Pharmaceutical composition, preparation method therefor, and use thereof

Abstract

The present invention relates to a pharmaceutical composition, a preparation method therefor, and a use thereof in the preparation of a formulation for treating an ocular disease. The composition comprises phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof, and water as a solvent, wherein the composition comprises hyaluronic acid or a pharmaceutically acceptable salt or ester thereof and / or the composition does not comprise disodium ethylenediaminetetraacetate or ethylenediaminetetraacetic acid or calcium disodium ethylenediaminetetraacetate. The pharmaceutical composition of the present invention has excellent storage stability. The present invention further relates to a method for improving the storage stability of a pharmaceutical composition in the form of an aqueous solution comprising phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof.

Description

Pharmaceutical compositions, their preparation methods and uses

[0001] This application claims priority to Chinese Patent Application No. 202411864933.5, filed on December 17, 2024, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0002] This invention generally relates to the pharmaceutical field. Specifically, this invention relates to pharmaceutical compositions, methods of their preparation, their use in the preparation of formulations for treating eye diseases, and methods for improving the storage stability of pharmaceutical compositions. Background Technology

[0003] Sodium 4-phenylbutyrate, also known as sodium phenylbutyrate, is currently used to treat urea cycle disorders in children. In the United States, this drug is marketed under the brand name BUPHENYL.

[0004] Sodium 4-phenylbutyrate is unstable in aqueous solution and is prone to oxidative degradation during long-term storage, generating impurities and making solution formulation difficult. The main impurities in sodium 4-phenylbutyrate include impurity A (3-benzoylpropionic acid), impurity B (1-tetrahydronaphthone), and other unknown impurities. Impurity A is the primary degradation impurity, while impurity B and other impurities are process impurities. Excessive levels of impurities, such as impurity A, may cause side effects and local discomfort. Therefore, currently marketed sodium 4-phenylbutyrate products are all solid dosage forms. The FDA requires that impurity A not exceed 0.1% and total impurities not exceed 0.5% for such marketed solid dosage forms, which are relatively stringent limits.

[0005] Recently, the use of sodium 4-phenylbutyrate as a myopia prevention / inhibitor has also been proposed. However, as mentioned above, due to the poor storage stability of aqueous sodium 4-phenylbutyrate, it is not suitable for formulation into eye drops. Therefore, no sodium 4-phenylbutyrate product has been approved for this indication, making the development of corresponding formulations particularly important.

[0006] Therefore, it is desirable to provide a sodium 4-phenylbutyrate aqueous solution formulation that can effectively reduce the problem of increased total impurities, especially impurity A, during long-term storage and improve the storage stability of sodium 4-phenylbutyrate. Summary of the Invention

[0007] This invention is made in response to the aforementioned problems existing in the prior art.

[0008] In a first aspect, the present invention provides a pharmaceutical composition having improved storage stability, wherein the increase in the content of impurity A is significantly reduced after long-term storage; the content of impurity A (relative to the mass of the phenylbutyric acid active substance (i.e., the phenylbutyric acid or its pharmaceutically acceptable salt or ester initially contained in the composition) after storage at 60°C for 30 days is not more than 0.1%, for example not more than 0.09%, for example not more than 0.08%, for example not more than 0.07%, for example not more than 0.06%, for example not more than 0.05%, for example not more than 0.04%, for example not more than 0.03%, for example not more than 0.02%.

[0009] In a second aspect, the present invention provides a method for preparing a pharmaceutical composition according to the first aspect of the present invention.

[0010] In a third aspect, the present invention provides the use of a pharmaceutical composition according to the first aspect of the invention in the preparation of an ophthalmic formulation for treating myopia.

[0011] In a fourth aspect, the present invention provides a method for improving the storage stability of a pharmaceutical composition comprising an aqueous solution of phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof, the method comprising: adding hyaluronic acid or a pharmaceutically acceptable salt or ester thereof to the aqueous solution; and / or not adding disodium ethylenediaminetetraacetate or ethylenediaminetetraacetic acid or calcium sodium ethylenediaminetetraacetate to the aqueous solution.

[0012] Aqueous solutions of phenylbutyric acid, such as 4-phenylbutyric acid or its pharmaceutically acceptable salts or esters, such as sodium 4-phenylbutyrate, undergo oxidative degradation during storage, primarily producing impurity A (3-benzoylpropionic acid) (i.e., the increase in impurity content during storage is mainly caused by impurity A), leading to decreased stability, reduced efficacy after long-term storage, and potential side effects from the presence of impurities. Therefore, it is necessary to improve the storage stability of such aqueous solutions; and examining changes in the content of impurity A reflects the storage stability of the aqueous solution. The applicant has discovered that by adding hyaluronic acid or its pharmaceutically acceptable salts or esters, such as sodium hyaluronate, the generation of impurity A during storage can be effectively reduced, thereby improving the storage stability of the aqueous solution.

[0013] The applicant also found that the addition of stabilizers such as ethylenediaminetetraacetic acid (EDTA), disodium EDTA, or calcium sodium EDTA to the aqueous solution is detrimental to the storage stability of the aqueous solution and increases the generation of impurity A; when stabilizers such as EDTA, disodium EDTA, or calcium sodium EDTA are not added, the generation of impurity A during storage can be effectively reduced, thereby improving the storage stability of the aqueous solution.

[0014] Specifically, the present invention is achieved as follows.

[0015] 1. A pharmaceutical composition comprising:

[0016] Phthalic acid or its pharmaceutically acceptable salts or esters.

[0017] Hyaluronic acid or its pharmaceutically acceptable salts or esters; and

[0018] Solvent: water.

[0019] 2. The composition according to item 1, wherein the pharmaceutically acceptable salt of said phenylbutyric acid comprises or is a sodium salt, preferably said phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof comprises or is sodium 4-phenylbutyrate.

[0020] 3. The composition according to any one of items 1-2, comprising 0.01-5.0% w / v, for example 0.01-4.0% w / v, for example 0.01-3.0% w / v of phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof.

[0021] 4. The composition according to any one of items 1-3, wherein the hyaluronic acid or a pharmaceutically acceptable salt or ester thereof comprises or is sodium hyaluronate.

[0022] 5. The composition according to any one of items 1-4, comprising 0.01-1.0% w / v of hyaluronic acid or a pharmaceutically acceptable salt or ester thereof.

[0023] 6. The composition according to any one of items 1-5, further comprising a buffer, said buffer comprising, for example, or selected from one or more of: sodium dihydrogen phosphate and / or sodium citrate, preferably sodium dihydrogen phosphate, said buffer being in an amount of, for example, 0.01-2.0% w / v, such as 0.02-1.0% w / v, for example, the composition comprising 0.01-0.7% w / v, preferably 0.02%-0.7% w / v of sodium dihydrogen phosphate and / or 0.01-0.85% w / v of sodium citrate.

[0024] 7. The composition according to any one of items 1-6, further comprising an osmotic pressure regulator, said osmotic pressure regulator comprising, for example, one or more selected from: sodium chloride, glycerol, and / or mannitol.

[0025] 8. The composition according to any one of items 1-7, wherein the osmotic pressure of the composition is 260-400 mOsmol / kg, for example 260-340 mOsmol / kg.

[0026] 9. The composition according to any one of items 1-8, further comprising a pH adjuster, said pH adjuster comprising, for example, one or more selected from: HCl and / or NaOH.

[0027] 10. The composition according to any one of items 1-9, wherein the pH of the composition is 6.5-8.0, preferably 6.5-7.5.

[0028] 11. The composition according to any one of items 1-10, wherein the hyaluronic acid or its pharmaceutically acceptable salt or ester has a weight-average molecular weight of 30,000 to 1,500,000, preferably 300,000 to 1,200,000.

[0029] 12. The composition according to any one of items 1-11, wherein it does not contain ethylenediaminetetraacetic acid or disodium ethylenediaminetetraacetic acid or calcium sodium ethylenediaminetetraacetic acid.

[0030] 13. The composition according to any one of items 1-12, wherein it does not contain a stabilizer.

