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 a pharmaceutical composition containing a specific preservative. The pharmaceutical composition according to the present invention is particularly stable and has a beneficial shelf life. [Background technology]

[0002] Peptides represent a crucial segment of the pharmaceutical industry. While the production of active pharmaceutical ingredients (APIs) has advanced dramatically, the production of peptide-based drug products remains highly challenging. The difficulties associated with peptide formulation development are often overlooked or ignored.

[0003] Generally, peptides are defined as polypeptides consisting of fewer than 50 amino residues and often lack an organized tertiary or globular structure. Some adopt a secondary structure, but this tends to be limited, such as a single-turn α-helix. Smaller peptides are easier to deliver across biological barriers than larger proteins, although their formulation can be problematic.

[0004] Some of the formulation difficulties, particularly those related to peptides, include chemical instability; the adoption of multiple conformational isomers; their tendency to self-associate; and complex physical instability, such as gel formation, amyloid formation, and / or precipitation.

[0005] The most common difficulties are 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 determines the extent to which it is affected by deamidation and / or oxidation reactions. The oxidation rate of specific residues, such as Met residues, correlates with the degree of solvent exposure. Since peptides do not possess a spherical structure that can sequestrate reactive groups, almost all side chains of peptide residues are fully exposed to the solvent, allowing 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 degree of flexibility of the peptide chain leads to a higher rate of deamidation compared to more complex proteins. However, it is important to note that the properties of the amino acids after deamidation, such as the amino acids after Asn, also affect the rate of deamidation. Peptides lacking steric bulk and the ability to hydrogen bond to the Asn side chain may undergo the reaction even more rapidly. Typically, the amino acid combinations Asn-Gly, Asn-Ala, Asn-Ser, and Asn-Asp exhibit reaction rates that scientists must take into account and test to ensure stable pharmaceutical compositions. The greatest control over hydrolysis reactions, including deamidation, is achieved through 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 of the active ingredient (solubilizers) and / or to improve or maintain its stability (buffers, antioxidants, chelating agents, cryoprotective agents, and lyophilization protective agents). Excipients are often important in parenteral formulations to ensure safety (antimicrobial preservatives), minimize pain and irritation during injection (isotonic agents), and control or extend drug delivery (polymers). These are all examples of positive or synergistic interactions between excipients and pharmaceutical products. However, any excipient added to a composition may produce negative effects such as loss of peptide solubility, activity, and / or chemical / physical stability; or increased self-aggregation or fibrillation, which could render the pharmaceutical product unsafe to administer.

[0007] Preservatives may be added to pharmaceutical compositions to kill microbial contaminants that could be introduced into the composition, such as when numerous aliquots are used or drawn from a container holding a large dose of the medicine. While pharmaceutical compositions can be sealed and stored in a sterile condition without the presence of preservatives, any accidental introduction of microorganisms can render the contents unsuitable for further medical use when a container is used to hold the composition. Therefore, effectively preserving the pharmaceutical contents is important, especially when the composition is stored in large quantities for several doses. When a container is used to hold a large quantity of preservative-free pharmaceutical composition, the absence of preservatives can mean that a large portion of the contents will be wasted. Preservatives advantageously enable the storage of pharmaceutical compositions for months or even 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 a portion of the composition has been used.

[0008] However, despite the advantages of using preservatives, the inclusion of preservatives in pharmaceutical compositions can be problematic because they may interact adversely with other components of the composition, particularly the active ingredient. Such interactions can lead to a reduction in the preservative's effect, or a reduction or complete loss of the pharmaceutical composition's medical efficacy. For example, preservatives can lead to chemical instability of activators. In the case of peptide activators, preservatives may participate in or promote decomposition reactions such as isomerization, racemization, hydrolysis, deamidation, or oxidation of the peptide, resulting in a loss of the peptide's pharmacological activity. Alternatively, preservatives may be detrimental to the physical stability of peptide activators, increasing the aggregation of peptides into inactive covalent oligomers and / or causing the peptides to precipitate from solution. Such loss of physical stability not only reduces the medical potency of the peptide, but if the composition is delivered by injection, the formation of particulate matter has practical and safety implications.

[0009] Peptides exhibit great sequence diversity and therefore a wide range of chemical structures; consequently, 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 in International Publication No. 2018104561) disclosed in International Publication No. 2018104561, which describes the compounds and their uses in detail. [Prior art documents] [Patent Documents]

[0011] [Patent Document 1] International Publication No. 2018104561 brochure [Overview of the Initiative] [Means for solving the problem]

[0012] This application provides a composition 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 human subjects.

[0013] GLP-1 / GLP-2 dual agonists are peptides. Certain preservatives have been identified that can be used in compositions containing specific GLP-1 / GLP-2 dual agonist peptides and specific buffers without substantially affecting the chemical or physical stability of the peptides. Surprisingly, these specific preservatives have been found to have little to no effect on the chemical stability and oligomerization of the peptides in Tris buffer.

