TW202010752A - APOE mimetic peptide compositions - Google Patents

Abstract

Disclosed herein are aqueous compositions comprising a mixture of synthetic apolipoprotein E (ApoE)-mimicking peptides, a polyethylene sorbitan ester, and a cationic amino acid. Also disclosed is the use of these aqueous compositions for reducing plasma cholesterol.

Description

APOE peptide composition

Lipoprotein E (ApoE) plays an important role in the metabolism of triglyceride-rich lipoproteins, such as very low density lipoprotein (VLDL) and chylomicrons. Lipoprotein E mediates the high affinity binding of apo E-containing lipoproteins to low-density lipoprotein (LDL) receptors (apo B, E receptors) and members of its gene family, including LDL receptor-related proteins (LRP ), very low density lipoprotein receptor (VLDLR) and apoE2 receptor (apoE2R) (Mahley, RW, (1988) Science 240, 622-630). The hypothetical and complex role of apo E in atherosclerosis has been emphasized by several observations: (i) mice that overexpress human apo E have lower levels of total plasma cholesterol (Shimono, HN et al., ( 1992) Eur. J. Clin. Invest. 90,2084-2991), (ii) intravenous injection of human apo E into rabbits fed cholesterol to protect these animals from atherosclerosis (Yamada et al., (1989 ) Proc. Natl. Acad. Sci. USA 86,665-669), and (iii) apo E gene loss in mice produces spontaneous atherosclerosis (Zhang, SH et al., (1992) Science 258,468-471), It is improved when starting macrophage-specific apo E performance in mice lacking apo E (Spangenberg, J. et al. (1997) Biochem. Biophys. Acta 1349, 109-121).

Pseudo-synthetic ApoE peptides that enhance LDL/VLDL binding, increase LDL/VLDL degradation and reduce LDL/VLDL cholesterol in individuals with atherosclerosis have been previously described, and include, for example, Ac-he18A-NH ₂ ( AEM-28), Ac-[R]he18A-NH2 (AEM-28(R)), Aha-[R]hE18A-NH ₂ (AES-21), Myr[R]hE18A-NH ₂ (AEM-28- 14) and Octa[R]hE18A-NH ₂ (AEM-28-08). See for example US 6,506,880, WO 2009/032702 and WO 2016/0188665. Regardless of the ability to significantly reduce the total content of cholesterol, ApoE peptides such as AEM-28-08 and AEM-28-14 were found to have poor water solubility. See PCT/US2017/041663. This problem is solved by adding polyoxyethylene sorbitan fatty acid esters to the formulations containing these peptides. See PCT/US2017/041663. However, it has now been found that these peptides are not well tolerated in animal models. Therefore, there are means for reducing the toxicity of these other effective peptides.

It has now been found that peptides containing synthetic lipoprotein element E (ApoE) (such as, for example, AEM-28-08 and AEM-28-14) and polyoxyethylene sorbitan fatty acid esters (such as, for example, polysorbose) Aqueous formulations of alcohol ester 20 (eg, Tween ^™ 20) or polysorbate 80 (eg, Tween ^™ 80) are undesirably toxic. For example, administration of an aqueous formulation containing Tween ^™ 20 at a concentration of AEM-28-14 as low as 15 mg/kg resulted in full thickness necrosis (infarction) of the tail of the rat. In addition, administration of Tween ^TM 20 and ≥ 10 mg/kg AEM-28-14 resulted in acute bleeding, subcutaneous lens, perivascular inflammatory cell infiltration, and proportional muscle atrophy. However, it has now been found that the addition of the cationic amino acid spermine acid reduces hemolysis and provides formulations that are well tolerated in rats at levels up to 15 mg/kg AEM-28-14. See Example 4 . In addition, arginine seems to have little or no effect on the total cholesterol-lowering effect of the formulation. See for example Figure 1 . Therefore, there is little or no damage to efficacy.

Therefore, provided herein is an aqueous pharmaceutical composition comprising: i) a peptide that mimics synthetic lipoprotein element E (ApoE); ii) polyoxyethylene sorbitan fatty acid ester; and iii) a cationic amino acid.

Further provide methods for reducing plasma cholesterol, methods for affecting plasma LDL and/or plasma VLDL, and treatment of lipid disorders, atherosclerosis, or acute coronary syndromes using one or more of the disclosed pharmaceutical formulations described herein (ACS) method.

This application claims the priority of US Provisional Application No. 62/655,995 filed on April 11, 2018. The entire contents of this application are incorporated herein by reference. A. General description of the composition

In a first exemplary embodiment, provided herein is an aqueous pharmaceutical composition comprising: i) a simulated synthetic lipoprotein of the formula CH ₃ (CH ₂ ) _x C(O)-LRY ¹ LRY ² RLLR-DWLKAFYDKVAEKLKEAF-NH ₂ Peptide E (ApoE) or a pharmaceutically acceptable salt thereof, where x is an integer from 1 to 20, and Y ¹ and Y ² are each independently lysine or arginine; ii) polyethylene dehydration Sorbitol ester; and iii) cationic amino acid. B. Definition

The terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

By convention, peptides are written from left to right from N-terminus to C-terminus. Therefore, when writing -NH ₂ on the C-terminus, it should be understood that the C-terminus is amide, that is, -C(=O)NH ₂ . Similarly, when writing H ₃ C(CO)- on the N-terminus, it should be understood that the amine on the N-terminus is protected by acetyl, that is, H ₃ C(CO)-.

Ac-hE18A-NH ₂ used interchangeably with AEM-28 refers to a peptide that simulates synthetic lipoprotein element E (ApoE) with the structure H ₃ C(CO)-LRKLRKRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ .

Interchangeable with AEM-28-14 Myr[R]hE18A-NH ₂ refers to the structure MyrLRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ or alternatively written as CH ₃ (CH ₂ ) ₁₂ C(O)LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ The peptides that mimic synthetic lipoprotein element E (ApoE) can be used interchangeably.

Octa[R]hE18A-NH ₂ used interchangeably with AEM-28-08 or AEM-28-8 means having the structure OctaLRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ or alternatively written as CH ₃ (CH ₂ ) ₆ C(O) The peptides of LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ which simulate synthetic lipoprotein element E (ApoE) can be used interchangeably.

