FORMULATIONS OF GLUCAGON-LIKE PEPTIDE TYPE 2 (GLP-2) ANALOGUES

Abstract

Liquid formulations of GLP-2 analogues are described that make them suitable for long-term storage as liquids and / or particularly suitable for administration via a drug delivery device. Solid compositions comprising acetate salts of glucagon-like peptide-2 (GLP-2) analogues, useful for preparing the liquid formulations, are also described.The development of these liquid formulations is based on the finding that the acetate present in the formulation that comes from GLP-2 analogues has an effect on the viscosity of the formulation, that during long-term storage at 2-8 °C of GLP-2 analogues, the concentration dependence for the formation of covalent oligomers is inversely dependent on the increase in the concentration of the GLP-2 analogue, and that the GLP-2 analogues used in the formulations are not compatible with the phosphate buffer commonly used in the prior art for reconstituted powder or lyophilized GLP-2 compositions.

Description

FORMULATIONS OF GLUCAGON-LIKE PEPTIDE TYPE 2 (GLP-2) ANALOGUES FIELD OF INVENTION The present invention relates to formulations of glucagon-like peptide-2 (GLP-2) analogues and their medical use, for example, in the treatment and / or prevention of disorders of the stomach and intestines and for mitigating the side effects of chemotherapy and radiation therapy. Furthermore, solid compositions comprising acetate salts of glucagon-like peptide-2 (GLP-2) analogues, useful for preparing the liquid formulations, are also described. BACKGROUND OF THE INVENTION Human GLP-2 is a 33-amino-acid peptide with the sequence: Hy-HisAla-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-lle-Leu-Asp-Asn-Leu-Ala-Ala-ArgAsp-Phe-lle-Asn-Trp-Leu-lle-GIn-Thr-Lys-lle-Thr-Asp-OH. It is derived from the specific post-translational processing of proglucagon in enteroendocrine L cells of the intestine and in specific regions of the brainstem. GLP-2 binds to a single G protein-coupled receptor belonging to the class II glucagon secretin family. GLP-2 has been reported to induce significant growth of the small intestinal mucosal epithelium by stimulating stem cell proliferation in the crypts and inhibiting apoptosis in the villi (Drucker et al., 1996, Proc. Nati. Acad. Sci. USA 93: 7911-7916). GLP-2 also has growth effects in the colon. Moreover, GLP-2 also inhibits gastric emptying and gastric acid secretion (Wojdemann et al., 1999, J. Clin. Endocrinol. Metab. 84: 2513-2517), improves intestinal barrier function (Benjamin et al., 2000, Gut 47: 112-119), stimulates intestinal hexose transport by upregulating glucose transporters (Cheeseman, 1997, Am. J. Physiol. R1965-71), and increases intestinal blood flow (Guan et al., 2003, Gastroenterology, 125: 136-147). I 7 7C*nn / l 7Π7 / E / YΙΛΙ It has been recognized in the art that glucagon-like peptide-2 receptor analogs have therapeutic potential for the treatment of intestinal diseases. However, native hGLP-2, a 33-amino-acid gastrointestinal peptide, is not clinically useful due to its short half-life in humans, which is approximately 7 minutes for full-length GLP-2 [1-33] and 27 minutes for truncated GLP-2 [3-33]. This short half-life is largely due to degradation by the enzyme dipeptidyl peptidase IV (DPP-IV). Consequently, there have been attempts in the art to develop GLP-2 receptor agonists with improved pharmacokinetic characteristics, particularly to enhance the half-life of GLP-2 molecules. For example, GLP-2 analogs with substitutions have been suggested, such as, e.g.GLP-2 analogs containing a Gly substitution at position 2 ([hGly2]GLP-2, teduglutide) increase the half-life from seven minutes (native GLP-2) to approximately two hours. Acylation of peptide drugs with fatty acid chains has also proven beneficial in prolonging systemic circulation and increasing enzyme stability without altering biological potency. However, while these attempts have improved the pharmacokinetics of GLP-2 analogs, and they are sometimes described in the art as long-acting, it is important to note that this is in comparison to native hGLP-2, which has half-lives on the order of several hours, rather than minutes. This, in turn, means that GLP-2 analogs must be administered to patients once or more daily. US patent 5,789,379 discloses GLP-2 analogues for administration by injection. The analogues are provided as powdered peptides and are mixed with phosphate-buffered saline (PBS) prior to injection at a pH of 7.3–7.4 with a GLP-2 concentration of 130 mg / mL. In some examples, the GLP-2 / PBS composition was mixed with gelatin to provide a depot consisting of a 130 mg / L GLP-2 solution in 15% PBS / gelatin. US patent 5,789,379 does not disclose stable aqueous liquid formulations of GLP-2 analogues, and the GLP-2 analogues are generally reconstituted from powder prior to injection. In documents WO 97 / 39031 and US 6,184,201, the analogue of is revealed. I 7 7C*nn / l 7Π7 / E / YΙΛΙ GLP-2, [Gly2]GLP-2. In this case, the alanine at position 2 has been replaced with glycine to make the peptide resistant to cleavage by DPP IV. As in US patent 5,789,379, the GLP-2 analogue was provided as a powdered peptide and mixed with saline, PBS, or 5% dextrose prior to injection, optionally adding acetic acid as a solubility enhancer. WO 02 / 066511 describes GLP-2 analogues with a prolonged in vivo half-life and their use as medicaments in the treatment of gastrointestinal disorders, such as inflammatory bowel disease. The GLP-2 analogues were stored in lyophilized form and reconstituted for administration in media, for example, using saline solution or PBS. WO 01 / 41779 describes the use of h[Gly2]GLP-2 as a pretreatment to inhibit chemotherapy-induced apoptosis and promote cell survival. h[Gly2]GLP-2 is administered by subcutaneous or intravenous injection or by infusion after reconstitution of the analogue in PBS. WO 2001 / 049314 pertains to formulations of GLP-2 peptides and their analogues that exhibit superior stability after storage and / or exposure to elevated temperatures. The GLP-2 compositions comprise a GLP-2 peptide or analogue, a phosphate buffer, L-histidine, and mannitol. WO 2006 / 117565 describes GLP-2 analogues comprising one or more substitutions compared to [hGly2]GLP-2 that improve in vivo biological activity and / or chemical stability, e.g., as assessed in in vitro stability assays. In particular, it describes GLP-2 analogues having substitutions at one or more of positions 8, 16, 24, and / or 28 of the wild-type GLP-2 sequence, optionally in combination with additional substitutions at position 2 and one or more of positions 3, 5, 7, 10, and 11, and / or a deletion of one or more of amino acids 31 to 33. These substitutions may also be combined with the addition of an N-terminal or C-terminal stabilizing peptide sequence. Daily or twice-daily administration of these GLP-2 analogues is also described. Among the molecules revealed in the document I 7 7C*nn / l 7Π7 / E / YΙΛΙ WO 2006 / 117565 contains glepaglutide (ZP1848), which has been designed to be stable in liquid formulations, and is usually administered by daily dosing using an injection pen. Improving the formulation of GLP-2 analogues remains a challenge in this area, particularly providing stable liquid formulations capable of long-term storage without undue physical or chemical degradation of the active monomeric form of the peptide. In liquid formulations of peptide drugs, chemical pathways that can occur include the formation of covalently linked dimers and oligomers of the peptide, reducing the amount of the active monomeric form of the peptide through the formation of these high-molecular-weight, covalently linked oligomeric products. The law of mass action dictates that, generally, the higher the concentration of a peptide drug in a formulation, the greater the likelihood of covalently linked oligomeric product formation. Another objective in the field of GLP-2 analogue formulation would be to provide formulations in which the viscosity of the formulation is controlled within a range that makes it suitable for use in delivery devices, such as pre-filled syringes, infusion pumps, portable injectors, or auto-injectors. BRIEF DESCRIPTION OF THE INVENTION In general terms, the present invention is based on the studies reported in the examples that led to surprising findings in relation to liquid formulations of GLP-2 analogues that make them suitable for long-term storage as liquids and / or make them especially suitable for administration by means of a drug delivery device. In an initial study, the inventors discovered that the acetate present in the formulation, derived from GLP-2 analogues, affects the formulation's viscosity. This allows for the control of the formulation's viscosity by changing and / or controlling the acetate concentration. The liquid formulation with a low viscosity range is clinically useful because it offers advantages in the development and manufacture of drug delivery devices by potentially reducing fragmentation, dosage errors, dosage inaccuracy, and other malfunctions during drug preparation and / or patient use. Furthermore, the low viscosity may allow for faster injection and / or the use of narrower gauge (i.e., larger gauge) needles, which, in turn, can reduce injection discomfort.This allows for the delivery of GLP-2 analog formulations in the form of a drug delivery device, such as a pre-filled syringe, adjustable-dose auto-injector, disposable auto-injector, portable injector, or infusion pump, thus providing patients with a ready-to-use formulation in a simpler, safer, and more patient-friendly device. Controlling the formulation to a higher viscosity could be appropriate in other drug delivery devices. In a second study, the present inventors discovered that during long-term storage of ZP1848 (glepaglutide) at 2–8 °C, the formation of covalently linked oligomers is concentration-dependent. However, contrary to the usual situation where the law of mass action implies that the formation of covalent oligomers increases with increasing concentration of a peptide drug, the present inventors discovered that the concentration dependence of oligomer formation is inversely dependent on increasing concentration of the GLP-2 analogue.Without wishing to be bound to any particular theory, the present inventors believe that the reduction in the formation of covalently linked oligomers as the concentration of the GLP-2 analogue increases is a result of the lysine tail of the GLP-2 analogue promoting the formation of self-associated structural assemblies of the native peptide, which hinders the formation of covalently linked oligomers in the formulation. This means that the weakly self-associated species are able to dissociate to release the biologically active monomer after administration to a patient, rather than causing a loss. I 7 7C*nn / l 7Π7 / E / YILI of active species as occurs when covalently bonded oligomers are formed. In a third study, the present inventors discovered that the GLP-2 analogues used in the formulations of the present invention are not compatible with the phosphate buffer commonly used in the prior art for reconstituted powdered or lyophilized GLP-2 compositions. This study found that only a few buffers were compatible with the formulation of these GLP-2 analogues in a manner suitable for long-term storage in liquid form. Accordingly, in a first aspect, the present invention provides a stable liquid pharmaceutical formulation, the formulation comprising a glucagon-like peptide-2 (GLP-2) analogue, wherein the GLP-2 analogue is represented by the following formula: R1 - Z1 - His - Gly - Glu - Gly - X5 - Phe - Ser - Ser - Glu - Leu - R1 is hydrogen, Ci-4 alkyl (e.g., methyl), acetyl, formyl, benzoyl or trifluoroacetyl; X5 is Ser or Thr; X11 is Wing or Being; R2 is NH2 or OH; and Z1 and Z2 are independently absent or are a peptide sequence of 1-6 amino acid units of Lys; or a pharmaceutically acceptable salt or derivative thereof; in which the formulation comprises: (a) the GLP-2 analogue at a concentration of approximately 2 mg / ml to approximately 30 mg / ml; (b) a buffer selected from the group consisting of a histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, Bis-Tris buffer and MOPS buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM; I 7 7C*nn / l 7P7 / E / YILI (c) a non-ionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol and trehalose at a concentration of approximately 90 mM to approximately 360 mM; and (d) arginine qs to provide a formulation having a pH of approximately 6.6 to approximately 7.4. In some embodiments, the formulation contains 5% or less of the GLP-2 analogue in the form of covalently linked oligomeric products. Alternatively or additionally, the concentration of total acetate from the GLP-2 analogue in the formulation is less than or equal to 11% acetate per mg of GLP-2 analogue. Alternatively or additionally, the formation of covalently linked oligomers of the GLP-2 analogue is inversely dependent on the concentration of the GLP-2 analogue in the formulation. The formulation components and their quantities provide a formulation with a content of at least 90% of the GLP-2 analogue and with less than 10% of chemical degradation products when stored for at least 18 months at 2-8 °C. In a further aspect, the present invention provides a manufacturing article or kit comprising a container holding the stable pharmaceutical formulation of the present invention. In a further aspect, the present invention provides a delivery device containing a liquid formulation comprising a GLP-2 analogue of the present invention. In a further aspect, the present invention provides a formulation of the glucagon-like peptide-2 (GLP-2) analogue of the present invention for use in therapy. In a further aspect, the present invention provides a formulation of the glucagon-like peptide-2 (GLP-2) analogue of the present invention for use in a procedure for the treatment and / or prevention of a stomach and intestine-related disorder in a human patient. In a further aspect, the present invention provides a process for producing a stable liquid pharmaceutical formulation comprising a I 7 7C*nn / l 7P7 / E / YILI glucagon-like peptide-2 (GLP-2) analogue, wherein the GLP-2 analogue is represented by the following formula: R1 - Z1 - His - Gly - Glu - Gly - X5 - Phe - Ser - Ser - Glu - Leu - R1 is hydrogen, Ci-4 alkyl (e.g., methyl), acetyl, formyl, benzoyl, or trifluoroacetyl X5 is Ser or Thr X11 is Wing or Being R2esNH2oOH; Z1 and Z2 are independently absent or are a peptide sequence of 1-6 amino acid units of Lys; or a pharmaceutically acceptable salt or derivative thereof; wherein the process comprises formulating (a) the GLP-2 analogue at a concentration of approximately 2 mg / ml to approximately 30 mg / ml, (b) with a buffer selected from the group consisting of a histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, BisTris buffer and MOPS buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM; (c) with a nonionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol and trehalose, the tonicity modifier being present at a concentration of approximately 90 mM to approximately 360 mM; and (d) with arginine qs to provide a formulation having a pH of approximately 6.6 to approximately 7.4; in which the formulation contains 5% or less of the GLP-2 analogue in the form of covalently bound oligomeric products. In a further aspect, the present invention provides the use of a formulation comprising a glucagon-like peptide-2 (GLP-2) analogue, wherein the GLP-2 analogue is represented by the following formula: R1-Z1-His-Gly-Glu-Gly-X5-Phe-Ser-Ser-Glu-Leu-X11-Thr-Ille-Leu-Asp-Ala-Leu-AlaAla-Arg-Asp-Phe-Ille-Ala-Trp-Leu-Ille-Ala-Thr-Lys-Ille-Thr-Asp-Z2-R2 I 7 7C*nn / l 7Π7 / Ε / ΥΙΛΙ > κ C ι\ 2 C in which: fc R1 is hydrogen, Ci-4 alkyl (e.g., methyl), acetyl, formyl, benzoyl or trifluoroacetyl X5 is Ser or Thr X11 is Ala or Ser R2 is NH2 or OH; Z1 and Z2 are independently absent or are a peptide sequence of 1-6 amino acid units of Lys; or a pharmaceutically acceptable salt or derivative thereof; to provide a liquid pharmaceutical formulation that is stable for 24 months when stored at 2-8 °C, wherein the formulation comprises: (a) the GLP-2 analogue at a concentration of approximately 2 mg / ml to approximately 30 mg / ml; (b) a buffer selected from the group consisting of a histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, Bis-Tris buffer and MOPS buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM; (c) a non-ionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol and trehalose at a concentration of approximately 90 mM to approximately 360 mM; and (d) arginine qs to provide a formulation having a pH of approximately 6.6 to approximately 7.4. In a further aspect, the present invention provides a method for modulating the viscosity of a stable liquid pharmaceutical formulation comprising a glucagon-like peptide-2 (GLP-2) analogue, wherein the GLP-2 analogue is represented by the following formula: R1 - Z1 - His - Gly - Glu - Gly - X5 - Phe - Ser - Ser - Glu - Leu - R1 is hydrogen, Ci-4 alkyl (e.g., methyl), acetyl, formyl, benzoyl, or trifluoroacetyl X5 is Ser or Thr X11 is Wing or Being R2esNH2oOH; Z1 and Z2 are independently absent or are a peptide sequence of 1-6 amino acid units of Lys; or a pharmaceutically acceptable salt or derivative thereof; wherein the process comprises formulating (a) the GLP-2 analogue at a concentration of approximately 2 mg / ml to approximately 30 mg / ml, (b) with a buffer selected from the group consisting of a histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, BisTris buffer, or MOPS buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM; (c) with a nonionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol, and trehalose, the tonicity modifier being present at a concentration of approximately 90 mM to approximately 360 mM; and (d) with arginine qs to provide a formulation having a pH of approximately 6.6 to approximately 7.4; wherein the total acetate concentration from the GLP2 analogue in the formulation is less than or equal to 11% acetate per mg of GLP-2 analogue and wherein the formulation has a viscosity greater than 0.8 and less than or equal to 2.0 mPa / s measured at 25 °C. In a further aspect, the present invention provides a method for reducing the formation of covalently bound oligomeric products of a glucagon-like peptide-2 (GLP-2) analogue in a stable liquid pharmaceutical formulation comprising a GLP-2 analogue represented by the formula: R1 - Z1 - His - Gly - Glu - Gly - X5 - Phe - Ser - Ser - Glu - Leu - R1 is hydrogen, Ci-4 alkyl (e.g., methyl), acetyl, formyl, benzoyl or I 7 7C*nn / l 7Π7 / Ε / ΥΙΛΙ trifluoroacetyl X5 is Ser or Thr X11 is Wing or Being R2esNH2oOH; Z1 and Z2 are independently absent or are a peptide sequence of 1-6 amino acid units of Lys; or a pharmaceutically acceptable salt or derivative thereof; wherein the process comprises formulating (a) the GLP-2 analogue at a concentration of approximately 2 mg / ml to approximately 30 mg / ml, (b) with a buffer selected from the group consisting of a histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, BisTris buffer, or MOPS buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM; (c) with a nonionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol, and trehalose, the tonicity modifier being present at a concentration of approximately 90 mM to approximately 360 mM; and (d) with arginine qs to provide a formulation having a pH of approximately 6.6 to approximately 7.4; wherein the formulation contains 5% or less of the GLP-2 analogue in the form of covalently bonded oligomeric products. In some cases, in this aspect of the present invention, the formation of covalently bonded oligomers of the GLP-2 analogue is inversely dependent on the concentration of the GLP-2 analogue in the formulation. In a further aspect, the present invention provides the use of a formulation for reducing the formation of covalently bound oligomeric products of a glucagon-like peptide-2 (GLP-2) analogue, wherein the GLP-2 analogue is represented by the following formula: R1-Z1-His-Gly-Glu-Gly-X5-Phe-Ser-Ser-Glu-Leu-X11-Thr-Ille-Leu-Asp-Ala-Leu-AlaAla-Arg-Asp-Phe-Ille-Ala-Trp-Leu-Ille-Ala-Thr-Lys-Ille-Thr-Asp-Z2-R2, wherein: R1 is hydrogen, Ci-4 alkyl (e.g., methyl), acetyl, formyl, benzoyl or I 7 7C*nn / l 7Π7 / Ε / ΥΙΛΙ trifluoroacetyl X5 is Ser or Thr X11 is Wing or Being R2esNH2oOH; Z1 and Z2 are independently absent or are a peptide sequence of 1-6 amino acid units of Lys; or a pharmaceutically acceptable salt or derivative thereof; in a liquid pharmaceutical formulation that is stable for 24 months when stored at 2-8 °C, wherein the formulation comprises: (a) the GLP-2 analogue at a concentration of approximately 2 mg / ml to approximately 30 mg / ml; (b) a buffer selected from the group consisting of a histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, Bis-Tris buffer and MOPS buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM; (c) a non-ionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol and trehalose at a concentration of approximately 90 mM to approximately 360 mM; and (d) arginine qs to provide a formulation having a pH of approximately 6.6 to approximately 7.4; wherein the formulation contains 5% or less of the GLP-2 analogue in the form of covalently bonded oligomeric products. In some cases, in this aspect of the present invention, the formation of covalently bonded oligomers of the GLP-2 analogue is inversely dependent on the concentration of the GLP-2 analogue in the formulation. In a further aspect, the present invention provides a use of a formulation for modulating the viscosity of a liquid pharmaceutical formulation comprising a glucagon-like peptide-2 (GLP-2) analogue, wherein the GLP-2 analogue is represented by the following formula: R1-Z1-His-Gly-Glu-Gly-X5-Phe-Ser-Ser-Glu-Leu-X11-Thr-lle-Leu-Asp-Ala-LeuAla-Ala-Arg-Asp-Phe-lle-Ala-Trp-Leu-lle-Ala-Thr-Lys-lle-Thr-Asp-Z2-R2 I 7 7C*nn / l 7Π7 / Ε / ΥΙΛΙ > κ C ι\ 2 C in which: fc R1 is hydrogen, Ci-4 alkyl (e.g., methyl), acetyl, formyl, benzoyl or trifluoroacetyl X5 is Ser or Thr X11 is Ala or Ser R2 is NH2 or OH; Z1 and Z2 are independently absent or are a peptide sequence of 1-6 amino acid units of Lys; or a pharmaceutically acceptable salt or derivative thereof; in a liquid pharmaceutical formulation that is stable for 24 months when stored at 2-8 °C, wherein the formulation comprises: (a) the GLP-2 analogue at a concentration of approximately 2 mg / ml to approximately 30 mg / ml; (b) a buffer selected from the group consisting of a histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, Bis-Tris buffer and MOPS buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM; (c) a non-ionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol and trehalose at a concentration of approximately 90 mM to approximately 360 mM; and (d) arginine qs to provide a formulation having a pH of approximately 6.6 to approximately 7.4; wherein the total acetate concentration from the GLP2 analogue in the formulation is less than or equal to 11% acetate per mg of GLP-2 analogue and the formulation has a viscosity between 0.8 and 2.0 mPa / s measured at 25 °C. In a further aspect, the present invention provides a solid composition comprising an acetate salt of a glucagon-like peptide-2 (GLP-2) analogue having the formula: (H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH) where x is 1.0 to 8.0. In a further aspect, the present invention provides a stable aqueous pharmaceutical formulation, the formulation comprising (a) the solid composition of the present invention at a concentration of approximately 2 mg / ml to approximately 30 mg / ml; (b) a buffer selected from the group consisting of a histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, Bis-Tris buffer and MOPS buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM; (c) a non-ionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol and trehalose at a concentration of approximately 90 mM to approximately 360 mM; and (d) arginine qs to provide a formulation having a pH of approximately 6.6 to approximately 7.4; wherein the formulation contains 5% or less of the GLP-2 analogue in the form of covalently bonded oligomeric products and wherein the formulation has a viscosity between 0.8 and 2.0 mPa / s measured at 25 °C. In all aspects of the invention described herein, the buffer may be selected from the group consisting of a histidine buffer, mesylate buffer, and acetate buffer. In all aspects of the invention described herein, the non-ionic tonicity modifier may be selected from the group consisting of mannitol, sucrose, glycerol, and sorbitol. In some embodiments, the formulation contains 5% or less of the GLP-2 analogue in the form of covalently linked oligomeric products. Alternatively or additionally, the concentration of total acetate from the GLP-2 analogue in the formulation is less than or equal to 11% acetate per mg of GLP-2 analogue. Alternatively or additionally, the formation of covalently linked oligomers of the GLP-2 analogue is inversely dependent on the concentration of the GLP-2 analogue in the formulation. In a further aspect, the present invention relates to a stable liquid pharmaceutical formulation, the formulation comprising a glucagon-like peptide-2 (GLP-2) analogue, wherein the GLP-2 analogue is represented I 7 7C*nn / l 7Π7 / Ε / ΥΙΛΙ using the following formula: R1-His-Gly-Glu-Gly-X5-Phe-Ser-Ser-Glu-Leu-X11-Thr-lle-Leu-Asp-Ala-LeuAla-Ala-Arg-Asp-Phe-lle-Ala-Trp-Leu-lle-Ala-Thr-Lys-lle-Thr-Asp-Z2-R2 in which: R1 is hydrogen, Ci-4 alkyl (e.g., methyl), acetyl, formyl, benzoyl or trifluoroacetyl; X5 is Ser or Thr; X11 is Wing or Being; R2 is NH2 or OH; and Z2 is a peptide sequence of 6 amino acid units of Lys; or a pharmaceutically acceptable salt or derivative thereof, the formulation comprising the components as set forth in any one of the aspects of the invention set forth herein. In this aspect of the present invention, formulations comprising a glucagon-like peptide-2 (GLP-2) analogue, or salts thereof, may be used for the treatment and / or prevention of disorders related to the stomach and intestine, such as ulcers, digestive disorders, malabsorption syndromes, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease, celiac sprue (e.g., from gluten-induced enteropathy or celiac disease), tropical sprue, hypogammaglobulinemic sprue, enteritis, regional enteritis (Crohn's disease), ulcerative colitis, small bowel damage, or short bowel syndrome.Alternatively or additionally, glucagon-like peptide-2 (GLP-2) analogue may be used for the treatment and / or prevention of disorders of the stomach and intestines, such as radiation enteritis, infectious or post-infectious enteritis, or small bowel damage due to toxic or other chemotherapeutic agents. In this case, treatment with the GLP-2 analogue may optionally be combined with one or more anticancer therapies, and may therefore include administering one or more chemotherapeutic agents to the patient or treating the patient with radiation therapy. In some embodiments of the present invention, in the above formula, X5 I 7 7C*nn / l 7P7 / E / YILI is Thr and / or X11 is Ala. Examples of these glucagon-like peptide-2 (GLP-2) analogues include: ZP1848 H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2 (SEQ ID NO: 1) ZP2949 H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKK-OH (SEQ ID NO: 2); ZP2711 H-HGEGTFSSELATILDALAARDFIAWLIATKITDKK-OH (SEQ ID NO: 3); ZP2469 H-HGEGTFSSELATILDALAARDFIAWLIATKITDK-OH (SEQ ID NO: 4); ZP1857 H-HGEGTFSSELATILDALAARDFIAWLIATKITD-NH2(SEQ ID NO: 5); either ZP2530 H-HGEGTFSSELATILDALAARDFIAWLIATKITD-OH (SEQ ID NO: 6). In some embodiments of the present invention, in the above formula X5 is Ser and / or X11 is Ser. Examples of these glucagon-like peptide-2 (GLP-2) analogues include: ZP1846 H-HGEGSFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH2(SEQ ID NO: 7); ZP1855 H-HGEGSFSSELSTILDALAARDFIAWLIATKITD-NH2(SEQ ID NO: 8); either ZP2242 H-HGEGSFSSELSTILDALAARDFIAWLIATKITDK-OH (SEQ ID NO: 9). The embodiments of the present invention are described below by way of example and not for the purpose of limitation, with reference to the accompanying figures. However, several other aspects and embodiments of the present invention will be readily apparent to a person skilled in the art from this disclosure. and / or, when used herein, should be understood as the specific disclosure of each of the two specified features or components with or without the other. For example, A and / or B should be considered as a specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if I 7 7C*nn / l 7Π7 / Ε / ΥΙΛΙ set out each individually in this document. Unless the context dictates otherwise, the descriptions and definitions of the features set forth above are not limited to any particular aspect or embodiment of the invention and apply equally to all aspects and embodiments described. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows a typical chromatogram showing the separation of oligomers of the peptide ZP1848. Figure 2 shows how viscosity (squares) and hydrodynamic radius (z-average) (circles) varied as a function of acetate concentration after formulation preparation. The data show that above 11% acetate, viscosity and hydrodynamic radius (z-average) begin to increase. Figure 3 shows the stability assessment at 20 mg / ml (normalized to 100% at baseline) using different buffers at 40QC for 0 to 3 weeks. Figure 4 shows the stability assessment at 2 mg / ml (normalized to 100% at baseline) using different buffers at 40QC for 0 to 3 weeks. Figure 5 shows the stability assessment at 20 mg / ml (normalized to 100% at baseline) using different buffers at 40QC for 0 to 3 weeks. Figure 6 shows the stability assessment at 2 mg / ml (normalized to 100% at baseline) using different buffers at 40QC for 0 to 3 weeks. Figure 7 shows the purity of Formulations 1 to 5 using different concentrations of ZP1848 acetate salt, a different salt form, a different tonicity agent, and a different buffer. Figure 8 shows the stability of the peptide in combination with different preservatives at 25 °C for 13 weeks. Figure 9 shows the HPLC purity of the formulations investigated at 25 °C (accelerated conditions). I 7 7C*nn / l 7Π7 / E / YΙΛΙ DETAILED DESCRIPTION OF THE INVENTION Definitions Unless otherwise specified, the following definitions are provided for the specific terms used in the written description above. Throughout the description and claims, conventional one-letter and three-letter codes are used for naturally occurring amino acids. All amino acid residues in the peptides of the invention are preferably of the L configuration; however, D configuration amino acids may also be present. The preferred compounds of the present invention have at least one GLP-2 biological activity, particularly in promoting intestinal growth. This can be evaluated in in vivo assays, for example, as described in the examples (e.g.) of WO 2006 / 117565, in which the mass of the intestine, or a portion thereof, is determined after a test animal has been treated or exposed to a GLP-2 analogue. In some aspects of the present invention, the liquid formulations comprising a GLP-2 analogue have a total acetate concentration in the formulation less than or equal to 11% acetate per mg of GLP-2 analogue, and more preferably less than or equal to 10% acetate per mg of GLP-2 analogue, more preferably less than or equal to 9% acetate per mg of GLP-2 analogue, more preferably less than or equal to 8% acetate per mg of GLP-2 analogue, more preferably less than or equal to 7% acetate per mg of GLP-2 analogue, more preferably less than or equal to 6% acetate per mg of GLP-2 analogue, more preferably less than or equal to 5% acetate per mg of GLP-2 analogue, more preferably less than or equal to 4% acetate per mg of GLP-2 analogue, more preferably less than or equal to 3% acetate per mg of GLP-2 analogue, and more preferably less than or equal to 2% acetate per mg of GLP-2 analogue. The concentration of acetate in the lyophilized drug substance can be controlled by adjusting the concentration of acetic acid in the mobile phase used during the final chromatographic step. This will result in a substance I 7 7C*nn / l 7P7 / E / YILI pharmacological with an acetate content below 11%. Therefore, for example, for a formulation containing 20 mg / ml of the GLP-2 analogue, the total acetate concentration will be less than or equal to 37 mM. For reference, a total acetate concentration of 10% is equivalent to 34 mM, 9% to 30 mM, 8% to 27 mM, 7% to 24 mM, and 6% to 20 nM. The total acetate concentration can be determined using procedures known in the art, e.g., HPLC. The following examples show that the viscosity of the liquid formulations of the present invention depends on the total acetate concentration. Preferably, the formulations have a viscosity between 0.8 and 2.0 mPa / s measured at 25 °C. Conveniently, the viscosity can be measured using microVISC™. In parallel, the hydrodynamic radius can be measured using a dynamic light scattering plate reader (DDL) (Wyatt DynaPro II). Samples were prepared containing a GLP-2 analogue drug substance (DS) with 6% acetate, and to simulate DS containing 7.8–15% acetate, acetate was subsequently added. The preparation data for