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

[0015] Among the specific advantages, the effect of the preservative in the composition of the present invention allows the composition to be provided in a multi-dose administration setting. The composition of the present invention can be provided in a device used to administer sequential therapeutic doses of the composition at intervals over a long period of time. The effect of the preservative inhibits microbial growth in the composition over this period, while maintaining the chemical and physical stability of the peptide. This has the practical benefit that the device only needs to be filled once, rather than preparing a new dose for each administration.

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

[0017] In some embodiments, the present invention is (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 which 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)]}{ One or more GLP-1 / GLP-2 dual agonists comprising; (b) One or more preservatives comprising m-cresol and / or phenol, or being m-cresol and / or phenol; and (c) Tris buffer A composition comprising is provided.

[0018] In some embodiments, specific and particular compositions, such as isotonic parenteral compositions, are described in detail in the description of the invention.

[0019] The chemical stability of the GLP-1 / GLP-2 dual agonist at time point Y in any of the tested compositions disclosed herein is represented as the relative purity X Y of the GLP-1 / GLP-2 dual agonist, and is determined by measuring the absolute purity X' of the GLP-1 / GLP-2 dual agonist and normalizing it to the absolute purity X 0 of the GLP-1 / GLP-2 dual agonist on day zero (day 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 do not oligomerize when the m-cresol preservative is combined with Tris buffer rather than phosphate buffer.

[0021] Also, the present invention (i) In subjects requiring it, to increase intestinal mass, improve intestinal function, increase intestinal blood flow, or repair intestinal damage or dysfunction; or (ii) Prevention or treatment of malabsorption, ulcers, short bowel syndrome, duct blindness syndrome, inflammatory bowel disease, irritable bowel syndrome, cystitis, celiac sprue, tropical sprue, hypogammaglobulinemia sprue, mucositis induced by chemotherapy or radiotherapy, diarrhea induced by chemotherapy or radiotherapy, mild inflammation, metabolic endotoxemia, necrotizing enterocolitis, primary biliary cirrhosis, hepatitis, fatty liver, or gastrointestinal side effects of inflammatory conditions in subjects requiring such treatment; or (iii) reducing or inhibiting weight gain, reducing gastric emptying or intestinal transit, reducing food intake, reducing appetite, or promoting weight loss in persons who require it; or (iv) Prevention or treatment of obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, inadequate glucose control, glucose intolerance, dyslipidemia, diabetes mellitus, prediabetes, metabolic syndromes, or hypertension in persons who require it. The present invention provides compositions for use in [the specified field].

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

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

[0024] compound The composition of the present invention, 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, where at least one of X5 and X7 is T, and [Ψ] represents an L or D lysine residue which is an albumin-binding moiety conjugated to a GLP-1 / GLP-2 dual agonist, the albumin-binding moiety being [K([17-carboxy-heptadecanoyl]-isoGlu)]} Contains one or more GLP-1 / GLP-2 dual agonists, including [specific ingredient / method].

[0025] In some embodiments, one or more GLP-1 / GLP-2 dual agonists containing general formula A are general formula B: H[Aib]EG-X5-FT-SELATILD-[Ψ]-QAARDFIAWLI-X28-HKITD(B) {In the formula, 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 which 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, one or more GLP-1 / GLP-2 dual agonists containing general formula A or B include the sequence: H[Aib]EGSFTSELATILD[Ψ]QAARDFIAWLIQHKITD (Sequence ID 1). In some embodiments, one or more GLP-1 / GLP-2 dual agonists containing general formula A or B consist of the sequence: H[Aib]EGSFTSELATILD[Ψ]QAARDFIAWLIQHKITD (Sequence ID 1).

[0027] In some embodiments, one or more GLP-1 / GLP-2 dual agonists comprising general formula A are 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, one or more GLP-1 / GLP-2 dual agonists comprising general formula A are 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, a chloride salt, or an acetate salt, preferably a chloride salt.

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

[0030] The term "GLP-1 / GLP-2 dual agonist," as used herein, refers to a peptide having activity toward both the GLP-1 and GLP-2 receptors. A GLP-1 / GLP-2 dual agonist comprising formula A or B may be the peptide of SEQ ID NO: 1, or a peptide modified by one or more amino acids compared to SEQ ID NO: 1. Such agonists and / or peptides may further comprise one or more side chains covalently bonded to the GLP-1 / GLP-2 dual agonist. The term "side chain" may also be referred to as "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. Since salts consist of a corresponding number of cations (positively charged ions) and anions (negatively charged ions), the products are electrically neutral (have no net charge). These component ions are inorganic, for example, chlorides (Cl - ), or organic, for example, acetate (CH3CO 2- ) may also be a single atom, for example, a fluoride (F - ), or polyatomic, for example, sulfates (SO4 2- ) is also acceptable.

