Novel compositions

Abstract

The present invention relates to novel compositions, in particular aqueous solution compositions having a pH in the range of 4.0 to 7.5 comprising: a peptide therapeutic agent; optionally one or more buffering agents, which are substances having at least one ionizable group with a pKa in the range of 3.0 to 8.5 and the pKa is within 2 pH units of the pH of the composition; and a stabilizer; wherein the peptide therapeutic agent does not contain an ionizable group with a pKa in the range of 3.0 to 8.5 and wherein the buffering agent(s) is present in the composition in a total concentration of 0 to 5 mM.

Description

[0001] The applicant filed PCT application PCT / GB2018 / 053769 on December 21, 2018, entitled "Novel Composition". This PCT application entered the Chinese national phase on June 8, 2020, with application number 201880079289.7. This application is a divisional application of that Chinese application. Technical Field

[0002] This invention relates to therapeutic agents, particularly peptides, in aqueous compositions at low buffer concentrations. Background Technology

[0003] Many therapeutic agents are peptides. Although the number of protein-based drugs on the market and in mass production is increasing, peptides continue to play an important role due to their production complexity, lower production cost, and good efficacy and tolerability in humans.

[0004] When formulated as aqueous solutions, peptides are unstable and prone to structural degradation during storage, resulting in a loss of biological activity. Structural degradation is typically chemical in nature, including hydrolytic cleavage, cyclic imide formation, isomerization, or oxidation. In some cases, degradation can be physical (e.g., aggregation or gel formation), although these processes are relatively less common in peptides than in larger proteins.

[0005] The rate of degradation is directly proportional to temperature, and peptide therapeutics are generally more stable at lower temperatures. However, to ensure patient convenience, it is often necessary to develop products that are stable at elevated temperatures, such as up to 25°C or 30°C, over a specific period of time or throughout their shelf life.

[0006] One of the most critical parameters for controlling the stability of peptide therapeutics is pH. Therefore, pH optimization is a key step in formulation development. Many therapeutic peptides are formulated at selected pH values ​​between 4.0 and 7.5. It is considered important to ensure that the pH remains at the selected value and that pH fluctuations are minimized. Therefore, it is understandable that the formulation needs to have a certain degree of buffering capacity. While some peptide therapeutics inherently provide buffering capacity within the pH range of 4.0–7.5 (i.e., self-buffering), others do not. Generally, formulations containing at least one pK a Peptides with ionizable groups in the range of approximately 3.0–8.5 provide buffering capacity at least partially within a pH range of 4.0–7.5. In such cases, the provision of buffering capacity is essentially based on the pK of the ionizable group. a Within approximately one pH unit. Admittedly, a certain buffering capacity is achieved by using a buffer with at least one pH unit. aThis is provided by molecules with ionizable groups whose pH differs from the composition by more than one pH unit (e.g., within approximately two pH units), however, compared to the use of molecules with pK a Compared to buffer molecules with ionizable groups that are close to the pH of the composition, buffer molecules typically require significantly higher concentrations to achieve comparable pH stabilizing effects.

[0007] In the case of peptides composed of natural amino acids, if the side chains of free aspartic acid, free glutamic acid (i.e., aspartic and glutamic acid side chains that do not participate in amide or other bonds), histidine, or free cysteine ​​(i.e., cysteine ​​side chains that do not participate in disulfide or other bonds) are part of the primary amino acid sequence, then a certain buffering capacity can be expected in at least a portion of the pH range between 4.0 and 7.5. In such cases, the buffering capacity is essentially the pK of the aforementioned amino acids present in the peptide structure. a The buffering capacity is provided within a pH range of approximately 1 unit. Peptides that do not contain any of these four amino acid side chains do not provide any meaningful buffering capacity in the pH range of 4.0–7.5 unless they contain an ionizable non-peptide moiety that can contribute to buffering capacity. Ionizable groups that may be present at the N-terminus and / or C-terminus of a peptide typically have a pK of less than 3.0 (C-terminal carboxyl group) and greater than 8.5 (N-terminal amino group). a Therefore, it does not provide substantial buffering capacity in the pH range of 4.0–7.5.

[0008] This invention addresses the stability problem of peptide therapeutic agents in aqueous compositions, particularly those that do not provide any substantial buffering capacity in the pH range of 4.0-7.5.

[0009] Liquid formulations of peptide therapeutics are designed for use in various routes of administration, including intravenous (IV), subcutaneous (SC), intramuscular (IM), and oral administration. Depending on the specific route of administration, certain formulation parameters are desired or preferred. For example, formulations designed for SC and IM administration are very preferably approximately isotonic (e.g., 200-500 mOsm / L, preferably about 300 mOsm / L). In contrast, IV products (especially those delivered after dilution in IV bags) can be strongly hypotonic or hypertonic if desired.

[0010] WO2006 / 138181A2 (AMGEN, INC.) discloses a self-buffered protein formulation that is essentially free of other buffers.

[0011] US2016 / 0106840A1 (EAGLE PHARMACEUTICALS INC.) discloses bivalirudin compositions with a pH of about 3 to about 5 and which are substantially free of buffers.

[0012] US8420081B2 (ABBVIE INC.) discloses an aqueous formulation of an antibody, wherein the conductivity of the formulation is less than about 2.5 mS / cm.

[0013] WO2008 / 084237 (ARECOR LIMITED) discloses protein compositions that do not contain significant amounts of conventional buffers. Instead, a "displacement buffer," namely pK, is used. a An additive whose pH value is at least one unit lower or one unit higher than the pH of the composition. Summary of the Invention

[0014] Therefore, according to the present invention, an aqueous composition having a pH in the range of 4.0 to 7.5 is provided, comprising: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; and - Stabilizer; The peptide therapeutic agent described herein does not contain pK a The composition contains ionizable groups in the range of 3.0 to 8.5, and the buffer is present in the composition at a total concentration of 0-5 mM. Attached Figure Description

[0015] Figure 1 ： The structure of vasopressin.

[0016] Figure 2 ： The structure of desmopressin.

[0017] Figure 3 ： The structure of lypressin.

[0018] Figure 4 ： The structure of atosiban.

[0019] Figure 5 ： The structure of carbetocin.

[0020] Figure 6 ： The structure of oxytocin.

[0021] Figure 7 ： The structure of octreotide.

[0022] Figure 8 ： The structure of caspofungin.

[0023] Figure 9 ： The structure of anidulafungin.

[0024] Figure 10 ： The structure of micafungin.

[0025] Figure 11 ： The structure of terlipressin. Detailed Implementation

[0026] This article describes stable aqueous solutions of peptide therapeutic agents with no buffer or very low buffer concentration.

[0027] It should be noted that all references to "pH" in this article refer to the pH measured at 25°C. All references to "pK" are also incomplete. a "All refer to the pK value of ionizable groups measured at 25°C." a (See CRC Handbook of Chemistry and Physics, 79th edition, 1998, DR Lide). If necessary, a suitable calculator can be used to estimate the pK when amino acid side chains are present in the peptide. a value.

[0028] The inventors have discovered that buffers adversely affect the stability of peptide therapeutics in a concentration-dependent manner. Therefore, the concentration of buffers in the composition should be limited as much as possible.

[0029] In the presence of a buffer, it will have buffering capacity at the pH of the composition. Buffers typically contain pK. a The ionizable groups within one pH unit of the composition, however, have pK a The portion of an ionizable group that is one pH unit higher or lower than the pH of the composition can also provide a buffering effect (if present in sufficient quantity). In one embodiment, the buffer (or one of the buffers) comprises pK a An ionizable group within one pH unit of the pH of the composition. In another embodiment, the buffer (or one of the buffers) comprises pK. a The ionizable groups are within 1.5 pH units of the pH of the composition (e.g., pH units between 1 and 1.5 of the pH of the composition). In a further embodiment, the buffer (or one of the buffers) comprises pK aIonizable groups within 2 pH units of the pH of the composition (e.g., between 1.5 and 2 pH units of the pH of the composition).

