Water-soluble composition and use thereof

Abstract

This disclosure relates to a water-soluble composition and its use. The water-soluble composition of this disclosure includes a pharmaceutically active ingredient, a cationic lipid, and a penetration enhancer, wherein the solubility of the pharmaceutically active ingredient in water is less than or equal to 1 mg / mL, the cationic lipid includes dioleoylpropyltrimethylammonium chloride, and the penetration enhancer includes polyethylene glycol glycerol linoleate. This disclosure improves the solubility of a poorly water-soluble pharmaceutically active ingredient in water and enhances its in vivo efficacy by using the cationic lipid and the penetration enhancer in combination.

Description

Technical Field

[0001] This disclosure relates to the pharmaceutical field, specifically to a water-soluble composition and its uses. Background Technology

[0002] The solubility of a drug is closely related to its therapeutic effect; reduced drug solubility may greatly reduce the drug's efficacy in the body.

[0003] Taking eye diseases as an example, endoplasmic reticulum stress inhibitors are a novel approach for the prevention and treatment of myopia. However, most known endoplasmic reticulum stress inhibitors are poorly water-soluble drugs. This low solubility reduces their in vivo efficacy, significantly limiting their development and use.

[0004] Therefore, there is an urgent need to develop a water-soluble composition to improve the solubility of poorly soluble active pharmaceutical ingredients in water, thereby improving their bioavailability and therapeutic effect. Summary of the Invention

[0005] In view of this, the present disclosure provides a water-soluble composition and its use, which aims to improve the problem of low solubility of poorly soluble drug active ingredients in water and further improve the in vivo efficacy of poorly soluble drug active ingredients.

[0006] According to one embodiment of the present disclosure, a water-soluble composition is provided, the water-soluble composition comprising a pharmaceutical active ingredient, a cationic lipid, and a penetration enhancer, wherein the solubility of the pharmaceutical active ingredient in water is less than or equal to 1 mg / mL, the cationic lipid comprises dioleoylpropyltrimethylammonium chloride, and the penetration enhancer comprises polyethylene glycol glycerol linoleate.

[0007] According to one embodiment of the present disclosure, the use of a water-soluble composition according to the present disclosure in the preparation of a medicament for treating, preventing or diagnosing a disease is provided, optionally, the disease includes diseases that benefit from the inhibition of endoplasmic reticulum stress, further optionally, the disease includes an eye disease, and more optionally, the disease includes at least one of myopia, thinning of the choroid or sclera, increased refractive power, and axial elongation.

[0008] According to one embodiment of the present disclosure, the use of cationic lipids and penetration enhancers in improving the solubility of a pharmaceutical active ingredient in water, wherein the solubility of the pharmaceutical active ingredient in water is less than or equal to 1 mg / mL, wherein the cationic lipid comprises dioleoylpropyltrimethylammonium chloride, and the penetration enhancer comprises polyethylene glycol glycerol linoleate.

[0009] Using a single surfactant is no longer sufficient to meet the need to improve the solubility of poorly soluble pharmaceutical active ingredients in water. This disclosure promotes the dissolution of poorly soluble pharmaceutical active ingredients in water by combining cationic lipids and penetration enhancers, thereby significantly improving their solubility in water and enhancing their in vivo efficacy.

[0010] The above description is merely an overview of the technical solution disclosed herein. In order to better understand the technical means of this disclosure and to implement it in accordance with the contents of the specification, and to make the above and other objects, features and advantages of this disclosure more apparent and understandable, specific embodiments of this disclosure are described below. Detailed Implementation

[0011] Unless otherwise stated, all figures used in this specification and claims to represent content, concentration, proportion, weight, particle size, percentage, technical effect, etc., should in any instance be understood to be modified by the terms “about” or “approximately”. Therefore, unless indicated to the contrary, the numerical parameters listed in the following specification and appended claims are approximate values. Unless otherwise stated, the terminology used herein has its common meaning as understood by one of ordinary skill in the art. It may vary for those skilled in the art depending on the desired properties and effects sought through this disclosure, and each numerical parameter should be interpreted according to the number of significant figures and conventional rounding methods or as understood by those skilled in the art.

[0012] Although the numerical ranges and parameters described in this disclosure are approximate, the values ​​presented in the specific embodiments are provided as precisely as possible. However, any numerical value will inherently contain some errors, which are necessarily caused by the standard deviation found in its corresponding test measurements. Each numerical range given in this specification will include every narrower numerical range falling within that wider range, as if these narrower numerical ranges were explicitly stated herein.

[0013] When used in this paper, the expression "A and B" includes three cases: (1) A; (2) B; (3) A and B. The meanings of similar expressions can be inferred by analogy.

[0014] Water-soluble composition

[0015] This disclosure provides a water-soluble composition comprising a pharmaceutical active ingredient, a cationic lipid, and a penetration enhancer, wherein the solubility of the pharmaceutical active ingredient in water is less than or equal to 1 mg / mL, the cationic lipid comprises dioleoylpropyltrimethylammonium chloride, and the penetration enhancer comprises polyethylene glycol glycerol linoleate.

[0016] When used in this document, the term "cationic lipid" refers to a class of lipid molecules with a positive charge.

[0017] When used in this article, the term "penetration enhancer" refers to a component that can improve the permeability of a substance.

[0018] This disclosure combines cationic lipids and penetration enhancers, which is beneficial for promoting the dissolution of poorly water-soluble active pharmaceutical ingredients in water, increasing their solubility in water, and enhancing their in vivo efficacy.

[0019] In this paper, the term "solubility" refers to the mass of solute that dissolves in 100g of solvent at a given temperature (e.g., 25°C) to reach saturation.

[0020] The solubility of the active pharmaceutical ingredient in water can be measured using methods and equipment known in the art. Specifically, the relevant description of solubility in the General Principles of the Pharmacopoeia of the People's Republic of China can be used for measurement.

