Pharmaceutical compositions of GLP-1 / GLP-2 dual agonists

Abstract

The present invention relates to pharmaceutical compositions containing certain preservatives.

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions containing specific preservatives. The pharmaceutical compositions according to the invention are particularly stable and have a beneficial shelf life. [Background technology]

[0002] Peptides are an important segment of the pharmaceutical industry. Although there have been tremendous advances in the production of active pharmaceutical ingredients (APIs), the production of peptide-based drug products remains a significant challenge. The challenges associated with peptide formulation development are often overlooked or ignored.

[0003] Peptides are generally defined as polypeptides of fewer than 50 amino acid residues, often lacking organized tertiary or globular structure. Some adopt secondary structures, but these tend to be limited, such as a single α-helix. While smaller sizes make them easier to deliver through biological barriers than larger proteins, their formulation can be problematic.

[0004] Some of the formulation challenges particularly associated with peptides include chemical instability; adoption of multiple conformers; their tendency to self-associate; and complex physical instability, such as gel formation, amyloid formation, and / or precipitation.

[0005] The most common challenge is the chemical degradation of peptides and proteins through degradation mechanisms such as isomerization, racemization, hydrolysis, deamidation, and oxidation. The amino acid sequence of a given peptide dictates the extent to which it is susceptible to deamidation and / or oxidation reactions. The oxidation rate of particular residues, such as Met residues, correlates with the degree of solvent exposure. Because peptides lack a globular structure that can sequester reactive groups, nearly all side chains of peptide residues are fully exposed to solvent, allowing maximum access to reactive oxygen species. Deamidation involves the hydrolysis of the amide side chains of amino acid residues, such as Asn and Gln. Furthermore, the degree of flexibility of the peptide chain results in a higher rate of deamidation compared to more complex proteins. However, it is important to note that the nature of the post-deamidation amino acid, e.g., the amino acid after Asn, also affects the deamidation rate. Peptides lacking steric bulk and the ability to hydrogen bond to the Asn side chain may further accelerate the reaction. Typically, the amino acid combinations Asn-Gly, Asn-Ala, Asn-Ser, and Asn-Asp exhibit reaction kinetics that scientists must take into account and test to ensure stable pharmaceutical compositions. The greatest control over hydrolysis reactions, including deamidation, is exerted by a stable and reliable pH and buffer system. However, such a stable and reliable pH and buffer system is affected by additional excipients added to the composition.

[0006] Excipients are added to pharmaceutical compositions to improve or maintain the solubility (solubilizers) and / or stability (buffers, antioxidants, chelating agents, cryoprotectants, and lyoprotectants) of the active ingredient. Excipients are often important in parenteral formulations to ensure safety (antimicrobial preservatives), minimize pain and irritation upon injection (tonicity agents), and control or prolong drug delivery (polymers). These are all examples of positive or synergistic interactions between excipients and pharmaceutical products. However, any excipient added to a composition has the potential to produce negative effects, such as loss of peptide solubility, activity, and / or chemical / physical stability; increased self-aggregation or fibrillation, which may render the pharmaceutical product unsafe for administration.

[0007] Preservatives can be added to pharmaceutical compositions to destroy microbial contaminants that may be introduced into the composition, such as when multiple aliquots are used or withdrawn from a container holding a large dose of a pharmaceutical. Although pharmaceutical compositions can be sealed and stored in a sterile environment without the presence of a preservative, when the container holding the composition is used, any accidental introduction of microorganisms can render the contents unsuitable for further medical use. Therefore, it is important to effectively preserve the pharmaceutical contents, especially when the composition is stored in a large volume for several administrations. When a container holding a large volume of a preservative-free pharmaceutical composition is used, the absence of a preservative can mean that most of the contents are wasted. Preservatives advantageously allow for storage of pharmaceutical compositions for months or years at low temperatures (e.g., refrigerated at approximately 5°C), or for shorter periods, such as days or weeks, at higher temperatures, such as room temperature, even after portions of the composition have been used.

[0008] However, despite the benefits of using preservatives, their inclusion in pharmaceutical compositions can be problematic because they can adversely interact with other components of the composition, particularly active ingredients. Such interactions can result in a reduction in the preservative's effectiveness or a reduction or complete loss of the pharmaceutical composition's medical efficacy. For example, preservatives can cause chemical instability of the active agent. In the case of peptide active agents, preservatives can participate in or promote degradation reactions such as isomerization, racemization, hydrolysis, deamidation, or oxidation of the peptide, resulting in a loss of the peptide's pharmacological activity. Alternatively or additionally, preservatives can be detrimental to the physical stability of peptide active agents, enhancing the aggregation of the peptide into inactive covalent oligomers and / or causing the peptide to precipitate from solution. Not only does such loss of physical stability reduce the medical efficacy of the peptide, but the formation of particulate matter has practical and safety implications when the composition is delivered by injection.

[0009] Because peptides have a great deal of sequence diversity and therefore a wide range of chemical structures, it is inherently unpredictable whether a given substance will act as an effective preservative for a particular therapeutic peptide composition without negatively affecting the peptide as described above.

[0010] The present invention relates to pharmaceutical compositions comprising selected peptides (e.g., compound 18 of WO2018104561) disclosed in WO2018104561, which describes the compounds and their uses in detail. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] International Publication No. 2018104561 Brochure Summary of the Invention [Means for solving the problem]

[0012] The present application provides compositions comprising one or more GLP-1 / GLP-2 dual agonists and one or more preservatives in a buffer solution. In some embodiments, the composition is an isotonic parenteral pharmaceutical composition suitable for administration to a human subject.

[0013] The GLP-1 / GLP-2 dual agonist is a peptide. Specific preservatives have been identified that can be used in compositions containing particular GLP-1 / GLP-2 dual agonist peptides and specific buffers without substantially affecting the chemical or physical stability of the peptide. It has surprisingly been discovered that the specific preservatives have little to no effect on the chemical stability and oligomerization of the peptide in Tris buffer.

[0014] Therefore, the compositions of the present invention benefit from the advantages associated with preservatives, ie, the prevention or reduction of microbial contamination.

[0015] Among other advantages, the preservative effect in the compositions of the present invention allows the compositions to be provided in a multi-dose administration setting. The compositions of the present invention can be provided in a device used to administer successive therapeutic doses of the composition at intervals over an extended period of time. The preservative effect prevents microbial growth in the composition over this period, while maintaining the chemical and physical stability of the peptide. This has the practical benefit of requiring only one loading of the device, rather than preparing a new dose for each administration.

[0016] In one aspect, the pharmaceutical composition according to the invention is for administration in a multi-dose device or is suitable for administration in a multi-dose device.

[0017] In some aspects, the present invention provides a method for producing a pharmaceutical composition comprising: (a) General formula A: H[Aib]EG-X5-F-X7-SELATILD-[Ψ]-QAARDFIAWLI-X28-HKITD(A) wherein X5 is T or S; X7 is T or S; X28 is Q, E, A, H, Y, L, K, R or S, and at least one of X5 and X7 is T; [Ψ] represents an L or D lysine residue that is the albumin binding moiety conjugated to the GLP-1 / GLP-2 dual agonist; the albumin binding moiety is [K([17-carboxy-heptadecanoyl]-isoGlu)]} one or more GLP-1 / GLP-2 dual agonists, including: (b) one or more preservatives that include or are m-cresol and / or phenol; and (c) Tris buffer A composition comprising:

[0018] In some aspects, particular and special compositions, such as isotonic parenteral compositions, are detailed in the description of the invention.

[0019] The chemical stability at time Y of the GLP-1 / GLP-2 dual agonist in any of the tested compositions disclosed herein is determined by the relative purity X of the GLP-1 / GLP-2 dual agonist. Y The absolute purity of the GLP-1 / GLP-2 dual agonist, X', can be expressed as the absolute purity of the GLP-1 / GLP-2 dual agonist on day 0 (day 0), X 0 , and the absolute purity is determined by identifying the purity of the peak corresponding to the GLP-1 / GLP-2 dual agonist by HPLC at a given time point Y.

[0020] Surprisingly, it has been found that the peptides of the present invention are more stable and less likely to oligomerize when the m-cresol preservative is combined with a Tris buffer rather than a phosphate buffer.

[0021] The present invention also provides (i) increasing intestinal mass, improving intestinal function, increasing intestinal blood flow, or repairing intestinal damage or dysfunction in a subject in need thereof; or (ii) preventing or treating the gastrointestinal side effects of malabsorption, ulcers, short bowel syndrome, blind tract syndrome, inflammatory bowel disease, irritable bowel syndrome, pouchitis, celiac sprue, tropical sprue, hypogammaglobulinemic sprue, chemotherapy- or radiation-induced mucositis, chemotherapy- or radiation-induced diarrhea, low-grade inflammation, metabolic endotoxemia, necrotizing enterocolitis, primary biliary cirrhosis, hepatitis, fatty liver, or an inflammatory condition in a subject in need thereof; or (iii) reducing or inhibiting weight gain, reducing gastric emptying or intestinal transit, reducing food intake, reducing appetite, or promoting weight loss in a subject in need thereof; or (iv) preventing or treating obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, inadequate glucose control, glucose tolerance, dyslipidemia, diabetes, prediabetes, metabolic syndrome, or hypertension in a subject in need thereof; The present invention provides a composition according to the present invention for use in

[0022] The present invention further provides a method for preserving a composition comprising one or more GLP-1 / GLP-2 dual agonists of the present invention and a Tris buffer, the method comprising the step of adding one or more preservatives to the composition, wherein the one or more preservatives include, or are, m-cresol and / or phenol.