[0032] The terms “pharmaceutically acceptable salt of CPD1” or “salt of CPD1” as used herein describe a salt of the 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, for example, Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH in a neutralization reaction. Thus, [HCl] refers to a chloride salt.

[0033] "Pharmacologically acceptable salt," as used herein, refers to a salt that is safe and effective for use in mammals and possesses the desired biological activity. Pharmacologically acceptable salts include salts of the acidic or basic groups present in CPD1. For an overview 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 existing 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 drug substances in powder form.

[0036] [Table 2]

[0037] The "albumin-binding moiety" promotes the circulation of GLP-1 / GLP-2 dual agonists in the bloodstream and also has the effect of extending the duration of action of GLP-1 / GLP-2 dual agonists. The albumin-binding moiety binds GLP-1 / GLP-2 dual agonists to albumin present in the blood, and the action of GLP-1 / GLP-2 dual agonists is extended because they are released slowly from albumin. The term "albumin-binding moiety" may also be referred to as a "side chain" or "substituent."

[0038] As used herein, the term “natural amino acids” refers to amino acids 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) (as shown in the usual three-letter and one-letter abbreviations in parentheses). Unless otherwise specified, amino acids represented by a single capital letter indicate the L-iso form, while amino acids represented by a lowercase letter are used / applied to represent their D-form. For example, K (i.e., L-lysine) and k (i.e., D-lysine).

[0039] In relation to the compounds disclosed herein, the abbreviation "Hy-" refers to hydrogen. This abbreviation is chosen to avoid confusion between hydrogen and the initial histidine (H) in the sequence.

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

[0041] concentration of the compound In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, contains at least about 1 mg / mL of a GLP-1 / GLP-2 dual agonist, for example, at least about 2 mg / mL of a GLP-1 / GLP-2 dual agonist. In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, contains at least about 1 mg / mL to about 33 mg / mL of a GLP-1 / GLP-2 dual agonist, for example, at least about 2 mg / mL to about 33 mg / mL of a GLP-1 / GLP-2 dual agonist. In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, comprises at least about 1 mg / mL to about 25 mg / mL of a GLP-1 / GLP-2 dual agonist, for example, at least about 2 mg / mL to about 25 mg / mL of a GLP-1 / GLP-2 dual agonist, for example, at least about 4 mg / mL to about 25 mg / mL of a GLP-1 / GLP-2 dual agonist, for example, at least about 6 mg / mL to about 25 mg / mL of a GLP-1 / GLP-2 dual agonist, for example, at least about 8 mg / mL to about 25 mg / mL of a GLP-1 / GLP-2 dual agonist, for example, at least about 10 mg / mL to about 25 mg / mL of a GLP-1 / GLP-2 dual agonist.

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

[0043] Preferably, the composition of the present invention contains about 2 mg / mL to about 25 mg / mL of GLP-1 / GLP-2 dual agonist, preferably about 6 mg / mL to about 25 mg / mL of GLP-1 / GLP-2 dual agonist. Most preferably, the composition of the present invention contains about 15 mg / mL of GLP-1 / GLP-2 dual agonist.

[0044] Dual agonist synthesis It is preferable to synthesize the dual agonists of the present invention by solid-phase or liquid-phase peptide synthesis methods. In this regard, refer to International Publication No. 98 / 11125, and among many others, Fields, GB et 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 of the present invention are, for example, (a) Synthesizing a dual agonist by solid-phase or liquid-phase peptide synthesis and recovering the synthesized dual agonist thus obtained; or (b) The step of expressing a precursor peptide sequence from a nucleic acid construct encoding a precursor peptide, recovering the expression product, and modifying the precursor peptide to obtain the compound of the present invention. It can be synthesized or produced by several means, including methods that include [the specified element].

[0045] The precursor peptide can be modified by introducing one or more non-proteinogenic amino acids, such as Aib, Orn, Dap, or Dab, introducing an albumin-binding moiety, or introducing an appropriate terminal group -OH or -NH2.

[0046] Expression typically occurs from nucleic acids encoding precursor peptides, which can be carried out in cells containing such nucleic acids or in cell-free expression systems.

[0047] Preservatives The composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, contains one or more preservatives. In some embodiments, one or more preservatives include m-cresol and / or phenol, or m-cresol and / or phenol. In some embodiments, the preservative is m-cresol or phenol. The composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, contains a preservative, and the preservative includes m-cresol and / or phenol, or m-cresol and / or phenol. In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, contains one type of preservative, and the preservative includes m-cresol or phenol, or m-cresol or phenol. In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, contains two types of preservatives, and the preservatives include m-cresol and phenol, or m-cresol and phenol.