formulations with varying acetate concentrations from 6.7–15% are shown below in Figure 2.The effect of controlling the total acetate concentration is that the injectability of the formulations of the present invention can be modulated, for example, by reducing the total acetate concentration to provide a less viscous formulation that can be injected more easily. The liquid formulations according to the present invention are preferably isosmotic. Isosmotic means that the formulations of the present invention have the same or similar osmotic pressure as body fluids. Preferably, the formulations of the present invention have an osmolarity of approximately 300 ± 60 mOsm as measured by an osmometer. Furthermore, or alternatively, the present invention demonstrates that the formation of covalently bonded oligomers of the GLP-2 analogue is inversely dependent on the concentration of the GLP-2 analogue in the formulation. As shown in the Examples, this amount of covalently bonded oligomers can be determined using size-exclusion chromatography. The sizes were determined by measuring the area under the peaks for the monomeric GLP-2 analog and the oligomers, respectively. This can be performed using a Dionex Ultimate3000 HPLC system, providing a linear gradient, at a flow rate of 0.5 ml / min, which was used for the analysis. The mobile phase consisted of 0.1% TFA in 45% acetonitrile and 55% Milli-Q water. A wavelength of 215 nm was used for detection. This means that the formulations of the present invention generally contain the GLP-2 analog at a concentration of approximately 2 mg / ml to approximately 30 mg / ml, more preferably at a concentration of approximately 15 mg / ml to approximately 25 mg / ml, and most preferably at a concentration of approximately 20 mg / ml. In further embodiments, the present invention generally contains the GLP-2 analogue at a concentration of approximately 2 mg / ml, 5 mg / ml, 10 mg / ml or 20 mg / ml.In some aspects of the present invention, it is preferred that the concentration of the GLP-2 analogue be selected such that the formulation contains 10% or less, more preferably 5% or less, more preferably 4% or less, more preferably 3% or less, and more preferably 2% or less of the GLP-2 analogue in the form of covalently bound oligomeric products, preferably after 18 months of storage. By way of illustration, the amount of covalently bound oligomeric products may be in the range of 2% to 5%, more preferably in the range of 2% to 4%, and most preferably in the range of 2% to 3%. In some cases, the formulation of the present invention may be used in a once- or twice-daily dosing regimen. In some cases, the formulation of the present invention may be used in a once- or twice-weekly dosing regimen. Alternatively or additionally, the dosing regimen of the GLP-2 analogues of the present invention may comprise a plurality or cycle of doses separated in time by 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, or 12 days. In a preferred embodiment, the doses are separated in time by 3, 3.5, 4, 5, 6, 7, or 8 days. In a preferred embodiment, the doses are separated in the I 7 7C*nn / l 7P7 / B / YILI time for 3 days, 3.5 days, 4 days, or 7 days. As will be seen in the subject matter, the time between doses can be varied to some extent so that each and every dose is not separated by precisely the same amount of time. This will often be directed at the physician's discretion. Therefore, the doses may be separated in time by a clinically acceptable interval, e.g., from approximately 2 days to approximately 10 days or from approximately 3 or 4 days to approximately 7 or 8 days. The formulations of the present invention are stable liquid pharmaceutical formulations of GLP-2 analogues. A stable formulation is one in which the peptide therein essentially maintains its physical and / or chemical stability and / or biological activity after storage. Preferably, the formulation essentially maintains its physical and chemical stability, as well as its biological activity, after storage. The storage period is generally selected based on the intended shelf life of the formulation. The formulations of the present invention are provided as stable liquid formulations, e.g., stable aqueous liquid formulations. Several analytical techniques for measuring protein stability are available in the art and are reviewed 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), for example. In the present invention, stable formulations include formulations in which at least 80%, more preferably at least 90%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, and most preferably at least 99% of the GLP-2 analogue is active in the formulation after it has been stored at 2-8 °C for at least 18 months. Stability can be measured at a selected temperature for a selected period of time, for example, by using an elevated temperature to reduce the period during which a formulation is tested. Generally, storage at a temperature between 2 and 8 °C denotes storage under normal refrigeration conditions. In certain In these embodiments, the formulation is stable under these conditions for at least 12 months, more preferably for at least 18 months, and more preferably for at least 24 months. Stability can be assessed qualitatively and / or quantitatively in various ways, including assessing aggregate formation (e.g., using size exclusion chromatography, measuring turbidity, and / or by visual inspection); assessing charge heterogeneity using cation exchange chromatography, capillary isoelectric focusing (icIEF), or capillary zone electrophoresis; amino-terminal or carboxy-terminal sequence analysis; mass spectrometry analysis; SDS-PAGE analysis to compare the reduced and intact antibody; peptide map analysis (e.g., tryptic or LYS-C); assessing the antibody's biological activity or antigen-binding function; etc.Instability may involve any one or more of: aggregation, deamidation (e.g., deamidation of Asn), oxidation (e.g., oxidation of Met), isomerization (e.g., isomerization of Asp), cleavage / hydrolysis / fragmentation (e.g., fragmentation of the hinge region), succinimide formation, unpaired cysteine(s), N-terminal extension, C-terminal processing, glycosylation differences, etc. A peptide maintains its physical stability in a pharmaceutical formulation if it shows no (or only slight) signs of aggregation, precipitation, and / or denaturation, e.g., when visually examining color and / or clarity, or when measured by UV light scattering, dynamic light scattering, circular dichroism, or size exclusion chromatography, and is deemed to still maintain its biological activity. A peptide maintains its chemical stability in a pharmaceutical formulation if its chemical stability at a given time is such that the peptide is considered to still maintain its biological activity, as defined below. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the peptide. Chemical alteration may involve isomerization, oxidation, or size modification (e.g., cleavage), which can be assessed by HPLC or size-exclusion chromatography, SDS-PAGE, and / or mass spectrometry, for example. Other types of chemical alteration include I 7 7C*nn / l 7Π7 / Β / YILI alteration of the charge n (e.g., that which occurs as a result of deamidation) that can be assessed by HPLC or ion exchange chromatography or icIEF, for example. GLP-2 analogues The GLP-2 analogues present in the formulations of the present invention have one or more amino acid substitutions, deletions, inversions, or additions compared to native GLP-2 as defined above. This definition also includes the synonymous terms GLP-2 mimetics and / or GLP-2 agonists. Furthermore, the analogue of the present invention may additionally have a chemical modification of one or more of its amino acid side groups, α-carbon atoms, terminal amino group, or terminal carboxylic acid group. A chemical modification includes, but is not limited to, adding chemical residues, creating new bonds, and removing chemical residues. Modifications to amino acid side groups include, without limitation, acylation of the ε-amino groups of lysine, N-alkylation of arginine, histidine, or lysine, alkylation of glutamic or aspartic carboxylic acid groups, and deamidation of glutamine or asparagine.Amino-terminal modifications include, without limitation, desamino, lower N-alkyl, lower N-dialkyl, and nacyl modifications. Carboxy-terminal modifications include, without limitation, amide, lower alkyl amide, dialkylamide, and lower alkyl ester modifications. Preferably, in this document, the lower alkyl is C104 alkyl. Furthermore, one or more side groups, or terminal groups, may be protected by protecting groups known to a peptide chemist skilled in the subject. The α-carbon of an amino acid may be mono- or di-methylated. In some aspects, the liquid formulations of the present invention employ an analogue of glucagon-like peptide-2 (GLP-2) represented by the formula: R1-Z1-His-Gly-Glu-Gly-X5-Phe-Ser-Ser-Glu-Leu-X11-Thr-lle-Leu-Asp-Ala-LeuAla-Ala-Arg-Asp-Phe-lle-Ala-Trp-Leu-lle-Ala-Thr-Lys-lle-Thr-Asp-Z2-R2 I 7 7C*nn / l 7Π7 / Β / ΥΙΛΙ in which: R1 is hydrogen, Ci-4 alkyl (e.g., methyl), acetyl, formyl, benzoyl or trifluoroacetyl; X5 is Ser or Thr; X11 is Wing or Being; R2 is NH2 or OH; and Z1 and Z2 are independently absent or are a peptide sequence of 1-6 amino acid units of Lys; or a pharmaceutically acceptable salt or derivative thereof. In some embodiments of the present invention, in the above formula, X5 is Thr and / or X11 is Ala. Examples of these glucagon-like peptide-2 (GLP-2) analogues include: ZP1848 H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2 (SEQ ID NO: 1) ZP2949 H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKK-OH (SEQ ID NO: 2); ZP2711 H-HGEGTFSSELATILDALAARDFIAWLIATKITDKK-OH (SEQ ID NO: 3); ZP2469 H-HGEGTFSSELATILDALAARDFIAWLIATKITDK-OH (SEQ ID NO: 4); ZP1857 H-HGEGTFSSELATILDALAARDFIAWLIATKITD-NH2(SEQ ID NO: 5); either ZP2530 H-HGEGTFSSELATILDALAARDFIAWLIATKITD-OH (SEQ ID NO: 6). In one embodiment of the present invention, the glucagon-like peptide-2 (GLP-2) analogue is ZP1848 HHGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2 (SEQ ID NO: 1). In some embodiments of the present invention, in the above formula X5 is Ser and / or X11 is Ser. Examples of these glucagon-like peptide-2 (GLP-2) analogues include: ZP1846 H-HGEGSFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH2(SEQ ID NO: 7); I 7 7C*nn / l 7Π7 / Β / YΙΛΙ ΖΡ1855 H-HGEGSFSSELSTILDALAARDFIAWLIATKITD-NH2 (SEQ ID NO: 8); either ZP2242 H-HGEGSFSSELSTILDALAARDFIAWLIATKITDK-OH (SEQ ID NO: 9). In one embodiment of the present invention, the glucagon-like peptide-2 (GLP-2) analogue is ZP1846 HHGEGSFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH2(SEQ ID NO: 7). It should be understood that the peptides (pharmaceutical substance) of the invention may also be provided in the form of a salt or other derivative. Salts include pharmaceutically acceptable salts, such as acid addition salts and basic salts. Examples of acid addition salts include hydrochloride salts, citrate salts, chloride salts, and acetate salts. Preferably, the salt is acetate. In general, it is preferred that the salt not be a chloride salt. Examples of basic salts include salts in which the cation is selected from alkali metals, such as sodium and potassium, alkaline earth metals, such as calcium, and ammonium+N ions (R3)s(R4), in which R3 and R4 independently designate optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted aryl, or optionally substituted heteroaryl. Further examples of pharmaceutically acceptable salts are described in Remington's Pharmaceutical Sciences, 17th edition.Ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 and more recent editions, and in the Encyclopedia of Pharmaceutical Technology. In preferred embodiments, the acetate salt of a GLP-2 analogue of the invention is selected from the group consisting of ZP1848-acetate, ZP2949-acetate, ZP2711-acetate, ZP2469-acetate, ZP1857-acetate, ZP2530-acetate, ZP1846-acetate, ZP1855-acetate, and ZP2242-acetate. In the present context, the expression ZP1848-acetate refers to the fact that the ZP1848 molecule is in the form of its acetate salt. The acetate salts of GLP-2 analogues can be represented by the formula (GLP-2 analogue), x(CH3COOH) where x is 1.0 to 8.0, i.e., where x is 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, or 8.0. In any composition of the acetate salts of GLP-2 analogues, there may be I 7 7C*nn / l 7P7 / E / YILI molecules with different numbers of acetate molecules, so x is not necessarily an integer. In some cases, x is from 4.0 to 8.0, x is from 6.0 to 8.0, ox is from 4.0 to 6.5. In some cases x is from 4.0 to 6.0, x is from 2.0 to 7.0, x is from 3.0 to 6.0, x is from 4.0 to 6.0 ox is from 4.0 to 8.0. In a preferred embodiment, the GLP-2 analog is either ZP1848-acetate or H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2 acetate (SEQ ID NO: 1) or (H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH) where x is 1.0 a 8.0. Accordingly, in a further aspect, the present invention provides solid compositions comprising an acetate salt of a glucagon-like peptide-2 (GLP-2) analogue. The solid compositions are useful for formulation with the excipients used to prepare the liquid formulations of the present invention. In one embodiment, the present invention provides a solid composition comprising an acetate salt of a glucagon-like peptide-2 (GLP-2) analogue having the formula: (H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH) where x is 1.0 to 8.0. An upper limit of 8.0 acetate molecules per GLP-2 analogue equates to an acetate content of less than 11% acetate and can be formulated to have a viscosity between 0.8 and 2.0 mPa / s measured at 25 °C. The range of the number of acetate molecules associated with each molecule of GLP-2 analogs defines a molecular weight range for this formulation component. For example, for the acetate salts of ZP1848, the range of the number of acetate molecules associated with each molecule of GLP-2 analogs defines a molecular weight range for ZP1848 acetate. As an example, 1 equivalent of acetate with each molecule of ZP1848 provides a molecular weight of 4316 + 60 = 4376 Da. Therefore, the molecular weights for increasing the number of acetate equivalents with ZP1848 are as follows: 1 equivalent of acetate = 4376 Da; 2 equivalents of acetate = 4436 Da; 3 equivalents of acetate = 4496 Da; 4 equivalents of acetate = 4556 Da; 5 equivalents of acetate = 4616 Da; 6 equivalents of acetate = 4676 Da; 7 I 7 7C*nn / l 7P7 / B / YILI equivalents of acetate = 4736 Da and 8 equivalents of acetate = 4796 Da. This, in turn, defines the molecular weight ranges as follows: 1-8 equivalents of acetate = 4376 Da-4796 Da; 4-8 equivalents of acetate = 4556 Da-4796 Da and 68 equivalents of acetate = 4676 Da-4796 Da. Other derivatives of the GLP-2 analogues of the invention include coordination complexes with metal ions such as Mn2+ and Zn2+, esters such as in vivo hydrolyzable esters, free acids or bases, hydrates, prodrugs, or lipids. Esters can be formed between the hydroxyl or carboxylic acid groups present in the compound and a carboxylic acid or alcohol, the other component involved in the reaction, using well-known techniques. Derivatives that, like the prodrugs of the compounds, are convertible in vivo or in vitro into one of the parent compounds. Typically, at least one of the biological activities of the compound will be reduced in the prodrug form of the compound and can be activated by conversion of the prodrug to release the compound or a metabolite thereof.Examples of prodrugs include the use of protective groups that can be removed in situ, releasing the active compound, or serve to inhibit drug clearance in vivo. Z1 and Z2 are independently present and / or absent, or are a peptide sequence of 1-6 lysine amino acid units, i.e., 1, 2, 3, 4, 5, or 6 lysine residues. The lysine residues may have a D or L configuration, although they have an L configuration. Particularly preferred Z sequences are sequences of four, five, or six consecutive lysine residues, and particularly six consecutive lysine residues. Example Z sequences are shown in WO 01 / 04156. In certain embodiments, Z1 is absent. In such cases, Z2 may be present or absent. GLP-2 analogue formulations The formulation of GLP-2 analogues is a ready-to-use formulation. The term "ready-to-use," as used herein, refers to a formulation that does not require preparation or dilution with a prescribed amount of diluent, e.g., water for injection or another diluent. I 7 7C*nn / l 7Π7 / Β / YILI suitable, before use by the designated route of administration. As described herein, the liquid formulations