Parenteral pharmaceutical compositions of dual glp1 / 2 agonists

Abstract

The present invention relates to pharmaceutical compositions suitable for parenteral administration in human subjects. In particular, the present invention relates to isotonic pharmaceutical compositions for parenteral administration.

Description

[0001] This application claims priority to EP patent application no. 19180233.9, filed on June 14, 2019, the entire contents of which are expressly incorporated herein by reference. Technical Field

[0002] This application relates to pharmaceutical compositions suitable for parenteral administration in human subjects. Therefore, this application relates to isotonic pharmaceutical compositions for parenteral administration. The pharmaceutical compositions according to the invention are particularly stable and have an advantageous shelf life. Background Technology

[0003] Peptides are an important part of the pharmaceutical industry. Despite significant advancements in the production of active pharmaceutical ingredients (APIs), the manufacture of peptide-based pharmaceutical products remains a major challenge. The challenges associated with peptide formulation development are often overlooked or ignored.

[0004] Generally, peptides are defined as polypeptides with fewer than 50 amino residues and typically lack organized tertiary or globular structures. Some employ secondary structures, although this tends to be limited, such as single-turn α-helices. While their smaller size makes them more likely to cross biological barriers than larger proteins, their formulation can be challenging.

[0005] Some formulation challenges involving peptides specifically include: chemical instability; the use of multiple conformational isomers; their tendency to self-associate; and complex physical instabilities such as gel formation, amyloid formation, and / or precipitation.

[0006] The most common challenge is the chemical degradation of peptides and proteins through degradation mechanisms such as deamidation and oxidation. The amino acid sequence of a given peptide defines the extent to which it is affected by deamidation and / or oxidation reactions. The oxidation rate of specific residues, such as Met residues, is related to the degree of solvent exposure. Because peptides do not have a globular structure that can chelate reactive groups, the side chains of almost all residues in a peptide are fully solvent exposed to allow for maximum contact with reactive oxygen species. Deamidation involves the hydrolysis of the amide side chains of amino acid residues, such as Asn and Gln. Furthermore, the high flexibility of peptide chains compared to more complex proteins leads to high deamidation rates. However, it is important to note the properties of the amino acids after deamidation; for example, the properties of the amino acids after Asn also affect the deamidation rate. Peptides lacking spatial volume and the ability to form hydrogen bonds with Asn side chains can even accelerate the reaction. Typically, Asn-Gly, Asn-Ala, Asn-Ser, and Asn-Asp amino acid combinations demonstrate the reaction rates that scientists must consider and test to ensure stable pharmaceutical compositions. Maximum control over hydrolysis reactions, including deamidation, is achieved by stable and reliable pH and buffer systems. However, such a stable and reliable pH and buffer system will be affected by additional excipients added to the composition.

[0007] For comfort during administration, many dosage forms must be isotonic with the fluids at the injection site, such as parenteral, ocular, and nasal solutions. If the formulation is hypertonic or hypotonic, pain and irritation can occur at the application site. Furthermore, isotonic compositions prevent osmotic shock at the injection site. The intrinsic tonicity of each peptide affects the total tonicity, which depends on the total concentration of peptides in the isotonic parenteral drug composition and the level of tonic agent required to achieve tonicity. Tonicity is the "effective osmotic concentration" and is equal to the sum of the concentrations of solutes capable of exerting osmotic force across the membrane. Biological systems are compatible with solutions having similar osmotic pressures, i.e., an equal number of dissolved substances, and this is therefore desirable for parenteral drug products. For example, red blood cells, plasma, and a 0.9% sodium chloride solution contain approximately the same number of solute particles per unit volume and are described as isotonic and isotonic. If a solution does not contain the same number of dissolved substances, i.e., it contains more (hypertonic) or less (hypotonic) dissolved substances, the composition of the solution may subsequently need to be modified to bring it into an acceptable range. A range of nonionic and ionic tonics are available. Nonionic tonics can be selected from dextran, propylene glycol, glycerol, mannitol such as D-mannitol and sorbitol. Ionic tonics may contain alkali metal or earth metal halides, such as CaCl2, KBr, KCl, LiCl, NaI, NaBr, NaCl, or Na2SO4.

[0008] Hypotonicity and hypertonicity can be addressed through the specific selection of excipients and their amounts in the formulation. For example, formulation scientists can increase or decrease the concentration of some components of the formulation to achieve optimal possible chemical or physical stability, as well as shelf life and other desired pharmaceutical product characteristics.

[0009] Excipients are added to parenteral formulations to enhance or maintain the solubility (solvent) and / or stability (buffers, antioxidants, chelating agents, cryoprotectants, and lyophilization protectants) of the active ingredient. Excipients are important in parenteral formulations in many cases to ensure safety (antimicrobial preservatives), minimize post-injection pain and irritation (tension agents), and control or prolong drug delivery (polymers). These are some examples of positive or synergistic interactions between excipients and pharmaceutical products. However, any excipient added to a composition has the potential to have negative effects, such as loss of peptide solubility, activity, and / or chemical / physical stability, increased self-aggregation or fibrillation, which in turn can lead to unsafe administration of the pharmaceutical product.

[0010] Therefore, considering all interactions between excipients and drugs in parenteral formulations, including synergistic and antagonistic interactions, formulation scientists have had to study and optimize all components in pharmaceutical compositions. This invention provides unexpectedly stable pharmaceutical compositions comprising selected peptides.

[0011] This invention relates to pharmaceutical compositions for parenteral administration of selected peptides (e.g., compound 18 of WO2018104561) disclosed in WO2018104561, which describes these compounds and their uses in detail. Example 4 of WO2018104561 provides a test formulation of the disclosed compounds; however, it does not provide any parenteral pharmaceutical compositions (e.g., none of them contain a tonic agent).

[0012] WO2016066818 discloses GLP-1 agonists, GLP-2 agonists and combinations thereof, as well as other GLP-1 / GLP-2 dual agonists and formulations comprising a PBS buffer containing 3% mannitol and 0.6% L-His, suitable for parenteral administration of the disclosed GLP1 / 2 dual agonists.

[0013] WO2013164484 discloses GLP-2 analogues and separately lists a series of tonic agents (i.e. isotonic generating agents) and suitable pH buffers, as well as pH ranges considered suitable for these compounds.

[0014] None of these documents disclose the unexpectedly stable pharmaceutical compositions suitable for parenteral administration according to the present invention. Summary of the Invention

[0015] This application provides a chemically stable parenteral pharmaceutical composition comprising one or more GLP-1 / GLP-2 dual agonists. Therefore, this application provides an isotonic pharmaceutical composition comprising one or more GLP-1 / GLP-2 dual agonists comprising general formula A suitable for parenteral administration to human subjects.

[0016] In some aspects, the present invention provides chemically stable parenteral pharmaceutical compositions comprising one or more GLP-1 / GLP-2 dual agonists, comprising at least about 1 mg / mL of a GLP-1 / GLP-2 dual agonist comprising the following general formula A:

[0017] H[Aib]EG-X5-F-X7-SELATILD-[Ψ]-QAARDFIAVVLI-X28-X29-KITD(A),

[0018] Where X5 is T or S; X7 is T or S; X28 is Q, E, A, H, Y, L, K, R, or S; X29 is H, Y, or Q and at least one of X5 and X7 is T, and [Ψ] represents an L or D lysine residue, wherein the side chain is conjugated with a GLP-1 / GLP-2 dual agonist, and wherein the side chain is selected from the list of the following compositions: K([17-carboxy-heptadecanoyl]-isoGlu), K([17-carboxy-heptadecanoyl]-isoGlu) -KEK-Peg3), K([17-carboxy-heptadecanoyl]-isoGlu-Peg3), K([19-carboxy-nonadecanyl]-isoGlu), K([19-carboxy-nonadecanyl]-isoGlu-KEK), K([19-carboxy-nonadecanyl]-isoGlu-KEK-Peg3), K([19-carboxy-nonadecanyl]-isoGlu-KEK-Peg3-Peg3), K([19-carboxy-nonadecanyl]-isoGlu-KEK-Peg3-Peg3), K([19-carboxy-nonadecanyl]-isoGlu-KEK-Peg3-Peg3) The composition comprises [[19-carboxy-nonadecanyl]-isoGlu-Peg3-Peg3), K([19-carboxy-nonadecanyl]-isoLys-Peg3-Peg3-Peg3), K([hexadecanoyl]-βAla-, K([hexadecanoyl]-isoGlu), or K(octadecanoyl), and wherein the composition further comprises about 20 to 200 mM of a buffer component, or about 5 mM to about 50 mM of a phosphate buffer component, preferably about 10 mM to about 40 mM. M, more preferably about 15 mM to about 30 mM, and most preferably about 20 mM, of a phosphate buffer component; and about 1 to 360 mM of one or more tensioning agents, preferably about 150 to 250 mM, wherein the one or more tensioning agents are ionic or nonionic tensioning agents, wherein the ionic tensioning agent is selected from salts, alkali metals or earth metal halides, and the nonionic tensioning agent is mannitol, such as D-mannitol, and wherein the pH of the composition is about pH 7.0 to about pH 8.2.

[0019] In some aspects, specific and particular isotonic parenteral compositions are described in detail in the specification of the invention and in non-limiting aspects of the numbers included in the specification of the invention.

[0020] The chemical stability of the GLP-1 / GLP-2 dual agonist in any test composition disclosed herein at time point Y can be expressed as the relative purity X of the GLP-1 / GLP-2 dual agonist. Y This is indicated by measuring the absolute purity X' of the GLP-1 / GLP-2 dual agonist and comparing it with the absolute purity X' of the GLP-1 / GLP-2 dual agonist on day zero (day 0). 0The absolute purity is determined by normalization, wherein the purity is determined by HPLC at a given time point Y by identifying the purity of the peak corresponding to the GLP-1 / GLP-2 dual agonist.

[0021] Unexpectedly, when combined with the buffer L-histidine, the GLP-1 / GLP-2 dual agonist disclosed in parenteral drug compositions containing mannitol as a nonionic tonic agent exhibits stable and high chemical stability compared to drug compositions containing other tonic agents (e.g., sucrose, dextran, glycerol, propylene glycol, and mannitol).

[0022] Unexpectedly, the GLP-1 / GLP-2 dual agonist disclosed in parenteral pharmaceutical compositions containing ionic tonics such as NaCl exhibits chemical stability that is at least as good (i.e. comparable) to pharmaceutical compositions that do not contain any tonics, and higher normalized stability than compositions containing other tonics such as sucrose, dextrose, and glycerol. Detailed Implementation

[0023] In some aspects of the invention, a chemically stable parenteral composition comprising one or more GLP-1 / GLP-2 dual agonists is provided, comprising at least about 1 mg / mL of a GLP-1 / GLP-2 dual agonist comprising the following general formula A:

[0024] H[Aib]EG-X5-F-X7-SELATILD-[Ψ]-QAARDFIAVVLI-X28-X29-KITD(A),

[0025] Wherein X5 is T or S; X7 is T or S; X28 is Q, E, A, H, Y, L, K, R, or S; X29 is H, Y, or Q and at least one of X5 and X7 is T, and wherein [Ψ] represents an L or D lysine residue, wherein the side chain is conjugated to a GLP-1 / GLP-2 dual agonist, and wherein the side chain is [K([17-carboxy-heptadecanoyl]-isoGlu)], and wherein the composition further comprises about 20 to 200 mM of a buffer. The composition comprises, or about 5 mM to about 50 mM of a phosphate buffer component, preferably about 10 mM to about 40 mM, more preferably about 15 mM to about 30 mM, and most preferably about 20 mM of a phosphate buffer component; and about 1 to 360 mM of one or more extensants, preferably about 150 to 250 mM of one or more extensants, wherein the one or more extensants are nonionic extensants such as mannitol, and wherein the pH of the composition is about pH 7.0 to about pH 8.2.

[0026] In a preferred aspect, the present invention provides an isotonic parenteral pharmaceutical composition comprising:

[0027] a. At least about 1 mg / mL of one or more GLP-1 / GLP-2 dual agonists containing general formula A:

[0028] H[Aib]EG-X5-F-X7-SELATILD-[ψ]-QAARDFIAVVLI-X28-X29-KITD(A),

[0029] Where X5 is T or S; X7 is T or S; X28 is Q, E, A, H, Y, L, K, R, or S; X29 is H and at least one of X5 and X7 is T, and

[0030] Where [Ψ] represents an L or D lysine residue, the albumin-binding portion of which is conjugated to a dual GLP-1 / GLP-2 agonist, and

[0031] The albumin-binding moiety is [K([17-carboxy-heptadecanoyl]-isoGlu)]; and

[0032] b. A phosphate buffer component of about 5 mM to about 50 mM, preferably about 10 mM to about 40 mM, more preferably about 15 mM to about 30 mM, and most preferably about 20 mM; and

[0033] c. One or more tension agents, ranging from about 190 mM to about 240 mM.

[0034] The one or more tension agents are nonionic tension agents, and the nonionic tension agent is mannitol.

[0035] The composition further comprises a solvent, and

[0036] The pH of the composition is from about pH 6.0 to about pH 8.2, preferably from about pH 7.0 to about pH 8.0.

[0037] In some aspects, the present invention provides chemically stable parenteral compositions comprising one or more GLP-1 / GLP-2 dual agonists, comprising at least about 1 mg / mL of a GLP-1 / GLP-2 dual agonist comprising the following general formula A:

[0038] H[Aib]EG-X5-F-X7-SELATILD-[Ψ]-QAARDFIAVVLI-X28-X29-KITD(A),

[0039] Wherein X5 is T or S; X7 is T or S; X28 is Q, E, A, H, Y, L, K, R, or S; X29 is H, Y, or Q and at least one of X5 and X7 is T, and wherein [Ψ] represents an L or D lysine residue, wherein the side chain is conjugated with a GLP-1 / GLP-2 dual agonist, and wherein the side chain is [K([17-carboxy-heptadecanoyl]-isoGlu)], and wherein the composition further comprises about 20 to 200 mM of a buffer component and about 1 to 360 mM of one or more extensors, preferably about 150 to 250 mM of one or more extensors, wherein the one or more extensors are ionic extensors selected from salts, alkali metals, or earth metal halides, and wherein the pH of the composition is about pH 7.0 to about pH 8.2.

[0040] In some aspects, the present invention provides chemically stable parenteral compositions comprising one or more GLP-1 / GLP-2 dual agonists, comprising at least about 1 mg / mL of a GLP-1 / GLP-2 dual agonist comprising the following general formula A:

[0041] H[Aib]EG-X5-F-X7-SELATILD-[Ψ]-QAARDFIAVVLI-X28-X29-KITD(A),

[0042] Wherein X5 is T or S; X7 is T or S; X28 is Q, E, A, H, Y, L, K, R, or S; X29 is H, Y, or Q and at least one of X5 and X7 is T, and wherein [Ψ] represents an L or D lysine residue, wherein the side chain is conjugated with a GLP-1 / GLP-2 dual agonist, and wherein the side chain is [K([17-carboxy-heptadecanoyl]-isoGlu)], and wherein the composition further comprises about 20 to 200 mM of a buffer component and about 1 to 360 mM of one or more extensors, preferably about 150 to 250 mM of one or more extensors, wherein the one or more extensors are ionic extensors selected from CaCl2, KBr, KCl, LiCl, NaI, NaBr, NaCl, Na2SO4, preferably NaCl or KCl, and wherein the pH of the composition is about pH 7.0 to about pH 8.2.

[0043] In some aspects, the chemical stability of one or more GLP-1 / GLP-2 dual agonists contained in the isotonic parenteral pharmaceutical compositions of the present invention is expressed as the relative purity of the GLP-1 / GLP-2 dual agonist peak (i.e., the main peak), which is determined by HPLC at a given time point and normalized relative to the absolute purity of the GLP-1 / GLP-2 dual agonist peak (i.e., the main peak) at time zero, set to 100%. Therefore, at time zero, the chemical stability of the GLP-1 / GLP-2 dual agonist in the isotonic parenteral pharmaceutical compositions of the present invention is 100%.

[0044] Unexpectedly, it was found that, when combined with the buffer L-histidine, the chemical stability of the one or more GLP-1 / GLP-2 dual agonists contained in one or more parenteral pharmaceutical compositions of the present invention, as disclosed in some aspects of the invention, is stable and high compared to pharmaceutical compositions containing other tonic agents (e.g., sucrose, dextran, glycerol, propylene glycol, and mannitol).

[0045] Unexpectedly, it was found that when combined with the buffer L-histidine, the chemical stability of the one or more GLP-1 / GLP-2 dual agonists contained in one or more parenteral pharmaceutical compositions of the present invention, as disclosed in some aspects of the invention, wherein mannitol (e.g., D-mannitol) is selected as the tensioning agent, is stable and higher than that of pharmaceutical compositions containing other tensioning agents (e.g., sucrose, dextran, glycerol, propylene glycol, and mannitol).

[0046] Unexpectedly, it was found that the chemical stability of the one or more GLP-1 / GLP-2 dual agonists contained in one or more parenteral pharmaceutical compositions of the present invention, which contain salts (e.g., NaCl) as tonic agents, is at least as good (i.e. comparable) as that of pharmaceutical compositions that do not contain any tonic agents, and is higher than that of compositions containing other tonic agents (e.g., sucrose, dextrose, and glycerol).

[0047] compound

[0048] In some aspects, the GLP-1 / GLP-2 dual agonist comprising general formula A has the following general formula B:

[0049] H[Aib]EG-X5-FT-SELATILD-[Ψ]-QAARDFIAVVLI-X28-HKITD(B),

[0050] Where X5 is T or S; X28 is Q, E, A, H, Y, L, K, R or S, and [Ψ] represents an L or D lysine residue, wherein the side chain is conjugated with a GLP-1 / GLP-2 dual agonist, and wherein the side chain is [K([17-carboxy-heptadecanoyl]-isoGlu)].

[0051] In some aspects, the one or more GLP-1 / GLP-2 dual agonists of formula A contained in one or more parenteral pharmaceutical compositions of the present invention are:

[0052] H[Aib]EGSFFTSELATILD[Ψ]QAARDFIAVVLIQHKITD (SEQ ID NO: 1).

[0053] In some aspects, the one or more GLP-1 / GLP-2 dual agonists of formula A contained in one or more parenteral pharmaceutical compositions of the present invention are:

[0054] Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAVVLIQHKITD-OH(CPD1OH),

[0055] Or any of its medicinal salts.

[0056] In some aspects, the one or more GLP-1 / GLP-2 dual agonists of formula A contained in one or more parenteral pharmaceutical compositions of the present invention are:

[0057] Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAVVLIQHKITD-NH2(CPD1NH2),

[0058] Or any of its medicinal salts.

[0059] In some aspects, the one or more GLP-1 / GLP-2 dual agonists of formula A included in one or more parenteral pharmaceutical compositions of the present invention are CPD1OH or any pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutically acceptable salt of CPD1OH is a chloride salt.