[0021] In some embodiments of this disclosure, the solubility of the active pharmaceutical ingredient in water is less than or equal to 1 mg / mL. It is understood that the solubility of the active pharmaceutical ingredient in water can be any value within the range of less than or equal to 1 mg / mL, such as 1 mg / mL, 0.99 mg / mL, 0.9 mg / mL, 0.8 mg / mL, 0.7 mg / mL, 0.6 mg / mL, 0.5 mg / mL, 0.4 mg / mL, 0.3 mg / mL, 0.2 mg / mL, 0.1 mg / mL, 0.01 mg / mL, or other unlisted values ​​within the range of less than or equal to 1 mg / mL.

[0022] In some embodiments of this disclosure, the water-soluble composition may further include a second pharmaceutically active ingredient, the solubility of which in water may be less than or equal to 1 mg / mL or greater than 1 mg / mL.

[0023] In some embodiments of this disclosure, the mass ratio of the cationic lipid to the active pharmaceutical ingredient is less than 1.2:1 and greater than 0.1:1.

[0024] In some embodiments of this disclosure, the mass ratio of the cationic lipid to the active pharmaceutical ingredient is less than or equal to 1:1 and greater than or equal to 0.2:1.

[0025] In some embodiments of this disclosure, the mass ratio of the cationic lipid to the active pharmaceutical ingredient is less than or equal to 0.5:1 and greater than or equal to 0.25:1.

[0026] In some embodiments of this disclosure, the mass ratio of the cationic lipid to the active pharmaceutical ingredient can be any ratio within the range of less than 1.2:1 and greater than 0.1:1, for example, it can be 1.19:1, 1.15:1, 1.1:1, 1.05:1, 1:1, 0.95:1, 0.9:1, 0.85:1, 0.8:1, 0.75:1, 0.7:1, 0.65:1, 0.6:1, 0.55:1, 0.5:1, 0.45:1, 0.4:1, 0.35:1, 0.3:1, 0.25:1, 0.2:1, 0.15:1, 0.11:1, or other unlisted ratios within the range of less than 1.2:1 and greater than 0.1:1.

[0027] When the mass ratio of cationic lipids to active pharmaceutical ingredients is within the above range, it is beneficial to further promote the dissolution of water-poorly soluble active pharmaceutical ingredients in water.

[0028] In some embodiments of this disclosure, the mass ratio of the penetration enhancer to the active pharmaceutical ingredient is less than 55:1 and greater than 0.8:1.

[0029] In some embodiments of this disclosure, the mass ratio of the penetration enhancer to the active pharmaceutical ingredient is less than or equal to 50:1 and greater than or equal to 1:1.

[0030] In some embodiments of this disclosure, the mass ratio of the penetration enhancer to the active pharmaceutical ingredient is less than or equal to 10:1 and greater than or equal to 5:1.

[0031] In some embodiments of this disclosure, the mass ratio of the penetration enhancer to the active ingredient can be any ratio within the range of less than 55:1 and greater than 0.8:1, for example, 54.9:1, 54:1, 53:1, 52:1, 51:1, 49:1, 48:1, 47:1, 46:1, 45:1, 44:1, 43:1, 42:1, 41:1, 40:1, 39:1, 38:1, 37:1, 36:1, 35:1, 34:1, 33:1, 32:1, 31:1, 3 0:1, 29:1, 28:1, 27:1, 26:1, 25:1, 24:1, 23:1, 22:1, 21:1, 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 0.9:1, 0.81:1, or any other unlisted ratio within the range of less than 55:1 and greater than 0.8:1.

[0032] When the mass ratio of the penetration enhancer to the active pharmaceutical ingredient is within the above range, it is beneficial to further promote the dissolution of water-poorly soluble active pharmaceutical ingredients in water.

[0033] In some embodiments of this disclosure, the cationic lipid has a mass-volume percentage of 0.02%-0.1%, where % refers to the mass of the cationic lipid contained in 100 ml of the water-soluble composition, and the mass of the cationic lipid is expressed in grams.

[0034] When used herein, the term 0.02%-0.1% by mass volume of the cationic lipid specifically means that the mass range of the cationic lipid is 0.02g-0.1g per 100mL of the water-soluble composition.

[0035] When used in this document, the specific meaning of the mass-volume ratio M% of a certain component in a water-soluble composition is that the mass of a certain component is M grams per 100 mL of the water-soluble composition.

[0036] When used herein, the unit % for mass-volume percentage can also be replaced with the unit g / 100mL, where 100mL refers to a volume of 100mL of the water-soluble composition.

[0037] In some embodiments of this disclosure, the cationic lipid has a mass-volume percentage of 0.04% to 0.07%.

[0038] In some embodiments of this disclosure, the cationic lipid has a mass-volume percentage of 0.05%.

[0039] In some embodiments of this disclosure, the mass-volume percentage of the cationic lipid can be any value in the range of 0.02% to 0.1%, such as 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%, 0.075%, 0.08%, 0.085%, 0.09%, 0.095%, 0.1%, or other unlisted values ​​in the range of 0.02% to 0.1%.

[0040] The mass-volume percentage of cationic lipids within the above range is beneficial for further promoting the dissolution of poorly water-soluble active pharmaceutical ingredients in water.

[0041] In some embodiments of this disclosure, the mass-volume percentage of the penetration enhancer is 0.1%-5%, wherein the unit % of the mass-volume percentage of the penetration enhancer refers to the mass of the penetration enhancer contained in every 100 ml of the water-soluble composition, and the unit of the mass of the penetration enhancer is grams.

[0042] When used herein, the term 0.1%-5% by mass volume of the penetration enhancer specifically means that the mass range of the penetration enhancer is 0.1g-5g per 100mL of the water-soluble composition.

[0043] In some embodiments of this disclosure, the penetration enhancer has a mass-volume percentage of 0.5% to 2%.

[0044] In some embodiments of this disclosure, the penetration enhancer has a mass-volume percentage of 1%.

[0045] In some embodiments of this disclosure, the mass-volume percentage of the penetration enhancer can be any value within the range of 0.1% to 5%, for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%. %, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, or other unlisted values ​​in the range of 0.1% to 5%.

[0046] When the mass-volume percentage of the penetration enhancer is within the above range, it is beneficial to further promote the dissolution of the active pharmaceutical ingredient in water.