[0048] m-cresol In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, comprises one or more preservatives, one or more of which comprises m-cresol. In some embodiments, one or more of the preservatives is m-cresol. In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, comprises a preservative that is m-cresol. In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, comprises 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 composition 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 composition of the present invention at a concentration of about 1.15 mg / mL. In some embodiments, m-cresol is present in the composition of the present invention at a concentration of about 5.15 mg / mL. Preferably, m-cresol is present in the composition of the present invention at a concentration of about 3.15 mg / mL.

[0052] phenol In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, comprises one or more preservatives, one or more of which comprises phenol. In some embodiments, one or more of the preservatives is phenol. In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, comprises a preservative that is phenol. In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, comprises phenol.

[0053] Phenol is an organic compound also known as benzenol. Phenol has the chemical formula C6H5OH 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, for example, the isotonic parenteral pharmaceutical compositions of the present invention, contain Tris buffer. In some embodiments, Tris buffer is present in the composition, for example, the isotonic parenteral pharmaceutical composition, at a final concentration of about 5 mM to about 50 mM, for example, about 5 mM to about 20 mM. In some embodiments, Tris buffer is present in the composition at a final concentration of about 5 mM. In some embodiments, Tris buffer is present in the composition at a final concentration of about 50 mM. Preferably, 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 and has the chemical formula (HOCH2)3CNH2 and the following structural formula.

[0058] [ka]

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

[0060] In some embodiments, the pH of the composition of the present invention, for example, an isotonic parenteral pharmaceutical composition, is about pH 6.0 to about pH 8.5, for example, 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, for example, an 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, for example, an isotonic parenteral pharmaceutical composition, is about pH 7.0. In some embodiments, the pH of the composition of the present invention, for example, an 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 preferred embodiments, the pH is about 8.0.

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

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

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

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

[0065] In some embodiments, the compositions of the present invention, for example, the isotonic parenteral pharmaceutical compositions of the present invention, contain one or more isotonic agents.

[0066] The term "isotonic agent" refers to an excipient added to the composition according to the present invention to achieve isotonicity with respect to body fluids. A range of ionic and nonionic isotonic agents are used in pharmaceutical compositions. Nonionic isotonic agents may be selected from dextrose, propylene glycol, glyceryl, mannitol, e.g., D-mannitol, and sorbitol. Ionic isotonic agents may include alkali metals or earth halides, e.g., CaCl2, KBr, KCl, LiCl, NaI, NaBr, NaCl, and Na2SO4. In one embodiment, the isotonic agent may be selected from mannitol, NaCl, and propylene glycol.

[0067] An "ionic compound" is a compound of two or more ions that are held together by attractive forces. An example of an ionic compound is table salt, which consists of positive sodium ions and negative chloride ions. 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, one or more isotonic agents include or are mannitol. Preferably, one or more isotonic agents are D-mannitol. In some embodiments, mannitol, for example 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, more preferably about 190 mM to about 240 mM. In some embodiments, mannitol, for example D-mannitol, is present in the composition of the present invention at about 230 mM.

[0069] In some embodiments, one or more isotonic agents include or are NaCl. In some embodiments, NaCl is present in the composition 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] When used herein, the term "isotonic" refers to the osmotic pressure relative to body fluids at the injection site, i.e., IV or SC. Therefore, the term "isotonic" is used to describe a pharmaceutical composition having the same osmotic pressure at the injection site as body fluids, such as red blood cells and / or plasma. A composition having a weight-osmolality of approximately 300 mOsmol / kg, for example, approximately 280–320 mOsmol / kg or approximately 290–320 mOsmol / kg, is considered isotonic.

[0071] Isotonicity is important for parenteral pharmaceutical compositions because "low osmotic pressure" solutions cause cell swelling, while "high osmotic pressure" solutions cause cell contraction. While it relates to gravimetric osmolality, osmotic pressure also takes into account the ability of solutes to pass through cell membranes.

[0072] Composition of the present invention In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, contains a solvent. In some embodiments, the solvent is water.

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

[0074] In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, comprises a GLP-1 / GLP-2 dual agonist containing the amino acid sequence of formula A, m-cresol, and Tris buffer.

[0075] In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, comprises a GLP-1 / GLP-2 dual agonist containing the amino acid sequence of formula A, phenol, and Tris buffer.

[0076] In some embodiments, the compositions of the present invention, for example, the isotonic parenteral pharmaceutical compositions of the present invention, include a GLP-1 / GLP-2 dual agonist containing the amino acid sequence of formula A, m-cresol, Tris buffer, and mannitol, for example, D-mannitol.

[0077] In some embodiments, the compositions of the present invention, for example, the isotonic parenteral pharmaceutical compositions of the present invention, comprise a GLP-1 / GLP-2 dual agonist containing the amino acid sequence of formula A, phenol, Tris buffer, and mannitol, such as D-mannitol.

