Method of administration of adrenomedullin

Abstract

The present application provides a method of administration that maximizes the therapeutic effect of adrenomedullin, and a drug containing adrenomedullin provided by the method of administration. The above problem is solved by providing a drug for treating a disease, which contains adrenomedullin or a derivative thereof having adrenomedullin activity, etc. as an effective ingredient, characterized in that the disease is a disease for which a therapeutic effect is expected to be obtained by administration of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and the effective ingredient is administered intermittently.

Description

Technical Field

[0001] This invention relates to a method of administering adrenomedullin. The invention also relates to a medicament comprising adrenomedullin delivered by intermittent administration. Background Technology

[0002] Adrenomedullin (AM) is a physiologically active peptide isolated and identified from chromaffin cell tissue in 1993. Initially, it was determined that AM exerted a potent vasodilatory and hypotensive effect. Furthermore, subsequent studies have clarified that AM exerts multiple pharmacological effects, including anti-inflammatory, angiogenic, cardiovascular protective, and tissue repair-promoting effects.

[0003] Because AM exerts the pharmacological effects described above, it is expected to be useful as a treatment for cerebrovascular diseases, dementia, inflammatory bowel disease, autoimmune diseases, infectious diseases, pulmonary hypertension, peripheral vascular disease, heart disease, etc.

[0004] For example, Non-Patent Literature 1 describes the implementation plan of a physician-led clinical trial, AMFIS, for studying the safety and efficacy of AM in the treatment of ischemic stroke.

[0005] Existing technical documents

[0006] Non-patent literature

[0007] Non-patent literature 1: Yoshimoto et al., Journal of Stroke and Cerebrovascular Diseases, vol. 30 (6), 105761, 2021 Summary of the Invention

[0008] The problem that the invention aims to solve

[0009] However, to date, the dosing method for maximizing the therapeutic effect of AM is unknown.

[0010] Therefore, the object of the present invention is to provide a method of administration that maximizes the therapeutic effect of AM, and to provide a medicament comprising AM administered by the method of administration.

[0011] Methods for solving problems

[0012] In order to solve the above-mentioned problems, the inventors conducted in-depth research and unexpectedly discovered for the first time that intermittent administration of AM had a high therapeutic effect in the AMFIS clinical trial, a physician-led clinical trial in which AM was administered to patients with acute cerebral infarction. Based on this insight, the present invention was completed.

[0013] That is, one aspect of the present invention relates to the following.

[0014] [1] A drug for treating a disease, comprising adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient.

[0015] The disease is characterized in that it is a disease for which a therapeutic effect is expected to be achieved through administration of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof.

[0016] The active ingredient is administered intermittently.

[0017] [2] The drug as described in [1], wherein the adrenomedullin or its derivative having adrenomedullin activity is a peptide selected from the group consisting of:

[0018] (i) A peptide composed of the amino acid sequence of adrenaline medullaris,

[0019] (ii) A peptide consisting of the amino acid sequence of adrenomedullin, wherein two cysteine ​​residues in the amino acid sequence form a disulfide bond.

[0020] (iii) In the peptide of (ii), the disulfide bond is replaced by an ethylene group, and the peptide has adrenomedullin activity.

[0021] (iv) A peptide in any one of (i) to (iii) in which 1 to 15 amino acid residues are deleted, substituted, or added, and which has adrenomedullin activity.

[0022] (v) Of any of the peptides in (i) to (iv), the C-terminus of which is amidated, and

[0023] (vi) Of any of the peptides in (i) to (iv), a peptide with a glycine residue added to the C-terminus.

[0024] [3] The drug as described in [1] or [2], wherein the adrenomedullin or its derivative having adrenomedullin activity is a peptide selected from the group consisting of:

[0025] (a) A peptide consisting of the amino acid sequence of sequence number 1, or a peptide consisting of the amino acid sequence of sequence number 1, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0026] (b) A peptide consisting of the amino acid sequence of sequence number 4, or a peptide consisting of the amino acid sequence of sequence number 4, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0027] (c) A peptide consisting of the amino acid sequence of sequence number 6, or a peptide consisting of the amino acid sequence of sequence number 6, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0028] (d) A peptide consisting of the amino acid sequence number 8, or a peptide consisting of the amino acid sequence number 8, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0029] (e) A peptide consisting of the amino acid sequence of sequence number 10, or a peptide consisting of the amino acid sequence of sequence number 10, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond.

[0030] (f) A peptide consisting of the amino acid sequence of sequence number 12, or a peptide consisting of the amino acid sequence of sequence number 12, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond.

[0031] (g) In any one of (a) to (f) a peptide in which the disulfide bond is replaced by an ethylene and has adrenomedullin activity;

[0032] (h) A peptide in any one of (a) to (g) in which 1 to 15 amino acid residues are deleted, substituted or added and which has adrenomedullin activity;

[0033] (i) Of any of the peptides in (a) to (h), the C-terminus is amidated; and

[0034] (j) A peptide in any of (a) to (h) that has a glycine residue added to its C-terminus.

[0035] [4] The drug as described in any one of [1] to [3], wherein the disease is a disease for which therapeutic effects are expected to be achieved through the anti-inflammatory, angiogenic, cardiovascular protective and / or tissue repair promoting effects of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof.

[0036] [5] The drug as described in any one of [1] to [4], wherein the disease is selected from at least one of the group consisting of cerebrovascular disease, dementia, inflammatory bowel disease, autoimmune disease, infectious disease, pulmonary hypertension, peripheral vascular disease and heart disease.

[0037] [6] The drug as described in any one of [1] to [5], wherein the intermittent administration is administration within 23 hours every day.

[0038] [7] The drug as described in any one of [1] to [6], wherein the intermittent administration is administration within 23 hours every day for 3 to 30 days.

[0039] [8] A method of treating a disease, comprising the step of administering to a subject a therapeutically effective amount of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

[0040] The disease is characterized in that it is a disease for which a therapeutic effect is expected to be achieved through administration of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof.

[0041] The administration is intermittent.

[0042] [9] An adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the treatment of a disease,

[0043] The disease is characterized in that it is a disease for which a therapeutic effect is expected to be achieved through administration of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof.

[0044] It was administered intermittently.

[0045]

[10] The use of an adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in the manufacture of a medicament for treating a disease.

[0046] The disease is characterized in that it is a disease for which a therapeutic effect is expected to be achieved through administration of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof.

[0047] The therapeutic drug is administered intermittently.

[0048] [Invention Effects]

[0049] According to the present invention, since an optimized method of administration of AM is provided, the therapeutic effect of AM can be maximized. Furthermore, by reducing the total dosage of AM, side effects can be reduced. Moreover, according to the present invention, since the therapeutic effect is achieved through intermittent administration, hospitalization is not always necessary, and outpatient treatment becomes possible. Therefore, administration of AM is possible not only in clinics or other facilities without inpatient facilities, but also at home or in nursing facilities. Detailed Implementation

[0050] The following is a detailed description of one embodiment of the present invention, but the present invention is not limited to these embodiments.

[0051] (Summary of the Invention)

[0052] As mentioned above, AM is a substance that exerts a variety of pharmacological effects, including anti-inflammatory, angiogenic, cardiovascular protective, and tissue repair promoting effects. Because of these pharmacological effects, AM is expected to be useful as a treatment for cerebrovascular diseases, dementia, inflammatory bowel disease, autoimmune diseases, infectious diseases, pulmonary hypertension, peripheral vascular disease, and heart disease.

[0053] However, due to the relatively short half-life of AM in the body (22 minutes), continuous administration of sufficient amounts of AM over a long period was once considered the optimal method of administration to achieve therapeutic effects. However, to date, no detailed studies have been conducted on administration methods that maximize the therapeutic effect of AM.

[0054] The inventors conducted in-depth research on the aforementioned issues, and as a result, in the physician-led AMFIS clinical trial, which administered AM to patients with acute ischemic stroke, they discovered that high therapeutic efficacy was achieved through intermittent dosing. More specifically, it was completely unexpected and serendipitous to discover that by administering AM intermittently for 7 days at a frequency of 8 hours / day immediately after the onset of ischemic stroke, excellent improvement in motor function was achieved. This result is a surprising outcome that could not have been predicted under previous understanding, given the short half-life of AM and the need for long-term continuous dosing to achieve its effects.