[0023] In addition, the present invention provides the use of a preservative for preserving a composition comprising one or more GLP-1 / GLP-2 dual agonists of the present invention and a Tris buffer, wherein the preservative comprises or is m-cresol and / or phenol. DETAILED DESCRIPTION OF THE INVENTION

[0024] compound The compositions of the present invention have the general formula A: H[Aib]EG-X5-F-X7-SELATILD-[Ψ]-QAARDFIAWLI-X28-HKITD(A) X7 is T or S; X28 is Q, E, A, H, Y, L, K, R, or S, at least one of X5 and X7 is T, and [Ψ] represents an L or D lysine residue that is an albumin binding moiety conjugated to a GLP-1 / GLP-2 dual agonist, said albumin binding moiety being [K([17-carboxy-heptadecanoyl]-isoGlu)]. The compound includes one or more GLP-1 / GLP-2 dual agonists, including:

[0025] In some embodiments, the one or more dual GLP-1 / GLP-2 agonists comprising general formula A are represented by general formula B: H[Aib]EG-X5-FT-SELATILD-[Ψ]-QAARDFIAWLI-X28-HKITD(B) wherein 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 that is an albumin-binding moiety conjugated to a GLP-1 / GLP-2 dual agonist, and the albumin-binding moiety is [K([17-carboxy-heptadecanoyl]-isoGlu)]. It is a GLP-1 / GLP-2 dual agonist.

[0026] In some embodiments, the one or more GLP-1 / GLP-2 dual agonists comprising general formula A or B comprise the sequence: H[Aib]EGSFTSELATILD[Ψ]QAARDFIAWLIQHKITD (SEQ ID NO: 1). In some embodiments, the one or more GLP-1 / GLP-2 dual agonists comprising general formula A or B consist of the sequence: H[Aib]EGSFTSELATILD[Ψ]QAARDFIAWLIQHKITD (SEQ ID NO: 1).

[0027] In some embodiments, the one or more GLP-1 / GLP-2 dual agonists comprising general formula A is Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH(CPD1OH) or any pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt of CPD1OH is a sodium salt, a chloride salt, or an acetate salt, preferably a chloride salt.

[0028] In some embodiments, the one or more GLP-1 / GLP-2 dual agonists comprising general formula A is Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-NH2(CPD1NH2) or any pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt of CPD1NH2 is a sodium salt, chloride salt, or acetate salt, preferably a chloride salt.

[0029] In a preferred embodiment, the one or more GLP-1 / GLP-2 dual agonists is CPD1OH or any pharmaceutically acceptable salt thereof, preferably the chloride salt thereof.

[0030] The term "GLP-1 / GLP-2 dual agonist," as used herein, refers to a peptide having activity at the GLP-1 receptor and the GLP-2 receptor. A GLP-1 / GLP-2 dual agonist comprising Formula A or B can be a peptide of SEQ ID NO: 1 or a peptide in which one or more amino acids have been modified compared to SEQ ID NO: 1. Such agonists and / or peptides can further comprise one or more side chains covalently attached to the GLP-1 / GLP-2 dual agonist. The term "side chain" can also be referred to as a "substituent."

[0031] The term "salt," as used herein, refers to an ionic compound that can be formed by the neutralization reaction of an acid and a base. Because salts consist of a related number of cations (positively charged ions) and anions (negative ions), the product is electrically neutral (has no net charge). These component ions can be inorganic, e.g., chloride (Cl - ), or organic, such as acetate (CHCO 2- ) or monoatomic, such as fluoride (F - ), or polyatomic, such as sulfate (SO4 2- ) may also be used.

[0032] The terms "pharmaceutically acceptable salt of CPD1" or "salt of CPD1," as used herein, describe a salt of a compound comprising SEQ ID NO: 1. "Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH.[acid]" as used herein identifies a salt of Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH, where [acid] refers to an acid that forms a salt of the compound, e.g., Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH, in a neutralization reaction. Accordingly, [HCl] refers to the chloride salt.

[0033] As used herein, "pharmaceutically acceptable salts" refers to salts that are safe and effective for use in mammals and possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in CPD1. For a review of pharmaceutically acceptable salts, see Berge et al., 66 J. Pharm. Sci. 1-19 (1977), incorporated herein by reference.

[0034] [Table 1]

[0035] The abbreviation CPD1 refers to any form of the compound containing SEQ ID NO: 1. However, CPD1OH simply discloses the compound containing SEQ ID NO: 1 in the OH form (free acid). The CPD1NH2 form refers to the -NH2 form (amidated form) of the compound. Both CPD1OH and CPD1NH2 can be converted to pharmaceutically acceptable salts to provide the drug substance in powder form.

[0036] [Table 2]

[0037] The "albumin binding moiety" has the effect of promoting the circulation of the GLP-1 / GLP-2 dual agonist in the bloodstream and prolonging the duration of action of the GLP-1 / GLP-2 dual agonist. The albumin binding moiety binds the GLP-1 / GLP-2 dual agonist to albumin present in the blood, and due to the fact that the GLP-1 / GLP-2 dual agonist is released only slowly from albumin, the action of the GLP-1 / GLP-2 dual agonist is prolonged. The term "albumin binding moiety" may also be referred to as a "side chain" or a "substituent."

[0038] As used herein, the term "natural amino acid" refers to an amino acid (according to its conventional three-letter and one-letter symbols in parentheses) selected from the group consisting of 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). Unless otherwise specified, amino acids designated with a single capital letter designation indicate the L isoform, whereas when an amino acid is designated with a lower case letter, this amino acid is used / applied as its D form, e.g., K (i.e., L-lysine), k (i.e., D-lysine).

[0039] The abbreviation "Hy-" in the context of the compounds disclosed herein refers to hydrogen. This abbreviation was chosen to be shown as "Hy-" to avoid confusion between hydrogen and histidine (H) at the beginning of the sequence.

[0040] Throughout this description and claims, commonly accepted three-letter symbols are used for other "α-amino acids," such as sarcosine (Sar), norleucine (Nle), α-aminoisobutyric acid (Aib), 2,3-diaminopropanoic acid (Dap), 2,4-diaminobutanoic acid (Dab), and 2,5-diaminopentanoic acid (ornithine; Orn). Such other α-amino acids, when used in general formulas or sequences herein, may be indicated in square brackets "[]" (e.g., "[Aib]"), especially when the remainder of the formula or sequence is shown using single-letter symbols.

[0041] Compound concentration In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, contain at least about 1 mg / mL of the GLP-1 / GLP-2 dual agonist, e.g., at least about 2 mg / mL of the GLP-1 / GLP-2 dual agonist. In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, contain at least about 1 mg / mL to about 33 mg / mL of the GLP-1 / GLP-2 dual agonist, e.g., at least about 2 mg / mL to about 33 mg / mL of the GLP-1 / GLP-2 dual agonist. In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, comprise at least about 1 mg / mL to about 25 mg / mL of the GLP-1 / GLP-2 dual agonist, e.g., at least about 2 mg / mL to about 25 mg / mL of the GLP-1 / GLP-2 dual agonist, e.g., at least about 4 mg / mL to about 25 mg / mL of the GLP-1 / GLP-2 dual agonist, e.g., at least about 6 mg / mL to about 25 mg / mL of the GLP-1 / GLP-2 dual agonist, e.g., at least about 8 mg / mL to about 25 mg / mL of the GLP-1 / GLP-2 dual agonist, e.g., at least about 10 mg / mL to about 25 mg / mL of the GLP-1 / GLP-2 dual agonist.

[0042] In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical composition of the present invention, contain about 1 mg / mL of the GLP-1 / GLP-2 dual agonist. In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical composition of the present invention, contain about 2 mg / mL of the GLP-1 / GLP-2 dual agonist. In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical composition of the present invention, contain about 4 mg / mL of the GLP-1 / GLP-2 dual agonist. In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical composition of the present invention, contain about 6 mg / mL of the GLP-1 / GLP-2 dual agonist. In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical composition of the present invention, contain about 8 mg / mL of the GLP-1 / GLP-2 dual agonist. In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical composition of the present invention, contain about 10 mg / mL of the GLP-1 / GLP-2 dual agonist. In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical composition of the present invention, contain about 15 mg / mL of the GLP-1 / GLP-2 dual agonist. In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical composition of the present invention, contain about 20 mg / mL of the GLP-1 / GLP-2 dual agonist. In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical composition of the present invention, contain about 25 mg / mL of the GLP-1 / GLP-2 dual agonist. In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical composition of the present invention, contain about 33 mg / mL of the GLP-1 / GLP-2 dual agonist.

[0043] Preferably, the compositions of the present invention contain about 2 mg / mL to about 25 mg / mL of the GLP-1 / GLP-2 dual agonist, preferably about 6 mg / mL to about 25 mg / mL of the GLP-1 / GLP-2 dual agonist, and most preferably about 15 mg / mL of the GLP-1 / GLP-2 dual agonist.