"Myr" means nutmeg amide, that is, CH ₃ (CH ₂ ) ₁₂ C(O)-.

"Octa" means octane, that is, CH ₃ (CH ₂ ) ₆ C(O)-.

The apo E-mimicking peptide disclosed herein includes an amino acid containing a base (for example, -NH ₂ ) and an acid group (for example, -COOH). When the Apo E-simulating peptide is dissolved in an acidic aqueous solution, the base matrix can be protonated; and when the Apo E-simulating peptide is dissolved in an alkaline solution, the acid group can be deprotonated. "Their pharmaceutically acceptable salts" refer to peptides that have been obtained from such a solution containing an acid or base suitable for medical use that mimics Apo E, such as hydrochloric acid, hydrobromic acid, phosphoric acid, partial Phosphoric acid, nitric acid, sulfuric acid, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid , Malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric acid. Suitable pharmaceutically acceptable basic salts include, for example, ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA, 1990, page 1445, the disclosure of which is hereby incorporated by reference.

Cationic amino acids refer to natural and unnatural amino acids containing positively charged side chains. Such amino acids include, for example, arginine, lysine, histidine, and ornithine.

As used herein, polyethylene sorbitan fatty acid ester is an amphiphilic nonionic surfactant composed of fatty acid ester of polyoxyethylene sorbitan. Generally, "fatty acid ester of polyoxyethylene sorbitan" refers to a mixture of fatty acid esters of polyoxyethylene sorbitan, such as mainly sorbitan polyoxyethylene (20) sorbitan Sugar alcohol monolaurate or sorbitan polyoxyethylene (20) sorbitan oleic acid (eg, at least 50% w/w, 60% w/w, 70% w/w, 80% w /w or 90% w/w) mixture of fatty acid esters of polyoxyethylene. Examples include, but are not limited to, polysorbate 20 (containing polyoxyethylene (20) sorbitan monolaurate), such as Tween ^™ 20, which includes, for example, polyethylene with a calculated molecular weight of 1,225 Daltons Sorbitan ester, presenting 20 ethylene oxide units, 1 sorbitol and 1 lauric acid as primary fatty acids; polysorbate 40 (including polyoxyethylene (20) sorbitan monopalmitic acid Ester), such as, for example, Tween ^™ 40; polysorbate 60 (containing polyoxyethylene (20) sorbitan monostearate), such as, for example, Tween ^™ 60; and polysorbate 80 (containing Polyoxyethylene (20) sorbitan monooleate), such as for example Tween ^™ 80, which contains, for example, polyethylene sorbitan ester with a calculated molecular weight of 1,310 Daltons, presenting 20 ethylene oxide Unit, 1 sorbitol and 1 oleic acid as the primary fatty acid. Examples include Tween ^™ 80.

As used herein, "effective amount" means an amount sufficient to provide the desired effect of the composition or Apo E mimic. For example, an effective amount of Apo E mimetics can be an amount that provides a therapeutic effect after treatment is discontinued and provides a sustained therapeutic effect. The effective amount of Apo E simulant is an amount that can cause the benefits described below: reduced atherosclerosis, reduced arterial wall hardness, reduced independent systolic hypertension, reduced arterial inflammation, high density lipoprotein (HDL) fraction The increased antioxidant capacity and/or increased myocardial function, and the amount of sustained therapeutic effect allowed after the withdrawal of the Apo E simulant. The precise amount required will vary from individual to individual depending on the species, age and general condition of the individual, the severity of the disease (or potential genetic defect) being treated, the specific compound used, its mode of administration and similar factors. Therefore, it is impossible to specify an accurate "effective amount". However, an appropriate "effective amount" can be determined by a person of ordinary skill using only routine experiments. "Therapeutically effective amount" and "effective amount" can be used interchangeably. In one aspect, the effective amount of the ApoE-like peptide described herein is in the range of 0.1 mg/kg to 20 mg/kg for human subjects, such as 5 mg/kg.

As used herein, "subject" refers to a target, such as an animal. Therefore, the individual of the disclosed method may be a vertebrate, such as a mammal. For example, the individual may be a human. The term does not indicate a specific age or gender. Individuals can be used interchangeably with "individual" or "patient".

As used herein, the term "treatment (treat/treating)" refers to reversing, relieving a disease or disorder as described herein, or one or more symptoms thereof, delaying its onset, or inhibiting its progression. In some embodiments, treatment may be administered after one or more symptoms have developed, that is, therapeutic treatment. In other embodiments, the treatment can be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals prior to the onset of symptoms (eg, in view of the history of symptoms and/or in view of genetic or other susceptibility factors), that is, to reduce the likelihood of disease. Susceptible individuals are individuals who are at risk of suffering from one or more of the conditions listed herein.

The phrase "dyslipidemia" refers to a situation where an individual has excess lipid or increased inflamed lipid in their blood. Lipids include, but are not limited to, lipids, such as ox-LDL (ie, oxidized PAPC (1-palmitoyl 2-eicosapentaylphosphatidylcholine). PAPC or PLPC (low density lipoprotein (LDL ) Lipid component) oxidation produces oxidized lipids. Having lipid disorders can make you more likely to suffer from inflammatory diseases such as atherosclerosis and heart disease. Lipid disorders can be caused by genetic susceptibility or diet. Lipid disorders include, for example Coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer's disease, peripheral arterial disease (PAD), cerebrovascular disease, diabetes-derived cardiovascular disease, macular degeneration, congestive heart failure, high triglycerides Bloody pancreatitis, sepsis, and systemic lupus.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the disclosed methods and compositions belong. C. Composition

As described above, in the first embodiment, provided herein is an aqueous pharmaceutical composition comprising: i) a simulated synthesis of the formula CH ₃ (CH ₂ ) _x C(O)-LRY ¹ LRY ² RLLR-DWLKAFYDKVAEKLKEAF-NH ₂ A peptide of lipoprotein element E (ApoE) or a pharmaceutically acceptable salt thereof, wherein x is an integer from 1 to 20, and Y ¹ and Y ² are each independently lysine or arginine; ii) polyoxygen Ethylene sorbitan fatty acid ester; and iii) cationic amino acid.

