is neuropeptide Y RA. In a specific embodiment, it is neuropeptide Y.

[0340] In an embodiment, the peptide or protein is a PP / PY analog. In a specific embodiment, it is obinepitide. In an embodiment, the peptide or protein is a dual agonist GIP / GLP-1, selected from the group consisting of dual agonists GIP / GLP-1 disclosed in WO2016111971, and specifically tepoxetine.

[0341] In an embodiment, the peptide or protein is a dual agonist GIP / GLP-1 selected from the group consisting of RG7697 (from Roche) and telpotide.

[0342] In an embodiment, the peptide or protein is telpotide.

[0343] In an embodiment, the peptide or protein is the dual agonist GLP-1 / glucagon.

[0344] In an embodiment, the peptide or protein is a dual agonist glucagon / GLP-1 selected from the group consisting of cotadutide, dualAG (from Merck), efenipegdutide, pegapamudutide, mastudutide, BI4569906, pemvidutide (from Altimmune).

[0345] In an embodiment, the peptide or protein is the triple agonist glucagon / GIP / GLP-1, also referred to as GGG. In a specific embodiment, the GGG is selected from the group consisting of: retaglutide, NN9423 (from NovoNordisk) and HM15211 (from Hanmi).

[0346] In an embodiment, the peptide or protein is a dual agonist GLP-1 / GLP-2. In a specific embodiment, it is selected from the group consisting of: dapiglutide.

[0347] In an embodiment, the peptide or protein is an analog of oxyntomodulin.

[0348] In an embodiment, the peptide or protein is parathyroid hormone (PTH) or a PTH analog selected from the group consisting of human PTH and PTH analogs.

[0349] In an embodiment, the peptide or protein is an interleukin (IL) or an IL analog selected from the group consisting of IL-11 and analogs.

[0350] In an embodiment, the peptide or protein is growth hormone (GH) or a GH analogue selected from the group consisting of human growth hormone and analogues, in particular human growth hormone with an acylation graft.

[0351] In an embodiment, the peptide or protein is an insulin growth factor (IGF) or an IGF analogue selected from the group consisting of IGF-1.

[0352] In an embodiment, the peptide or protein is an interferon (IFN) or an IFN analogue selected from the group consisting of INFβ-1a, INFβ-1b and INFγ.

[0353] In an embodiment, the peptide is MC4 RA (melanocortin 4 receptor agonist). In a specific embodiment, the MC4 RA is setmelanotide.

[0354] In an embodiment, the peptide is leptin.

[0355] In an embodiment, the peptide or protein is a leptin analog. The leptin analog may be selected from metreleptin.

[0356] In an embodiment, the peptide or protein is a ghrelin antagonist. In a specific embodiment, it is selected from the group consisting of [D-Lys3]-GHRP-6 and RM-853 (from Takeda).

[0357] In an embodiment, the peptide or protein is a ghrelin agonist. Among the ghrelin agonists, mention may be made of relamorelin (RM-131) and ulimorelin (TZP 101).

[0358] In an embodiment, the peptide or protein is a fibroblast growth factor (FGF) analog, specifically FGF-21 or a FGF-21 analog. In a specific embodiment, the FGF is selected from the group consisting of FGF-21, pegbelfermin, efrexufermin, NN9499 (as disclosed in U2010 / 216715), YH25724 (dual FGF21 / GLP1 RA from Yuhancorporation).

[0359] In an embodiment, the peptide or protein is a cholecystokinin peptide (CCK) or an analogue. In a specific embodiment, it is selected from the group consisting of: a cholecystokinin peptide, GI181771X (from GSK) and NN9056 (from NovoNordisk).

[0360] In an embodiment, the peptide or protein is gastrin or an analog thereof. In a specific embodiment, it is selected from the group consisting of: gastrin-34, gastrin-17, gastrin-14 and ZP3022 (dual agonist Glp-1 / gastrin, from Zealand).

[0361] In an embodiment, the peptide or protein is apelin or an analog thereof. In a specific embodiment, it is selected from the group consisting of apelin-36, apelin-17, apelin-13, pyroglutamylated-13 apelin and acylated apelin. In an embodiment, the peptide or protein is xelin or an analog thereof. In a specific embodiment, it is selected from the group consisting of clawed toad peptide-25 and acylated clawed toad peptide-25 [Lys13PAL] (synthesized by the University of Ulster) and the hybrid [dAla2]GIP / clawed toad peptide-8-Gln.

[0362] In an embodiment, the peptide or protein is Growth Differentiation Factor 15 (GDF 15) or an analog thereof. In a specific embodiment, it is selected from the group consisting of Growth Differentiation Factor 15 (GDF 15) and an acylated analog thereof.

[0363] In an embodiment, the peptide or protein is a modified peptide or protein comprising a covalently modified form, such as linked to the side chains of one or more amino acids of a hydrophilic peptide or protein.

[0364] In an embodiment, the peptide or protein is a peptide or protein comprising modifications in the form of linkages of amides, carbohydrates, alkyls, acyls, esters, PEGylations, and the like.

[0365] In an embodiment, the peptide or protein is a modified peptide or protein comprising in the form of a linkage at least one acyl group, said acyl group comprising at least 10 carbon atoms.

[0366] In an embodiment, the acyl moiety is -OEG-OEG-γ-L-Glu-octadecandioyl, wherein OEG is -COCH2O(CH2)2O(CH2)2NH-.

[0367] In an embodiment, the peptide or protein is a modified peptide or protein comprising at least one PEGylated linkage.

[0368] In an embodiment, the composition does not comprise a growth hormone. In a specific embodiment, the composition does not comprise a growth hormone as disclosed in WO2014060512.

[0369] In an embodiment, the composition does not comprise human growth hormone.

[0370] In an embodiment, the composition does not comprise insulin.

[0371] In an embodiment, the composition does not comprise a long-acting insulin. In a specific embodiment, the composition does not comprise a long-acting insulin, in particular a long-acting insulin as disclosed in WO2005012347, WO2009063072 and WO9507931.

[0372] In another specific embodiment, the composition does not comprise peptides or proteins, in particular insulin, such as the insulin disclosed in WO2012140155 and WO2014060447.

[0373] In an embodiment, the composition does not comprise insulin comprising an acylated graft.

[0374] In an embodiment, the weight ratio of AC-aa-NS / peptide or protein is 1:1 to 200:1.

[0375] In an embodiment, the weight ratio of AC-aa-NS / peptide or protein is 1:1 to 100:1.

[0376] In an embodiment, the weight ratio of AC-aa-NS / peptide or protein is 1:1 to 50:1.