[0044] Synthesis of dual agonists It is preferred to synthesize the dual agonist of the present invention by solid-phase or liquid-phase peptide synthesis. In this connection, reference may be made to WO 98 / 11125 and, among many others, Fields, GB et al., 2002, "Principles and practice of solid-phase peptide synthesis". In: Synthetic Peptides (2nd Edition), as well as the examples therein. In accordance with the present invention, the dual agonist of the present invention can be prepared, for example, by (a) synthesizing a dual agonist by solid-phase or liquid-phase peptide synthesis and recovering the synthesized dual agonist; or (b) expressing the precursor peptide sequence from a nucleic acid construct encoding the precursor peptide, recovering the expression product, and modifying the precursor peptide to obtain a compound of the invention. It can be synthesized or produced in several ways, including by a method comprising:

[0045] The precursor peptide may be modified by the introduction of one or more non-proteinogenic amino acids, such as Aib, Orn, Dap or Dab, by the introduction of an albumin binding moiety, or by the introduction of suitable terminal groups -OH or -NH2.

[0046] Expression is typically from nucleic acid encoding the precursor peptide, which may be in a cell containing such nucleic acid or in a cell-free expression system.

[0047] preservatives The compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, comprise one or more preservatives. In some embodiments, the one or more preservatives include m-cresol and / or phenol, or are m-cresol and / or phenol. In some embodiments, the preservative is m-cresol or phenol. The compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, comprise a preservative, and the preservative includes m-cresol and / or phenol, or is m-cresol and / or phenol. In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, comprise one type of preservative, and the preservative includes m-cresol or phenol, or is m-cresol or phenol. In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, comprise two types of preservatives, and the preservative includes m-cresol and phenol, or is m-cresol and phenol.

[0048] m-Cresol In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, comprise one or more preservatives, wherein the one or more preservatives comprise m-cresol. In some embodiments, the one or more preservatives are m-cresol. In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, comprise a preservative that is m-cresol. In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, comprise m-cresol.

[0049] m-Cresol is an organic compound also known as meta-cresol, 3-cresol, 3-methylphenol, 3-methylbenzenol, 3-hydroxytoluene, or 1-hydroxy-3-methylbenzene. m-Cresol has the chemical formula CH3C6H4(OH) and the following structural formula:

[0050] [ka]

[0051] In some embodiments, m-cresol is present in the compositions of the present invention at a concentration of about 1.15 mg / mL to about 5.15 mg / mL. In some embodiments, m-cresol is present in the compositions of the present invention at a concentration of about 1.15 mg / mL. In some embodiments, m-cresol is present in the compositions of the present invention at a concentration of about 5.15 mg / mL. Preferably, m-cresol is present in the compositions of the present invention at a concentration of about 3.15 mg / mL.

[0052] phenol In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, comprise one or more preservatives, wherein the one or more preservatives comprise phenol. In some embodiments, the one or more preservatives are phenol. In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, comprise a preservative that is phenol. In some embodiments, the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, comprise phenol.

[0053] Phenol, also known as benzenol, is an organic compound with the chemical formula CHOH and the following structural formula:

[0054] [ka]

[0055] In some embodiments, phenol is present in the composition of the present invention at a concentration of about 2.5 mg / mL to about 8.5 mg / mL. In some embodiments, phenol is present in the composition of the present invention at a concentration of about 2.5 mg / mL. In some embodiments, phenol is present in the composition of the present invention at a concentration of about 8.5 mg / mL. Preferably, phenol is present in the composition of the present invention at a concentration of about 5.5 mg / mL.

[0056] Tris buffer and pH The compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, contain Tris buffer. In some embodiments, the Tris buffer is present in the composition, e.g., the isotonic parenteral pharmaceutical composition, at a final concentration of about 5 mM to about 50 mM, e.g., about 5 mM to about 20 mM. In some embodiments, the Tris buffer is present in the composition at a final concentration of about 5 mM. In some embodiments, the Tris buffer is present in the composition at a final concentration of about 50 mM. Preferably, the Tris buffer is present in the composition at a final concentration of about 20 mM.

[0057] The term "Tris" is an abbreviation for tris(hydroxymethyl)aminomethane. Tris is also known as 2-amino-2-(hydroxymethyl)propane-1,3-diol, which has the chemical formula (HOCH2)3CNH2 and the following structural formula:

[0058] [ka]

[0059] The term "Tris buffer" refers to a buffer containing Tris molecules.

[0060] In some embodiments, the pH of the composition of the present invention, e.g., the isotonic parenteral pharmaceutical composition, is about pH 6.0 to about pH 8.5, e.g., about pH 6.0 to about pH 8.4, about pH 6.0 to about pH 8.3, about pH 6.0 to about pH 8.2, about pH 6.0 to about pH 8.1, or about pH 6.0 to about pH 8.0. In some embodiments, the pH is preferably about pH 7.0 to about pH 8.0. In some embodiments, the pH is about pH 6.5 to about pH 8.5. In some embodiments, the pH of the composition of the present invention, e.g., the isotonic parenteral pharmaceutical composition, is about pH 7.0 to about pH 8.0. In some embodiments, the pH of the composition of the present invention, e.g., the isotonic parenteral pharmaceutical composition, is about pH 7.0. In some embodiments, the pH of the composition of the present invention, e.g., the isotonic parenteral pharmaceutical composition, is about pH 8.0. In some embodiments, the pH of the composition of the present invention is about pH 8.2. In some embodiments, the pH of the composition of the present invention is about pH 6.0. In some embodiments, the pH of the composition of the present invention is about pH 7.0 to about pH 8.2, preferably about pH 7.5 or about pH 8.2. In some embodiments, the pH of the composition of the present invention is about pH 7.0 to about pH 8.2, preferably about pH 7.6 or about pH 8.0. In some embodiments, the pH of the composition of the present invention is about pH 7.0 to about pH 8.2, preferably about pH 7.6 or about pH 7.7. In some embodiments, the pH of the composition of the present invention is about pH 7.0 to about pH 8.2, preferably about pH 7.6. In some embodiments, the pH of the composition of the present invention is about pH 7.0 to about pH 8.2, preferably about pH 8.0. In some embodiments, the pH of the composition of the present invention is about pH 7.0 to about pH 8.2, preferably about pH 7.0. In a preferred embodiment, the pH is about 8.0.

[0061] In some embodiments, in the compositions of the present invention, the pH is adjusted as needed with either NaOH or HCl.

[0062] Osmotic and tonicity agents In some embodiments, the compositions of the present invention are isotonic parenteral pharmaceutical compositions.

[0063] In some embodiments, compositions of the invention comprising one or more GLP-1 / GLP-2 dual agonists comprising Formula A or B are isotonic. In some embodiments, compositions of the invention comprising one or more GLP-1 / GLP-2 dual agonists comprising SEQ ID NO: 1 are isotonic.

[0064] In some embodiments, the osmolality of the compositions of the present invention is about 300±120 mOsmol / kg. In some embodiments, the osmolality of the compositions of the present invention is about 290±70 mOsmol / kg. In some embodiments, the osmolality of the compositions of the present invention is about 230 mOsmol / kg to about 370 mOsmol / kg. In some embodiments, the osmolality of the compositions of the present invention is about 280 mOsmol / kg to about 320 mOsmol / kg. In some embodiments, the osmolality of the compositions of the present invention is about 290 mOsmol / kg to about 320 mOsmol / kg.

[0065] In some embodiments, the compositions of the present invention, eg, the isotonic parenteral pharmaceutical compositions of the present invention, comprise one or more tonicity agents.

[0066] The term "tonicity adjusting agent" refers to an excipient added to a composition according to the present invention to achieve isotonicity with respect to body fluids. A range of ionic and non-ionic tonicity adjusting agents are used in pharmaceutical compositions. Non-ionic tonicity adjusting agents may be selected from dextrose, propylene glycol, glyceryl, mannitol, e.g., D-mannitol, and sorbitol. Ionic tonicity adjusting agents may include alkali metals or earth halides, e.g., CaCl, KBr, KCl, LiCl, NaI, NaBr, NaCl, NaSO. In one embodiment, the tonicity adjusting agent may be selected from mannitol, NaCl, and propylene glycol.

[0067] An "ionic compound" is two or more ions held together by attractive forces. An example of an ionic compound is table salt. It consists of a positive sodium ion and a negative chloride ion. They have high melting and boiling points and are hard or brittle. They can also be dissolved in water. The definition of a "nonionic compound" is that the chemical bonds in this compound are nonionic. They usually have chemical bonds that share electron density.

[0068] In some embodiments, the one or more tonicity adjusting agents include or are mannitol. Preferably, the one or more tonicity adjusting agents are D-mannitol. In some embodiments, mannitol, e.g., D-mannitol, is present in the composition of the present invention at a concentration of about 130 mM to about 330 mM, preferably about 150 mM to about 300 mM, and more preferably about 190 mM to about 240 mM. In some embodiments, mannitol, e.g., D-mannitol, is present in the composition of the present invention at about 230 mM.

[0069] In some embodiments, the one or more tonicity agents include or are NaCl. In some embodiments, NaCl is present in the compositions of the present invention at a concentration of about 50 mM to about 450 mM, preferably about 65 mM to about 165 mM. Preferably, NaCl is present at a concentration of about 125 mM.

[0070] The term "isotonic," as used herein, refers to the osmotic pressure relative to bodily fluids at the site of injection, i.e., IV or SC. Thus, the term "isotonic" is used to describe a pharmaceutical composition having the same osmotic pressure as bodily fluids, e.g., red blood cells and / or plasma, at the injection site. Compositions having an osmolality of about 300 mOsmol / kg, e.g., about 280-320 mOsmol / kg or about 290-320 mOsmol / kg, are considered to be isotonic.