[0060] In some aspects, the one or more GLP-1 / GLP-2 dual agonists of formula A included in one or more parenteral pharmaceutical compositions of the present invention are CPD1NH2 or any pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutically acceptable salt of CPD1NH2 is a chloride salt.

[0061] In a preferred aspect, the one or more GLP-1 / GLP-2 dual agonists is CPD1OH or any pharmaceutically acceptable salt thereof, preferably its chloride salt.

[0062] Table 1 - Selected GLP-1 / GLP-2 dual components included in one or more parenteral compositions of the present invention agonists

[0063]

[0064] Therefore, the abbreviation CPD1 refers to any form of the compound containing SEQ ID NO: 1; however, CPD1OH only discloses compounds containing SEQ ID NO: 1, wherein the compound is in its -OH form (free acid). CPD1 NH2 Form refers to - NH2 Compounds in the amidated form. CPD1OH and CPD1 NH2 Both can be converted into medicinal salts to provide pharmaceutical substances in powder form.

[0065] Table 2 - Amino acid sequences contained in one or more GLP-1 / GLP-2 dual agonists of the present invention

[0066]

[0067] Tension and tension agents

[0068] In some aspects, the isotonic parenteral pharmaceutical compositions of the present invention comprising one or more GLP-1 / GLP-2 dual agonists of formula A or B are isotonic. In some embodiments, the osmolality of the composition as described herein is about 300 ± 120 mOsmol / kg. In some embodiments, the osmolality of the composition as described herein is about 290 ± 70 mOsmol / kg. In some embodiments, the osmolality of the composition as described herein is about 280 mOsmol / kg to about 320 mOsmol / kg. In some embodiments, the osmolality of the composition as described herein is about 290 mOsmol / kg to about 320 mOsmol / kg.

[0069] In some aspects, the isotonic parenteral pharmaceutical compositions of the present invention comprising one or more GLP-1 / GLP-2 dual agonists containing SEQ ID NO: 1 are isotonic.

[0070] In some aspects, the one or more tension agents contained in the parenteral pharmaceutical compositions of the present invention are nonionic tension agents, such as mannitol, for example, D-mannitol.

[0071] In some aspects, the one or more tonic agents included in one or more parenteral pharmaceutical compositions of the present invention are ionic tonic agents, such as salts, alkali metals, or earth metal halides. In some aspects, the ionic tonic agent is selected from the list of the following compositions: CaCl2, KBr, KCl, LiCl, NaI, NaBr, NaCl, or Na2SO4. In some aspects, the one or more tonic agents included in one or more parenteral pharmaceutical compositions of the present invention are ionic tonic agents, which are salts, such as NaCl. In some aspects, the one or more tonic agents included in one or more parenteral pharmaceutical compositions of the present invention are ionic tonic agents, which are salts, such as KCl.

[0072] In some aspects, the one or more tension agents contained in one or more parenteral pharmaceutical compositions of the present invention are mixtures of ionic and nonionic tension agents, such as a mixture of salt and mannitol (e.g., D-mannitol).

[0073] In a preferred aspect of the invention, the tensioning agent comprises mannitol, preferably D-mannitol.

[0074] In a preferred aspect of the invention, the tension agent is composed of mannitol, preferably D-mannitol.

[0075] In a preferred aspect of the invention, the tensioning agent is mannitol, preferably D-mannitol.

[0076] In some aspects, the one or more tonic agents included in one or more parenteral drug compositions of the present invention are mannitol, such as D-mannitol, and are present in the isotonic parenteral drug composition at a final concentration of about 150 mM to about 360 mM. In some aspects, the one or more tonic agents included in one or more parenteral drug compositions of the present invention are mannitol, such as D-mannitol, and are present in the isotonic parenteral drug composition at a final concentration of about 150 mM to about 300 mM. In some aspects, the one or more tonic agents included in one or more parenteral drug compositions of the present invention are mannitol, such as D-mannitol, and are present in the isotonic parenteral drug composition at a final concentration of about 150 mM to about 250 mM. In some aspects, the one or more tonic agents included in one or more parenteral drug compositions of the present invention are mannitol, such as D-mannitol, and are present in the isotonic parenteral drug composition at a final concentration of about 210 mM to about 240 mM. In some aspects, the one or more tonic agents included in one or more parenteral drug compositions of the present invention are mannitol, such as D-mannitol, and are present in the isotonic parenteral drug composition at a final concentration of about 210 mM to about 230 mM. In some aspects, the one or more tonic agents included in one or more parenteral drug compositions of the present invention are mannitol, such as D-mannitol, and are present in the isotonic parenteral drug composition at a final concentration of about 360 mM. In some aspects, the one or more tonic agents included in one or more parenteral drug compositions of the present invention are mannitol, such as D-mannitol, and are present in the isotonic parenteral drug composition at a final concentration of about 300 mM. In some aspects, the one or more tonic agents included in one or more parenteral drug compositions of the present invention are mannitol, such as D-mannitol, and are present in the isotonic parenteral drug composition at a final concentration of about 250 mM. In some aspects, the one or more tension agents included in one or more parenteral pharmaceutical compositions of the present invention are mannitol, such as D-mannitol, and are present in the isotonic parenteral pharmaceutical composition at a final concentration of about 230 mM.

[0077] In a preferred aspect, mannitol is present in the isotonic parenteral pharmaceutical composition at a final concentration of about 190 mM to about 240 mM, preferably about 230 mM. Preferably, the mannitol is D-mannitol.

[0078] In some aspects, the one or more tonic agents included in one or more parenteral drug compositions of the present invention are NaCl or KCl, and are present in the isotonic parenteral drug composition at a final concentration of about 50 mM to about 250 mM. In some aspects, the one or more tonic agents included in one or more parenteral drug compositions of the present invention are NaCl or KCl, and are present in the isotonic parenteral drug composition at a final concentration of about 150 mM to about 200 mM. In some aspects, the one or more tonic agents included in one or more parenteral drug compositions of the present invention are NaCl or KCl, and are present in the isotonic parenteral drug composition at a final concentration of about 200 mM to about 250 mM.

[0079] buffer

[0080] In some respects, the buffer component is selected from phosphate buffers, citrate buffers, histidine buffers, or tris buffers, or combinations thereof.

[0081] In some respects, the buffer component is selected from phosphate buffers, citrate buffers, or tris buffers, or combinations thereof.

[0082] In some respects, the buffer component may be selected from phosphate buffers, tris buffers, or combinations thereof.

[0083] In some aspects, the buffer component included in one or more parenteral pharmaceutical compositions of the present invention is a phosphate buffer. In some aspects, the buffer component included in one or more parenteral pharmaceutical compositions of the present invention is a sodium phosphate buffer.

[0084] In some aspects, the buffer component included in one or more parenteral pharmaceutical compositions of the present invention is a phosphate buffer. In some aspects, the buffer component included in one or more parenteral pharmaceutical compositions of the present invention is a sodium phosphate buffer, such as Na₂HPO₄.

[0085] In some aspects, the buffer component included in one or more parenteral pharmaceutical compositions of the present invention is a phosphate buffer, and said phosphate buffer is present in the isotonic parenteral pharmaceutical composition at a final concentration of about 1 mM to about 200 mM, for example about 15 mM to about 200 mM, or about 15 mM to about 15 to 25 mM. The final concentration may be from about 2 mM to about 190 mM, from about 3 mM to about 180 mM, from about 4 mM to about 170 mM, from about 5 mM to about 160 mM, from about 6 mM to about 150 mM, from about 7 mM to about 140 mM, from about 8 mM to about 140 mM, from about 9 mM to about 130 mM, from about 10 mM to about 120 mM, from about 11 mM to about 100 mM, from about 12 mM to about 80 mM, from about 13 mM to about 60 mM, from about 14 mM to about 40 mM, from about 15 mM to about 30 mM, from about 16 mM to about 27 mM, from about 17 mM to about 25 mM, or from about 18 mM to about 23 mM. In some aspects, the buffer component included in one or more parenteral pharmaceutical compositions of the present invention is a phosphate buffer and wherein the phosphate buffer is present in the isotonic parenteral pharmaceutical composition at a final concentration of about 20 mM. In some aspects, the buffer component included in one or more parenteral pharmaceutical compositions of the present invention is a phosphate buffer, and wherein the phosphate buffer is present in the isotonic parenteral pharmaceutical composition at a final concentration of about 100 mM.

[0086] In a preferred aspect, the phosphate buffer is present in the isotonic parenteral pharmaceutical composition at a final concentration of about 15 mM to about 30 mM.

[0087] Preferably, the phosphate buffer is present in the isotonic parenteral drug composition at a final concentration of about 5 mM to about 50 mM, more preferably about 10 mM to about 40 mM, more preferably about 15 mM to about 30 mM, and most preferably about 20 mM.

[0088] In a preferred aspect, the buffer is a phosphate buffer, preferably a sodium phosphate buffer, and more preferably disodium phosphate, sodium dihydrogen phosphate, or a combination thereof.

[0089] In one aspect, disodium phosphate is present in the isotonic parenteral pharmaceutical composition at a final concentration of about 15 mM to about 19 mM, preferably 18 mM to 19 mM.

[0090] In one aspect, sodium dihydrogen phosphate is present in the isotonic parenteral pharmaceutical composition at a final concentration of about 1 mM to about 3 mM, preferably 1 mM to 2 mM.

[0091] In one aspect, the final concentration of the disodium phosphate and sodium dihydrogen phosphate buffer components together is about 5 mM to about 50 mM, preferably about 10 mM to about 40 mM, more preferably about 15 mM to about 30 mM.

[0092] In one of the most preferred aspects, the final concentration of the disodium phosphate and sodium dihydrogen phosphate buffer components together is about 20 mM.

[0093] In some respects, the buffer is not a histidine buffer and / or does not contain histidine, such as L-histidine.

[0094] In some aspects, the pH of the isotonic parenteral pharmaceutical composition of the present invention is from about pH 6.0 to about pH 8.2, preferably from about pH 7.0 to about pH 8.0. In some aspects, the pH of the isotonic parenteral pharmaceutical composition of the present invention is from about pH 7.0 to about pH 8.0. In some aspects, the pH of the isotonic parenteral pharmaceutical composition of the present invention is about pH 7.0. In some aspects, the pH of the isotonic parenteral pharmaceutical composition of the present invention is about pH 8.0. In some aspects, the pH of the isotonic parenteral pharmaceutical composition of the present invention is about pH 8.2. In some aspects, the pH of the isotonic parenteral pharmaceutical composition of the present invention is about pH 6.0. In some aspects, the pH of the isotonic parenteral pharmaceutical composition of the present invention is from about pH 7.0 to about pH 8.2, preferably about pH 7.5 or about pH 8.2. In some aspects, the pH of the isotonic parenteral pharmaceutical composition of the present invention is from about pH 7.0 to about pH 8.2, preferably about pH 7.6 or about 8.0. In some aspects, the pH of the isotonic parenteral pharmaceutical composition of the present invention is from about pH 7.0 to about pH 8.2, preferably about pH 7.6 or about pH 7.7. In some aspects, the pH of the isotonic parenteral pharmaceutical composition of the present invention is from about pH 7.0 to about pH 8.2, preferably about pH 7.6. In some aspects, the pH of the isotonic parenteral pharmaceutical composition of the present invention is from about pH 7.0 to about pH 8.2, preferably about pH 8.0. In some aspects, the pH of the isotonic parenteral pharmaceutical composition of the present invention is from about pH 7.0 to about pH 8.2, preferably about pH 7.0.

[0095] In a preferred aspect, the pH is approximately pH 8.0.

[0096] In some aspects, in the isotonic parenteral pharmaceutical composition of the present invention, the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists comprise the amino acid sequence of formula A, wherein the pH is about pH 7.0 to about pH 8.0, preferably about pH 8.0. In some aspects, in the isotonic parenteral pharmaceutical composition of the present invention, the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists comprise an amino acid sequence of formula B, wherein the pH is about pH 7.0 to about pH 8.0, preferably about pH 8.0.

[0097] In some aspects, in the isotonic parenteral pharmaceutical composition of the present invention, the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists comprise the amino acid sequence of SEQ ID NO: 1, wherein the pH is about pH 7.0 to about pH 8.0, preferably about pH 8.0.

[0098] In some aspects, in the isotonic parenteral pharmaceutical composition of the present invention, the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists are CPD1OH, wherein the pH is about pH 7.0 to about pH 8.0, preferably about pH 8.0.

[0099] In some aspects, in the isotonic parenteral pharmaceutical composition of the present invention, the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists are salts of CPD1, wherein the pH is about pH 7.0 to about pH 8.0, preferably about pH 8.0.

[0100] In some aspects, in the isotonic parenteral pharmaceutical composition of the present invention, the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists are chloride salts of CPD1, wherein the pH is about pH 7.0 to about pH 8.0, preferably about pH 8.0.

[0101] In some aspects, in the isotonic parenteral pharmaceutical compositions of the present invention, the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM; the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM; and the one or more GLP-1 / GLP-2 dual agonists are CPD1NH2, wherein the pH is about pH 7.0 to about pH 8.0, preferably about pH 8.0. In some aspects, the compositions of the present invention comprise the following ingredients:

[0102]

[0103]

[0104] CPD1 is a medicinal salt of CPD1.

[0105] In some aspects, the compositions of the present invention comprise the following components:

[0106]

[0107] CPD1 is a medicinal salt of CPD1.

[0108] concentration of compound

[0109] In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises at least about 1 mg / mL to about 15 mg / mL of a GLP-1 / GLP-2 dual agonist. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises at least about 1 mg / mL of a GLP-1 / GLP-2 dual agonist. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises at least about 2 mg / mL of a GLP-1 / GLP-2 dual agonist. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 2 mg / mL of a GLP-1 / GLP-2 dual agonist.

[0110] In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 2 mg / mL of a GLP-1 / GLP-2 dual agonist, and said one or more GLP-1 / GLP-2 dual agonists are composed of formula A. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 2 mg / mL to about 10 mg / mL of a GLP-1 / GLP-2 dual agonist. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 2 mg / mL to about 10 mg / mL of a GLP-1 / GLP-2 dual agonist, and said one or more GLP-1 / GLP-2 dual agonists are composed of formula A. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 10 mg / mL of a GLP-1 / GLP-2 dual agonist. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 10 mg / mL of a GLP-1 / GLP-2 dual agonist, and said one or more GLP-1 / GLP-2 dual agonists are composed of formula A.

[0111] In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 2 mg / mL of a GLP-1 / GLP-2 dual agonist, and said one or more GLP-1 / GLP-2 dual agonists are composed of formula B. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 2 mg / mL to about 10 mg / mL of a GLP-1 / GLP-2 dual agonist. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 2 mg / mL to about 10 mg / mL of a GLP-1 / GLP-2 dual agonist, and said one or more GLP-1 / GLP-2 dual agonists are composed of formula B. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 10 mg / mL of a GLP-1 / GLP-2 dual agonist. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 10 mg / mL of a GLP-1 / GLP-2 dual agonist, and said one or more GLP-1 / GLP-2 dual agonists are composed of formula B.

[0112] In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 2 mg / mL of a GLP-1 / GLP-2 dual agonist, and said one or more GLP-1 / GLP-2 dual agonists is CPDIOH. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 2 mg / mL to about 10 mg / mL of a GLP-1 / GLP-2 dual agonist. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 2 mg / mL to about 10 mg / mL of a GLP-1 / GLP-2 dual agonist, and said one or more GLP-1 / GLP-2 dual agonists is CPD1OH. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 10 mg / mL of a GLP-1 / GLP-2 dual agonist. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 10 mg / mL of a GLP-1 / GLP-2 dual agonist, and said one or more GLP-1 / GLP-2 dual agonists is CPD1OH.

[0113] In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 2 mg / mL of a GLP-1 / GLP-2 dual agonist, and said one or more GLP-1 / GLP-2 dual agonists is CPD1NH2. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 2 mg / mL to about 10 mg / mL of a GLP-1 / GLP-2 dual agonist. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 2 mg / mL to about 10 mg / mL of a GLP-1 / GLP-2 dual agonist, and said one or more GLP-1 / GLP-2 dual agonists is CPD1NH2. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 10 mg / mL of a GLP-1 / GLP-2 dual agonist. In some aspects, the isotonic parenteral pharmaceutical composition of the present invention comprises about 10 mg / mL of a GLP-1 / GLP-2 dual agonist, and said one or more GLP-1 / GLP-2 dual agonists is CPD1NH2.

[0114] In a preferred aspect, the isotonic parenteral pharmaceutical composition of the present invention comprises about 2 mg / mL to about 10 mg / mL of a dual GLP-1 / GLP-2 agonist.

[0115] preservative

[0116] In some respects, isotonic parenteral drug compositions do not contain preservatives.

[0117] In some respects, isotonic parenteral drug compositions contain preservatives.

[0118] Indications

[0119] In some aspects, the pharmaceutical compositions of the present invention are applied to persons who require prevention or treatment of intestinal damage and dysfunction, weight regulation, and prevention or treatment of metabolic dysfunction.

[0120] In some aspects, the pharmaceutical compositions of the present invention are applied to persons who require prevention or treatment of malabsorption, ulcers (e.g., peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, and ulcers associated with infection or other pathogens), short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), irritable bowel syndrome (IBS), pouchitis, and abdominal spermia. Gastrointestinal side effects of sprue (e.g., gluten-induced enteropathy or celiac disease), tropical sprue diarrhea, hypogammaglobulinemic sprue diarrhea, mucositis induced by chemotherapy or radiation therapy, diarrhea induced by chemotherapy or radiation therapy, low-grade inflammation, metabolic endotoxemia, necrotizing enterocolitis, primary biliary cirrhosis, hepatitis, fatty liver disease (including parenteral nutrition-associated intestinal atrophy, PNALD, NAFLD, and NASH), or inflammatory conditions (e.g., pancreatitis) or graft-versus-host disease (GVHD).

[0121] In some aspects, the pharmaceutical compositions of the present invention are applied to persons who require prevention or treatment of the following: obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, inadequate glucose control, glucose tolerance, dyslipidemia (e.g., elevated LDL levels or decreased HDL / LDL ratio), diabetes (e.g., type 2 diabetes, gestational diabetes), prediabetes, metabolic syndrome, or hypertension.

[0122] In some aspects, the pharmaceutical compositions of the present invention are applied to human subjects to promote biological effects selected from the following in subjects in need: improved intestinal quality, improved intestinal function (especially intestinal barrier function), increased intestinal blood flow, and repair of intestinal damage or dysfunction.

[0123] In some aspects, the pharmaceutical compositions of the present invention are applied to human subjects who require prevention or treatment of bowel dysfunction or damage caused by or related to GVHD, and prevention or treatment of side effects caused by or related to GVHD, such as diarrhea.

[0124] In some aspects, the pharmaceutical compositions of the present invention are applied to persons who require prevention or treatment of obesity, morbid obesity, obesity-related gallbladder disease, and obesity-induced sleep apnea.