[0031] 14. The composition according to any one of items 1-13, comprising the following:

[0032] Sodium 4-phenylbutyrate, 0.01-5.0% w / v

[0033] Sodium dihydrogen phosphate, 0.02%-0.7% w / v;

[0034] Sodium hyaluronate, 0.01-1.0% w / v;

[0035] Optional osmotic pressure regulator;

[0036] A pH adjuster, in an amount such that the pH of the resulting composition is 6.5-8.0; and

[0037] Solvent: water.

[0038] 15. The composition according to any one of items 1-14, wherein the content of impurity A after storage at 60°C for 30 days is not more than 0.1%, for example not more than 0.09%, for example not more than 0.08%, for example not more than 0.07%, for example not more than 0.06%, for example not more than 0.05%, for example not more than 0.04%, for example not more than 0.03%, for example not more than 0.02%, relative to the mass of phenylbutyric acid or its pharmaceutically acceptable salt or ester initially contained in the composition.

[0039] 16. A pharmaceutical composition comprising:

[0040] Phthalic acid or its pharmaceutically acceptable salts or esters; and

[0041] Solvent water;

[0042] The composition does not include disodium ethylenediaminetetraacetate, ethylenediaminetetraacetic acid, or calcium sodium ethylenediaminetetraacetate.

[0043] 17. The composition according to item 16, which does not contain a stabilizer.

[0044] 18. The composition according to any one of items 16-17, wherein the pharmaceutically acceptable salt of said phenylbutyric acid comprises or is a sodium salt, preferably the phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof comprises or is sodium 4-phenylbutyrate.

[0045] 19. The composition according to any one of items 16-18, comprising 0.01-5.0% w / v, for example 0.01-4.0% w / v, for example 0.01-3.0% w / v of phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof.

[0046] 20. The composition according to any one of items 16-19, further comprising a buffer, said buffer comprising, for example, or selected from one or more of: sodium dihydrogen phosphate and / or sodium citrate, preferably sodium dihydrogen phosphate, said buffer being in an amount of, for example, 0.01-2.0% w / v, such as 0.02-1.0% w / v, for example, the composition comprising 0.01-0.7% w / v, preferably 0.02%-0.7% w / v of sodium dihydrogen phosphate and / or 0.01-0.85% w / v of sodium citrate.

[0047] 21. The composition according to any one of items 16-20, further comprising an osmotic pressure regulator, said osmotic pressure regulator comprising, for example, one or more selected from: sodium chloride, glycerol, and / or mannitol.

[0048] 22. The composition according to any one of items 16-21, wherein the osmotic pressure of the composition is 260-400 mOsmol / kg, for example 260-340 mOsmol / kg.

[0049] 23. The composition according to any one of items 16-22, further comprising a pH adjuster, said pH adjuster comprising, for example, one or more selected from: HCl and / or NaOH.

[0050] 24. The composition according to any one of items 16-23, wherein the pH of the composition is 6.5-8.0, preferably 6.5-7.5.

[0051] 25. The composition according to any one of items 16-24, further comprising hyaluronic acid or a pharmaceutically acceptable salt or ester thereof.

[0052] 26. The composition according to item 25, wherein hyaluronic acid or a pharmaceutically acceptable salt or ester thereof comprises or is sodium hyaluronate.

[0053] 27. The composition according to any one of items 25-26, wherein the composition comprises 0.01-1.0% w / v of hyaluronic acid or a pharmaceutically acceptable salt or ester thereof.

[0054] 28. The composition according to any one of items 25-27, wherein the weight-average molecular weight of hyaluronic acid or its pharmaceutically acceptable salt or ester is 30,000 to 1,500,000, preferably 300,000 to 1,200,000.

[0055] 29. The composition according to any one of items 16-28, wherein the content of impurity A after storage at 60°C for 30 days is not more than 0.1%, for example not more than 0.09%, for example not more than 0.08%, for example not more than 0.07%, for example not more than 0.06%, for example not more than 0.05%, for example not more than 0.04%, for example not more than 0.03%, for example not more than 0.02%, relative to the mass of phenylbutyric acid or its pharmaceutically acceptable salt or ester initially contained in the composition.

[0056] 30. A composition according to any one of items 1-29, which is an ophthalmic pharmaceutical composition, such as eye drops.

[0057] 31. A method for preparing a composition according to any one of items 1-30, comprising:

[0058] The components are mixed evenly in water, and water is optionally added and the pH is adjusted. Water is then added to the full volume, and the mixture is optionally sterilized, filtered, and filled to provide the composition.

[0059] 32. Use of the composition according to any one of items 1-30 in the preparation of an formulation for treating an eye disease.

[0060] 33. A method for improving the storage stability of a pharmaceutical composition, said pharmaceutical composition being an aqueous solution comprising phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof, said method comprising:

[0061] Add hyaluronic acid or a pharmaceutically acceptable salt or ester thereof to the aqueous solution; and / or

[0062] No disodium ethylenediaminetetraacetate, ethylenediaminetetraacetic acid, or calcium sodium ethylenediaminetetraacetate is added to the aqueous solution.

[0063] The content of impurity A in the obtained pharmaceutical composition after storage at 60°C for 30 days is not more than 0.1%, for example not more than 0.09%, for example not more than 0.08%, for example not more than 0.07%, for example not more than 0.06%, for example not more than 0.05%, for example not more than 0.04%, for example not more than 0.03%, for example not more than 0.02%, relative to the mass of phenylbutyric acid or its pharmaceutically acceptable salt or ester initially contained in the obtained pharmaceutical composition.

[0064] The pharmaceutical composition of the present invention exhibits excellent storage stability. After long-term storage (e.g., storage at 60°C for 30 days), the increase in the content of impurity A is significantly reduced, and the content of impurity A does not exceed 0.1%, for example, not exceeding 0.09%, not exceeding 0.08%, not exceeding 0.07%, not exceeding 0.06%, not exceeding 0.05%, not exceeding 0.04%, not exceeding 0.03%, or not exceeding 0.02%. Therefore, its solution has good drug-like properties, and the formulation has consistent performance during long-term storage, which can extend the product's shelf life and / or improve the quality of the product's shelf life. Furthermore, the pharmaceutical composition of the present invention has low irritation and significant efficacy. Detailed Implementation

[0065] Unless otherwise specified, in this application, temperature refers to room temperature (25°C) and pressure refers to atmospheric pressure.

[0066] In this application, unless otherwise specified, the expression "%w / v" used when referring to the component content in ophthalmic pharmaceutical compositions means mass / volume percentage (g / ml), that is, the number of grams of solute contained in one hundred milliliters. The liquid formulations involved in this invention have a relative density of approximately 1.0, therefore, in actual preparation, it can be calculated as one hundred grams per one hundred milliliters. Therefore, mass / volume (g / ml) percentage can also be approximated as mass / mass (g / g) percentage.

[0067] In this application, unless otherwise specified, even if the term “about” is not used in the description of numerical values, the numerical value shall be understood to be modified by “about”; the term “about” includes a deviation of ±5% of the stated numerical value, that is, for the numerical value a, whether or not it is modified by “about”, it shall be understood to represent a range of a ± 5%a, that is, 0.95a to 1.05a.

[0068] This invention relates to pharmaceutical compositions, methods of their preparation, their use in the preparation of ophthalmic formulations for the treatment of myopia, and methods for improving the storage stability of pharmaceutical compositions comprising an aqueous solution of phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof.

[0069] The present invention will be described in detail below.

[0070] Pharmaceutical Composition

[0071] In a first aspect, the present invention relates to pharmaceutical compositions.

[0072] In a first embodiment of a first aspect of the present invention, the present invention relates to a pharmaceutical composition comprising:

[0073] Phthalic acid or its pharmaceutically acceptable salts or esters.

[0074] Hyaluronic acid or its pharmaceutically acceptable salts or esters; and

[0075] Solvent: water.