[0078] In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, comprises a GLP-1 / GLP-2 dual agonist comprising the amino acid sequence of formula A, a preservative being 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 a preservative being phenol at a final concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL, and Tris buffer present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM.

[0079] In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, comprises a GLP-1 / GLP-2 dual agonist comprising the amino acid sequence of formula A, a preservative being 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 Tris buffer at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM.

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

[0081] In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, comprises a GLP-1 / GLP-2 dual agonist comprising the amino acid sequence of formula A, 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, or phenol at a final concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL, and Tris buffer present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM.

[0082] In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, comprises a GLP-1 / GLP-2 dual agonist comprising the amino acid sequence of formula A, 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; a preservative being 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 Tris buffer present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM.

[0083] In some embodiments, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, comprises a GLP-1 / GLP-2 dual agonist comprising the amino acid sequence of formula A, 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; a preservative being phenol at a final concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL; and Tris buffer present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM.

[0084] In some embodiments, in the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present 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. - The preservative is cresol, or phenol at a final concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL; Tris buffer is present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM; and the isotonic agent is mannitol, such as 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, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, comprises a GLP-1 / GLP-2 dual agonist comprising the amino acid sequence of formula A, present at a concentration of at least 1 mg / mL to about 25 mg / mL, preferably at least 6 mg / mL to about 25 mg / mL; a preservative being m-cresol at a final concentration of about 1.15 mg / mL to about 5.15 mg / mL, preferably about 3.15 mg / mL; a Tris buffer present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM; and an isotonic agent being mannitol, such as 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, the composition of the present invention, for example, the isotonic parenteral pharmaceutical composition of the present invention, comprises a GLP-1 / GLP-2 dual agonist comprising the amino acid sequence of formula A, 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; a preservative being phenol at a final concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL; a Tris buffer present at a final concentration of about 5 mM to about 50 mM, preferably about 20 mM; and an isotonic agent being mannitol, such as 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, for example, in the isotonic parenteral pharmaceutical compositions of the present invention, the GLP-1 / GLP-2 dual agonist is preferably CPD1OH or a pharmaceutically acceptable salt thereof 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; 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, for example, in the isotonic parenteral pharmaceutical compositions of the present invention, the GLP-1 / GLP-2 dual agonist is preferably CPD1OH or a pharmaceutically acceptable salt thereof 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, for example, in the isotonic parenteral pharmaceutical compositions of the present invention, the GLP-1 / GLP-2 dual agonist is preferably CPD1OH or a pharmaceutically acceptable salt thereof 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, for example, the isotonic parenteral pharmaceutical compositions of the present invention, the GLP-1 / GLP-2 dual agonist is preferably CPD1OH or a pharmaceutically acceptable salt thereof 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, and the preservative is about 1.15 mg / mL to about 5.15 mg / mL, preferably about 3.1 The preservative is either m-cresol at a final concentration of 5 mg / mL, or 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 isotonic agent is mannitol, such as 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, for example, in the isotonic parenteral pharmaceutical compositions of the present invention, the GLP-1 / GLP-2 dual agonist is preferably CPD1OH or a pharmaceutically acceptable salt thereof 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; 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 isotonic agent is mannitol, such as 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.

[0092] In some embodiments, in the compositions of the present invention, for example, in the isotonic parenteral pharmaceutical compositions of the present invention, the GLP-1 / GLP-2 dual agonist is preferably CPD1OH or a pharmaceutically acceptable salt thereof 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; 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 isotonic agent is mannitol, such as 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.

[0093] Indications In some embodiments, the pharmaceutical compositions of the present invention are administered to human subjects who require the prevention or treatment of intestinal injury and dysfunction, weight regulation, and prevention or treatment of metabolic dysfunction.

[0094] In some embodiments, the pharmaceutical compositions of the present invention are used to treat malabsorption, ulcers (e.g., peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, and ulcers associated with infection or other pathogens), short bowel syndrome, blind duct syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), irritable bowel syndrome (IBS), cystitis, celiac sprue (e.g., resulting from gluten-induced irritability or celiac disease), tropical sprue, hypogammaglobulinemia sprue, mucositis induced by chemotherapy or radiotherapy, diarrhea induced by chemotherapy or radiotherapy, mild 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)). It is administered to humans who need to prevent or treat gastrointestinal side effects of inflammatory conditions, such as pancreatitis or graft-versus-host disease (GVHD), including non-alcoholic steatohepatitis (NASH), or inflammatory conditions.