[0125] In some aspects, the pharmaceutical compositions of the present invention are administered to human subjects who require improved glucose tolerance and / or glucose control. In some aspects, the pharmaceutical compositions of the present invention are administered to human subjects who require regulation (e.g., improvement) of circulating cholesterol levels, reduction of circulating triglyceride or LDL levels, and improvement of the HDL / LDL ratio.

[0126] application

[0127] In some aspects, the pharmaceutical compositions of the present invention are aqueous compositions. In some aspects, the pharmaceutical compositions of the present invention are suitable for parenteral administration by subcutaneous, intramuscular, or intravenous injection using a syringe, optionally a pen-type syringe. In some aspects, the pharmaceutical compositions of the present invention are suitable for subcutaneous or intravenous injection into a patient.

[0128] In some aspects, the isotonic parenteral drug compositions of the present invention are suitable for single-dose administration. In some aspects, the isotonic parenteral drug compositions of the present invention, containing preservatives, are suitable for multiple-dose administration.

[0129] Features

[0130] All chemical stabilityes mentioned below in this section can be measured and determined by HPLC, such as RP-HPLC, according to Determination III or other equivalent methods.

[0131] In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 100% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) on day 3 (D3). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 99% or higher for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) on day 3 (D3). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 99% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) on day 3 (D3).

[0132] In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 99% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) on day 7 (D7). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 98% or higher for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) on day 7 (D7). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 98% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) on day 7 (D7). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 97.5% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) on day 7 (D7).

[0133] In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 98% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) on day 14 (D14). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 97% or higher for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) on day 14 (D14). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 96% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) on day 14 (D14). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 96.5% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) on day 14 (D14).

[0134] In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 97% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) on day 24 (D24). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 96% or higher for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) on day 24 (D24). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 96% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) on day 24 (D24). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 95.5% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) on day 24 (D24).

[0135] In any aspect, the isotonic parenteral pharmaceutical compositions of the present invention do not result in the chemical stability of the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) being less than 94.5% on day 24 (D24). In any aspect, the isotonic parenteral pharmaceutical compositions of the present invention do not result in the chemical stability of the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) being less than 60% on day 24 (D24). In any aspect, the isotonic parenteral pharmaceutical compositions of the present invention do not result in the chemical stability of the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) being less than 50% on day 24 (D24).

[0136] In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 100% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) in the first month (M1). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 99% or higher for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) in the first month (M1). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 99% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) in the first month (M1).

[0137] In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 100% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) at month 2 (M2). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 99% or higher for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) at month 2 (M2). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 99% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) at month 2 (M2).

[0138] In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 100% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) at month 3 (M3). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 98% or 99% or higher for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) at month 3 (M3). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 98% or 99% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) at month 3 (M3).

[0139] In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 100% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) at month 4 (M4). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 99% or higher for the one or more GLP-1 / GLP-2 dual agonists at month 4 (M4). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 99% for the one or more GLP-1 / GLP-2 dual agonists at month 4 (M4).

[0140] In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 100% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) at 6 months (M6). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 94% or 96% or higher for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) at 6 months (M6). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 94% or 96% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) at 6 months (M6).

[0141] In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 100% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) at month 9 (M9). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 94% or higher for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) at month 9 (M9). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 94% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) at month 9 (M9).

[0142] In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 97% or 98% or more for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) at 12 months (M12). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 91% or 94% or higher for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPDI or any pharmaceutically acceptable salt thereof) at 12 months (M12). In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 91% or 94% for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) at 12 months (M12).

[0143] In some aspects, the pharmaceutical compositions of the present invention result in a chemical stability of about 98% or 99% or more for the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) at 24 months (M24). This chemical stability may be achieved at a storage temperature of about 5°C or about 25°C, preferably 5°C.

[0144] In a preferred aspect, the chemical stability is about 91% or higher after 12 months. Preferably, the chemical stability is about 97% or 98% after 12 months at a storage temperature of about 5°C.

[0145] In a preferred aspect, the chemical stability is about 91% or higher after 12 months. Preferably, the chemical stability is about 91% or 94% after 12 months at a storage temperature of about 25°C.

[0146] In a preferred aspect, the chemical stability is about 98% or higher after 24 months. Preferably, the chemical stability is about 98% or 99% after 24 months at a storage temperature of about 5°C.

[0147] In some embodiments, the isotonic parenteral drug composition described herein causes the one or more GLP-1 / GLP-2 dual agonists (e.g., CPD1 or any pharmaceutically acceptable salt thereof) to be primarily in their trimer form.

[0148] In some embodiments, the isotonic parenteral drug compositions described herein exhibit good or improved stability. Stability can be improved relative to equivalent compositions that do not contain mannitol as a tonic agent.

[0149] In some embodiments, the isotonic parenteral drug compositions described herein have good or improved chemical stability. Chemical stability can be improved relative to equivalent compositions that do not contain mannitol as a tonic agent.

[0150] In some embodiments, the isotonic parenteral drug compositions described herein have good or improved relative purity. The relative purity can be improved relative to equivalent compositions that do not contain mannitol as a tonic agent.

[0151] In some embodiments, the isotonic parenteral drug compositions described herein have physical stability.

[0152] In one aspect, the present invention provides a method for improving the stability, chemical stability, relative purity, and / or physical stability of pharmaceutical compositions comprising any of the GLP-1 / GLP-2 dual agonists described herein, wherein the method comprises adding mannitol, preferably D-mannitol, to the composition as a tonic agent as described herein. The composition may also comprise any of the buffering components described herein. The composition may also comprise any of the pH adjusters and / or solvents described herein.

[0153] The present invention also provides the use of mannitol, preferably D-mannitol, as described herein, for improving the stability, chemical stability, relative purity, and / or physical stability of compositions comprising any of the GLP-1 / GLP-2 dual agonists described herein. The composition may also contain any of the buffer components described herein. The composition may also contain any of the pH adjusters and / or solvents described herein.

[0154] The improvement can be achieved by using D-mannitol as a tensioning agent, rather than in compositions that do not contain mannitol.

[0155] Bioactivity

[0156] In some aspects, the peptides included in the pharmaceutical compositions of the present invention are peptides of formula A and SEQ ID NO: 1 previously described in patent application WO2018104561, which describes the compounds, their preparation and purification, and their biological activities (Table 5, WO2018104561). Example 2 in WO2018104561 contains data on the in vitro potency of GLP-1 and GLP-2 receptors, and Examples 3 and 4 relate to the solubility and stability of the compounds.

[0157] Synthesis of dual agonists

[0158] The dual agonists of the present invention are preferably synthesized via solid-phase or liquid-phase peptide synthesis methods. In this context, reference can be made to WO 98 / 11125 and, in particular, Fields, GB.gt al., 2002, "Principles and practice of solid-phase peptide synthesis". In: Synthetic Peptides (2nd edition), and the examples herein. According to the present invention, the dual agonists can be synthesized or produced in a variety of ways, including, for example, methods comprising:

[0159] (a) synthesizing a dual agonist by a solid-phase or liquid-phase peptide synthesis method and recovering the synthesized dual agonist therefrom; or (b) expressing a precursor peptide sequence from a nucleic acid construct encoding a precursor peptide, recovering the expression product, and modifying the precursor peptide to produce the compound of the present invention.

[0160] Precursor peptides can be modified by introducing one or more non-proteinogenic amino acids (e.g., Aib, Orn, Dap, or Dab), introducing an albumin-binding moiety, or introducing appropriate terminal groups such as -OH or -NH2.

[0161] Expression is typically carried out by a nucleic acid encoding the precursor peptide, and the expression can be performed in a cell- or cell-free expression system containing such a nucleic acid.

[0162] Chemical stability

[0163] The isotonic parenteral pharmaceutical compositions of the present invention provide good or improved chemical stability.

[0164] The chemical stability of the GLP-1 / GLP-2 dual agonist in any test composition disclosed herein at time point Y can be expressed as the relative purity X of the GLP-1 / GLP-2 dual agonist. Y This is indicated by measuring the absolute purity X' of the GLP-1 / GLP-2 dual agonist and comparing it with the absolute purity X' of the GLP-1 / GLP-2 dual agonist on day zero (day 0). 0 The absolute purity is determined by normalization, wherein the purity is determined by HPLC at a given time point Y by identifying the purity of the peak corresponding to the GLP-1 / GLP-2 dual agonist.

[0165] Therefore, on day zero (day 0), the absolute purity X' and the absolute purity X 0 The same, and therefore the chemical stability of the GLP-1 / GLP-2 dual agonist in the test composition was determined by relative purity X. Y =100% means that Y = day 0.

[0166] Relative purity can be calculated in the following ways:

[0167] X Y =(X' / X) 0 )*100

[0168] Where X is the relative purity of Y at a given time point, X 0 X' is the absolute purity at day 0, and X' is the absolute purity at a given time point Y.

[0169] The absolute purity X of the GLP-1 / GLP-2 dual agonist in the test composition was among the factors considered. 0Alternatively, the purity of X' can be determined by HPLC analysis of the peak corresponding to the GLP-1 / GLP-2 dual agonist.

[0170] Unexpectedly, when combined with the buffer L-histidine, the chemical stability of the one or more GLP-1 / GLP-2 dual agonists contained in one or more parenteral pharmaceutical compositions of the present invention, which contain other excitonants (e.g., sucrose, dextran, glycerol, propylene glycol, and mannitol), is stable and higher than that of pharmaceutical compositions containing other excitonants (e.g., sucrose, dextran, glycerol, propylene glycol, and mannitol), wherein the one or more excitonants are selected from salts and / or mannitol.

[0171] Unexpectedly, when combined with the buffer L-histidine, the chemical stability of the one or more GLP-1 / GLP-2 dual agonists contained in one or more parenteral pharmaceutical compositions of the present invention, wherein mannitol (e.g., D-mannitol) is selected as the elicitor, is stable and higher compared to pharmaceutical compositions containing other elicitors (e.g., sucrose, dextran, glycerol, propylene glycol, and mannitol). It was also unexpectedly found that the stability of the GLP-1 / GLP-2 dual agonists in pharmaceutical compositions containing mannitol (e.g., D-mannitol) is very high, and even without preservatives, such compositions can be expected to have a shelf life of one year or longer, for example, up to two years, at 5°C.

[0172] In some aspects, the shelf life of the pharmaceutical compositions of the present invention is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months or longer. Preferably, the shelf life is at least about 12 months or longer. More preferably, the shelf life is at least about 24 months or longer.

[0173] Preferably, the shelf life is at least about 24 months or longer at a storage temperature of about 5°C.

[0174] Unexpectedly, it was found that the chemical stability of the one or more GLP-1 / GLP-2 dual agonists contained in one or more parenteral pharmaceutical compositions of the present invention, which contain salts (e.g., NaCl) as tonic agents, is at least as good (i.e. comparable) as that of pharmaceutical compositions that do not contain any tonic agents, and is higher than that of compositions containing other tonic agents (e.g., sucrose, dextrose, and glycerol).

[0175] stability

[0176] If a peptide shows no signs of aggregation, precipitation, and / or denaturation (or shows very few signs) when examined visually for color and / or clarity, or when measured by UV light scattering, dynamic light scattering (DLS), circular dichroism, or size exclusion chromatography (SEC), then the peptide “maintains its physical stability” or “has good physical stability” in pharmaceutical formulations and is considered to retain its biological activity. SEC measures the formation of soluble oligomers, which may or may not be precursors to visible aggregates.

[0177] A variety of analytical techniques for measuring protein stability are available in the field and have been reviewed in, for example, Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, NY, Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10: 29-90 (1993).

[0178] In this invention, a “stable” formulation includes a formulation in which, after the formulation has been stored at 2°C to 8°C for at least about 2 years, at least 80%, more preferably at least 90%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, and most preferably at least 99% of the GLP1- / GLP-2 dual agonist is active.

[0179] In some aspects, the pharmaceutical compositions of the present invention are optimized to improve the chemical stability of the GLP-1 / GLP-2 dual agonist, expressed as the relative purity of the GLP-1 / GLP-2 dual agonist, to maintain the bioactivity of the peptide even after day 0 for extended periods, such as about 2 weeks, about 3 weeks, about 4 weeks, about 1 month or longer.

[0180] List of abbreviations

[0181] abbreviation explain AUC Analytical ultracentrifugation iv Intravenous sc subcutaneous HPLC High performance liquid chromatography ND Undetermined NP Particle-free part / cont Particles / Containers RP-HPLC Reversed-phase high-performance liquid chromatography CPD compound SEQ ID NO Serial Number

[0182] Terms and Definitions

[0183] The compounds contained in one or more isotonic pharmaceutical compositions disclosed herein are described by general formulas such as formula A and / or formula B, or by their amino acid sequences such as SEQ ID NO: 1. Specific forms of compounds (CPDs) containing the same amino acid sequence, such as -NH2 or -OH forms, are named herein as follows (Table 3), exemplified by compounds containing SEQ ID NO: 1 or composed of SEQ ID NO: 1.

[0184] Table 3:

[0185]

[0186] Therefore, the abbreviation CPD1 refers to any form of a compound containing or consisting of SEQ ID NO: 1, while CPD1OH refers to a compound containing SEQ ID NO: 1, wherein the compound is in its -OH form.

[0187] As used herein, unless otherwise specified, CPD1 refers to CPD1OH or CPDNH2, and any pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt may be a chloride salt, and salts of CPD1OH may also be described as, for example...

[0188] Hy-H[Aib]EGSFTSELATILD[K([17-carboxyl-heptadecanoyl]-isoGlu)]QAARDFIAVVLIQHKITD-OH.[HCl].

[0189] When used in this document, the term “natural amino acid” is selected from the following amino acids (and in parentheses are the usual three-letter code and one-letter code): glycine (Gly and G), proline (Pro and P), alanine (Ala and A), valine (Val and V), leucine (Leu and L), isoleucine (Ile and I), methionine (Met and M), cysteine ​​(Cys and C), phenylalanine (Phe and F), tyrosine (Tyr and Y), tryptophan (Trp and W), histidine (His and H), lysine (Lys and K), arginine (Arg and R), glutamine (Gln and Q), asparagine (Asn and N), glutamic acid (Glu and E), aspartic acid (Asp and D), serine (Ser and S), and threonine (Thr and T). Wherein any reference is made to the GLP-1 / 2GLP-1 / GLP-2 dual agonist, agonist, analogue, or GLP-1 / GLP-2 dual agonist according to the invention, it is meant to contain or not contain an amino acid of the type G, P, A, V, L, I, M, C, F, Y, H, K, R, Q, N, E, D, S, or T (unless otherwise indicated). Unless otherwise indicated, amino acids represented by single-letter codes in uppercase letters represent the L-isotype; however, if an amino acid is represented by a lowercase letter, it is used / applied in its D-type, such as K (i.e., L-lysine) or k (i.e., D-lysine).

[0190] The abbreviation "Hy-" associated with the compounds disclosed herein refers to hydrogen. The abbreviation "Hy" was chosen to avoid confusion with histidine (H) at the beginning of the sequence.

[0191] Throughout this specification and claims, commonly accepted three-letter codes for other "α-amino acids" are used, such as sarcosine (Sar), ortholeucine (NIe), α-aminoisobutyric acid (Aib), 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), and 2,5-diaminovaleric acid (ornithine; Orn). Such other α-amino acids may be indicated in square brackets "[]" (e.g., "[Aib]") when used in the general formula or sequence in this specification, particularly when the remainder of the formula or sequence is indicated using a single-letter code.

[0192] Therefore, as used herein, the terms "dual GLP-1 / 2 agonist," "dual GLP-1 / 2 peptide," or "GLP1 / 2 agonist" refer to peptides that are active against both GLP-1 and GLP-2 receptors and are interchangeable. A dual GLP-1 / GLP-2 agonist comprising formula A or B may be a peptide of SEQ ID NO: 1 or a peptide in which one or more amino acids are modified relative to SEQ ID NO: 1. Such agonists and / or peptides may also comprise one or more side chains covalently linked to the GLP-1 / GLP-2 agonist. The term "side chain" may also be referred to as a "substituent." Therefore, a GLP-1 / GLP-2 agonist comprising such a side chain may be a "derived" GLP-1 / GLP-2 agonist or a "derived" GLP1 / GLP-2 dual peptide or sometimes simply referred to as a "GLP1 / 2 derivative." Thus, a GLP1 / 2 derivative may be a GLP-1 / GLP-2 agonist.

[0193] In one particular aspect, the side chain can form non-covalent aggregates with albumin and is therefore also referred to as the "albumin-binding moiety," thereby promoting the circulation of the derivative in the bloodstream and also having the effect of prolonging the duration of action of the derivative due to the fact that the aggregates of the dual GLP-1 / GLP-2 dual agonist derivative and albumin disintegrate only slowly to release the active pharmaceutical ingredient. Therefore, the "substituent" or "side chain" is preferably referred to as the "albumin-binding moiety."

[0194] The dual GLP-1 / GLP-2 agonists or GLP-1 / 2 derivatives of the present invention exhibit good physical stability. The term "physical stability" in the context of the dual GLP-1 / 2 agonists or their formulations according to the present invention refers to the tendency of the dual GLP-1 / 2 agonist not to form biologically inactive and / or insoluble aggregates due to exposure to thermomechanical stress and / or interactions with unstable interfaces and surfaces, such as hydrophobic surfaces and surfaces. The physical stability of dual GLP-1 / GLP-2 agonist formulations can be evaluated by visual inspection of the particle size and color changes of the pharmaceutical composition. Physical stability can also be assessed by evaluating the content of subvisible particles in the formulation.

[0195] The dual GLP-1 / 2 agonists of the present invention exhibit good chemical stability. The term "chemical stability" in the context of the dual GLP-1 / 2 agonists or formulations thereof according to the present invention refers to a low degree of chemical change in the structure of the dual GLP-1 / 2 agonist, thus avoiding the formation of chemical degradation products that have potentially lower potency and / or potentially enhanced immunogenic properties compared to the parental (natural) dual GLP-1 / 2 agonist structure. A variety of chemical degradation products can be formed, depending on the type and nature of the parental dual GLP-1 / 2 agonist and the environment in which the dual GLP-1 / 2 agonist is exposed. As is known to those skilled in the art, chemical degradation cannot be completely avoided, and increased amounts of chemical degradation products are often seen during the storage and use of peptide formulations. Most peptides readily undergo deamidation, which is the process of hydrolyzing the side-chain amide group of the glutamine acyl or asparaginamide residue to form a free carboxylic acid. Other degradation pathways involve the formation of high molecular weight conversion products, in which two or more peptide molecules covalently bind to each other through transamidation and / or disulfide interactions, resulting in the formation of covalently bound dimers, oligomers, and polymeric degradation products (Stability of Protein Pharmaceuticals, Ahern TJ & Manning MC, Plenum Press, New York 25 1992). Oxidation (e.g., oxidation of methionine residues) is mentioned as another variation of chemical degradation. The chemical stability of GLP1 / GLP-2 dual agonist formulations can be evaluated by measuring the relative purity of the peptide at multiple time points and thus the chemical degradation of the peptide after exposure to different environmental conditions (e.g., time and temperature) (which can typically be accelerated by, for example, increasing the temperature from room temperature to 40°C or by applying physical pressure (e.g., shaking) to promote degradation product formation). The purity level of the peptide at each individual time point is determined by separating the peptide peak and degradation products based on molecular size and / or charge using a variety of chromatographic techniques (e.g., SEC-HPLC and / or RP-HPLC). The absolute amount of peptide in the main peak (peptide peak) at time zero is set to 100% relative purity, and subsequent individual measurements at later time points are normalized relative to this absolute amount and expressed as a percentage.