[0076] In this application, the description of phenylbutyric acid and hyaluronic acid as "pharmaceuticalally acceptable salts" can be inorganic salts or organic salts or any combination thereof. Inorganic salts can be, for example, sodium salts, potassium salts, calcium salts, magnesium salts, zinc salts, iron salts, ammonium salts, etc.; organic salts can be, for example, trialkylamine salts (where each alkyl group can be independently selected from, for example, C1-C6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl), guanidine salts, etc.

[0077] In this application, the description of "pharmaceutical-acceptable ester" for, for example, phenylbutyric acid and hyaluronic acid refers to esters formed by the stated acid and pharmaceutically acceptable alcohols such as C1-C6 monohydric alcohols, such as methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester, tert-butyl ester, n-pentyl ester (and its various pentyl isomers), n-hexyl ester (and its various hexyl isomers), etc.

[0078] In a preferred embodiment, the phenylbutyric acid includes or is 4-phenylbutyric acid.

[0079] In a preferred embodiment, the pharmaceutically acceptable salt of the phenylbutyric acid includes or is a sodium salt.

[0080] In a preferred embodiment, the phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof includes or is one of the various salts or esters described above; for example, sodium phenylbutyrate.

[0081] In a preferred embodiment, the phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof comprises or is sodium 4-phenylbutyrate.

[0082] In a preferred embodiment, the composition comprises 0.01-5.0% w / v, for example 0.01-4.0% w / v, for example 0.01-3.0% w / v, for example, amounts of phenylbutyric acid or its pharmaceutically acceptable salts or esters as follows: 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0. 40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, 2.0 0, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40, 2.45, 2.50, 2.55, 2.60, 2.65, 2.70, 2.75, 2.80, 2.85, 2.90, 2.95, 3.00, 3.05, 3.10, 3.15, 3.20, 3.25, 3.30, 3.35, 3.40, 3.45, 3.50, 3.55, 3.6 0, 3.65, 3.70, 3.75, 3.80, 3.85, 3.90, 3.95, 4.00, 4.05, 4.10, 4.15, 4.20, 4.25, 4.30, 4.35, 4.40, 4.45, 4.50, 4.55, 4.60, 4.65, 4.70, 4.75, 4.80, 4.85, 4.90, 4.95, 5.00% w / v, or a range defined by any two of these.

[0083] In a preferred embodiment, the amount of phenylbutyric acid or its pharmaceutically acceptable salt or ester, such as sodium phenylbutyrate, in the composition is in the range of 0.01-3.0% w / v. Within this range, the prepared formulation is more likely to meet the pharmaceutical requirements that the osmotic pressure of ophthalmic preparations should be isotonic with that of the human body, and is therefore more suitable for use as an ophthalmic preparation such as eye drops.

[0084] In an embodiment, the composition comprises hyaluronic acid or a pharmaceutically acceptable salt or ester thereof, such as sodium hyaluronate. For aqueous solutions containing phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof, such as sodium 4-phenylbutyrate, oxidative degradation occurs during storage, generating impurities, with impurity A being the primary oxidative degradation impurity; therefore, the content and variation of impurity A in the composition reflect the storage stability of the aqueous solution of phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof, such as sodium 4-phenylbutyrate. The applicant has found that by adding hyaluronic acid or a pharmaceutically acceptable salt or ester thereof, such as sodium hyaluronate, the generation of impurity A during storage can be effectively reduced, thereby improving the storage stability of the aqueous solution.

[0085] In a preferred embodiment, the composition comprises 0.01-1.0% w / v, for example, the following amounts of hyaluronic acid or a pharmaceutically acceptable salt or ester thereof, such as sodium hyaluronate: 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00% w / v, or a range defined by any two thereof. Within the defined quantity range, in addition to effectively reducing the generation of impurity A in the composition during storage, it does not cause an excessive increase in the viscosity of the composition, thus the composition has high fluidity and can be easily subjected to processes requiring high fluidity, such as sterile filtration. Therefore, it is suitable for preparing sterile preparations in accordance with the requirements of the Chinese Pharmacopoeia. Furthermore, the sterile preparation is an ophthalmic preparation, such as eye drops.

[0086] In a preferred embodiment, the weight-average molecular weight of the hyaluronic acid or its pharmaceutically acceptable salt or ester, such as sodium hyaluronate, can be 30,000 to 1,500,000, for example, 300,000 to 1,500,000, such as 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 1,500,000, or any range defined by both. The molecular weight can be measured, for example, by gel permeation chromatography (GPC). Using hyaluronic acid or its pharmaceutically acceptable salt or ester, such as sodium hyaluronate, within the defined molecular weight range can further reduce the formation of impurity A in the composition during storage, thereby improving the storage stability of the composition. Preferably, the hyaluronic acid or its pharmaceutically acceptable salt or ester, such as sodium hyaluronate, has a weight-average molecular weight of 300,000 to 1,200,000. Within this preferred range, on the one hand, a lower molecular weight can further reduce the generation of impurity A in the composition during storage, thereby improving the storage stability of the composition; on the other hand, the composition will not experience an excessive increase in viscosity due to the addition of the hyaluronic acid or its pharmaceutically acceptable salt or ester, such as sodium hyaluronate, thus the composition has high fluidity and can be easily subjected to treatments requiring high fluidity, such as sterile filtration. Therefore, it is suitable for preparing sterile preparations according to the requirements of the Chinese Pharmacopoeia. Further, the sterile preparation is an ophthalmic preparation, such as eye drops.

[0087] In a preferred embodiment, the composition comprises a pharmaceutically acceptable buffer. The buffer is not particularly limited and may include, for example, one or more selected from: boric acid, borates such as sodium tetraborate (borax) and / or potassium tetraborate, phosphates such as dihydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, and dihydrogen phosphates such as sodium dihydrogen phosphate and potassium dihydrogen phosphate, tris(hydroxymethyl)aminomethane, 2-amino-2-methyl-1-propanol (AMP), tromethamine, citrates such as sodium citrate and potassium citrate, histidine, acetates such as sodium acetate and potassium acetate, preferably dihydrogen phosphates such as sodium dihydrogen phosphate and citrates such as sodium citrate, more preferably dihydrogen phosphates such as sodium dihydrogen phosphate. When dihydrogen phosphates such as sodium dihydrogen phosphate and citrates such as sodium citrate are used, the generation of impurity A in the composition during storage can be significantly reduced compared to other buffer systems such as borate buffers, thus improving the storage stability of the composition.

[0088] In a preferred embodiment, the composition comprises 0.01-2.0%, for example 0.02-1.0% w / v, of a buffer in amounts such as: 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.6 5, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, 2.00% w / v, or a range defined by any two of these. For example, the composition may include 0.01-0.7%, preferably 0.02%-0.7% w / v sodium dihydrogen phosphate and / or 0.01-0.85% w / v sodium citrate; within the range, the composition may have a slightly lower content of impurity A during storage relative to higher amounts, thereby exhibiting slightly better storage stability; and when applied to the human body, such as the eyes, it is less likely to cause irritation to the human body, such as the eyes.

[0089] In a preferred embodiment, the composition comprises a pharmaceutically acceptable osmoregulator. The osmoregulator is not particularly limited and can be appropriately selected according to the intended purpose, and may include, for example, one or more selected from: mannitol, glycerol, metal ion-containing osmoregulators such as sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, or any combination of two or more thereof, preferably sodium chloride, glycerol, and / or mannitol. In one embodiment, the osmotic pressure regulator may be present in the composition in an amount such that the composition has an osmotic pressure of, for example, 260-400 mosmol / kg, such as 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400 mOsm / kg, or a range defined by any two thereof; preferably, the osmotic pressure is 260-340 mosmol / kg, within which the composition meets the pharmaceutical requirement that ophthalmic preparations should be isotonic, and is therefore suitable for use as an ophthalmic preparation such as eye drops. For example, the composition may include an osmotic pressure regulator in amounts of 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% w / v, or a range defined by any two thereof.