of the GLP-2 analogues of the present invention include a buffer, a nonionic tonicity modifier, and arginine to provide the pH of the final formulation. In accordance with standard pharmaceutical practice, the formulations of the present invention are sterile and / or free of reducing agents. In some cases, the liquid formulations of the present invention are aqueous liquid formulations. In some cases, the liquid formulations of the present invention are non-aqueous liquid formulations. The term buffer, as used herein, denotes a pharmaceutically acceptable excipient that stabilizes the pH of a pharmaceutical formulation. Suitable buffers are well known in the field and can be found in the literature. Selection experiments in the examples show that the formulations of the present invention preferably include a buffer selected from a histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, Bis-Tris buffer, and MOPS buffer, as these buffers provided stable formulations in which the GLP-2 analogues dissolved without becoming viscous, clouding, or precipitating the peptide drug. In preferred embodiments, the buffer is a histidine buffer, e.g., L-histidine.Generally, the buffer will be present at a concentration of approximately 5 mM to approximately 50 mM, more preferably at a concentration of approximately 5 mM to approximately 25 mM, and most preferably at a concentration of approximately 15 mM. Based on the experiments in this application, the buffer is preferably not a phosphate buffer, a citrate buffer, a citrate / Tris buffer, and / or a succinate buffer. The term "tonicity modifier," as used herein, denotes pharmaceutically acceptable tonicity agents used to modulate the tonicity of the formulation. The formulations of the present invention are preferably isosmotic, that is, they have an osmotic pressure substantially equal to that of human blood serum. The modifiers of the The tonicity modifiers used in the formulations are preferably non-ionic and are preferably selected from the group consisting of mannitol, sucrose, glycerol, sorbitol, and trehalose. A preferred non-ionic tonicity modifier is mannitol, e.g., D-mannitol. The concentration of the tonicity modifier will depend on the concentration of other components in the formulation, especially when the formulation is intended to be isosmotic. Typically, the non-ionic tonicity modifier will be used at a concentration of approximately 90 mM to approximately 360 mM, more preferably at a concentration of approximately 150 mM to approximately 250 mM, and most preferably at a concentration of approximately 230 mM. Generally, the components and quantities of the liquid formulations of the present invention are selected to provide a formulation with a pH of approximately 6.6 to approximately 7.4, more preferably a pH of approximately 6.8 to approximately 7.2, and most preferably a pH of approximately 7.0. Arginine quantum sufficit (qs) (cs) may be added to adjust the pH so that it is within a desired pH range. From the experiments shown in the examples, it is preferred that the pH adjustment not be made using hydrochloric acid or sodium hydroxide. In one embodiment, the liquid formulations of the present invention consist of the GLP-2 analogue at a concentration of approximately 2 mg / ml to approximately 30 mg / ml, a buffer selected from the group consisting of a histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, Bis-Tris buffer, and MOPS buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM, a non-ionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol, and trehalose at a concentration of approximately 90 mM to approximately 360 mM, and arginine qs to provide a pH of approximately 6.6 to approximately 7.4. In one embodiment, the liquid formulations of the present invention consist of the GLP-2 analogue at a concentration of approximately 2 mg / ml to approximately 30 mg / ml, a buffer selected from the group that I 7 7C*nn / l 7P7 / B / YILI consists of a histidine buffer, mesylate buffer and acetate buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM, a non-ionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol and sorbitol at a concentration of approximately 90 mM to approximately 360 mM, arginine qs to provide a pH of approximately 6.6 to approximately 7.4. In a further embodiment, the liquid formulations of the present invention comprise the GLP-2 analogue at a concentration of approximately 20 mg / ml, histidine buffer at a concentration of approximately 15 mM, mannitol at a concentration of approximately 230 mM, and arginine qs to provide a pH of approximately 7.0. In a further embodiment, the liquid formulations of the present invention comprise the GLP-2 analogue at a concentration of approximately 20 mg / ml, histidine buffer at a concentration of approximately 15 mM, mannitol at a concentration of approximately 230 mM, and the pH is approximately 7.0. In a further embodiment, the liquid formulations of the present invention comprise ZP1848-acetate or HHGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2 acetate (SEQ ID NO: 1) at a concentration of approximately 20 mg / ml, histidine buffer at a concentration of approximately 15 mM, mannitol at a concentration of approximately 230 mM, and arginine qs to provide a pH of approximately 7.0. In a further embodiment, the liquid formulations of the present invention comprise ZP1848-acetate or HHGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2 acetate (SEQ ID NO: 1) at a concentration of approximately 20 mg / ml, histidine buffer at a concentration of approximately 15 mM, mannitol at a concentration of approximately 230 mM and the pH is approximately 7.0. In a further embodiment, the liquid formulations of the present invention comprise an acetate salt of a peptide analogue similar to I 7 7C*nn / l 7P7 / B / YILI glucagon type 2 (GLP-2) having the formula: (HHGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH) wherein x is 1.0 to 8.0, at a concentration of approximately 20 mg / ml, histidine buffer at a concentration of approximately 15 mM, mannitol at a concentration of approximately 230 mM and pH is approximately 7.0. In a further embodiment, the liquid formulations of the present invention comprise an acetate salt of a glucagon-like peptide-2 (GLP-2) analogue having the formula: (HHGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH) wherein x is 1.0 to 8.0, at a concentration of approximately 20 mg / ml, histidine buffer at a concentration of approximately 15 mM, mannitol at a concentration of approximately 230 mM and pH is approximately 7.0, in a once- or twice-daily dosing regimen. In a further embodiment, the liquid formulations of the present invention comprise an acetate salt of a glucagon-like peptide-2 (GLP-2) analogue having the formula: (HHGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH) wherein x is 1.0 to 8.0, at a concentration of approximately 20 mg / ml, histidine buffer at a concentration of approximately 15 mM, mannitol at a concentration of approximately 230 mM and pH is approximately 7.0, in a dosing regimen of once or twice a week. In a further embodiment, the liquid formulations of the present invention comprise ZP1846 HHGEGSFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH2 (SEQ ID NO: 7); at a concentration of approximately 20 mg / ml, histidine buffer at a concentration of approximately 15 mM, mannitol at a concentration of approximately 230 mM, and arginine qs to provide a pH of approximately 7.0. In a further embodiment, the liquid formulations of the present invention comprise ZP1846 HHGEGSFSSELSTILDALAARDFIAWLIATKITDKKKKKK-NH2(SEQ ID NO: 7); at a concentration of approximately 20 mg / ml, histidine buffer at a concentration I 7 7C*nn / l 7Π7 / Β / YILI of approximately 15 mM, mannitol at a concentration of approximately 230 mM and the pH is approximately 7.0. In some cases, the liquid formulations of the present invention further comprise a preservative. In some cases, the preservative is one selected from the group consisting of benzalkonium chloride, chlorobutanol, methylparaben, and potassium sorbate. Generally, the preservative is present at a concentration of approximately 0.1% to approximately 1% of the final volume of the formulation. In a further embodiment, the liquid formulation is selected from the group consisting of an aqueous liquid formulation, a liquid formulation in various hydrophilic or hydrophobic solvents, an emulsion, and a liquid suspension. In a preferred embodiment, the liquid formulation is an aqueous liquid formulation. By way of example, the liquid formulations of the present invention can be prepared by mixing stock solutions of the GLP-2 analogue, buffer, nonionic tonicity modifier, and, optionally, preservative in water, optionally diluting the resulting solution and adjusting it to the target pH. Conveniently, the buffer and nonionic tonicity modifier solutions can be mixed first to provide a desired concentration of each excipient. The GLP-2 analogue solution can then be added, and, if necessary, the pH adjusted, for example, using 0.5 M acetic acid / L-arginine. Water is then added to the final volume. Preferably, the glucagon-like peptide-2 (GLP-2) analogue is administered to patients parenterally, preferably by injection, most commonly by subcutaneous, intramuscular, intravenous, or intraperitoneal injection. Subcutaneous injection is preferred. The injection may be administered by a physician, nurse, or other healthcare professional, or it may be self-administered by the patient. As set forth herein, in some respects, the formulations of the present invention have a viscosity that facilitates loading the formulation into a pre-filled syringe, injection pen, or other injection device. This may have the advantage of predetermining the dose of the formulation administered to the patient, e.g. I J7C*nn / l 7P7 / E / YILI without the need to measure it in a multipurpose vial. Accordingly, in other respects, the present invention provides a manufactured article or a kit comprising a container holding the stable, such as, e.g., a stable aqueous pharmaceutical formulation of the GLP-2 analogue according to the present invention, or a pre-filled syringe or injector device or injector pen containing an aqueous liquid formulation comprising the GLP-2 analogue according to the present invention. Medical conditions The GLP-2 analogue formulations of the present invention are useful as a pharmaceutical agent for preventing or treating gastrointestinal disorders, including those affecting the upper esophagus, by administering an effective amount of a GLP-2 analogue, or a salt thereof, as described herein. Disorders of the stomach and intestines include ulcers of any etiology (e.g., peptic ulcers, drug-induced ulcers, ulcers related to infections or other pathogens), digestive disorders, malabsorption syndromes, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease, celiac sprue (e.g., arising from gluten-induced enteropathy or celiac disease), tropical sprue, hypogammaglobulinemic sprue, enteritis, ulcerative colitis, small bowel damage, and chemotherapy-induced diarrhea (CID) / mucositis. As mentioned previously, in general, individuals who would benefit from an increase in small bowel mass and the achievement and / or maintenance of normal small bowel mucosal structure and function are candidates for treatment with GLP-2 analogues. Specific conditions that can be treated with GLP-2 analogues include various forms of sprue, including celiac sprue, which results from a toxic reaction to alpha-gliadin in gluten and may result from heat-induced enteropathy or celiac disease, and is characterized by significant loss of small bowel villi; and tropical sprue, which results from a I 7 7C*nn / l 7P7 / B / YILI infection and is characterized by partial flattening of the villi; hypogammaglobulinemic sprue, which is usually observed in patients with common variable immunodeficiency or hypogammaglobulinemia and is characterized by a significant decrease in villous height. The therapeutic efficacy of treatment with the GLP-2 analogue can be monitored by enteric biopsy to examine villous morphology, by biochemical evaluation of nutrient absorption, by the patient's weight gain, or by improvement of symptoms associated with these conditions. Another particular condition that can be treated with the GLP-2 analogues of the invention, or for which the GLP-2 analogues may be useful therapeutically and / or prophylactically, is short bowel syndrome (SBS), also known as short bowel syndrome or simply short bowel, which results from surgical resection, a congenital defect, or malabsorption in the intestine associated with disease, in which patients are unable to maintain fluid, electrolyte, and nutrient balance on a conventional diet. Despite adaptation that generally occurs within two years of resection, patients with SBS have reduced dietary absorption and fluid loss. Other conditions that can be treated with the GLP-2 analogues of the invention, or for which the GLP-2 analogues may be useful prophylactically, include, in addition to the radiation enteritis, infectious or post-infectious enteritis mentioned above, and damage to the small intestine due to chemotherapeutic or toxic agents for the treatment of cancer. GLP-2 analogues can also be used for the treatment of malnutrition, for example, cachexia and anorexia. One particular embodiment of the invention relates to the use of the present peptides for the prevention and / or treatment of intestinal damage and dysfunction. Such damage and dysfunction is a well-known side effect of chemotherapy treatment for cancer. The administration of chemotherapy is normally associated with undesirable side effects related to the gastrointestinal system, such as mucositis, diarrhea, bacterial translocation, I 7 7C*nn / l 7P7 / B / YILI malabsorption, abdominal cramps, gastrointestinal bleeding, and vomiting. These side effects are clinical consequences of structural and functional damage to the intestinal epithelium and frequently necessitate reducing the dose and frequency of chemotherapy. The administration of these GLP-2 peptide agonists can enhance the trophic effect on intestinal crypts and rapidly provide new cells to replace damaged intestinal epithelium following chemotherapy. The ultimate goal of administering these peptides is to reduce morbidity related to gastrointestinal damage in patients undergoing chemotherapy while simultaneously developing the most optimal chemotherapy regimen for cancer treatment. Concurrent prophylactic or therapeutic treatment according to the present invention can be provided to patients undergoing or about to undergo radiation therapy. Small intestinal mucosal stem cells are particularly susceptible to the cytotoxic effects of chemotherapy due to their rapid proliferation rate (Keefe et al., Gut, 47: 632-7, 2000). Chemotherapy-induced damage to the small intestinal mucosa is often clinically termed gastrointestinal mucositis and is characterized by impaired absorption and barrier function in the small intestine. For example, widely used chemotherapeutic agents 5-FU, irinotecan, and methotrexate have been shown to increase apoptosis leading to villous atrophy and crypt hypoplasia in the small intestine of rodents (Keefe et al., Gut 47: 632-7, 2000; Gibson et al., J Gastroenterol. Hepatol. Sep;18(9):1095-1100, 2003; Tamaki et al., J. Int. Med. Res. 31 (1):6-16, 2003).Chemotherapeutic agents have been shown to increase apoptosis in intestinal crypts within 24 hours of administration and subsequently reduce villus area, crypt length, mitotic count per crypt, and enterocyte height three days post-chemotherapy in humans (Keefe et al., Gut, 47: 632-7, 2000). Thus, structural changes within the small intestine directly produce intestinal dysfunction and, in some cases, diarrhea. Gastrointestinal mucositis following cancer chemotherapy is a I 7 7C*nn / l 7P7 / B / YILI is a growing problem that is essentially intractable once established, although it gradually remits. Studies conducted with commonly used cytostatic cancer drugs, 5-FU and irinotecan, have shown that effective chemotherapy with these drugs predominantly affects the structural integrity and function of the small intestine, while the colon is less sensitive and responds mainly with increased mucus formation (Gibson et al., J. Gastroenterol. Hepatol. Sep;18(9):1095-1100, 2003; Tamaki et al., J. Int. Med. Res. 31 (1):6-16, 2003). The formulations of the present invention comprising GLP-2 analogues may be useful in the prevention and / or treatment of gastrointestinal lesions and side effects of chemotherapeutic agents. This potentially important therapeutic application can be applied to