[0196] The chemical stability of the GLP-1 / GLP-2 dual agonist in any test composition disclosed herein at time point Y can be expressed as the relative purity X of the GLP-1 / GLP-2 dual agonist. Y This is expressed as the absolute purity X' of the GLP-1 / GLP-2 dual agonist measured and compared with the absolute purity X' of the GLP-1 / GLP-2 dual agonist on day zero (day 0). 0The absolute purity is determined by normalization, wherein the purity is determined by HPLC at a given time point Y by identifying the purity of the peak corresponding to the GLP-1 / GLP-2 dual agonist.

[0197] Therefore, on day zero (day 0), the absolute purity X' and the absolute purity X 0 The same, and therefore the chemical stability of the GLP-1 / GLP-2 dual agonist in the test composition was determined by relative purity X. Y =100% means that Y = day 0.

[0198] Relative purity can be calculated in the following ways:

[0199] X Y =(X' / X) 0 )*100

[0200] Where X is the relative purity of Y at a given time point, X 0 X' is the absolute purity at day 0, and X' is the absolute purity at a given time point Y.

[0201] The absolute purity X of the GLP-1 / GLP-2 dual agonist in the test composition was among the factors considered. 0 Alternatively, the purity of X' can be determined by HPLC analysis of the peak corresponding to the GLP-1 / GLP-2 dual agonist.

[0202] When terms related to numerical values, such as “about” and “approximately,” are used, a person skilled in the art will immediately recognize that any effect or result that can be associated with a given value is achievable within a certain tolerance of that particular value. Therefore, as used herein, the term “about” means within a reasonable range of the stated numerical value, for example, plus or minus 10%. When the term “about” is used in this patent application regarding chemical stability, a reasonable range would be less than 2%, for example, 0.5% or 0.75%, 1% or 1.5%.

[0203] The term “major” as used herein in relation to the physical properties and / or form of GLP-1 / GLP-2 dual agonists means that at least about 94% of the GLP-1 / GLP-2 dual agonist is present in the formulation in the specific form as described and that no more than about 6% of the GLP-1 / GLP-2 dual agonist is in another form.

[0204] As used herein, the term "isotonic" refers to the surface tension relative to body fluids at the injection site (i.e., IV or SC). Therefore, the term "isotonic" is used to describe one or more pharmaceutical compositions described herein that have the same surface tension as body fluids (e.g., red blood cells and / or plasma). Compositions having an osmolality of about 300 mOsmol / kg, for example about 280 to 320 mOsmol / kg or about 290 to 320 mOsmol / kg, are considered isotonic.

[0205] Osmotic tension is the "effective osmotic concentration" and is equal to the sum of the concentrations of solutes that have the ability to exert osmotic force across the membrane. Biological systems are compatible with solutions having similar osmotic pressures, i.e., an equal number of dissolved substances, and this is therefore desirable for parenteral drug products.

[0206] Isotonicity is important for parenteral drug compositions because "hypotonic" solutions cause cell swelling, while "hypertonic" solutions cause cell contraction. Although it is related to osmolality concentration, tonicity also takes into account the ability of the solute to cross the cell membrane.

[0207] As disclosed herein, the terms "tonic agent," "isotonic agent," or "isoosmotic agent" refer to a pharmaceutical agent added to one or more pharmaceutical compositions disclosed herein to achieve isotonicity relative to body fluids. A range of ionic and nonionic tonic agents are used in pharmaceutical compositions. Nonionic tonic agents may be selected from dextran, propylene glycol, glycerol, mannitol (e.g., D-mannitol), and sorbitol. Ionic tonic agents may comprise alkali metal or earth metal halides, such as CaCl2, KBr, KCl, LiCl, NaI, NaBr, NaCl, and Na2SO4.

[0208] An "ionic compound" is two or more ions bound together by attractive forces. An example of an ionic compound is table salt. Table salt is composed of sodium ions (positive) and chloride ions (negative). It has high melting and boiling points and is hard or brittle. It is also soluble in water. A "nonionic compound" is defined as a compound in which the chemical bonds are nonionic. It typically has chemical bonds that share electron density.

[0209] As used in this article, the term "solvent" refers to a substance that dissolves a solute (a chemically distinct liquid, solid, or gas) to produce a solution. Solvents are typically liquids, but can also be solids, gases, or supercritical fluids. Solvents are generally classified by polarity and are considered polar or nonpolar, as indicated by their dielectric constant. Typically, solvents with a dielectric constant greater than about 5 are considered "polar," and solvents with a dielectric constant less than 5 are considered "nonpolar."

[0210] "Protic solvent" in this paper is considered to be a solvent having a hydrogen atom bonded to oxygen (as in hydroxyl groups), nitrogen (as in amine groups), or fluorine (as in hydrogen fluoride). Generally, solvents containing unstable H atoms... + Any solvent that readily donates a proton (H) to a reagent is called a proton solvent. + Conversely, “aprotic solvents” do not provide hydrogen. Therefore, water, such as milliQ water, is considered a polar protic solvent in this paper.

[0211] As used in this article, the term "salt" refers to an ionic compound that can be formed through a neutralization reaction between an acid and a base. A salt consists of a relevant number of cations (positively charged ions) and anions (negative ions) so that the product is electrically neutral (without a net charge). These component ions can be inorganic, such as chloride ions (Cl-). - Or organic, such as acetate (CH3CO) 2- ); and can be monatomic, such as fluoride ions (F ions). - ), or polyatomic, such as sulfate (SO4). 2- The term “medicinal salt of CPD1” or “salt of CPD1” as used herein describes a salt comprising the compound SEQ ID NO: 1. “Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAVVLIQHKITD-OH.[acid]” as used herein is identified as a salt of Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAVVLIQHKITD-OH.[HCl], where [acid] refers to the acid that forms the salt of said compound in a neutralization reaction, such as Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAVVLIQHKITD-OH.[HCl], and therefore refers to a chloride salt. The term “medicinal salt” as used herein refers to a salt that is safe and effective for use in mammals and has the desired biological activity. Medicinable salts include salts containing acidic or basic groups present in CPD1. For a review of medicinal salts, see Berge et al., 66 J. Pharm. Sci. 1-19 (1977), which is incorporated herein by reference.

[0212] General methods used

[0213] Methods for the preparation of GLP-1 / GLP-2 dual agonists - Laboratory scale and scale-up batches (Assay I)

[0214] The GLP-1 / GLP-2 dual agonist was prepared according to the instructions in patent application WO2018104561, which describes, for example, the compounds in Examples 1 to 4, their preparation and purification, and detailed analysis.

[0215] CPD1 was synthesized using a solid-phase peptide synthesis (SPPS) method and a standard Fmoc coupling method. After synthesis, the peptide sequence was deprotected and cleaved from the solid support, and the crude peptide was purified by preparative reversed-phase HPLC. The peptide was then converted to an acceptable salt form and lyophilized to provide the final CPD1 pharmaceutical substance.

[0216] Methods for the preparation and analysis of pharmaceutical compositions (Assay II)

[0217] Sample solutions for laboratory-scale and scale-up batch compositions

[0218] The GLP-1 / GLP-2 dual agonist drug substance was prepared according to assay I and dissolved in MQW. The pH value was measured. The ingredients as shown in Table 10 were then added and mixed. As shown in the tables and examples in this application, the final concentrations of the GLP-1 / GLP-2 dual agonist were 0.2 mg / mL, 2 mg / mL, or 10 mg / mL. The pH was then adjusted to a suitable level using 1M NaOH / HCl as needed.

[0219] For the 2 mg / mL CPD1 formulation, dissolve mannitol (41.9 g), NaH₂PO₄ (0.16 g), and Na₂HPO₄ (2.65 g) in approximately 0.7 L of water for injection (WFI). Add an appropriate amount of sodium hydroxide (1 N aqueous solution) to pre-adjust the pH. Dissolve the CPD1 peptide (2.0 g, adjusted for purity) in approximately 0.20 L of WFI. Add the CPD1 peptide solution to the excipient solution. Mix the solutions thoroughly, measure the pH, and adjust the pH to the desired pH with 1 N NaOH and / or 1 N HCl if necessary. Add water to 1.0 L, aseptically filter the formulation through a 0.22 μm filter, and fill into suitable containers.

[0220] Laboratory-scale compositions are prepared in volumes of less than and more than 0.5 mL to about 2 mL, while amplification batches are prepared in volumes of 2 L to about 5.5 L, with the sample of the amplification batch typically being about 1.2 mL, evaluated by any of the following determinations.

[0221] For stability testing, the composition was stored as a batch sample in a dark room (i.e., with the lights off) at a specified temperature (see Examples).

[0222] The formulation was stored under these conditions for the durations shown in the table (e.g., D0 = day 0, D3 = day 3, D7 = day 7, D14 = day 14, D24 = day 24, 0M = 0 months = day 0, 1M = 1 month, 2M = 2 months, 3M = 3 months, 6M = 6 months, 9M = 9 months, or 12M = 12 months) and analyzed by RP-HPLC according to determination III at the relevant time points, and diluted to a concentration of 0.5 mg / mL in eluent A (750 μL added) before analysis by RP-HPLC.

[0223] Used to measure the purity of GLP-1 / GLP-2 dual agonists and to determine the normalized GLP-1 / GLP-2 dual agonist Method for determining the purity of the agent (%) (Determination III)

[0224] The chemical stability of the GLP-1 / GLP-2 dual agonist (peptide) herein is expressed as the relative purity of the peptide peak (i.e., the main peptide peak) determined by HPLC at a given time point and normalized relative to the absolute purity of the peptide peak (i.e., the main peptide peak) set to 100% purity on day zero (day 0 (D0)). Therefore, the chemical stability is expressed as a percentage of the dual agonist.

[0225] The chemical stability of the GLP-1 / GLP-2 dual agonist (peptide) prepared according to determination I, contained in the parenteral drug composition prepared according to determination II, was analyzed according to the following method:

[0226] RP-HPLC General Method (Determination of IIIa)

[0227] A Dionex Ultimate 3000 HPLC system with a linear gradient was used for analysis at a flow rate of 0.5 mL / min. The mobile phase consisted of 0.3% TFA in 90% acetonitrile / 10% MQW and 0.3% TFA in MQW. Detection was performed at a wavelength of 215 nm. The injection volume was 2 μg of peptide. The column used for HPLC analysis was a Phenomenex Kinetex C18, 150 × 3.0 mm, with a particle size of 2.6 μm. The run time was 25 min.

[0228] Table 4 - Detailed information on RP-HPLC methods

[0229]

[0230]

[0231] The results shown in Table 10 were measured by RP-HPLC after incubation under stress conditions (e.g., 0, 3, 7, 14, or 24 days at 40°C). This purity is a measure of the purity of the remaining intact compound after incubation in the stress solution relative to day 0 (D0, day zero) and is expressed as a percentage of normalized CPD1 agonist purity.

[0232] These results do not take into account potential hidden degradation products that may not be observed by this analytical RP-HPLC method.

[0233] Methods for determining physical stability (Determination IV)

[0234] Physical stability was determined by visual inspection (IVa measurement) and detection of subvisible particles (IVb measurement) or by measuring the aggregation tendency of ThT (IVc measurement).

[0235] Visual inspection of the solution (determination of IVa)

[0236] Effective May 1, 2016, visual inspections will be conducted in accordance with the standards of USP > 790 < official standards.

[0237] Detection of subvisible particles (determination of IVb)

[0238] Since May 1, 2013, the detection of subvisible particles has been carried out according to the following standards: USP > 788 < official standards.

[0239] The physical stability of ThT was evaluated by pH measurement (IVc determination).

[0240] Aggregation in the form of fibrils was detected using the amyloid-specific dye thiosulfate T (ThT), which is frequently used to demonstrate the presence of fibrils in solution (see, for example, Groenning, M.). J.Chem.Biol. 3(1)(2010), pp. 1-18; Groenning et al., J.Struct.Biol. 158 (2007), pp. 358-369; and Levine, H., III, Protein Sci. 2 (1993), pp. 404-410.

[0241] Samples were prepared with a total volume of 0.5 mL API (e.g., CPD1 in this paper), and stock solutions were prepared by dissolving API in demineralized water at ambient temperature (typically 25 °C) to achieve API concentrations of 5 and 25 mg / mL, respectively. Eight working solutions were prepared: 1) 40 mM phosphate and 80 μM ThT at pH 6; 2) 40 mM phosphate and 80 μM ThT at pH 6.5; 3) 40 mM phosphate and 80 μM ThT at pH 7; 4) 40 mM phosphate and 80 μM ThT at pH 8; 5) 40 mM phosphate, 540 mM mannitol and 80 μM ThT at pH 6; 6) 40 mM phosphate, 540 mM mannitol and 80 μM ThT at pH 6.5; 7) 40 mM phosphate, 540 mM mannitol and 80 μM ThT at pH 7; and 8) 40 mM phosphate, 540 mM mannitol and 80 μM ThT at pH 8.

[0242] 200 μL of API stock solution was mixed with 250 μL of working solution, the pH was measured and adjusted to the target, and then demineralized water was added to a final volume of 500 μL. Samples were packaged in triplicate (3 × 150 μL) into 96-well black fluorescent plates (transparent bottom). Data were collected at fixed intervals of 10 minutes over 96 hours at 40 °C, with 300 seconds of automatic mixing (stirring) before each collection. Physical stability, expressed as hysteresis time (in hours) for fibril formation, was defined as the intersection of two linear regressions representing the initial stationary and growth phases.

[0243] Used to evaluate polymers by analytical ultracentrifugation (AUC) Methods for determining content (V)

[0244] Sedimentation velocity experiments were conducted using both interference and absorbance measurements on a Beckman Coulter Optima XL-I analytical ultracentrifuge. Samples were placed in titanium cuvettes with a 12 mm optical path length. The experiments were performed at 20 °C. An angular velocity of 50 krpm was applied. As shown in the results graph, solvent density and viscosity were calculated incrementally based on buffer composition. The partial specific volume of the solute was calculated incrementally based on the amino acid / lipid composition (approximately 0.748 mL / g). Evaluation was performed using Sedfit v.15.01b as an approximate solution to the Lamm equation. Molecular triboelectric properties were treated as floating parameters according to the friction ratio f = f0.

[0245] Samples were prepared for AUC analysis according to determination II.

[0246] Some non-limiting aspects of the present invention

[0247] The following portions of the specification contain specific, non-limiting aspects of the invention. The aspects described below may be combined with any aspects of the invention described above, below, and herein:

[0248] 1. An isotonic parenteral drug composition comprising:

[0249] a. One or more GLP-1 / GLP-2 dual agonists comprising at least about 1 mg / mL of the following general formula A:

[0250] H[Aib]EG-X5-F-x7-SELATILD-[Ψ]-QAARDFIAVVLI-X28-X29-KITD(A),

[0251] Where X5 is T or S; X7 is T or S; X28 is Q, E, A, H, Y, L, K, R, or S; X29 is H and at least one of X5 and X7 is T, and

[0252] Where [Ψ] represents an L or D lysine residue, the albumin-binding portion of which is conjugated to a dual GLP-1 / GLP-2 agonist, and

[0253] The albumin-binding moiety is [K([17-carboxy-heptadecanoyl]-isoGlu)]; and

[0254] b. Buffer components ranging from about 1 mM to about 200 mM, for example, from about 20 mM to about 200 mM; and

[0255] c. One or more tensioning agents, preferably one or more, from about 1 mM to about 360 mM, preferably from about 150 mM to about 250 mM.

[0256] The one or more tension agents are ionic or nonionic tension agents, wherein the ionic tension agent is selected from salts, alkali metals, or earth metal halides, and the nonionic tension agent is mannitol, such as D-mannitol.

[0257] The composition further comprises a solvent, and

[0258] The pH of the composition is from about pH 6.0 to about pH 8.2, preferably from about pH 7.0 to about pH 8.0.

[0259] 2. The isotonic parenteral drug composition described in aspect 1, comprising:

[0260] One or more straining agents of about 150 mM to about 250 mM, wherein the one or more straining agents are ionic straining agents selected from CaCl2, KBr, KCl, LiCl, NaI, NaBr, NaCl or Na2SO4, preferably wherein the ionic straining agent is NaCl or KCl.

[0261] 3. The parenteral drug composition according to any one of the foregoing aspects, wherein the one or more GLP-1 / GLP-2 dual agonists comprising general formula A have the following general formula B:

[0262] H[Aib]EG-X5-FT-SELATILD-[Ψ]-QAARDFIAVVLI-X28-HKITD(B),

[0263] Where X5 is T or S; X28 is Q, E, A, H, Y, L, K, R or S, and

[0264] Where [Ψ] represents an L or D lysine residue, the albumin-binding portion of which is conjugated to a dual GLP-1 / GLP-2 agonist, and

[0265] The albumin-binding moiety is [K([17-carboxy-heptadecanoyl]-isoGlu)].

[0266] 4. The parenteral drug composition according to any one of the foregoing aspects, wherein the composition is isotonic.

[0267] 5. The parenteral drug composition according to any one of the foregoing aspects, wherein the one or more GLP-1 / GLP-2 dual agonists comprising general formula A or B comprises the following sequence:

[0268] H[Aib]EGSFFTSELATILD[Ψ]QAARDFIAVVLIQHKITD (SEQ ID NO: 1).

[0269] 6. The parenteral drug composition according to any one of the foregoing aspects, wherein one or more GLP-1 / GLP-2 dual agonists comprising general formula A or B are:

[0270] a.Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAVVLIQHKITD-OH(CPD1OH); or

[0271] b.Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAVVLIQHKITD-NH2(CPD1NH2).

[0272] 7. The isotonic parenteral pharmaceutical composition according to aspect 6, wherein one or more GLP-1 / GLP-2 dual agonists comprising general formula A or B are CPD1OH or any pharmaceutically acceptable salt thereof.

[0273] 8. The isotonic parenteral pharmaceutical composition according to aspect 7, wherein one or more GLP-1 / GLP-2 dual agonists comprising general formula A or B are pharmaceutically acceptable salts of CPD1OH, preferably chloride salts.

[0274] 9. The isotonic parenteral pharmaceutical composition according to aspect 6, wherein one or more GLP-1 / GLP-2 dual agonists comprising general formula A or B are CPD1NH2.