[0030] In one embodiment, the composition is free of a buffer. In one embodiment, the composition contains a single buffer. In one embodiment, the composition contains two buffers.

[0031] In one embodiment, the total concentration of the buffer in the composition is less than 5 mM, such as less than 4 mM, less than 3 mM, less than 2 mM, less than 1 mM, less than 0.5 mM, less than 0.4 mM, less than 0.3 mM, or less than 0.2 mM. In one embodiment, the total concentration of the buffer is 0.1-5 mM, such as 0.5-5 mM, 0.1-4 mM, 0.5-4 mM, 0.1-3 mM, 0.5-3 mM, 0.1-2 mM, 0.5-2 mM, 0.1-1 mM, or 0.5-1 mM. In one embodiment, the aqueous composition is substantially free of buffer. As used herein, "substantially free" means that the aqueous composition contains less than 0.1 mM of buffer. When considering the concentration of the buffer in solution, any buffering capacity of the peptide therapeutic agent itself should be excluded.

[0032] Adding an acid decreases the pH of an aqueous solution, while adding a base increases it. At a given temperature and atmospheric pressure, the magnitude of the pH decrease upon adding an acid or the magnitude of the pH increase upon adding a base depends on (1) the amount of acid or base added, (2) the initial pH of the aqueous solution (i.e., before the addition of the acid or base), and (3) the presence of a buffer. Therefore, (1) starting at a given pH, adding a larger amount of acid or base will result in a larger pH change; (2) at a neutral pH (i.e., pH 7.0), adding a given amount of acid or base will result in the largest pH change, and the magnitude of the pH change will decrease as the initial pH moves away from pH 7.0; and (3) starting at a given pH, the magnitude of the pH change will be smaller in the presence of a buffer than in the absence of a buffer. Therefore, if an acid or base is added to a solution, a buffer has the ability to reduce pH changes.

[0033] Suitablely, when the addition of a strong acid or strong base results in an increase of 0.1 mM in the acid or base in the solution, a substance is considered a buffer if it can reduce the pH change of the solution by 75%, preferably 50%, most preferably 25% (compared to the same solution without the buffer).

[0034] Conversely, it is appropriate that when the addition of a strong acid or base results in an increase of 0.1 mM in the acid or base in the solution, a substance is not considered a buffer if it cannot reduce the pH change of the solution by 75%, preferably 50%, most preferably 25% (compared to the same solution without the substance).

[0035] In one embodiment, the buffer or a buffering agent is an amino acid. In another embodiment, the buffer or a buffering agent is not an amino acid.

[0036] When present, suitable buffers include, but are not limited to: histidine, maleate, sulfite, glyoxylate, aspartame, glucuronide, aspartate, glutamate, tartrate, glucuronide, lactate, glycolic acid, adenine, succinate, ascorbate, benzoate, phenylacetate, gallate, cytosine, right Aminobenzoic acid, sorbate, acetate, propionate, alginate, urate, 2-( N -morpholino)ethanesulfonic acid, bicarbonate, bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane, N -(2-acetamido)-2-iminodiacetic acid, 2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid, piperazine, N , N '-Bis(2-ethanesulfonic acid), phosphate, N , N -bis(2-hydroxyethyl)-2-aminoethanesulfonic acid, 3-[ N , N [-bis(2-hydroxyethyl)amino]-2-hydroxypropanesulfonic acid, triethanolamine, piperazine- N , N '-bis(2-hydroxypropanesulfonic acid), tris(hydroxymethyl)aminomethane, N -Tris(hydroxymethyl)glycine and N -Tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid and its salts, and combinations thereof. In one embodiment, the buffer is selected from the group consisting of histidine, maleate, tartrate, lactate, benzoate, acetate, bicarbonate, phosphate, and tris(hydroxymethyl)aminomethane, particularly histidine, lactate, acetate, phosphate, and tris(hydroxymethyl)aminomethane. In one embodiment, the buffer is citrate.

[0037] In one embodiment, the composition further comprises a substance selected from the group consisting of gentianate and salicylate. These substances may be present, for example, at a concentration of up to 5 mM. In one embodiment, these substances are not present in the composition.

[0038] In one embodiment, the composition does not contain malic acid.

[0039] In one embodiment, the composition solvent comprises (by volume) at least 80% water, such as at least 85%, at least 90%, at least 95%, or at least 99% water. In one embodiment, the solvent is water, meaning that water is the only solvent present in the composition. Preferably, the composition does not contain ethanol.

[0040] As used in this article, the term "peptide therapeutic agent" refers to a peptide that does not contain pK. a Peptides with ionizable groups in the pH range of 3.0 to 8.5. Thus, peptide therapeutics do not provide any substantial buffering capacity in the pH range of 4.0–7.5, i.e., they are not “self-buffering”.

[0041] Generally, when the addition of a strong acid or strong base results in an increase of 0.1 mM in the acid or base in the solution, the peptide therapeutic agent is considered to provide substantial buffering capacity if it can reduce the pH change of the solution by 75%, preferably 50%, and most preferably 25% (compared to the same solution without the peptide therapeutic agent).

[0042] Conversely, generally, when the addition of a strong acid or base results in an increase of 0.1 mM in the acid or base in the solution, if the peptide therapeutic agent cannot reduce the pH change of the solution by 75%, preferably 50%, most preferably 25% (compared to the same solution without the peptide therapeutic agent), then the peptide therapeutic agent is considered to provide no substantial buffering capacity.

[0043] One embodiment provides an aqueous composition with a pH in the range of 4.0 to 7.5, comprising: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; and - Stabilizer; The buffer is present in the composition at a total concentration of 0-5 mM, and the peptide therapeutic agent cannot reduce the pH change of the solution by 75%, preferably 50%, and most preferably 25% (compared to the same solution without the peptide therapeutic agent) when the addition of a strong acid or strong base results in an increase of 0.1 mM in the acid or base in the solution.

[0044] One embodiment provides an aqueous composition with a pH in the range of 4.0 to 7.5, comprising: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; and - Stabilizer; The buffer is present in the composition at a total concentration of 0-5 mM, and the peptide therapeutic agent is pK-free. a The ionizable groups are in the range of 3.0 to 8.5, and the peptide therapeutic agent cannot reduce the pH change of the solution by 75%, preferably 50%, and most preferably 25% (compared to the same solution without the peptide therapeutic agent) when the addition of a strong acid or strong base results in an increase of 0.1 mM in the acid or base in the solution.

[0045] In one embodiment, the peptide therapeutic agent does not contain pK a Ionizable groups in the range of 2.0 to 9.5.

[0046] In one embodiment, the peptide therapeutic agent does not contain any free aspartic acid, free glutamic acid, histidine, or free cysteine ​​side chains, the pK of which are... a The values ​​are all between 3.0 and 8.5. The term "free" refers to the presence of intact CO2H or COO2 in the side chains of aspartic acid and glutamic acid. - The side chain functional group (i.e., does not participate in amide or other bonds), and the cysteine ​​side chain contains complete SH or S. - Side chain functional groups (i.e., those that do not participate in disulfide bonds or other bonds).

[0047] Peptide therapeutics, particularly relatively small peptide therapeutics, may contain relatively high amounts of non-pharmacologically active counterions to balance the charge. In the case of positively charged molecules, counterions (e.g., chloride or acetate ions) are needed, while in the case of negatively charged molecules, counterions (e.g., sodium ions) are needed. Counterions (e.g., acetate ions) may themselves have buffering capacity. However, any such counterions should be excluded from evaluation when considering whether the peptide therapeutic provides any buffering capacity in the pH range of 4.0–7.5. Therefore, peptide therapeutics may associate with non-pharmacologically active counterions capable of buffering in the pH range of 4.0–7.5, provided that the peptide therapeutic itself does not provide any buffering capacity in the pH range of 4.0–7.5 according to the invention. However, when calculating the buffer concentration in an aqueous composition, any such counterions with buffering capacity should be included in the total concentration of the buffer.