[0055] According to the present invention, a superior administration method compared to conventional methods is provided in achieving the effects of adrenaline. Furthermore, according to the present invention, since therapeutic effects are obtained through intermittent administration, hospitalization is not always necessary, making outpatient treatment possible. Therefore, the present invention holds great promise for the treatment of various diseases in which therapeutic effects are expected to be achieved through administration of adrenaline or its derivatives having adrenaline activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof (hereinafter sometimes referred to as "AM, etc.").

[0056] (definition)

[0057] In this instruction manual, "intermittent administration" means administering the therapeutic drug continuously intravenously for a specified period of time, and not administering the therapeutic drug at other times. Typically, intermittent administration is performed by setting the duration of continuous intravenous administration of the therapeutic drug at any given time and the rest of the time as a rest period, and this process is repeated.

[0058] In this specification, "treatment" means achieving the desired pharmacological and / or physiological effect. This effect can be preventative from the viewpoint of completely or partially preventing the disease or its symptoms, and can also be therapeutic from the viewpoint of partially or completely curing the disease and / or its side effects. That is, in this specification, "prevention" is also included in the concept of "treatment."

[0059] "Treatment" refers to any treatment of diseases in mammals, particularly humans, including, for example, the following: (a) preventing the onset of disease in individuals with a predisposition to disease but not yet diagnosed with it; (b) suppressing disease, i.e., preventing its occurrence; and (c) alleviating disease (i.e., causing relief from the disease). When "treatment" is the aforementioned therapeutic treatment, for example, in individuals suffering from disease, it can be the suppression (e.g., inhibiting progression), reduction, repair, and / or cure of symptoms that have occurred (or manifested).

[0060] In this instruction manual, "therapeuticly effective amount" means an amount of active ingredient sufficient to effectively treat the disease when administered to the subject. The "therapeuticly effective amount" varies depending on the active ingredient, the disease and its severity, and the age and weight of the subject being treated.

[0061] In this specification, "subject" means a subject or patient who needs to be treated by administration of AM or similar drugs.

[0062] In this manual, "acute cerebral infarction" refers to cerebral infarction that typically occurs within 72 hours of onset, particularly within 24 hours. Based on pathogenesis, cerebral infarction is classified into embolic cerebral infarction and non-embolic (e.g., thrombotic or hemodynamic) cerebral infarction. Additionally, based on clinical patterns, it is classified into lacunar infarction, atherosclerotic thrombotic cerebral infarction, and cardiogenic cerebral embolism, among others.

[0063] (Adrenaline)

[0064] In various embodiments of the present invention, AM can be not only a human-derived peptide isolated and identified from human chromaffin cell tissue (Sequence No. 1), but also a peptide (ortholog) derived from other non-human mammals (e.g., warm-blooded animals) such as pigs (Sequence No. 4), dogs (Sequence No. 6), cattle (Sequence No. 8), rats (Sequence No. 10), or mice (Sequence No. 12). In vivo, these peptides form a disulfide bond with two cysteine ​​residues in their amino acid sequence, and the C-terminus is amidated. In this specification, peptides having disulfide bonds and a C-terminal amide group are sometimes referred to as "natural adrenaline medullaris" or simply "adrenaline medullaris." In various embodiments of the present invention, any of the peptides described can also be used as an active ingredient.

[0065] In this specification, "C-terminal amidation" refers to a post-translational modification of peptides in vivo, specifically, the reaction in which the carboxyl group of the main chain of the C-terminal amino acid residue of a peptide is converted into an amide group. Additionally, in this specification, "formation of a disulfide bond of a cysteine ​​residue" or "disulfide formation of a cysteine ​​residue" refers to a post-translational modification of peptides in vivo, specifically, the reaction in which two cysteine ​​residues in the amino acid sequence of a peptide form a disulfide bond (-SS-). Many bioactive peptides produced in vivo are initially biosynthesized as larger precursor proteins. During intracellular transfer, these precursor proteins undergo post-translational modifications such as C-terminal amidation and / or disulfide formation of cysteine ​​residues to become mature bioactive peptides. C-terminal amidation is typically carried out by C-terminal amidases acting on the precursor protein. In the case of bioactive peptides with a C-terminal amide group, in their precursor protein, a Gly residue is bound to the amidated C-terminal carboxyl group, which is then converted into a C-terminal amide group by a C-terminal amidase. Furthermore, the C-terminal propeptide of the precursor protein contains repetitive sequences of basic amino acid residue combinations such as Lys-Arg or Arg-Arg (Mizuno, Biochemistry, Vol. 61, No. 12, pp. 1435-1461 (1989)). Cysteine ​​disulfide can occur under oxidizing conditions. In vivo, cysteine ​​disulfide is usually carried out by protein disulfide isomerases acting on the precursor protein.

[0066] (Adrenal medullary derivative)

[0067] In various embodiments of the present invention, not only natural AM itself, but also its derivatives having adrenomedullin activity can be used as active ingredients. In various embodiments of the present invention, "adrenomedullin derivative" or "adrenomedullin derivative" means a compound having a peptide chain corresponding to AM in a portion of its structure. The term "AM derivative having adrenomedullin activity" is not limited, but examples include compounds disclosed in International Publications No. 2015 / 141819, No. 2017 / 047788, and No. 2018 / 181638. Those skilled in the art can prepare the compound based on the aforementioned documents by purchasing AM derivatives having adrenomedullin activity, applying appropriate conversion reactions to the purchased compound, or by self-preparation. The AM derivatives disclosed in the aforementioned documents can exert the pharmacological effects of adrenomedullin sustainably without substantially producing undesirable side effects. Therefore, in various embodiments of the present invention, by using the AM derivative disclosed in the aforementioned documents as an active ingredient, it is possible to substantially avoid the occurrence of undesirable side effects, while simultaneously treating diseases for which therapeutic effects are expected to be achieved through administration of AM or the like via the adrenal medulla activity of the AM derivative.

[0068] In various embodiments of the present invention, "adrenal medullary activity" means, for example, the various physiological effects exemplified below, and in particular, physiological effects that can participate in the treatment of symptoms of cerebral infarction, such as the control of inflammation in cerebral infarction through the anti-inflammatory effect of AM, the mitigation of tissue damage caused by acute ischemia through the vasodilatory effect of AM, and the induction of angiogenesis through the angiogenesis effect of AM.

[0069] (1) Cardiovascular system: vasodilatory effect, blood pressure lowering effect, blood pressure rise inhibition effect, increase cardiac output and improve heart failure, improve pulmonary hypertension, angiogenesis effect, lymphangiogenesis effect, improve vascular endothelial function, anti-atherosclerotic effect, cardioprotective effect (e.g., cardioprotective effect in ischemia-reperfusion injury or inflammation), inhibition of remodeling after myocardial infarction, inhibition of cardiac hypertrophy, and inhibition of angiotensin-converting enzyme.

[0070] (2) Kidney-water and electrolyte system: diuretic effect, sodium diuretic effect, antidiuretic hormone inhibition, aldosterone-lowering effect, renal protection (e.g., myocardial protection in hypertension or ischemia-reperfusion injury), water drinking behavior inhibition, and salt demand inhibition.

[0071] (3) Brain and nervous system: neuroprotective and brain injury inhibitory effects, anti-inflammatory effects (e.g., the effect of controlling inflammation in cerebral infarction), vasodilatory effects (e.g., the effect of alleviating tissue damage caused by acute ischemia), angiogenesis effects (e.g., the effect of inducing angiogenesis), apoptosis inhibition effects (e.g., the effect of inhibiting apoptosis in ischemia-reperfusion injury or inflammation), autoregulation maintenance effects, oxidative stress inhibition effects, dementia improvement effects, and sympathetic nerve inhibition effects.

[0072] (4) Urogenital organs: improves erection, improves blood flow, and promotes implantation.