[0377] In an embodiment, the weight ratio of AC-aa-NS / peptide or protein is 2:1 to 40:1.

[0378] In an embodiment, the weight ratio of AC-aa-NS / peptide or protein is 4:1 to 30:1.

[0379] In an embodiment, the weight ratio of AC-aa-NS / peptide or protein is 6:1 to 20:1.

[0380] In an embodiment, the composition comprises less than 10% w / w water.

[0381] In an embodiment, the composition comprises less than 5% w / w water.

[0382] In an embodiment, the composition comprises less than 2% w / w water.

[0383] In an embodiment, the composition comprises less than 1% w / w water.

[0384] In a specific embodiment, the solid composition comprises: a mixture of particles comprising AC-aa-NS and particles comprising a peptide or protein. Specifically, AC-aa-NS and the peptide or protein are present in the composition in the ratios and percentages disclosed above.

[0385] In a specific embodiment, the solid composition consists of a mixture of particles comprising AC-aa-NS and particles comprising a peptide or protein. Specifically, AC-aa-NS and the peptide or protein are present in the composition in the ratios and percentages disclosed above.

[0386] In an embodiment, the solid composition comprises particles, wherein AC-aa-NS and a peptide or protein are mixed, in particular, in the ratios and percentages disclosed above.

[0387] In a specific embodiment, the solid composition consists of particles in which AC-aa-NS and a peptide or protein are mixed, in particular, in the ratios and percentages disclosed above.

[0388] In a specific embodiment, the solid composition consists of particles in which AC-aa-NS and a peptide or protein are mixed, in particular, in the ratios and percentages disclosed above.

[0389] Particles comprising both the peptide or protein and AC-aa-NS can be obtained via lyophilization, freeze drying, spray drying, wet granulation or dry granulation.

[0390] In an embodiment, the particles are selected in the group consisting of microparticles (5-0.5 mm, excluding 0.5 mm), microparticles (0.5 mm-1 μm, excluding 1 μm), or nanoparticles (1000-1 nm), and mixtures thereof.

[0391] In an embodiment, the particles are microparticles (number average mean diameter of 5.0-0.5 mm), for example, as measured by laser granulometry.

[0392] In an embodiment, the particles are microparticles (number average mean diameter of 5.0 mm to 1 μm), for example, as measured by light obscuration.

[0393] In an embodiment, the particles are nanoparticles (number average mean diameter 1000-1 nm), for example, as measured by electron microscopy.

[0394] Among the production methods in order to achieve these specific sizes, the following may be mentioned: wet granulation, dry granulation, spray drying, milling, nanoprecipitation.

[0395] In an embodiment, the particles are independent of each other.

[0396] In another embodiment, the particles are held together.

[0397] In an embodiment, the composition comprises an excipient selected from the list consisting of a lubricant, a surfactant, a pH adjuster, a disintegrant, a binder, a filler, a glidant, a diluent, a polymer for sustained or delayed release (e.g., Eudragit polymers produced by Evonik), and a preservative.

[0398] In an embodiment, the composition comprises only excipients selected from the list consisting of lubricants, surfactants, pH adjusters, disintegrants, binders, fillers, glidants, diluents and preservatives.

[0399] In an embodiment, the composition comprises only excipients selected from the list consisting of: lubricants, pH adjusting agents.

[0400] In an embodiment, the composition comprises at most 20% w / w of excipients, in particular excipients as listed above, more particularly components belonging to the list in paragraph 3 above.

[0401] "Excipient" refers to components of the composition other than the penetration enhancer and the protease inhibitor.

[0402] In an embodiment, the composition comprises at most 15% w / w of excipients, in particular excipients as listed above.

[0403] In an embodiment, the total amount of binder, filler and glidant is up to 10% w / w of the composition.

[0404] In an embodiment, the composition comprises at least one pH adjusting agent.

[0405] In an embodiment, the pH adjuster may be selected from the group consisting of sodium carbonate (chemical formula: Na2CO3), phosphate, citrate, citric acid, tartrate and tartaric acid.

[0406] The citrate may be monosodium citrate, disodium citrate and / or trisodium citrate. Specifically, it may be trisodium citrate.

[0407] The tartrate may be monosodium tartrate and / or disodium tartrate. Specifically, it is monosodium tartrate.

[0408] In an embodiment, the pH adjuster is sodium carbonate (chemical formula: Na2CO3).

[0409] In an embodiment, the composition comprises at least 1% w / w pH adjusting agent.

[0410] In an embodiment, the composition comprises at least 2% w / w of the pH adjusting agent.

[0411] In an embodiment, the composition comprises at least 5% w / w pH adjusting agent.

[0412] In an embodiment, the composition comprises at most 15% w / w pH adjusting agent.

[0413] In an embodiment, the composition comprises at most 10% w / w pH adjusting agent.

[0414] In an embodiment, the composition comprises at most 8% w / w pH adjusting agent.

[0415] In an embodiment, the composition comprises at least one lubricant.

[0416] In an embodiment, the lubricant is selected from the group consisting of magnesium stearate or glyceryl dibehenate.

[0417] In an embodiment, the lubricant is magnesium stearate.

[0418] In an embodiment, the lubricant is glyceryl dibehenate.

[0419] In an embodiment, the composition comprises greater than or equal to 0.1% w / w lubricant.

[0420] In an embodiment, the composition comprises greater than or equal to 0.2% w / w lubricant.

[0421] In an embodiment, the composition comprises greater than or equal to 0.5% w / w lubricant.

[0422] In an embodiment, the composition comprises less than 5% w / w lubricant.

[0423] In an embodiment, the composition comprises less than 3% w / w lubricant.

[0424] In an embodiment, the composition comprises less than 2.5% w / w lubricant.

[0425] In an embodiment, the composition comprises less than 2% w / w lubricant.

[0426] In an embodiment, the composition comprises less than 1% w / w lubricant.

[0427] In an embodiment, the composition comprises between 0.25 and 2.5% w / w lubricant.

[0428] In an embodiment, the composition is in the form of unit solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules.

[0429] In an embodiment, the composition is in the form of a unit solid dosage form, such as capsules, tablets, dragees, pills, lozenges, powders and granules, wherein the unit dosage form comprises at least 50 mg of AC-aa-NS.

[0430] In an embodiment, the unit solid dosage form is in the form of a capsule.

[0431] In an embodiment, the unit solid dosage form is in the form of a hard capsule.

[0432] In an embodiment, the unit solid dosage form is in the form of a soft gel capsule.

[0433] The capsule may contain a powder, granules, or crushed tablet comprising the peptide or protein and one or more inert ingredients. The capsule may be formulated to have a delayed release profile.