[0048] Peptide therapeutics are not proteins. The term "protein" refers to an amino acid chain (more than 25 amino acids) of sufficient length to produce a high level of secondary and / or tertiary and / or quaternary structure. As defined herein, a "peptide" is a short chain of up to 25 (e.g., up to 20, 15, 12, or 10) amino acid monomers linked by peptide bonds.

[0049] Therefore, in one embodiment, the peptide therapeutic agent contains up to 25 amino acids (e.g., up to 20, 15, 12, or 10). The peptide therapeutic agent can be unbranched, branched, linear, cyclic, and / or partially cyclic. The peptide therapeutic agent may consist of one or more amino acid chains linked by one or more suitable linkers (e.g., via disulfide bonds), provided that the total number of amino acids does not exceed 25, 20, 15, 12, or 10. The amino acids in the peptide therapeutic agent may include amino acids selected from 20 natural (proteinogenic) amino acids, their derivatives, and other α-amino acids, including non-natural amino acids. Derivatives of natural amino acids include derivatives in which the carboxylate group is converted to an ester or amide, such as C... 1-6 Alkyl esters such as methyl or ethyl esters, or amides such as primary amides (i.e., amides formed by condensation with ammonia), secondary amides (e.g., amides formed by condensation with methylamine), or tertiary amides (e.g., amides formed by condensation with dimethylamine), especially primary amides; or wherein the amine group is converted to an amide, such as -NH(CO)C 1-5 Alkyl groups, such as acetamide. Suitablely, peptide therapeutics contain amino acids specifically selected from 20 natural (proteinogenic) amino acids and their derivatives (e.g., selected from 20 natural (proteinogenic) amino acids).

[0050] Peptide therapeutic agents may have a free amine (-NH2) group at the N-terminus. Alternatively, the N-terminal amine group may be derivatized, such as an amide group (e.g., -NH(CO)C). 1-20 Alkyl groups, such as -NH(CO)C 1-5 Alkyl groups, particularly acetamides. Peptide therapeutics may have a free carboxylic acid (-COOH) group at the C-terminus. Alternatively, the C-terminal carboxylic acid group may be derivatized, such as an amide group (e.g., a primary amide (i.e., an amide formed by condensation with ammonia), a secondary amide (e.g., an amide formed by condensation with a primary amine such as methylamine), or a tertiary amide (e.g., an amide formed by condensation with a secondary amine such as dimethylamine, particularly a primary amide) or an ester group (e.g., C-alkyl groups). 1-6 Alkyl esters, such as methyl esters or ethyl esters.

[0051] Alternatively, the peptide therapeutic agent may be cyclic, whereby the N-terminus and C-terminus are linked directly or via linkers. Alternatively, the peptide therapeutic agent may be partially cyclic, whereby the N-terminus or C-terminus is linked directly or via linkers to an amino acid side chain. Amino acid side chains that can be linked to the N-terminus or C-terminus include those derived from cysteine, glutamic acid, and aspartic acid. Linkers may be chains of, for example, 2-10 atoms in length, said atoms selected from carbon, nitrogen, sulfur, and oxygen atoms. Linkers may contain functionalized atoms (e.g., atoms substituted with hydroxyl, amino, or oxo groups) and / or have carbon-containing side chains.

[0052] Cyclic and partially cyclic peptide therapeutics include those involving intramolecular disulfide bonds (e.g., between two cysteine ​​side chains).

[0053] In a preferred embodiment, the peptide therapeutic agent does not have a free N-terminal amine group or a free C-terminal carboxylic acid group, and preferably does not have either a free N-terminal amine group or a free C-terminal carboxylic acid group, for example because the peptide therapeutic agent is cyclic or partially cyclic, and / or because the N-terminus is derivatized (e.g., as an amide) and / or the C-terminus is derivatized (e.g., as an ester or amide).

[0054] The aqueous composition of the present invention can be used in any peptide therapeutic agent of interest, provided that the peptide therapeutic agent does not contain pK. a It contains ionizable groups in the range of 3.0 to 8.5 and suitably does not contain free aspartic acid, free glutamic acid, histidine or free cysteine ​​side chains.

[0055] Peptide therapeutics can be naturally occurring or non-natural. They do not contain pK. a Examples of peptide therapeutic agents with ionizable groups in the range of 3.0 to 8.5 include vasopressin and its analogues. In one embodiment, the peptide therapeutic agent is vasopressin (also known as arginine vasopressin, see below). Figure 1 In one implementation, the peptide therapeutic agent is desmopressin (see...). Figure 2 In one embodiment, the peptide therapeutic agent is lysine vasopressin (also known as lysine vasopressin, see [link]). Figure 3 Other suitable peptide therapeutics include atosiban (see [link to relevant information]). Figure 4 ), carbetocin (see Figure 5 ), oxytocin (see) Figure 6 ), Octreotide (see) Figure 7 ), caspofungin (see) Figure 8 Anifene (see also) Figure 9 ) and micafungin (see Figure 10 In one implementation, the peptide therapeutic agent is terlipressin (see...). Figure 11It is important to understand that these types of peptide therapeutics can be used in formulations in any form of their pharmaceutically acceptable salt.

[0056] The following specific substances are not peptide therapeutic agents covered by this invention as defined herein: insulin, insulin analogs such as insulin lispro, insulin aspart, insulin glutathione, or insulin glargine; glucagon, human growth hormone, gonadotropins, human thyroid-stimulating hormone, granulocyte colony-stimulating hormone, streptokinase, asparaginase, uricase; antigens of vaccines such as hepatitis B vaccine, malaria vaccine, human papillomavirus vaccine, meningitis A vaccine, meningitis C vaccine, pertussis vaccine, and polio vaccine; antibodies such as anti-epidermal growth factor receptor (EGFR) monoclonal antibody, anti-HER2 monoclonal antibody, anti-CD52 monoclonal antibody, and anti-CD20 monoclonal antibody, polyclonal antibodies; interferon, erythropoietin, darbopoietin alpha; coagulation factors such as factor VIII and factor IX human albumin; protein C; general hormones; microbial proteins; metabolic proteins; soluble forms of structural proteins; and the direct thrombin inhibitor bivalirudin. The substances were excluded because they are proteins (i.e., not peptides), and / or because they contain pK. a Ionizable groups, particularly ionizable amino acid side chains, in the range of 3.0 to 8.5.

[0057] The concentration of the peptide therapeutic agent in the composition is typically 0.001-50 mg / ml, such as 0.01-10 mg / ml or 0.1-5 mg / ml.

[0058] The inventors have discovered that, in addition to minimizing buffer concentration, adding a stabilizer to the composition can provide further stability benefits. A stabilized amount of stabilizer will be used.

[0059] In one embodiment, the stabilizer is selected from amino acids, particularly natural amino acids such as α-amino acids. It has pK a Amino acids with side chains in the range of 3.0 to 8.5 are not suitable as stabilizers. In one embodiment, the stabilizer is an amino acid selected from methionine, arginine, glycine, and proline, particularly selected from methionine, arginine, and proline, or methionine alone. The amino acid serving as a stabilizer is present at a concentration sufficient to provide a stabilizing effect. In one embodiment, the amino acid serving as a stabilizer is present at a concentration of 1-200 mM, such as 10-100 mM or 10-50 mM.