[0090] In a preferred embodiment, the composition includes a pharmaceutically acceptable pH adjuster. The pH adjuster is not particularly limited and can be appropriately selected according to the intended purpose, for example, it may include or be selected from one or more of the following: phosphoric acid, sodium hydroxide, potassium hydroxide, HCl, or any combination thereof, such as HCl and / or NaOH. In a preferred embodiment, the amount of the pH adjuster is such that the pH of the resulting composition is 6.5-8.0, preferably 6.5-7.5, for example, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, or a range defined by any two thereof. Within this range, compared to pH values ​​outside the range, such as lower pH values, the composition produces lower levels of impurity A and is less irritating to the human body during long-term storage. Preferably, the amount of the pH adjuster is such that the pH of the resulting composition is 6.5-7.5, which, within the preferred range, is less irritating to the human body, for example, to the eyes, and is therefore suitable for use as eye drops. For example, the composition may include the pH adjuster in amounts of: 0.01, 0.02, 0.05, 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, 1.8, 1.9, 2.0% w / v, or a range defined by any two thereof.

[0091] In a preferred embodiment, the composition does not include ethylenediaminetetraacetic acid (EDTA), disodium EDTA, or calcium sodium EDTA. The applicant has found that including EDTA, disodium EDTA, or calcium sodium EDTA in the composition increases the generation of impurity A during storage, reducing the storage stability of the composition. By omitting the addition of EDTA or disodium EDTA, the generation of impurity A during storage can be further effectively reduced, improving the storage stability of the aqueous solution.

[0092] In a preferred embodiment, the composition does not include any pharmaceutically acceptable stabilizers commonly used in the art, such as ethylenediaminetetraacetic acid (EDTA), disodium EDTA, calcium sodium EDTA, diethylenetriaminepentamethylenephosphonic acid (DTPMP), EDTA, butylamine-1,2,4-tricarboxylic acid, 2-hydroxyphosphonoacetic acid, or physiologically acceptable salts thereof, such as sodium salts. Even in the absence of stabilizers, the composition can exhibit excellent, or even better, storage stability.

[0093] The composition may optionally further include other additive components, such as:

[0094] Tackifiers, such as hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium sulfobutylcyclodextrin, carbomer, or any combination of two or more thereof; and / or

[0095] Surfactants or penetration enhancers, such as Tween, propylene glycol, diethyl propylene glycol, polyethylene glycol, polyethylene glycol stearate, polyoxyethylene castor oil, tylosap, nonylphenol ether, octylphenol polyether, glyceryl monostearate, polyethylene glycol 15-hydroxystearate, dimethyl silicone oil, borneol, peppermint oil, camphor, eucalyptol, anethole, terpineol, bisabolol, or any combination of two or more thereof.

[0096] In a preferred embodiment, the composition comprises the following:

[0097] Sodium 4-phenylbutyrate, 0.01-5.0% w / v

[0098] Sodium dihydrogen phosphate, 0.02%-0.7% w / v;

[0099] Sodium hyaluronate, 0.01-1.0% w / v;

[0100] Optional osmotic pressure regulators, such as sodium chloride;

[0101] A pH adjuster, in an amount such that the pH of the resulting composition is 6.5-8.0; and

[0102] Solvent: water.

[0103] In a second embodiment of the first aspect of the present invention, the present invention relates to a pharmaceutical composition comprising:

[0104] Phthalic acid or its pharmaceutically acceptable salts or esters; and

[0105] Solvent water;

[0106] The composition does not include disodium ethylenediaminetetraacetate, ethylenediaminetetraacetic acid, or calcium sodium ethylenediaminetetraacetate.

[0107] In a preferred embodiment, the phenylbutyric acid includes or is 4-phenylbutyric acid.

[0108] In a preferred embodiment, the pharmaceutically acceptable salt of the phenylbutyric acid includes or is a sodium salt.

[0109] In a preferred embodiment, the phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof includes or is one of the various salts or esters described in the first embodiment above; for example, sodium phenylbutyrate.

[0110] In a preferred embodiment, the phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof comprises or is sodium 4-phenylbutyrate.

[0111] In a preferred embodiment, the composition comprises 0.01-5.0% w / v, for example 0.01-4.0% w / v, for example 0.01-3.0% w / v, for example, amounts of phenylbutyric acid or its pharmaceutically acceptable salts or esters as follows: 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0. 40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, 2.0 0, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40, 2.45, 2.50, 2.55, 2.60, 2.65, 2.70, 2.75, 2.80, 2.85, 2.90, 2.95, 3.00, 3.05, 3.10, 3.15, 3.20, 3.25, 3.30, 3.35, 3.40, 3.45, 3.50, 3.55, 3.6 0, 3.65, 3.70, 3.75, 3.80, 3.85, 3.90, 3.95, 4.00, 4.05, 4.10, 4.15, 4.20, 4.25, 4.30, 4.35, 4.40, 4.45, 4.50, 4.55, 4.60, 4.65, 4.70, 4.75, 4.80, 4.85, 4.90, 4.95, 5.00% w / v, or a range defined by any two thereof. When the amount of chlorinated butyric acid or its pharmaceutically acceptable salt or ester, such as sodium chlorate, in the composition is in the range of 0.01-3.0% w / v, the prepared formulation is more likely to meet the pharmaceutical requirements of isotonicity with the human body for ophthalmic preparations, and is therefore more suitable for use as ophthalmic preparations such as eye drops.

[0112] In this embodiment, the composition does not include disodium ethylenediaminetetraacetate (EDTA), EDTA, or calcium sodium EDTA. The applicant has found that including EDTA, EDTA, or calcium sodium EDTA in the composition increases the generation of impurity A during storage, reducing the storage stability of the composition; while omitting EDTA, EDTA, or calcium sodium EDTA effectively reduces the generation of impurity A during storage, improving the storage stability of the aqueous solution.

[0113] In a preferred embodiment, the composition does not include any pharmaceutically acceptable stabilizers, such as ethylenediaminetetraacetic acid (EDTA), disodium EDTA, calcium sodium EDTA, diethylenetriaminepentamethylenephosphonic acid (DTPMP), EDTA, butylamine-1,2,4-tricarboxylic acid, 2-hydroxyphosphonoacetic acid, or physiologically acceptable salts thereof, such as sodium salts. Even in the absence of stabilizers, the composition can exhibit excellent, or even better, storage stability.

[0114] In a preferred embodiment, the composition comprises a pharmaceutically acceptable buffer. The buffer is not particularly limited and may include, for example, one or more selected from: boric acid, borates such as sodium tetraborate (borax) and / or potassium tetraborate, phosphates such as dihydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, and dihydrogen phosphates such as sodium dihydrogen phosphate and potassium dihydrogen phosphate, tris(hydroxymethyl)aminomethane, 2-amino-2-methyl-1-propanol (AMP), tromethamine, citrates such as sodium citrate and potassium citrate, histidine, acetates such as sodium acetate and potassium acetate, preferably dihydrogen phosphates such as sodium dihydrogen phosphate and citrates such as sodium citrate, more preferably dihydrogen phosphates such as sodium dihydrogen phosphate. When dihydrogen phosphates such as sodium dihydrogen phosphate and citrates such as sodium citrate are used, the generation of impurity A in the composition during storage can be significantly reduced compared to other buffer systems such as borate buffers, thus improving the storage stability of the composition.

[0115] In a preferred embodiment, the composition comprises 0.01-2.0%, for example 0.02-1.0% w / v, of a buffer in amounts such as: 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.6 5, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, 2.00% w / v, or a range defined by any two of these. For example, the composition may include 0.01-0.7%, preferably 0.02%-0.7% w / v sodium dihydrogen phosphate and / or 0.01-0.85% w / v sodium citrate; within the range, the composition may have a slightly lower content of impurity A during storage relative to higher amounts, thereby exhibiting slightly better storage stability; and when applied to the human body, such as the eyes, it is less likely to cause irritation to the human body, such as the eyes.