[0434] In embodiments, the composition is encapsulated or the like to allow the swallowed composition to contact the gastrointestinal system.

[0435] In embodiments, encapsulation allows for delivery of the composition in the stomach.

[0436] Thus, the composition may be in the form of a film-coated tablet having a thin layer of a water-soluble material that dissolves rapidly in the stomach.

[0437] In another embodiment, encapsulation allows for delivery of the composition in the intestine.

[0438] Thus, the composition may be encapsulated with an enteric coating. The enteric coating may be in the form of a polymer coating or polymer capsule that controls disintegration and release of the composition.

[0439] The enteric coating may be a soft technology. In an embodiment, it is a soft capsule technology.

[0440] The enteric coating may be hard technology. In an embodiment, it is hard capsule technology.

[0441] The term "enteric coating" refers to a coating that controls disintegration and release of an oral dosage form.

[0442] The disintegration and release site of the solid dosage form can be designed based on the pH of the target area where absorption of the peptide or protein is desired, thus also including an acid resistant protective coating.

[0443] In an embodiment, the solid oral dosage form allows release at pH 4.5 and above.

[0444] In an embodiment, the solid oral dosage form allows release at pH 4.75 and above.

[0445] In an embodiment, the solid oral dosage form allows release at pH 5.0 and above.

[0446] In an embodiment, the solid oral dosage form allows release at pH 5.25 and above.

[0447] In an embodiment, the solid oral dosage form allows release at pH 5.5 and above.

[0448] In an embodiment, the solid oral dosage form allows release at pH 5.75 and above.

[0449] In an embodiment, the solid oral dosage form allows release at pH 6.0 and above.

[0450] Solid oral dosage forms can be engineered to site disintegration and release using delayed release technology, such as polymers with controlled dissolution rates in aqueous media, for example, Eudragit RL or RS polymers.

[0451] In an embodiment, a solid oral dosage form according to the present invention is considered to be an immediate release solid oral dosage form at pH 4.5.

[0452] In an embodiment, a solid oral dosage form according to the present invention is considered to be an immediate release solid oral dosage form at pH 5.0.

[0453] In an embodiment, a solid oral dosage form according to the present invention is considered to be an immediate release solid oral dosage form at pH 5.5.

[0454] In an embodiment, a solid oral dosage form according to the present invention is considered to be an immediate release solid oral dosage form at pH 6.0.

[0455] Being considered an immediate-release solid oral dosage form means that the solid oral dosage form meets the conditions disclosed in the following: "Dissolution Testing and Acceptance Criteria for Immediate-Release Solid Oral Dosage Form Drug Products Containing High Solubility Drug Substances Guidance for Industry" - August 2018 (other copies are available from: Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993-0002 Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov http: / / www.fda.gov / Drugs / GuidanceComplianceRegulatoryInf ormation / Guidances / default.htm ).

[0456] In an embodiment, the solid oral dosage form comprises 50 to 250 mg of SBTI, KTI, BBI, SFTI and mixtures thereof, and specifically SBTI.

[0457] In an embodiment, the solid oral dosage form comprises 60 to 200 mg of SBTI, KTI, BBI, SFTI and mixtures thereof, and specifically SBTI.

[0458] In an embodiment, the solid oral dosage form comprises 70 to 150 mg of SBTI, KTI, BBI, SFTI and mixtures thereof, and specifically SBTI.

[0459] In an embodiment, the composition is for use as a medicament.

[0460] In an embodiment, the composition is used to prevent or treat obesity, type 1 diabetes, type 2 diabetes, NASH, thrombocytopenia, short bowel syndrome (SBS), adult GH deficiency, GH disorders, short stature syndrome, Turner syndrome, achondroplasia, Prader-Willi syndrome, short stature in children, osteoporosis and hypoparathyroidism, multiple sclerosis, bone disorders.

[0461] In an embodiment, the composition is used to prevent or treat obesity.

[0462] In an embodiment, the composition is used to prevent or treat type 1 diabetes.

[0463] In an embodiment, the composition is used to prevent or treat type 2 diabetes.

[0464] In an embodiment, the composition is used to prevent or treat NASH.

[0465] In an embodiment, the composition is used to prevent or treat thrombocytopenia.

[0466] In an embodiment, the composition is for use in preventing or treating short bowel syndrome (SBS).

[0467] In an embodiment, the composition is used to prevent or treat GH deficiency, GH disorders, short stature syndrome, Turner's syndrome, achondroplasia, Prader-Willi syndrome, or short stature in children in adults.

[0468] In an embodiment, the composition is used to prevent or treat osteoporosis.

[0469] In an embodiment, the composition is for use in preventing or treating hypoparathyroidism.

[0470] In an embodiment, the composition is used to prevent or treat multiple sclerosis.

[0471] In an embodiment, the composition is for use in preventing or treating a bone disorder.

[0472] According to an embodiment, the composition comprises AC-aa-NS, a peptide or a protein, and a lubricant.According to an embodiment, the composition comprises AC-aa-NS wherein the AC group comprises 8 carbon atoms, a peptide or a protein, a protease inhibitor, and a lubricant.

[0473] AC refers to -COR1 from formula I. Thus, when AC contains n carbon atoms, this means that R1 contains (n-1) carbon atoms.

[0474] According to an embodiment, the composition comprises AC-aa-NS, a peptide or a protein and a lubricant selected from the group consisting of magnesium stearate or glyceryl dibehenate.

[0475] According to an embodiment, the composition comprises AC-aa-NS, a peptide or protein and other penetration enhancers.

[0476] According to an embodiment, the composition comprises AC-aa-NS, a peptide or protein and a further penetration enhancer selected from the group consisting of decanoate, specifically sodium decanoate, octanoate, specifically sodium octanoate, bile salts, 8-(2-hydroxybenzamido)octanoate, specifically sodium 8-(2-hydroxybenzamido)octanoate (SNAC).

[0477] According to an embodiment, the composition comprises AC-aa-NS, a peptide or protein, and a pH adjuster.

[0478] According to an embodiment, the composition comprises AC-aa-NS, a peptide or a protein, and a pH adjuster selected from the group consisting of sodium carbonate (chemical formula Na2CO3), phosphate, citrate, citric acid, tartrate and tartaric acid.

[0479] According to an embodiment, the composition comprises AC-aa-NS, a peptide or protein and a protease inhibitor.

[0480] According to an embodiment, the composition comprises AC-aa-NS, a peptide or protein, a pH adjuster and a protease inhibitor.