[0275] 10. The isotonic parenteral pharmaceutical composition according to aspect 9, wherein one or more GLP-1 / GLP-2 dual agonists comprising general formula A or B are pharmaceutically acceptable salts of CPD1NH2, preferably chloride salts.

[0276] 11. The isotonic parenteral pharmaceutical composition according to any one of the preceding aspects, wherein the solvent is a polar aprotic solvent, a polar protic solvent, or a nonpolar solvent.

[0277] 12. The isotonic parenteral drug composition according to any one of the foregoing aspects, wherein the one or more tonic agents are nonionic tonic agents and are mannitol, such as D-mannitol, or wherein the one or more tonic agents are ionic tonic agents selected from NaCl or KCl.

[0278] 13. The isotonic parenteral drug composition according to any one of the foregoing aspects, wherein the one or more tonic agents are nonionic tonic agents and are mannitol, such as D-mannitol.

[0279] 14. The isotonic parenteral drug composition according to any one of the foregoing aspects, wherein the pH is adjusted with NaOH or HCl as needed.

[0280] 15. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein it does not contain histidine.

[0281] 16. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein it does not contain L-histidine.

[0282] 17. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein it does not contain any tonic agent selected from dextran, sucrose, propylene glycol or glycerin.

[0283] 18. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein it does not contain any excipient selected from dextran, sucrose, propylene glycol or glycerin.

[0284] 19. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein it does not contain propylene glycol.

[0285] 20. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein it does not contain dextran.

[0286] 21. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein it does not contain sucrose.

[0287] 22. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more tonic agents are mannitol, such as D-mannitol, and are present in the isotonic parenteral pharmaceutical composition at a final concentration of about 150 mM to about 360 mM.

[0288] 23. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more tonic agents are mannitol, such as D-mannitol, and are present in the isotonic parenteral pharmaceutical composition at a final concentration of about 150 mM to about 300 mM.

[0289] 24. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more tonic agents are mannitol, such as D-mannitol, and are present in the isotonic parenteral pharmaceutical composition at a final concentration of about 150 mM to about 250 mM.

[0290] 25. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more tonic agents are mannitol, such as D-mannitol, and are present in the isotonic parenteral pharmaceutical composition at a final concentration of about 210 mM to about 240 mM.

[0291] 26. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more tonic agents are mannitol, such as D-mannitol, and are present in the isotonic parenteral pharmaceutical composition at a final concentration of about 210 mM to about 230 mM.

[0292] 27. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more tonic agents are mannitol, such as D-mannitol, and are present in the isotonic parenteral pharmaceutical composition at a final concentration of about 360 mM.

[0293] 28. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more tonic agents are mannitol, such as D-mannitol, and are present in the isotonic parenteral pharmaceutical composition at a final concentration of about 300 mM.

[0294] 29. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more tonic agents are mannitol, such as D-mannitol, and are present in the isotonic parenteral pharmaceutical composition at a final concentration of about 250 mM.

[0295] 30. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more tonic agents are mannitol, such as D-mannitol, and are present in the isotonic parenteral pharmaceutical composition at a final concentration of about 230 mM.

[0296] 31. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more tonic agents are salts and are present in the isotonic parenteral pharmaceutical composition at a final concentration of about 1 mM to about 360 mM.

[0297] 32. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more tonic agents are salts and are present in the isotonic parenteral pharmaceutical composition at a final concentration of about 50 mM to about 250 mM.

[0298] 33. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more tonic agents are salts and are present in the isotonic parenteral pharmaceutical composition at a final concentration of about 150 mM to about 200 mM.

[0299] 34. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more tonic agents are salts and are present in the isotonic parenteral pharmaceutical composition at a final concentration of about 200 mM to about 230 mM.

[0300] 35. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more tonic agents are NaCl or KCl and are present in the isotonic parenteral pharmaceutical composition at a final concentration of about 50 mM to about 230 mM.

[0301] 36. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more tonic agents are NaCl or KCl and are present in the isotonic parenteral pharmaceutical composition at a final concentration of about 150 mM to about 200 mM.

[0302] 37. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more tonic agents are NaCl or KCl and are present in the isotonic parenteral pharmaceutical composition at a final concentration of about 200 mM to about 250 mM.

[0303] 38. The isotonic parenteral drug composition according to any one of the preceding aspects, wherein the buffer component is selected from phosphate buffers, citrate buffers, histidine buffers or tris buffers, bis tris, or combinations thereof.

[0304] 39. The isotonic parenteral drug composition according to any one of the preceding aspects, wherein the buffer component is selected from phosphate buffers, tris buffers, or combinations thereof.

[0305] 40. The isotonic parenteral drug composition according to any one of the preceding aspects, wherein the buffer component is a phosphate buffer.

[0306] 41. The isotonic parenteral drug composition according to any one of the foregoing aspects, wherein the buffer component is a sodium phosphate buffer.

[0307] 42. The isotonic parenteral drug composition according to any one of the foregoing aspects, wherein the buffer component is a sodium phosphate buffer, such as Na2HPO4.

[0308] 43. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is not a tris buffer.

[0309] 44. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is not a citrate buffer.

[0310] 45. The isotonic parenteral pharmaceutical composition according to any one of the preceding aspects, comprising less than about 6% L-histidine.

[0311] 46. ​​The isotonic parenteral pharmaceutical composition according to any one of the preceding aspects, comprising less than about 5% L-histidine, preferably less than about 3% L-histidine.

[0312] 47. The isotonic parenteral pharmaceutical composition according to any one of the preceding aspects, comprising less than about 1% L-histidine.

[0313] 48. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the buffer component is not a histidine buffer or a buffer containing histidine, such as L-histidine.

[0314] 49. The isotonic parenteral pharmaceutical composition according to any one of the preceding aspects, wherein the buffer component is not a buffer containing histidine or L-histidine.

[0315] 50. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the buffer component is a phosphate buffer, the one or more tonic agents are mannitol, such as D-mannitol, and the one or more GLP1 / GLP-2 dual agonists comprise the sequence of formula A.

[0316] 51. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer, the one or more tonic agents are mannitol, such as D-mannitol, and the one or more GLP1 / GLP-2 dual agonists comprise the sequence of formula B.

[0317] 52. The isotonic parenteral pharmaceutical composition of any one of aspects 50 to 51, wherein the one or more GLP1 / GLP-2 dual agonists comprises the sequence of SEQ ID NO: 1.

[0318] 53. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein one or more GLP1 / GLP-2 dual agonists is CPD1.

[0319] 54. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein one or more GLP1 / GLP-2 dual agonists are pharmaceutically acceptable salts of CPD1.

[0320] 55. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein one or more GLP1 / GLP-2 dual agonists is CPD1OH.

[0321] 56. The isotonic parenteral pharmaceutical composition of aspect 55, wherein one or more GLP1 / GLP-2 dual agonists are pharmaceutically acceptable salts of CPD1OH.

[0322] 57. The isotonic parenteral pharmaceutical composition of any one of aspects 50 to 51, wherein one or more GLP1 / GLP-2 dual agonists is CPD1NH2.

[0323] 58. The isotonic parenteral pharmaceutical composition of aspect 57, wherein one or more GLP1 / GLP-2 dual agonists are pharmaceutically acceptable salts of CPD1NH2.

[0324] 59. The isotonic parenteral pharmaceutical composition according to any one of the preceding aspects, wherein the buffer component is a phosphate buffer and wherein the phosphate buffer is present in the isotonic parenteral pharmaceutical composition at a final concentration of about 1 mM to about 200 mM.

[0325] 60. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer and wherein the phosphate buffer is present in the isotonic parenteral pharmaceutical composition at a final concentration of about 1 mM to about 100 mM.

[0326] 61. The isotonic parenteral drug composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer and wherein the phosphate buffer is present in the isotonic parenteral drug composition at a final concentration of about 100 mM.

[0327] 62. The isotonic parenteral drug composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer and wherein the phosphate buffer is present in the isotonic parenteral drug composition at a final concentration of about 1 mM to about 50 mM.

[0328] 63. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer and wherein the phosphate buffer is present in the isotonic parenteral pharmaceutical composition at a final concentration of about 1 mM to about 20 mM.

[0329] 64. The isotonic parenteral drug composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer and wherein the phosphate buffer is present in the isotonic parenteral drug composition at a final concentration of about 15 mM to about 50 mM.

[0330] 65. The isotonic parenteral drug composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer and wherein the phosphate buffer is present in the isotonic parenteral drug composition at a final concentration of about 15 mM to about 25 mM.

[0331] 66. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer and wherein the phosphate buffer is present in the isotonic parenteral pharmaceutical composition at a final concentration of about 20 mM.

[0332] 67. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists comprise the amino acid sequence of formula A, wherein the pH is about pH 7.0 to about pH 8.0, most preferably about pH 8.0.

[0333] 68. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists comprise an amino acid sequence of formula B, wherein the pH is about pH 7.0 to about pH 8.0, most preferably about pH 8.0.

[0334] 69. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists comprise the amino acid sequence of SEQ ID NO: 1, wherein the pH is about pH 6.0 to about pH 8.0, preferably about pH 7.0 to about pH 8.0, and most preferably about pH 8.0.

[0335] 70. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists comprise an amino acid sequence of formula A, wherein the pH is about pH 6.0 to about pH 8.0, preferably about pH 7.0 to about pH 8.0, and most preferably about pH 8.0.

[0336] 71. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists comprise an amino acid sequence of formula B, wherein the pH is about pH 6.0 to about pH 8.0, preferably about pH 7.0 to about pH 8.0, and most preferably about pH 8.0.

[0337] 72. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists are CPD1OH, wherein the pH is about pH 7.0 to about pH 8.0, most preferably about pH 8.0.

[0338] 73. The isotonic parenteral drug composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists are CPD1NH2, wherein the pH is about pH 7.0 to about pH 8.0, most preferably about pH 8.0.

[0339] 74. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the pH is from about pH 7.0 to about pH 8.2, most preferably about pH 8.0.

[0340] 75. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the pH is from about pH 7.0 to about pH 8.2, preferably about pH 7.5 or about pH 8.0.

[0341] 76. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the pH is from about pH 7.0 to about pH 8.2, preferably about pH 7.6 or about pH 8.0.

[0342] 77. The isotonic parenteral pharmaceutical composition according to any of the preceding aspects, wherein the pH is from about pH 7.0 to about pH 8.2, preferably about pH 7.6 or about pH 7.7.

[0343] 78. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the pH is from about pH 7.0 to about pH 8.2, preferably about 7.6.

[0344] 79. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the pH is from about pH 7.0 to about pH 8.2, preferably about pH 8.0.

[0345] 80. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the pH is from about pH 7.0 to about pH 8.2, preferably about pH 7.0.

[0346] 81. The isotonic parenteral pharmaceutical composition according to any one of the preceding aspects, wherein the pH is about pH 8.0.

[0347] 82. The isotonic parenteral pharmaceutical composition according to any one of the preceding aspects, wherein the pH is about pH 7.0.

[0348] 83. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, and the one or more tension agents are mannitol, such as D-mannitol, with a final concentration of about 210 mM to about 240 mM, preferably about 230 mM.

[0349] 84. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, and the one or more tension agents are mannitol, such as D-mannitol, with a final concentration of about 210 mM to about 240 mM.

[0350] 85. The isotonic parenteral drug composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, and the one or more tension agents are mannitol, such as D-mannitol, with a final concentration of about 230 mM.

[0351] 86. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists are CPD1OH or CPD1NH2, or any pharmaceutically acceptable salt thereof.

[0352] 87. The isotonic parenteral pharmaceutical composition of any one of aspects 83 to 86, wherein one or more GLP-1 / GLP-2 dual agonists is CPD1OH or any pharmaceutically acceptable salt thereof.

[0353] 88. The isotonic parenteral pharmaceutical composition of any one of aspects 83 to 86, wherein one or more GLP-1 / GLP-2 dual agonists is CPD1NH2 or any pharmaceutically acceptable salt thereof.

[0354] 89. The isotonic parenteral pharmaceutical composition according to any one of the preceding aspects, comprising about 1 mg / mL to about 15 mg / mL of a GLP-1 / GLP-2 dual agonist or any pharmaceutically acceptable salt thereof.

[0355] 90. The isotonic parenteral pharmaceutical composition according to any one of the preceding aspects, comprising at least about 2 mg / mL of a dual GLP-1 / GLP-2 agonist or any pharmaceutically acceptable salt thereof.

[0356] 91. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, comprising about 2 mg / mL to about 10 mg / mL of a GLP-1 / GLP-2 dual agonist or any pharmaceutically acceptable salt thereof.

[0357] 92. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, comprising about 2 mg / mL of a dual GLP-1 / GLP-2 agonist or any pharmaceutically acceptable salt thereof.

[0358] 93. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, comprising about 10 mg / mL of a dual GLP-1 / GLP-2 agonist or any pharmaceutically acceptable salt thereof.

[0359] 94. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the pharmaceutical composition is an aqueous composition.

[0360] 95. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the osmotic concentration of the composition as described herein is from about 230 mOsmol / kg to about 370 mOsmol / kg.

[0361] 96. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the osmotic concentration of the composition as described herein is from about 280 mOsmol / kg to about 320 mOsmol / kg.

[0362] 97. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the osmotic concentration of the composition as described herein is from about 290 mOsmol / kg to about 320 mOsmol / kg.

[0363] 98. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, and the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 210 mM to about 240 mM, preferably about 230 mM, wherein the isotonic parenteral pharmaceutical composition comprises about 10 mg / mL of CPD1OH or any pharmaceutically acceptable salt thereof, and the pH is about pH 7.0 to about pH 8.2, preferably about pH 8.0.

[0364] 99. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, and the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 210 mM to about 240 mM, preferably about 230 mM, wherein the isotonic parenteral pharmaceutical composition comprises about 10 mg / mL of CPD1NH2 or any pharmaceutically acceptable salt thereof, and the pH is about pH 7.0 to about pH 8.2, preferably about pH 8.0.

[0365] 100. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, and the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 210 mM to about 240 mM, preferably about 230 mM, wherein the isotonic parenteral pharmaceutical composition contains about 2 mg / mL of CPD1OH or any pharmaceutically acceptable salt thereof, and has a pH of about pH 7.0 to about pH 8.2, preferably about pH 8.0.

[0366] 101. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, and the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 210 mM to about 240 mM, wherein the isotonic parenteral pharmaceutical composition comprises about 2 mg / mL of CPD1NH2 or any pharmaceutically acceptable salt thereof, preferably about 230 mM, and has a pH of about pH 7.0 to about pH 8.2, preferably about pH 8.0.

[0367] 102. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, and the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 210 mM to about 240 mM, preferably about 230 mM, wherein the isotonic parenteral pharmaceutical composition comprises about 10 mg / mL of CPD1OH or any pharmaceutically acceptable salt thereof, and the pH is about pH 7.0 to about pH 8.2, preferably about pH 7.0.

[0368] 103. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, and the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 210 mM to about 240 mM, preferably about 230 mM, wherein the isotonic parenteral pharmaceutical composition contains about 10 mg / mL of CPD1NH2 or any pharmaceutically acceptable salt thereof, and the pH is about pH 7.0 to about pH 8.2, preferably about pH 7.0.

[0369] 104. The isotonic parenteral pharmaceutical composition according to any one of the preceding aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, and the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 210 mM to about 240 mM, preferably about 230 mM, wherein the isotonic parenteral pharmaceutical composition comprises about 2 mg / mL of CPD1OH or any pharmaceutically acceptable salt thereof, and the pH is about pH 7.0 to about pH 8.2, preferably about pH 7.0.

[0370] 105. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, and the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 210 mM to about 240 mM, preferably about 230 mM, wherein the isotonic parenteral pharmaceutical composition contains about 2 mg / mL of CPD1NH2 or any pharmaceutically acceptable salt thereof, and the pH is about pH 7.0 to about pH 8.2, preferably about pH 7.0.

[0371] 106. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists comprise an amino acid sequence of formula A, wherein the pH is about pH 7.0 to about pH 8.0, preferably about pH 8.0.

[0372] 107. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists comprise an amino acid sequence of formula B, wherein the pH is about pH 7.0 to about pH 8.0, preferably about pH 8.0.

[0373] 108. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists comprise the amino acid sequence of SEQ ID NO: 1, wherein the pH is about pH 7.0 to about pH 8.0, preferably about pH 8.0.

[0374] 109. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists comprise an amino acid sequence of formula A, wherein the pH is about pH 7.0 to about pH 8.0, preferably about pH 8.0.

[0375] 110. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists comprise an amino acid sequence of formula B, wherein the pH is about pH 7.0 to about pH 8.0, preferably about pH 8.0.

[0376] 111. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists are CPD1OH or any pharmaceutically acceptable salt thereof, wherein the pH is about pH 7.0 to about pH 8.0, preferably about pH 8.0.

[0377] 112. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 25 mM, preferably about 20 mM, the one or more tonic agents are mannitol, such as D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists are CPD1NH2 or any pharmaceutically acceptable salt thereof, wherein the pH is about pH 7.0 to about pH 8.0, preferably about pH 8.0.

[0378] 113. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the chemical stability of the one or more GLP-1 / GLP-2 dual agonists or any pharmaceutically acceptable salt thereof provided by the composition, on a percentage basis, is at least 99% on day 3, and / or at least 98% on day 7, and / or at least 97% on day 14, and / or at least 95% on day 24, wherein the chemical stability is determined according to determination III.

[0379] 114. The isotonic parenteral drug composition of any one of the foregoing aspects, wherein the composition is selected from the list of formulations in Table 5: formulation 1, formulation 2, formulation 3, formulation 4, formulation 5, formulation 5a, formulation 6, formulation 7, formulation 8, formulation 9, formulation 13, formulation 14, formulation 15, formulation 16, formulation 17, formulation 18, formulation 19, and formulation 21.

[0380] Table 5 - The formulations of the present invention have a chemical stability of at least 99% on day 3, and / or on day 7, by percentage. The chemical stability is at least 98% on day 14, and / or at least 97% on day 14, and / or at least 95% on day 24, wherein said chemical stability Sex is determined based on determination III.

[0381]

[0382]

[0383] 115. The isotonic parenteral drug composition of any one of the foregoing aspects, wherein the composition is selected from the list of formulations in Table 6: formulation 1, formulation 2, formulation 3, formulation 4, formulation 5, formulation 6, formulation 7, formulation 8, formulation 9, formulation 13, formulation 14, formulation 15, formulation 16, formulation 17, formulation 18, and formulation 19.

[0384] 116. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the chemical stability of the one or more GLP-1 / GLP-2 dual agonists provided by the composition, on a percentage basis, is at least 99% on day 3, and / or at least 98% on day 7, and / or at least 97% on day 14, wherein the chemical stability is determined according to determination III.