[0073] (5) Digestive system: anti-ulcer effect, tissue repair effect, mucosal regeneration effect, blood flow improvement effect, anti-inflammatory effect, and liver function improvement effect.

[0074] (6) Plastic surgery system: osteoblast stimulation and arthritis improvement.

[0075] (7) Endocrine and metabolic system: adipocyte differentiation, lipolysis control, insulin sensitivity improvement, insulin secretion control, antidiuretic hormone secretion inhibition, and aldosterone secretion inhibition.

[0076] (8) Other effects: circulation improvement, anti-inflammatory effect, cytokine control effect, organ protection effect, oxidative stress inhibition effect, tissue repair effect (e.g., anti-bedsore effect), improvement effect of septic shock, inhibition effect of multiple organ failure, inhibition effect of autoimmune diseases, antibacterial effect, hair growth effect, and hair nourishment effect.

[0077] The adrenomedullin or its derivatives having adrenomedullin activity are preferably peptides selected from the group consisting of:

[0078] (i) A peptide composed of the amino acid sequence of adrenaline medullaris,

[0079] (ii) A peptide consisting of the amino acid sequence of adrenomedullin, wherein two cysteine ​​residues in the amino acid sequence form a disulfide bond.

[0080] (iii) In the peptide of (ii), the disulfide bond is replaced by an ethylene group, and the peptide has adrenomedullin activity.

[0081] (iv) A peptide in any one of (i) to (iii) in which 1 to 15 amino acids are missing, substituted, or added, and which has adrenomedullin activity.

[0082] (v) Of any of the peptides in (i) to (iv), the C-terminus of which is amidated, and

[0083] (vi) Of any of the peptides in (i) to (iv), a peptide with a glycine residue added to the C-terminus.

[0084] In one embodiment of the invention, the adrenomedullin or its derivative having adrenomedullin activity is more preferably a peptide selected from the group consisting of:

[0085] (i) A peptide composed of the amino acid sequence of adrenaline medullaris,

[0086] (ii) A peptide consisting of the amino acid sequence of adrenomedullin, wherein two cysteine ​​residues in the amino acid sequence form a disulfide bond.

[0087] (v) In either (i) or (ii) the peptide whose C-terminus is amidated, and

[0088] (vi) In the peptides of (i) or (ii), a peptide with a glycine residue added to the C-terminus.

[0089] Of the peptides (i) to (vi), the peptide contained in (v) that consists of the amino acid sequence of adrenomedullin, has its C-terminus amidated, and has two cysteine ​​residues in that amino acid sequence forming a disulfide bond corresponds to mature, native adrenomedullin. The peptide of (i) consisting of the amino acid sequence of adrenomedullin corresponds to the native adrenomedullin in its immature form before receiving post-translational modifications such as C-terminal amidation and disulfide formation of cysteine ​​residues. Of the peptides (i) to (vi), the other peptides besides those described above correspond to derivatives (modified forms) of adrenomedullin.

[0090] The peptide of (ii) can be formed by converting the thiol groups of the two cysteine ​​residues of the peptide of (i) into disulfide bonds through air oxidation or oxidation with a suitable oxidizing agent. By using the peptide of (ii), the spatial structure of the peptide can be made similar to that of natural adrenomedullin. Thus, the adrenomedullin activity of the peptide of (ii) can be substantially equivalent to that of natural adrenomedullin.

[0091] The peptide in (iii) can be formed by replacing the disulfide bond of the peptide in (ii) with an ethylidene. Substitution from the disulfide bond to the ethylidene can be carried out by methods known in the art (O. Keller et al., Helv. Chim. Acta, 1974, Vol. 57, p. 1253). By using the peptide in (iii), the spatial structure of the peptide can be stabilized. Thus, the peptide in (iii) can sustainably exert adrenomedullin activity in vivo.

[0092] In the peptide of (iv), the number of amino acid residues that are deleted, substituted, or added is preferably in the range of 1 to 15, more preferably in the range of 1 to 10, further preferably in the range of 1 to 8, particularly preferably in the range of 1 to 5, and most preferably in the range of 1 to 3. A suitable peptide of (iv) is a peptide in which amino acid residues at positions 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 5, or 1 to 3 from the N-terminus are deleted, and which has adrenomedullin activity. More suitable peptides of (iv) are peptides in which amino acid residues at positions 1 to 15, 1 to 10, or 1 to 5 from the N-terminus are deleted, and which have adrenomedullin activity. In the suitable peptide, one or more amino acid residues (e.g., 1 to 5, 1 to 3, or 1 or 2) may be further deleted, substituted, or added. By using the peptide described in (iv), the adrenomedullin activity of the peptide can be made substantially equivalent to that of natural adrenomedullin. Furthermore, by using the peptide described in (iv), the peptide can sustainably exert its adrenomedullin activity in vivo.

[0093] The peptide (vi) can be converted into the peptide (v) by C-terminal amidase, which converts the C-terminal glycine residue into a C-terminal amide group. Therefore, by administering the peptide (vi) to a subject, a C-terminal amidated peptide can be formed in the subject's body after a certain period of time. Thus, the peptide (vi) can sustainably exert adrenomedullin activity in the body.

[0094] The adrenomedullin or its derivatives having adrenomedullin activity are more preferably peptides selected from the group consisting of:

[0095] (a) A peptide consisting of the amino acid sequence of sequence number 1, or a peptide consisting of the amino acid sequence of sequence number 1, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0096] (b) A peptide consisting of the amino acid sequence of sequence number 4, or a peptide consisting of the amino acid sequence of sequence number 4, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0097] (c) A peptide consisting of the amino acid sequence of sequence number 6, or a peptide consisting of the amino acid sequence of sequence number 6, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0098] (d) A peptide consisting of the amino acid sequence number 8, or a peptide consisting of the amino acid sequence number 8, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0099] (e) A peptide consisting of the amino acid sequence of sequence number 10, or a peptide consisting of the amino acid sequence of sequence number 10, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond.

[0100] (f) A peptide consisting of the amino acid sequence of sequence number 12, or a peptide consisting of the amino acid sequence of sequence number 12, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond.

[0101] (g) In any one of (a) to (f) a peptide in which the disulfide bond is replaced by an ethylene and has adrenomedullin activity;

[0102] (h) A peptide in any one of (a) to (g) in which 1 to 15 amino acids are missing, substituted or added and which has adrenomedullin activity;

[0103] (i) Of any of the peptides in (a) to (h), the C-terminus is amidated; and

[0104] (j) A peptide in any of (a) to (h) that has a glycine residue added to its C-terminus.

[0105] In one embodiment of the invention, the adrenomedullin or its derivative having adrenomedullin activity is further preferably a peptide selected from the group consisting of:

[0106] (a) A peptide consisting of the amino acid sequence of sequence number 1, or a peptide consisting of the amino acid sequence of sequence number 1, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0107] (b) A peptide consisting of the amino acid sequence of sequence number 4, or a peptide consisting of the amino acid sequence of sequence number 4, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0108] (c) A peptide consisting of the amino acid sequence of sequence number 6, or a peptide consisting of the amino acid sequence of sequence number 6, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0109] (d) A peptide consisting of the amino acid sequence number 8, or a peptide consisting of the amino acid sequence number 8, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0110] (e) A peptide consisting of the amino acid sequence of sequence number 10, or a peptide consisting of the amino acid sequence of sequence number 10, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond.

[0111] (f) A peptide consisting of the amino acid sequence of sequence number 12, or a peptide consisting of the amino acid sequence of sequence number 12, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond.

[0112] (i) Of any of the peptides in (a) to (f), the C-terminus is amidated; and

[0113] (j) A peptide in any of (a) to (f) that has a glycine residue added to its C-terminus.