[0481] According to an embodiment, the composition comprises AC-aa-NS, a peptide or protein, other penetration enhancers and a protease inhibitor.

[0482] According to an embodiment, the composition comprises AC-aa-NS, a peptide or protein, a lubricant and a protease inhibitor.

[0483] According to an embodiment, the composition comprises AC-aa-NS, a peptide or protein, a pH adjuster, other penetration enhancers and a protease inhibitor.

[0484] According to an embodiment, the composition comprises N-octanoyl-phenylalanine, a peptide or protein and a lubricant.

[0485] According to an embodiment, the composition comprises N-octanoyl-phenylalanine, a peptide or a protein and a lubricant selected from the group consisting of: magnesium stearate or glyceryl dibehenate.

[0486] According to an embodiment, the composition comprises N-octanoyl-phenylalanine, a peptide or protein and other penetration enhancers.

[0487] According to an embodiment, the composition comprises N-octanoyl-phenylalanine, a peptide or protein and a further penetration enhancer selected from the group consisting of decanoate, in particular sodium decanoate, octanoate, in particular sodium octanoate, bile salts, 8-(2-hydroxybenzamido)octanoate, in particular sodium 8-(2-hydroxybenzamido)octanoate (SNAC).

[0488] According to an embodiment, the composition comprises N-octanoyl-phenylalanine, a peptide or protein and a pH adjuster.

[0489] According to an embodiment, the composition comprises N-octanoyl-phenylalanine, a peptide or a protein and a pH adjuster selected from the group consisting of sodium carbonate (chemical formula Na2CO3), phosphate, citrate, citric acid, tartrate and tartaric acid.

[0490] According to an embodiment, the composition comprises N-octanoyl-phenylalanine, a peptide or protein, a pH adjuster and a protease inhibitor.

[0491] According to an embodiment, the composition comprises N-octanoyl-phenylalanine, a peptide or protein, other penetration enhancers and a protease inhibitor.

[0492] According to an embodiment, the composition comprises N-octanoyl-phenylalanine, a peptide or protein, a lubricant and a protease inhibitor.

[0493] According to an embodiment, the composition comprises N-octanoyl-phenylalanine, a peptide or protein, a pH adjuster, other penetration enhancers and a protease inhibitor.

[0494] According to an embodiment, the composition comprises AC-aa-NS, a peptide or a protein and a lubricant which is magnesium stearate.

[0495] According to an embodiment, the composition comprises AC-aa-NS, a peptide or a protein and a lubricant which is glyceryl dibehenate.

[0496] According to an embodiment, the composition comprises AC-aa-NS, a peptide or protein, and a pH adjuster.

[0497] According to an embodiment, the composition comprises AC-aa-NS, a peptide or a protein and a pH adjuster which is sodium carbonate.

[0498] According to an embodiment, the composition comprises AC-aa-NS, a peptide or protein, a lubricant, and a pH adjuster.

[0499] According to an embodiment, the composition comprises AC-aa-NS, a peptide or a protein, a lubricant which is magnesium stearate, and a pH adjuster.

[0500] According to an embodiment, the composition comprises AC-aa-NS, a peptide or a protein, a lubricant which is magnesium stearate, and a pH adjuster which is sodium carbonate.

[0501] According to an embodiment, the composition comprises AC-aa-NS, a peptide or a protein, a lubricant which is glyceryl dibehenate, and a pH adjuster.

[0502] According to an embodiment, the composition comprises AC-aa-NS, a peptide or a protein and a lubricant which is glyceryl dibehenate and a pH adjuster which is sodium carbonate.

[0503] According to an embodiment, the composition comprises AC-aa-NS, a peptide or protein, a lubricant and a disintegrant.

[0504] According to an embodiment, the composition comprises AC-aa-NS, a peptide or protein, a lubricant which is magnesium stearate, and a disintegrant.

[0505] According to an embodiment, the composition comprises AC-aa-NS, a peptide or a protein, a lubricant as dibehenylglycerol, and a disintegrant.

[0506] According to an embodiment, the composition comprises AC-aa-NS, a peptide or protein, a lubricant, a pH adjuster and a disintegrant.

[0507] According to an embodiment, the composition comprises AC-aa-NS, a peptide or a protein, a lubricant as magnesium stearate, a pH adjuster and a disintegrant.

[0508] According to an embodiment, the composition comprises AC-aa-NS, a peptide or protein, a lubricant which is magnesium stearate, a pH adjuster which is sodium carbonate, and a disintegrant.

[0509] According to an embodiment, the composition comprises AC-aa-NS, a peptide or a protein, a lubricant which is glyceryl dibehenate, a pH adjuster, and a disintegrant.

[0510] According to an embodiment, the composition comprises AC-aa-NS, a peptide or a protein, and a lubricant which is glyceryl dibehenate, a pH adjuster which is sodium carbonate, and a disintegrant.

[0511] According to an embodiment, the composition comprises AC-aa-NS wherein the AC group comprises 8 carbon atoms and aa is selected from aromatic amino acids selected from the group consisting of phenylalanine (Phe), phenylglycine (PGly), tryptophan (Trp) and tyrosine (Tyr), a peptide or protein, a lubricant as magnesium stearate, a pH adjuster and a disintegrant.

[0512] According to an embodiment, the composition comprises AC-aa-NS wherein the AC group comprises 8 carbon atoms and aa is selected from aromatic amino acids selected from the group consisting of phenylalanine (Phe), phenylglycine (PGly), tryptophan (Trp) and tyrosine (Tyr), a peptide or protein, a lubricant as magnesium stearate, a pH adjuster as sodium carbonate, and a disintegrant.

[0513] According to an embodiment, the composition comprises AC-aa-NS wherein the AC group comprises 8 carbon atoms and aa is selected from aromatic amino acids selected from the group consisting of phenylalanine (Phe), phenylglycine (PGly), tryptophan (Trp) and tyrosine (Tyr), a peptide or protein, a lubricant as dibehenylglycerol, a pH adjuster and a disintegrant.

[0514] According to an embodiment, the composition comprises NaGly(N-Bn)C8, a peptide or protein, a lubricant as dibehenylglycerol, a pH adjuster as sodium carbonate, and a disintegrant.

[0515] According to an embodiment, the composition comprises NaGly(N-Bn)C8, a peptide or protein, a lubricant, a pH adjuster and a disintegrant.

[0516] According to an embodiment, the composition comprises NaGly(N-Bn)C8, a peptide or protein, a lubricant, a pH adjuster which is sodium carbonate, and a disintegrant.

[0517] According to an embodiment, the composition comprises NaGly(N-Bn)C8, a peptide or protein, a lubricant, a pH adjuster, a disintegrant and a protease inhibitor.