currently used chemotherapeutic agents, such as, but not limited to: 5-FU, Altretamine, Bleomycin, Busulfan, Capecitabine, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine, Chrysantaspase, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Docetaxel, Doxorubicin, Epirubicin, Etoposide, Fludarabine, Fluorouracil, Gemcitabine, Hydroxycarbamide, Idarubicin, Ifosfamide, Irinotecan, Liposomal Doxorubicin, Leucovorin, Lomustine, Melphalan, Mercaptopurine, Mesna, Methotrexate, Mitomycin, Mitoxantrone, Oxaliplatin, Paclitaxel, Pemetrexed, Pentostatin, Procarbazine, Raltitrexed, Streptozocin, Tegafur-uracil, Temozolomide, ThiotepaThioguanine, Topotecan, Treosulfan, Vinblastine, Vincristine, Vindesine, Vinorelbine, Bleomycin, Busulfan, Capecitabine, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine, Chrysantaspase, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Docetaxel, Doxorubicin, Epirubicin, Etoposide, Fludarabine, Fluorouracil, Gemcitabine, Hydroxycarbamide, Idarubicin, Ifosfamide, Irinotecan, Liposomal Doxorubicin, Leucovorin, Lomustine, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitoxantrone, Oxaliplatin, Paclitaxel, Pemetrexed, Pentostatin, Procarbazine, Raltitrexed Streptozocin, Tegafur-uracil, Temozolomide, Thiotepa, Thioguanine, Topotecan, Treosulfan, Vinblastine, Vincristine, Vindesine, and Vinorelbine. I 7 7C*nn / l 7Π7 / Β / YΙΛΙ Administration of formulations In some respects, the present invention relates to a ready-to-use formulation of GLP-2 analogues intended for parenteral administration, and suitable for use, e.g., in vials, pre-filled syringes, infusion pumps, portable injectors, disposable auto-injectors, or adjustable-dose auto-injectors. Examples The following examples are provided to illustrate preferred aspects of the invention and are not intended to limit its scope. GLP-2 analogues administered according to the dosage regimens described herein may be prepared according to procedures such as solid-phase peptide synthesis described in WO 2006 / 117565, the contents of which are expressly incorporated herein by reference in their entirety. Example 1. Synthesis of ZP1848-acetate / similar GLP-2 analogues The peptide ZP1848-acetate was synthesized using a solid-phase peptide synthesis (SPFS) approach from Fmoc under standard docking conditions. After synthesis was complete, the peptide sequence was deprotected and cleaved from the solid support, and the crude peptide was purified by preparative reversed-phase HPLC. The peptide was converted to the desired acetate salt form by applying a mobile phase during the final chromatographic step with an appropriate concentration of acetic acid, followed by lyophilization. The resulting drug product had an acetate content below 11% or below 8 acetate equivalents: Batch 1 (6% acetate, 4.6 acetate equivalents), Batch 2 (7% acetate, 5.4 acetate equivalents), and Batch 3 (6% acetate, 4.6 acetate equivalents).This synthesis and purification protocol can be adapted to prepare other GLP-2 analogues used in the formulations of the present invention. I 7 7C*nn / l 7Π7 / Β / YΙΛΙ Example 2. Investigation of the formation of covalently linked oligomers in pharmaceutical formulations of the GLP-2 analogue ZP1848-acetate Materials and procedures For the detection of covalently bonded oligomers, a Dionex Ultimate3000 HPLC system was used, providing a linear gradient at a flow rate of 0.5 mL / min. The mobile phase consisted of 0.1% TFA in 45% acetonitrile and 55% Milli-Q water. A wavelength of 215 nm was used for detection. The injection amount was 4 pg of peptide. The column used for the separation of the covalently bonded peptides was a TSKgel SuperSW2000 (TSK BioScience) with a particle size of 4 pm and dimensions of 300 × 4.6 mm. The total run time was 25 minutes. For the evaluation of the chemical stability of the peptide monomer, a C18 column with an acidic mobile phase and an acetonitrile gradient was used. Stock solutions of mannitol (700 mM), L-histidine (200 mM), and the peptide ZP1848 (acetate salt; 60 mg / mL) in water (Milli-Q) were prepared. The mannitol and histidine solutions were mixed in appropriate amounts to obtain 230 mM mannitol and 15 mM histidine. The peptide stock solution was added to final concentrations of 0.2, 2, and 20 mg / mL, respectively. Water was added to 90% of the final volume. If necessary, the pH was adjusted to 7 using 1 M acetic acid / 0.5 M L-arginine. Water was added to the final volume. Results and discussion It is known in the art that increasing the concentration of peptide or protein drugs in a liquid formulation increases the concentration of higher-order dimers, trimers, and oligomers as a result of bulk action effects, which lead to a higher probability of covalent reactions (see van Maarschalkerweerd et al., Intrinsically Disord. Proteins. 2015; 3(1): e1071302). Therefore, the formation of high-molecular-weight covalent degradation products (cPMDPs) increases with the concentration of the drug substance and has the effect of reducing the amount of biologically active monomeric peptide available in the formulation. Therefore, this was investigated in I 7 7C*nn / l 7Π7 / Β / ΥΙΛΙ the formulations of the GLP-2 analogue, ZP1848-acetate. Figure 1 shows a typical chromatogram of the separation of oligomers from the ZP1848-acetate monomer. The ZP1848-acetate oligomers are well separated from the ZP1848-acetate monomer and all integrate as a single peak. The percentage peak area was used to quantify the amount of oligomers, particularly the covalently bonded dimers and trimers. Formulations containing 0.2, 2, and 20 mg / ml of ZP1848 were analyzed after 24 months of storage at 2–8 °C. The primary oligomer formation (two covalently bonded ZP1848-acetate molecules) was observed, but trimer formation was also present to some extent (verified by LC-MS). The 0.2 mg / ml formulation contained 2.6% oligomers, the 2 mg / ml formulation 1.91%, and the 20.0 mg / ml formulation 1.35%. The initial oligomer content was less than 0.1%. I 7 7C*nn / l 7Π7 / Β / YΙΛΙ Table 1: Formation of covalently bonded oligomers with long-term stability at 2-8 °C after 24 months Concentration of the pharmaceutical product, ZP1848-acetate Covalently linked oligomers 0.2 mg / ml 2.60% 2 mg / ml 1.91% 20 mg / ml 1.35% During long-term storage of ZP1848-acetate (glepaglutide) at 2–8 °C, it has been surprisingly discovered that the formation of covalently linked oligomers is concentration-dependent, but contrary to general expectation, the concentration dependence of oligomer formation is inversely dependent on increasing concentration of the GLP-2 analogue. Without wishing to be bound to any particular theory, the present inventors believe that the reduction in the formation of covalently linked oligomers as the drug concentration increases results from the lysine tail of the GLP-2 analogue promoting a competitive reaction that leads to the formation of higher-order species in which the GLP-2 analogue molecules are weakly associated with each other, rather than covalently linked.This means that these weakly associated species are able to dissociate to release the biologically active monomer, rather than causing a loss of active species, as occurs when covalently bonded oligomers are formed. Example 3: Selection of buffers for formulations of the GLP-2 analogue ZP1848-acetate A study was conducted to examine the effects of different buffer salts on the stability of ZP1848-acetate (4 mg / ml) formulations. The total buffer concentration in the formulations was 20 mM. Materials / procedures The buffer solutions indicated in Table 2 below were prepared. The pH of the buffers was adjusted with 1 M HCl / 1 M NaOH. The peptide ZP1848 (acetate salt) was dissolved in the relevant buffer to 80% of the final sample volume to obtain 4 mg / mL in the final formulation. If necessary, the pH was subsequently adjusted to the desired pH of the formulation using 200 mM acetic acid or 100 mM L-arginine. Buffer solution was added to reach the final volume. Each formulation was filled into suitable vials (1 mL / vial) for stability testing. Results and discussion Visual inspection showed that all formulations containing citrate buffer, citrate / Tris buffer, or succinate buffer were viscous and / or cloudy (see Table 2). Acetate buffer (20 mM, pH 5), mesylate buffer (20 mM, pH 6), histidine buffer (15 mM, pH 7), and histidine-arginine (15+5 mM, pH 7) produced formulations that passed visual inspection as being clear and non-viscous. I 7 7C*nn / l 7Π7 / Β / YΙΛΙ Table 2: Formulations for selecting the effect of different tampons I 7 7C*nn / l 7Π7 / Β / YΙΛΙ Formulation pH Buffer Buffer Concentration (mM) Visual Inspection Clear and non-viscous? 1 4.0 Citrate-TRIS 20 No 2 5.0 Citrate-TRIS 20 No 3 6.0 Citrate-TRIS 20 No 4 7.0 Citrate-TRIS 20 No 5 8.0 Citrate-TRIS 20 No 6 5.0 Succinate 20 No 7 5.0 Acetate 20 Yes 8 5.0 Histidine 20 Yes 9 6.0 Succinate 20 No 10 6.0 Mesylate 20 Yes 11 6.0 Histidine 20 Yes 12 7.0 Citrate 20 No 13 7.0 TRIS 20 Yes 14 7.0 Histidine + Arginine 15 + 5 Yes Example 4: Incompatibility of phosphate buffer with GLP-2 analogue ZP18485 acetate Materials / procedures Stock solutions of mannitol (700 mM), phosphate buffer (200 mM), and ZP1848 peptide acetate (60.2 mg / mL) in water (Milli-Q) were prepared. The stock solutions were mixed in appropriate amounts to obtain the formulations shown in Table 3 below. Water was added to reach 90% of the final volume. If necessary, the pH was then adjusted to the desired pH of the formulation using 1 M acetic acid / 0.5 M L-arginine. Water was added to reach the final volume. Sample containers were visually inspected for clarity and viscosity after 24 hours at room temperature. Table 3: Formulations for analyzing the effect of phosphate buffer I 7 7C*nn / l 7Π7 / Β / YΙΛΙ ZP1848 Concentration [mg / ml] pH Phosphate [mM] Mannitol [mM] Visual Inspection Clear and non-viscous? 0 mg / ml 7.0 20 230 Yes 20 mg / ml 6.5 20 230 No 20 mg / ml 7.0 20 230 No 20 mg / ml 7.0 50 230 No 20 mg / ml 7.5 20 230 No Results and discussion Visual inspection showed that ZP1848-acetate formulations at 20 mg / mL at pH 6.5–7.5 containing 20–50 mM phosphate buffer were cloudy and / or highly viscous after 24 hours at room temperature. Therefore, it was concluded that the phosphate buffer was not compatible with ZP1848-acetate in these formulations. Example 5: Effect of acetate content on the viscosity of GLP-2 analogue formulations ZP1848-acetate A study was conducted to determine the effect of acetate content on the viscosity of the ZP1848-acetate formulation. Materials and procedures Samples were prepared with a drug substance (DS) of the GLP-2 analogue ZP1848-acetate containing 6% acetate. Acetate was added to explore the effects of higher acetate content in the range of 7.8–15% acetate (see Table 4). Stock solutions of mannitol (700 mM), acetic acid (1000 mM), histidine (200 mM), and ZP1848 peptide acetate (60 mg / mL) in water (MilliQ) were prepared. The stock solutions were mixed in appropriate amounts to obtain the formulations shown in Table 4 below. Water was added to reach 90% of the final volume. If necessary, the pH was then adjusted to the desired pH of the formulation using 250 mM arginine. Water was added to reach the final volume. Each formulation was filled into suitable vials for stability testing. The vials were visually inspected for clarity and viscosity. Viscosity was measured using a microVISC™ viscometer. The hydrodynamic radius was measured using a Wyatt DynaPro II dynamic light scattering (DDL) plate reader. The sample size loaded onto the plates was 170 µL. I 7 7C*nn / l 7Π7 / Β / YΙΛΙ Table 4: Formulation containing 20 mg / ml of ZP1848-acetate at pH 7 with different acetate concentrations Formulation n.9 Mannitol [mM] Histidine [mM] % acetate Acetate [mM] 1 230 15 6 20.3 2 230 15 7 23.7 3 230 15 8 27.1 4 230 15 9 30.5 5 230 15 10 33.9 6 230 15 11 37.3 7 230 15 12 40.7 8 230 15 13 44.0 9 230 15 14 47.4 10 230 15 15 50.8 Results and discussion Figure 2 shows the viscosity and hydrodynamic radius of the formulations with varying acetate concentrations. The results demonstrate that the viscosity of the ZP1848-acetate formulation increases unexpectedly and nonlinearly with increasing acetate concentration. Therefore, it is advantageous to control viscosity at a low / unchanged level if the total acetate concentration in the formulation is less than or equal to 11% acetate per mg of GLP-2 analogue, as this provides the possibility of supplying GLP-2 analogue formulations in the form of a drug delivery device. Example 6: Effect of buffer salts on the stability of GLP-2 analogue ZP1848-acetate formulations at 2 and 20 mg / ml A study was conducted to examine the effects of different buffer salts on the stability of ZP1848-acetate formulations (2 and 20 mg / ml). All buffers were at a concentration of 15 mM. Materials and procedures Stock solutions of mannitol (700 mM), L-histidine (200 mM), glycine (400 mM), lysine (200 mM), TRIS (200 mM), bis-TRIS (200 mM), MOPS (100 mM), succinic acid (200 mM), MES (2-(N-morpholino)ethanesulfonic acid) (200 mM), mesylate (200 mM), phosphate (200 mM), and peptide ZP1848 (acetate salt; approx. 50 mg / mL) in water (Milli-Q) were prepared. The excipient solutions were mixed in appropriate amounts to obtain the formulations shown in Tables 5 and 6 below. All formulations contained 230 mM mannitol and 15 mM buffer. The peptide stock solution was added. Water was added to a final volume of 90%. If necessary, the pH was adjusted to pH 7 using 1 M acetic acid / 0.5 M L-arginine. Water was added to the final volume. The formulations were filled into vials and placed in a stability study at 40 °C. Results and discussion According to the observed results, buffering agents histidine, glycine, lysine, TRIS, Bis-TRIS, MOPS, mesylate and MES at a concentration of 15 mM were acceptable for use in ZP1848-acetate formulations at 2 mg / ml and 20 mg / ml peptide and pH 7.0. I 7 7C*nn / l 7Π7 / Β / YΙΛΙ Table 5: Stability of formulations prepared with different buffers I J7C*nn / l 7Π7 / Β / YΙΛΙ Formulation Peptide Content Buffer Visual Inspection Clear and non-viscous? 0 weeks 3 weeks (40 °C) 1 20 Histidine Yes Yes 2 20 Glycine Yes Yes 3 20 Lysine No Yes 4 20 TRIS Yes Yes 5 20 Bis-TRIS Yes Yes 6 2 Histidine Yes Yes 7 2 Glycine Yes Yes 8 2 Lysine Yes Yes 9 2 TRIS Yes Yes 10 2 Bis-TRIS Yes Yes 11 20 MOPS Yes Yes 12 20 Succinic Acid No No 13 20 MES Yes Yes 14 20 Mesylate Yes Yes 15 20 Phosphate No No 16 2 MOPS Yes Yes 17 2 Succinic Acid Yes No 18 2 MES Yes Yes 19 2 Mesylate Yes Yes 20 2 Phosphate Yes No Table 6: Formation of covalently linked oligomers in formulations using different buffers Formulation Peptide Content DDL Buffer (Average Z, nm) 0 weeks 3 weeks (40 °C) 1 20 Histidine 1.6 1.7 2 20 Glycine 1.7 1.8 3 20 Lysine 41.9 4.4 4 20 TRIS 35.2 4.3 Formulation Peptide Content DDL Buffer (Z-Average, nm) 0 weeks 3 weeks (40 °C) 5 20 Bis-TRIS 1.7 1.7 6 2 Histidine 2.7 3.1 7 2 Glycine 2.4 3.6 8 2 Lysine 3.9 4 9 2 TRIS 3.8 4.1 10 2 Bis-TRIS 4.7 4.1 11 20 MOPS 2.3 2.5 12 20 Succinic Acid 27.4 192.5 13 20 MES 2.3 3.2 14 20 Mesylate 25.5 4 15 20 Phosphate 21.1 244.5 16 2 MOPS 3.3 70.1 17 2 Succinic Acid 82.5 259.3 18 2 MES 3.8 3.9 19 2 Mesylate 3.7 4.1 20 2 Phosphate 333.9 214.5 I 7 7C*nn / l 7Π7 / Β / YΙΛΙ The formation of covalently bonded oligomers was evaluated for the different buffers (Table 6). At 20 mg / ml, succinic acid formed a gel after 1 week, but stability could not be assessed at 2 and 3 weeks. At 2 mg / ml, the same buffer showed significantly greater formation (2.1%) of covalently bonded oligomers. The overall trend is that the 2 mg / ml formulations exhibit greater formation of covalently bonded oligomers compared to the 20 mg / ml formulations after 3 weeks of accelerated storage at 40 °C. The phosphate buffer and succinate buffer were not compatible with ZP184810 acetate at 2 and 20 mg / ml in these formulations. The monomeric stability of the peptide was assessed by determining its purity using HPLC over a 3-week stability period at 40 °C. The results are presented in Figure 3 and Table 7. Due to the gel formation described above, it was only possible to evaluate succinic acid for the initial time points of 15 to 20 mg / ml. Results were obtained for all three weeks at 2 mg / ml. Only small, non-significant differences were detected between the buffers tested. Therefore, the choice of buffer does not appear to affect the stability of the peptide monomer. I 7 7C*nn / l 7Π7 / Β / YΙΛΙ Table 7: Formation of covalently linked oligomers using different buffers at 40SC for 0 to 3 weeks Time / weeks at 40 °C Formulation Buffer agent 0 1 2 3 % week 1 20 mg / ml Histidine 0.14 0.40 0.55 0.69 0.18 2 Glycine 0.15 0.39 0.53 0.64 0.16 3 Lysine 0.15 0.38 0.51 0.64 0.16 4 TRIS 0.10 0.38 0.51 0.63 0.17 5 Bis-Tris 0.15 0.42 0.58 0.72 0.19 11 MOPS 0.14 0.38 0.49 0.59 0.15 12 Succinic acid 0.14 0.40 Not possible to evaluate 13 MONTH 0.14 0.37 0.49 0.61 0.15 14 Mesylate 0.14 0.40 0.53 0.65 0.17 15 Phosphate Not possible to evaluate 6 2 mg / ml Histidine 0.16 0.54 0.75 1.0 0.26 7 Glycine 0.16 0.49 0.69 0.79 0.21 8 Lysine 0.15 0.57 0.76 0.94 0.26 9 TRIS 0.15 0.52 0.71 0.84 0.23 10 Bis-Tris 0.19 0.81 1.19 1.5 0.43 16 MOPS 0.15 0.53 0.71 0.82 0.22 17 Succinic acid 0.21 0.72 1.4 2.1 0.63 18 MES 0.16 0.57 0.75 0.88 0.23 19 20 Mesylate Phosphate 0.16 0.60 No e 0.82 s possible ev 1.0 aluar 0.26 Example 7: Effect of tonicity modifiers on the stability of 10 formulations of the GLP-2 analogue ZP1848-acetate at 2 and 20 mg / ml A study was conducted to examine the effects of different tonicity modifiers on the stability of ZP1848-acetate formulations (2 and 20 mg / ml). I 7 7C*nn / l 7Π7 / Β / YΙΛΙ Materials and procedures Stock solutions of L-histidine (200 mM), sucrose (730 mM), glycerol (977 mM), D-sorbitol (801 mM), dehydrated D-(+) trehalose (500 mM), D-mannitol (700 mM), and peptide ZP1848-acetate (acetate salt; approx. 