[0114] In the peptide of (h), the number of amino acid residues that are deleted, substituted or added is preferably in the range of 1 to 12, more preferably in the range of 1 to 10, further preferably in the range of 1 to 8, particularly preferably in the range of 1 to 5, and most preferably in the range of 1 to 3. Suitable peptides (h) are peptides in any of (a) to (g) where amino acids at positions 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 5, or 1 to 3 from the N-terminus are deleted, and which possess adrenomedullin activity. More suitable peptides (h) are peptides in any of (a) to (d) where amino acid residues at positions 1 to 15, 1 to 10, or 1 to 5 from the N-terminus are deleted, and which possess adrenomedullin activity; or peptides in (e) or (f) where amino acid residues at positions 1 to 13, 1 to 8, or 1 to 5 from the N-terminus are deleted, and which possess adrenomedullin activity. In the suitable peptides, one or more amino acids (e.g., 1 to 5, 1 to 3, or 1 or 2) may be further deleted, substituted, or added. By using the peptide described in (h), the adrenomedullin activity of the peptide can be made substantially equivalent to that of natural adrenomedullin. Furthermore, by using the peptide described in (h), the peptide can sustainably exert its adrenomedullin activity in vivo.

[0115] (Salts of adrenaline or its derivatives)

[0116] In various embodiments of the present invention, the AM or its derivatives having adrenal medullary activity used as the active ingredient includes not only the compound itself but also its salt. When the AM or its derivatives having adrenal medullary activity are in the form of a salt, a pharmaceutically acceptable salt is preferred. The counter ion of the salt of the AM or its derivatives having adrenal medullary activity is not limited, but is preferably, for example, a cation such as sodium ion, potassium ion, calcium ion, magnesium ion, or substituted or unsubstituted ammonium ion, or a chloride ion, bromide ion, iodide ion, phosphate ion, nitrate ion, sulfate ion, carbonate ion, bicarbonate ion, perchlorate ion, formate ion, acetate ion, trifluoroacetate ion, propionate ion, lactate ion, maleate ion, hydroxymaleate ion, methylmaleate ion, fumarate ion, adipic acid ion, benzoate ion, 2-acetoxybenzoate ion The compound contains anions such as p-aminobenzoate, nicotinic acid, cinnamate, ascorbate, dihydroxynaphthate, succinate, salicylate, dimethylene salicylate, oxalate, tartrate, malate, citrate, gluconate, aspartate, stearate, palmitate, itaconic acid, glycolate, glutamate, benzenesulfonate, cyclohexylaminosulfonate, methanesulfonate, ethanesulfonate, hydroxyethylsulfonate, benzenesulfonate, p-toluenesulfonate, or naphthalenesulfonate. When AM or its derivatives with adrenal medullary activity are in the form of salts of the aforementioned counterions, the adrenal medullary activity of this compound can be substantially equivalent to that of natural adrenal medullary.

[0117] (Solvation of adrenaline or its salts)

[0118] In various embodiments of the present invention, the AM or its derivatives having adrenomedullin activity used as the active ingredient includes not only the compound itself but also solvates of the compound or its salts. When the AM or its derivatives having adrenomedullin activity, or its salts, are in the form of a solvate, a pharmaceutically acceptable solvate is preferred. The solvent capable of forming a solvate with the compound or its salts is not limited, but is preferably, for example, water, or organic solvents such as methanol, ethanol, 2-propanol (isopropanol), dimethyl sulfoxide (DMSO), acetic acid, ethanolamine, acetonitrile, or ethyl acetate. When the AM or its derivatives having adrenomedullin activity, or its salts, are in the form of a solvate with the aforementioned solvent, the adrenomedullin activity of the compound can be substantially equivalent to that of natural adrenomedullin.

[0119] Furthermore, in various embodiments of the present invention, the AM or its derivatives having adrenal medullaris activity used as active ingredients also include mixtures of stereoisomers of the compound, such as the enantiomers and diastereomers of the compound, as well as racemic mixtures.

[0120] (disease)

[0121] In various embodiments of the present invention, the disease is one for which a therapeutic effect is expected to be achieved through administration of AM. Since the present invention provides a method of administration that maximizes the therapeutic effect of AM, it is applicable to all diseases treated by administration of AM. That is, any disease for which a therapeutic effect is expected through administration of AM can be a disease treated by administration of AM. In other words, such a disease is one for which a therapeutic effect (being treated) is expected through the anti-inflammatory, angiogenic, cardiovascular protective, and / or tissue repair promoting effects of AM.

[0122] Diseases for which therapeutic effects are expected to be achieved through administration of AM include, for example, cerebrovascular diseases, dementia, inflammatory bowel disease, autoimmune diseases, infectious diseases, pulmonary hypertension, peripheral vascular disease, and heart disease.

[0123] Cerebrovascular diseases include stroke, cerebral infarction (such as cerebral thrombosis, cerebral embolism, etc.), cerebral hemorrhage (such as intracerebral hemorrhage, subarachnoid hemorrhage, etc.), acute epidural hematoma, acute subdural hematoma, chronic subdural hematoma, etc.

[0124] Examples of dementia include Alzheimer's disease (AD), vascular dementia, Lewy body dementia, Pick's disease, frontotemporal dementia (FTD), AIDS-related dementia syndrome, age-related cognitive impairment, age-related memory impairment, and other neurodegenerative diseases associated with dementia.

[0125] Examples of inflammatory bowel diseases include ulcerative colitis, Crohn's disease, intestinal Behcet's disease, infectious enteritis, drug-induced enteritis, ischemic enteritis, and intestinal tuberculosis.

[0126] Examples of autoimmune diseases include chronic rheumatoid arthritis, collagen diseases (such as systemic lupus erythematosus), multiple sclerosis, and neuromyelitis optica.

[0127] Examples of infectious diseases include respiratory infections (e.g., sepsis, pneumonia), urinary tract infections (e.g., pyelonephritis), digestive system infections (e.g., peritonitis, cholecystitis), infections following burns or surgery, and viral infections (e.g., COVID-19). In one embodiment of the invention, the infectious disease may be a severe infection.

[0128] Examples of pulmonary hypertension include arterial pulmonary hypertension, pulmonary hypertension associated with left ventricular heart disease, pulmonary hypertension caused by lung disease and hypoxemia, chronic thromboembolic pulmonary hypertension, and pulmonary hypertension caused by a combination of factors of unknown cause.

[0129] Examples of peripheral vascular diseases include carotid artery stenosis, subclavian artery stenosis, renal artery stenosis, occlusive arteriosclerosis, acute arterial occlusive disease, thromboangiitis obliterans, and varicose veins of the lower extremities.

[0130] Examples of heart diseases include myocardial infarction (such as acute myocardial infarction, subacute myocardial infarction, and old myocardial infarction), angina pectoris, heart failure, and valvular disease. From a treatment perspective, acute myocardial infarction is preferred.

[0131] (drug)

[0132] In this type of medicament, AM or its derivatives with adrenomedullin activity can be used alone as the active ingredient, or in combination with one or more pharmaceutically acceptable ingredients. This type of medicament can also be provided as a pharmaceutical composition containing adrenomedullin or its derivatives with adrenomedullin activity, and one or more pharmaceutically acceptable carriers. In the case of this embodiment, in addition to the aforementioned ingredients, the pharmaceutical composition may also contain one or more pharmaceutically acceptable media (e.g., solvents such as sterile water or solutions such as physiological saline), excipients, binders, carriers, dissolving aids, preservatives, stabilizers, disintegrants, disintegrant inhibitors, bulking agents, lubricants, surfactants, emulsifiers, oily liquids (e.g., vegetable oils), suspending agents, buffers, analgesics, antioxidants, sweeteners, and flavorings, etc.

[0133] The dosage form of the drug in this method is not particularly limited as long as it is intended for intravenous administration. Examples of preparations intended for intravenous administration include sterile solutions or suspensions of injectable formulations that are mixed with water or other pharmaceutically acceptable liquids. Additives that can be mixed into the injectable formulation are not limited, but include, for example, carriers such as isotonic solutions containing physiological saline, glucose, or other adjuvants (e.g., D-sorbitol, D-mannitol, or sodium chloride); solubilizers such as alcohols (e.g., ethanol or benzyl alcohol), esters (e.g., benzyl benzoate), and polyols (e.g., propylene glycol or polyethylene glycol); nonionic surfactants such as polysorbate 80 or polyoxyethylene hydrogenated castor oil; oily liquids such as sesame oil or soybean oil; buffers such as phosphate buffer or sodium acetate buffer; analgesics such as benzalkonium chloride or procaine hydrochloride; stabilizers, preservatives, and antioxidants such as human serum albumin or polyethylene glycol. The prepared injection is typically filled into a suitable container (such as a vial or ampoule) and stored under appropriate conditions until it is ready for use.