[0518] According to an embodiment, the composition comprises NaGly(N-Bn)C8, a peptide or protein, a lubricant, a pH adjuster which is sodium carbonate, a disintegrant and a protease inhibitor.

[0519] According to an embodiment, the composition comprises NaGly(N-Bn)C8, a peptide or protein, a lubricant which is magnesium stearate, a pH adjuster, and a disintegrant.

[0520] According to an embodiment, the composition comprises NaGly(N-Bn)C8, a peptide or protein, a lubricant which is magnesium stearate, a pH adjuster which is sodium carbonate, and a disintegrant.

[0521] According to an embodiment, the composition comprises NaGly(N-Bn)C8, a peptide or protein, a lubricant as dibehenylglycerol, a pH adjuster and a disintegrant.

[0522] In an embodiment, the composition comprises AC-aa-NS wherein the AC group comprises 8 carbon atoms and a protein or peptide.

[0523] In an embodiment, the composition comprises AC-aa-NS and other penetration enhancers, specifically SNAC.

[0524] In an embodiment, the composition comprises AC-aa-NS and a protease inhibitor, specifically a protease inhibitor selected from the group consisting of: SBTI, BBI and KTI.

[0525] In an embodiment, the composition comprises 100 to 400 mg / g of AC-aa-NS and a protease inhibitor, in particular a protease inhibitor selected from the group consisting of SBTI, BBI and KTI and mixtures thereof, and in particular SBTI.

[0526] In an embodiment, the composition comprises 120 to 300 mg / g of AC-aa-NS and a protease inhibitor, in particular a protease inhibitor selected from the group consisting of SBTI, BBI and KTI and mixtures thereof, and in particular SBTI.

[0527] In an embodiment, the composition comprises 140 to 250 mg / g of AC-aa-NS and a protease inhibitor, in particular a protease inhibitor selected from the group consisting of SBTI, BBI and KTI and mixtures thereof, and in particular SBTI.

[0528] In an embodiment, the composition comprises 150 to 200 mg / g of AC-aa-NS and a protease inhibitor, in particular a protease inhibitor selected from the group consisting of SBTI, BBI and KTI and mixtures thereof, and in particular SBTI.

[0529] In an embodiment, the composition comprises AC-aa-NS and a divalent cation chelator, specifically EDTA.

[0530] In an embodiment, the composition comprises AC-aa-NS and a pH adjuster, specifically a carbonate, more specifically Na2CO3.

[0531] In an embodiment, the composition comprises AC-aa-NS and a disintegrant, specifically croscarmellose.

[0532] In an embodiment, the composition comprises AC-aa-NS, other penetration enhancers, in particular SNAC, and a protease inhibitor, in particular a protease inhibitor selected from the group consisting of SBTI, BBI and KTI.

[0533] In an embodiment, the composition comprises AC-aa-NS, another penetration enhancer, specifically SNAC, and a divalent cation chelator, specifically EDTA.

[0534] In an embodiment, the composition comprises AC-aa-NS, another penetration enhancer, specifically SNAC, and a pH adjuster, specifically a carbonate, more specifically Na2CO3.

[0535] In an embodiment, the composition comprises AC-aa-NS, another penetration enhancer, specifically SNAC, and a disintegrant, specifically croscarmellose.

[0536] In an embodiment, the composition comprises AC-aa-NS, a protease inhibitor, in particular a protease inhibitor selected from the group consisting of SBTI, BBI and KTI, and a divalent cation chelator, in particular EDTA.

[0537] In an embodiment, the composition comprises AC-aa-NS, a protease inhibitor, particularly a protease inhibitor selected from the group consisting of SBTI, BBI and KTI, and a pH adjuster, particularly a carbonate, more particularly Na2CO3.

[0538] In an embodiment, the composition comprises AC-aa-NS, a protease inhibitor, in particular a protease inhibitor selected from the group consisting of SBTI, BBI and KTI, and a disintegrant, in particular croscarmellose.

[0539] In an embodiment, the composition comprises AC-aa, specifically AC-aa according to formula I, more specifically AC-aa according to formula Ia, and more specifically AC aa wherein AC is -CO(R1) and R1 is Co7 or C8 alkyl, a protein or peptide, other penetration enhancers, specifically SNAC, a protease inhibitor, specifically a protease inhibitor selected from the group consisting of SBTI, BBI and KTI, and a divalent cation chelator, specifically EDTA.

[0540] In an embodiment, the composition comprises AC-aa-NS, other penetration enhancers, specifically SNAC, a protease inhibitor, specifically a protease inhibitor selected from the group consisting of SBTI, BBI and KTI, and a pH adjuster, specifically carbonates, more specifically Na2CO3.

[0541] In an embodiment, the composition comprises AC-aa-NS, other penetration enhancers, in particular SNAC, a protease inhibitor, in particular a protease inhibitor selected from the group consisting of SBTI, BBI and KTI, and a disintegrant, in particular croscarmellose.

[0542] In an embodiment, the composition comprises AC-aa-NS, another penetration enhancer, specifically SNAC, a divalent cation chelator, specifically EDTA, and a pH adjuster, specifically a carbonate, more specifically Na2CO3.

[0543] In an embodiment, the composition comprises AC-aa-NS, another penetration enhancer, specifically SNAC, a divalent cation chelator, specifically EDTA, and a disintegrant, specifically croscarmellose.

[0544] In an embodiment, the composition comprises AC-aa-NS, a protease inhibitor, specifically a protease inhibitor selected from the group consisting of SBTI, BBI and KTI, a divalent cation chelator, specifically EDTA, and a pH adjuster, specifically carbonate, more specifically Na2CO3.

[0545] In an embodiment, the composition comprises AC-aa-NS, a protease inhibitor, in particular a protease inhibitor selected from the group consisting of SBTI, BBI and KTI, a divalent cation chelator, in particular EDTA, and a disintegrant, in particular croscarmellose.

[0546] In an embodiment, the composition comprises AC-aa-NS, a protease inhibitor, in particular a protease inhibitor selected from the group consisting of SBTI, BBI and KTI, a pH adjuster, in particular a carbonate, more particularly Na2CO3, and a disintegrant, in particular croscarmellose.

[0547] In an embodiment, the composition comprises AC-aa-NS, other penetration enhancers, specifically SNAC, a protease inhibitor, specifically a protease inhibitor selected from the group consisting of SBTI, BBI and KTI, a divalent cation chelator, specifically EDTA, and a pH adjuster, specifically carbonate, more specifically Na2CO3.