50 mg / mL) in water (Milli-Q) were prepared. The excipient solutions were mixed in appropriate amounts to obtain the formulations shown in Table 8 below. All formulations contained 15 mM histidine. The necessary peptide stock solution was added to obtain the peptide content shown in Table 8. Water was added to reach 90% of the final volume. If necessary, the pH was adjusted to pH 7 using 1 M acetic acid / 0.5 M L-arginine. Water was added to reach the final volume. Each formulation was filled into vials and placed in stability studies at 40 °C.The sample containers were visually inspected to check clarity and viscosity, and the hydrodynamic radius was analyzed using DDL (dynamic light scattering) analysis. Results and discussion According to the results observed in Table 8, mannitol, sucrose, glycerol, sorbitol, and trehalose were acceptable for use in these formulations with ZP1848-acetate at 2 mg / ml and 20 mg / ml and pH 7.0. Table 8: Formulations prepared using different tonicity modifiers Formulation Peptide Content Tonicity Modifier Visual Inspection Clear and non-viscous? 0 weeks 3 weeks (40 °C) 1 20 Mannitol Yes Yes 2 20 Sucrose Yes Yes 3 20 Glycerol Yes Yes 4 20 Sorbitol Yes Yes 5 20 Trehalose Yes Yes 6 2 Mannitol Yes Yes 7 2 Sucrose Yes Yes Formulation Peptide Content Tonicity Modifier Visual Inspection Clear and non-viscous? 0 weeks 3 weeks (40 °C) 8 2 Glycerol Yes Yes 9 2 Sorbitol Yes Yes 10 2 Trehalose Yes Yes I 7 7C*nn / l 7Π7 / Β / YΙΛΙ The formation of covalent oligomers was measured for formulations 1 to 10 for up to 3 weeks at 40 °C. The results are shown in Table 9. Differences in the formation of covalent oligomers for the ten formulations 5 can be observed as early as 1 week after the stability test. Additionally, the rate (slope) is fairly consistent throughout the test period. Formulations 3 (20 mg / ml - Glycerol), 7 (2 mg / ml - Sucrose), 8 (2 mg / ml Glycerol), and 9 (2 mg / ml - Sorbitol) exhibit significantly higher covalently bonded oligomer formation than the others. Mannitol showed the lowest covalently bonded oligomer formation. The overall trend is that 2 mg / ml results in higher covalently bonded oligomer formation compared to 20 mg / ml for all the tonicity agents investigated. Table 9: Formation of covalently bonded oligomers of the formulations -10 to 40°C for 0 to 3 weeks Time / weeks at 40 °C Formulation Tonicity Agent 0 1 2 3 % per week 1 20 mg / ml Mannitol 0.22 0.40 0.57 0.90 0.22 2 Sucrose 0.27 0.50 0.84 1.3 0.34 3 Glycerol 0.6 2.0 2.8 4.0 1.11 4 Sorbitol 0.25 0.60 0.84 1.1 0.28 5 Trehalose 0.26 0.60 0.90 1.3 0.34 6 2 mg / ml Mannitol 0.34 0.70 0.90 1.2 0.28 7 Sucrose 0.37 1.4 2.7 4.3 1.31 8 Glycerol 1.8 12.2 16.4 21.5 6.34 Time / weeks at 40 °C Formulation Tonicity Agent 0 1 2 3 % sem 9 Sorbitol 0.51 1.9 2.8 3.8 1.08 10 Trehalose 0.45 1.1 1.9 2.9 0.81 I 7 7C*nn / l 7Π7 / Β / YΙΛΙ The monomeric stability of the peptide was assessed by determining its purity using HPLC over a 3-week stability test at 40 °C. Similar to covalently bonded oligomers, the chemical stability when using glycerol is poor and differs from that of the other tonicity agents. The results are presented in Figure 5 and Figure 6. Example 8: Impact of the physical stability of acids and bases used for pH adjustment in formulations of the GLP-2 analogue ZP1848-acetate Materials and procedures Stock solutions of mannitol, histidine, and the peptide ZP1848 acetate were prepared in water. The mannitol and histidine stock solutions were added to water and mixed, and the peptide solution was added to obtain a final peptide content of 10 mg / mL. Water was added to 90% of the final volume. The pH was then adjusted to 7 using 250 mM arginine / 1 M AcOH or 1 M NaOH / 1 M HCl (see Table 10). Water was added to the final volume. Each formulation was filled into vials for stability testing and placed in stability studies at 5 °C, 25 °C, and 40 °C. Sample vials were visually inspected for clarity and viscosity. Results and discussion The results shown in Table 10 show that the use of 1 M NaOH / 1 M HCl for pH adjustment has an adverse effect on the physical stability of the ZP1848-acetate formulation. Table 10: Effect of acid / base on physical stability Formulation pH Adjusting Agents Visual Inspection Clear and non-viscous? Time zero 40 °C 4 weeks 25 °C 26 weeks 5 °C 52 weeks 1 L-Arg 0.25 M / AcOH 1 M Yes Yes Yes Yes 2 NaOH 1 M / HCl 1 M Yes Yes Yes No (precipitates at 13 weeks) Example 9: Use of the acetate salt of peptide ZP1848 and the chloride salt of peptide ZP1848 for GLP-2 analogue peptide ZP1848 formulations A study was conducted to examine the effect of salts using the acetate salt of peptide ZP1848 and the chloride salt of peptide ZP1848 in selected ZP1848 formulations. The effects of salt type, concentration, buffer, and tonicity modifiers were examined after accelerated storage at 40 °C. Synthesis of the sodium salt of peptide ZP1848 was attempted but not successful. Materials and procedures Stock solutions of mannitol (700 mM), histidine (200 mM), sorbitol (700 mM), mesylate (200 mM), and peptide ZP1848 solution (chloride salt; approx. 50 mg / mL) in Milli-Q water were prepared. The excipient solutions were mixed in appropriate amounts to obtain the formulations shown in Tables 11 and 12 below. The peptide stock solution was added to obtain the desired final peptide content. Water was added to reach 90% of the final volume. If necessary, the pH was then adjusted to the desired pH of the formulation using 1 M acetic acid / 0.5 M L-arginine. Water was added to reach the final volume. Each formulation was filled into vials and placed in stability studies at 40 °C. Sample vials were visually inspected for clarity and viscosity, and the hydrodynamic radius was analyzed using DDL. Results and discussion The results shown in Tables 11 and 12 indicate that the Z-score, viscosity, and visual appearance of formulations 1, 2, 3, and 4 remained unchanged after 3 weeks at 40°C, as assessed by visual appearance and DDL. Formulation 5 showed changes in stability over time, as assessed by Z-score, viscosity, and visual appearance. Table 11: Effect of peptide salt type N.2 of formulation: Peptide salt Peptide content Mannitol Histidine Sorbitol Mesylate Visual inspection Clear and non-viscous? 0 weeks 3 weeks (40 °C) 1 acetate salt of ZP1848 20 230 15 - - Yes Yes 2 chloride salt of ZP1848 20 230 15 - - Yes Yes 3 chloride salt of ZP1848 2 230 15 - - Yes Yes 4 chloride salt of ZP1848 20 - 15 230 - Yes Yes 5 chloride salt of ZP1848 20 230 - - 15 No No Table 12: Effect of peptide salt type Formulation Peptide salt Peptide content Mannitol Histidine Sorbitol Mesylate DDL (Average Z, nm) 0 weeks 3 weeks (40 °C) 1 acetate salt of ZP1848 20 230 15 - - 1.5 2.1 2 chloride salt of ZP1848 20 230 15 - - 2.3 3.3 3 chloride salt of 2 230 15 - - 2.7 2.8 Formulation Peptide salt Peptide content Mannitol Histidine Sorbitol Mesylate DDL (Average Z, nm) 0 weeks 3 weeks (40 °C) ZP1848 4 chloride salt of ZP1848 20 - 15 230 - 2.2 3.3 5 chloride salt of ZP1848 20 230 - - 15 24.1 6.9 The chemical stability of Formulations 1 to 5 was monitored for up to 4 weeks at 40 °C. The resulting purity was normalized to 100% at release. The results are shown in the Figure. No significant differences in the chemical stability of the peptide monomer were observed in Formulations 1, 2, 4, and 5. Formulation 3 showed slightly lower chemical stability, but acceptable chemical stability after 4 weeks, likely due to its lower concentration. Covalent oligomer formation was measured for Formulations 1 through 5 for up to 4 weeks at 40 °C. The results are shown in Table 13. Differences in covalent oligomer formation among the five formulations were observed after 1 week of stability testing. Furthermore, the rate (slope) was fairly consistent throughout the testing period. Formulation 1 (20 mg / mL, ZP1848 acetate salt, histidine as a tonicity agent) was the most stable formulation, with approximately 1.1% covalent oligomer formation after 4 weeks of stability at 40 °C. Formulation 5 (20 mg / mL, ZP1848 chloride salt, mesylate as a tonicity agent) was the second most stable formulation, with approximately 2.1% covalent oligomer formation after 4 weeks of stability at 40 °C. The third most stable was Formulation 3 (2 mg / ml, ZP1848 chloride salt, histidine as the tonicity agent).The fourth most stable formulation is Formulation 2 (20 mg / ml, ZP1848 chloride salt, histidine as a tonic agent). The least stable formulation is Formulation 4 (20 mg / ml, ZP1848 chloride salt, sorbitol as a tonic agent). A slight tendency towards lower stability has previously been observed when using sorbitol compared to mannitol for the acetate salt of ZP1848 after 3 weeks at 40 °C (0.9% for mannitol and 1.1% for sorbitol), see Example 7. The difference between a formulation containing sorbitol and mannitol is more pronounced when comparing the acetate and chloride salts, where the formulation containing chloride salt and sorbitol at 20 mg / ml has approximately 3.9% covalent oligomer formation. When comparing the 2 mg / ml and 20 mg / ml formulations of the chloride salt, covalent oligomer formation was 2.4% for 2 mg / ml (0.53% increase per week) and 3.3% for 20 mg / ml (0.75% increase per week) after 4 weeks at 40 °C. This is surprising, as it is not what is observed for the acetate salt.For the acetate salt at 20 mg / ml, the formation of covalent oligomers after 3 weeks at 40 °C was 0.9% (0.21% increase per week), while at 2 mg / ml it was 1.2% (0.27% increase per week). This greater formation of covalently bonded oligomers at lower concentrations of the acetate salt also coincides with what was observed during long-term stability. However, for the chloride salt, the situation was reversed, with greater formation of covalently bonded oligomers with increasing concentration of ZP1848. I 7 7C*nn / l 7Π7 / Β / YΙΛΙ Table 13: Formation of covalently bonded oligomers from formulations 1-5 at 40 °C for 0 to 4 weeks Time / Weeks at 40 °C Rate 0 1 2 3 4 % per week Formulation 1 0.13 0.43 0.67 0.89 1.1 0.24 Formulation 2 0.22 1.5 2.2 2.8 3.3 0.75 Formulation 3 0.22 0.99 1.5 1.9 2.4 0.53 Formulation 4 0.23 1.7 2.5 3.4 3.9 0.91 Formulation 5 0.22 0.86 1.3 1.6 2.1 0.44 Example 10: Use of the acetate salt of peptide ZP1848 and preservatives for formulations of the GLP-2 analogue ZP1848 peptide at 20 mg / ml A study was conducted to examine the compatibility of the acetate salt of peptide ZP1848 with commonly used preservatives. The effects of preservative and temperature were examined following accelerated storage. Materials and procedures Stock solutions of mannitol (700 mM), histidine (200 mM), and peptide ZP1848 (acetate salt; approx. 50 mg / mL) in Milli-Q water were prepared. The final peptide concentration was 20 mg / mL, mannitol 230 mM, and histidine 15 mM. The preservative solutions were mixed in appropriate amounts to obtain the formulations shown in Table 14 below. The peptide stock solution was added to obtain the desired final peptide content. Water was added to reach 90% of the final volume. If necessary, the pH was then adjusted to the desired pH of the formulation using 1 M acetic acid / 0.5 M L-arginine. Water was added to reach the final volume. Each formulation was filled into vials. Sample containers were visually inspected for clarity and viscosity, and covalently bonded oligomers were analyzed by CET, and the stability of peptide monomers was analyzed by HPLC. Results and discussion The results of the study are broken down in Table 14, Table 15 and Figure 8. The formulations do not appear to be affected by the addition of a preservative compared to Formulation 1 in which no preservative is added. Chemical stability was assessed by determining the covalently bonded oligomers and the stability of the peptide monomer (purity). Formulation 4 (potassium sorbate) exhibits a higher formation of covalently bonded oligomers, but this is within the acceptable range. All other formulations have a similar amount of covalently bonded oligomers. The purity, normalized after 13 weeks at 25 °C, shows that ZP1848-acetate I 7 7C*nn / l 7Π7 / Β / YILI has similar stability, again with formulation 4 which has a purity with a slightly lower, but acceptable level. I 7 7C*nn / l 7Π7 / Β / YΙΛΙ Table 14: Effect of preservative selection at 25 °C for 26 weeks Formulation N.9: Benzalkonium chloride Methylparaben Potassium sorbate Visual inspection Clear and not viscous? 0 weeks 26 weeks (25 °C) 1 - - - Clear Clear 2 0.02 % - - Clear Clear 3 - 0.2 % - Clear Clear 4 - - 0.2 % Clear Clear Table 15 Formation of covalently linked oligomers of different preservatives at 25 °C for 13 weeks Time / Weeks at 25 °C Rate 0 2 4 8 13 % sem Formulation 1 0.12 0.27 0.35 0.47 0.62 0.04 Formulation 2 0.13 0.26 0.35 0.48 0.59 0.03 Formulation 3 0.14 0.34 0.49 0.79 1.15 0.08 Formulation 4 0.14 0.93 1.73 3.46 5.4 0.41 Example 11: Use of the acetate salt of peptide ZP1848 and preservatives for GLP-2 analogue peptide ZP1848 formulations at 2 and 20 mg / ml Materials and procedures Stock solutions of mannitol (700 mM), histidine (200 mM), and peptide ZP1848 (acetate salt; approx. 50 mg / mL) were prepared in Milli-Q water. The final peptide concentrations were 20 and 2 mg / mL, mannitol 230 mM, and histidine 15 mM. Preservative solutions (m-cresol and phenol) were mixed in appropriate amounts to obtain the formulations shown in Table 14 below. Water was added to reach 90% of the final volume. If necessary, the pH was then adjusted to the desired pH of the formulation (7.0) using 1 M acetic acid / 0.5 M L-arginine. Water was added to reach the final volume. Each formulation was filled into vials. The sample vials were visually inspected for clarity and viscosity, and the stability of the peptide monomers was analyzed by HPLC. Results and discussion The results of the study are detailed in Table 16 below. The long-term stability of all formulations was analyzed at 5 °C for 52 weeks. All solutions tested remained clear and non-viscous during the investigated time interval. I 7 7C*nn / l 7Π7 / Β / YΙΛΙ Table 16: Formulations subjected to physical appearance testing after 52 weeks of stability at 5 °C Formulation No.6: mg / ml m-cresol (mg / ml) Phenol (mg / ml) Visual inspection Clear and non-viscous? 0 weeks 52 weeks (5 °C) 1 2 0 0 Clear Clear 2 2 3.2 0 Clear Clear 3 2 0 5.5 Clear Clear Figure 9 shows the evaluation of ZP1848-acetate after accelerated stability testing at 25 °C using HPLC. Slightly lower chemical stability was observed for the formulation containing phenol, while the m-cresol formulation exhibited similar chemical stability to the unpreserved formulation. In long-term stability testing at 5 °C, no apparent differences were observed between the samples after 12 months of stability, and all samples had a normalized ZP1848-acetate purity greater than 94% (data not shown). Therefore, all the formulations tested are stable for at least 52 weeks of long-term stability. Although the present invention has been described in conjunction with the embodiments described above, many equivalent modifications and variations will be evident to those skilled in the art upon disclosure. Accordingly, the embodiments of the invention set forth herein are considered illustrative and not limiting. Various changes may be made to the described embodiments without departing from the spirit and scope of the invention. All documents cited herein are expressly incorporated by reference in their entirety for all purposes.