[0116] In a preferred embodiment, the composition comprises a pharmaceutically acceptable osmoregulator. The osmoregulator is not particularly limited and can be appropriately selected according to the intended purpose, and may include, for example, one or more selected from: mannitol, glycerol, metal ion-containing osmoregulators such as sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, or any combination of two or more thereof, preferably sodium chloride, glycerol, and / or mannitol. In one embodiment, the osmotic pressure regulator may be present in the composition in an amount such that the composition has an osmotic pressure of, for example, 260-400 mosmol / kg, such as 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400 mOsm / kg, or a range defined by any two thereof; preferably, the osmotic pressure is 260-340 mosmol / kg, within which the composition meets the pharmaceutical requirement that ophthalmic preparations should be isotonic, and is therefore suitable for use as an ophthalmic preparation such as eye drops. For example, the composition may include an osmotic pressure regulator in amounts of 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% w / v, or a range defined by any two thereof.

[0117] In a preferred embodiment, the composition includes a pharmaceutically acceptable pH adjuster. The pH adjuster is not particularly limited and can be appropriately selected according to the intended purpose, for example, it may include or be selected from one or more of the following: phosphoric acid, sodium hydroxide, potassium hydroxide, HCl, or any combination thereof, such as HCl and / or NaOH. In a preferred embodiment, the amount of the pH adjuster is such that the pH of the resulting composition is 6.5-8.0, preferably 6.5-7.5, for example, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, or a range defined by any two thereof. Within this range, compared to pH values ​​outside the range, such as lower pH values, the composition produces lower levels of impurity A and is less irritating to the human body during long-term storage. Preferably, the amount of the pH adjuster is such that the pH of the resulting composition is 6.5-7.5. Within this preferred range, it is less irritating to the human body, such as to the eyes, and therefore more suitable for use as eye drops. For example, the composition may include the pH adjuster in amounts of: 0.01, 0.02, 0.05, 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, 1.8, 1.9, 2.0% w / v, or a range defined by any two thereof.

[0118] In a preferred embodiment, the composition comprises hyaluronic acid or a pharmaceutically acceptable salt or ester thereof, such as sodium hyaluronate. By adding hyaluronic acid or a pharmaceutically acceptable salt or ester thereof, such as sodium hyaluronate, the generation of impurity A during storage can be further effectively reduced, thereby improving the storage stability of the aqueous solution.

[0119] In a preferred embodiment, the composition comprises 0.01-1.0% w / v, for example, the following amounts of hyaluronic acid or a pharmaceutically acceptable salt or ester thereof, such as sodium hyaluronate: 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00% w / v, or a range defined by any two thereof. Within the defined quantity range, in addition to further effectively reducing the generation of impurity A in the composition during storage, it does not cause an excessive increase in the viscosity of the composition, thus the composition has high fluidity and can be easily subjected to processes requiring high fluidity, such as sterile filtration. Therefore, it is more suitable for preparing ophthalmic preparations, such as eye drops, that are required to be sterile according to the requirements of the Chinese Pharmacopoeia.

[0120] In a preferred embodiment, the weight-average molecular weight of the hyaluronic acid or its pharmaceutically acceptable salt or ester, such as sodium hyaluronate, can be 30,000 to 1,500,000, for example, 300,000 to 1,500,000, such as 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 1,500,000, or any range defined by both. The molecular weight can be measured, for example, by gel permeation chromatography (GPC). Using hyaluronic acid or its pharmaceutically acceptable salt or ester, such as sodium hyaluronate, within the defined molecular weight range can further reduce the formation of impurity A in the composition during storage, thereby improving the storage stability of the composition. Preferably, the weight-average molecular weight of the hyaluronic acid or its pharmaceutically acceptable salt or ester, such as sodium hyaluronate, is 300,000 to 1,200,000. Within this preferred range, on the one hand, a lower molecular weight can further reduce the generation of impurity A in the composition during storage, thereby improving the storage stability of the composition; on the other hand, the composition will not experience an excessive increase in viscosity due to the addition of the hyaluronic acid or its pharmaceutically acceptable salt or ester, such as sodium hyaluronate, thus the composition has high fluidity and can be easily subjected to treatments requiring high fluidity, such as sterile filtration. Therefore, it is suitable for preparing ophthalmic preparations, such as eye drops, that are required to be sterile according to the requirements of the Chinese Pharmacopoeia.

[0121] The composition may optionally further include other additive components, such as:

[0122] Tackifiers, such as hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium sulfobutylcyclodextrin, carbomer, or any combination of two or more thereof; and / or

[0123] Surfactants or penetration enhancers, such as Tween, propylene glycol, diethyl propylene glycol, polyethylene glycol, polyethylene glycol stearate, polyoxyethylene castor oil, tylosap, nonylphenol ether, octylphenol polyether, glyceryl monostearate, polyethylene glycol 15-hydroxystearate, dimethyl silicone oil, borneol, peppermint oil, camphor, eucalyptol, anethole, terpineol, bisabolol, or any combination of two or more thereof.

[0124] The compositions of the first and second embodiments of the first aspect of the present invention exhibit excellent storage stability, producing very little impurity A during storage (e.g., after long-term storage, such as storage at 60°C for 30 days, the content of impurity A does not exceed 0.1%, for example, not more than 0.09%, for example, not more than 0.08%, for example, not more than 0.07%, for example, not more than 0.06%, for example, not more than 0.05%, for example, not more than 0.04%, for example, not more than 0.03%, for example, not more than 0.02%, relative to the mass of phenylbutyric acid or its pharmaceutically acceptable salt or ester initially contained in the composition). Furthermore, the composition is less irritating; further suitable for formulation into ophthalmic preparations, and further suitable for formulation into eye drops.

[0125] Composition preparation method

[0126] In a second aspect, the present invention relates to a method for preparing the pharmaceutical composition of the first aspect of the invention, the method comprising:

[0127] Mix the ingredients thoroughly in water, optionally add water and adjust the pH, and add water to the full volume to provide the composition.

[0128] For example, the composition of the present invention can be prepared by dissolving all components simultaneously or sequentially in water and mixing them thoroughly, then optionally adding water, optionally adjusting the pH, then adding water to the full volume, optionally sterilizing and filtering, and filling. In the case of sequential dissolution, preferably, the next component is added and dissolved after the previous component has been completely dissolved.

[0129] The dissolution and mixing can be carried out at room temperature or at elevated temperatures (e.g., 30-90°C) with stirring, depending on the solubility of the reagents used.

[0130] For example, when the composition includes a polymeric component such as hyaluronic acid or a pharmaceutically acceptable salt or ester thereof, the composition can be prepared, for example, by:

[0131] (1) Dissolve the polymer component, such as hyaluronic acid or its pharmaceutically acceptable salt or ester, such as sodium hyaluronate (e.g. at room temperature or at elevated temperatures (e.g., 30-90°C)), in water (e.g., prepare about 75% of the total amount) to obtain a first solution;

[0132] (2) Then, the remaining components other than sodium 4-phenylbutyrate, such as buffers and osmotic pressure regulators, are added to the first solution and mixed evenly to obtain the second solution;

[0133] (3) Add sodium 4-phenylbutyrate to the second solution and mix well to obtain the third solution;

[0134] (4) Mix the third solution with water (e.g., to a total of about 97% of the total amount prepared with the water in step (1)) and mix thoroughly to obtain the fourth solution;

[0135] (5) Optionally adjust the pH of the fourth solution with a pH adjuster (e.g., to 6.5-8.0);

[0136] (6) Add water to make up the full amount and mix well;

[0137] (7)Optionally, sterile filtration and filling.

[0138] For example, when the composition does not include a polymeric component such as hyaluronic acid or its pharmaceutically acceptable salt or ester, the composition may be prepared, for example, by:

[0139] (1) Add other components, such as buffers and osmotic pressure regulators, except for sodium 4-phenylbutyrate to water and mix them evenly to obtain the first solution;

[0140] (2) Add sodium 4-phenylbutyrate to the first solution and mix well to obtain the second solution;

[0141] (3) Mix the second solution with water (e.g., to a total of about 97% of the total amount prepared with the water in step (1)) and mix thoroughly to obtain the third solution;

[0142] (4) Optionally adjust the pH of the third solution with a pH adjuster (e.g., to 6.5-8.0);

[0143] (5) Add water to make up the full amount and mix well;

[0144] (6)Optionally, sterile filtration and filling.