[0385] Table 6 - Formulations of the present invention - The chemical stability of the formulations of the present invention, expressed as a percentage, is at least [value missing] on day 3. 99%, and / or at least 98% on day 7, and / or at least 97% on day 14, wherein said chemical stability is based on root Determined by measurement III.

[0386]

[0387]

[0388] 117. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the composition is selected from the list of formulations in Table 7: formulation 1, formulation 2, formulation 3, formulation 4, formulation 5, formulation 6, formulation 7, formulation 8, formulation 9, formulation 13, formulation 14, formulation 15, formulation 16, formulation 17, formulation 18, and formulation 19.

[0389] 118. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the chemical stability of the one or more GLP-1 / GLP-2 dual agonists provided by the composition, on a percentage basis, is at least 99% on day 3, and / or at least 98% on day 7, and / or at least 97% on day 14, wherein the chemical stability is determined according to determination III.

[0390] Table 7 - Formulations of the present invention - The chemical stability of the formulations of the present invention, expressed as a percentage, is at least [value missing] on day 3. 99%, and / or at least 98% on day 7, and / or at least 97% on day 14, wherein said chemical stability is based on root Determined by measurement III.

[0391]

[0392]

[0393] 119. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the composition is selected from the list of formulations in Table 8: formulation 1, formulation 2, formulation 3, formulation 13, formulation 14, formulation 15, formulation 16, formulation 17, formulation 18, and formulation 19.

[0394] 120. The isotonic parenteral drug composition according to any one of the foregoing aspects, wherein the chemical stability of the one or more GLP-1 / GLP-2 dual agonists provided by the composition, on a percentage basis, is at least 99% on day 3, and / or at least 98% on day 7, and / or at least 97% on day 14, wherein the chemical stability is determined according to determination III.

[0395] Table 8 - Formulations of the Invention - Formulations of the Invention containing mannitol as a tensioning agent have chemical properties (in percentage). Stability was at least 99% on day 3, and / or at least 98% on day 7, and / or at least 97% on day 14, wherein... The chemical stability described herein is determined according to determination III.

[0396]

[0397]

[0398] 121. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the composition comprises mannitol, such as D-mannitol, and is selected from the list of formulations in Table 9: formulation 4, formulation 5, formulation 6, formulation 7, formulation 8, and formulation 9.

[0399] Table 9 - Formulations of the present invention - Chemical stability of formulations of the present invention containing salt as a tensioning agent, by percentage. The sex ratio is at least 99% on day 3, and / or at least 98% on day 7, and / or at least 97% on day 14, wherein the chemical... The stability of the material was determined according to determination III.

[0400]

[0401]

[0402] 122. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the chemical stability of the one or more GLP-1 / GLP-2 dual agonists provided by the composition, on a percentage basis, is at least 100% on day 3, and / or at least 99% on day 7, and / or at least 98% on day 14 and / or optionally at least 96% on day 24, wherein the chemical stability is determined according to determination III.

[0403] 123. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the composition comprises mannitol, such as D-mannitol, and is selected from the list of formulations disclosed in Table 8: formulation 13, formulation 15, and formulation 16.

[0404] 124. The isotonic parenteral pharmaceutical composition according to any of the foregoing aspects, wherein the composition is formulation 1 as shown in Table 7 or 8.

[0405] 125. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the composition is formulation 2 as disclosed in Table 7 or 8.

[0406] 126. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the composition is formulation 3 as disclosed in Table 7 or 8.

[0407] 127. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the composition is formulation 4 as disclosed in Table 7.

[0408] 128. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the composition is formulation 5 as disclosed in Table 7.

[0409] 129. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the composition is formulation 6 as disclosed in Table 7.

[0410] 130. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the composition is formulation 7 as disclosed in Table 7.

[0411] 131. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the composition is a formulation 8 disclosed in Table 7.

[0412] 132. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the composition is formulation 9 as disclosed in Table 7.

[0413] 133. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the composition is a formulation 13 disclosed in Table 7 or 8.

[0414] 134. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the composition is formulation 14 disclosed in Table 7 or 8.

[0415] 135. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the composition is formulation 14 as disclosed in Table 7 or 8, wherein the GLP-1 / GLP-2 dual agonist is CPD1OH.

[0416] 136. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the composition is formulation 14 disclosed in Table 7 or 8, wherein the GLP-1 / GLP-2 dual agonist is CPD1NH2.

[0417] 137. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the composition is formulation 15 disclosed in Table 7 or 8.

[0418] 138. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the composition is formulation 15 disclosed in Table 7 or 8, wherein the GLP-1 / GLP-2 dual agonist is CPD1OH.

[0419] 139. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the composition is formulation 15 disclosed in Table 7 or 8, wherein the GLP-1 / GLP-2 dual agonist is CPD1NH2.

[0420] 140. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the composition is formulation 16 as disclosed in Table 7.

[0421] 141. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the composition is a formulation 17 disclosed in Table 7 or 8.

[0422] 142. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the composition is a formulation 18 disclosed in Table 7 or 8.

[0423] 143. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the composition is a formulation 19 disclosed in Table 7 or 8.

[0424] 144. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, optionally further comprising a preservative.

[0425] 145. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the preservative is present at a concentration of about 0.1 to about 10 mg / mL.

[0426] 146. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the preservative is present at a concentration of about 1 to about 5 mg / mL.

[0427] 147. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the preservative is present at a concentration of about 2.5 to about 4 mg / mL.

[0428] 148. The isotonic parenteral pharmaceutical composition according to any one of the preceding aspects, wherein it does not contain preservatives.

[0429] 149. The isotonic parenteral pharmaceutical composition according to any one of the preceding aspects, wherein the pH is from about pH 7.0 to about pH 8.0, and wherein the one or more GLP-1 / GLP-2 agonists are present primarily in their trimer form.

[0430] 150. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the pH is from about pH 7.0 to about pH 8.0, and wherein about 94% or more of the one or more GLP-1 / GLP-2 agonists are in trimer form.

[0431] 151. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, wherein the pH is from about pH 7.0 to about pH 8.0, and wherein about 94% or more of the one or more GLP-1 / GLP-2 agonists are in trimer form and less than about 6% or less of the one or more GLP-1 / GLP-2 dual agonists are in tetramer, octamer, 18-mer or 27-mer form.

[0432] 152. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the composition comprises the following components:

[0433]

[0434] 153. The isotonic parenteral drug composition according to any one of the foregoing aspects, wherein the composition comprises the following components:

[0435]

[0436] 154. The isotonic parenteral drug composition according to any one of the foregoing aspects, wherein the composition comprises the following components:

[0437]

[0438] 155. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the composition comprises the following components:

[0439]

[0440] 156. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the composition comprises the following components:

[0441]

[0442]

[0443] 157. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the composition comprises the following components:

[0444]

[0445] 158. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, which is suitable for injection with a single-use device.

[0446] 159. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, which is suitable for parenteral administration by subcutaneous, intramuscular or intravenous injection using a syringe, optionally a pen-shaped syringe.

[0447] 160. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, which is suitable for SC or IV injection into a human subject.

[0448] 161. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, which is administered to a human subject by subcutaneous injection.

[0449] 162. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, which is administered to a human subject by intravenous injection.

[0450] 163. The isotonic parenteral drug composition of any one of the foregoing aspects, which is delivered by a single-use injection device selected from an injection pen or a single-use syringe.

[0451] 164. The pharmaceutical composition according to any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, having a chemical stability of about 100% of the one or more GLP-1 / GLP-2 dual agonists in the composition stored at 40°C on day 3 (D3), wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity on day 0 at 40°C.

[0452] 165. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, having a chemical stability of about 99% or higher on day 3 (D3) of the one or more GLP-1 / GLP-2 dual agonists in the composition stored at 40°C, wherein the chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method as disclosed herein in Determination III, and wherein the chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of the absolute GLP-1 / GLP-2 dual agonist purity on day 0 at 40°C.

[0453] 166. The pharmaceutical composition according to any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, having a chemical stability of about 99% of the one or more GLP-1 / GLP-2 dual agonists in the composition stored at 40°C on day 3 (D3), wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity on day 0 at 40°C.

[0454] 167. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, having a chemical stability of about 99% of the one or more GLP-1 / GLP-2 dual agonists in the composition stored at 40°C on day 7 (D7), wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method as disclosed herein in Determination III, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity on day 0 at 40°C.

[0455] 168. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, having a chemical stability of about 98% or higher on day 7 (D7) of the one or more GLP-1 / GLP-2 dual agonists in the composition stored at 40°C, wherein the chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method as disclosed herein in Determination III, and wherein the chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of the absolute GLP-1 / GLP-2 dual agonist purity on day 0 at 40°C.

[0456] 169. The pharmaceutical composition according to any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, having a chemical stability of about 98% of the one or more GLP-1 / GLP-2 dual agonists in the composition stored at 40°C on day 7 (D7), wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method as disclosed herein in Determination III, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity on day 0 at 40°C.

[0457] 70. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of about 97.5% of the one or more GLP-1 / GLP-2 dual agonists in the composition stored at 40°C on day 7 (D7), wherein the chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method as disclosed herein, and wherein the chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of the absolute GLP-1 / GLP-2 dual agonist purity on day 0 at 40°C.

[0458] 171. The pharmaceutical composition according to any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, having a chemical stability of about 98% of the one or more GLP-1 / GLP-2 dual agonists in the composition stored at 40°C on day 14 (D14), wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity on day 0 at 40°C.

[0459] 172. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, having a chemical stability of about 97% or higher on day 14 (D14) of the one or more GLP-1 / GLP-2 dual agonists in the composition stored at 40°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method as disclosed herein in Determination III, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity on day 0 at 40°C.

[0460] 173. The pharmaceutical composition according to any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, having a chemical stability of about 96% of the one or more GLP-1 / GLP-2 dual agonists in the composition stored at 40°C on day 14 (D14), wherein the chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method as disclosed herein in Determination III, and wherein the chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of the absolute GLP-1 / GLP-2 dual agonist purity on day 0 at 40°C.

[0461] 174. The pharmaceutical composition of any one of the foregoing aspects, comprising about 1 mg / mL to about 15 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, having a chemical stability of about 96.5% on day 14 (D14) of one or more GLP-1 / GLP-2 dual agonists in the composition stored at 40°C, wherein the chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method as disclosed herein, and wherein the chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity on day 0 at 40°C.

[0462] 175. The pharmaceutical composition according to any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, having a chemical stability of about 96% of the one or more GLP-1 / GLP-2 dual agonists in the composition stored at 40°C on day 24 (D24), wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method as disclosed herein in Determination III, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity on day 0 at 40°C.

[0463] 176. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, having a chemical stability of about 96% or higher on day 24 (D24) of the one or more GLP-1 / GLP-2 dual agonists in the composition stored at 40°C, wherein the chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method as disclosed herein in Determination III, and wherein the chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of the absolute GLP-1 / GLP-2 dual agonist purity on day 0 at 40°C.

[0464] 177. The pharmaceutical composition according to any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, having a chemical stability of about 95.5% of the one or more GLP-1 / GLP-2 dual agonists in the composition stored at 40°C on day 24 (D24), wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of the absolute GLP-1 / GLP-2 dual agonist purity on day 0 at 40°C.

[0465] 178. The pharmaceutical composition according to any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, having a chemical stability of at least about 94.5% of the one or more GLP-1 / GLP-2 dual agonists in the composition stored at 40°C on day 24 (D24), wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of the absolute GLP-1 / GLP-2 dual agonist purity on day 0 at 40°C.

[0466] 179. The pharmaceutical composition according to any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, preferably about 1 mg / mL to about 10 mg / mL, having a chemical stability of at least about 85% of the one or more GLP-1 / GLP-2 dual agonists in the composition stored at 40°C for 3 months (3M) after day 0, wherein the chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method as disclosed herein, and wherein the chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of the absolute GLP-1 / GLP-2 dual agonist purity at 40°C on day 0.

[0467] 180. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of at least about 97% as measured in the composition stored at 5°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0468] 181. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 2 mg / mL to about 10 mg / mL, having a chemical stability of at least about 97% as measured in the composition stored at 5°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0469] 182. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 97% as measured in the composition stored at 5°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0470] 183. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of at least about 98% as measured in the composition stored at 5°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0471] 184. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL to about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 98% as measured in the composition stored at 5°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0472] 185. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 98% as measured in the composition stored at 5°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0473] 186. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of at least about 99% as measured in the composition stored at 5°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0474] 187. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 2 mg / mL to about 10 mg / mL, having a chemical stability of at least about 99% as measured in the composition stored at 5°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0475] 188. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 99% as measured in the composition stored at 5°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0476] 189. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of at least about 100% as measured in the composition stored at 5°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0477] 190. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL to about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 100% as measured in the composition stored at 5°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0478] 191. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 100% as measured in the composition stored at 5°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0479] 192. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 100% as measured in the composition after 12 months from day 0 when stored at 5°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0480] 193. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of at least about 100% as measured % after 9 months from day 0 in the composition stored at 5°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0481] 194. The pharmaceutical composition according to any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 2 mg / mL to about 10 mg / mL, having a chemical stability of at least about 100% as measured % after 9 months from day 0 in the composition stored at 5°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0482] 195. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 100% as measured % after 9 months from day 0 in the composition stored at 5°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0483] 196. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of at least about 100% as measured % after 6 months from day 0 in the composition stored at 5°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0484] 197. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL to about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 100% as measured % after 6 months from day 0 in the composition stored at 5°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to the determination ITI disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0485] 198. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 100% as measured % after 6 months from day 0 in the composition stored at 5°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0486] 199. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of at least about 100% as measured in the composition stored at 5°C for 1 to 3 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0487] 200. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 2 mg / mL to about 10 mg / mL, having a chemical stability of at least about 100% as measured in the composition stored at 5°C for 1 to 3 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0488] 201. The pharmaceutical composition according to any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 100% as measured in the composition stored at 5°C for 1 to 3 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0489] 202. The pharmaceutical composition according to any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of at least about 100% as measured % after one month following day 0 in the composition stored at 5°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0490] 203. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL to about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 100% as measured % after one month following day 0 in the composition stored at 5°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0491] 204. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 100% as measured % after one month following day 0 in the composition stored at 5°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0492] 205. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of at least about 100% as measured % after two months from day 0 in the composition stored at 5°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0493] 206. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL to about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 100% as measured % after 2 months from day 0 in the composition stored at 5°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0494] 207. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 100% as measured % after two months from day 0 in the composition stored at 5°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0495] 208. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of at least about 100% as measured % after 10 months from day 0 in the composition stored at 5°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0496] 209. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL to about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 100% as measured in the composition after 10 months from day 0 when stored at 5°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0497] 210. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 100% as measured % after 10 months from day 0 in the composition stored at 5°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 5°C on day 0.

[0498] 211. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of at least about 91% as measured in the composition stored at 25°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0499] 212. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL to about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 91% as measured in the composition stored at 25°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0500] 213. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 91% as measured in the composition stored at 25°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0501] 214. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of at least about 94% as measured in the composition stored at 25°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0502] 215. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL to about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 94% as measured in the composition stored at 25°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0503] 216. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 94% as measured in the composition stored at 25°C for 1 to 12 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0504] 217. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of at least about 94% as measured after 9 months from day 0 in the composition stored at 25°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0505] 218. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL to about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 94% as measured after 9 months from day 0 in the composition stored at 25°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0506] 219. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 94% as measured after 9 months from day 0 in the composition stored at 25°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0507] 220. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of at least about 96% as measured % after 6 months from day 0 in the composition stored at 25°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0508] 221. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL to about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 96% as measured % after 6 months from day 0 in the composition stored at 25°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0509] 222. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 96% as measured % after 6 months from day 0 in the composition stored at 25°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0510] 223. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of at least about 96% as measured in the composition stored at 25°C for 1 to 6 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0511] 224. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL to about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 96% as measured in the composition stored at 25°C for 1 to 6 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0512] 225. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 96% as measured in the composition stored at 25°C for 1 to 6 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0513] 226. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of at least about 98% to 100% as measured in the composition stored at 25°C for 1 to 3 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0514] 227. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 2 mg / mL to about 10 mg / mL, having a chemical stability of at least about 98% to 100% as measured in the composition stored at 25°C for 1 to 3 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0515] 228. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 98% to 100% as measured in the composition stored at 25°C for 1 to 3 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0516] 229. The pharmaceutical composition of any one of the foregoing aspects, comprising one or more GLP-1 / GLP-2 dual agonists at a concentration of about 1 mg / mL to about 15 mg / mL, having a chemical stability of at least about 99% to 100% as measured in the composition stored at 25°C for 1 to 3 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0517] 230. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL to about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 99% to 100% as measured in the composition stored at 25°C for 1 to 3 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0518] 231. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of at least about 99% to 100% as measured in the composition stored at 25°C for 1 to 3 months after day 0, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0519] 232. The pharmaceutical composition of any one of the foregoing aspects, comprising about 1 mg / mL to about 15 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of about 100% as measured % after one month following day 0 in the composition stored at 25°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity on day 0 at 25°C.

[0520] 233. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL to about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of about 100% as measured % after one month following day 0 in the composition stored at 25°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity on day 0 at 25°C.

[0521] 234. The pharmaceutical composition of any one of the foregoing aspects, comprising about 2 mg / mL or about 10 mg / mL of one or more GLP-1 / GLP-2 dual agonists, having a chemical stability of about 100% as measured % after one month following day 0 in the composition stored at 25°C, wherein said chemical stability is determined by HPLC, such as RP-HPLC, or an equivalent method according to determination III as disclosed herein, and wherein said chemical stability is expressed as relative GLP-1 / GLP-2 dual agonist purity as a percentage of absolute GLP-1 / GLP-2 dual agonist purity at 25°C on day 0.

[0522] 235. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, having retained chemical and / or physical stability of the one or more GLP-1 / GLP-2 dual agonists.

[0523] 236. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, administered to the subject by subcutaneous injection in a volume per unit volume of a GLP-1 / GLP-2 dual agonist to be delivered to a human subject in a total amount of about 0.1 mg or more.

[0524] 237. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, administered to the subject by subcutaneous injection in a volume permissible amount for a total dose of about 0.3 mg or more of the one or more GLP-1 / GLP-2 dual agonists to be delivered to a human subject.

[0525] 238. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, administered to the subject by subcutaneous injection in a volume per unit volume of the one or more GLP-1 / GLP-2 dual agonists to be delivered to a human subject in a total amount of about 1 mg or more.

[0526] 239. The isotonic parenteral pharmaceutical composition of any one of the foregoing aspects, administered to the subject by subcutaneous injection in a volume permissible amount for a total dose of about 3 mg or more of the one or more GLP-1 / GLP-2 dual agonists to be delivered to a human subject.

[0527] 240. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, administered to the subject by subcutaneous injection in a volume per unit volume of the one or more GLP-1 / GLP-2 dual agonists to be delivered to a human subject in a total amount of about 6 mg or more.