Claims

1. A stable liquid pharmaceutical formulation, the formulation comprising a glucagon-like peptide-2 (GLP-2) analogue, wherein the GLP-2 analogue is represented by the formula: R1-Z1-His-Gly-Glu-Gly-X5-Phe-Ser-Ser-Glu-Leu-X11-Thr-lle-Leu-Asp-Ala-LeuAla-Ala-Arg-Asp-Phe-lle-Ala-Trp-Leu-lle-Ala-Thr-Lys-lle-Thr-Asp-Z2-R2 wherein: R1 is hydrogen, Ci-4 alkyl (e.g., methyl), acetyl, formyl, benzoyl or trifluoroacetyl; X5 is Ser or Thr; X11 is Ala or Ser; R2 is NH2OOH; and Z1 and Z2 are independently absent or are a peptide sequence of 1-6 amino acid units of Lys; or a pharmaceutically acceptable salt or derivative thereof; wherein the formulation comprises: (a) the GLP-2 analogue at a concentration of approximately 2 mg / ml to approximately 30 mg / ml; (b) a buffer selected from the group consisting of a histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, Bis-Tris buffer and MOPS buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM; (c) a nonionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol, and trehalose at a concentration of approximately 90 mM to approximately 360 mM; and (d) arginine qsto provide a formulation having a pH of approximately 6.6 to approximately 7.4; wherein the formulation contains 5% or less of the GLP-2 analogue in the form of covalently bonded oligomeric products.

2. The formulation according to claim 1, wherein the concentration of total acetate from the GLP-2 analogue in the formulation is less than or equal to 11% acetate per mg of GLP-2 analogue.

3. The formulation according to claim 1 or claim 2, wherein the formation of covalently bonded oligomers of the GLP-2 analogue is inversely dependent on the concentration of the GLP-2 analogue in the formulation.

4. The formulation according to any one of claims 1 to 3, wherein the formulation is an aqueous formulation. 5.The formulation according to any one of claims 1 to 4, wherein the formulation is stable for at least 18 months when stored at 2-8 °C.

6. The formulation according to any one of the preceding claims, wherein the formulation has a viscosity between 0.8 and 2.0 mPa / s measured at 25 °C.

7. The formulation according to any one of the preceding claims, wherein the GLP-2 analogue is present in the formulation at a concentration of approximately 15 mg / ml to approximately 25 mg / ml.

8. The formulation according to any one of the preceding claims, wherein the formulation is a ready-to-use formulation.

9. The formulation according to any one of the preceding claims, wherein the GLP-2 analogue is present in the formulation at a concentration of approximately 20 mg / ml. 10.The formulation according to any one of the preceding claims, wherein the buffer is present in the formulation at a concentration of approximately 5 mM to approximately 25 mM.

11. The formulation according to any one of the preceding claims, wherein the buffer is a histidine buffer.

12. The formulation according to claim 11, wherein the histidine buffer is present in the formulation at a concentration of approximately 15 mM.

13. The formulation according to any one of the preceding claims, wherein the nonionic tonicity modifier is present in the formulation at a concentration of approximately 150 mM to approximately 250 mM.

14. The formulation according to any one of the preceding claims, wherein the nonionic tonicity modifier is mannitol. 15.The formulation according to claim 14, wherein mannitol is present in the formulation at a concentration of approximately 230 mM.

16. The formulation according to any one of the preceding claims, wherein the formulation has a pH of approximately 6.8 to approximately 7.

2.

17. The formulation according to any one of the preceding claims, wherein the formulation has a pH of approximately 7.

0. 18.The formulation according to any one of the preceding claims, wherein the formulation consists of the GLP-2 analogue at a concentration of approximately 2 mg / ml to approximately 30 mg / ml, a buffer selected from the group consisting of a histidine buffer, mesylate buffer and acetate buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM, a non-ionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol and sorbitol at a concentration of approximately 90 mM to approximately 360 mM, arginine qs to provide a pH of approximately 6.6 to approximately 7.

4. 19.The formulation according to any one of the preceding claims, wherein the formulation comprises the GLP-2 analogue at a concentration of approximately 20 mg / ml, histidine buffer at a concentration of approximately 15 mM, mannitol at a concentration of approximately 230 mM, and arginine qs to provide a pH of approximately 7.

0.

20. The formulation according to any one of the preceding claims, wherein the histidine buffer is L-histidine.

21. The formulation according to any one of the preceding claims, wherein the mannitol is D-mannitol.

22. The formulation according to any one of the preceding claims, wherein the arginine acid is L-arginine / acetic acid.

23. The formulation according to any one of the preceding claims, wherein the formulation is free of a reducing agent. 24.The formulation according to any one of the preceding claims, wherein the formulation is stable at 2-8 °C for at least 6 months, at least 12 months, at least 18 months, or at least 24 months.

25. The formulation according to claim 24, wherein the GLP-2 analogue in the formulation retains at least approximately 90% of its biological activity after 18 months of storage at 2-8 °C.

26. The formulation according to any one of the preceding claims, wherein it is sterile.

27. The formulation according to any one of the preceding claims, wherein the formulation is administered to a subject by injection.

28. The formulation according to claim 27, wherein the injection is a subcutaneous injection.

29. The formulation according to any one of the preceding claims, wherein the GLP-2 analogue is provided as an acetate salt. 30.The formulation according to any one of the preceding claims, wherein the GLP-2 analogue is ZP1848 or ZP1848-acetate.

31. The formulation according to any one of the preceding claims, wherein the formulation consists of ZP1848-acetate at a concentration of approximately 20 mg / ml, histidine buffer at a concentration of approximately 15 mM, mannitol at a concentration of approximately 230 mM, and arginine qs to provide a pH of approximately 7.

0.

32. A manufactured article or kit comprising a container holding the stable pharmaceutical formulation of any one of claims 1 to 31.

33. A delivery device containing a liquid formulation comprising a GLP-2 analogue of any one of claims 1 to 31. 34.The delivery device of claim 33, wherein the delivery device is a pre-filled syringe, an injector device, an injector pen, an adjustable-dose auto-injector, a disposable auto-injector, a portable injector, or an infusion pump.

35. A formulation of the glucagon-like peptide-2 (GLP-2) analogue of any one of claims 1 to 31 for use in therapy.

36. A formulation of the glucagon-like peptide-2 (GLP-2) analogue of any one of claims 1 to 31 for use in a procedure for the treatment and / or prevention of a stomach and intestine-related disorder in a human patient. 37.The formulation of the glucagon-like peptide-2 (GLP-2) analogue for use in the treatment and / or prevention process of claim 36, wherein the stomach and intestine-related disorder is ulcers, digestive disorders, malabsorption syndromes, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease, celiac sprue (e.g., arising from gluten-induced enteropathy or celiac disease), tropical sprue, hypogammaglobulinemic sprue, enteritis, regional enteritis (Crohn's disease), ulcerative colitis, small bowel damage, or short bowel syndrome.

38. The formulation of the glucagon-like peptide-2 (GLP-2) analogue for use in the treatment and / or prevention process of claim 37, wherein the stomach and intestine-related disorder is short bowel syndrome.