[0047] In some embodiments of this disclosure, the mass-volume percentage of the active pharmaceutical ingredient is 0.1%-0.2%, wherein the unit % of the mass-volume percentage of the active pharmaceutical ingredient refers to the mass of the active pharmaceutical ingredient contained in every 100 ml of the water-soluble composition, and the unit of the mass of the active pharmaceutical ingredient is grams.

[0048] When used herein, the term 0.1%-0.2% by mass volume of the active pharmaceutical ingredient specifically means that the active pharmaceutical ingredient in 100 mL of the water-soluble composition is in the range of 0.1 g-0.2 g by mass.

[0049] In some embodiments of this disclosure, the mass-volume percentage of the active pharmaceutical ingredient can be any value in the range of 0.1% to 0.2%, such as 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, or other values ​​not listed in the range of 0.1% to 0.2%.

[0050] In some embodiments of this disclosure, the active pharmaceutical ingredient includes an endoplasmic reticulum stress inhibitor.

[0051] In some embodiments of this disclosure, the endoplasmic reticulum stress inhibitor includes at least one of rapamycin, desloratadine, melatonin, pioglitazone, celecoxib, telmisartan, sulphurin, sulforaphane, amoxapine, or a tautomer, stereoisomer, enantiomer, diastereomer, racemic mixture, solvate, isotope derivative, basic form, prodrug, acidic form, metabolite, ester, pharmaceutically acceptable salt, or solvate.

[0052] In some embodiments of this disclosure, the endoplasmic reticulum stress inhibitor includes at least one of rapamycin, desloratadine, melatonin, pioglitazone, celecoxib, telmisartan, or a tautomer, stereoisomer, enantiomer, diastereomer, racemic mixture, isotope derivative, basic form, prodrug, acidic form, metabolite, ester, pharmaceutically acceptable salt, or solvate.

[0053] When used in this article, rapamycin refers to the compound with CAS number 53123-88-9, which has the following chemical structural formula:

[0054]

[0055] When used in this article, desloratadine refers to the compound with CAS number 100643-71-8, which has the following chemical structural formula:

[0056]

[0057] When used in this article, melatonin refers to the compound with CAS number 73-31-4, which has the following chemical structural formula:

[0058]

[0059] When used in this article, pioglitazone refers to the compound with CAS number 145350-09-0, which has the following chemical structural formula:

[0060]

[0061] When used in this article, celecoxib refers to the compound with CAS number 169590-42-5, which has the following chemical structural formula:

[0062]

[0063] When used in this article, telmisartan refers to the compound with CAS number 144701-48-4, which has the following chemical structural formula:

[0064]

[0065] When used in this article, succinic acid refers to the compound with CAS number 480-40-0, which has the following chemical structural formula:

[0066]

[0067] When used in this article, sulforaphane refers to the compound with CAS number 4478-93-7, which has the following chemical structural formula:

[0068]

[0069] When used in this article, amoxapine refers to the compound with CAS number 14028-44-5, which has the following chemical structural formula:

[0070]

[0071] In this paper, the term "tautomer" refers to two isomers containing heteroatoms (such as nitrogen, oxygen, or sulfur atoms) whose structural differences lie only in the migration of protons and corresponding double bonds, and which coexist in an equilibrium system and transform into each other at a fairly high rate.

[0072] In this paper, the term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule.

[0073] When used in this document, the term "enantiomer" refers to a stereoisomer that is a real object and its mirror image but cannot be superimposed.

[0074] When used in this document, the term “diastereomer” refers to a stereoisomer that has two or more chiral centers and is not a mirror image of the other molecules.

[0075] When used in this document, the term "racemate" refers to an equimolar mixture of an optically active chiral molecule and its enantiomer.

[0076] As used herein, the term "solvent" refers to the association of one or more solvent molecules with the pharmaceutically active ingredient or a salt thereof disclosed herein. Solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, ethyl acetate, or acetic acid.

[0077] As used herein, the term "isotope derivative" refers to a chemical structure having the pharmaceutical active ingredient of this disclosure, wherein one or more atoms are replaced by isotopic atoms having a selected atomic mass or mass number. Isotopes that may be incorporated into the pharmaceutical active ingredient of this disclosure include, for example, isotopes of hydrogen.

[0078] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological activity required to preserve the active pharmaceutical ingredient of this common drug and exhibits lower undesirable toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final separation and purification of the compound, or by reacting the purified compound, in its free acid or free base form, separately with a suitable base or acid.

[0079] Rapamycin, desloratadine, melatonin, pioglitazone, celecoxib, telmisartan, sulphurin, sulforaphane, and amoxapine are poorly water-soluble endoplasmic reticulum stress inhibitors. Adding a single surfactant cannot improve their water solubility, thus reducing their in vivo efficacy. This disclosure improves the water solubility of these compounds and enhances their efficacy by combining cationic lipids and penetration enhancers.

[0080] In some embodiments of this disclosure, the water-soluble composition includes one or more of a surfactant, pH adjuster, osmotic pressure regulator, thickener, or stabilizer.

[0081] In some embodiments of this disclosure, the water-soluble composition includes a surfactant, which includes a nonionic surfactant.

[0082] In some embodiments of this disclosure, the nonionic surfactant includes at least one of tylosap, polysorbate-80, polysorbate-20, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, or polyethylene glycol 15-hydroxystearate.

[0083] In some embodiments of this disclosure, the surfactant has a mass-volume percentage of 0.05%-5%, wherein the mass-volume percentage of the surfactant is expressed in % as the mass of the surfactant contained in 100 ml of the water-soluble composition, and the mass of the surfactant is expressed in grams.

[0084] When used herein, the term 0.05%-5% by mass volume of the surfactant specifically means that the surfactant is present in a mass of 0.05g-5g per 100mL of the water-soluble composition.

[0085] In some embodiments of this disclosure, the mass-volume percentage of the surfactant can be any value within the range of 0.05% to 5%, for example, 0.05%, 0.10%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.60%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0. 0.95%, 1.0%, 1.1%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0%, or other unlisted values ​​in the range of 0.05% to 5%.