[0095] In some embodiments, the pharmaceutical compositions of the present invention are administered to human subjects who require the prevention or treatment of obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, inadequate glucose control, impaired glucose tolerance, dyslipidemia (e.g., high LDL levels or low HDL / LDL ratio), diabetes (e.g., type 2 diabetes, gestational diabetes), prediabetes, metabolic syndrome, or hypertension.

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

[0097] In some embodiments, the pharmaceutical compositions of the present invention are administered to human subjects who require the prevention or treatment of intestinal dysfunction or injury caused by or associated with GVHD, and the 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 human subjects who require 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 who need to improve glucose tolerance and / or glucose control. In some embodiments, the pharmaceutical compositions of the present invention are administered to human subjects who need to modulate (e.g., improve) circulating cholesterol levels, enable a decrease in circulating triglyceride or LDL levels, and increase the HDL / LDL ratio.

[0100] Administration In some embodiments, the pharmaceutical composition of the present invention is an aqueous composition. In some embodiments, the pharmaceutical composition of the present invention is suitable for parenteral administration by subcutaneous (SC), intramuscular (IM), or intravenous (IV) injection using a syringe, which may be a pen-shaped syringe. In some embodiments, the pharmaceutical composition of the present invention is suitable for SC injection into human subjects. In some embodiments, the pharmaceutical composition of the present invention is suitable for IV injection into human subjects.

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

[0103] biological activity In some embodiments, the peptides contained in the pharmaceutical compositions of the present invention are the peptides described in Formula A and Sequence ID No. 1, which have been previously described in International Publication Brochure No. 2018104561 describing the compounds, their preparation and purification, and their biological activity (International Publication Brochure No. 2018104561, Table 5). Example 2 in International Publication Brochure No. 2018104561 includes data on in vitro efficacy against GLP-1 and GLP-2 receptors.

[0104] Chemical stability (purity) The compositions of the present invention, for example, the isotonic parenteral pharmaceutical compositions of the present invention, offer 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 equivalent compositions according to the present invention that do not contain preservatives, as described herein.

[0105] In some embodiments, the compositions of the invention have excellent or improved relative purity. The relative purity can be equivalent to or improved as compared to an equivalent composition without the preservative according to the invention, as described herein.

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

[0107] The chemical stability of the GLP-1 / GLP-2 dual agonist at time point Y in any of the test compositions disclosed herein is represented as the relative purity X of the GLP-1 / GLP-2 dual agonist Y and is determined by measuring the absolute purity X' of the GLP-1 / GLP-2 dual agonist and normalizing it to the absolute purity X of the GLP-1 / GLP-2 dual agonist on day zero (day 0), 0 wherein 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] Thus, on day zero (day 0), the absolute purity X' is the same as the absolute purity X 0 and thus the chemical stability of the GLP-1 / GLP-2 dual agonist in the tested composition is represented as relative purity X Y = 100%, with Y = day 0.

[0109] The relative purity is X Y = (X' / X 0 ) × 100 {wherein X is the relative purity at a given time point Y, 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 Alternatively, 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 point in time can be calculated by multiplying the purity gradient by the number of weeks in storage and subtracting the coefficient of this value from 100%.

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

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

[0113] Various analytical techniques for measuring peptide stability are available in this art and are outlined, 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 was found that the peptides of the present invention are more stable and less oligomerized when the m-cresol preservative is combined with Tris buffer instead of phosphate buffer.

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

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

[0117] [Table 3]

[0118] Terms and Definitions When terms such as “about” and “approximately” are used in relation to numerical values, a person skilled in the art will immediately recognize that any effect or result that may be associated with a given value can be obtained within a certain tolerance from a particular value. Therefore, as used herein, the term “about” means within a reasonable vicinity of the numerical value being referred to, for example, within a 10% increase or decrease. When the term “about” is used in relation to chemical stability in this patent application, a reasonable vicinity is less than 2%, for example, 0.5% or 0.75%, 1% or 1.5%.

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

[0120] Non-limiting aspects of the present invention The following portions of this description include 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, 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] indicates an L or D lysine residue, which is the albumin-binding moiety conjugated to a GLP-1 / GLP-2 dual agonist. The albumin-binding portion is [K([17-carboxy-heptadecanoyl]-isoGlu)]. One or more GLP-1 / GLP-2 dual agonists, including [specific GLP-1 / GLP-2 agonists]; (b) one or more preservatives comprising m-cresol and / or phenol, or m-cresol and / or phenol; and (c) Tris buffer solution A composition containing the following:

[0122] 2. The composition according to embodiment 1, which is an isotonic parenteral pharmaceutical composition.

[0123] 3. The composition according to embodiment 1 or 2, wherein one or more preservatives contain or are m-cresol, preferably with m-cresol present at a concentration of about 1.15 mg / mL to about 5.15 mg / mL, and more preferably with m-cresol present at a concentration of about 3.15 mg / mL.