[0060] In another embodiment, the stabilizer is a polyol, suitably selected from the group consisting of glycerol, mannitol, propylene glycol, PEG 300, PEG 400, sucrose, trehalose, and lactose. Preferred polyol stabilizers are selected from glycerol, mannitol, propylene glycol, and sucrose. The polyol as a stabilizer is present at a concentration sufficient to provide a stabilizing effect. In one embodiment, the polyol as a stabilizer is present at a concentration of 1-1000 mM, such as 10-500 mM or 100-500 mM. When the stabilizer is a polyol, it can also act as a tension modifier. In some embodiments, the stabilizer is a polyol, but the composition contains additional tension modifiers (i.e., in addition to the polyol). Thus, in one embodiment, the composition contains a polyol as a stabilizer (suitably glycerol, mannitol, propylene glycol, or sucrose) and additional tension modifiers. The additional tension modifiers can be charged or uncharged, for example, as defined below.

[0061] The pH of the composition is between 4.0 and 7.5, preferably between 4.0 and 7.0 or between 4.0 and 6.0.

[0062] The composition may contain a tension modifier, which may be charged or uncharged. Examples of uncharged tension modifiers include glycerol, 1,2-propanediol, mannitol, sorbitol, trehalose, PEG300, and PEG400. When an uncharged tension modifier is included, it is typically used in the composition at a concentration of 50-1000 mM, for example, 200-500 mM, such as about 300 mM. Examples of charged tension modifiers include sodium chloride, sodium sulfate, and amino acids such as glycine or arginine. [The last sentence appears to be incomplete and possibly refers to a pK value.] a Amino acids with side chains in the range of 3.0 to 8.5 are not suitable as tension modifiers. When charged tension modifiers are included, they are typically used in the composition at concentrations of 25-500 mM, for example, 50-250 mM, such as about 150 mM. Uncharged tension modifiers are generally preferred over charged ones.

[0063] The composition may contain a nonionic surfactant.

[0064] A particularly suitable class of nonionic surfactants are polysorbates (fatty acid esters of ethoxylated sorbitol), such as polysorbate 20 or polysorbate 80. Polysorbate 20 is a monoester formed from lauric acid and polyoxyethylene (20) sorbitol, where the number 20 indicates the number of oxyethylidene groups in the molecule. Polysorbate 80 is a monoester formed from oleic acid and polyoxyethylene (20) sorbitol, where the number 20 indicates the number of oxyethylidene groups in the molecule. Polysorbate 20 is known to have a number of trademark names, including Tween 20 and Alkest TW 20. Polysorbate 80 is known to have a number of trademark names, including Tween 80 and Alkest TW 80. Other suitable polysorbates include polysorbate 40 and polysorbate 60.

[0065] Another suitable class of nonionic surfactants are alkyl glycosides, particularly dodecyl maltodextrin. Other alkyl glycosides include dodecyl glucoside, octyl glucoside, octyl maltodextrin, decyl glucoside, decyl maltodextrin, tridecyl glucoside, tridecyl maltodextrin, tetradecyl glucoside, tetradecyl maltodextrin, hexadecyl glucoside, hexadecyl maltodextrin, sucrose monocaprylate, sucrose monodecanoate, sucrose monodecanoate, sucrose monotetradecanoate, and sucrose monohexadecanoate.

[0066] Another suitable class of nonionic surfactants are block copolymers of polyethylene glycol and polypropylene glycol, also known as poloxamers, particularly poloxamer 188, poloxamer 407, poloxamer 171, and poloxamer 185. Poloxamers are also known under the trademarks Pluronics or Koliphors. For example, poloxamer 188 is marketed as Pluronic F-68.

[0067] Another suitable class of nonionic surfactants are alkyl ethers of polyethylene glycol, particularly those known by the trademark Brij, such as those selected from polyethylene glycol (2) hexadecyl ether (Brij 52), polyethylene glycol (2) oleyl ether (Brij 93), and polyethylene glycol (2) dodecyl ether (Brij L4). Other suitable Brij surfactants include polyethylene glycol (4) lauryl ether (Brij 30), polyethylene glycol (10) lauryl ether (Brij 35), polyethylene glycol (20) hexadecyl ether (Brij 58), and polyethylene glycol (10) stearyl ether (Brij 78).

[0068] Another suitable class of nonionic surfactants are alkylphenyl ethers of polyethylene glycol, particularly 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol, also known by the trademark name Triton X-100.

[0069] In one embodiment, the nonionic surfactant is polysorbate or poloxamer, with polysorbate being preferable. The concentration of the nonionic surfactant in the composition is typically in the range of 10-2000 µg / ml, such as 50-1000 µg / ml, 100-500 µg / ml, or about 200 µg / ml.

[0070] In one embodiment, the nonionic surfactant is selected from the group consisting of alkyl glycosides, polysorbates, alkyl ethers of polyethylene glycol, block copolymers of polyethylene glycol and polypropylene glycol, and alkyl phenyl ethers of polyethylene glycol.

[0071] The compositions of the present invention may additionally contain preservatives, such as phenolic or benzyl preservatives. Preservatives are suitably selected from the group consisting of phenol, m-cresol, chlorocresol, benzyl alcohol, propylparaben, and methylparaben, particularly phenol, m-cresol, and benzyl alcohol. The concentration of the preservative is typically 10-100 mM, for example 20-80 mM, such as 25-50 mM. The optimal concentration of the preservative in the composition is selected to ensure that the composition passes the USP antimicrobial efficacy test. <51> Volume 32).

[0072] In one embodiment, an aqueous composition having a pH in the range of 4.0 to 7.5 is provided, comprising the following substances: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; - Stabilizer; - One or more preservatives may be present; - One or more nonionic surfactants may be present; and - One or more tension modifiers may be present; The peptide therapeutic agent described herein does not contain pK a The composition contains ionizable groups in the range of 3.0 to 8.5, and the buffer is present in the composition at a total concentration of 0-5 mM.

[0073] In one embodiment, an aqueous composition having a pH in the range of 4.0 to 7.5 is provided, comprising the following substances: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; - Stabilizer; - One or more preservatives may be present; - One or more nonionic surfactants may be present; and - One or more tension modifiers may be present; The peptide therapeutic agent described herein does not contain pK a The composition contains ionizable groups in the range of 3.0 to 8.5, wherein the buffer is present in the composition at a total concentration of 0-5 mM, such as 0.5 to 5 mM, and wherein the stabilizer is an amino acid, such as methionine, arginine, or proline (especially methionine), or a polyol, such as glycerol, mannitol, propylene glycol, or sucrose.

[0074] In one embodiment, an aqueous composition having a pH in the range of 4.0 to 7.5 is provided, comprising the following substances: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; - Stabilizer; - One or more preservatives may be present; - One or more nonionic surfactants may be present; and - One or more tension modifiers may be present; The peptide therapeutic agent therein does not contain any free aspartic acid, free glutamic acid, histidine or free cysteine ​​side chains, the buffer is present in the composition at a total concentration of 0-5 mM, such as 0.5-5 mM, and the stabilizer is an amino acid, such as methionine, arginine or proline (especially methionine), or a polyol, such as glycerol, mannitol, propylene glycol or sucrose.

[0075] In one embodiment, an aqueous composition having a pH in the range of 4.0 to 7.5 is provided, comprising the following substances: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pKa Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; - Stabilizer; - One or more preservatives may be present; - One or more nonionic surfactants may be present; and - One or more tension modifiers may be present; The peptide therapeutic agent described herein does not contain pK a The composition contains ionizable side chains in the range of 3.0 to 8.5, such as free aspartic acid, free glutamic acid, histidine, or free cysteine, wherein the buffer is present in the composition at a total concentration of 0-5 mM, such as 0.5-5 mM, and wherein the stabilizer is an amino acid, such as methionine, arginine, or proline (especially methionine), or a polyol, such as glycerol, mannitol, propylene glycol, or sucrose.