[0086] This disclosure does not specifically limit the type of pH adjuster, and those skilled in the art can selectively use different types of pH adjusters depending on the specific pH value of the water-soluble composition. In some embodiments of this disclosure, the pH adjuster includes at least one of hydrochloric acid, boric acid, phosphoric acid, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, borax, acetic acid, sodium acetate, citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, acetate buffer, citrate buffer, or borate buffer. In some embodiments of this disclosure, the pH adjuster includes at least one of hydrochloric acid, sodium hydroxide, or sodium dihydrogen phosphate.

[0087] This disclosure does not specifically limit the type of osmotic pressure regulator. Those skilled in the art can selectively use different types of osmotic pressure regulators depending on the specific osmotic pressure of the water-soluble composition. In some embodiments of this disclosure, the osmotic pressure regulator includes at least one of sodium chloride, mannitol, glycerol, laurocapram, potassium chloride, boric acid, borax, sodium sulfate, potassium sulfate, sodium nitrate, potassium nitrate, sodium acetate, propylene glycol, sorbitol, 2-(4-n-octylphenylethyl)-2-aminopropanediol hydrochloride, glucose, sucrose, fructose, or lactose. In some embodiments of this disclosure, the osmotic pressure regulator includes at least one of sodium chloride and glycerol.

[0088] This disclosure does not specifically limit the type of thickener, and those skilled in the art can selectively use different types of thickeners depending on the specific circumstances of the water-soluble composition. In some embodiments of this disclosure, the thickener includes at least one selected from sodium hyaluronate, carbomer, polycarbofil, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, or povidone. In some embodiments of this disclosure, the thickener includes at least one selected from povidone, hydroxypropyl methylcellulose, methylcellulose, polyvinyl alcohol, sodium hyaluronate, carbomer, and polycarbofil.

[0089] This disclosure does not specifically limit the type of stabilizer, and those skilled in the art can selectively use different types of stabilizers depending on the specific stability of the water-soluble composition. In some embodiments, the stabilizer includes at least one of disodium edetate and sodium sulfite.

[0090] In some embodiments of this disclosure, the pH value of the water-soluble composition is 6.5-8.0.

[0091] In some embodiments of this disclosure, the pH value of the water-soluble composition is 6.8-7.8.

[0092] In some embodiments of this disclosure, the pH value of the water-soluble composition can be any value in the range of 6.5-8.0, such as 6.5, 6.6, 6.7, 6.8, 6.85, 6.9, 6.95, 7, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, or other unlisted values ​​in the range of 6.5-8.0.

[0093] In some embodiments of this disclosure, the osmotic pressure of the water-soluble composition is 260-320 mOsmol / kg.

[0094] In some embodiments of this disclosure, the osmotic pressure of the water-soluble composition is 270-310 mOsmol / kg.

[0095] In some embodiments of this disclosure, the osmotic pressure of the water-soluble composition can be any value in the range of 260-320 mOsmol / kg, such as 260 mOsmol / kg, 270 mOsmol / kg, 275 mOsmol / kg, 280 mOsmol / kg, 285 mOsmol / kg, 290 mOsmol / kg, 295 mOsmol / kg, 300 mOsmol / kg, 305 mOsmol / kg, 310 mOsmol / kg, 320 mOsmol / kg, or other unlisted values ​​in the range of 260-320 mOsmol / kg.

[0096] use

[0097] This disclosure also provides the use of the water-soluble compositions according to any embodiment of this disclosure in the preparation of medicaments for treating, preventing or diagnosing diseases.

[0098] In this article, the term “treatment” means to alleviate or improve a disease or disorder (i.e., to slow or stop the development of a disease or at least one clinical symptom); or to alleviate or improve at least one physical parameter or biomarker associated with the disease or disorder.

[0099] In some embodiments of this disclosure, the disease includes those that benefit from suppressing endoplasmic reticulum stress.

[0100] In some embodiments of this disclosure, the disease includes an eye disease.

[0101] In some embodiments of this disclosure, the disease includes at least one of myopia, choroidal scleral thinning, increased refractive power, or axial elongation.

[0102] Myopia, the most common refractive error, refers to a refractive state in which parallel light rays, when relaxed, are refracted by the eye's refractive system and focus in front of the retina. The pathogenesis of myopia is very complex, involving multiple factors, including genetics, environment, age, intensity of eye use, and even dietary habits. Axial myopia is the main type of myopia. Changes in axial length and refractive power can reflect the effectiveness of myopia treatment and / or improvement.

[0103] Treatment

[0104] This disclosure also provides a method for treating, preventing, or diagnosing a disease, the method comprising administering a therapeutically effective dose of a water-soluble composition according to any embodiment of this disclosure to a subject requiring the treatment.

[0105] In this document, the term "subject" refers to primates (e.g., humans), dogs, rabbits, guinea pigs, pigs, rats, and mice. In some embodiments, the subject is a primate. In some specific embodiments, the subject is a human.

[0106] In this paper, a subject is considered "needing" the treatment if the subject benefits from it biologically, medically, or in terms of quality of life.

[0107] As used herein, the term "therapeutic effective dose" refers to an amount that results in benefit or treatment of a disease in a corresponding subject who did not receive that amount, but is sufficiently low within the range of reasonable medical judgment to avoid serious side effects. The therapeutic effective dose of a water-soluble composition will vary depending on the specific compound chosen (e.g., taking into account the compound's potency, efficacy, and half-life); the chosen route of administration; the disease being treated; the severity of the disease being treated; the age, body type, weight, and physical condition of the patient being treated; the patient's medical history; the duration of treatment; the nature of concurrent treatments; the desired therapeutic effect, etc., but can still be determined by those skilled in the art in a conventional manner.

[0108] This disclosure also provides the use of cationic lipids and penetration enhancers in improving the solubility of a pharmaceutical active ingredient in water, wherein the solubility of the pharmaceutical active ingredient in water is less than or equal to 1 mg / mL, wherein the cationic lipid comprises dioleoylpropyltrimethylammonium chloride, and the penetration enhancer comprises polyethylene glycol glycerol linoleate.