[0124] 4. The composition according to any one of embodiments 1 to 3, wherein one or more preservatives contain phenol or are phenol, preferably with phenol present at a concentration of about 2.5 mg / mL to about 8.5 mg / mL, and more preferably with phenol present at a concentration of about 5.5 mg / mL.

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

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

[0127] 7. One or more GLP-1 / GLP-2 dual agonists are administered using 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 which is the albumin-binding moiety conjugated to the GLP-1 / GLP-2 dual agonist. The albumin-binding portion is [K([17-carboxy-heptadecanoyl]-isoGlu)]. A composition according to any one of embodiments 1 to 6, which is a GLP-1 / GLP-2 dual agonist.

[0128] 8. One or more GLP-1 / GLP-2 dual agonists are included in the sequence: H[Aib]EGSFTSELATILD[Ψ]QAARDFIAWLIQHKITD(Sequence ID 1) A composition according to any one of embodiments 1 to 7, including the following:

[0129] 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-NH2(CPD1NH2) The composition according to any one of embodiments 1 to 8, or a pharmaceutically acceptable salt of CPD1OH or CPD1NH2, preferably a chloride salt of CPD1OH or CPD1NH2.

[0130] 10. The composition according to any one of embodiments 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, about 2 mg / mL to about 33 mg / mL, for example, about 1 mg / mL to about 25 mg / mL, for example, about 6 mg / mL to about 25 mg / mL.

[0131] 11. The composition according to embodiment 11, wherein a GLP-1 / GLP-2 dual agonist is present at a concentration of approximately 2 mg / mL, approximately 15 mg / mL, or approximately 25 mg / mL.

[0132] 12. The composition according to any one of embodiments 1 to 11, further comprising one or more isotonic agents.

[0133] 13. The composition according to embodiment 12, wherein one or more isotonic agents include mannitol, preferably D-mannitol, or D-mannitol.

[0134] 14. The composition according to embodiment 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, and preferably about 230 mM.

[0135] 15. The composition according to embodiment 12, wherein one or more isotonic agents contain NaCl or are NaCl, preferably at a concentration of about 50 mM to about 450 mM, preferably about 65 mM to about 165 mM, and preferably about 125 mM.

[0136] 16. The composition according to any one of embodiments 1 to 15, wherein the weight osmolality of the composition is approximately 230 mOsmol / kg to approximately 370 mOsmol / kg.

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

[0138] 18. The composition according to any one of embodiments 1 to 17, wherein one or more preservatives are m-cresol at a concentration of about 1.15 mg / mL to about 5.15 mg / mL, preferably about 3.15 mg / mL, 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 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 according to any one of embodiments 1 to 18, wherein one or more preservatives are phenol at a concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL, 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 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 according to any one of embodiments 1 to 19, wherein one or more GLP-1 / GLP-2 dual agonists are CPD1OH or CPD1NH2, preferably CPD1OH, or a chloride salt of CPD1OH or CPD1NH2, preferably a chloride salt of CPD1OH, one or more preservatives are m-cresol at a concentration of about 1.15 mg / mL to about 5.15 mg / mL, preferably about 3.15 mg / mL, 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 at a concentration of about 230 mM, preferably D-mannitol, water, and sodium hydroxide and / or hydrochloric acid for pH adjustment to about pH 8.0.

[0141] 21. The composition according to any one of embodiments 1 to 20, wherein one or more GLP-1 / GLP-2 dual agonists are CPD1OH or CPD1NH2, preferably CPD1OH, or a chloride salt of CPD1OH or CPD1NH2, preferably a chloride salt of CPD1OH, one or more preservatives are phenol at a concentration of about 2.5 mg / mL to about 8.5 mg / mL, preferably about 5.5 mg / mL, 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 at a concentration of about 230 mM, preferably D-mannitol, water, and sodium hydroxide and / or hydrochloric acid for pH adjustment to about pH 8.0.

[0142] 22. A composition according to any one of embodiments 1 to 21, which is suitable for subcutaneous (sc) or intravenous (iv) injection into human subjects.

[0143] 23. (i) In subjects in need thereof, to increase intestinal mass, improve intestinal function, increase intestinal blood flow, or repair intestinal damage or dysfunction; or (ii) Prevention or treatment of malabsorption, ulcers, short bowel syndrome, duct blindness syndrome, inflammatory bowel disease, irritable bowel syndrome, cystitis, celiac sprue, tropical sprue, hypogammaglobulinemia sprue, mucositis induced by chemotherapy or radiotherapy, diarrhea induced by chemotherapy or radiotherapy, mild inflammation, metabolic endotoxemia, necrotizing enterocolitis, primary biliary cirrhosis, hepatitis, fatty liver, or gastrointestinal side effects of inflammatory conditions in subjects requiring such treatment; or (iii) reducing or inhibiting weight gain, reducing gastric emptying or intestinal transit, reducing food intake, reducing appetite, or promoting weight loss in persons who require it; or (iv) Prevention or treatment of obesity, morbid obesity, obesity-related gallbladder disease, obesity-induced sleep apnea, inadequate glucose control, glucose intolerance, dyslipidemia, diabetes mellitus, prediabetes, metabolic syndromes, or hypertension in persons who require it. A composition according to any one of embodiments 1 to 22 for use in [the specified context].