[0134] The drug of this method can also be used in combination with one or more other pharmaceutical agents. In this case, the drug of this method can also be provided as a single drug containing AM or its derivatives with adrenomedullin activity and one or more other pharmaceutical agents, or as a combination of drugs or a kit containing multiple formulations of AM or its derivatives with adrenomedullin activity and one or more other pharmaceutical agents, each separately formulated. In the case of a combination of drugs or a kit, the respective formulations can be administered simultaneously or separately (e.g., sequentially).

[0135] When AM or its derivatives having adrenomedullin activity are used for pharmaceutical purposes, AM or its derivatives having adrenomedullin activity include not only the compound itself, but also pharmaceutically acceptable salts of the compound and their pharmaceutically acceptable solvates. The pharmaceutically acceptable salts and solvates of AM or its derivatives having adrenomedullin activity are not limited, but are preferably, for example, the salts or solvates exemplified above. When AM or its derivatives having adrenomedullin activity are in the form of the aforementioned salts or solvates, the compound can be used for the desired pharmaceutical purpose.

[0136] The active ingredient of the drug of this method, AM or its derivatives having adrenomedullin activity, is derived from adrenomedullin, a naturally occurring physiologically active peptide. Therefore, AM or its derivatives having adrenomedullin activity are safe and have low toxicity. Thus, the drug of this method is suitable for treating a wide variety of subjects who require treatment of diseases for which therapeutic effects are expected through administration of AM, etc. The subjects are preferably human or non-human mammals (e.g., warm-blooded animals such as pigs, dogs, cattle, rats, mice, guinea pigs, rabbits, chickens, sheep, cats, monkeys, Arabian baboons, or chimpanzees), or more preferably human patients. By intermittently administering the drug of this method to the subject, the disease in that subject can be treated.

[0137] When administering medications of this manner to subjects, particularly human patients, the correct usage and dosage should be determined by the attending physician, taking into account many factors such as the subject's age, sex, the appropriate status (e.g., severity) of the symptoms, disease, and / or disorder to be prevented or treated, and the route of administration. Therefore, in medications of this manner, AM, or its derivatives having adrenomedullin activity, as the active ingredient, is administered to the subject in a therapeutically effective manner and at a dosage (e.g., dosage and route of administration).

[0138] In this type of medicament, the active ingredient AM or its derivatives having adrenomedullin activity are preferably administered intermittently intravenously. In this embodiment, the dosage form of the medicament is, for example, an injectable preparation of a sterile solution or suspension with water or other pharmaceutically acceptable liquids (e.g., physiological saline). The intravenous administration is preferably carried out at a rate in the range of 1.0 to 20.0 ng of active ingredient / kg body weight / minute, more preferably in the range of 6.0 to 12.0 ng of active ingredient / kg body weight / minute. If the administration rate of AM or its derivatives having adrenomedullin activity exceeds the upper limit, undesirable side effects may occur, such as a decrease or fluctuation in blood pressure, worsening of cerebral infarction, or complications of hemorrhagic cerebral infarction. Conversely, if the administration rate of AM or its derivatives having adrenomedullin activity is below the lower limit, adequate therapeutic effects may not be achieved. Therefore, by intermittently administering the drug intravenously at the rate of administration within the aforementioned range, the disease can be treated without producing undesirable side effects.

[0139] In this method of medication, intermittent administration is not limited to the cerebrovascular disease described in the examples. It is applicable to any disease for which a therapeutic effect is expected through AM administration (e.g., cerebrovascular disease, dementia, inflammatory bowel disease, autoimmune disease, infectious diseases, pulmonary hypertension, peripheral vascular disease, heart disease, etc.). That is, the embodiments of this application use cerebrovascular disease as an example of a disease for intermittent administration of AM according to the present invention, and the effect has been confirmed.

[0140] In this method of administration, the intravenous administration is preferably performed intermittently within 23 hours per day, more preferably intermittently within 15 hours, even more preferably intermittently within 12 hours, particularly more preferably intermittently within 10 hours, and especially preferably intermittently within 8 hours per day. For example, after continuous intravenous administration of AM within 8 hours, a rest period of 16 hours or more is set until the start of the next administration, and then this operation is repeated. In addition, the intravenous administration is preferably performed for 3 to 30 days under the conditions within the range mentioned above (i.e., intermittent administration within 23 hours, 15 hours, 12 hours, 10 hours, or 8 hours per day), more preferably for 4 to 25 days, even more preferably for 5 to 20 days, particularly more preferably for 6 to 16 days, particularly preferably for 7 to 14 days, and extremely preferably for 7 days. If the dosage of AM or its derivatives with adrenomedullin activity is below the lower limit, adequate therapeutic effect may not be achieved. Therefore, by intermittently administering the drug in this manner intravenously within the dosage range, the disease can be treated with greater therapeutic efficacy.

[0141] In this method of administration, intermittent administration of AM or its derivatives with adrenal medullaris activity is preferably initiated immediately after the onset of the disease (e.g., cerebral infarction). In conventional administration methods, it is generally considered effective to switch to intermittent administration after several days of continuous administration, for example, immediately after the onset of the disease (e.g., cerebral infarction). However, according to the present invention, intermittent administration immediately after the onset of the disease can improve the therapeutic effect.

[0142] The preferred method of administration of the drug is as follows: AM as the active ingredient, or its derivative having adrenomedullin activity, is preferably administered intravenously at a rate ranging from 1.0 to 20.0 ng of active ingredient / kg body weight / minute, more preferably from 6.0 to 12.0 ng of active ingredient / kg body weight / minute, and this intravenous administration is based on a dosing schedule consisting of continuous dosing for 8 hours over 7 days followed by 16 hours of dosing-free administration. By intermittently administering the drug of this method intravenously based on the aforementioned dosing schedule, the disease can be treated with greater therapeutic efficacy.

[0143] In various embodiments of the present invention, when the subject of treatment by administration of AM or its derivatives with adrenomedullin activity is, for example, a subject with acute cerebral infarction, the therapeutic effect can be determined, for example, by administering a drug containing AM or its derivatives with adrenomedullin activity as an active ingredient to the subject with acute cerebral infarction, and evaluating the symptoms of cerebral infarction in the subject using, for example, the Stroke Severity Assessment Scale (SS), the Modified Rankin Scale (mRS), clinical examinations (e.g., hematological examinations and blood biochemistry examinations), vital signs (e.g., blood pressure and electrocardiogram), head imaging findings (e.g., using CT and / or MRI to evaluate for hemorrhage, infarction, and high-degree stenosis), nuclear medicine examinations, or ultrasound examinations. For example, when using the NIHSS to evaluate the symptoms of cerebral infarction in a subject with acute cerebral infarction, the change in the NIHSS after 1 week is used as the average value, for example, in the range of -1.5 to -4.5.

[0144] (Other implementation methods)

[0145] The present invention also relates to the following.

[0146] [8] A method of treating a disease, comprising the step of administering to a subject a therapeutically effective amount of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

[0147] The disease is characterized in that it is a disease for which a therapeutic effect is expected to be achieved through administration of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof.

[0148] The administration is intermittent.

[0149] [8a] The method as described in [8], wherein the adrenomedullin or its derivative having adrenomedullin activity is a peptide selected from the group consisting of:

[0150] (i) A peptide composed of the amino acid sequence of adrenaline medullaris,

[0151] (ii) A peptide consisting of the amino acid sequence of adrenomedullin, wherein two cysteine ​​residues in the amino acid sequence form a disulfide bond.

[0152] (iii) In the peptide of (ii), the disulfide bond is replaced by an ethylene group, and the peptide has adrenomedullin activity.