[0528] 241. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, administered to the subject by subcutaneous injection in a volume permissible amount for a total dose of about 10 mg or more of the one or more GLP-1 / GLP-2 dual agonists to be delivered to a human subject.

[0529] 242. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, which is administered to the subject by subcutaneous injection in a volume permissible for a total amount of about 0.1 mg to about 10 mg of a GLP-1 / GLP-2 dual agonist to be delivered to a human subject.

[0530] 243. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, administered to the subject by subcutaneous injection in a volume permissible amount for a total dose of about 0.1 mg of the GLP-1 / GLP-2 dual agonist to be delivered to a human subject.

[0531] 244. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, which is administered to the subject by subcutaneous injection in a volume permissible amount for a total dose of about 0.3 mg of the GLP-1 / GLP-2 dual agonist to be delivered to a human subject.

[0532] 245. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, which is administered to the subject by subcutaneous injection in a volume per unit volume of the GLP-1 / GLP-2 dual agonist to be delivered to a human subject in a total amount of about 1 mg.

[0533] 246. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, which is administered to the subject by subcutaneous injection in a volume permissible amount of a total of about 3 mg of a dual agonist of GLP-1 / GLP-2 to be delivered to a human subject.

[0534] 247. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, which is administered to the subject by subcutaneous injection in a volume permissible amount of a total of about 6 mg of a dual agonist of GLP-1 / GLP-2 to be delivered to a human subject.

[0535] 248. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, which is administered to the subject by subcutaneous injection in a volume permissible amount of a total of about 9 mg of a dual agonist of GLP-1 / GLP-2 to be delivered to a human subject.

[0536] 249. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, which is administered to the subject by subcutaneous injection in a volume permissible amount of a total of about 10 mg of a dual agonist of GLP-1 / GLP-2 to be delivered to a human subject.

[0537] 250. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, for use in persons who require: prevention or treatment of intestinal injury and dysfunction, weight regulation, and prevention or treatment of metabolic dysfunction.

[0538] 251. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, for use in persons requiring prevention or treatment of: malabsorption, ulcers (e.g., peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, and ulcers associated with infection or other pathogens), short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), irritable bowel syndrome. Gastrointestinal side effects of inflammatory conditions such as IBS syndrome, pouchitis, abdominal sprue (e.g., gluten-induced enteropathy or celiac disease), tropical sprue, hypogammaglobulinemic sprue, mucositis induced by chemotherapy or radiation therapy, diarrhea induced by chemotherapy or radiation therapy, low-grade inflammation, metabolic endotoxemia, necrotizing enterocolitis, primary biliary cirrhosis, hepatitis, fatty liver disease (including parenteral nutrition-associated intestinal atrophy, PNALD, NAFLD, and NASH), or inflammatory conditions (e.g., pancreatitis) or graft-versus-host disease (GVHD).

[0539] 252. The isotonic parenteral pharmaceutical composition according to any one of the preceding aspects, for use in persons who require prevention or treatment of: obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, inadequate glucose control, glucose tolerance, dyslipidemia (e.g., elevated LDL levels or decreased HDL / LDL ratio), diabetes (e.g., type 2 diabetes, gestational diabetes), prediabetes, metabolic syndrome, or hypertension.

[0540] 253. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, for use in persons who require: prevention or treatment of bowel dysfunction or damage caused by or related to GVHD, and prevention or treatment of side effects caused by or related to GVHD, such as diarrhea.

[0541] 254. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, for use in persons who require prevention or treatment of obesity, morbid obesity, obesity-related gallbladder disease, and obesity-induced sleep apnea.

[0542] 255. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, for use in subjects requiring prevention or treatment of glucose tolerance and / or glucose control that require improvement. In some aspects, the pharmaceutical composition of the invention is administered to subjects requiring regulation (e.g., improvement) of circulating cholesterol levels, reduction of circulating triglyceride or LDL levels, and improvement of the HDL / LDL ratio.

[0543] 256. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, when administered to a human subject to promote biological effects selected from the following in subjects in need: improved intestinal quality, improved intestinal function (especially intestinal barrier function), increased intestinal blood flow, and repair of intestinal damage or dysfunction.

[0544] The present invention is also described in the following aspects:

[0545] 1. An isotonic parenteral drug composition comprising:

[0546] a. One or more GLP-1 / GLP-2 dual agonists comprising at least about 1 mg / mL of the following general formula A:

[0547] H[Aib]EG-X5-F-X7-SELATILD-[Ψ]-QAARDFIAVVLI-X28-X29-KITD(A),

[0548] Where X5 is T or S; X7 is T or S; X28 is Q, E, A, H, Y, L, K, R, or S; X29 is H and at least one of X5 and X7 is T, and

[0549] Where [Ψ] represents an L or D lysine residue, the albumin-binding portion of which is conjugated to a dual GLP-1 / GLP-2 agonist, and

[0550] The albumin-binding moiety is [K([17-carboxy-heptadecanoyl]-isoGlu)]; and

[0551] b. A buffer component of approximately 20 mM to approximately 200 mM; and

[0552] c. One or more tensioning agents, preferably one or more, from about 1 mM to about 360 mM, preferably from about 150 mM to about 250 mM.

[0553] The one or more tension agents are ionic or nonionic tension agents, wherein the ionic tension agent is selected from salts, alkali metals, or earth metal halides, and the nonionic tension agent is mannitol, such as D-mannitol.

[0554] The composition further comprises a solvent, and

[0555] The pH of the composition is from about pH 6.0 to about pH 8.2, preferably from about pH 7.0 to about pH 8.0.

[0556] 2. The isotonic parenteral drug composition according to aspect 1, comprising:

[0557] One or more tensioning agents of about 150 mM to about 250 mM, wherein the one or more tensioning agents are ionic tensioning agents selected from CaCl2, KBr, KCl, LiCl, NaI, NaBr, NaCl or Na2SO4, preferably wherein the ionic tensioning agent is NaCl or KCl.

[0558] 3. The parenteral drug composition according to any one of the foregoing aspects, wherein the one or more GLP-1 / GLP-2 dual agonists comprising general formula A have the following general formula B:

[0559] H[Aib]EG-X5-FT-SELATILD-[Ψ]-QAARDFIAVVLI-X28-HKITD(B),

[0560] Where X5 is T or S; X28 is Q, E, A, H, Y, L, K, R or S, and

[0561] Where [Ψ] represents an L or D lysine residue, the albumin-binding portion of which is conjugated to a dual GLP-1 / GLP-2 agonist, and

[0562] The albumin-binding moiety is [K([17-carboxy-heptadecanoyl]-isoGlu)].

[0563] 4. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more GLP-1 / GLP-2 dual agonists comprising general formula A or B comprises the following sequence:

[0564] H[Aib]EGSFFTSELATILD[Ψ]QAARDFIAVVLIQHKITD (SEQ ID NO: 1).

[0565] 5. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein one or more GLP-1 / GLP-2 dual agonists comprising general formula A or B are:

[0566] a.Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAVVLIQHKITD-OH(CPD1OH); or

[0567] b.Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAVVLIQHKITD-NH2(CPD1NH2).

[0568] 6. The isotonic parenteral drug composition according to any one of the foregoing aspects, wherein the buffer component is selected from phosphate buffers, citrate buffers, histidine buffers, tris buffers or bis tris, or combinations thereof, preferably selected from phosphate buffers, citrate buffers, tris buffers or bis tris, or combinations thereof.

[0569] 7. The isotonic parenteral drug composition according to any one of the foregoing aspects, wherein the buffer component is a sodium phosphate buffer.

[0570] 8. The isotonic parenteral drug composition according to any one of the foregoing aspects, wherein the osmotic concentration of the composition is from about 230 mOsmol / kg to about 370 mOsmol / kg.

[0571] 9. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 200 mM, preferably about 20 mM, the one or more tonic agents are mannitol, preferably D-mannitol, with a final concentration of about 190 mM to about 240 mM, preferably about 230 mM, and the one or more GLP-1 / GLP-2 dual agonists comprise SEQ ID NO: 1 or any pharmaceutically acceptable salt thereof, wherein the pH is about 7.0 to about 8.0, preferably about 8.0.

[0572] 10. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the buffer component is a phosphate buffer with a final concentration of about 15 mM to about 30 mM, the one or more tonic agents are mannitol with a final concentration of about 230 mM, preferably D-mannitol, and the one or more GLP-1 / GLP-2 dual agonists comprise SEQ ID NO: 1 or any pharmaceutically acceptable salt thereof, wherein the pH is about 7.0 to about 8.0, preferably about 8.0.

[0573] 11. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, wherein the one or more GLP-1 / GLP-2 dual agonists are present at a concentration of about 1 mg / mL to about 15 mg / mL.

[0574] 12. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, comprising SEQ ID NO: 1 or its chloride salt, a phosphate buffer at a concentration of about 15 mM to about 30 mM, preferably about 20 mM, mannitol, preferably D-mannitol, at a concentration of about 230 mM, water for injection, and sodium hydroxide and / or hydrochloric acid for adjusting the pH to about pH 8.0, wherein the one or more GLP-1 / GLP-2 dual agonists is CPD1OH or CPD1NH2, preferably Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAVVLIQHKITD-OH(CPD1OH), and is present at about 2 mg / mL.

[0575] 13. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, comprising SEQ ID NO: 1 or its chloride salt, a phosphate buffer at a concentration of about 15 mM to about 30 mM, preferably about 20 mM, mannitol, preferably D-mannitol, at a concentration of about 230 mM, water for injection, and sodium hydroxide and / or hydrochloric acid for adjusting the pH to about pH 8.0, wherein the one or more GLP-1 / GLP-2 dual agonists is CPD1OH or CPD1NH2, preferably Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAVVLIQHKITD-OH(CPD1OH), and is present at about 10 mg / mL.

[0576] 14. The isotonic parenteral pharmaceutical composition of aspect 12 or 13, wherein one or more GLP-1 / GLP-2 dual agonists is Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAVVLIQHKITD-OH(CPD1OH).

[0577] 15. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, which is suitable for SC or IV injection into a human subject.

[0578] 16. The isotonic parenteral pharmaceutical composition according to any one of the foregoing aspects, used for:

[0579] (i) to improve intestinal quality, intestinal function, intestinal blood flow, or repair intestinal damage or dysfunction in individuals who require this; or

[0580] (ii) To prevent or treat, in individuals with this need, malabsorption, ulcers, short bowel syndrome, blind tube syndrome, inflammatory bowel disease, irritable bowel syndrome, cryptitis, abdominal spreorrhea, tropical spreorrhea, hypogammaglobulinemic spreorrhea, mucositis induced by chemotherapy or radiation therapy, diarrhea induced by chemotherapy or radiation therapy, low-grade inflammation, metabolic endotoxemia, necrotizing enterocolitis, primary biliary cirrhosis, hepatitis, fatty liver disease, or gastrointestinal side effects of inflammatory conditions; or

[0581] (iii) To reduce or inhibit weight gain, reduce gastric emptying or intestinal transit, reduce food intake, reduce appetite, or promote weight loss in individuals who require this; or

[0582] (iv) To prevent or treat obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, inadequate glucose control, glucose tolerance, dyslipidemia, diabetes, prediabetes, metabolic syndrome or hypertension in individuals with this need.

[0583] Example

[0584] Example 1: Chemical stability of the laboratory-scale isotropic composition of the present invention containing CPD1.

[0585] This embodiment investigated the chemical stability of CPD1 as expressed as the relative purity of the peptide peak (i.e., the main CPD1 peak) determined by HPLC at a given time point and normalized relative to the absolute purity of the peptide peak (i.e., the main CPD1 peak) on day zero (day 0 (D0)) set to 100% purity, and therefore the chemical stability is expressed as a percentage of the dual agonist.

[0586] CPD1 is generated according to Assay I, the pharmaceutical composition (i.e., formulation) is prepared and stored according to Assay II, and the absolute purity of CPD1 is measured according to Assay III by HPLC, such as RP-HPLC, at each time point (DX, where X is 0, 3, 7, 14, or 24 days). Chemical stability, i.e., normalized CPD1 purity expressed as a percentage, is determined according to the calculations described in Assay III. Formulations 1 to 24 contain CPD1OH consisting of the amino acid sequence of Formula A. CPD1OH is interchangeable with CPD1NH2.

[0587] The results showed that formulations containing mannitol, such as D-mannitol, as a tonic agent exhibited higher chemical stability compared to all other tested formulations, including those without a tonic agent (e.g., high purity of the GLP-1 / GLP-2 dual agonist, exemplified by CPD1). Therefore, mannitol, such as D-mannitol, was shown to stabilize the chemical stability of the GLP-1 / GLP-2 dual agonist. L-histidine was shown to partially offset the stabilizing effect of mannitol, such as D-mannitol. On the other hand, when the isotonic parenteral drug composition contained mannitol, such as D-mannitol, a pH range of approximately 7.0 to approximately 8.0 showed little effect on the chemical stability of the GLP-1 / GLP-2 dual agonist. Chemical stability was also relatively stable when the phosphate buffer concentration varied from approximately 20 mM to approximately 100 mM.

[0588] The results also showed that pharmaceutical compositions containing salts such as sodium chloride or potassium chloride as tonic agents exhibited high chemical stability, comparable to that of formulations without tonic agents, and significantly better chemical stability than GLP-1 / GLP-2 dual agonists in pharmaceutical compositions containing tonic agents selected from sucrose, dextran, glycerol, and propylene glycol.

[0589] Table 10 also shows that sucrose, dextran, glycerol and propylene glycol reduce chemical stability and are therefore not the best choice for isotonic pharmaceutical compositions containing compounds of formula A, and are not if they contain CPD1.

[0590]

[0591] Example 2: Long-term stability of samples from a scale-up batch (2.5L) containing CPD1 at 5°C.

[0592] CPD1 is generated according to assay I, the pharmaceutical composition (i.e., the formulation) is prepared and stored according to assay II, and the absolute purity of CPD1 is measured according to assay III by HPLC, such as RP-HPLC, at each of the following time points as shown in Tables 11 to 14: i.e., after storage in rubber-stopped vials at 5°C ± 3°C for 1 month (1M), 2 months (2M), 3 months (3M), 6 months (6M), 9 months (9M), 12 months (12M), and 24 months (24M).

[0593] Table 11 Long-term chemical stability of a scale-up batch (2.5 L) containing 2 mg / mL CPD1 at 5 °C, wherein chemical stability is expressed as normalized CPD1 purity in % as described in Determination III.

[0594]

[0595] Table 12Visually inspect the long-term physical stability of a scaled-up batch (2.5 L) of solution containing 2 mg / mL CPD1 at 5 °C. Visual inspection was performed according to IVa determination.

[0596]

[0597] Table 13 Visual inspection was performed on the long-term physical stability of particles, a scaled-up batch (2.5 L) containing 2 mg / mL CPD1, at 5°C. Visual inspection was conducted according to IVa determination.

[0598]

[0599] Table 14 Sub-visible particles, scale-up batch (2.5L) (Formulation 15) containing 2 mg / mL CPD1, long-term physical stability at 5°C (NP = no particles, and part / cont = particles / container).

[0600] The detection of subvisible particles is based on the determination of IVb.

[0601]

[0602] Example 3: Long-term stability of samples from a 10 mg / mL amplification batch (2.5 L) containing CPD1 at 5 °C.

[0603] CPD1 is generated according to assay I, the pharmaceutical composition (i.e., the formulation) is prepared and stored according to assay II, and the absolute purity of CPD1 is measured according to assay III by HPLC, such as RP-HPLC, at each of the following time points as shown in Tables 15 to 18: i.e., after storage in rubber-stopped vials at 5°C ± 3°C for 1 month (1M), 2 months (2M), 3 months (3M), 6 months (6M), 9 months (9M), 12 months (12M), and 24 months (24M).

[0604] Table 15 Long-term chemical stability of a scale-up batch (2.5 L) containing 10 mg / mL CPD1 at 5 °C, wherein chemical stability is expressed as normalized CPD1 purity in % as described in Determination III.

[0605]

[0606] Table 16 Visually inspect the long-term physical stability of a scaled-up batch (2.5 L) of solution containing 10 mg / mL CPD1 at 5 °C. Visual inspection was performed according to IVa determination.

[0607]

[0608] Table 17 Visual inspection was performed on the long-term physical stability of particles, a scaled-up batch (2.5 L) containing 10 mg / mL CPD1, at 5°C. Visual inspection was conducted according to IVa determination.

[0609]

[0610] Table 18 Subvisible particles, a scaled-up batch (2.5L) (Formulation 16) containing 10 mg / mL CPD1, were tested for long-term physical stability at 5°C (NP = no particles, and part / cont = particles / container). Subvisible particles were detected based on IVb assays.

[0611]

[0612] Example 4: Long-term chemical stability of samples from a scale-up batch (2.5 L) containing CPD1 at 25°C Qualitative analysis.

[0613] CPD1 is generated according to Assay I, the pharmaceutical composition (i.e., the formulation) is prepared and stored according to Assay II, and the absolute purity of CPD1 is measured according to Assay III by HPLC, such as RP-HPLC, at each of the following time points as shown in Tables 19 to 22: i.e., after storage in rubber-stopped vials at 25°C ± 5°C / 60% RH ± 5% RH for 1 month (1M), 2 months (2M), 3 months (3M), 6 months (6M), 9 months (9M), and 12 months (12M).

[0614] Table 19 Long-term chemical stability of a scale-up batch (2.5 L) containing 2 mg / mL CPD1 at 25 °C, wherein chemical stability is expressed as normalized CPD1 purity in % as described in Determination III.

[0615]

[0616] Table 20 Visually inspect the long-term physical stability of a scaled-up batch (2.5 L) of solution containing 2 mg / mL CPD1 at 25 °C. Visual inspection was performed according to IVa determination.

[0617]

[0618] Table 21 Visual inspection was performed on the long-term physical stability of particles, a scaled-up batch (2.5 L) containing 2 mg / mL CPD1, at 25°C. Visual inspection was conducted according to IVa determination.

[0619]

[0620] Table 22 Subvisible particles, a scaled-up batch (2.5L) (Formulation 15) containing 2 mg / mL CPD1, were subjected to long-term data analysis at 25°C (NP = no particles, and part / cont = particles / container). Detection of subvisible particles was performed according to the determination of IVb.

[0621]

[0622] Example 5: Long-term chemical stability of a sample from a scale-up batch (2.5 L) containing CPD1 at 25 °C Qualitative analysis.

[0623] CPD1 is generated according to assay I, the pharmaceutical composition (i.e., the formulation) is prepared and stored according to assay II, and the absolute purity of CPD1 is measured according to assay III by HPLC, such as RP-HPLC, at each of the following time points as shown in Tables 23 to 26: i.e., after storage in rubber-stopped vials at 25°C ± 5°C / 60% RH ± 5% RH for 1 month (1M), 2 months (2M), 3 months (3M), 6 months (6M), 9 months (9M), and 12 months (12M).