[0145] use

[0146] In a third aspect, the present invention relates to the use of the composition of the first aspect of the invention in the preparation of an formulation for treating eye diseases.

[0147] All descriptions above relating to the first aspect of the invention are applicable here.

[0148] The preparation for treating eye diseases may be, for example, an ophthalmic preparation for treating myopia.

[0149] The formulation for treating eye diseases of the present invention exhibits excellent storage stability, with a significantly reduced increase in the content of impurity A after long-term storage. After long-term storage, such as at 60°C for 30 days, the content of impurity A in the pharmaceutical composition is no more than 0.1%, for example, no more than 0.09%, no more than 0.08%, no more than 0.07%, no more than 0.06%, no more than 0.05%, no more than 0.04%, no more than 0.03%, or no more than 0.02%, relative to the mass of phenylbutyric acid or its pharmaceutically acceptable salts or esters initially contained in the composition. Therefore, it has a long shelf life and maintains consistent product quality throughout the shelf life.

[0150] Methods for improving the storage stability of pharmaceutical compositions

[0151] In a fourth aspect, the present invention provides a method for improving the storage stability of a pharmaceutical composition, said pharmaceutical composition being an aqueous solution comprising phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof, said method comprising:

[0152] Add hyaluronic acid or a pharmaceutically acceptable salt or ester thereof to the aqueous solution; and / or

[0153] No disodium ethylenediaminetetraacetate, ethylenediaminetetraacetic acid, or calcium sodium ethylenediaminetetraacetate is added to the aqueous solution.

[0154] The content of impurity A in the obtained pharmaceutical composition after storage at 60°C for 30 days is not more than 0.1%, for example not more than 0.09%, for example not more than 0.08%, for example not more than 0.07%, for example not more than 0.06%, for example not more than 0.05%, for example not more than 0.04%, for example not more than 0.03%, for example not more than 0.02%, relative to the mass of phenylbutyric acid or its pharmaceutically acceptable salt or ester initially contained in the obtained pharmaceutical composition.

[0155] Regarding the resulting composition, all the above descriptions concerning the first to third aspects of the present invention apply to it, and will not be repeated here.

[0156] Example

[0157] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be regarded as limiting the scope of the present invention.

[0158] Experimental materials

[0159] Sodium hyaluronate: Shandong Zhongshan Biotechnology Co., Ltd., with weight-average molecular weight (Mw) ranges of 10,000-300,000, 100,000-300,000, 400,000-600,000, 1,000,000-1,200,000, and 1,300,000-1,500,000 (laboratory-determined weight-average molecular weights are approximately 30,000, 300,000, 600,000, 1,200,000, and 1,500,000). Sodium hyaluronate with a molecular weight of 10,000-30,000 is... EXC sodium hyaluronate (pharmaceutical grade), other molecular weight (100,000-1,500,000) sodium hyaluronates are all... OPH grade sodium hyaluronate (eye drop grade)

[0160] Hydroxypropyl methylcellulose: Shanghai Calcare Coating Technology Co., Ltd., Grade E5

[0161] Experimental instruments

[0162] Magnetic stirrer: IKA

[0163] pH meter: Mettler FE28

[0164] Electronic balance: Ohaus AR2140

[0165] HPLC: Waters Alliance e2695

[0166] Thermostatic water bath: HWS-26

[0167] Strip retinoscope: YZ24

[0168] Previous section - OCT: CASIA2

[0169] Measurement methods

[0170] Impurity A content: HPLC (High Performance Liquid Chromatography) method, Chinese Pharmacopoeia 0512

[0171] Osmotic pressure: Chinese Pharmacopoeia 0632

[0172] Eye stimulation: slit-lamp detection method

[0173] Reference example 1

[0174] Prepare a control sample according to the composition shown in Table 1. Add an appropriate amount of water to a beaker, then add the prescribed amount of sodium 4-phenylbutyrate and stir to dissolve. After visually confirming that there are no insoluble substances, adjust the pH of the solution to neutral with an appropriate amount of sodium hydroxide / hydrochloric acid solution, add water to the total volume, and stir well.

[0175] Examples 1-8

[0176] Prepare the formulations of Examples 1-8 according to the compositions shown in Table 1. Add an appropriate amount of water to a beaker, add sodium hyaluronate and stir until fully dissolved. Then add the prescribed amount of sodium dihydrogen phosphate to the beaker and stir until dissolved. After visually confirming that there are no insoluble substances, add the prescribed amount of sodium 4-phenylbutyrate and stir until dissolved. Adjust the pH of the solution to neutral with an appropriate amount of sodium hydroxide / hydrochloric acid solution, add water to the total volume, and stir until homogeneous.

[0177] Example 9

[0178] The formulation of Example 9 was prepared in the same manner as in Example 5, except that sodium hyaluronate was not added according to the formulation composition shown in Table 1 below.

[0179] Sodium 4-phenylbutyrate undergoes oxidative degradation during storage, primarily producing impurity A. Therefore, for each formulation prepared in Reference Example 1 and Examples 1-9, the content of impurity A was measured under storage conditions of 60°C for 30 days to assess formulation stability. The results are shown in Table 1 below.

[0180] The content of impurity A refers to the mass percentage of the measured amount of impurity A relative to the amount of sodium 4-phenylbutyrate initially added to the formula.

[0181] Table 1

[0182] A comparison between Reference Example 1, Example 5, and Example 9 shows that by adding sodium hyaluronate to the formulation, the content of impurity A after storage at 60°C for 30 days is significantly reduced, thereby improving the storage stability of the formulation; and the addition of the buffer sodium dihydrogen phosphate can also reduce the generation of impurity A, thereby improving the storage stability of the formulation.

[0183] As can be seen from Table 1 above, for various formulations with sodium 4-phenylbutyrate concentrations of 0.01-5%, the increase in impurity A content after storage at 60°C for 30 days by adding sodium hyaluronate to each formulation was not significant, and none of them exceeded 0.05%, or even 0.02%. This indicates that adding sodium hyaluronate can improve the storage stability of sodium 4-phenylbutyrate solutions of various concentrations.

[0184] Example 10

[0185] The formulation of Example 10 was prepared according to the composition shown in Table 2 below. An appropriate amount of water was added to a beaker, followed by sodium hyaluronate, which was stirred until fully dissolved. Then, sodium dihydrogen phosphate and disodium oxalate were added to the beaker in the prescribed amounts, and stirred until dissolved. After visually confirming the absence of insoluble matter, sodium 4-phenylbutyrate was added in the prescribed amount, and stirred until dissolved. The pH of the solution was adjusted to neutral with an appropriate amount of sodium hydroxide / hydrochloric acid solution, and water was added to the final volume, stirring thoroughly.

[0186] Examples 11-13

[0187] The formulations of Examples 11-13 were prepared in the same manner as in Example 10, according to the composition shown in Table 2 below, except that: sodium hyaluronate was not added, and boric acid and borax were used as buffers for Examples 11-12, and the amount of EDTA was changed to 0.03% for Example 11.

[0188] For each of the prepared formulations, the content of impurity A was determined after the samples were stored at 60°C for 30 days to assess the stability of the formulations. The results are shown in Table 2 below.

[0189] Table 2

[0190] A comparison of Example 9 with Examples 11-13, especially Example 13, shows that adding EDTA to the formulation significantly increases the content of impurity A to more than 0.1% after storage at 60°C for 30 days; by omitting EDTA, the content of impurity A significantly decreases to less than 0.05% after storage at 60°C for 30 days, thereby improving the storage stability of sodium 4-phenylbutyrate aqueous solution.

[0191] In addition, as can be seen from the table above, the addition of sodium hyaluronate to the formulation significantly reduced the content of impurity A after 30 days of storage at 60°C, and improved the storage stability of sodium 4-phenylbutyrate aqueous solution, even for formulations containing EDTA.