[0548] In an embodiment, the composition comprises AC-aa-NS, other penetration enhancers, specifically SNAC, a protease inhibitor, specifically a protease inhibitor selected from the group consisting of SBTI, BBI and KTI, a divalent cation chelator, specifically EDTA, and a disintegrant, specifically croscarmellose.

[0549] In an embodiment, the composition comprises AC-aa-NS, other penetration enhancers, specifically SNAC, a protease inhibitor, specifically a protease inhibitor selected from the group consisting of SBTI, BBI and KTI, a pH adjuster, specifically carbonates, more specifically Na2CO3, and a disintegrant, specifically croscarmellose.

[0550] In an embodiment, the composition comprises AC-aa-NS, other penetration enhancers, specifically SNAC, divalent cation chelators, specifically EDTA, pH adjusters, specifically carbonates, more specifically Na2CO3, and disintegrants, specifically croscarmellose.

[0551] In an embodiment, the composition comprises AC-aa-NS, a protease inhibitor, in particular a protease inhibitor selected from the group consisting of SBTI, BBI and KTI, a divalent cation chelator, in particular EDTA, a pH adjuster, in particular carbonate, more particularly Na2CO3, and a disintegrant, in particular croscarmellose.

[0552] In an embodiment, the composition comprises AC-aa-NS, other penetration enhancers, specifically SNAC, a protease inhibitor, specifically a protease inhibitor selected from the group consisting of SBTI, BBI and KTI, a divalent cation chelator, specifically EDTA, a pH adjuster, specifically carbonate, more specifically Na2CO3, and a disintegrant, specifically croscarmellose.

[0553] In an embodiment, the solid composition comprises 1 to 10% w / w peptide, 50 to 95% w / w AC-aa-NS according to Formula I, and 0 to 15% pH adjuster.

[0554] In an embodiment, the solid composition comprises 1 to 10% w / w peptide, 50 to 95% w / w AC-aa-NS according to Formula I, 2 to 20% w / w protease inhibitor, and 0 to 15% pH adjuster.

[0555] In specific embodiments according to the first two embodiments above, said AC-aa-NS is according to formula I, wherein -R1 contains 6 to 8 carbon atoms.

[0556] In specific embodiments according to the first two embodiments above, the AC-aa-NS is according to Formula I, wherein R2 is -(CH2)m-Aro, wherein m is an integer selected from 1 to 4, and Aro is phenyl.

[0557] In a specific embodiment according to the first two embodiments above, the AC-aa-NS is according to formula I, wherein -R1 is an alkyl group containing 6 to 8 carbon atoms, and R2 is -(CH2)m-Aro, wherein m is an integer selected from 1 to 4, and Aro is phenyl.

[0558] In a specific embodiment according to the first two embodiments above, AC-aa-NS according to formula I is NaGly(N-Bn)C8.

[0559] In a specific embodiment according to the second of the first two embodiments above, the protease inhibitor is selected from the group consisting of SBTI, BBI, KTI, SFTI and mixtures thereof.

[0560] In a specific embodiment according to the first two embodiments above, the pH adjuster is sodium carbonate.

[0561] Example

[0562] AC-AA-NS can be obtained by acylation of amino acids, which can be easily carried out using acylating agents known in the art that react with (for example) free α-amino groups. Amino acids can be connected to acids via N-acylation, i.e., resulting in the formation of amide bonds. The AC-aa of the present invention can be prepared using the following method: Leone-Bay et al. (1995): "N-acylated alpha-amino acids as novel oral delivery agents for proteins", Journal of Medicinal Chemistry, 38 (21), 4263-4269. Alkylation of the nitrogen of amino acids can be carried out by classical reactions.

[0563] Part A—Preparation of Compositions

[0564] A.1. Solid composition

[0565] Method A-1

[0566] The solid composition is prepared by first mixing AC-aa-NS with the peptide or protein and other excipients in aqueous solution in appropriate proportions. The total solute concentration is in the range of 20-500 mg / g solution. The solution is then freeze-dried to obtain a uniform solid lyophilisate. The solid is then crushed into a powder suitable for further processing using a mortar and pestle. The resulting blend is then manually introduced into Enteric VCap, size 00 (Capsugel).

[0567] The capsules were then sealed using the following protocol: 10 μL of a 50 / 50 (vol / vol) mixture of ethanol and water was introduced between the lower portion of the capsule and the upper cover using a syringe. The sealing solution was then dried under hot air (45° C.) for 1 minute, thereby forming an impermeable seal between the two portions of the capsule.

[0568] Example A.1.1: Preparation of a solid composition of NaGly(N-Bn)C8 and semaglutide.

[0569] Composition A.1.1 was prepared according to method A.1 so that each capsule contained 14 mg semaglutide, 400 mg NaOOCCH2N(CH2Ph)COC7H15 (also known as NaGly(N-Bn)C8) and 43 mg sodium carbonate.

[0570] Example A.1.2: Preparation of a solid composition of NaGly(N-Bn)C8 and semaglutide incorporating the protease inhibitor SBTI.

[0571] Composition A.1.2 was prepared according to method A.1 so that the contents of each capsule were 14 mg semaglutide, 400 mg NaGly(N-Bn)C8, 43 mg sodium carbonate and 20 mg SBTI.

[0572] Example A.1.3: Preparation of a solid composition of NaGly(N-Bn)C8 and semaglutide incorporating the protease inhibitor aprotinin.

[0573] Composition A.1.3 was prepared according to method A.1 so that each capsule contained 14 mg semaglutide, 400 mg NaGly(N-Bn)C8, 21 mg sodium carbonate and 80 mg aprotinin.

[0574] Example A.1.4: Preparation of a solid composition of NaGly(N-Bn)C8 and semaglutide incorporating the protease inhibitor SFTI.

[0575] Composition A.1.4 was prepared according to method A.1 so that the contents of each capsule were 14 mg semaglutide, 400 mg NaGly(N-Bn)C8, 21 mg sodium carbonate and 80 mg SFTI.

[0576] Section C—Pharmacokinetics

[0577] Example C1: Pharmacokinetic Study in Beagle Dogs

[0578] A pharmacokinetic (PK) study was conducted in beagle dogs to evaluate the exposure and bioavailability of semaglutide after oral administration of Composition A.1.1 comprising semaglutide and NaGly(N-Bn)C8 as described in Example A.1.1 and after intravenous (iv) administration of semaglutide. As a reference, in a separate study, oral administration of (Oral semaglutide from NovoNordisk).