In a second embodiment, the cationic amino acid in the composition described herein is selected from arginine, lysine, histidine and ornithine. Alternatively, the cationic amino acid in the composition described herein is selected from arginine and lysine. In yet another alternative, the cationic amino acid in the composition described herein is arginine.

In the third embodiment, x in the peptide described herein is an integer from 3 to 18, wherein the remaining features are as described in the first or second embodiment. Alternatively, x is 4 to 16, wherein the remaining features are as described in the first or second embodiment. In another alternative, x is 5 to 14, wherein the remaining features are as described in the first or second embodiment. In another alternative, x is 5 to 13, wherein the remaining features are as described in the first or second embodiment. In another alternative, x is 6 to 12, wherein the remaining features are as described in the first or second embodiment.

In a fourth embodiment, the ApoE-mimetic peptide in the aqueous composition described herein has the formula CH ₃ (CH ₂ ) ₁₂ C(O)-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ or a pharmaceutically acceptable salt thereof , Where the remaining features are as described in the first or second embodiment.

In a fifth embodiment, the ApoE-mimetic peptide in the aqueous composition described herein has the formula CH ₃ (CH ₂ ) ₁₂ C(O)-LRKLRKRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ or a pharmaceutically acceptable salt thereof , Where the remaining features are as described in the first or second embodiment.

In a sixth embodiment, the ApoE-mimetic peptide in the aqueous composition described herein has the formula CH ₃ (CH ₂ ) ₆ C(O)-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ or a pharmaceutically acceptable salt thereof , Where the remaining features are as described in the first or second embodiment.

In a seventh embodiment, the ApoE-mimetic peptide in the aqueous composition described herein has the formula CH ₃ (CH ₂ ) ₆ C(O)-LRKLRKRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ or a pharmaceutically acceptable salt thereof , Where the remaining features are as described in the first or second embodiment.

In an eighth embodiment, the aqueous pharmaceutical composition comprises sterile water for injection (WFI), physiological saline or phosphate buffered physiological saline (PBS), or a combination thereof, wherein the remaining characteristics are first, second, third, It is described in the fourth, fifth, sixth or seventh embodiment.

In a ninth embodiment, the polyoxyethylene sorbitan fatty acid ester in the aqueous composition described herein is selected from polysorbate 20, polysorbate 40, polysorbate 60 And polysorbate 80, wherein the remaining features are as described in the first, second, third, fourth, fifth or sixth embodiment. Alternatively, the polyoxyethylene sorbitan fatty acid ester in the aqueous composition described herein is selected from polysorbate 20 and polysorbate 80, wherein the remaining characteristics are as first, second, It is described in the third, fourth, fifth, sixth, seventh or eighth embodiment. In another alternative, the polyoxyethylene sorbitan fatty acid ester in the aqueous composition described herein is polysorbate 80, wherein the remaining characteristics are as first, second, third, first 4. The fifth, sixth, seventh or eighth embodiment is described.

In the tenth embodiment, the molar ratio of the ApoE-mimetic peptide to the cationic amino acid present in the aqueous composition described herein is in the range of 1:1 to 1:90, with the remaining features as the first, It is described in the second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment. Alternatively, the molar ratio of the ApoE-mimetic peptide to the cationic amino acid present in the aqueous composition described herein is in the range of 1:3 to 1:60, with the remaining features such as first, second, and first The third, fourth, fifth, sixth, seventh, eighth or ninth embodiment is described. In another alternative, the molar ratio of ApoE-mimetic peptide to cationic amino acid present in the aqueous composition described herein is in the range of 1:30 to 1:60, wherein the remaining features are as follows: It is described in the second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment. In another alternative, the molar ratio of the ApoE-mimetic peptide to the cationic amino acid present in the aqueous composition described herein is in the range of 1:40 to 1:60, with the remaining features as the first, It is described in the second, third, fourth, fifth, sixth, seventh or eighth embodiment. In another alternative, the molar ratio of the ApoE-mimetic peptide to the cationic amino acid present in the aqueous composition described herein is in the range of 1:45 to 1:55, with the remaining features as the first, It is described in the second, third, fourth, fifth, sixth, seventh or eighth embodiment. In another alternative, the molar ratio of the ApoE-mimetic peptide to the cationic amino acid present in the aqueous composition described herein is 1:48, with the remaining characteristics such as first, second, third, It is described in the fourth, fifth, sixth, seventh, eighth or ninth embodiment.

In the eleventh embodiment, the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition described herein is less than 0.20, for example, less than or equal to 0.18, Less than or equal to 0.17, less than or equal to 0.16, less than or equal to 0.15, less than or equal to 0.14, or less than or equal to 0.12, where the remaining features are first, second, third, fourth, fifth, sixth, seventh , The eighth ninth or tenth embodiment. Alternatively, the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition described herein is in the range of 0.01 to 0.17, wherein the remaining characteristics are as follows: Second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment are described. In another alternative, the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition described herein is in the range of 0.01 to 0.05, with the remaining characteristics as It is described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiments. In another alternative, the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition described herein is in the range of 0.01 to 0.02, wherein the remaining characteristics are as follows It is described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiments. In another alternative, the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition described herein is in the range of 0.02 to 0.17, wherein the remaining characteristics are as follows It is described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiments. In another alternative, the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition described herein is in the range of 0.03 to 0.17, wherein the remaining characteristics are as follows It is described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiments. In another alternative, the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition described herein is in the range of 0.05 to 0.17, with the remaining characteristics as It is described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiments. In another alternative, the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition described herein is in the range of 0.05 to 0.19. In another alternative, the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition described herein is in the range of 0.10 to 0.19, wherein the remaining characteristics are as follows It is described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiments. In another alternative, the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition described herein is in the range of 0.3 to 0.18, wherein the remaining characteristics are as follows It is described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiments. In another alternative, the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition described herein is in the range of 0.5 to 0.17, wherein the remaining characteristics are as follows It is described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiments. In another alternative, the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition described herein is 0.16, wherein the remaining characteristics are as follows: Second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment are described.