[0071] Isotonicity is important for parenteral pharmaceutical compositions because "hypotonic" solutions cause cell swelling, while "hypertonic" solutions cause cell shrinkage. Although it is related to osmolality, osmolality also considers the ability of solutes to cross cell membranes.

[0072] Compositions of the Invention In some embodiments, the compositions of the present invention, such as the isotonic parenteral pharmaceutical compositions of the present invention, comprise a solvent. In some embodiments, the solvent is water.

[0073] In some embodiments, the compositions of the present invention, eg, the isotonic parenteral pharmaceutical compositions of the present invention, comprise a tonicity agent and a solvent.

[0074] In some embodiments, a composition of the invention, eg, an isotonic parenteral pharmaceutical composition of the invention, comprises a GLP-1 / GLP-2 dual agonist comprising the amino acid sequence of Formula A, m-cresol, and Tris buffer.

[0075] In some embodiments, a composition of the invention, eg, an isotonic parenteral pharmaceutical composition of the invention, comprises a GLP-1 / GLP-2 dual agonist comprising the amino acid sequence of Formula A, phenol, and Tris buffer.

[0076] In some embodiments, the compositions of the invention, e.g., the isotonic parenteral pharmaceutical compositions of the invention, comprise a GLP-1 / GLP-2 dual agonist comprising an amino acid sequence of Formula A, m-cresol, Tris buffer, and mannitol, e.g., D-mannitol.

[0077] In some embodiments, the compositions of the invention, e.g., the isotonic parenteral pharmaceutical compositions of the invention, comprise a GLP-1 / GLP-2 dual agonist comprising an amino acid sequence of Formula A, phenol, Tris buffer, and mannitol, e.g., D-mannitol.

[0078] In some embodiments, in the compositions of the invention, e.g., the isotonic parenteral pharmaceutical compositions of the invention, the GLP-1 / GLP-2 dual agonist comprises the amino acid sequence of Formula A, the preservative is m-cresol at a final concentration of about 1.15 mg / mL to about 5.15 mg / mL, preferably about 3.15 mg / mL, or the preservative is phenol at a final concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL, and the Tris buffer is present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM.

[0079] In some embodiments, in the compositions of the invention, e.g., the isotonic parenteral pharmaceutical compositions of the invention, the GLP-1 / GLP-2 dual agonist comprises the amino acid sequence of Formula A, the preservative is m-cresol at a final concentration of about 1.15 mg / mL to about 5.15 mg / mL, preferably about 3.15 mg / mL, and the Tris buffer is present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM.

[0080] In some embodiments, in the compositions of the invention, e.g., the isotonic parenteral pharmaceutical compositions of the invention, the GLP-1 / GLP-2 dual agonist comprises the amino acid sequence of Formula A, the preservative is phenol at a final concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL, and the Tris buffer is present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM.

[0081] In some embodiments, in the compositions of the invention, e.g., the isotonic parenteral pharmaceutical compositions of the invention, the GLP-1 / GLP-2 dual agonist comprises the amino acid sequence of Formula A and is present in a concentration of at least 1 mg / mL to about 33 mg / mL, preferably at least 1 mg / mL to about 25 mg / mL, preferably at least 6 mg / mL to about 25 mg / mL; the preservative is m-cresol at a final concentration of about 1.15 mg / mL to about 5.15 mg / mL, preferably about 3.15 mg / mL; or the preservative is phenol at a final concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL; and the Tris buffer is present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM.

[0082] In some embodiments, in the compositions of the invention, e.g., the isotonic parenteral pharmaceutical compositions of the invention, the GLP-1 / GLP-2 dual agonist comprises the amino acid sequence of Formula A and is present at a concentration of at least 1 mg / mL to about 33 mg / mL, preferably at least 1 mg / mL to about 25 mg / mL, preferably at least 6 mg / mL to about 25 mg / mL, the preservative is m-cresol at a final concentration of about 1.15 mg / mL to about 5.15 mg / mL, preferably about 3.15 mg / mL, and the Tris buffer is present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM.

[0083] In some embodiments, in the compositions of the invention, e.g., the isotonic parenteral pharmaceutical compositions of the invention, the GLP-1 / GLP-2 dual agonist comprises the amino acid sequence of Formula A and is present at a concentration of at least 1 mg / mL to about 33 mg / mL, preferably at least 1 mg / mL to about 25 mg / mL, preferably at least 6 mg / mL to about 25 mg / mL, the preservative is phenol at a final concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL, and the Tris buffer is present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM.

[0084] In some embodiments, in the compositions of the invention, e.g., isotonic parenteral pharmaceutical compositions of the invention, the GLP-1 / GLP-2 dual agonist comprises the amino acid sequence of Formula A and is present at a concentration of at least 1 mg / mL to about 33 mg / mL, preferably at least 1 mg / mL to about 25 mg / mL, preferably at least 6 mg / mL to about 25 mg / mL, and the preservative is present at a final concentration of about 1.15 mg / mL to about 5.15 mg / mL, preferably about 3.15 mg / mL. -cresol, or the preservative is phenol at a final concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL, the Tris buffer is present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM, and the tonicity agent is mannitol, e.g., D-mannitol, at a final concentration of about 130 mM to about 330 mM, preferably about 150 mM to about 300 mM, preferably about 190 mM to about 240 mM, preferably about 230 mM.

[0085] In some embodiments, in the compositions of the invention, e.g., the isotonic parenteral pharmaceutical compositions of the invention, the GLP-1 / GLP-2 dual agonist comprises the amino acid sequence of Formula A and is present in a concentration of at least 1 mg / mL to about 25 mg / mL, preferably at least 6 mg / mL to about 25 mg / mL; the preservative is m-cresol at a final concentration of about 1.15 mg / mL to about 5.15 mg / mL, preferably about 3.15 mg / mL; the Tris buffer is present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM; and the tonicity agent is mannitol, e.g., D-mannitol, at a final concentration of about 130 mM to about 330 mM, preferably about 150 mM to about 300 mM, preferably about 190 mM to about 240 mM, preferably about 230 mM.

[0086] In some embodiments, in the compositions of the invention, e.g., the isotonic parenteral pharmaceutical compositions of the invention, the GLP-1 / GLP-2 dual agonist comprises the amino acid sequence of Formula A and is present in a concentration of at least 1 mg / mL to about 33 mg / mL, preferably at least 1 mg / mL to about 25 mg / mL, preferably at least 6 mg / mL to about 25 mg / mL; the preservative is phenol at a final concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL; the Tris buffer is present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM; and the tonicity agent is mannitol, e.g., D-mannitol, at a final concentration of about 130 mM to about 330 mM, preferably about 150 mM to about 300 mM, preferably about 190 mM to about 240 mM, preferably about 230 mM.

[0087] In some embodiments, in the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, the GLP-1 / GLP-2 dual agonist is CPD1OH or a pharmaceutically acceptable salt thereof, preferably at a final concentration of about 1 mg / mL to about 33 mg / mL, preferably about 1 mg / mL to about 25 mg / mL, preferably about 2 mg / mL to about 25 mg / mL, and more preferably about 6 mg / mL to about 25 mg / mL; the preservative is m-cresol at a final concentration of about 1.15 mg / mL to about 5.15 mg / mL, preferably about 3.15 mg / mL, or the preservative is phenol at a final concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL; and the Tris buffer is present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM.

[0088] In some embodiments, in the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, the GLP-1 / GLP-2 dual agonist is CPD1OH or a pharmaceutically acceptable salt thereof, preferably at a final concentration of about 1 mg / mL to about 33 mg / mL, preferably about 1 mg / mL to about 25 mg / mL, preferably about 2 mg / mL to about 25 mg / mL, and more preferably about 6 mg / mL to about 25 mg / mL; the preservative is m-cresol at a final concentration of about 1.15 mg / mL to about 5.15 mg / mL, preferably about 3.15 mg / mL; and the Tris buffer is present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM.

[0089] In some embodiments, in the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, the GLP-1 / GLP-2 dual agonist is CPD1OH or a pharmaceutically acceptable salt thereof, preferably at a final concentration of about 1 mg / mL to about 33 mg / mL, preferably about 1 mg / mL to about 25 mg / mL, preferably about 2 mg / mL to about 25 mg / mL, and more preferably about 6 mg / mL to about 25 mg / mL; the preservative is phenol at a final concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL; and the Tris buffer is present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM.

[0090] In some embodiments, in the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, the GLP-1 / GLP-2 dual agonist is CPD1OH or a pharmaceutically acceptable salt thereof, preferably at a final concentration of about 1 mg / mL to about 33 mg / mL, preferably about 1 mg / mL to about 25 mg / mL, preferably about 2 mg / mL to about 25 mg / mL, more preferably about 6 mg / mL to about 25 mg / mL, and the preservative is CPD1OH or a pharmaceutically acceptable salt thereof, preferably at a final concentration of about 1.15 mg / mL to about 5.15 mg / mL, preferably about 3.1 The preservative is m-cresol at a final concentration of 5 mg / mL, or the preservative is phenol at a final concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL, the Tris buffer is present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM, and the tonicity agent is mannitol, e.g., D-mannitol, at a final concentration of about 130 mM to about 330 mM, preferably about 150 mM to about 300 mM, preferably about 190 mM to about 240 mM, preferably about 230 mM.