[0076] In one embodiment, an aqueous composition having a pH in the range of 4.0 to 7.5 is provided, comprising the following substances: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; - Stabilizer; - One or more preservatives may be present; - One or more nonionic surfactants may be present; and - One or more tension modifiers may be present; The peptide therapeutic agent is selected from the group consisting of: vasopressin, lysine vasopressin, desmopressin, atosiban, carbetocin, oxytocin, octreotide, caspofungin, anidofungin, and micafungin, wherein the buffer is present in the composition at a total concentration of 0-5 mM, such as 0.5 to 5 mM, and wherein the stabilizer is an amino acid, such as methionine, arginine, or proline (especially methionine), or a polyol, such as glycerol, mannitol, propylene glycol, or sucrose.

[0077] In one embodiment, an aqueous composition having a pH in the range of 4.0 to 7.5 is provided, comprising the following substances: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pKa Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; - Stabilizer; - One or more preservatives may be present; - One or more nonionic surfactants may be present; and - One or more tension modifiers may be present; The peptide therapeutic agent is selected from the group consisting of: vasopressin, lysine vasopressin, desmopressin, atosiban, carbetocin, oxytocin, octreotide, caspofungin, anisofungin, micafungin, and terlipressin, wherein the buffer is present in the composition at a total concentration of 0-5 mM, such as 0.5 to 5 mM, and wherein the stabilizer is an amino acid, such as methionine, arginine, or proline (especially methionine), or a polyol, such as glycerol, mannitol, propylene glycol, or sucrose.

[0078] In one embodiment, an aqueous composition having a pH in the range of 4.0 to 7.5 is provided, comprising the following substances: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within one pH unit of the pH of the composition; - Stabilizer; - One or more preservatives may be present; - One or more nonionic surfactants may be present; and - One or more tension modifiers may be present; The peptide therapeutic agent described herein does not contain pK a The composition contains ionizable groups in the range of 3.0 to 8.5, wherein the buffer is present in the composition at a total concentration of 0-5 mM, and wherein the stabilizer is an amino acid, such as methionine, arginine, or proline (especially methionine), or a polyol, such as glycerol, mannitol, propylene glycol, or sucrose.

[0079] In one embodiment, an aqueous composition having a pH in the range of 4.0-7.5 is provided, comprising: - Select a peptide therapy consisting of vasopressin, lysine vasopressin, desmopressin, atosiban, carbetocin, oxytocin, octreotide, caspofungin, anisofungin, and micafungin; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; and - Stabilizer; The buffer is present in the composition at a total concentration of 0-5 mM.

[0080] In one embodiment, an aqueous composition having a pH in the range of 4.0-7.5 is provided, comprising: - Select a peptide therapy consisting of vasopressin, lysine vasopressin, desmopressin, atosiban, carbetocin, oxytocin, octreotide, caspofungin, anidoxetine, micafungin, and terlipressin; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; and - Stabilizer; The buffer is present in the composition at a total concentration of 0-5 mM.

[0081] In one embodiment, an aqueous composition having a pH in the range of 4.0-7.5 is provided, comprising the following substances: - Select a peptide therapy consisting of vasopressin, lysine vasopressin, desmopressin, atosiban, carbetocin, oxytocin, octreotide, caspofungin, anisofungin, and micafungin; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; - Stabilizer; - One or more preservatives may be present; - One or more nonionic surfactants may be present; and - One or more tension modifiers may be present; The buffer is present in the composition at a total concentration of 0-5 mM.

[0082] In one embodiment, an aqueous composition having a pH in the range of 4.0-7.5 is provided, comprising the following substances: - Select a peptide therapy consisting of vasopressin, lysine vasopressin, desmopressin, atosiban, carbetocin, oxytocin, octreotide, caspofungin, anidoxetine, micafungin, and terlipressin; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; - Stabilizer; - One or more preservatives may be present; - One or more nonionic surfactants may be present; and - One or more tension modifiers may be present; The buffer is present in the composition at a total concentration of 0-5 mM.

[0083] In one embodiment, an aqueous composition having a pH in the range of 4.0-7.5 is provided, comprising the following substances: - Select a peptide therapy consisting of vasopressin, lysine vasopressin, desmopressin, atosiban, carbetocin, oxytocin, octreotide, caspofungin, anisofungin, and micafungin; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; - Stabilizer; - One or more preservatives may be present; - One or more nonionic surfactants may be present; and - One or more tension modifiers may be present; The buffer is present in the composition at a total concentration of 0-5 mM, and the stabilizer is an amino acid, such as methionine, arginine, or proline (especially methionine), or a polyol, such as glycerol, mannitol, propylene glycol, or sucrose.

[0084] In one embodiment, an aqueous composition having a pH in the range of 4.0-7.5 is provided, comprising the following substances: - Select a peptide therapy consisting of vasopressin, lysine vasopressin, desmopressin, atosiban, carbetocin, oxytocin, octreotide, caspofungin, anidoxetine, micafungin, and terlipressin; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; - Stabilizer; - One or more preservatives may be present; - One or more nonionic surfactants may be present; and - One or more tension modifiers may be present; The buffer is present in the composition at a total concentration of 0-5 mM, and the stabilizer is an amino acid, such as methionine, arginine, or proline (especially methionine), or a polyol, such as glycerol, mannitol, propylene glycol, or sucrose.

[0085] In one embodiment, an aqueous composition having a pH in the range of 4.0-7.5 is provided, comprising: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; - Stabilizers, which are amino acids selected from methionine, arginine, and proline; and - Non-charged tension modifiers selected from glycerol, 1,2-propanediol, mannitol, sorbitol, trehalose, PEG300 and PEG400; The peptide therapeutic agent described herein does not contain pK a The composition contains ionizable groups in the range of 3.0 to 8.5, and the buffer is present in the composition at a total concentration of 0-5 mM.

[0086] In one embodiment, an aqueous composition having a pH in the range of 4.0-7.5 is provided, comprising the following substances: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; - Stabilizers, which are amino acids selected from methionine, arginine, and proline; and - Non-charged tension modifiers selected from glycerol, 1,2-propanediol, mannitol, sorbitol, trehalose, PEG300 and PEG400; The peptide therapeutic agent described herein does not contain pK a The composition contains ionizable groups in the range of 3.0 to 8.5, and the buffer is present in the composition at a total concentration of 0-5 mM.

[0087] In one embodiment, an aqueous composition having a pH in the range of 4.0-7.5 is provided, comprising: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; - Stabilizer, which is methionine; and - A non-charged tension modifier, namely mannitol; The peptide therapeutic agent described herein does not contain pK a The composition contains ionizable groups in the range of 3.0 to 8.5, and the buffer is present in the composition at a total concentration of 0-5 mM.

[0088] In one embodiment, an aqueous composition having a pH in the range of 4.0-7.5 is provided, comprising the following substances: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; - Stabilizer, which is methionine; and - A non-charged tension modifier, namely mannitol; The peptide therapeutic agent described herein does not contain pK a The composition contains ionizable groups in the range of 3.0 to 8.5, and the buffer is present in the composition at a total concentration of 0-5 mM.

[0089] The claimed invention stems from the unexpected observation that compositions containing peptide therapeutic agents are stable at low buffer concentrations. Such solutions can be further stabilized by adding stabilizers such as amino acids or polyols. The solutions can be further stabilized by adding uncharged tonic agents.

[0090] Suitablely, the composition of the present invention remains a clear solution after being stored at 2-8°C for a long period of time, such as at least 12 months, preferably 18 months, and most preferably at least 24 months.

[0091] Suitablely, the compositions of the present invention remain clear solutions after being stored at 25°C for extended periods, such as at least 6 months, preferably at least 12 months, such as at least 18 months, such as at least 24 months.

[0092] Suitablely, the compositions of the present invention remain clear solutions after being stored at 30°C for extended periods, such as at least 6 months, preferably at least 12 months, such as at least 18 months, such as at least 24 months.