[0579] For oral administration, 10 beagles weighing about 10 kg were fasted overnight before the start of the experiment and fasted from 0 to 6 h after dosing. The capsules containing the composition were placed at room temperature for 15 minutes before administration, and no more than 30 minutes. Each dog was orally administered a capsule containing composition A.1.1, which contained semaglutide and NaGly (N-Bn) C8 as described in Example A.1.1. 5 mL of water was administered with a syringe immediately after oral administration to facilitate swallowing.

[0580] For intravenous (iv) administration, semaglutide solution (10 μmol / L) was injected into 10 beagle dogs through a catheter placed in the cephalic vein.

[0581] For oral administration, blood was sampled at a predetermined time up to 5 h, and for iv administration, blood was sampled at a predetermined time up to 192 h. Each blood sampling time point was collected in a K2EDTA tube containing a protease inhibitor cocktail (which was stored on ice for less than 45 min before centrifugation). Centrifugation was performed as follows: at +4°C, centrifuged at 1300G for 10 min. Plasma was collected in two cryovials, with a minimum of 100 μL in each cryovial. The cryovials were stored at -80°C until analysis.

[0582] After protein precipitation, plasma concentrations of semaglutide were determined using LC-MS / MS analysis.

[0583] The non-compartmental PK analysis of semaglutide plasma concentration data was performed using Phoenix WinNonlin V8.3 software (Pharsight, Mountain View, Calif. 94041, USA). For each dog, the following parameters were estimated: maximum plasma concentration (Cmax), time to reach maximum concentration (tmax), and area under the curve from 0 to 5h (AUC0-5h). Since blood sampling was stopped after 5h, it was unreliable to extrapolate AUC to infinity. Therefore, the bioavailability (F) of composition A.1.1 was estimated as the maximum cumulative number of copies obtained from plasma PK deconvolution. The unit impulse response (UIR) function for deconvolution was obtained from the IV injection described in Example C1. The summary statistics of PK parameters are expressed as medians and arithmetic means with corresponding standard deviations (SD). In the case of high inter-subject variability with a small sample size, the median appears to be a better PK parameter estimator than the arithmetic mean (i.e., no extreme value effect).

[0584] result

[0585] The following table reports the PK parameters calculated as individual medians and means (SD) following oral administration of composition A.1.1 comprising semaglutide and NaGly(N-Bn)C8 as described in Example A.1.1:

[0586]

[0587] The following table reports oral administration PK parameters calculated after each median and mean (SD):

[0588]

[0589] The results showed that after oral administration of the composition A.1.1 comprising semaglutide and NaGly(N-Bn)C8 described in Example A.1.1, absorption was observed in all individual dogs. For the composition A.1.1 comprising semaglutide and NaGly(N-Bn)C8 described in Example A.1, the bioavailability of semaglutide ranged from 0.03% to 0.59%, and for the composition A.1.1 comprising semaglutide and NaGly(N-Bn)C8 described in Example C1, the bioavailability of semaglutide ranged from 0.03% to 0.59%. The bioavailability of semaglutide ranged from 0.05% to 16.56%. Based on the median and SD values, In comparison, composition A.1.1 comprising semaglutide and NaGly(N-Bn)C8 described in Example A.1 showed comparable bioavailability (median F(%): 0.30% vs. 0.21%) and lower inter-subject variability (SD: 0.18% vs. 5.16%).

[0590] Example C2: Pharmacokinetic Study in Beagle Dogs

[0591] A pharmacokinetic (PK) study was conducted in beagle dogs to evaluate the exposure and bioavailability of semaglutide following oral administration of composition A.1.2 comprising semaglutide, NaGly(N-Bn)C8 and SBTI as described in Example A.1.

[0592] A similar procedure as described in Example C1 was used. Summary statistics of PK parameters were expressed as median and arithmetic mean with corresponding standard deviation (SD).

[0593] result

[0594] The following table reports the individual median and mean (SD) calculated PK parameters following oral administration of composition A.1.2 comprising semaglutide, NaGly(N-Bn)C8 and SBTI as described in Example C2:

[0595] The following table reports the individual median and mean (SD) calculated PK parameters following oral administration of semaglutide, NaGly(N-Bn)C8 and SBTI as described in Example A.1.2:

[0596]

[0597] The results show that after oral administration of the composition A.1.2 comprising semaglutide, NaGly(N-Bn)C8 and SBTI described in Example A.1.2, absorption was observed for all individual dogs. For the composition A.1.2 comprising semaglutide, NaGly(N-Bn)C8 and SBTI described in Example A.1.2, the bioavailability of semaglutide ranged from 0.03% to 4.05%, and for the composition A.1.2 comprising semaglutide, NaGly(N-Bn)C8 and SBTI as shown in Example C1. The bioavailability of semaglutide ranged from 0.05% to 16.56%. Based on the median and SD values, In comparison, composition A.1.2 comprising semaglutide, NaGly(N-Bn)C8 and SBTI described in Example A.1.2 showed greater bioavailability (median F(%): 0.44% vs. 0.21%) and lower inter-subject variability (SD: 1.22% vs. 5.16%).

[0598] Example C3: Additional Pharmacokinetic Studies in Beagle Dogs

[0599] Two additional pharmacokinetic studies in beagle dogs according to the same protocol as disclosed above showed that for compositions A.1.3 and A.1.4 (with aprotinin and SFTI as protease inhibitors, respectively), There was a similar trend toward improved exposure and reduced inter-subject variability.

[0600] Section D—In vitro biology

[0601] Example D1: In vitro enzymatic degradation

[0602] In vitro enzymatic degradation studies were performed to evaluate the protective effects of SBTI, NaGly(N-Bn)C8 and their combination against enzymatic degradation.Porcine pancreatic enzymes dissolved in fasting state simulated intestinal fluid (FasSIF, pH=6.5+ / -0.2) were used as a model of intestinal enzymatic degradation.

[0603] Formulations containing semaglutide (50 mg / mL), semaglutide + NaGly (N-Bn) C8, semaglutide + SBTI and semaglutide + SBTI + NaGly (N-Bn) C8 at the relevant API / NaGly (N-Bn) C8 / SBTI ratio. At T = 0 min, pancreatic enzyme (5 U / mL) was added to the formulation to initiate the degradation process by gentle mixing. All samples were incubated at 37 ° C with stirring at 100 rpm. Samples were removed at time intervals of 0 min, 5 min, 15 min, 30 min and 45 min, and the enzyme activity was quenched to enable quantitative determination of the intact peptide remaining in the solution.

[0604] The samples were then analyzed by RP-HPLC with UV detection (lower limit of quantification = 0.7 μg / mL, corresponding to 1.4% of the initial semaglutide concentration).