[0091] In some embodiments, in the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, the GLP-1 / GLP-2 dual agonist is CPD1OH or a pharmaceutically acceptable salt thereof, preferably at a final concentration of about 1 mg / mL to about 33 mg / mL, preferably about 1 mg / mL to about 25 mg / mL, preferably about 2 mg / mL to about 25 mg / mL, and more preferably about 6 mg / mL to about 25 mg / mL; the preservative is m-cresol at a final concentration of about 1.15 mg / mL to about 5.15 mg / mL, preferably about 3.15 mg / mL; the Tris buffer is present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM; and the tonicity agent is mannitol, e.g., D-mannitol, at a final concentration of about 130 mM to about 330 mM, preferably about 150 mM to about 300 mM, preferably about 190 mM to about 240 mM, and preferably about 230 mM.

[0092] In some embodiments, in the compositions of the present invention, e.g., the isotonic parenteral pharmaceutical compositions of the present invention, the GLP-1 / GLP-2 dual agonist is CPD1OH or a pharmaceutically acceptable salt thereof, preferably at a final concentration of about 1 mg / mL to about 33 mg / mL, preferably about 1 mg / mL to about 25 mg / mL, preferably about 2 mg / mL to about 25 mg / mL, and more preferably about 6 mg / mL to about 25 mg / mL; the preservative is phenol at a final concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL; the Tris buffer is present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM; and the tonicity agent is mannitol, e.g., D-mannitol, at a final concentration of about 130 mM to about 330 mM, preferably about 150 mM to about 300 mM, preferably about 190 mM to about 240 mM, and preferably about 230 mM.

[0093] Indications In some embodiments, the pharmaceutical compositions of the present invention are administered to a human subject in need of prevention or treatment of intestinal damage and dysfunction, weight regulation, and prevention or treatment of metabolic dysfunction.

[0094] In some embodiments, the pharmaceutical compositions of the present invention are useful for treating various conditions, including malabsorption, ulcers (e.g., peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, and ulcers associated with infections or other pathogens), short bowel syndrome, blind canal syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), irritable bowel syndrome (IBS), pouchitis, celiac sprue (e.g., resulting from gluten-sensitive enteropathy or celiac disease), tropical sprue, hypogammaglobulinemic sprue, chemotherapy- or radiation-induced mucositis, chemotherapy- or radiation-induced diarrhea, low-grade inflammation, metabolic endotoxemia, necrotizing enterocolitis, primary biliary cirrhosis, hepatitis, fatty liver (parenteral nutrition-associated intestinal atrophy, parenteral nutrition-associated liver disease (PNALD), non-alcoholic fatty liver disease (NAFLD), and other conditions. The compounds are administered to human subjects in need of prophylaxis or treatment of gastrointestinal side effects of inflammatory conditions, including liver cirrhosis (IL-1) and non-alcoholic steatohepatitis (NASH), or inflammatory conditions such as pancreatitis or graft versus host disease (GVHD).

[0095] In some embodiments, the pharmaceutical compositions of the invention are administered to a human subject in need of prevention or treatment of obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, poor glucose control, glucose tolerance, dyslipidemia (e.g., high LDL levels or low HDL / LDL ratio), diabetes (e.g., type 2 diabetes, gestational diabetes), pre-diabetes, metabolic syndrome, or hypertension.

[0096] In some embodiments, the pharmaceutical compositions of the present invention are administered to a human subject to promote a biological effect selected from the group consisting of increasing intestinal mass, improving intestinal function (especially intestinal barrier function), increasing intestinal blood flow, and repairing intestinal damage or dysfunction in a subject in need thereof.

[0097] In some embodiments, the pharmaceutical compositions of the invention are administered to a human subject in need of prevention or treatment of intestinal dysfunction or damage caused by or associated with GVHD, and prevention or treatment of side effects, such as diarrhea, caused by or associated with GVHD.

[0098] In some embodiments, the pharmaceutical compositions of the present invention are administered to a human subject in need of prevention or treatment of obesity, morbid obesity, obesity-related gallbladder disease, and obesity-induced sleep apnea.

[0099] In some embodiments, the pharmaceutical compositions of the present invention are administered to human subjects in need of improved glucose tolerance and / or glucose control. In some embodiments, the pharmaceutical compositions of the present invention are administered to human subjects in need of modulating (e.g., improving) circulating cholesterol levels, enabling a reduction in circulating triglyceride or LDL levels, and in need of an increased HDL / LDL ratio.

[0100] Administration In some embodiments, the pharmaceutical compositions of the present invention are aqueous compositions. In some embodiments, the pharmaceutical compositions of the present invention are suitable for parenteral administration by subcutaneous (sc), intramuscular (im) or intravenous (iv) injection via a syringe, which may be a pen-like syringe. In some embodiments, the pharmaceutical compositions of the present invention are suitable for sc injection into a human subject. In some embodiments, the pharmaceutical compositions of the present invention are suitable for iv injection into a human subject.

[0101] In some embodiments, the isotonic parenteral pharmaceutical composition of the present invention is suitable for single-dose administration. In some embodiments, the isotonic parenteral pharmaceutical composition is an injection and is suitable for injection in a single-use device. In some embodiments, the single-use device is selected from an injector pen or a single-use syringe. In some embodiments, the isotonic parenteral pharmaceutical composition of the present invention is suitable for multi-dose administration.

[0102] In some embodiments, the isotonic parenteral pharmaceutical composition of the present invention is administered by sc injection to a human subject in a volume that allows a total amount of about 1 mg to about 25 mg of the GLP-1 / GLP-2 dual agonist to be delivered to the subject. In some embodiments, the isotonic parenteral pharmaceutical composition of the present invention is administered by sc injection to a human subject in a volume that allows a total amount of about 1 mg or more of the GLP-1 / GLP-2 dual agonist to be delivered to the subject. In some embodiments, the isotonic parenteral pharmaceutical composition of the present invention is administered by sc injection to a human subject in a volume that allows a total amount of about 2 mg to about 25 mg of the GLP-1 / GLP-2 dual agonist to be delivered to the subject, preferably a total amount of about 6 mg to about 25 mg of the GLP-1 / GLP-2 dual agonist to be delivered to the subject. In some embodiments, the isotonic parenteral pharmaceutical compositions of the present invention are administered by sc injection to a human subject in a volume that allows a total of about 1 mg or more of the GLP-1 / GLP-2 dual agonist to be delivered to the subject. In some embodiments, the isotonic parenteral pharmaceutical compositions of the present invention are administered by sc injection to a human subject in a volume that allows a total of about 2 mg or more of the GLP-1 / GLP-2 dual agonist to be delivered to the subject. In some embodiments, the isotonic parenteral pharmaceutical compositions of the present invention are administered by sc injection to a human subject in a volume that allows a total of about 3 mg or more of the GLP-1 / GLP-2 dual agonist to be delivered to the subject. In some embodiments, the isotonic parenteral pharmaceutical compositions of the present invention are administered by sc injection to a human subject in a volume that allows a total of about 4 mg or more of the GLP-1 / GLP-2 dual agonist to be delivered to the subject. In some embodiments, the isotonic parenteral pharmaceutical compositions of the present invention are administered by sc injection to a human subject in a volume that allows a total amount of about 5 mg or more of the GLP-1 / GLP-2 dual agonist to be delivered to the subject.In some embodiments, the isotonic parenteral pharmaceutical compositions of the present invention are administered by sc injection to a human subject in a volume that allows a total of about 6 mg or more of the GLP-1 / GLP-2 dual agonist to be delivered to the subject. In some embodiments, the isotonic parenteral pharmaceutical compositions of the present invention are administered by sc injection to a human subject in a volume that allows a total of about 9 mg or more of the GLP-1 / GLP-2 dual agonist to be delivered to the subject. In some embodiments, the isotonic parenteral pharmaceutical compositions of the present invention are administered by sc injection to a human subject in a volume that allows a total of about 10 mg or more of the GLP-1 / GLP-2 dual agonist to be delivered to the subject. In some embodiments, the isotonic parenteral pharmaceutical compositions of the present invention are administered by sc injection to a human subject in a volume that allows a total amount of about 7, 8, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg or more of the GLP-1 / GLP-2 dual agonist to be delivered to the subject.

[0103] biological activity In some embodiments, the peptide included in the pharmaceutical composition of the present invention is the peptide set forth in Formula A and SEQ ID NO: 1, which has been previously described in patent application WO2018104561 (WO2018104561, Table 5), which describes the compounds, their preparation and purification, and biological activity. Example 2 in WO2018104561 contains data on in vitro potency against GLP-1 and GLP-2 receptors.

[0104] Chemical stability (purity) The compositions of the present invention, such as the isotonic parenteral pharmaceutical compositions of the present invention, provide excellent chemical stability. In other words, in the compositions of the present invention, the GLP-1 / GLP-2 dual agonist remains chemically stable during storage. The chemical stability may be comparable to that of an equivalent composition described herein that does not contain a preservative according to the present invention.

[0105] In some embodiments, the compositions of the present invention have superior or improved relative purity, which may be comparable to or improved compared to an equivalent composition without a preservative according to the present invention as described herein.

[0106] When the "chemical stability" of the compositions of the present invention is referred to herein, it refers to the chemical stability of the GLP-1 / GLP-2 dual agonist contained in the composition. In some embodiments, the chemical stability of the GLP-1 / GLP-2 dual agonist is determined using Assay I described herein.