[0109] The limitations of this disclosure regarding the use of cationic lipids and penetration enhancers in improving the solubility of pharmaceutical active ingredients in water are the same as those for a water-soluble composition in any embodiment of this disclosure, and will not be repeated here.

[0110] The various embodiments and preferences described above with respect to the water-soluble compositions of this disclosure can be combined with each other (as long as they are not inherently contradictory) and are equally applicable to the use of the water-soluble compositions of this disclosure. All embodiments formed by such combinations are considered part of this disclosure.

[0111] The technical solutions of this disclosure will be illustrated more clearly and explicitly below with reference to embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of protection of this disclosure. The scope of protection of this disclosure is defined only by the claims.

[0112] Example

[0113] The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application. Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in this field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0114] Materials and methods

[0115] Materials: Rapamycin (soluble in water less than 1 mg / mL) and Tyloxacillin were purchased from Curia Italy Srl; Desloratadine (soluble in water less than 1 mg / mL) was purchased from Beijing Ailijia Pharmaceutical Technology Co., Ltd.; Melatonin (soluble in water less than 1 mg / mL) was purchased from Suzhou Yifan Pharmaceutical Co., Ltd.; Pioglitazone (soluble in water less than 1 mg / mL) was purchased from Shanghai Huayuan Pharmaceutical Technology Development Co., Ltd.; Celecoxib (soluble in water less than 1 mg / mL) was purchased from Hunan Jiudian Hongyang Pharmaceutical Co., Ltd.; Telmisartan (soluble in water less than 1 mg / mL) was purchased from Shandong Yijian Pharmaceutical Co., Ltd.; Dilinoleyl methyl ester dimethyl methacrylate (DLin-MC3-DMA), Dimyristic glycerol-polyethylene glycol 2000 (DMG-PEG2000), and Dioleoylpropyltrimethylammonium chloride (DOTMA) were purchased from Aivito (Shanghai) Pharmaceutical Technology Co., Ltd.; PEG-glycerol linoleate ( CMG-6EP / NF), polyglycerol oleate ( MPGO), polyethylene glycol oleate (MPGO), oleic acid polyethylene glycol glyceride (MPGO) AKG-6EP / NF was purchased from Jingxi Pharmaceutical Technology (Shenzhen) Co., Ltd.; Polyoxyethylene 35 castor oil, Polyoxyethylene 40 hydrogenated castor oil, and 15-hydroxystearic acid polyethylene glycol ester were purchased from BASF (China) Co., Ltd.; Polysorbate-80 and Polysorbate-20 were purchased from Croda Inc.; Sodium chloride was purchased from Tianjin Haiguang Pharmaceutical Co., Ltd.; and Hydrochloric acid and Sodium hydroxide were purchased from Nanjing Chemical Reagent Co., Ltd.

[0116] Instruments: IKA magnetic stirrer, Mettler FE28 pH meter, Ohaus AR2140 electronic balance, OM-819.C osmometer, YZ24 strip retinoscope, CASIA2 anterior segment-OCT, Triple Quad™ 5500+ high performance liquid chromatography-mass spectrometry (Exion LC™), and OMNI-PREP tissue homogenizer.

[0117] General testing methods:

[0118] The dissolution of the active pharmaceutical ingredient was characterized visually. Specifically, if the final mixed solution was observed to be a homogeneous solution without the appearance of particles, flocculent matter, separation after standing, or precipitation, it was considered dissolved. If the final mixed solution showed the appearance of particles, flocculent matter, separation after standing, or precipitation, it was considered undissolved. Experimental Example 1: Preparation of compositions with the addition of different cationic lipids, penetration enhancers, and / or surfactants.

[0119] Example 1-1

[0120] Preparation method:

[0121] Add 90 mL of water for injection to a beaker, and sequentially disperse and dissolve 0.1 g of cationic lipid dioleoylpropyltrimethylammonium chloride and 5 g of penetration enhancer linoleic acid polyethylene glycol glycerol ester, stirring thoroughly to obtain a mixed solution. Measure the pH of the mixed solution using a pH meter, and adjust the pH to 7.4 with hydrochloric acid or sodium hydroxide. Add 0.1 g of rapamycin to the above mixed solution and stir thoroughly. Make up the volume of the mixed solution to 100 mL using water for injection, and observe the dissolution of the added rapamycin using the visual method described above.

[0122] The preparation methods of Comparative Examples 1-1 to 1-21 are the same as those of Example 1-1, except that the types of cationic lipids, penetration enhancers and / or surfactants added are different, or none of the above substances are added, as shown in Table 1 below.

[0123] Table 1

[0124]

[0125]

[0126] Note: " / " indicates that the substance is not included in this category.

[0127] According to the table above, as shown in Example 1-1, the combined use of the cationic lipid dioleoylpropyltrimethylammonium chloride and the penetration enhancer polyethylene glycol glycerol linoleate can effectively promote the dissolution of rapamycin in water. Specifically, comparing Example 1-1 with Comparative Examples 1-1 to 1-7, it is evident that rapamycin is poorly soluble in water, and the use of different types of nonionic surfactants at the maximum dosage suitable for ophthalmic preparations alone cannot effectively improve its solubility in water. Comparing Example 1-1 with Comparative Examples 1-8 to 1-13, it is evident that a single cationic lipid or a single penetration enhancer cannot effectively improve the solubility of rapamycin in water. Comparing Example 1-1 with Comparative Examples 1-14 to 1-21, it is evident that the combination of the cationic lipid dioleoylpropyltrimethylammonium chloride and the penetration enhancer polyethylene glycol glycerol linoleate used in this disclosure can effectively promote the dissolution of rapamycin in water compared to other combinations.

[0128] Experimental Example 2: Preparation of water-soluble compositions by adding different proportions of active pharmaceutical ingredients and cationic lipids

[0129] The preparation and testing methods of Examples 2-1 to 2-3 and Comparative Examples 2-1 to 2-2 are the same as those of Example 1-1, except that the mass-volume percentage of the added active pharmaceutical ingredient and / or cationic lipid is different, as shown in Table 2 below.