[0093] Suitablely, the compositions of the present invention exhibit improved storage stability at 2-8°C or elevated temperatures compared to equivalent compositions containing higher concentrations of the same one or more buffers.

[0094] Suitablely, the compositions of the present invention exhibit improved storage stability at 2-8°C or elevated temperatures compared to equivalent compositions without stabilizers.

[0095] In one embodiment, after being stored at 2-8°C for at least 12 months, preferably 18 months, and most preferably 24 months, the composition of the present invention contains no more than 5% total impurities, such as no more than 4%, no more than 3%, and no more than 2% total impurities (measured by RP-HPLC or similar suitable techniques based on the total weight of the peptide therapeutic agents in the composition).

[0096] In one embodiment, after being stored at 25°C for at least 6 months, preferably 12 months, such as 18 months or 24 months, the composition of the present invention contains no more than 5% total impurities, such as no more than 4%, no more than 3%, no more than 2% total impurities (measured by RP-HPLC or similar suitable technique based on the total weight of the peptide therapeutic agents in the composition).

[0097] In one embodiment, after being stored at 30°C for at least 6 months, preferably 12 months, such as 18 months or 24 months, the composition of the present invention contains no more than 5% total impurities, such as no more than 4%, no more than 3%, no more than 2% total impurities (measured by RP-HPLC or similar suitable technique based on the total weight of the peptide therapeutic agents in the composition).

[0098] In one embodiment, after being stored at 40°C for at least 2 weeks, preferably 4 weeks, such as 6 weeks, the composition of the present invention contains no more than 5% total impurities, such as no more than 4%, such as no more than 3%, such as no more than 2% total impurities (measured by RP-HPLC or similar suitable technique based on the total weight of the peptide therapeutic agents in the composition).

[0099] In one embodiment, after being stored at 2-8°C for at least 12 months, preferably 18 months, and most preferably 24 months, the composition of the present invention contains lower levels of impurities (measured by RP-HPLC or similar suitable techniques) than commercially available compositions containing the same pharmaceutical ingredient (measured by RP-HPLC or similar suitable techniques).

[0100] In one embodiment, after being stored at 25°C for at least 6 months, preferably 12 months, such as 18 months or 24 months, the impurity levels (measured by RP-HPLC or similar suitable techniques) of the compositions of the present invention are lower than those of commercially available compositions containing the same pharmaceutical ingredient (measured by RP-HPLC or similar suitable techniques).

[0101] In one embodiment, after being stored at 30°C for at least 6 months, preferably 12 months, such as 18 months or 24 months, the impurity levels (measured by RP-HPLC or similar suitable techniques) of the compositions of the present invention are lower than those (measured by RP-HPLC or similar suitable techniques) of commercially available compositions containing the same pharmaceutical ingredients.

[0102] In a further aspect of the invention, a method is provided for improving the stability of an aqueous composition comprising a peptide therapeutic agent in the pH range of 4.0 to 7.5, the method comprising adding a stabilizer to the composition and maintaining a low buffer concentration, wherein the peptide therapeutic agent is pK-free. a The composition contains ionizable groups in the range of 3.0 to 8.5, and the buffer is present in the composition at a concentration of 0-5 mM.

[0103] In a further aspect of the invention, a stabilizer is provided to improve the stability of an aqueous composition comprising a peptide therapeutic agent in the pH range of 4.0 to 7.5, wherein the peptide therapeutic agent is free of pK. a The ionizable group is in the range of 3.0 to 8.5, and wherein the one or more buffers are substances having at least one ionizable group, the pK of the ionizable group is... a Within the range of 3.0 to 8.5, and the pK a The one or more buffers are present in the composition at a total concentration of 0-5 mM within 2 pH units of the pH of the composition.

[0104] In a further aspect of the invention, it is provided to improve the stability of aqueous compositions containing a peptide therapeutic agent in a pH range of 4.0 to 7.5 using a minimum amount of buffer, wherein the peptide therapeutic agent is pK-free. aThe composition comprises an ionizable group in the range of 3.0 to 8.5, wherein the composition includes a stabilizer, and wherein the one or more buffers are substances having at least one ionizable group, the pK of which is... a Within the range of 3.0 to 8.5, and the pK a The one or more buffers are present in the composition at a total concentration of 0-5 mM within 2 pH units of the pH of the composition.

[0105] In one embodiment, the composition of the present invention is a therapeutic composition. In another embodiment, the composition of the present invention is a pharmaceutical composition.

[0106] One embodiment provides an aqueous composition for treatment with a pH in the range of 4.0-7.5, comprising: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; and - Stabilizer; The peptide therapeutic agent described herein does not contain pK a The composition contains ionizable groups in the range of 3.0 to 8.5, and the buffer is present in the composition at a total concentration of 0-5 mM.

[0107] One embodiment provides an aqueous composition with a pH in the range of 4.0-7.5, which is a pharmaceutical composition comprising: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; and - Stabilizer; The peptide therapeutic agent described herein does not contain pK a The ionizable groups are in the range of 3.0 to 8.5, wherein the buffer is present in the composition at a total concentration of 0-5 mM.

[0108] All embodiments described above regarding the aqueous solution composition are equally applicable to the methods and uses of the present invention.

[0109] A container, made of, for example, plastic or glass, is also provided for containing one or more doses of the composition as described herein. The container may be, for example, a vial, a pre-filled syringe, a pre-filled infusion bag, or a cartridge designed as a replaceable part for use with an injection device.

[0110] The compositions of the present invention can be suitably packaged for injection, particularly intravenous infusion, intravenous injection, subcutaneous injection or intramuscular injection.

[0111] One aspect of the invention is an injection device for single or multiple uses, particularly suitable for subcutaneous or intramuscular injection, comprising a container holding one or more doses of the composition of the invention along with an injection needle. In one embodiment, the container is a replaceable cartridge holding multiple doses. In one embodiment, the needle is replaceable, for example, after each use. In one embodiment, the injection device is in pen form.

[0112] As described herein, the compositions according to the present invention are expected to have good physical and chemical stability.

[0113] In addition, this application also provides the following implementation schemes.

[0114] 1. An aqueous composition having a pH in the range of 4.0-7.5, comprising: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; and - Stabilizer; The peptide therapeutic agent described herein does not contain pK a The composition contains ionizable groups in the range of 3.0 to 8.5, and the buffer is present in the composition at a total concentration of 0-5 mM.

[0115] 2. The aqueous composition with a pH range of 4.0-7.5 according to embodiment 1, comprising: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; - A stabilizer, wherein the stabilizer is an amino acid selected from methionine, arginine, and proline; and - A non-charged tension modifier, wherein the non-charged tension modifier is selected from glycerol, 1,2-propanediol, mannitol, sorbitol, trehalose, PEG300 and PEG400; The peptide therapeutic agent described herein does not contain pK a The composition contains ionizable groups in the range of 3.0 to 8.5, and the buffer is present in the composition at a total concentration of 0-5 mM.

[0116] 3. The aqueous composition according to embodiment 1 or embodiment 2, wherein the peptide therapeutic agent is free of any free aspartic acid, free glutamic acid, histidine or free cysteine ​​side chain.

[0117] 4. An aqueous composition according to any one of embodiments 1 to 3, wherein the peptide therapeutic agent does not have a free N-terminal amine group or a free C-terminal carboxylic acid group.

[0118] 5. The aqueous composition according to embodiment 1 or embodiment 2, wherein the peptide therapeutic agent is vasopressin or an analogue, such as lysine vasopressin or desmopressin, or atosiban, carbetocin, oxytocin, octreotide, caspofungin, anisofungin or micafungin.

[0119] 6. The aqueous composition according to embodiment 1 or embodiment 2, wherein the peptide therapeutic agent is terlipressin.