[0107] The chemical stability at time Y of the GLP-1 / GLP-2 dual agonist in any of the tested compositions disclosed herein is determined by the relative purity X of the GLP-1 / GLP-2 dual agonist. Y The absolute purity of the GLP-1 / GLP-2 dual agonist, X', can be expressed as the absolute purity of the GLP-1 / GLP-2 dual agonist on day 0 (day 0), X 0 , and the absolute purity is determined by identifying the purity of the peak corresponding to the GLP-1 / GLP-2 dual agonist by HPLC at a given time point Y.

[0108] Therefore, on day zero (day 0), the absolute purity X' is 0 and therefore the chemical stability of the GLP-1 / GLP-2 dual agonist in the tested composition is equal to the relative purity X Y = 100%, Y = day 0.

[0109] The relative purity is X Y =(X' / X 0 ) x 100 where X is the relative purity at a given time point Y and X 0 is the absolute purity on day 0, and X' is the absolute purity at a given time point Y} The absolute purity of the GLP-1 / GLP-2 dual agonist in the tested composition can be calculated by: X 0 or X' is determined by HPLC to identify the purity of the peak corresponding to the GLP-1 / GLP-2 dual agonist.

[0110] The relative purity at a given time point can be calculated by multiplying the slope of the purity by the number of weeks of storage and subtracting the factor of this value from 100%.

[0111] In some embodiments, the pharmaceutical compositions of the present invention provide a relative purity of said one or more GLP-1 / GLP-2 dual agonists, e.g., CPD1 or any pharmaceutically acceptable salt thereof, of at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, e.g., after at least 2 weeks of storage, e.g., at 40° C. In some embodiments, the pharmaceutical compositions of the present invention provide a relative purity of said one or more GLP-1 / GLP-2 dual agonists, e.g., CPD1 or any pharmaceutically acceptable salt thereof, of at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, e.g., after at least 26 weeks of storage, e.g., at 25° C. In some embodiments, the pharmaceutical compositions of the present invention provide a relative purity of said one or more GLP-1 / GLP-2 dual agonists, e.g., CPD1 or any pharmaceutically acceptable salt thereof, of at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, e.g., after storage at 5°C, e.g., for at least 52 weeks.

[0112] Chemical stability: oligomerization Peptides in solution can aggregate to form therapeutically inactive covalently linked oligomers. Peptide oligomerization can be measured using size exclusion chromatography (SEC) as described in Assay II herein.

[0113] A variety of analytical techniques for measuring peptide stability are available in the art and are summarized, for example, in 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).

[0114] Surprisingly, it has been found that the peptides of the present invention are more stable and less likely to oligomerize when the m-cresol preservative is combined with a Tris buffer rather than a phosphate buffer.

[0115] The relative total non-oligomerized peptide at a given time point can be calculated by multiplying the oligomer slope by the number of weeks of storage and subtracting the factor of this value from 100%.

[0116] In some embodiments, the pharmaceutical compositions of the present invention provide at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% relative total non-oligomerized peptide (monomer) of said one or more dual GLP-1 / GLP-2 agonists, e.g., CPD1 or any pharmaceutically acceptable salt thereof, after storage, e.g., at 40°C, for at least 2 weeks. In some embodiments, the pharmaceutical compositions of the present invention provide at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% relative total non-oligomerized peptide of said one or more dual GLP-1 / GLP-2 agonists, e.g., CPD1 or any pharmaceutically acceptable salt thereof, e.g., after storage for at least 26 weeks, e.g., at 25°C. In some embodiments, the pharmaceutical compositions of the invention provide at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% relative total non-oligomerized peptide of said one or more dual GLP-1 / GLP-2 agonists, e.g., CPD1 or any pharmaceutically acceptable salt thereof, after storage, e.g., at 5°C, for at least 52 weeks.

[0117] [Table 3]

[0118] Terms and Definitions When using terms such as "about" and "approximately" in relation to numerical values, those skilled in the art will immediately recognize that any effect or result that may accompany a given value can be obtained within a certain tolerance from the particular value. Thus, the term "about" as used herein means within a reasonable vicinity of the referenced numerical value, for example, within 10% plus or minus. When the term "about" is used in this patent application with respect to chemical stability, a reasonable vicinity is less than 2%, for example, 0.5% or 0.75%, 1% or 1.5%.

[0119] The term "solvent," as used herein, means a substance that dissolves a solute (a chemically distinct liquid, solid, or gas), resulting in a solution. Solvents are usually liquids, but may also be solids, gases, or supercritical fluids. Solvents are generally classified by polarity and are considered to be either polar or nonpolar, as indicated by their dielectric constant. Generally, solvents with a dielectric constant greater than about 5 are considered "polar," while solvents with a dielectric constant less than 5 are considered "nonpolar."

[0120] Non-limiting aspects of the present invention The following part of this description includes certain non-limiting aspects of the present invention. The aspects described below may be combined with any of the aspects of the present invention described above and below and herein.

[0121] 1. (a) General formula A: H[Aib]EG-X5-F-X7-SELATILD-[Ψ]-QAARDFIAWLI-X28-HKITD(A) wherein X5 is T or S; X7 is T or S; X28 is Q, E, A, H, Y, L, K, R or S, and at least one of X5 and X7 is T; [Ψ] represents an L or D lysine residue that is the albumin binding moiety conjugated to the GLP-1 / GLP-2 dual agonist; the albumin binding moiety is [K([17-carboxy-heptadecanoyl]-isoGlu)]} one or more GLP-1 / GLP-2 dual agonists, including: (b) one or more preservatives that include or are m-cresol and / or phenol; and (c) Tris buffer A composition comprising:

[0122] 2. The composition of aspect 1, which is an isotonic parenteral pharmaceutical composition.

[0123] 3. The composition of aspect 1 or 2, wherein the one or more preservatives include or are m-cresol, preferably wherein the m-cresol is present at a concentration of about 1.15 mg / mL to about 5.15 mg / mL, more preferably wherein the m-cresol is present at a concentration of about 3.15 mg / mL.

[0124] 4. The composition of any one of aspects 1-3, wherein the one or more preservatives comprises or is phenol, and preferably the phenol is present at a concentration of about 2.5 mg / mL to about 8.5 mg / mL, more preferably the phenol is present at a concentration of about 5.5 mg / mL.

[0125] 5. The composition of any one of aspects 1 to 4, wherein the Tris buffer is present at a concentration of about 5 mM to about 50 mM, preferably the Tris buffer is present at a concentration of about 20 mM.

[0126] 6. The composition according to any one of aspects 1 to 5, having a pH of about pH 6.0 to about pH 8.5, preferably about pH 6.5 to about pH 8.5, preferably about pH 7.0 to about pH 8.0, more preferably about pH 8.0.

[0127] 7. The one or more GLP-1 / GLP-2 dual agonists have the general formula B: H[Aib]EG-X5-FT-SELATILD-[Ψ]-QAARDFIAWLI-X28-HKITD(B) wherein 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 that is an albumin binding moiety conjugated to a GLP-1 / GLP-2 dual agonist; the albumin binding moiety is [K([17-carboxy-heptadecanoyl]-isoGlu)]} 7. The composition according to any one of aspects 1 to 6, wherein the GLP-1 / GLP-2 dual agonist is

[0128] 8. One or more GLP-1 / GLP-2 dual agonists have the sequence: H[Aib]EGSFTSELATILD[Ψ]QAARDFIAWLIQHKITD (SEQ ID NO: 1) 8. The composition of any one of aspects 1 to 7, comprising:

[0129] 9. One or more GLP-1 / GLP-2 dual agonists are: Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH(CPD1OH); or Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-NH2(CPD1NH2) or a pharmaceutically acceptable salt of CPD1OH or CPD1NH2, preferably the chloride salt of CPD1OH or CPD1NH2.

[0130] 10. The composition of any of aspects 1 to 9, wherein the GLP-1 / GLP-2 dual agonist is present at a concentration of at least about 1 mg / mL, preferably at a concentration of about 1 mg / mL to about 33 mg / mL, for example, at a concentration of about 2 mg / mL to about 33 mg / mL, for example, at a concentration of about 1 mg / mL to about 25 mg / mL, for example, at a concentration of about 6 mg / mL to about 25 mg / mL.

[0131] 11. The composition of aspect 11, wherein the GLP-1 / GLP-2 dual agonist is present in a concentration of about 2 mg / mL, about 15 mg / mL, or about 25 mg / mL.

[0132] 12. The composition of any one of aspects 1 to 11, further comprising one or more tonicity agents.

[0133] 13. The composition of aspect 12, wherein the one or more tonicity agents comprises or is mannitol, preferably D-mannitol.

[0134] 14. The composition of aspect 13, wherein mannitol is present at a concentration of about 130 mM to about 330 mM, preferably about 150 mM to about 300 mM, preferably about 190 mM to about 240 mM, preferably about 230 mM.

[0135] 15. The composition of aspect 12, wherein the one or more tonicity agents comprises or is NaCl, and preferably the NaCl is present at a concentration of about 50 mM to about 450 mM, preferably about 65 mM to about 165 mM, preferably about 125 mM.

[0136] 16. The composition of any one of aspects 1-15, wherein the osmolality of the composition is from about 230 mOsmol / kg to about 370 mOsmol / kg.

[0137] 17. The composition of any one of aspects 1 to 16, further comprising a solvent, preferably water.

[0138] 18. The composition of any one of aspects 1 to 17, wherein the one or more preservatives is m-cresol at a concentration of about 1.15 mg / mL to about 5.15 mg / mL, preferably about 3.15 mg / mL; the Tris buffer is present at a concentration of about 5 mM to about 50 mM, preferably about 20 mM; the composition further comprises mannitol, preferably D-mannitol, at a concentration of about 130 mM to about 330 mM, preferably about 150 mM to about 300 mM, preferably about 190 mM to about 240 mM, preferably about 230 mM; and the pH of the composition is about pH 7.0 to about pH 8.0, preferably about pH 8.0.