[0130] Table 2

[0131]

[0132] According to the table above, a comparison of Examples 1-1, 2-1 to 2-3 and Comparative Examples 2-1 to 2-2 shows that when the mass ratio of the cationic lipid dioleoylpropyltrimethylammonium chloride to the active pharmaceutical ingredient is less than 1.2:1 and greater than 0.1:1, it is beneficial to promote the dissolution of the active pharmaceutical ingredient rapamycin in water. Furthermore, based on the observed dissolution rates, the dissolution rates of Examples 2-2, 2-1, and 1-1 decrease sequentially. That is, when the mass ratio of the cationic lipid dioleoylpropyltrimethylammonium chloride to the active pharmaceutical ingredient is less than or equal to 1:1 and greater than or equal to 0.2:1, and further, less than or equal to 0.5:1 and greater than or equal to 0.25:1, it is beneficial to further increase the dissolution rate of the active pharmaceutical ingredient rapamycin in water.

[0133] According to the table above, a comparison of Examples 1-1, 2-1 to 2-3 and Comparative Examples 2-1 to 2-2 shows that when the mass-volume percentage of the cationic lipid dioleoylpropyltrimethylammonium chloride is 0.02%-0.1%, it is beneficial to promote the dissolution of the active pharmaceutical ingredient rapamycin in water. Furthermore, based on the dissolution rates of Examples 2-2, 2-1, and 1-1, it is evident that when the mass-volume percentage of the cationic lipid dioleoylpropyltrimethylammonium chloride is 0.05%, it is beneficial to further increase the dissolution rate of the active pharmaceutical ingredient rapamycin in water.

[0134] Experimental Example 3: Preparation of water-soluble compositions with different proportions of active pharmaceutical ingredients and penetration enhancers

[0135] The preparation and testing methods of Examples 3-1 to 3-3 and Comparative Examples 3-1 to 3-2 are the same as those of Example 1-1, except that the mass-volume percentage of the added active pharmaceutical ingredient and / or penetration enhancer is different, as shown in Table 3 below.

[0136] Table 3

[0137]

[0138] According to the table above, a comparison of Examples 1-1, 3-1 to 3-3, and Comparative Examples 3-1 to 3-2 shows that when the mass ratio of the penetration enhancer linoleic acid polyethylene glycol glyceride to the active pharmaceutical ingredient is less than 55:1 and greater than 0.8:1, it is beneficial to promote the dissolution of the active pharmaceutical ingredient rapamycin in water. Furthermore, based on the observed dissolution rates, the solubility in Examples 3-2, 1-1, and 3-1 decreases sequentially. That is, when the mass ratio of the penetration enhancer linoleic acid polyethylene glycol glyceride to the active pharmaceutical ingredient is less than or equal to 50:1 and greater than or equal to 1:1, and further, less than or equal to 10:1 and greater than or equal to 5:1, it is beneficial to further increase the dissolution rate of the active pharmaceutical ingredient rapamycin.

[0139] According to the table above, a comparison of Examples 1-1, 3-1 to 3-3, and Comparative Examples 3-1 to 3-2 shows that when the mass-volume percentage of the penetration enhancer linoleic acid polyethylene glycol glyceride is 0.1%-5.0%, it is beneficial to promote the dissolution of the active pharmaceutical ingredient rapamycin in water. Furthermore, based on the dissolution rates of the solubility in Examples 3-2, 1-1, and 3-1, it is evident that when the mass-volume percentage of the penetration enhancer linoleic acid polyethylene glycol glyceride is 1%, it is beneficial to further increase the dissolution rate of the active pharmaceutical ingredient rapamycin in water.

[0140] Experimental Example 4: Preparation of a water-soluble composition using a combination of cationic lipids, penetration enhancers, and surfactants

[0141] Example 4-1

[0142] Preparation method:

[0143] Add 90 mL of water for injection to a beaker, and sequentially disperse and dissolve 0.1 g of the cationic lipid dioleoylpropyltrimethylammonium chloride and 5 g of the penetration enhancer linoleic acid polyethylene glycol glycerol ester, stirring thoroughly to obtain a mixed solution. Add an appropriate amount of sodium chloride to the mixed solution to adjust the osmotic pressure to 300 mOsmol / kg. Measure the pH of the mixed solution with a pH meter and adjust the pH to 7.4 with hydrochloric acid or sodium hydroxide. Add 0.1 g of rapamycin to the above mixed solution and stir thoroughly. Make up the volume of the mixed solution to 100 mL using water for injection. Observe the dissolution of the added rapamycin using the above visual method.

[0144] The preparation methods of Examples 4-1 to 4-7 are the same as those of Example 4-1, except that different surfactants with a mass-volume percentage of 0.05% are added, and the surfactants are added to an appropriate amount of water for injection before the cationic lipids, as shown in Table 4 below.

[0145] Table 4

[0146]

[0147] Note: " / " indicates that this type of substance was not added.

[0148] According to the table above, a comparison of Examples 4-1 and 4-2 to 4-7 shows that the combined use of cationic dioleoylpropyltrimethylammonium chloride and the penetration enhancer polyethylene glycol glycerol linoleate can improve the solubility of the active pharmaceutical ingredient rapamycin in water, regardless of whether a surfactant is used or not, and regardless of the type of surfactant used.

[0149] Experimental Example 5: Pharmacological Efficacy and Tissue Distribution Experiment of Water-Soluble Compositions

[0150] Example 5-1

[0151] Preparation method:

[0152] Add 90 mL of water for injection to a beaker, and sequentially disperse and dissolve 0.05 g of the surfactant tyloxapine, 0.1 g of the cationic lipid dioleoylpropyltrimethylammonium chloride, and 5 g of the penetration enhancer polyethylene glycol ester (PEG-1,4-dioleoyl ester), stirring thoroughly to obtain a mixed solution. Add an appropriate amount of sodium chloride to the mixed solution to adjust the osmotic pressure to 300 mOsmol / kg. Measure the pH of the mixed solution using a pH meter and adjust the pH to 7.4 using hydrochloric acid or sodium hydroxide. Add 0.1 g of rapamycin to the above mixed solution and stir thoroughly. Make up the volume of the mixed solution to 100 mL using water for injection. Observe the dissolution of the added rapamycin using the above visual method.