In a twelfth embodiment, the concentration of the ApoE-mimetic peptide or pharmaceutically acceptable salt present in the aqueous composition described herein is in the range of 0.1 mg/mL to 10 mg/mL, with the remaining The features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh embodiments. Alternatively, the concentration of the ApoE-mimetic peptide or its pharmaceutically acceptable salt present in the aqueous composition described herein is in the range of 0.8 mg/mL to 8.0 mg/mL, wherein the remaining characteristics are as follows: It is described in the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh embodiments. In another alternative, the concentration of the ApoE-mimetic peptide or pharmaceutically acceptable salt present in the aqueous composition described herein is in the range of 1.0 mg/mL to 5.5 mg/mL, with the remaining features As described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh embodiment. In another alternative, the concentration of the ApoE-mimetic peptide or pharmaceutically acceptable salt present in the aqueous composition described herein is in the range of 4.0 mg/mL to 6.5 mg/mL, with the remaining features As described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh embodiment. In another alternative, the concentration of the ApoE-mimetic peptide or pharmaceutically acceptable salt present in the aqueous composition described herein is in the range of 5.0 mg/mL to 6.0 mg/mL, with the remaining features As described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh embodiment. In another alternative, the concentration of the ApoE-mimetic peptide or pharmaceutically acceptable salt present in the aqueous composition described herein is 1 mg/mL, 2.5 mg/mL, or 5 mg/mL, The remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh embodiments. In another alternative, the concentration of the ApoE-mimetic peptide or its pharmaceutically acceptable salt present in the aqueous composition described herein is 5 mg/mL, wherein the remaining characteristics are first, second, It is described in the third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh embodiments.

In the thirteenth embodiment, the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester in the aqueous composition described herein form particles, wherein the remaining characteristics are as first, second, third, It is described in the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments.

In the fourteenth embodiment, the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester in the aqueous composition described herein form particles with an average particle size of less than 20 nm, wherein the remaining features are as the first , Second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiment. Alternatively, the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester in the aqueous composition described herein form particles with an average particle size in the range of 2 nm to 17 nm, wherein the remaining characteristics are as the first , Second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiment. In another alternative, the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester in the aqueous composition described herein form particles having an average particle size in the range of 5 nm to 15 nm, of which the remaining The features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. In another alternative, the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester in the aqueous composition described herein form particles having an average particle size in the range of 5 nm to 12 nm, of which the remaining The features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments. In another alternative, the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester in the aqueous composition described herein form particles having an average particle size in the range of 6 nm to 10 nm, of which the remaining The features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments.

In the fifteenth embodiment, the ApoE-mimetic peptide and polyoxyethylene sorbitan fatty acid ester in the aqueous composition described herein are formed into microcell particles, wherein the remaining features are as the first and second , Third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or fourteenth embodiment.

In the sixteenth embodiment, the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester in the aqueous composition described herein are formed into particles of microcells, and the microcells are evenly distributed throughout the aqueous In the composition, the remaining characteristics such as the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, fourteenth or Described in the fifteenth embodiment.

Other examples of compositions including the independent components of the peptides and/or phospholipids described herein are provided in the illustration. In an embodiment, the compositions described herein encompass all disclosed peptides and phospholipids, as well as combinations and variations thereof as further illustrated in the illustration. D. Use and administration

Disclosed herein is a method for affecting plasma LDL, plasma very low density lipoprotein (VLDL), or both, which comprises administering a composition comprising: i) Formula CH ₃ (CH ₂ ) _x C(O)-LRY ¹ LRY ² RLLR-DWLKAFYDKVAEKLKEAF-NH ₂ analog synthetic lipoprotein element E (ApoE) peptide or a pharmaceutically acceptable salt thereof, where x is an integer from 1 to 20, and Y ¹ and Y ² are each independently Lysine or arginine; ii) phospholipids as described herein; and iii) cationic amino acids. In one aspect, plasma LDL, plasma VLDL, or both are affected. In another aspect, the binding of LDL to individual cells is enhanced. In another aspect, the individual's cells have increased degradation of LDL. In another aspect, the LDL cholesterol in the individual is reduced. In another aspect, the binding of VLDL to individual cells is enhanced. In another aspect, the individual's cells have increased degradation of VLDL. In another aspect, the VLDL cholesterol in the individual is reduced. In another aspect, the total plasma concentration of cholesterol in the individual is reduced. In one aspect, in a method that affects plasma LDL, plasma VLDL, or both, the disclosed peptides simulating synthetic lipoprotein element E (ApoE) range from about 0.1 mg/kg to about 20 mg/kg, such as 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 mg/kg or any range in between.

This article also discloses a method for treating atherosclerosis, which comprises administering to a subject in need a simulated synthetic lipid of formula i) CH ₃ (CH ₂ ) _x C(O)-LRY ¹ LRY ² RLLR-DWLKAFYDKVAEKLKEAF-NH ₂ A peptide of protein element E (ApoE) or a pharmaceutically acceptable salt thereof, wherein x is an integer from 1 to 20, and Y ¹ and Y ² are each independently lysine or arginine; and iii) cationic amine Base acid. In one aspect of the method for treating atherosclerosis, the disclosed peptides simulating synthetic lipoprotein element E (ApoE) range from about 0.01 mg/kg to about 20 mg/kg, such as 0.1, 1, 2, 3 , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 mg/kg or any range in between.

Also disclosed is a method of treating individuals suffering from lipid disorders, which comprises administering to a subject in need a simulated synthetic lipid of formula i) CH ₃ (CH ₂ ) _x C(O)-LRY ¹ LRY ² RLLR-DWLKAFYDKVAEKLKEAF-NH ₂ A peptide of protein element E (ApoE) or a pharmaceutically acceptable salt thereof, wherein x is an integer from 1 to 20, and Y ¹ and Y ² are each independently lysine or arginine; and iii) cationic amine Base acid. In one aspect, the lipid disorder is selected from coronary artery disease, rheumatoid arthritis, systemic lupus, diabetes, Alzheimer's disease, peripheral arterial disease (PAD), diabetes-derived cardiovascular disease, macular degeneration , Hypertriglyceridemia pancreatitis, sepsis and congestive heart failure. In one aspect of the method for treating lipid disorders, the disclosed peptides simulating synthetic lipoprotein element E (ApoE) range from about 0.01 mg/kg to about 20 mg/kg, such as 0.1, 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 mg/kg or any range in between.