[0139] 19. The composition of any of aspects 1 to 18, wherein the one or more preservatives is phenol at a concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL; the Tris buffer is present at a concentration of about 5 mM to about 50 mM, preferably about 20 mM; the composition further comprises mannitol, preferably D-mannitol, at a concentration of about 130 mM to about 330 mM, preferably about 150 mM to about 300 mM, preferably about 190 mM to about 240 mM, preferably about 230 mM; and the pH of the composition is about pH 7.0 to about pH 8.0, preferably about pH 8.0.

[0140] 20. The composition of any of aspects 1 to 19, wherein the one or more GLP-1 / GLP-2 dual agonists is CPD1OH or CPD1NH2, preferably CPD1OH, or the chloride salt of CPD1OH or CPD1NH2, preferably the chloride salt of CPD1OH; the one or more preservatives is m-cresol at a concentration of about 1.15 mg / mL to about 5.15 mg / mL, preferably about 3.15 mg / mL; the Tris buffer is present at a concentration of about 5 mM to about 50 mM, preferably about 20 mM; and the composition further comprises mannitol, preferably D-mannitol, at a concentration of about 230 mM, water, and sodium hydroxide and / or hydrochloric acid for pH adjustment to a pH of about pH 8.0.

[0141] 21. The composition of any of aspects 1 to 20, wherein the one or more GLP-1 / GLP-2 dual agonists is CPD1OH or CPD1NH2, preferably CPD1OH, or the chloride salt of CPD1OH or CPD1NH2, preferably the chloride salt of CPD1OH; the one or more preservatives is phenol at a concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL; the Tris buffer is present at a concentration of about 5 mM to about 50 mM, preferably about 20 mM; and the composition further comprises mannitol, preferably D-mannitol, at a concentration of about 230 mM, water, and sodium hydroxide and / or hydrochloric acid for pH adjustment to a pH of about pH 8.0.

[0142] 22. The composition of any one of aspects 1 to 21, which is suitable for subcutaneous (sc) or intravenous (iv) injection into a human subject.

[0143] 23. (i) increasing intestinal mass, improving intestinal function, increasing intestinal blood flow, or repairing intestinal damage or dysfunction in a subject in need thereof; or (ii) preventing or treating the gastrointestinal side effects of malabsorption, ulcers, short bowel syndrome, blind tract syndrome, inflammatory bowel disease, irritable bowel syndrome, pouchitis, celiac sprue, tropical sprue, hypogammaglobulinemic sprue, chemotherapy- or radiation-induced mucositis, chemotherapy- or radiation-induced diarrhea, low-grade inflammation, metabolic endotoxemia, necrotizing enterocolitis, primary biliary cirrhosis, hepatitis, fatty liver, or an inflammatory condition in a subject in need thereof; or (iii) reducing or inhibiting weight gain, reducing gastric emptying or intestinal transit, reducing food intake, reducing appetite, or promoting weight loss in a subject in need thereof; or (iv) preventing or treating obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, inadequate glucose control, glucose tolerance, dyslipidemia, diabetes, prediabetes, metabolic syndrome, or hypertension in a subject in need thereof; 23. The composition of any of aspects 1 to 22 for use in

[0144] 24. General formula A: H[Aib]EG-X5-F-X7-SELATILD-[Ψ]-QAARDFIAWLI-X28-X29-KITD(A) 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, and at least one of X5 and X7 is T; [Ψ] represents an L or D lysine residue that is the albumin binding moiety conjugated to the GLP-1 / GLP-2 dual agonist; The albumin binding moiety is [K([17-carboxy-heptadecanoyl]-isoGlu)]} 1. A method for storing a composition comprising one or more GLP-1 / GLP-2 dual agonists, comprising: The composition comprises a Tris buffer; the method includes adding one or more preservatives to the composition, wherein the one or more preservatives include or are m-cresol and / or phenol; method.

[0145] 25. General formula A: H[Aib]EG-X5-F-X7-SELATILD-[Ψ]-QAARDFIAWLI-X28-HKITD(A) wherein X5 is T or S; X7 is T or S; X28 is Q, E, A, H, Y, L, K, R or S, and at least one of X5 and X7 is T; [Ψ] represents an L or D lysine residue that is the albumin binding moiety conjugated to the GLP-1 / GLP-2 dual agonist; the albumin binding moiety is [K([17-carboxy-heptadecanoyl]-isoGlu)]} Use of a preservative for preserving a composition comprising one or more GLP-1 / GLP-2 dual agonists, comprising: The composition comprises a Tris buffer; the preservative comprises or is m-cresol and / or phenol; use.

[0146] Common methods used Method I - Method for the preparation of GLP-1 / GLP-2 dual agonists The GLP-1 / GLP-2 dual agonist was synthesized as described in Example 1 and based on General Peptide Synthesis in patent application WO 2018 / 104561.

[0147] CPD1 (corresponding to compound 18 in WO 2018 / 104561) was synthesized using solid phase peptide synthesis (SPPS) techniques and standard Fmoc coupling methods. After synthesis was complete, the peptide sequence was deprotected, cleaved from the solid support, and the crude peptide was purified using preparative reverse-phase HPLC. The peptide was converted to an acceptable salt form (HCl, acetate, or Na) and lyophilized to obtain the final CPD1 drug substance.

[0148] Method II - Methods for the preparation and analysis of pharmaceutical compositions Research-scale sample solutions GLP-1 / GLP-2 dual agonist drug substance (CPD1) was prepared according to Method I and dissolved in MilliQ water (MQW) to obtain a stock solution of 40 mg / mL of the active ingredient (API). The pH was measured. Following this, the ingredients exemplified in Tables 5-10 were added and mixed, after which the pH was adjusted using 1 M NaOH / HCl as needed to reach the appropriate pH. The final concentration was 2 or 25 mg / mL of CPD1, as indicated in the tables and examples in this application. Research-scale compositions were prepared in volumes of 0.5 to approximately 2 mL.

[0149] For stability testing, samples were stored in the dark (i.e., with lights off) at 40° C. for 2 weeks. Samples were analyzed by RP-HPLC and SEC-HPLC according to Assays I and II, respectively.

[0150] Assay I - Measurement of GLP-1 / GLP-2 Dual Agonist Purity and Determination of Normalized GLP-1 / GLP-2 Dual Agonist Purity (%) Using RP-HPLC The chemical stability of a GLP-1 / GLP-2 dual agonist (peptide) is determined by HPLC at a given time point and expressed herein as the relative purity of the peptide peak (i.e., the major peptide peak) normalized to the absolute purity of the peptide peak (i.e., the major peptide peak) at day 0 (T=0), which is set to a normalized purity of 100%. The RP-HPLC method can detect CPD1 degradation products (deamidation, isomerization, hydrolysis, and racemization). The RP-HPLC method cannot detect covalent oligomers, in which two or more CPD1 molecules are linked together through covalent chemical bonds—see Assay II for further information on the detection of covalent oligomers.

[0151] The chemical stability of the GLP-1 / GLP-2 dual agonist (peptide) prepared according to Method I contained in the parenteral pharmaceutical composition prepared according to Method II is analyzed according to the following method.

[0152] A Dionex Ultimate 3000 HPLC system (Thermo Fisher) with a linear gradient at a flow rate of 0.5 mL / min was used for the analysis. The mobile phase consisted of 0.3% trifluoroacetic acid (TFA) in 90% acetonitrile / 10% MQW and 0.3% TFA in MQW. A wavelength of 215 nm was used for detection. The injection amount was 2 μg of peptide. The column used for HPLC analysis was a Phenomenex Kinetex C18, 150 × 3.0 mm, 2.6 μm particle size. The run time was 25 min.

[0153] [Table 4]

[0154] The results are shown in Tables 5-7 as the degradation slope calculated from the normalized purity results. The slope is a measure of how quickly CPD1 degrades. Lower numbers (i.e., numbers further from 0) represent higher degradation.

[0155] Assay II - Method for evaluation of covalent oligomers by size exclusion chromatography (SEC) Size-exclusion chromatography (SEC) experiments were performed on a Dionex Ultimate 3000 HPLC system (Thermo Fisher) using isocratic elution at a flow rate of 0.5 mL / min. The mobile phase consisted of 0.1% TFA, 45% acetonitrile in MQW. A wavelength of 215 nm was used for detection. The injection amount was 2 μg of peptide. The column used for SEC analysis was a TSKgel SuperSW2000 (Tosoh Corporation), 4 μm, 30 × 4.6 mm, and the column temperature was 25 °C. The run time was 12 min.

[0156] The SEC method is capable of detecting covalent oligomers in which two or more CPD1 molecules are linked together through covalent chemical bonds.

[0157] The covalent oligomer data are shown in Tables 5-7. The data are presented as the slope calculated from the covalent oligomer results. The slope is a measure of how quickly CPD1 forms covalent oligomers. Higher values ​​represent higher covalent oligomer formation. [Example]

[0158] These examples investigate the chemical stability and oligomerization of CPD1 in compositions containing various preservatives and buffers stored at various temperatures for various periods of time.