[0605] result

[0606] The percentage of intact semaglutide (compared to t=0) is reported in the following table:

[0607]

[0608] Semaglutide was rapidly degraded in pancreatic enzymes, as only 13.5% of intact peptide remained after 5 min of incubation, and no intact peptide was detected after 15 min. NaGly(N-Bn)C8 significantly slowed down the degradation kinetics of Semaglutide (45.5% intact peptide was present after 5 min and 1.8% after 15 min).

[0609] SBTI protected semaglutide from pancreatic degradation, as 52.9% of intact peptide was still present after 45 min of incubation. Co-formulation of NaGly(N-Bn)C8 with SBTI significantly affected enzymatic degradation, as more than 95% intact semaglutide was observed after 45 min, indicating the benefit of co-formulation of NaGly(N-Bn)C8 with SBTI in protecting the peptide from enzymatic degradation.

Claims

1. A composition comprising a peptide or protein and an AC-aa-NS having the following general formula I: R3OOC-CHR4-(CH2)n-NR2-COR1 Formula I in - n is an integer selected from 0, 1, 2, 3, 4 and 5, - R1 is an alkyl group containing 5 to 15 carbon atoms, an alkyl group containing 7 to 17 carbon atoms and having a carboxylate functional group or an alkyl group containing 7 to 17 carbon atoms and having an alcohol functional group, -R2 is an alkyl group containing 2 to 8 carbon atoms or -(CH2)m-Aro, wherein m is an integer selected from 1 to 4, Aro is selected from the group consisting of phenyl, naphthyl, anthracenyl, indole, pyridinyl, optionally substituted with an alkyl group containing 1 to 3 carbon atoms, methoxy or halogen, -R4 is the side chain of an amino acid, or -R2 and R4 together form -(CH2)o-Ar-(CH2)p-, -(CH2)o- is attached to the R2 position, and -(CH2)p- is attached to the R4 position, o is 0 or 1, p is 0, 1 or 2, the sum of o+p is 1 or 2, and Ar is phenyl or indolyl, and - R3 is hydrogen, or a cation, in particular selected from sodium and potassium.

2. The composition according to claim 1, characterized in that The composition is a solid composition.

3. A composition according to any one of the preceding claims, characterized in that The composition is an oral composition.

4. A composition according to any one of the preceding claims, characterized in that The AC-aa-NS has a critical micelle concentration, also referred to as CMC, of ​​at least 1 mM in solution in water, in the biologically relevant FASSIF buffer, at pH 6.5 and 25°C.

5. A composition according to any one of the preceding claims, characterized in that The composition comprises other penetration enhancers, specifically SNAC.

6. A composition according to any one of the preceding claims, characterized in that The composition further comprises a protease inhibitor other than AC-aa-NS.

7. A composition according to any one of the preceding claims, characterized in that The composition comprises a lubricant.

8. A composition according to any one of the preceding claims, characterized in that The composition comprises a pH adjuster, specifically a carbonate, more specifically Na2CO3.

9. The composition according to any one of claims 2 to 8, characterized in that The composition comprises a disintegrant, specifically croscarmellose.

10. A composition according to any one of the preceding claims, characterised in that The composition comprises 0.5 to 20 wt % of the peptide or protein.

11. A composition according to any one of the preceding claims, characterized in that The peptide or protein is selected from the group consisting of: GLP-1RA, GLP-2RA, insulin and insulin analogs, amylin RA, GIP RA, PYY RA, dual agonist GIP / glucagon, dual agonist GLP-1 / glucagon, parathyroid hormone (PTH) and PTH analogs, interleukins (IL) and IL analogs, growth hormone (GH) and GH analogs, insulin growth factor (IGF) and IGF analogs, interferon (IFN) and IFN analogs.

12. A composition according to any preceding claim for use as a medicament.

13. The composition according to claim 12, for preventing or treating obesity, type 1 diabetes, type 2 diabetes, NASH, thrombocytopenia, short bowel syndrome (SBS), adult GH deficiency, GH disorders, short stature syndrome, Turner syndrome, achondroplasia, Prader-Willi syndrome, short stature in children, osteoporosis and hypoparathyroidism, multiple sclerosis, bone disorders.

14. A unit solid dosage form comprising a peptide or protein and AC-aa-NS according to formula I: R3OOC-CHR4-(CH2)n-NR2-COR1 Formula I in - n is an integer selected from 0, 1, 2, 3, 4 and 5, - R1 is an alkyl group containing 5 to 15 carbon atoms, an alkyl group containing 7 to 17 carbon atoms and having a carboxylate functional group, or an alkyl group containing 7 to 17 carbon atoms and having an alcohol functional group, -R2 is an alkyl group containing 2 to 8 carbon atoms or -(CH2)m-Aro, wherein m is an integer selected from 1 to 4, Aro is selected from the group consisting of phenyl, naphthyl, anthracenyl, indole, pyridinyl, optionally substituted with an alkyl group containing 1 to 3 carbon atoms, methoxy or halogen, -R4 is the side chain of an amino acid, or -R2 and R4 together form -(CH2)o-Ar-(CH2)p-, -(CH2)o- is attached to the R2 position, and -(CH2)p- is attached to the R4 position, o is 0 or 1, p is 0, 1 or 2, the sum of o+p is 1 or 2, and Ar is phenyl or indolyl, and - R3 is hydrogen, or a cation, in particular selected from sodium and potassium.

15. A compound, designated AC-aa-NS, having Formula I: R3OOC-CHR4-(CH2)n-NR2-COR1 Formula I in - n is an integer selected from 0, 1, 2, 3, 4 and 5, - R1 is an alkyl group containing 5 to 15 carbon atoms, an alkyl group containing 7 to 17 carbon atoms and having a carboxylate functional group, or an alkyl group containing 7 to 17 carbon atoms and having an alcohol functional group, -R2 is an alkyl group containing 2 to 8 carbon atoms or -(CH2)m-Aro, wherein m is an integer selected from 1 to 4, Aro is selected from the group consisting of phenyl, naphthyl, anthracenyl, indole, pyridinyl, optionally substituted with an alkyl group containing 1 to 3 carbon atoms, methoxy or halogen, -R4 is the side chain of an amino acid, or -R2 and R4 together form -(CH2)o-Ar-(CH2)p-, -(CH2)o- is attached to the R2 position, and -(CH2)p- is attached to the R4 position, o is 0 or 1, p is 0, 1 or 2, the sum of o+p is 1 or 2, and Ar is phenyl or indolyl, and - R3 is hydrogen, or a cation, in particular selected from sodium and potassium.

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