[0192] Examples 14-15

[0193] The formulations of Examples 14-15 were prepared in the same manner as in Example 5, according to the composition shown in Table 3 below, except that sodium citrate and a mixture of boric acid and borax were used instead of sodium dihydrogen phosphate.

[0194] For each prepared formulation, the content of impurity A was determined after the sample was stored at 60°C for 30 days to assess the formulation stability. The results are shown in Table 3 below.

[0195] Table 3

[0196] As can be seen from the table above, under the storage conditions investigated, the phosphate, citrate, and borate buffer systems all resulted in impurity A content below 0.05% after 30 days of storage at 60°C, meeting the stability requirements of liquid formulations. Specifically, Example 5 using the phosphate buffer system and Example 14 using the citrate buffer system showed low and consistent levels of impurity A, with impurity A content below 0.02% after 30 days of storage at 60°C. However, Example 15 using the borate system showed a relatively higher impurity level under the investigated conditions, indicating that the phosphate and citrate buffer systems are superior to the borate buffer system.

[0197] Example 16

[0198] The formulation of Example 16 was prepared according to the composition shown in Table 4 below. An appropriate amount of water was added to a beaker and placed in a water bath at 80-90°C. Hydroxypropyl methylcellulose was added and stirred rapidly until fully dispersed. The beaker was then removed and placed at room temperature. Water was added and stirred. The prescribed amounts of sodium dihydrogen phosphate were added to the beaker sequentially and stirred until dissolved. After visual inspection to ensure no insoluble matter remained, the prescribed amounts of sodium 4-phenylbutyrate were added and stirred until dissolved. The pH of the solution was adjusted to neutral with an appropriate amount of sodium hydroxide solution. Water was added to the final volume, and the mixture was stirred until homogeneous.

[0199] For each of the prepared formulations, the content of impurity A was determined after the samples were stored at 60°C for 30 days to assess the formulation stability. The results are shown in Table 4 below.

[0200] Table 4

[0201] Although both hydroxypropyl methylcellulose and sodium hyaluronate can be used as thickeners, as can be seen from the table above, the addition of hydroxypropyl methylcellulose has almost no effect on the content of impurity A under various storage conditions, while the addition of sodium hyaluronate can significantly reduce the content of impurity A during storage and improve the storage stability of sodium 4-phenylbutyrate aqueous solution.

[0202] Examples 17-19

[0203] The formulations of Examples 17-19 were prepared in the same manner as in Example 5, according to the composition shown in Table 5 below, except that the amount of sodium hyaluronate was changed.

[0204] For each of the prepared formulations, the content of impurity A was determined after the samples were stored at 60°C for 30 days to assess the formulation stability. The results are shown in Table 5 below.

[0205] Table 5

[0206] As can be seen from the table above, the addition of different amounts of sodium hyaluronate reduced the content of impurity A under the storage conditions investigated and improved the storage stability of sodium 4-phenylbutyrate aqueous solution.

[0207] The addition of sodium hyaluronate leads to an increase in the viscosity of the formulation. Examples 5 and 17-18, which use sodium hyaluronate with contents of 0.01%, 0.1%, and 1%, respectively, have lower viscosity and therefore better flowability compared to Example 19, which uses sodium hyaluronate with a content of 2%. This makes it easier to perform sterile filtration that requires high flowability and is therefore more suitable for preparing ophthalmic formulations that are required to be sterile according to the Chinese Pharmacopoeia.

[0208] Examples 20-23

[0209] The formulations of Examples 20-23 were prepared in the same manner as in Example 17, according to the composition shown in Table 6 below, except that sodium hyaluronate of different molecular weights was used.

[0210] For each of the prepared formulations, the content of impurity A was determined after the samples were stored at 60°C for 30 days to assess the stability of the formulations. The results are shown in Table 6 below.

[0211] Table 6

[0212] As can be seen from the table above, regarding the content of impurity A after storage at 60°C for 30 days, compared with Example 9 which did not use sodium hyaluronate, Examples 17 and 20-23, which used sodium hyaluronate with various molecular weights (30,000-1,500,000), all reduced the content of impurity A under the investigated conditions to varying degrees. Moreover, Examples 17 and 21-23, which used higher molecular weights (300,000-1,500,000), showed a more significant reduction effect, and the level of impurity A was basically the same, with the content of impurity A being less than 0.03% after storage at 60°C for 30 days.

[0213] Furthermore, as the molecular weight of sodium hyaluronate increases, the viscosity of the formulation increases at the same addition amount. The formulations of Examples 17 and 20-22, using lower molecular weights (30,000-1,200,000), have lower viscosity and therefore better flowability compared to Example 23, which uses a higher molecular weight (1,500,000). This makes them easier to use for sterile filtration requiring high flowability, and thus more suitable for preparing ophthalmic formulations that are required to be sterile according to the Chinese Pharmacopoeia.

[0214] Examples 24-27

[0215] The formulations of Examples 24-27 were prepared in the same manner as in Example 5, according to the composition shown in Table 7 below, except that the pH values ​​were adjusted to the values ​​shown using NaOH and / or hydrochloric acid, respectively.

[0216] For each prepared formulation, the content of impurity A was determined after the sample was stored at 60°C for 30 days to assess the formulation stability. The results are shown in Table 7 below.

[0217] Table 7

[0218] As can be seen from the table above, under the storage conditions investigated, the content of impurity A in Examples 5 and 25-27, where the pH of the formulation is in the range of 6.5-8.0, is basically the same and lower than that in Example 24, where the pH is 6.0.

[0219] Examples 28-30

[0220] The formulations of Examples 28-30 were prepared in the same manner as in Example 5, according to the composition shown in Table 8 below, except that the amount of sodium dihydrogen phosphate was changed.

[0221] For each of the prepared formulations, the content of impurity A was determined after the samples were stored at 60°C for 30 days to assess the stability of the formulations. The results are shown in Table 8 below.

[0222] Table 8

[0223] As can be seen from the table above, Examples 5 and 28-30, which used different amounts of sodium dihydrogen phosphate, all had low levels of impurity A under the storage conditions investigated. Among them, Examples 5 and 28-29, with sodium dihydrogen phosphate dosages of 0.01-0.7%, showed slightly lower impurity A content and exhibited slightly better stability of sodium phenylbutyrate aqueous solution compared to Example 30, which had a sodium dihydrogen phosphate dosage of 0.8%.

[0224] Examples 31-38

[0225] Prepare the formulations of Examples 31-38 according to the compositions shown in Table 9 below. Add an appropriate amount of water to a beaker, add sodium hyaluronate and stir until fully dissolved. Then, add the prescribed amounts of sodium dihydrogen phosphate and an osmotic pressure regulator (sodium chloride, mannitol, or glycerol) to the beaker sequentially, stirring until dissolved. After visually confirming the absence of insoluble matter, add the prescribed amounts of sodium 4-phenylbutyrate and stir until dissolved. Adjust the pH of the solution with an appropriate amount of sodium hydroxide / hydrochloric acid solution, add water to the final volume, and stir until homogeneous.

[0226] For each of the prepared formulations, the content of impurity A was determined after the samples were stored at 60°C for 30 days to assess the stability of the formulations, and compared with Examples 1-7, which did not contain osmotic pressure regulators. The results are shown in Table 9 below.

[0227] Table 9

[0228] The comparisons between Examples 31-36 and Examples 1-6, and between Example 5 and Examples 37-38, show that the addition of the osmotic pressure regulator had almost no effect on the content of impurity A in the samples under the investigated conditions. The comparison between Example 35 and Examples 37-38 shows that the content of impurity A in the samples under the investigated conditions was low under different osmotic pressure regulators, and the changes were basically consistent, indicating that glycerol, mannitol, and sodium chloride can all be used to adjust osmotic pressure in the formulation, and that the corresponding formulations all have good storage stability.

[0229] In addition, the table above shows that when the content of sodium 4-phenylbutyrate is in the range of 0.01-3%, the osmotic pressure of each formulation can meet the requirements of isotonicity for ophthalmic preparations, and therefore it is more suitable for use as eye drops.