Also disclosed is a method for treating acute coronary syndrome (ACS), which includes administering a synthetic synthesis of i) formula CH ₃ (CH ₂ ) _x C(O)-LRY ¹ LRY ² RLLR-DWLKAFYDKVAEKLKEAF-NH _{2 to individuals} in need A peptide of lipoprotein element E (ApoE) or a pharmaceutically acceptable salt thereof, wherein x is an integer from 1 to 20, and Y ¹ and Y ² are each independently lysine or arginine; ii) as described herein Phospholipids as described in; and iii) cationic amino acids. In one aspect of the method for treating ACS, the disclosed peptides simulating synthetic lipoprotein element E (ApoE) range from about 0.01 mg/kg to about 20 mg/kg, such as 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 mg/kg or any range in between.

The dose (dose, dosage) of the composition described herein can vary depending on many factors, such as but not limited to the patient's age, condition, gender and degree of disease, route of administration, length of treatment cycle or whether other drugs are included in In the scheme, and can be determined by those skilled in the art.

The effective dose can be determined empirically, and it is within the skill of this technique to make such determinations. The dosage range of the administered composition is a dosage range large enough to produce the desired effect of treating the disease. For example, a dose may be an amount effective to provide a therapeutic effect and provide or allow a sustained therapeutic effect even after stopping treatment. The therapeutic effect may be, but not limited to, a reduction in atherosclerotic lesions, a decrease in atherosclerosis, a decrease in independent systolic hypertension, an increase in vasodilation, or an improvement in heart function. The therapeutic effect can be measured by markers of arterial inflammation, such as but not limited to C-reactive protein. The therapeutic effect can be measured by atherosclerosis imaging techniques, which include MRI, intravascular ultrasound, ultra-fast imaging CT scan, B-mode ultrasound, virtual histology intravascular ultrasound, optical coherence tomography Technique or other known methods.

The dose should not be so large as to cause adverse side effects, such as unwanted cross-reactions, allergic reactions, and similar effects. In the case of any contraindications, the dose can be adjusted by individual physicians. The dosage can vary and can be administered in one or more doses per day for one or more days. Guidance on the appropriate dosage of designated pharmaceutical products can be found in the literature.

In the methods described herein, any suitable route of administration can be used for the disclosed compositions. Suitable routes of administration may include, for example, topical, enteral, local, systemic, or parenteral. For example, administration may be supradermal, inhalation, enema, transconjunctival, eye drops, ear drops, alveoli, nasal, intranasal, enteral, oral, intraoral, oral, enteral, rectal , Intrarectal, transrectal, injection, infusion, intravenous, intraarterial, intramuscular, intracerebral, intraventricular, intraventricular, intracardiac, subcutaneous, intraosseous, intradermal, intrathecal, intraperitoneal, intravesical, Cavernous, intramedullary, intraocular, intracranial, transdermal, transmucosal, nasal, inhalation, intracisternal, epidural, peridural, intravitreal, etc. The disclosed composition can be used in and with any other therapy.

In one aspect, the disclosed composition is an aqueous formulation present in, for example, H ₂ O (eg, water for injection (WFI)), PBS (eg, sterile PBS), and the like.

The foregoing formulations and methods of administration are intended to be illustrative and non-limiting. It should be understood that using the teachings provided in this article, other suitable formulations and modes of administration can be easily designed. Examples Example 1 : General peptide synthesis

The peptides described herein are prepared via standard solid phase synthesis procedures. AEM-28, AEM-28-08 and AEM-28-14 were prepared according to the procedures described in US Patent No. 6,506,880 and WO 2016/018665 and following the following standard solid phase synthesis procedures. Example 2 : Stock solution preparation

The following shows a general method for preparing 5.0 mg/mL AEM-28-14 and AEM-28-8 stock formulations with Tween ^™ 80 and arginine in PBS. 5.0 mg / mL AEM-28-14 stock formulation (with arginine and Tween ^TM 80 in PBS) peptide: Tween ^TM 80 0 16 mole ratio peptide: arginine molar ratio of 1: 48

The stock formulation is 5.0 mg/mL of AEM-28-14 (active basis) in vehicle. The carrier is pH 1 adjusted to 7.0 in 1X-PBS (137 mM NaCl, 2.7 mM KCl, 9.5 mM phosphate buffer. Does not contain magnesium or calcium. For example, VWR phosphate buffer solution (PBS), product #97062 -818) of 11 mg/mL L-arginine and 10.6 mg/mL Tween ^TM 80. A 5 mg/mL stock solution can be used to prepare any comparison by diluting the 5 mg/mL stock solution with an appropriate volume of PBS Low AEM-28-14 dosing formulation. Note: L-arginine is very basic, and therefore a pH adjustment step is required after the addition of arginine to bring the carrier pH to 7.0-7.4.

The carrier is prepared by the following from 1X-PBS: 1) Add 11.0 mg/mL L-arginine to PBS (arginine should be easy to enter the solution with gentle mixing), 2) use 5 N Hydrochloric acid adjusts the pH of the PBS/spermine acid solution to pH 6.9-7.1, and 3) Add 10.6 mg/mL Tween ^TM 80 to the PBS/spermine acid solution (Tween ^TM 80 will mix gently within 10-15 minutes Into the solution under the circumstances). Note: Vortex or excessive stirring will cause Tween ^TM 80 to foam in the solution, so use gentle mixing or sonic treatment to avoid foaming.

Stock formulations were then prepared by weighing the peptide into a suitable glass bottle, and then adding the appropriate amount of vehicle by volume to produce a solution of 5.0 mg/mL active AEM-28-14. The mixture should be gently vortexed in a room temperature sonicated bath until all peptides are completely in solution (about 5 minutes, but larger batches can take longer). The peptide will initially form a slightly turbid mixture, but under more time and sonication, the peptide should completely enter the solution, resulting in a clear solution. Note: The AEM-28-14 peptide has 86.4% activity, so the peptide weighing step should consider the activity.