[0120] 7. An aqueous composition according to any one of embodiments 1 to 6, wherein the concentration of the peptide therapeutic agent in the composition is 0.001-50 mg / ml, such as 0.01-10 mg / ml or 0.1-5 mg / ml.

[0121] 8. The aqueous composition according to any one of embodiments 1 to 7, wherein the buffer comprises pK a An ionizable group within one unit of the pH of the composition.

[0122] 9. An aqueous composition according to any one of embodiments 1 to 8, wherein the total concentration of the buffer in the composition is 0.1-5 mM, such as 0.1-4 mM, 0.1-3 mM, 0.1-2 mM or 0.1-1 mM.

[0123] 10. An aqueous composition according to any one of embodiments 1 to 9, wherein the aqueous composition is substantially free of buffers.

[0124] 11. An aqueous composition according to any one of embodiments 1 to 9, wherein the one or more buffers are selected from the group consisting of: histidine, maleate, sulfite, glyoxylate, aspartame, glucuronide, aspartate, glutamate, tartrate, glucuronide, lactate, glycolic acid, adenine, succinate, ascorbate, benzoate, phenylacetate, gallate, cytosine, right Aminobenzoic acid, sorbate, acetate, propionate, alginate, urate, 2-( N -morpholino)ethanesulfonic acid, bicarbonate, bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane, N -(2-acetamido)-2-iminodiacetic acid, 2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid, piperazine, N , N '-Bis(2-ethanesulfonic acid), phosphate, N , N -bis(2-hydroxyethyl)-2-aminoethanesulfonic acid, 3-[ N , N [-bis(2-hydroxyethyl)amino]-2-hydroxypropanesulfonic acid, triethanolamine, piperazine- N , N '-bis(2-hydroxypropanesulfonic acid), tris(hydroxymethyl)aminomethane, N -Tris(hydroxymethyl)glycine and N - Tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid and its salts, as well as combinations thereof.

[0125] 12. The aqueous composition according to embodiment 11, wherein the buffer is selected from the group consisting of histidine, maleate, tartrate, lactate, benzoate, acetate, bicarbonate, phosphate and tris(hydroxymethyl)aminomethane.

[0126] 13. An aqueous composition according to embodiment 1 or according to any one of embodiments 3 to 12, wherein the stabilizer is an amino acid or a polyol.

[0127] 14. The aqueous composition according to embodiment 13, wherein the stabilizer is an amino acid selected from methionine, arginine, glycine and proline, particularly methionine.

[0128] 15. The aqueous composition according to embodiment 14, wherein the stabilizer is an amino acid selected from methionine, arginine and proline.

[0129] 16. The aqueous composition according to embodiment 13, wherein the stabilizer is a polyol selected from the group consisting of glycerol, mannitol, propylene glycol, PEG 300, PEG 400, sucrose, trehalose and lactose, particularly glycerol, mannitol, propylene glycol and sucrose.

[0130] 17. The aqueous composition according to embodiment 14, wherein the stabilizer is present at a concentration of 1-200 mM, such as 10-100 mM or 10-50 mM.

[0131] 18. The aqueous composition according to embodiment 16, wherein the stabilizer is present at a concentration of 1-1000 mM, such as 10-500 mM or 100-500 mM.

[0132] 19. An aqueous composition according to any one of embodiments 1 to 18, wherein the pH is between 4.0 and 7.0, such as between 4.0 and 6.0.

[0133] 20. The aqueous composition according to any one of embodiments 1 to 19, further comprising a tension modifier.

[0134] 21. The aqueous composition according to embodiment 20, wherein the tension modifier is a non-charged tension modifier and is suitably selected from glycerol, 1,2-propanediol, mannitol, sorbitol, trehalose, PEG300 and PEG400.

[0135] 22. The aqueous composition according to embodiment 21, wherein the tension modifier is a non-charged tension modifier and is selected from mannitol and sorbitol.

[0136] 23. The aqueous composition according to embodiment 21 or embodiment 22, wherein the concentration of the uncharged tension modifier is 50-1000 mM, such as 200-500 mM or about 300 mM.

[0137] 24. The aqueous composition according to embodiment 20, wherein the tension modifier is a charged tension modifier and is suitably selected from sodium chloride, sodium sulfate and amino acids, such as glycine or arginine.

[0138] 25. The aqueous composition according to embodiment 24, wherein the concentration of the charged tension modifier is 25-500 mM, such as 50-250 mM or about 150 mM.

[0139] 26. The aqueous composition according to any one of embodiments 1 to 25, further comprising a nonionic surfactant.

[0140] 27. The aqueous composition according to embodiment 26, wherein the nonionic surfactant is selected from the group consisting of alkyl glycosides, polysorbates, alkyl ethers of polyethylene glycol, block copolymers of polyethylene glycol and polypropylene glycol, and alkyl phenyl ethers of polyethylene glycol.

[0141] 28. The aqueous composition according to embodiment 27, wherein the nonionic surfactant is a polysorbate, such as polysorbate 20 or polysorbate 80.

[0142] 29. The aqueous composition according to any one of embodiments 26 to 28, wherein the nonionic surfactant is present at a concentration of 10-2000 µg / ml, such as 50-1000 µg / ml, 100-500 µg / ml, or about 200 µg / ml.

[0143] 30. The aqueous composition according to any one of embodiments 1 to 29, further comprising a preservative, such as a phenolic or benzyl preservative.

[0144] 31. The aqueous composition according to embodiment 30, wherein the phenolic or benzyl preservative is selected from the group consisting of: phenol, m-cresol, chlorocresol, benzyl alcohol, propylparaben, and methylparaben.

[0145] 32. The aqueous composition according to embodiment 30 or embodiment 31, wherein the preservative is present at a concentration of 10-100 mM, such as 20-80 mM or 25-50 mM.

[0146] 33. The aqueous composition according to any one of embodiments 1 to 32, which is a composition for treatment.

[0147] 34. The aqueous composition according to any one of embodiments 1 to 32 is a pharmaceutical composition.

[0148] Example

[0149] General methods

[0150] Reversed-phase chromatography (RP-HPLC)

[0151] Using Waters ACQUITY H class Bio UPLC ®The system was subjected to high-performance reversed-phase chromatography (HPLC) using a 1.7 μm ethylene-bridged hybrid particle, 130 Å pore resin, and a C18 ligand trifunctional fixation column in a 50 mm × 15 2.1 mm column. Mobile phase A was 0.1 M Na3PO4 adjusted to pH 3.0 with trifluoroacetic acid. Mobile phase B was prepared by mixing 2 parts (v / v) acetonitrile with 1 part (v / v) mobile phase A. The sample containing the formulated peptide was bound to mobile phase A and eluted using a gradient of mobile phases A and B. The sample volume was 10 μl, the flow rate was 0.4 mL / min, and detection was performed using 214 nm UV. All analyses were performed at 60 °C.

[0152] Example 1: Desmopressin

[0153] After storage at 40°C, the effect of acetate buffer concentration on the impurity formation rate in the desmopressin compositions was investigated using RP-HPLC as described in the general methods. This effect was studied in the presence of mannitol (300 mM). Increasing the buffer concentration showed that it impaired stability (Comparative compositions 1-6). It was also shown that using 1 mM acetate and adding methionine (5 mM) improved stability (Comparative compositions 2 and 7), while removing mannitol resulted in impaired stability (Comparative compositions 2 and 8). Replacing mannitol with sorbitol did not appear to affect stability (Comparative compositions 2 and 9). The best results were obtained by combining mannitol and methionine at a 1 mM buffer concentration.

[0154] Table 1. The levels of impurities in the desmopressin compositions increased after storage at 40°C for 4 and 6 weeks.