[0153] (iv) A peptide in any one of (i) to (iii) in which 1 to 15 amino acid residues are deleted, substituted, or added, and which has adrenomedullin activity.

[0154] (v) Of any of the peptides in (i) to (iv), the C-terminus of which is amidated, and

[0155] (vi) Of any of the peptides in (i) to (iv), a peptide with a glycine residue added to the C-terminus.

[0156] [8b] The method as described in [8] or [8a], wherein the adrenomedullin or its derivative having adrenomedullin activity is a peptide selected from the group consisting of:

[0157] (a) A peptide consisting of the amino acid sequence of sequence number 1, or a peptide consisting of the amino acid sequence of sequence number 1, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0158] (b) A peptide consisting of the amino acid sequence of sequence number 4, or a peptide consisting of the amino acid sequence of sequence number 4, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0159] (c) A peptide consisting of the amino acid sequence of sequence number 6, or a peptide consisting of the amino acid sequence of sequence number 6, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0160] (d) A peptide consisting of the amino acid sequence number 8, or a peptide consisting of the amino acid sequence number 8, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0161] (e) A peptide consisting of the amino acid sequence of sequence number 10, or a peptide consisting of the amino acid sequence of sequence number 10, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond.

[0162] (f) A peptide consisting of the amino acid sequence of sequence number 12, or a peptide consisting of the amino acid sequence of sequence number 12, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond.

[0163] (g) In any one of (a) to (f) a peptide in which the disulfide bond is replaced by an ethylene and has adrenomedullin activity;

[0164] (h) A peptide in any one of (a) to (g) in which 1 to 15 amino acid residues are deleted, substituted or added and which has adrenomedullin activity;

[0165] (i) Of any of the peptides in (a) to (h), the C-terminus is amidated; and

[0166] (j) A peptide in any of (a) to (h) that has a glycine residue added to its C-terminus.

[0167] [8c] The method of any one of [8] to [8b], wherein the disease is a disease for which therapeutic effects are expected to be achieved by the anti-inflammatory, angiogenic, cardiovascular protective and / or tissue repair promoting effects of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof.

[0168] [8d] The method as described in any one of [8] to [8c], wherein the disease is selected from at least one of the group consisting of cerebrovascular disease, dementia, inflammatory bowel disease, autoimmune disease, infectious disease, pulmonary hypertension, peripheral vascular disease and heart disease.

[0169] [8e] The method as described in any one of [8] to [8d], wherein the intermittent administration is administration within 23 hours every day.

[0170] [8f] The method as described in any one of [8] to [8e], wherein the intermittent administration is administration within 23 hours every day for 3 to 30 days.

[0171] In this method, the AM or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, administered have the same characteristics as the active ingredient of the medicament described above. Furthermore, this method can be performed with the same usage and dosage as the medicament described above. Moreover, this method can treat the same diseases as the medicament described above.

[0172] The present invention also relates to the following.

[0173] [9] An adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the treatment of a disease,

[0174] The disease is characterized in that it is a disease for which a therapeutic effect is expected to be achieved through administration of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof.

[0175] The medication was administered intermittently.

[0176] [9a] Adrenomedullin as described in [9] or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, wherein the adrenomedullin or its derivatives having adrenomedullin activity are peptides selected from the group consisting of:

[0177] (i) A peptide composed of the amino acid sequence of adrenaline medullaris,

[0178] (ii) A peptide consisting of the amino acid sequence of adrenomedullin, wherein two cysteine ​​residues in the amino acid sequence form a disulfide bond.

[0179] (iii) In the peptide of (ii), the disulfide bond is replaced by an ethylene group, and the peptide has adrenomedullin activity.

[0180] (iv) A peptide in any one of (i) to (iii) in which 1 to 15 amino acid residues are deleted, substituted, or added, and which has adrenomedullin activity.

[0181] (v) Of any of the peptides in (i) to (iv), the C-terminus of which is amidated, and

[0182] (vi) Of any of the peptides in (i) to (iv), a peptide with a glycine residue added to the C-terminus.

[0183] [9b] Adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, as described in [9] or [9a], wherein the adrenomedullin or its derivatives having adrenomedullin activity are peptides selected from the group consisting of:

[0184] (a) A peptide consisting of the amino acid sequence of sequence number 1, or a peptide consisting of the amino acid sequence of sequence number 1, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0185] (b) A peptide consisting of the amino acid sequence of sequence number 4, or a peptide consisting of the amino acid sequence of sequence number 4, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0186] (c) A peptide consisting of the amino acid sequence of sequence number 6, or a peptide consisting of the amino acid sequence of sequence number 6, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0187] (d) A peptide consisting of the amino acid sequence number 8, or a peptide consisting of the amino acid sequence number 8, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0188] (e) A peptide consisting of the amino acid sequence of sequence number 10, or a peptide consisting of the amino acid sequence of sequence number 10, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond.

[0189] (f) A peptide consisting of the amino acid sequence of sequence number 12, or a peptide consisting of the amino acid sequence of sequence number 12, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond.

[0190] (g) In any one of (a) to (f) a peptide in which the disulfide bond is replaced by an ethylene and has adrenomedullin activity;

[0191] (h) A peptide in any one of (a) to (g) in which 1 to 15 amino acid residues are deleted, substituted or added and which has adrenomedullin activity;

[0192] (i) Of any of the peptides in (a) to (h), the C-terminus is amidated; and

[0193] (j) A peptide in any of (a) to (h) that has a glycine residue added to its C-terminus.

[0194] [9c] Adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, as described in any one of [9] to [9b], wherein the disease is a disease for which therapeutic effects are expected to be achieved through the anti-inflammatory, angiogenic, cardiovascular protective and / or tissue repair promoting effects of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof.

[0195] [9d] Adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, as described in any one of [9] to [9c], wherein the disease is selected from at least one of the group consisting of cerebrovascular diseases, dementia, inflammatory bowel disease, autoimmune diseases, infectious diseases, pulmonary hypertension, peripheral vascular diseases and heart diseases.

[0196] [9e] Adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, as described in any one of [9] to [9d], wherein the intermittent administration is administration within 23 hours per day.

[0197] [9f] Adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, as described in any one of [9] to [9e], wherein the intermittent administration is administration within 23 hours every day for 3 to 30 days.

[0198] The AM, or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, in this formulation have the same characteristics as the active ingredients of the drugs described above. Furthermore, the AM, etc., in this formulation can be administered in the same manner and dosage as the drugs described above. Moreover, the AM, etc., in this formulation can treat the same diseases as the drugs described above.

[0199] The present invention also relates to the following.

[0200]

[10] The use of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, in the manufacture of medicaments for the treatment of diseases.

[0201] The disease is characterized in that it is a disease for which a therapeutic effect is expected to be achieved through administration of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof.

[0202] The therapeutic drug is administered intermittently.

[0203] [10a] The application as described in

[10] , wherein the adrenomedullin or its derivative having adrenomedullin activity is a peptide selected from the group consisting of:

[0204] (i) A peptide composed of the amino acid sequence of adrenaline medullaris,

[0205] (ii) A peptide consisting of the amino acid sequence of adrenomedullin, wherein two cysteine ​​residues in the amino acid sequence form a disulfide bond.

[0206] (iii) In the peptide of (ii), the disulfide bond is replaced by an ethylene group, and the peptide has adrenomedullin activity.

[0207] (iv) A peptide in any one of (i) to (iii) in which 1 to 15 amino acid residues are deleted, substituted, or added, and which has adrenomedullin activity.

[0208] (v) Of any of the peptides in (i) to (iv), the C-terminus of which is amidated, and

[0209] (vi) Of any of the peptides in (i) to (iv), a peptide with a glycine residue added to the C-terminus.