The final 5.0 mg/mL stock formulation should be a clear solution without any solids or contaminants at a pH between 6.90-7.10. The formulation for administration can be sterile filtered (0.2 μm poly-sand filter or the like). Administration formulations can be stored at room temperature for up to 24 hours, or at 2-8°C for 72 hours. [Dosage formulation should be warmed to room temperature before administration or filtration].

g. 無菌過濾溶液(0.2 μm聚碸膜)。 h. 當不使用時冷藏(2-8℃)儲存。在給藥或過濾之前升溫至室溫。 i. 經調配之溶液可在室溫下至多24小時，或保持冷藏至多72小時。For example, to prepare 40 mL of 5.0 mg/mL AEM-28-14 stock formulation (adjust to other volumes as needed):Preparation of vehicle 1) Add arginine to 100.0 mL of PBS solution. a. Weigh 1.100 +/- 0.005 g of L-arginine into a clean glass bottle (L-arginine USP, Sigma product #A4474 or similar). b. Mix or manually mix on a stirring plate until the solution is clear (less than 1 minute). c. Add a pH probe to detect the pH, and add 5 N HCl solution dropwise to bring the pH to 7.00-7.20. (HCl solution, 5.0 N, VWR product # BDH7419 or similar). This will add approximately 0.8% by volume, or for a 100 mL vehicle, 0.6-1.0 mL 5 N HCl. 2) Tween^TM 80 added to PBS/arginine solution a. Weigh 1.062 +/- 0.005 g Tween in a clean glass bottle^TM 80 (polysorbate 80, Sigma product #59924 or similar). b. Add 100 mL of pH-adjusted PBS/Arginine solution. c. Mix on a stirring plate until clear solution (10 minutes to 15 minutes).Active reserve formulation 3) Prepare 40 mL of the carrier (PBS/Arginine/Tween^TM 80) of 5.0 mg/mL AEM-28-14. a. Weigh 231.50 +/- 0.20 mg of AEM-28-14 (equivalent to 200.0 mg 86.4% active peptide) into a clean glass bottle. b. 40.00 +/- 0.10 mL PBS/Arginine/Tween by volume^TM Add 80 vehicle to the bottle. Close the cap. c. Treat the bottle with gentle manual vortex at room temperature (15℃-25℃) until all peptides are completely dissolved (approximately 10 minutes). Do not shake or vigorously mix the contents of the bottle because it can cause excessive foaming. d. Check that the pH is at 7.0 (6.85-7.15). If not, you can adjust the pH with 5 N HCl or 5 N NaOH, as long as you need to adjust no more than 0.8% of the total volume [for a 40 mL total formulation, adjust no more than an additional 0.50 mL]. e. Ensure a clear solution free of contaminants. f. 5.0 mg/mL AEM-28-14 stock formulation can be used to prepare any lower concentration formulation by volume dilution with PBS:

g. Sterile filtered solution (0.2 μm poly sieving membrane). h. Store in a refrigerator (2-8°C) when not in use. Warm to room temperature before administration or filtration. i. The formulated solution can be kept at room temperature for up to 24 hours, or kept refrigerated for up to 72 hours.

The AEM-28-8 formulation was prepared in the same way as the AEM-28-14 formulation. The same PBS/arginine/Tween ^™ 80 carrier can be used for both formulations. The formulated solution can be kept at room temperature for up to 24 hours, or kept refrigerated for up to 72 hours. Example 3 : Toxicity study

Conduct a study to determine whether a composition containing a peptide that mimics ApoE (AEM-28-14 or AEM-28-08) and a polyoxyethylene sorbitan fatty acid ester (Tween ^TM 20 or Tween ^TM 80) has and does not Potential toxicity with cationic amino acid L-spermine. Study A: When administered to Sprague Dawley rats at a full dosage form of a single intravenous injection, physiological saline containing AEM - 28 - 14 and Tween ^TM 20 having no L - arginine of the compositions Toxicity

^a 在第1天經由尾部靜脈經由一次全劑量靜脈內注射投與測試材料。^b 在第1天經由尾部靜脈在2-4分鐘內經由緩慢一次全劑量靜脈內注射投與測試材料。The experimental design of the test material without L-arginine is shown in Table 1 . Table 1

^a Test material was administered via a full-dose intravenous injection via the tail vein on day 1. ^b . The test material is administered via the tail vein via a slow full dose intravenous injection within 2-4 minutes on day 1.

The assessment of toxicity is based on mortality/dying, clinical observation, weight change, overall autopsy study results, and histopathological examination. On Day 1, due to adverse clinical signs, males and females of AEM-28-14 (Group 1) will be euthanized by a full-dose intravenous injection at 20 mg/kg for humane reasons. Relevant clinical signs were noted in surviving male and female animals given at 10 mg/kg (full dose group 2 and slow once full dose group 4) and 15 mg/kg slow dose full dose (group 3) . Clinical signs include skin discoloration of the tail (light, red, blue, and/or black), swollen tail, crust of the tail, and/or red urine. The clinical signs (discoloration, swelling, and crusting) associated with the tail are related to the relevant histology. Note the results of the related total autopsy study (dark discoloration of the tail) of males given at a slow full dose of 10 mg/kg (Group 4). Discoloration of the tail is associated with bleeding identified with a microscope in the soft tissue of the tail. Noted in rats administered with each of the 10 mg/kg (full once dose group 2 and slow once full dose group 4) and 15 mg/kg slow once full dose (group 3) experiments Results of treatment-related and undesirable histological studies. The most severe study results of full-thickness necrosis (infarction) of the tail can be seen in all tissues examined with a microscope, among which the incidence and severity are highest in animals administered with a slow full dose injection of 15 mg/kg.

In summary, due to the dying condition, for humane reasons, male and female rats administered with AEM-28-14 at 20 mg/kg via a full-dose intravenous injection (Group 1) were euthanized. When administered via a slow full-dose injection, microscopic studies of the tail include acute bleeding, subcutaneous crystals (probably bilirubin in males), epidermal necrosis (administered at 10 mg/kg in males only), blood vessels Infiltration of surrounding inflammatory cells and muscle atrophy. When administered via a full-dose injection, microscopic studies of the tail include serous cell scab (male only) and skeletal muscle atrophy. In addition, at all dose levels, thrombi are present in one or both tail veins and/or tail arteries. Based on these results, AEM-28-14 in 1% Tween ^TM 20 in saline was administered by intravenous injection (full dose once or slowly once dose) once daily at a content of ≥ 10 mg/kg Intolerance in rats. Study B: When in the form of a full dose of a single intravenous injection administered to Sprague Dawley rats, physiological saline containing AEM - 28 - 14 and Tween ^TM 20 having a L - arginine toxicity of the composition

^a 給藥第1組第一隻動物且監測(籠側觀測)最少1小時。由於未觀測到顯著不良的臨床徵象，給藥第1組剩餘動物。^b 在完成第1組給藥之後給藥第2組第一隻動物。由於在給藥之後不久觀測到顯著不良的臨床徵象，第2組剩餘3隻動物未給藥且免於研究。The experimental design of the test material with L-arginine is shown in Table 2 . The experiment was performed with a single full-dose intravenous injection into Spagdoli rats.