[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] indicates an L or D lysine residue, which is the albumin-binding moiety conjugated to a GLP-1 / GLP-2 dual agonist. The albumin-binding site is [K([17-carboxy-heptadecanoyl]-isoglu)]. A method for preserving a composition comprising one or more GLP-1 / GLP-2 dual agonists, including; The composition contains Tris buffer solution; The method comprises the step of adding one or more preservatives to a composition, wherein one or more preservatives include m-cresol and / or phenol, 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] indicates an L or D lysine residue, which is the albumin-binding moiety conjugated to a GLP-1 / GLP-2 dual agonist. The albumin-binding portion is [K([17-carboxy-heptadecanoyl]-isoGlu)]. The use of a preservative for preserving a composition containing one or more GLP-1 / GLP-2 dual agonists; The composition contains Tris buffer solution; The preservative contains m-cresol and / or phenol, or is m-cresol and / or phenol. use.

[0146] General laws 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 the General Peptide Synthesis described in the International Patent Application Publication Brochure 2018 / 104561.

[0147] CPD1 (corresponding to compound 18 in International Publication No. 2018 / 104561) was synthesized using solid-phase peptide synthesis (SPPS) and the standard Fmoc coupling method. After synthesis, 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 Sample solutions for research scale GLP-1 / GLP-2 dual agonist drug substances (CPD1) were prepared according to Method I and dissolved in Milli-Q water (MQW) to obtain a stock solution of 40 mg / mL of the active ingredient (API). The pH was measured. Subsequently, the components exemplified in Tables 5-10 were added and mixed, and the pH was then adjusted as needed using 1 M NaOH / HCl to reach a suitable pH. The final concentration was 2 or 25 mg / mL of CPD1 as shown in the tables and examples of this application. Study-scale compositions were prepared in volumes of 0.5 to about 2 mL.

[0149] For stability testing, the samples were stored in a dark room (i.e., with the lights off) at 40°C for two weeks. The samples were analyzed according to Assay I and II by RP-HPLC and SEC-HPLC, 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 GLP-1 / GLP-2 dual agonists (peptides) is determined by HPLC at a given time point and is 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 zero (T=0), which is set to 100% normalized purity. 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), which provides 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 volume was 2 μg of peptide. The column used for HPLC analysis was Phenomenex Kinetex C18, 150 × 3.0 mm, with a particle size of 2.6 μm. The runtime was 25 minutes.

[0153] [Table 4]

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

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

[0156] The SEC method can detect covalent oligomers in which two or more CPD1 molecules are linked together through covalent chemical bonds.

[0157] The shared oligomer data is shown in Tables 5-7. The data is presented as a slope calculated from the shared oligomer results. The slope is a measure of how quickly CPD1 forms shared oligomers. A higher value indicates higher shared oligomer formation. [Examples]

[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.

[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 main CPD1 peak) at each time point using HPLC, as described in Assay I. This value was then normalized 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 process was calculated from these relative purity values.

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

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

[0163] [Table 5]

[0164] [Table 6]

[0165] [Table 7]

[0166] In general, 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. Higher peptide concentrations have no effect on stability (represented by the purity gradient) or improve it.

[0167] Furthermore, the data shows that when the m-cresol preservative is combined with Tris buffer instead of phosphate buffer, the peptide is more stable and less oligomerized.

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 comprising: (b) one or more preservatives that include or are m-cresol and / or phenol; and (c) Tris buffer A composition comprising:

2. 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 comprises or is m-cresol, preferably said m-cresol is present at a concentration of about 1.15 mg / mL to about 5.15 mg / mL, more preferably said 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, preferably said phenol is present at a concentration of about 2.5 mg / mL to about 8.5 mg / mL, more preferably said 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 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 dual GLP-1 / GLP-2 agonists have the general formula B: H[Aib]EG-X5-FT-SELATILD-[Ψ]-QAARDFIAWLI-X28-HKITD(B) 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 pharmacy 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 at a concentration of about 1 mg / mL to about 33 mg / mL, such as 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, such as at a concentration of 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 according to any one of claims 1 to 11, further comprising one or more tonicity agents.

13. The composition according to claim 12, wherein the one or more tonicity agents comprise or are 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) 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. 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) 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. 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 dual GLP-1 / GLP-2 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 comprise 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)] 2. 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.