[0153] The preparation methods of the water-soluble compositions in Examples 5-2 to 5-4 and Comparative Examples 5-1 to 5-10 are the same as those in Example 5-1, except that the mass-volume percentages of the added cationic lipid dioleoylpropyltrimethylammonium chloride and / or the penetration enhancer linoleic acid polyethylene glycol glyceride are different, as shown in Table 5.

[0154] Myopia model drug efficacy test:

[0155] A form deprivation myopia model was established using 14-day-old tricolor guinea pigs. Unmodeled guinea pigs served as a blank control group. After successful modeling, the modeled guinea pigs were divided into a blank solvent group and an experimental group, with 30 modeled guinea pigs (half male and half female) in each group. Specifically, the blank control group consisted of animals without a form deprivation myopia model and received no eye drops. The blank solvent group (the aqueous solution composition did not contain any active pharmaceutical ingredient) and the experimental group received eye drops from animals with a form deprivation myopia model at a dose of 15 μl / eye / day for 21 days. After 21 days of administration, refractive error and axial length were measured in the guinea pigs according to the instrument's operating instructions. Refractive error was measured using a strip retinoscope, and axial length was measured using anterior segment-OCT testing. The results are shown in Table 5.

[0156] Organizational distribution test:

[0157] Healthy New Zealand rabbits were used as experimental animals and randomly divided into groups of four, half male and half female. In the experimental group, 15 μL of the drug was administered intraconjunctivally to both eyes of each rabbit, followed by gentle eyelid closure for one minute. Sixty minutes after drug administration, the conjunctival sacs of both rabbits were removed, and their tissue distribution was analyzed using high-performance liquid chromatography-mass spectrometry (HPLC-MS). The results are shown in Table 5.

[0158] The specific parameters of the high-performance liquid chromatography-mass spectrometry (HPLC-MS / MS) instrument are as follows:

[0159]

[0160]

[0161] Table 5

[0162]

[0163] Note: " / " indicates that the substance was not added or the test was not performed.

[0164] According to the table above, the ablative myopia model was successfully established using the blank control group and the blank solvent group. Comparisons between Example 5-1 and Comparative Examples 5-1 to 5-2, Example 5-2 and Comparative Examples 5-3 to 5-4, Example 5-3 and Comparative Examples 5-5 to 5-6, Example 4-3 and Comparative Examples 5-7 to 5-8, and Example 5-4 and Comparative Examples 5-9 to 5-10 show that the combined use of the cationic lipid dioleoylpropyltrimethylammonium chloride and the penetration enhancer polyethylene glycol ester linoleate significantly increases the solubility of water-poorly soluble active pharmaceutical ingredients, such as rapamycin, in water, which is beneficial for improving the refractive power and axial length changes in guinea pigs and for increasing the distribution and content of water-poorly soluble active pharmaceutical ingredients in tissues such as the cornea and sclera.

[0165] Furthermore, a comparison between Examples 5-4 and Examples 5-1 to 5-3 and 4-3 shows that when the mass-volume percentage of the cationic lipid dioleoylpropyltrimethylammonium chloride is 0.05% and the mass-volume percentage of the penetration enhancer linoleic acid polyethylene glycol glyceride is 1.00%, it is beneficial to further improve the changes in refractive power and axial length of guinea pigs, and to further increase the distribution and content of water-poorly soluble active pharmaceutical ingredients in tissues, such as the cornea and sclera.

[0166] Experiment Example 6: Preparation, efficacy, and tissue distribution experiments of water-soluble compositions containing different water-poorly soluble active pharmaceutical ingredients.

[0167] The preparation methods of the water-soluble compositions in Examples 6-1 to 6-5 and Comparative Examples 6-1 to 6-10 are the same as those in Example 5-1, except that the types of active pharmaceutical ingredients added are different, and the mass-volume percentages of the cationic lipid dioleoylpropyltrimethylammonium chloride and / or the penetration enhancer linoleic acid polyethylene glycol glyceride are different, as shown in Table 6.

[0168] Table 6

[0169]

[0170] Note: " / " indicates that this type of substance was not added.

[0171] As shown in the table above, the combination of the cationic lipid dioleoylpropyltrimethylammonium chloride and the penetration enhancer polyethylene glycol glyceride linoleate disclosed herein is suitable for improving the solubility of various water-poorly soluble active pharmaceutical ingredients in water, such as the solubility of various water-poorly soluble endoplasmic reticulum stress inhibitors in water. Specifically, it can promote the solubility of water-poorly soluble endoplasmic reticulum stress inhibitors such as desloratadine, melatonin, pioglitazone, celecoxib, and telmisartan in water.

[0172] The efficacy and tissue distribution tests of the myopia model were conducted using the same methods as in Example 5. Since the experiments were conducted in the same batch as in Example 5, the blank control group and the blank solvent group were identical. The specific results are shown in Table 7.

[0173] Table 7

[0174]

[0175]

[0176] Note: " / " indicates that the test was not performed.

[0177] As shown in the table above, the combination of the cationic lipid dioleoylpropyltrimethylammonium chloride and the penetration enhancer polyethylene glycol glyceride linoleate disclosed herein is suitable for improving changes in refractive power and axial length in guinea pigs after the use of various water-poorly soluble active pharmaceutical ingredients, and for increasing their distribution in tissues (e.g., cornea and sclera). For example, it can improve changes in refractive power and axial length in guinea pigs after the use of various water-poorly soluble endoplasmic reticulum stress inhibitors, and increase their distribution in tissues (e.g., cornea and sclera). Specifically, it can improve changes in refractive power and axial length in guinea pigs after the use of water-poorly soluble endoplasmic reticulum stress inhibitors such as desloratadine, melatonin, pioglitazone, celecoxib, and telmisartan, and increase their distribution in tissues (e.g., cornea and sclera).

[0178] In summary, the combined use of the cationic lipid dioleoylpropyltrimethylammonium chloride and the penetration enhancer polyethylene glycol glyceride linoleate is beneficial for promoting the dissolution of water-poorly soluble active pharmaceutical ingredients in water, thereby improving their bioavailability and efficacy.