[0624] Table 23 Long-term chemical stability of a scale-up batch (2.5 L) containing 10 mg / mL CPD1 at 25 °C, wherein chemical stability is expressed as normalized CPD1 purity in % as described in Determination III.

[0625]

[0626] Table 24 Visually inspect the long-term physical stability of a scaled-up batch (2.5 L) of solution containing 10 mg / mL CPD1 at 25 °C. Visual inspection was performed according to IVa determination.

[0627]

[0628] Table 25 Visual inspection was performed on the long-term physical stability of particles, a scaled-up batch (2.5 L) containing 10 mg / mL CPD1, at 25°C. Visual inspection was conducted according to IVa determination.

[0629]

[0630] Table 26 Subvisible particles, a scaled-up batch (2.5 L) (Formulation 16) containing 2 mg / mL CPD1, were tested for long-term physical stability at 25°C (NP = no particles, and part / cont = particles / container). Subvisible particles were detected based on IVb assays.

[0631]

[0632] Example 6: Accelerated long-term stability of samples from a 2.5L amplification batch containing CPD1 at 40°C Qualitative analysis.

[0633] CPD1 is generated according to assay I, the pharmaceutical composition (i.e., the formulation) is prepared and stored according to assay II, and the absolute purity of CPD1 is measured according to assay III by HPLC, such as RP-HPLC, at each of the following time points as shown in Tables 27 to 30: i.e., after storage in rubber-stopped vials at 40°C ± 5°C / 75% RH ± 5% RH for 1 month (1M), 2 months (2M), and 3 months (3M).

[0634] Table 27 Accelerated long-term chemical stability of a scale-up batch (2.5 L) containing 2 mg / mL CPD1 at 40 °C, wherein chemical stability is expressed as normalized CPD1 purity in % as described in Determination III.

[0635]

[0636] Table 28 Visually inspect the accelerated long-term physical stability of the solution, a scaled-up batch (2.5 L) containing 2 mg / mL CPD1, at 40 °C. Visual inspection was performed according to IVa determination.

[0637]

[0638] Table 29 Visual inspection was performed on the accelerated long-term physical stability of particles containing a scaled-up batch (2.5 L) of 2 mg / mL CPD1 at 40 °C. Visual inspection was performed according to IVa determination.

[0639]

[0640] Table 30 Subvisible particles, including a scaled-up batch (2.5L) (Formulation 15) at 2 mg / mL CPD1, were assessed for accelerated long-term physical stability at 40°C (NP. = no particles, and part / cont = particles / container). Detection of subvisible particles was performed based on IVb assay.

[0641]

[0642] Example 7: Accelerated long-term stability of samples from a 10 mg / mL amplification batch (2.5 L) containing CPD1 at 40 °C Qualitative analysis.

[0643] CPD1 is generated according to assay I, the pharmaceutical composition (i.e., the formulation) is prepared and stored according to assay II, and the absolute purity of CPD1 is measured according to assay III by HPLC, such as RP-HPLC, at each of the following time points as shown in Tables 31 to 34: i.e., after storage in rubber-stopped vials at 40°C ± 5°C / 75% RH ± 5% RH for 1 month (1M), 2 months (2M), 3 months (3M), 6 months (6M), 9 months (9M), and 12 months (12M).

[0644] Table 31 Accelerated long-term chemical stability of a scale-up batch (2.5 L) containing 10 mg / mL CPD1 at 40 °C, wherein chemical stability is expressed as normalized CPD1 purity in percent as described in Determination III.

[0645]

[0646] Table 32 Visually inspect the accelerated long-term physical stability of the solution, containing an amplified batch (2.5 L) of 10 mg / mL CPD1, at 40 °C. Visual inspection limits were determined by IVa assay.

[0647]

[0648] Table 33 Visual inspection was performed on the accelerated long-term physical stability of particles containing a 2.5L amplified batch of 10 mg / mL CPD1 at 40°C. Visual inspection limits were determined by IVa assay.

[0649]

[0650] Table 34 Subvisible particles, including a scaled-up batch (2.5L) (Formulation 16) at 2 mg / mL CPD1, were assessed for accelerated long-term physical stability at 40°C (NP = no particles, and part / cont = particles / container). Detection of subvisible particles was performed based on IVb assay.

[0651]

[0652] Example 8: Accelerated chemical stabilization of formulations with different buffer systems at 40°C for 14 days on a laboratory scale sex

[0653] CPD1 is generated according to assay I, the pharmaceutical composition (i.e., formulation) is prepared and stored according to assay II, and the absolute purity of CPD1 is measured according to assay III by HPLC, such as RP-HPLC, at each of the following time points as shown in Table 35: i.e., after storage for 14 days (14D) in a vial sealed with a rubber stopper at 40°C ± 5°C / 60%RH ± 5%RH.

[0654] Table 35 Accelerated long-term chemical stability of laboratory-scale compositions containing 0.2 mg / mL CPD1 at 40 °C, wherein chemical stability is expressed as normalized CPD1 purity in percent as described in Determination III.

[0655]

[0656]

[0657] Example 9: Accelerated physical stability of laboratory-scale formulations in the pH range of 6 to 8 at 40°C for 4 days.

[0658] pH determined the aggregation tendency of CPD1. No difference was detected between the formulation with mannitol as a tonic agent and the control (without a tonic agent). Amyloid formation was observed at pH 6 in 2 and 10 mg / mL CPD1, and fibrillation was not observed at pH 7 or 8.

[0659] Table 36: Based on the determination of Ivc at 2 mg / mL CPD1 aggregation (FD = fibrillation detected and FND = fibrillation not detected)

[0660] pH of the formulation and concentration of the buffer No tension agent added 270mM mannitol 20mM phosphate at pH 6 FD FD 20mM phosphate at pH 6.5 FND FND 20mM phosphate at pH 7 FND FND 20mM phosphate at pH 8 FND FND

[0661] Table 37: Based on the determination of Ivc aggregation at 10 mg / mL CPD1 (FD = fibrillation detected and FND = fibrillation not detected)

[0662] pH of the formulation and concentration of the buffer No tension agent added 270mM mannitol 20mM phosphate at pH 6 FD FD 20mM phosphate at pH 6.5 FND FND 20mM phosphate at pH 7 FND FND 20mM phosphate at pH 8 FND FND

[0663] Example 10: Laboratory-scale structural characterization of CPD1 at pH 6 to 8.

[0664] Structural properties were evaluated using AUC at pH 6, 7, and 8 in 20 mM phosphate buffer, 230 mM mannitol, and 2 mg / ml CPD1. The results are shown in Tables 38 and 39.

[0665] Table 38: The formulation composition of the sample was determined by AUC analysis.

[0666] preparation# composition 1 20 mM phosphate at pH 8, 230 mM mannitol, 2 mg / mL CPD1 2 20 mM phosphate at pH 7, 230 mM mannitol, 2 mg / mL CPD1 3 20 mM phosphate at pH 6, 230 mM mannitol, 2 mg / mL CPD1

[0667] Table 39: Sedimentation coefficients of formulations from Table 38.

[0668]

[0669] Formulation 1 (2 mg / mL; 20 mM phosphate (pH 8), 230 mM mannitol): Sedimentation coefficient distribution (SCD) showed that the major population (s) had a relative content of 98.8% and an apparent mass of 11.5 kDa. 20；w =1.23S). Therefore, the major group is temporarily designated as the trimeric peptide. The remaining substances represent oligomers / aggregates with a sedimentation coefficient as high as approximately 10S that settle more rapidly.

[0670] Formulation 2 (2 mg / mL; 20 mM phosphate (pH 7), 230 mM mannitol): a putative trimer (s) with an apparent mass of 11.2 kDa. 20；w The relative content of (=1.40S) is almost the same as that in formulation 1.

[0671] Formulation 3 (2 mg / mL; 20 mM phosphate (pH 6), 230 mM mannitol) exhibited the highest degree of self-association among all samples. Two major populations (s) were detected with comparable relative contents of 43.0% and 55.2%, respectively. 20；w =1.98S and 2.78S), but trimers are not present. A slightly less abundant group with an apparent mass of 17 kDa represents the presumed tetrameric peptide, and a more rapidly settling group with an average molar mass of 30 kDa contains the presumed heptamers or octamers. The broad morphology of the second group suggests the presence of additional size and conformational variants, such as hexamers and nonamers. The remaining material is distributed in larger oligomers up to 10S.

[0672] Example 11: Laboratory-scale testing of 2 and 10 mg / mL CPD1 at 5°C in 20 mM phosphate buffer at pH 8 Long-term stability in 115mM NaCl.

[0673] CPD1 was generated according to assay I, and the pharmaceutical composition (i.e., formulation) was prepared and stored on a laboratory scale according to assay II, having a final concentration of 115 mM NaCl instead of 230 mM mannitol. The absolute purity of CPD1 was measured according to assay III by HPLC, such as RP-HPLC, at each of the following time points as shown in Tables 40 to 41: i.e., after storage at 5 °C ± 3 °C in rubber-stopped vials for 1 month (1 M), 3 months (3 M), 6 months (6 M), 12 months (12 M), and 24 months (24).

[0674] Table 40 Long-term stability of 2 and 10 mg / mL CPD1 at 5 °C in 20 mM phosphate buffer 115 mM NaCl at pH 8 on a laboratory scale, wherein chemical stability is expressed as normalized CPD1 purity in % as described in Determination III.

[0675]

[0676] Table 41 Visually inspect the long-term stability of solutions of 2 and 10 mg / mL CPD1 at 5 °C in 20 mM phosphate buffer and 115 mM NaCl at pH 8 on a laboratory scale. Visual inspection was performed according to IVa determination.

[0677] sequence list <110> Zealand Pharma A / S <120> Parenteral drug composition of dual GLP1 / 2 agonists <130> P119722PCT <150> EP19180233.9 <151> 2019-06-14 <160> 3 <170> PatentIn version 3.5 <210> 1 <211> 33 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide sequence <220> <221> MISC_FEATURE <222> (2)..(2) <223> Xaa is [Aib] <220> <221> MISC_FEATURE <222> (16)..(16) <223> Xaa is an L or D lysine residue, wherein the side chain is conjugated to a GLP-1 / GLP-2 dual agonist, and wherein said side chain is [K([17-carboxy-heptadecanoyl]-isoGlu)]. <400> 1 His Xaa Glu Gly Ser Phe Thr Ser Glu Leu Ala Thr Ile Leu Asp Xaa 1 5 10 15 Gln Ala Ala Arg Asp Phe Ile Ala Trp Leu Ile Gln His Lys Ile Thr 20 25 30 Asp <210> 2 <211> 33 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide sequence <220> <221> MISC_FEATURE <222> (2)..(2) <223> Xaa is [Aib] <220> <221> MISC_FEATURE <222> (5)..(5) <223> Xaa is either T or S (where at least one of X5 and X7 is T). <220> <221> MISC_FEATURE <222> (7)..(7) <223> Xaa is either T or S (where at least one of X5 and X7 is T). <220> <221> MISC_FEATURE <222> (16)..(16) <223> Xaa is an L or D lysine residue in which the side chain is conjugated to a dual GLP-1 / GLP-2 agonist. <220> <221> MISC_FEATURE <222> (28)..(28) <223> Xaa is Q, E, A, H, Y, L, K, R, or S <220> <221> MISC_FEATURE <222> (29)..(29) <223> Xaa is H, Y, or Q <400> 2 His Xaa Glu Gly Xaa Phe Xaa Ser Glu Leu Ala Thr Ile Leu Asp Xaa 1 5 10 15 Gln Ala Ala Arg Asp Phe Ile Ala Trp Leu Ile Xaa Xaa Lys Ile Thr 20 25 30 Asp <210> 3 <211> 33 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide sequence <220> <221> MISC_FEATURE <222> (2)..(2) <223> Xaa is [Aib] <220> <221> MISC_FEATURE <222> (5)..(5) <223> Xaa is T or S <220> <221> MISC_FEATURE <222> (16)..(16) <223> Xaa is an L or D lysine residue, wherein the side chain is conjugated to a GLP-1 / GLP-2 dual agonist, and wherein said side chain is [K([17-carboxy-heptadecanoyl]-isoGlu)]. <220> <221> MISC_FEATURE <222> (28)..(28) <223> Xaa is Q, E, A, H, Y, L, K, R, or S <400> 3 His Xaa Glu Gly Xaa Phe Thr Ser Glu Leu Ala Thr Ile Leu Asp Xaa 1 5 10 15 Gln Ala Ala Arg Asp Phe Ile Ala Trp Leu Ile Xaa His Lys Ile Thr 20 25 30 Asp

Claims

1. An isotonic parenteral drug composition comprising: a. One or more GLP-1 / GLP-2 dual agonists at least 1 mg / mL, wherein the one or more GLP-1 / GLP-2 dual agonists is CPD1OH or any pharmaceutically acceptable salt thereof, wherein the CPD1OH is Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH; and b. Phosphate buffer components ranging from 5 mM to 50 mM; and c. Tenosynovial agents ranging from 190 mM to 240 mM, The tensioning agent mentioned above is mannitol. The composition further comprises a solvent. The composition has a pH of 7.0 to 8.2, and The composition described herein does not contain histidine.

2. The isotonic parenteral pharmaceutical composition of claim 1, wherein the mannitol is D-mannitol.

3. The isotonic parenteral drug composition of claim 1, wherein the composition comprises a phosphate buffer component of 10 mM to 40 mM.

4. The isotonic parenteral drug composition of claim 3, wherein the composition comprises a phosphate buffer component of 15 mM to 30 mM.

5. The isotonic parenteral drug composition of claim 3, wherein the composition comprises a 20 mM phosphate buffer component.

6. The isotonic parenteral pharmaceutical composition of claim 1, wherein the pH of the composition is from pH 7.0 to pH 8.

0.

7. The isotonic parenteral drug composition of claim 1, wherein the pH is pH 8.

0.

8. The isotonic parenteral drug composition according to claim 1, wherein the buffer component is a sodium phosphate buffer.

9. The isotonic parenteral drug composition of claim 8, wherein the sodium phosphate buffer is disodium phosphate or sodium dihydrogen phosphate, or a combination thereof.

10. The isotonic parenteral drug composition of claim 1, wherein the osmotic concentration of the composition is from 230 mOsmol / kg to 370 mOsmol / kg.

11. The isotonic parenteral pharmaceutical composition of claim 1, wherein the buffer component has a final concentration of 20 mM, the tensioner is mannitol with a final concentration of 190 mM to 240 mM, and wherein the pH is pH 7.0 to pH 8.

0.

12. The isotonic parenteral drug composition of claim 11, wherein the final concentration of mannitol is 230 mM.

13. The isotonic parenteral pharmaceutical composition of claim 1, wherein the final concentration of the buffer component is 15 mM to 30 mM, the tensioner is mannitol with a final concentration of 230 mM, and wherein the pH is pH 7.0 to pH 8.

0.

14. The isotonic parenteral pharmaceutical composition of claim 1, wherein one or more GLP-1 / GLP-2 dual agonists are present at a concentration of 1 mg / mL to 15 mg / mL.

15. The isotonic parenteral pharmaceutical composition of claim 1, comprising a phosphate buffer at a concentration of 15 mM to 30 mM, mannitol at a concentration of 230 mM, water for injection, and sodium hydroxide and / or hydrochloric acid for adjusting the pH to pH 8.0, wherein one or more GLP-1 / GLP-2 dual agonists are CPD1OH or its chloride salt and are present at 2 mg / mL.

16. The isotonic parenteral drug composition of claim 1, comprising a phosphate buffer at a concentration of 15 mM to 30 mM, mannitol at a concentration of 230 mM, water for injection, and sodium hydroxide and / or hydrochloric acid for adjusting the pH to pH 8.0, wherein one or more GLP-1 / GLP-2 dual agonists are CPD1OH or its chloride salt and are present at 10 mg / mL.

17. The isotonic parenteral pharmaceutical composition of claim 1, wherein the composition comprises the following components: 。 18. The isotonic parenteral pharmaceutical composition of claim 1, wherein the composition comprises the following components: 。 19. The isotonic parenteral pharmaceutical composition of claim 1, suitable for subcutaneous or intravenous injection into a human subject.

20. The isotonic parenteral pharmaceutical composition of claim 1, wherein the shelf life of the composition is at least one month.

21. The isotonic parenteral pharmaceutical composition of claim 20, wherein the shelf life of the composition is at least 2 months.

22. The isotonic parenteral pharmaceutical composition of claim 20, wherein the shelf life of the composition is at least 3 months.

23. The isotonic parenteral pharmaceutical composition of claim 20, wherein the shelf life of the composition is at least 4 months.

24. The isotonic parenteral pharmaceutical composition of claim 20, wherein the shelf life of the composition is at least 6 months.

25. The isotonic parenteral pharmaceutical composition of claim 20, wherein the shelf life of the composition is at least 12 months.

26. The isotonic parenteral pharmaceutical composition of claim 20, wherein the shelf life of the composition is at least 18 months.

27. The isotonic parenteral pharmaceutical composition of claim 20, wherein the shelf life of the composition is at least 24 months.

28. The isotonic parenteral pharmaceutical composition of claim 1, wherein the composition has a chemical stability of at least 90% after 12 months of storage.

29. The isotonic parenteral pharmaceutical composition of claim 1, wherein the composition has a chemical stability of at least 97% after 12 months of storage.

30. The isotonic parenteral pharmaceutical composition of claim 1, wherein the composition has a chemical stability of at least 97% after 24 months of storage.

31. The isotonic parenteral pharmaceutical composition of claim 29 or 30, wherein the composition is chemically stable at 5°C.

32. A method for improving the chemical stability of an isotonic parenteral pharmaceutical composition, said isotonic parenteral pharmaceutical composition comprising at least 1 mg / mL of one or more GLP-1 / GLP-2 dual agonists, wherein said one or more GLP-1 / GLP-2 dual agonists is CPD1OH or any pharmaceutically acceptable salt thereof, said CPD1OH is Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH, and wherein said composition does not contain histidine; The method includes adding mannitol to the composition at a final concentration of 190 mM to 240 mM. The composition contains a 5 mM to 50 mM phosphate buffer component. The composition further comprises a solvent, and The pH of the composition is from pH 7.0 to pH 8.

2.

33. Use of mannitol at a final concentration of 190 mM to 240 mM for improving the chemical stability of isotonic parenteral pharmaceutical compositions comprising at least 1 mg / mL of one or more GLP-1 / GLP-2 dual agonists, wherein the one or more GLP-1 / GLP-2 dual agonists is CPD1OH or any pharmaceutically acceptable salt thereof, wherein the CPD1OH is Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH, and wherein the composition does not contain histidine. The composition contains a 5 mM to 50 mM phosphate buffer component. The composition further comprises a solvent, and The pH of the composition is from pH 7.0 to pH 8.

2.

34. The method of claim 32 or the use of claim 33, wherein the mannitol is D-mannitol.

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