39. The formulation of the glucagon-like peptide-2 analogue (GLP-2).2) for use in a treatment procedure according to claim 36, wherein the stomach and intestine-related disorder is radiation enteritis, infectious or post-infectious enteritis, or damage to the small intestine due to toxic or other chemotherapeutic agents.

40. The formulation of the glucagon-like peptide-2 (GLP-2) analogue for use in a treatment procedure according to claim 39, wherein treatment with the GLP-2 analogue is combined with one or more anticancer therapies.

41. The formulation of the glucagon-like peptide-2 (GLP-2) analogue for use in a treatment procedure according to claim 40,wherein the anticancer therapy treatment comprises administering one or more chemotherapeutic agents to the patient or treating the patient with radiation therapy.

42. The formulation of the glucagon-like peptide-2 (GLP-2) analogue for use in a treatment procedure according to claim 40 or claim 41, wherein the formulation is used in the treatment and / or prevention of a side effect of chemotherapy or radiation treatment.

43. The formulation of the glucagon-like peptide-2 (GLP-2) analogue for use in a treatment procedure according to claim 42, wherein the side effect of chemotherapy is diarrhea, abdominal cramps,vomiting or structural and functional damage to the intestinal epithelium resulting from chemotherapy treatment.

44. The formulation of the glucagon-like peptide-2 (GLP2) analogue for use in a treatment procedure according to any one of claims 40 to 43, wherein the human patient is a patient having SIC with intestinal failure. I 7 7C*nn / l 7P7 / E / YILI 45. The formulation of the glucagon-like peptide-2 (GLP2) analogue for use in a treatment procedure according to any one of claims 40 to 44, wherein the human patient is a patient who is borderline between having SIC with intestinal insufficiency and SIC with intestinal failure.

46. ​​The formulation of the glucagon-like peptide-2 (GLP2) analogue for use in a treatment procedure according to any one of claims 35 to 45,wherein the procedure comprises administering the GLP-2 analogue to the patient once a week.

47. The formulation of the glucagon-like peptide-2 (GLP-2) analogue for use in a treatment procedure according to any one of claims 29 to 43, wherein the procedure comprises administering the GLP-2 analogue to the patient twice a week.

48. A process for producing a stable liquid pharmaceutical formulation comprising a glucagon-like peptide-2 (GLP-2) analogue, wherein the GLP-2 analogue is represented by the formula: R1-Z1-His-Gly-Glu-Gly-X5-Phe-Ser-Ser-Glu-Leu-X11-Thr-Ille-Leu-Asp-Ala-LeuAla-Ala-Arg-Asp-Phe-Ille-Ala-Trp-Leu-Ille-Ala-Thr-Lys-Ille-Thr-Asp-Z2-R2 wherein: R1 is hydrogen, Ci-4 alkyl (e.g., methyl), acetyl, formyl,benzoyl or trifluoroacetyl X5 is Ser or Thr X11 is Ala or Ser R2 is NH2OH; Z1 and Z2 are independently absent or are a peptide sequence of 1-6 amino acid units of Lys; or a pharmaceutically acceptable salt or derivative thereof; wherein the process comprises formulating (a) the GLP-2 analogue at a concentration of approximately 2 mg / ml to approximately 30 mg / ml, (b) with a buffer selected from the group consisting of a histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, BisTris buffer and MOPS buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM; (c) with a non-ionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol and trehalose,wherein the tonicity modifier is present at a concentration of approximately 90 mM to approximately 360 mM; and (d) with arginine qs to provide a formulation having a pH of approximately 6.6 to approximately 7.4; wherein the formulation contains 5% or less of the GLP-2 analogue in the form of covalently bonded oligomeric products.

49. The process according to claim 48, wherein the formation of covalently bonded oligomers of the GLP-2 analogue is inversely dependent on the concentration of the GLP-2 analogue in the formulation.

50. The process according to claim 48 or claim 49, wherein the formulation is stable for at least 18 months when stored at 2-8 °C.

51. The process according to any one of claims 48 to 50,wherein the concentration of total acetate from the GLP2 analogue in the formulation is less than or equal to 11% acetate per mg of GLP2 analogue.

52. The process according to any one of claims 48 to 51, wherein the formulation has a viscosity greater than 0.8 and less than or equal to 2.0 mPa / s measured at 25 °C. I 7 7C*nn / l 7P7 / B / YILI 53. Use of a formulation comprising a glucagon-like peptide-2 (GLP-2) analogue, wherein the GLP-2 analogue is represented by the formula: R1-Z1-His-Gly-Glu-Gly-X5-Phe-Ser-Ser-Glu-Leu-X11-Thr-Ille-Leu-Asp-Ala-LeuAla-Ala-Arg-Asp-Phe-Ille-Ala-Trp-Leu-Ille-Ala-Thr-Lys-Ille-Thr-Asp-Z2-R2 wherein: R1 is hydrogen, Ci-4 alkyl (e.g., methyl), acetyl, formyl,benzoyl or trifluoroacetyl X5 is Ser or Thr X11 is Ala or Ser R2 is NH2OH; Z1 and Z2 are independently absent or are a peptide sequence of 1-6 amino acid units of Lys; or a pharmaceutically acceptable salt or derivative thereof; to provide a liquid pharmaceutical formulation that is stable for 24 months when stored at 2-8 °C, wherein the formulation comprises: (a) the GLP-2 analogue at a concentration of approximately 2 mg / ml to approximately 30 mg / ml; (b) a buffer selected from the group consisting of a histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, Bis-Tris buffer and MOPS buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM; (c) a non-ionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol,sorbitol and trehalose at a concentration of approximately 90 mM to approximately 360 mM; and (d) arginine qs to provide a formulation having a pH of approximately 6.6 to approximately 7.4; wherein the formulation contains 5% or less of the GLP-2 analogue in the form of covalently bonded oligomeric products.

54. Use according to claim 53, wherein the formation of covalently bonded oligomers of the GLP-2 analogue is inversely dependent on the concentration of the GLP-2 analogue in the formulation.

55. Use according to claim 53 or claim 54, wherein the concentration of total acetate from the GLP-2 analogue in the formulation is less than or equal to 11% acetate per mg of GLP-2 analogue.

56. Use according to any one of claims 53 to 54, wherein the formulation has a viscosity between 0.8 and 2,0 mPa / s measured at 25 °C.

57. A method for modulating the viscosity of a stable liquid pharmaceutical formulation comprising a glucagon-like peptide-2 (GLP-2) analogue, wherein the GLP-2 analogue is represented by the formula: R1-Z1-His-Gly-Glu-Gly-X5-Phe-Ser-Ser-Glu-Leu-X11-Thr-lle-Leu-Asp-Ala-LeuAla-Ala-Arg-Asp-Phe-lle-Ala-Trp-Leu-lle-Ala-Thr-Lys-lle-Thr-Asp-Z2-R2 wherein: R1 is hydrogen, Ci-4 alkyl (e.g., methyl), acetyl, formyl, benzoyl, or trifluoroacetyl; X5 is Ser or Thr; X11 is Ala or Ser; R2 is NH2 or OH; Z1 and Z2 are independently absent or are a peptide sequence of 1-6 Lys amino acid units; or a pharmaceutically acceptable salt or derivative thereof; wherein the process comprises formulating (a) the GLP-2 analogue at a concentration of approximately 2 mg / ml to approximately 30 mg / ml, (b) with a buffer selected from the group consisting of a histidine buffer, mesylate buffer, acetate buffer,(c) with a nonionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol, and trehalose, the tonicity modifier being present at a concentration of approximately 5 mM to approximately 50 mM; and (d) with arginine qs to provide a formulation having a pH of approximately 6.6 to approximately 7.4; wherein the total acetate concentration from the GLP-2 analogue in the formulation is less than or equal to 11% acetate per mg of GLP-2 analogue and wherein the formulation has a viscosity greater than 0.8 and less than or equal to 2.0 mPa / s measured at 25 °C.

58. A process for reducing the formation of covalently bound oligomeric products of a glucagon-like peptide-2 (GLP-2) analogue in a stable liquid pharmaceutical formulation comprising a GLP-2 analogue represented by the formula: R1-Z1-His-Gly-Glu-Gly-X5-Phe-Ser-Ser-Glu-Leu-X11-Thr-Ille-Leu-Asp-Ala-LeuAla-Ala-Arg-Asp-Phe-Ille-Ala-Trp-Leu-Ille-Ala-Thr-Lys-Ille-Thr-Asp-Z2-R2 wherein: R1 is hydrogen, Ci-4 alkyl (e.g., methyl), acetyl, formyl, benzoyl, or trifluoroacetyl; X5 is Ser or Thr; X11 is Ala or Ser; R2 is NH2OOH; Z1 and Z2 are independently absent or are a peptide sequence of 1-6 Lys amino acid units; or a pharmaceutically acceptable salt or derivative thereof; wherein the process comprises formulating (a) the GLP-2 analogue at a concentration of approximately 2 mg / ml to approximately 30 mg / ml, (b) with a buffer selected from the group consisting of a histidine buffer,mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, BisTris buffer, or MOPS buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM; (c) with a nonionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol, and trehalose, the tonicity modifier being present at a concentration of approximately 90 mM to approximately 360 mM; and (d) with arginine qs to provide a formulation having a pH of approximately 6.6 to approximately 7.4; wherein the formulation contains 5% or less of the GLP-2 analogue in the form of covalently bound oligomeric products.

59. The process of claim 58,in which the formation of covalently linked oligomers of the GLP-2 analogue is inversely dependent on the concentration of the GLP-2 analogue in the formulation.

60. Use of a formulation for reducing the formation of covalently bound oligomeric products of a glucagon-like peptide-2 (GLP-2) analogue, wherein the GLP-2 analogue is represented by the formula: R1-Z1-His-Gly-Glu-Gly-X5-Phe-Ser-Ser-Glu-Leu-X11-Thr-Ille-Leu-Asp-Ala-LeuAla-Ala-Arg-Asp-Phe-Ille-Ala-Trp-Leu-Ille-Ala-Thr-Lys-Ille-Thr-Asp-Z2-R2 wherein: R1 is hydrogen, Ci-4 alkyl (e.g., methyl), acetyl, formyl, benzoyl or trifluoroacetyl; X5 is Ser or Thr; X11 is Ala or Ser; R2 is NH2 or OH; Z1 and Z2 are independently absent or are a peptide sequence of 1-6 amino acid units of Lys; or a pharmaceutically acceptable salt or derivative thereof; in a liquid pharmaceutical formulation that is stable for 24 months when stored at 2-8 °C,wherein the formulation comprises: (a) the GLP-2 analogue at a concentration of approximately 2 mg / ml to approximately 30 mg / ml; (b) a buffer selected from the group consisting of a histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, Bis-Tris buffer and MOPS buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM; (c) a non-ionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol and trehalose at a concentration of approximately 90 mM to approximately 360 mM; and (d) arginine qs to provide a formulation having a pH of approximately 6.6 to approximately 7.4; wherein the formulation contains 5% or less of the GLP-2 analogue in the form of covalently linked oligomeric products.

61. Use according to claim 60,in which the formation of covalently linked oligomers of the GLP-2 analogue is inversely dependent on the concentration of the GLP-2 analogue in the formulation.

62. Use of a formulation for modulating the viscosity of a liquid pharmaceutical formulation comprising a glucagon-like peptide-2 (GLP-2) analogue, wherein the GLP-2 analogue is represented by the formula: R1-Z1-His-Gly-Glu-Gly-X5-Phe-Ser-Ser-Glu-Leu-X11-Thr-lle-Leu-Asp-Ala-LeuAla-Ala-Arg-Asp-Phe-lle-Ala-Trp-Leu-lle-Ala-Thr-Lys-lle-Thr-Asp-Z2-R2 wherein: R1 is hydrogen, Ci-4 alkyl (e.g., methyl), acetyl, formyl, benzoyl or trifluoroacetyl; X5 is Ser or Thr; X11 is Ala or Ser; R2 is NH2 or OH; Z1 and Z2 are independently absent or are a peptide sequence of 1-6 amino acid units of Lys; or a pharmaceutically acceptable salt or derivative thereof; in a liquid pharmaceutical formulation that is stable for 24 months when stored at 2-8 °C,wherein the formulation comprises: (a) the GLP-2 analogue at a concentration of approximately 2 mg / ml to approximately 30 mg / ml; (b) a buffer selected from the group consisting of a histidine buffer, mesylate buffer, acetate buffer, glycine buffer, lysine buffer, TRIS buffer, Bis-Tris buffer and MOPS buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM; (c) a non-ionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol and trehalose at a concentration of approximately 90 mM to approximately 360 mM; and (d) arginine qs to provide a formulation having a pH of approximately 6.6 to approximately 7.4; wherein the concentration of total acetate from the GLP2 analogue in the formulation is less than or equal to 11% acetate per mg of GLP-2 analogue and the formulation has a viscosity between 0.8 and 2.0 mPa / s measured at 25 °C.

63. A solid composition comprising an acetate salt of a glucagon-like peptide-2 (GLP-2) analogue having the formula: (H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2), x(CH3COOH) wherein x is 1.0 to 8.

0.

64. The solid composition of claim 63, wherein x is 4.0 to 6.

0.

65. The solid composition of claim 63, wherein x is 2.0 to 7.

0.

66. The solid composition of claim 63, wherein x is 3.0 to 6.

0.

67. The solid composition of claim 63, wherein x is from 4.0 to 6.

0.

68. The solid composition of claim 63, wherein x is from 4.0 to 8.

0.

69. A stable aqueous pharmaceutical formulation, the formulation comprising (a) the solid composition of claims 63 to 67 at a concentration of approximately 2 mg / ml to approximately 30 mg / ml; (b) a buffer selected from the group consisting of a histidine buffer, mesylate buffer, acetate buffer,(a) glycine buffer, lysine buffer, TRIS buffer, Bis-Tris buffer, and MOPS buffer, the buffer being present at a concentration of approximately 5 mM to approximately 50 mM; (c) a nonionic tonicity modifier selected from the group consisting of mannitol, sucrose, glycerol, sorbitol, and trehalose at a concentration of approximately 90 mM to approximately 360 mM; and (d) arginine qs to provide a formulation having a pH of approximately 6.6 to approximately 7.4; wherein the formulation contains 5% or less of the GLP-2 analogue in the form of covalently bound oligomeric products and wherein the formulation has a viscosity between 0.8 and 2.0 mPa / s measured at 25 °C.

70. The formulation of claim 69, wherein the formulation is stable for at least 18 months when stored at 2-8 °C.

71. The formulation of claim 69 or claim 70,wherein the GLP-2 analogue in the formulation retains at least approximately 90% of its biological activity after 18 months of storage at 2-8 °C.