[0155]

[0156] Example 2: Atosiban

[0157] After storage at 40°C, the effect of acetate buffer concentration on the impurity formation rate in the atosiban compositions was investigated using RP-HPLC as described in the general methods. This effect was studied in the presence of mannitol (300 mM). Increasing the buffer concentration showed that stability was impaired (Comparative compositions 1-5). Further improvements in stability were also shown with the use of 1 mM acetate, the addition of proline (5 mM, Comparative compositions 2 and 6), or arginine (5 mM, Comparative compositions 2 and 7), while removal of mannitol resulted in impaired stability (Comparative compositions 2 and 8).

[0158] Table 2. After storage at 40°C for 4 weeks, the impurity levels in the desmopressin composition increased.

[0159]

[0160] Example 3: Oxytocin

[0161] After storage at 25°C, the effects of methionine, proline, mannitol, and sorbitol on the stability of oxytocin in the presence of 1 mM acetate buffer (pH 4.5) were investigated using RP-HPLC as described in the general method. The presence of all these excipients showed that the rate of impurity formation was reduced. Optimal results were obtained by combining mannitol and methionine.

[0162] Table 3. After storage at 25°C for 4 weeks, the level of impurities in the oxytocin composition increased.

[0163]

[0164] Example 4: Caspofungin

[0165] After storage at 25°C, the effect of acetate buffer concentration on the impurity formation rate in the caspofungin compositions was investigated using RP-HPLC as described in the general methods. This effect was also investigated in the presence of mannitol (300 mM). Increasing the buffer concentration showed impaired stability (Comparative compositions 1-4). Removal of mannitol also showed impaired stability. Using 1 mM acetate and removing mannitol also showed impaired stability (Comparative compositions 1-5), while replacing mannitol with sorbitol appeared to have no significant effect on the stability of caspofungin (Comparative compositions 1 and 6).

[0166] Table 4. After oxytocin was stored at 25°C for 4 weeks, the total impurities in oxytocin increased.

[0167]

Claims

1. An aqueous solution composition with a pH in the range of 4.0-7.5, comprising: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; and - Stabilizer; The peptide therapeutic agent described herein does not contain pK a The composition contains ionizable groups in the range of 3.0 to 8.5, and the buffer is present in the composition at a total concentration of 0-5 mM.

2. The aqueous solution composition with a pH range of 4.0-7.5 according to claim 1, comprising: - Peptide therapeutic agents; - Optionally, one or more buffers may be present, said buffer being a substance having at least one ionizable group, said ionizable group having a pK a Within the range of 3.0 to 8.5, and the pK a Within 2 pH units of the pH of the composition; - A stabilizer, wherein the stabilizer is an amino acid selected from methionine, arginine, and proline; and - A non-charged tension modifier, wherein the non-charged tension modifier is selected from glycerol, 1,2-propanediol, mannitol, sorbitol, trehalose, PEG300 and PEG400; The peptide therapeutic agent described herein does not contain pK a The composition contains ionizable groups in the range of 3.0 to 8.5, and the buffer is present in the composition at a total concentration of 0-5 mM.

3. The aqueous composition according to claim 1 or claim 2, wherein the peptide therapeutic agent is free of any free aspartic acid, free glutamic acid, histidine, or free cysteine ​​side chains; and / or The peptide therapeutic agent described herein does not have a free N-terminal amine group or a free C-terminal carboxylic acid group, for example The peptide therapeutic agent is vasopressin or an analogue, such as lysine vasopressin or desmopressin, or atosiban, carbetocin, oxytocin, octreotide, caspofungin, anisofungin, or micafungin, particularly terlipressin; and / or The concentration of the peptide therapeutic agent in the composition is 0.001-50 mg / ml, such as 0.01-10 mg / ml or 0.1-5 mg / ml.

4. The aqueous solution composition according to claim 1 or 2, wherein the buffer comprises pK a An ionizable group within one unit of the pH of the composition; and / or The total concentration of the buffer in the composition is 0.1-5 mM, such as 0.1-4 mM, 0.1-3 mM, 0.1-2 mM, or 0.1-1 mM; or the aqueous composition is substantially free of buffer; and / or The one or more buffers mentioned herein are selected from the group consisting of: histidine, maleate, sulfite, glyoxylate, aspartame, glucuronide, aspartate, glutamate, tartrate, glucuronide, lactate, glycolic acid, adenine, succinate, ascorbate, benzoate, phenylacetate, gallate, cytosine, right Aminobenzoic acid, sorbate, acetate, propionate, alginate, urate, 2-( N -morpholino)ethanesulfonic acid, bicarbonate, bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane, N -(2-acetamido)-2-iminodiacetic acid, 2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid, piperazine, N , N '-Bis(2-ethanesulfonic acid), phosphate, N , N -bis(2-hydroxyethyl)-2-aminoethanesulfonic acid, 3-[ N , N [-bis(2-hydroxyethyl)amino]-2-hydroxypropanesulfonic acid, triethanolamine, piperazine- N , N '-bis(2-hydroxypropanesulfonic acid), tris(hydroxymethyl)aminomethane, N -Tris(hydroxymethyl)glycine and N -Tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid and its salts, and combinations thereof, particularly wherein the buffer is selected from the group consisting of histidine, maleate, tartrate, lactate, benzoate, acetate, bicarbonate, phosphate and tris(hydroxymethyl)aminomethane.

5. The aqueous composition according to claim 1, wherein the stabilizer is an amino acid or a polyol, for example, wherein the stabilizer is an amino acid selected from methionine, arginine, glycine and proline, particularly an amino acid selected from methionine, arginine and proline, especially methionine, for example, wherein the stabilizer is present at a concentration of 1-200 mM, such as 10-100 mM or 10-50 mM; or The stabilizer is a polyol selected from the group consisting of glycerol, mannitol, propylene glycol, PEG 300, PEG 400, sucrose, trehalose and lactose, especially glycerol, mannitol, propylene glycol and sucrose, for example, the stabilizer is present at a concentration of 1-1000 mM, such as 10-500 mM or 100-500 mM.

6. The aqueous composition according to claim 1 or 2, wherein the pH is between 4.0 and 7.0, such as between 4.0 and 6.

0.

7. The aqueous composition according to claim 1 or 2, further comprising a tension modifier, particularly wherein the tension modifier is a non-charged tension modifier and suitably selected from glycerol, 1,2-propanediol, mannitol, sorbitol, trehalose, PEG300 and PEG400, for example wherein the tension modifier is a non-charged tension modifier and selected from mannitol and sorbitol, for example wherein the concentration of the non-charged tension modifier is 50-1000 mM, such as 200-500 mM or about 300 mM; or The tension modifier is a charged tension modifier and is suitably selected from sodium chloride, sodium sulfate and amino acids, such as glycine or arginine, for example, the concentration of the charged tension modifier is 25-500 mM, such as 50-250 mM or about 150 mM.

8. The aqueous composition according to claim 1 or 2, further comprising a nonionic surfactant, for example, said nonionic surfactant being selected from the group consisting of: alkyl glycosides, polysorbates, alkyl ethers of polyethylene glycol, block copolymers of polyethylene glycol and polypropylene glycol, and alkyl phenyl ethers of polyethylene glycol, particularly said nonionic surfactant being a polysorbate, such as polysorbate 20 or polysorbate 80, for example, said nonionic surfactant being present at a concentration of 10-2000 µg / ml, such as 50-1000 µg / ml, 100-500 µg / ml, or about 200 µg / ml; and / or It also contains preservatives, such as phenolic or benzyl preservatives, for example, said phenolic or benzyl preservatives selected from the group consisting of: phenol, m-cresol, chlorocresol, benzyl alcohol, propylparaben and methylparaben, for example, said preservatives are present at a concentration of 10-100 mM, such as 20-80 mM or 25-50 mM.

9. The aqueous composition according to claim 1 or 2, which is a composition for therapeutic purposes.

10. The aqueous composition according to claim 1 or 2, wherein it is a pharmaceutical composition.

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