[0210] [10b] The application as described in

[10] or [10a], wherein the adrenomedullin or its derivative having adrenomedullin activity is a peptide selected from the group consisting of:

[0211] (a) A peptide consisting of the amino acid sequence of sequence number 1, or a peptide consisting of the amino acid sequence of sequence number 1, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0212] (b) A peptide consisting of the amino acid sequence of sequence number 4, or a peptide consisting of the amino acid sequence of sequence number 4, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0213] (c) A peptide consisting of the amino acid sequence of sequence number 6, or a peptide consisting of the amino acid sequence of sequence number 6, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0214] (d) A peptide consisting of the amino acid sequence number 8, or a peptide consisting of the amino acid sequence number 8, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0215] (e) A peptide consisting of the amino acid sequence of sequence number 10, or a peptide consisting of the amino acid sequence of sequence number 10, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond.

[0216] (f) A peptide consisting of the amino acid sequence of sequence number 12, or a peptide consisting of the amino acid sequence of sequence number 12, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond.

[0217] (g) In any one of (a) to (f) a peptide in which the disulfide bond is replaced by an ethylene and has adrenomedullin activity;

[0218] (h) A peptide in any one of (a) to (g) in which 1 to 15 amino acid residues are deleted, substituted or added and which has adrenomedullin activity;

[0219] (i) Of any of the peptides in (a) to (h), the C-terminus is amidated; and

[0220] (j) A peptide in any of (a) to (h) that has a glycine residue added to its C-terminus.

[0221] [10c] An application as described in any one of

[10] to [10b], wherein the disease is a disease for which therapeutic effects are expected to be achieved through the anti-inflammatory, angiogenic, cardiovascular protective and / or tissue repair promoting effects of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof.

[0222] [10d] The application as described in any one of

[10] to [10c], wherein the disease is selected from at least one of the group consisting of cerebrovascular diseases, dementia, inflammatory bowel disease, autoimmune diseases, infectious diseases, pulmonary hypertension, peripheral vascular diseases and heart diseases.

[0223] [10e] The application as described in any one of

[10] to [10d], wherein the intermittent administration is administration within 23 hours every day.

[0224] [10f] The application as described in any one of

[10] to [10e], wherein the intermittent administration is administration within 23 hours every day for 3 to 30 days.

[0225] The AM or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof used in this method have the same characteristics as the active ingredient of the drug described above. Furthermore, this method can be used in the same manner and dosage as the drug described above. Moreover, the same disease as the drug described above can be treated with this method.

[0226] In addition, in one embodiment of the present invention, the following is provided.

[0227]

[11] The use of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, for the treatment of a disease.

[0228] The disease is characterized in that it is a disease for which a therapeutic effect is expected to be achieved through administration of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof.

[0229] The adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, are administered intermittently.

[0230] [11a] The application as described in

[11] , wherein the adrenomedullin or its derivative having adrenomedullin activity is a peptide selected from the group consisting of:

[0231] (i) A peptide composed of the amino acid sequence of adrenaline medullaris,

[0232] (ii) A peptide consisting of the amino acid sequence of adrenomedullin, wherein two cysteine ​​residues in the amino acid sequence form a disulfide bond.

[0233] (iii) In the peptide of (ii), the disulfide bond is replaced by an ethylene group, and the peptide has adrenomedullin activity.

[0234] (iv) A peptide in any one of (i) to (iii) in which 1 to 15 amino acid residues are deleted, substituted, or added, and which has adrenomedullin activity.

[0235] (v) Of any of the peptides in (i) to (iv), the C-terminus of which is amidated, and

[0236] (vi) Of any of the peptides in (i) to (iv), a peptide with a glycine residue added to the C-terminus.

[0237] [11b] The application as described in

[11] or [11a], wherein the adrenomedullin or its derivative having adrenomedullin activity is a peptide selected from the group consisting of:

[0238] (a) A peptide consisting of the amino acid sequence of sequence number 1, or a peptide consisting of the amino acid sequence of sequence number 1, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0239] (b) A peptide consisting of the amino acid sequence of sequence number 4, or a peptide consisting of the amino acid sequence of sequence number 4, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0240] (c) A peptide consisting of the amino acid sequence of sequence number 6, or a peptide consisting of the amino acid sequence of sequence number 6, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0241] (d) A peptide consisting of the amino acid sequence number 8, or a peptide consisting of the amino acid sequence number 8, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond.

[0242] (e) A peptide consisting of the amino acid sequence of sequence number 10, or a peptide consisting of the amino acid sequence of sequence number 10, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond.

[0243] (f) A peptide consisting of the amino acid sequence of sequence number 12, or a peptide consisting of the amino acid sequence of sequence number 12, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond.

[0244] (g) In any one of (a) to (f) a peptide in which the disulfide bond is replaced by an ethylene and has adrenomedullin activity;

[0245] (h) A peptide in any one of (a) to (g) in which 1 to 15 amino acid residues are deleted, substituted or added and which has adrenomedullin activity;

[0246] (i) Of any of the peptides in (a) to (h), the C-terminus is amidated; and

[0247] (j) A peptide in any of (a) to (h) that has a glycine residue added to its C-terminus.

[0248] [11c] The application as described in any one of

[11] to [11b], wherein the disease is a disease for which therapeutic effects are expected to be achieved through the anti-inflammatory, angiogenic, cardiovascular protective and / or tissue repair promoting effects of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof.

[0249] [11d] The application as described in any one of

[11] to [11c], wherein the disease is selected from at least one of the group consisting of cerebrovascular diseases, dementia, inflammatory bowel disease, autoimmune diseases, infectious diseases, pulmonary hypertension, peripheral vascular diseases and heart diseases.

[0250] [11e] The application as described in any one of

[11] to [11d], wherein the intermittent administration is administration within 23 hours per day.

[0251] [11f] The application as described in any one of

[11] to [11e], wherein the intermittent administration is administration within 23 hours every day for 3 to 30 days.

[0252] The AM or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof used in this embodiment have the same characteristics as the active ingredient of the drug of this embodiment described above. Furthermore, the use of this embodiment can be carried out in the same manner and dosage as the drug of this embodiment described above. Moreover, in the use of this embodiment, the same disease as the drug of this embodiment described above can be treated.

[0253]

Example

[0254] The following examples illustrate the invention in more detail, but do not limit the scope of the invention. Furthermore, in this embodiment, as an example of "a disease for which a therapeutic effect is expected to be obtained by administration of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof," an example of the applicability of the invention to a patient with "acute cerebral infarction," one of the cerebrovascular diseases.

[0255] <Trial I: The effect of intermittent administration of adrenaline for symptom relief in patients with acute ischemic stroke>

[0256] [I-1: Investigational Drug]

[0257] (a) Active ingredient:

[0258] Synthesize human adrenal medullaris (a peptide consisting of the amino acid sequence number 1, with the C-terminus amidated, and two cysteine ​​residues in the amino acid sequence forming a disulfide bond and a cyclic structure).

[0259] (b) Dosage form, content and properties:

[0260] This is an injectable preparation (lyophilized) made by sealing 500 μg of synthetic human adrenaline in a white block or powder in one vial. It contains 50 mg of D-mannitol.

[0261] (c) Preparation:

[0262] When using the test drug, inject 10 mL of physiological saline into the vial using a syringe to dissolve it without foaming. Take 10 mL of the dissolved test drug with a syringe and add 20 mL of physiological saline to dilute to a total volume of 30 mL.

[0263] (d) Storage:

[0264] After dissolving, store in a sealed container, protected from light and refrigerated (2-8°C). The control drug (placebo) does not contain the active ingredient (containing only 50 mg of D-mannitol) and is prepared with the same dosage form and properties as the test drug. The test drug and the control drug are indistinguishable in appearance.

[0265] [I-2: Object]

[0266] Patients with acute ischemic stroke were selected as subjects for this trial at the National Center for Cardiology and Otolaryngology, a national research and development corporation. Patients were selected based on the following criteria: ability to initiate medication within 24 hours of stroke onset; neurological symptoms with an NIHSS score of 1 or higher, and no conflict with exclusion criteria such as suspected embolic mechanisms. Patients selected based on these criteria were assigned to either the intermittent AM dosing group (n=20), the continuous intermittent AM dosing group (n=20), or the placebo group (n=20).