^a Administer the first animal in Group 1 and monitor (observe on the cage side) for at least 1 hour. Since no significant adverse clinical signs were observed, the remaining animals in Group 1 were administered. ^{b The} first animal in group 2 is administered after the completion of group 1 administration. Due to the observation of significant adverse clinical signs shortly after dosing, the remaining 3 animals in Group 2 were not dosed and were exempt from the study.

The assessment of toxicity is based on the following endpoints in the study: mortality examination and clinical observation. On Day 1, due to its dying condition shortly after the administration, for humane reasons, rats given 20 and 70 mg/kg of AEM-28-14/arginine were euthanized. However, clinical observations related to AEM-28-14 in males given AEM-28-14/arginine at 15 and 52.5 mg/kg included irregular breathing, which was normalized within 30 minutes after administration without further Adverse clinical signs. Overall, when combined with arginine in a single intravenous full-dose injection, AEM-28-14 administered at levels of 15 and 52.5 mg/kg, respectively, is well tolerated in rats . This data confirms that formulations containing arginine reduce toxicity. Example 4 : Lower total cholesterol

A comparative study between the efficacy of AEM-28-14 against negative (vehicle) controls in test formulations for reducing total serum cholesterol (CHOL) was performed. The summary of test items is shown below.

As determined by the staff veterinarian, a total of fifteen untreated female Apo-E (-/-) mice were assigned to the study based on acceptable health conditions. On the study day beginning at approximately 0800 hours, all animals were fasted for 4 hours, where food was recovered five (5) hours after the administration of blood collection. Prior to the 24-hour collection, the animals followed the same fasting protocol. The study design is as follows.

X = 所採集之樣品。^a 在4小時禁食之後採集之樣品。^b 在給藥之前採集之樣品。^c 在樣品採集之後恢復之食物。Each animal receives a single intravenous dose of the prepared test article at the target dose level and dose volume indicated above. As outlined in the sample collection table below, whole blood samples were collected from each animal by perforating the submandibular vein.

X = sample collected. ^a Sample collected after 4 hours of fasting. ^b Samples collected before administration. ^c Food recovered after sample collection.

All blood samples were collected into test tubes without additives and allowed to stand at room temperature for a minimum of 30 minutes to permit clump formation. After the complete clot was retracted, the sample was centrifuged at 2200 × g for 10 minutes at 22°C to separate the serum. The resulting serum was transferred to individual polypropylene test tubes in a 96-well tray format and immediately placed on dry ice until stored at a nominal -70°C. After the study was completed, serum samples were transferred to Charles River Immunology Laboratory, Shrewsbury MA for total cholesterol analysis using ELISA Wako Kit (ID# 439-17501). The total cholesterol results are shown in Figure 1 . As shown, the efficacy of AEM-28-14 with and without L-arginine is almost similar.

Figure 1 illustrates the change in cholesterol (mg/dL) of AEM-28-14 and AEM-28-14 with L-arginine at a concentration of 0.4 mg/kg over time, where a ) represents total cholesterol and b ) Represents the percentage (%) change in total cholesterol.

Claims (45)