[0159] CPD1 was produced according to Method I. Pharmaceutical compositions (i.e., formulations) containing various preservatives were prepared and stored according to Method II. The peptide is CPD1OH, consisting of the amino acid sequence of Formula A. CPD1OH may be interchangeable with CPD1NH2.

[0160] The chemical stability of CPD1 is expressed as the slope of the relative purity of the peptide over time. The slope was determined by measuring the absolute purity of the peptide peak (i.e., the major CPD1 peak) at each time point using HPLC as described in Assay I, and then normalizing this value to the absolute purity of the peptide peak at T=0 (set to 100% purity) to obtain the percentage of relative purity at each time point. The slope over the entire time course was calculated from these relative purity values.

[0161] CPD1 oligomerization, as determined at each time point using Assay II, is expressed as the slope of the proportion of covalent oligomers over time. [Example]

[0162] Chemical stability of CPD1 in compositions containing various preservatives In this example, compositions containing m-cresol or phenol preservatives (Formulations 1-25) were stored for 2 weeks at 40° C. The compositions of Formulations 1-25, along with their chemical stability (purity) and oligomerization trends, are shown in Tables 5-7.

[0163] [Table 5]

[0164] [Table 6]

[0165] [Table 7]

[0166] Overall, the data show that higher peptide concentrations reduce the amount of covalent oligomers in the presence of the preservatives m-cresol and phenol compared to lower peptide concentrations, which either have no effect on or improve stability (as represented by the purity slope).

[0167] Furthermore, the data show that the peptide is more stable and less likely to oligomerize when the m-cresol preservative is combined with Tris buffer rather than phosphate buffer.

Claims

1. (a) General formula A: H[Aib]EG-X5-F-X7-SELATILD-[Ψ]-QAARDFIAWLI-X28-HKITD(A) wherein X5 is T or S; X7 is T or S; X28 is Q, E, A, H, Y, L, K, R or S; and at least one of X5 and X7 is T; [Ψ] represents an L or D lysine residue that is the albumin binding moiety conjugated to the GLP-1 / GLP-2 dual agonist; the albumin binding moiety is [K([17-carboxy-heptadecanoyl]-isoGlu)]} one or more GLP-1 / GLP-2 dual agonists, including: (b) one or more preservatives that include or are m-cresol and / or phenol; and (c) Tris buffer A composition comprising:

2. 10. The composition of claim 1, which is an isotonic parenteral pharmaceutical composition.

3. 3. The composition of claim 1 or 2, wherein the one or more preservatives include or are m-cresol, preferably wherein the m-cresol is present at a concentration of about 1.15 mg / mL to about 5.15 mg / mL, more preferably wherein the m-cresol is present at a concentration of about 3.15 mg / mL.

4. 4. The composition of any of claims 1 to 3, wherein the one or more preservatives comprises or is phenol, and preferably the phenol is present at a concentration of about 2.5 mg / mL to about 8.5 mg / mL, more preferably the phenol is present at a concentration of about 5.5 mg / mL.

5. The composition of any of claims 1 to 4, wherein the Tris buffer is present at a concentration of about 5 mM to about 50 mM, preferably the Tris buffer is present at a concentration of about 20 mM.

6. 6. The composition according to any one of claims 1 to 5, having a pH of about pH 6.0 to about pH 8.5, preferably a pH of about pH 6.5 to about pH 8.5, preferably a pH of about pH 7.0 to about pH 8.0, more preferably a pH of about pH 8.

0.

7. The one or more GLP-1 / GLP-2 dual agonists have the general formula B: H[Aib]EG-X5-FT-SELATILD-[Ψ]-QAARDFIAWLI-X28-HKITD (B) wherein X5 is T or S; X28 is Q, E, A, H, Y, L, K, R or S; [Ψ] represents an L or D lysine residue that is the albumin binding moiety conjugated to the GLP-1 / GLP-2 dual agonist; the albumin binding moiety is [K([17-carboxy-heptadecanoyl]-isoGlu)]} The composition according to any one of claims 1 to 6, which is a GLP-1 / GLP-2 dual agonist.

8. The one or more GLP-1 / GLP-2 dual agonists have the sequence: H[Aib]EGSFTSELATILD[Ψ]QAARDFIAWLIQHKITD (SEQ ID NO: 1) The composition according to any one of claims 1 to 7, comprising:

9. one or more GLP-1 / GLP-2 dual agonists, Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH(CPD1OH); or Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-NH ２ (CPD1NH ２ ) Or CPD1OH or CPD1NH ２ a pharmaceutically acceptable salt of, preferably CPD1OH or CPD1NH ２ The composition according to any one of claims 1 to 8, wherein the compound is a chloride salt of

10. 10. The composition of any of claims 1 to 9, wherein the GLP-1 / GLP-2 dual agonist is present at a concentration of at least about 1 mg / mL, preferably from about 1 mg / mL to about 33 mg / mL, such as from about 2 mg / mL to about 33 mg / mL, for example from about 1 mg / mL to about 25 mg / mL, for example from about 6 mg / mL to about 25 mg / mL.

11. 11. The composition of claim 10, wherein the GLP-1 / GLP-2 dual agonist is present at a concentration of about 2 mg / mL, about 15 mg / mL, or about 25 mg / mL.

12. The composition of any one of claims 1 to 11, further comprising one or more tonicity agents.

13. 13. The composition of claim 12, wherein the one or more tonicity agents comprises or is mannitol, preferably D-mannitol.

14. 14. The composition of claim 13, wherein mannitol is present at a concentration of about 130 mM to about 330 mM, preferably about 150 mM to about 300 mM, preferably about 190 mM to about 240 mM, preferably about 230 mM.

15. 13. The composition of claim 12, wherein the one or more tonicity agents comprises or is NaCl, preferably said NaCl is present at a concentration of about 50 mM to about 450 mM, preferably about 65 mM to about 165 mM, preferably about 125 mM. (i) increasing intestinal mass, improving intestinal function, increasing intestinal blood flow, or repairing intestinal damage or dysfunction in a subject in need thereof; or (ii) prevention or treatment of gastrointestinal side effects of malabsorption, ulcers, short bowel syndrome, blind tract syndrome, inflammatory bowel disease, irritable bowel syndrome, pouchitis, celiac sprue, tropical sprue, hypogammaglobulinemic sprue, chemotherapy- or radiation-induced mucositis, chemotherapy- or radiation-induced diarrhea, low-grade inflammation, metabolic endotoxemia, necrotizing enterocolitis, primary biliary cirrhosis, hepatitis, fatty liver, or an inflammatory condition in a subject in need thereof; or (iii) reducing or inhibiting weight gain, reducing gastric emptying or intestinal transit, reducing food intake, reducing appetite, or promoting weight loss in a subject in need thereof; or (iv) preventing or treating obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, inadequate glucose control, glucose tolerance, dyslipidemia, diabetes, prediabetes, metabolic syndrome, or hypertension in a subject in need thereof; A composition according to any one of claims 1 to 15 for use in (i) increasing intestinal mass, improving intestinal function, increasing intestinal blood flow, or repairing intestinal damage or dysfunction in a subject in need thereof; or (ii) prevention or treatment of gastrointestinal side effects of malabsorption, ulcers, short bowel syndrome, blind tract syndrome, inflammatory bowel disease, irritable bowel syndrome, pouchitis, celiac sprue, tropical sprue, hypogammaglobulinemic sprue, chemotherapy- or radiation-induced mucositis, chemotherapy- or radiation-induced diarrhea, low-grade inflammation, metabolic endotoxemia, necrotizing enterocolitis, primary biliary cirrhosis, hepatitis, fatty liver, or an inflammatory condition in a subject in need thereof; or (iii) reducing or inhibiting weight gain, reducing gastric emptying or intestinal transit, reducing food intake, reducing appetite, or promoting weight loss in a subject in need thereof; or (iv) preventing or treating obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, inadequate glucose control, glucose tolerance, dyslipidemia, diabetes, prediabetes, metabolic syndrome, or hypertension in a subject in need thereof; Use of a composition according to any one of claims 1 to 15 in the preparation of a medicament for

18. General formula A: H[Aib]EG-X5-F-X7-SELATILD-[Ψ]-QAARDFIAWLI-X28-HKITD(A) wherein X5 is T or S; X7 is T or S; X28 is Q, E, A, H, Y, L, K, R or S; and at least one of X5 and X7 is T; [Ψ] represents an L or D lysine residue that is the albumin binding moiety conjugated to the GLP-1 / GLP-2 dual agonist; the albumin binding moiety is [K([17-carboxy-heptadecanoyl]-isoGlu)]} 1. A method for storing a composition comprising one or more GLP-1 / GLP-2 dual agonists, comprising: the composition comprises a Tris buffer; The method comprises the step of adding one or more preservatives to the composition, wherein the one or more preservatives include or are m-cresol and / or phenol.

19. General formula A: H[Aib]EG-X5-F-X7-SELATILD-[Ψ]-QAARDFIAWLI-X28-HKITD(A) wherein X5 is T or S; X7 is T or S; X28 is Q, E, A, H, Y, L, K, R or S, and at least one of X5 and X7 is T; [Ψ] represents an L or D lysine residue that is the albumin binding moiety conjugated to the GLP-1 / GLP-2 dual agonist; the albumin binding moiety is [K([17-carboxy-heptadecanoyl]-isoGlu)]} 1. Use of a preservative for preserving a composition comprising one or more GLP-1 / GLP-2 dual agonists, comprising: the composition comprises a Tris buffer; The above use, wherein the preservative comprises or is m-cresol and / or phenol.

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