[0267] [I-3: Dosing Schedule]

[0268] (a) Test drug

[0269] (First half of the queue)

[0270] The drug was continuously administered intravenously for 8 hours at a rate of 9 ng / kg / min for 7 days. During the withdrawal period up to 72 hours later, only normal saline was continuously administered intravenously (AM intermittent dosing group).

[0271] (The second half of the queue)

[0272] The drug was administered intravenously at a dose of 9 ng / kg / min for 72 hours. This was followed by 8-hour continuous intravenous administration for 4 days (AM continuous-intermittent dosing group).

[0273] (b) Control drug (placebo)

[0274] (First half of the queue)

[0275] Same as the test drug.

[0276] (The second half of the queue)

[0277] Same as the test drug.

[0278] [I-4: Evaluation Items]

[0279] (a) Main evaluation items:

[0280] Safety assessment item: Serious adverse events (SAEs) for which causation cannot be ruled out.

[0281] Validity evaluation item: National Intense Stroke Severity Scale (NIHSS)

[0282] (b) Secondary evaluation items:

[0283] Safety assessment items: Adverse events (AEs)

[0284] Validity evaluation item: Modified Rankin Scale (mRS)

[0285] (c) Other evaluation items:

[0286] Clinical examination (including hematological and blood biochemistry tests)

[0287] Vital signs (measurement of blood pressure and electrocardiogram)

[0288] Head imaging findings (using CT and / or MRI to evaluate for hemorrhage, infarction, and high-degree stenosis)

[0289] Highest blood concentration and efficacy evaluation items

[0290] (d) Exploratory evaluation projects:

[0291] AM blood concentration

[0292] [Result-1]

[0293] The primary and secondary evaluation items for safety and effectiveness are shown in Table 1.

[0294] Table 1

[0295]

[0296] (Safety evaluation project)

[0297] "Serious adverse events (SAEs) for which causality cannot be ruled out" were used as the primary evaluation criterion, but no such events were observed in any of the AM intermittent dosing group, AM continuous intermittent dosing group, or placebo group. This demonstrates that the AM intermittent dosing method of this invention can be safely implemented.

[0298] (Effectiveness evaluation items)

[0299] The LSM (95% CI) NIHSS scores in the intermittent AM dosing group, continuous-intermittent AM dosing group, and placebo group were 2.77 (2.35–3.19), 3.85 (3.38–4.32), and 3.07 (2.72–3.42) (8 hours after intervention); 2.32 (1.69–2.95), 3.50 (2.91–4.09), and 2.77 (2.41–3.13) (24 hours after intervention); 2.52 (1.35–3.69), 3.40 (2.69–4.11), and 2.62 (1.55–3.68) (72 hours after intervention); and 1.97 (0.92–3.03), 3.20 (2.46–3.93), and 2.27 (1.23–3.30) (last day of intervention). Early neurological improvements in NIHSS scores were observed in 8 cases (40.0%) in the intermittent AM dosing group, 3 cases (15.0%) in the continuous-intermittent AM dosing group, and 7 cases (35.0%) in the placebo group.

[0300] In addition, among 60 patients with non-cardiac acute ischemic stroke, outcomes were compared in the intermittent AM administration group (n=20), the continuous / intermittent AM administration group (n=20), and the placebo group (n=20). The results showed that 15 patients (75.0%) in the intermittent AM administration group, 13 patients (65.0%) in the continuous / intermittent AM administration group, and 13 patients (68.4%) in the placebo group achieved a good functional outcome (mRS 0-2). Furthermore, 18 patients (90.0%) in the intermittent AM administration group, 17 patients (85.0%) in the continuous / intermittent AM administration group, and 14 patients (73.7%) in the placebo group achieved a functional outcome of being able to walk (mRS 0-3).

[0301] Based on these results, it can be seen that the AM intermittent dosing group showed a good outcome.

[0302] [Result-2]

[0303] After adjusting for deviations in age, sex, and the proportion of patients receiving intravenous rt-PA therapy within each group, a multivariate analysis was performed on the change in NIHSS. The results are shown in Table 2.

[0304] Table 2

[0305]

[0306] As shown in Table 2, the NIHSS values ​​of the AM intermittent dosing group at 8 hours and 24 hours after the start of treatment showed statistically significant and good results.

[0307] [Potential for Industrial Applications]

[0308] According to the present invention, AM is extremely useful in the treatment of diseases for which therapeutic effects are expected to be achieved through AM due to its high therapeutic efficacy. This application is based on Japanese Patent Application No. 2024-011993 (filed on January 30, 2024), the contents of which are fully incorporated herein by reference.

Claims

1. A medicament for treating a disease, comprising adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient. Its features are, The disease is one in which a therapeutic effect can be expected through administration of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof. The active ingredient is administered intermittently.

2. The drug according to claim 1, wherein, The adrenomedullin or its derivatives having adrenomedullin activity are peptides selected from the group consisting of: (i) A peptide composed of the amino acid sequence of adrenaline medullaris, (ii) A peptide consisting of the amino acid sequence of adrenomedullin, wherein two cysteine ​​residues in the amino acid sequence form a disulfide bond. (iii) In the peptide of (ii), the disulfide bond is replaced by an ethylene group, and the peptide has adrenomedullin activity. (iv) A peptide in any one of (i) to (iii) in which 1 to 15 amino acid residues are deleted, substituted, or added, and which has adrenomedullin activity. (v) Of any of the peptides in (i) to (iv), the C-terminus of which is amidated, and (vi) Of any of the peptides in (i) to (iv), a peptide with a glycine residue added to the C-terminus.

3. The drug according to claim 1 or 2, wherein, The adrenomedullin or its derivatives having adrenomedullin activity are peptides selected from the group consisting of: (a) A peptide consisting of the amino acid sequence of sequence number 1, or a peptide consisting of the amino acid sequence of sequence number 1, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond. (b) A peptide consisting of the amino acid sequence of sequence number 4, or a peptide consisting of the amino acid sequence of sequence number 4, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond. (c) A peptide consisting of the amino acid sequence of sequence number 6, or a peptide consisting of the amino acid sequence of sequence number 6, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond. (d) A peptide consisting of the amino acid sequence number 8, or a peptide consisting of the amino acid sequence number 8, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond. (e) A peptide consisting of the amino acid sequence of sequence number 10, or a peptide consisting of the amino acid sequence of sequence number 10, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond. (f) A peptide consisting of the amino acid sequence of sequence number 12, or a peptide consisting of the amino acid sequence of sequence number 12, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond. (g) In any one of (a) to (f) a peptide in which the disulfide bond is replaced by an ethylene and has adrenomedullin activity; (h) A peptide in any one of (a) to (g) in which 1 to 15 amino acid residues are deleted, substituted or added and which has adrenomedullin activity; (i) Of any of the peptides in (a) to (h), the C-terminus is amidated; and (j) A peptide in any of (a) to (h) that has a glycine residue added to its C-terminus.

4. The drug according to claim 1 or 2, wherein, The disease is one in which therapeutic effects can be expected through the anti-inflammatory, angiogenic, cardiovascular protective, and / or tissue repair promoting effects of adrenomedullin or its derivatives with adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof.

5. The drug according to claim 1 or 2, wherein, The disease is selected from at least one of the following groups: cerebrovascular disease, dementia, inflammatory bowel disease, autoimmune disease, infectious disease, pulmonary hypertension, peripheral vascular disease, and heart disease.

6. The drug according to claim 1 or 2, wherein, Intermittent dosing refers to dosing within 23 hours every day.

7. The drug according to claim 1 or 2, wherein, The intermittent dosing refers to administration within 23 hours every day for 3 to 30 days.

8. A method of treating a disease, comprising the step of administering to a subject a therapeutically effective amount of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. Its features are, The disease is one in which a therapeutic effect can be expected through administration of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof. The administration is intermittent.

9. An adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the treatment of a disease. Its features are, The disease is one in which a therapeutic effect can be expected through administration of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof. It was administered intermittently.

10. The use of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, in the manufacture of medicaments for the treatment of diseases. Its features are, The disease is one in which a therapeutic effect can be expected through administration of adrenomedullin or its derivatives having adrenomedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof. The therapeutic drug is administered intermittently.

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