An aqueous pharmaceutical composition comprising i) a peptide that mimics synthetic lipoprotein element E (ApoE) of the formula CH ₃ (CH ₂ ) _x C(O)-LRY ¹ LRY ² RLLR-DWLKAFYDKVAEKLKEAF-NH ₂ or its pharmaceutical An acceptable salt, where x is an integer from 1 to 20, and Y ¹ and Y ² are each independently lysine or arginine; ii) polyoxyethylene sorbitan fatty acid ester; and iii) cation Amino acid. The aqueous pharmaceutical composition according to claim 1, wherein the cationic amino acid is selected from arginine, lysine, histidine and ornithine. The aqueous pharmaceutical composition according to claim 1 or 2, wherein the cationic amino acid is selected from arginine and lysine. The aqueous pharmaceutical composition according to any one of claims 1 to 3, wherein the cationic amino acid is arginine. The aqueous pharmaceutical composition according to any one of claims 1 to 4, wherein x is an integer of 3 to 18. The aqueous pharmaceutical composition according to any one of claims 1 to 5, wherein x is an integer of 4 to 16. The aqueous pharmaceutical composition according to any one of claims 1 to 6, wherein x is an integer of 5 to 14. The aqueous pharmaceutical composition according to any one of claims 1 to 7, wherein x is an integer of 5 to 13. The aqueous pharmaceutical composition according to any one of claims 1 to 8, wherein x is an integer of 6 to 12. The aqueous pharmaceutical composition according to any one of claims 1 to 9, wherein the ApoE-mimetic peptide has the formula CH ₃ (CH ₂ ) ₁₂ C(O)-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ or a pharmaceutically acceptable salt. The aqueous pharmaceutical composition according to any one of claims 1 to 9, wherein the ApoE-mimetic peptide has the formula CH ₃ (CH ₂ ) ₁₂ C(O)-LRKLRKRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ or a pharmaceutically acceptable salt. The aqueous pharmaceutical composition according to any one of claims 1 to 9, wherein the ApoE-mimetic peptide has the formula CH ₃ (CH ₂ ) ₆ C(O)-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ or a pharmaceutically acceptable salt. The aqueous pharmaceutical composition according to any one of claims 1 to 9, wherein the ApoE-mimetic peptide has the formula CH ₃ (CH ₂ ) ₆ C(O)-LRKLRKRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ or a pharmaceutically acceptable salt. The aqueous pharmaceutical composition according to any one of claims 1 to 13, wherein the polyoxyethylene sorbitan fatty acid ester is selected from polysorbate 20, polysorbate 40, polysorbate 60 and polysorbitol ester 80. The aqueous pharmaceutical composition according to any one of claims 1 to 14, wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 20 or polysorbate 80. The aqueous pharmaceutical composition according to any one of claims 1 to 15, wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 80. The aqueous pharmaceutical composition according to any one of claims 1 to 16, wherein the molar ratio of the ApoE-mimetic peptide to the cationic amino acid present in the aqueous composition is in the range of 1:1 to 1:90. The aqueous pharmaceutical composition according to any one of claims 1 to 17, wherein the molar ratio of the ApoE-mimetic peptide to the cationic amino acid present in the aqueous composition is in the range of 1:45 to 1:55. The aqueous pharmaceutical composition according to any one of claims 1 to 17, wherein the molar ratio of the ApoE-mimetic peptide to the cationic amino acid present in the aqueous composition is 1:48. The aqueous pharmaceutical composition according to any one of claims 1 to 19, wherein the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition is less than 0.20, less than or Equal to 0.17 or less than or equal to 0.15. The aqueous pharmaceutical composition according to any one of claims 1 to 19, wherein the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition is in the range of 0.01 to 0.17 Within, within the range of 0.01 to 0.05, within the range of 0.01 to 0.02, within the range of 0.02 to 0.17, within the range of 0.03 to 0.17, or within the range of 0.05 to 0.17. The aqueous pharmaceutical composition according to any one of claims 1 to 19, wherein the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition is less than 0.20. The aqueous pharmaceutical composition according to any one of claims 1 to 19, wherein the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition is in the range of 0.05 to 0.19 Inside. The aqueous pharmaceutical composition according to any one of claims 1 to 19, wherein the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition is in the range of 0.10 to 0.19 Inside. The aqueous pharmaceutical composition according to any one of claims 1 to 19, wherein the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition is in the range of 0.3 to 0.18 Inside. The aqueous pharmaceutical composition according to any one of claims 1 to 19, wherein the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition is in the range of 0.5 to 0.17 Inside. The aqueous pharmaceutical composition according to any one of claims 1 to 19, wherein the molar ratio of the ApoE-simulating peptide and polyoxyethylene sorbitan fatty acid ester present in the aqueous composition is 0.16. The aqueous pharmaceutical composition according to any one of claims 1 to 27, wherein the concentration of the ApoE-mimetic peptide or pharmaceutically acceptable salt present in the aqueous composition is 0.1 mg/mL to 10 mg/mL Within range. The aqueous pharmaceutical composition according to any one of claims 1 to 28, wherein the concentration of the ApoE-mimetic peptide or pharmaceutically acceptable salt thereof present in the aqueous composition is 0.8 mg/mL to 8.0 mg/ Within the range of mL. The aqueous pharmaceutical composition according to any one of claims 1 to 29, wherein the concentration of the ApoE-mimetic peptide or pharmaceutically acceptable salt thereof present in the aqueous composition is 1.0 mg/mL to 5.5 mg/ Within the range of mL. The aqueous pharmaceutical composition according to any one of claims 1 to 30, wherein the concentration of the ApoE-simulating peptide or its pharmaceutically acceptable salt present in the aqueous composition is 1 mg/mL, 2.5 mg/ mL or 5 mg/mL. The aqueous pharmaceutical composition according to any one of claims 1 to 31, wherein the concentration of the ApoE-mimetic peptide or its pharmaceutically acceptable salt present in the aqueous composition is 5 mg/mL. The aqueous pharmaceutical composition according to any one of claims 1 to 32, wherein the ApoE-mimetic peptide and polyoxyethylene sorbitan fatty acid ester form particles. The aqueous pharmaceutical composition according to any one of claims 1 to 33, wherein the ApoE-mimetic peptide and polyoxyethylene sorbitan fatty acid ester form particles having an average particle diameter of less than 20 nm. The aqueous pharmaceutical composition according to any one of claims 1 to 34, wherein the ApoE-mimetic peptide and polyoxyethylene sorbitan fatty acid ester form particles having an average particle diameter in the range of 2 nm to 17 nm. The aqueous pharmaceutical composition according to any one of claims 1 to 35, wherein the ApoE-mimetic peptide and polyoxyethylene sorbitan fatty acid ester form particles having an average particle diameter in the range of 5 nm to 15 nm. The aqueous pharmaceutical composition according to any one of claims 1 to 36, wherein the ApoE-mimetic peptide and polyoxyethylene sorbitan fatty acid ester form particles having an average particle diameter in the range of 5 nm to 12 nm. The aqueous pharmaceutical composition according to any one of claims 1 to 37, wherein the ApoE-mimetic peptide and polyoxyethylene sorbitan fatty acid ester form particles having an average particle diameter in the range of 6 nm to 10 nm. The aqueous pharmaceutical composition according to any one of claims 1 to 38, wherein the ApoE-mimetic peptide and polyoxyethylene sorbitan fatty acid ester are formed into particles of microcells. The aqueous pharmaceutical composition according to any one of claims 1 to 39, wherein the ApoE-mimetic peptide and polyoxyethylene sorbitan fatty acid ester are formed into particles of microcells, and the microcells are evenly distributed throughout the entire In an aqueous composition. A method for reducing plasma cholesterol in an individual in need thereof, which comprises administering to the individual an effective amount of the aqueous pharmaceutical composition according to any one of claims 1 to 40. A method of treating an individual suffering from a condition selected from atherosclerosis, acute coronary syndrome (ACS), coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer's disease, peripheral arterial disease ( PAD), cerebrovascular disease, diabetes-derived cardiovascular disease, macular degeneration, congestive heart failure, high triglyceride hemorrhagic pancreatitis, sepsis, and systemic lupus; the method involves administering an effective amount to the individual as requested Item 1 to 40 The aqueous pharmaceutical composition of any one. The method of claim 42, wherein the condition is atherosclerosis. The method of any one of claims 41 to 43, wherein the ApoE-mimetic peptide is administered at a concentration in the range of 0.1 mg/kg to 20 mg/kg. The method according to any one of claims 41 to 44, wherein the ApoE-mimetic peptide is administered at a concentration of 5 mg/kg.

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