[0179] This article uses specific examples to illustrate the principles and implementation methods of this disclosure. The description of the above embodiments is only for the purpose of helping to understand the technical solutions and core ideas of this disclosure. Those skilled in the art should understand that they can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. These modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this disclosure.

Claims

1. A water-soluble composition, characterized by, The water-soluble composition comprises a pharmaceutical active ingredient, a cationic lipid, and a penetration enhancer, wherein the solubility of the pharmaceutical active ingredient in water is less than or equal to 1 mg / mL, the cationic lipid comprises dioleoylpropyltrimethylammonium chloride, and the penetration enhancer comprises polyethylene glycol glycerol ester of linoleic acid.

2. The water-soluble composition of claim 1, wherein, The mass ratio of the cationic lipid to the active pharmaceutical ingredient is less than 1.2:1 and greater than 0.1:

1. Optionally, the mass ratio of the cationic lipid to the active pharmaceutical ingredient is less than or equal to 1:1 and greater than or equal to 0.2:

1. Further, the mass ratio of the cationic lipid to the active pharmaceutical ingredient is less than or equal to 0.5:1 and greater than or equal to 0.25:

1.

3. The water-soluble composition according to claim 1 or 2, characterized in that, The mass ratio of the penetration enhancer to the active pharmaceutical ingredient is less than 55:1 and greater than 0.8:

1. Optionally, the mass ratio of the penetration enhancer to the active pharmaceutical ingredient is less than or equal to 50:1 and greater than or equal to 1:

1. Further, the mass ratio of the penetration enhancer to the active pharmaceutical ingredient is less than or equal to 10:1 and greater than or equal to 5:

1.

4. The water-soluble composition according to any one of claims 1 to 3, characterized in that, The cationic lipid has a mass-volume percentage of 0.02%-0.1%, wherein the % of the mass-volume percentage of the cationic lipid refers to the mass of the cationic lipid contained in every 100 ml of the water-soluble composition, and the mass of the cationic lipid is expressed in grams; optionally, the mass-volume percentage of the cationic lipid is 0.04%-0.07%, and more preferably, the mass-volume percentage of the cationic lipid is 0.05%; and / or The mass volume percentage of the penetration enhancer is 0.1%-5%, wherein the unit % of the mass volume percentage of the penetration enhancer refers to the mass of the penetration enhancer contained in every 100 ml of the water-soluble composition, and the unit of the mass of the penetration enhancer is grams; optionally, the mass volume percentage of the penetration enhancer is 0.5%-2%, and more optionally, the mass volume percentage of the penetration enhancer is 1%.

5. The water-soluble composition according to any one of claims 1-4, wherein, The mass-volume percentage of the active pharmaceutical ingredient is 0.1%-0.2%, wherein the % of the mass-volume percentage of the active pharmaceutical ingredient refers to the mass of the active pharmaceutical ingredient contained in every 100 ml of the water-soluble composition, and the mass of the active pharmaceutical ingredient is in grams.

6. The water-soluble composition according to any one of claims 1-5, wherein, The active pharmaceutical ingredient includes an endoplasmic reticulum stress inhibitor, optionally comprising at least one of rapamycin, desloratadine, melatonin, pioglitazone, celecoxib, telmisartan, sulphurin, sulforaphane, amoxapine, or its tautomers, stereoisomers, enantiomers, diastereomers, racemic mixtures, isotope derivatives, basic forms, prodrugs, acidic forms, metabolites, esters, pharmaceutically acceptable salts, or solvates.

7. The water-soluble composition according to any one of claims 1-6, wherein, The water-soluble composition includes one or more of surfactants, pH adjusters, osmotic pressure adjusters, thickeners, or stabilizers. Optionally, the surfactant includes a nonionic surfactant. More preferably, the nonionic surfactant includes at least one of tylosap, polysorbate-80, polysorbate-20, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, or polyethylene glycol 15-hydroxystearate. More preferably, the surfactant has a mass-volume percentage of 0.05%-5%, wherein the mass-volume percentage of the surfactant is expressed in % (%), which refers to the mass of the surfactant contained in 100 ml of the water-soluble composition, and the mass of the surfactant is expressed in grams. Optionally, the pH adjuster includes at least one of hydrochloric acid, boric acid, phosphoric acid, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, borax, acetic acid, sodium acetate, citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, acetate buffer, citrate buffer, or borate buffer. Optionally, the osmotic pressure regulator includes at least one selected from sodium chloride, mannitol, glycerol, laurocapram, potassium chloride, boric acid, borax, sodium sulfate, potassium sulfate, sodium nitrate, potassium nitrate, sodium acetate, propylene glycol, sorbitol, 2-(4-n-octylphenylethyl)-2-aminopropanediol hydrochloride, glucose, sucrose, fructose, or lactose. Optionally, the thickener includes at least one selected from sodium hyaluronate, carbomer, polycarbofil, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, or povidone. Optionally, the stabilizer includes at least one of disodium edetate and sodium sulfite.

8. The water-soluble composition of any one of claims 1-7, wherein, The water-soluble composition has a pH value of 6.5-8.0, optionally, the water-soluble composition has a pH value of 6.8-7.8; and / or The osmotic pressure of the water-soluble composition is 260-320 mOsmol / kg, and optionally, the osmotic pressure of the water-soluble composition is 270-310 mOsmol / kg.

9. Use of a water-soluble composition according to any one of claims 1-8 in the preparation of a medicament for treating, preventing or diagnosing a disease, optionally, the disease includes a disease that benefits from the inhibition of endoplasmic reticulum stress, further optionally, the disease includes an ocular disease, and more optionally, the disease includes at least one of myopia, choroidal thinning, scleral thinning, increased refractive power or axial elongation.

10. Use of a cationic lipid and a penetration enhancer to increase the solubility of a pharmaceutically active ingredient in water, characterized in that, The active pharmaceutical ingredient has a solubility of less than or equal to 1 mg / mL in water, the cationic lipid includes dioleoylpropyltrimethylammonium chloride, and the penetration enhancer includes polyethylene glycol glycerol ester of linoleic acid.

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