[0230] Examples 39-44

[0231] Prepare the formulations of Examples 39-44 according to the compositions shown in Table 10 below. Add an appropriate amount of water to a beaker, add a thickener (sodium hyaluronate or hydroxypropyl methylcellulose), and stir until fully dissolved. Then, add the prescribed amounts of sodium dihydrogen phosphate and sodium chloride to the beaker sequentially, stirring until dissolved. After visually confirming the absence of insoluble matter, add the prescribed amount of sodium 4-phenylbutyrate and stir until dissolved. Adjust the pH of the solution with an appropriate amount of sodium hydroxide / hydrochloric acid solution, add water to the total volume, and stir until homogeneous.

[0232] For each of the prepared formulations, the content of impurity A was determined after the samples were stored at 60°C for 30 days to assess the formulation stability. The results are shown in Table 10 below.

[0233] Table 10

[0234] As can be seen from the table above, for different pH values ​​and different amounts of buffer, the addition of osmotic pressure regulator has almost no effect on the content of impurity A in the sample under the investigated conditions.

[0235] In addition, eye irritation tests were conducted on the formulations of Examples 35 and 39-44 using New Zealand white rabbits, ordinary grade, 6 rabbits / group (half male and half female), and eye irritation scores were given according to the amount of secretions, based on the evaluation criteria shown in Table 11 below. The experimental results are shown in Table 12 below.

[0236] Table 11

[0237] Table 12

[0238] As can be seen from the table above, regarding the conjunctival secretions observed in the eye stimulation test,

[0239] - No secretion infiltration was observed in animals in Example 35, which was superior to Example 44, indicating that sodium hyaluronate is significantly better than hydroxypropyl cellulose in terms of eye irritation and is therefore more suitable for the preparation of ophthalmic preparations such as eye drops.

[0240] - No or only slight secretion infiltration was observed in Examples 35 and 39-40, while local irritation was observed in Example 41, indicating that, in terms of eye irritation, using a pH range of 6.5-7.5 can reduce irritation compared to pH 8.0, and is therefore more suitable for preparing ophthalmic preparations such as eye drops;

[0241] Example 42 showed only slight secretion infiltration, while Example 43 showed local irritation, indicating that a phosphate content of 0.70% is less irritating to the eyes and is therefore more suitable for preparing ophthalmic preparations such as eye drops. In summary, the experimental results show that a disodium hydrogen phosphate concentration in the range of 0.02%-0.7% is more suitable for preparing ophthalmic preparations such as eye drops.

[0242] Reference example 2

[0243] Prepare a blank control sample according to the composition shown in Table 13 below. Add an appropriate amount of water to a beaker, add sodium hyaluronate and stir until fully dissolved. Then add the prescribed amounts of sodium dihydrogen phosphate and sodium chloride to the beaker and stir until dissolved. After visually confirming that there are no insoluble substances, adjust the pH of the solution to neutral with an appropriate amount of sodium hydroxide / hydrochloric acid solution, add water to the full volume, and stir evenly.

[0244] Using the formulations of Reference Example 2 and Examples 32 and 36, and employing a guinea pig deprivation myopia model, the refractive and axial length changes after 21 days of administration of 0.1% and 3% sodium 4-phenylbutyrate were verified.

[0245] Experimental methods: A deprivation myopia model was established using guinea pigs (tricolor guinea pigs, 14 days old). After screening, the experimental animals were divided into groups of 30 (half male and half female), and the drug was administered at a dose of 15 μl / eye / day for efficacy studies.

[0246] The experimental results are shown in Table 13 below.

[0247] Table 13

[0248] The efficacy test results given in the table above show that, in terms of refractive index, Examples 32 and 36 are significantly better than Reference Example 2 (blank control), indicating that the pharmaceutical composition of the present invention can effectively guarantee the efficacy of the drug.

[0249] Although specific embodiments of the invention have been described in detail, those skilled in the art will understand that various modifications and substitutions can be made to those details based on all the teachings disclosed, and all such changes are within the scope of protection of the invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims

1. A pharmaceutical composition comprising: Phthalic acid or its pharmaceutically acceptable salts or esters. Hyaluronic acid or its pharmaceutically acceptable salts or esters; and Solvent: water.

2. The composition according to claim 1, wherein the pharmaceutically acceptable salt of phenylbutyric acid comprises or is a sodium salt, preferably the phenylbutyric acid or its pharmaceutically acceptable salt or ester comprises or is sodium 4-phenylbutyrate.

3. The composition according to any one of claims 1-2, comprising 0.01-5.0% w / v, for example 0.01-4.0% w / v, for example 0.01-3.0% w / v, of phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof.

4. The composition according to any one of claims 1-3, wherein the hyaluronic acid or a pharmaceutically acceptable salt or ester thereof comprises or is sodium hyaluronate.

5. The composition according to any one of claims 1-4, comprising 0.01-1.0% w / v hyaluronic acid or a pharmaceutically acceptable salt or ester thereof.

6. The composition according to any one of claims 1-5, further comprising a buffer, said buffer comprising, for example, or selected from one or more of: sodium dihydrogen phosphate and / or sodium citrate, preferably sodium dihydrogen phosphate, said buffer being in an amount of, for example, 0.01-2.0% w / v, such as 0.02-1.0% w / v, for example, the composition comprising 0.01-0.7% w / v, preferably 0.02%-0.7% w / v of sodium dihydrogen phosphate and / or 0.01-0.85% w / v of sodium citrate.

7. The composition according to any one of claims 1-6, further comprising an osmotic pressure regulator, said osmotic pressure regulator comprising, for example, one or more selected from: sodium chloride, glycerol, and / or mannitol.

8. The composition according to any one of claims 1-7, wherein the osmotic pressure of the composition is 260-400 mOsmol / kg, for example 260-340 mOsmol / kg.

9. The composition according to any one of claims 1-8, further comprising a pH adjuster, said pH adjuster comprising, for example, one or more selected from: HCl and / or NaOH.

10. The composition according to any one of claims 1-9, wherein the pH of the composition is 6.5-8.0, preferably 6.5-7.

5.

11. The composition according to any one of claims 1-10, wherein the hyaluronic acid or its pharmaceutically acceptable salt or ester has a weight-average molecular weight of 30,000 to 1,500,000, preferably 300,000 to 1,200,000.

12. The composition according to any one of claims 1-11, wherein it does not contain ethylenediaminetetraacetic acid or disodium ethylenediaminetetraacetic acid or calcium sodium ethylenediaminetetraacetic acid.

13. The composition according to any one of claims 1-12, wherein it does not contain a stabilizer.

14. The composition according to any one of claims 1-13, comprising: Sodium 4-phenylbutyrate, 0.01-5.0% w / v Sodium dihydrogen phosphate, 0.02%-0.7% w / v; Sodium hyaluronate, 0.01-1.0% w / v; Optional osmotic pressure regulator; A pH adjuster, in an amount such that the pH of the resulting composition is 6.5-8.0; and Solvent: water.

15. The composition according to any one of claims 1-14, wherein the content of impurity A after storage at 60°C for 30 days is not more than 0.1%, for example not more than 0.09%, for example not more than 0.08%, for example not more than 0.07%, for example not more than 0.06%, for example not more than 0.05%, for example not more than 0.04%, for example not more than 0.03%, for example not more than 0.02%, relative to the mass of phenylbutyric acid or its pharmaceutically acceptable salt or ester initially contained in the composition.

16. A pharmaceutical composition comprising: Phthalic acid or its pharmaceutically acceptable salts or esters; and Solvent water; The composition does not include disodium ethylenediaminetetraacetate, ethylenediaminetetraacetic acid, or calcium sodium ethylenediaminetetraacetate.

17. The composition according to claim 16, wherein it does not contain a stabilizer.

18. The composition according to any one of claims 16-17, wherein the pharmaceutically acceptable salt of said phenylbutyric acid comprises or is a sodium salt, preferably the phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof comprises or is sodium 4-phenylbutyrate.

19. The composition according to any one of claims 16-18, comprising 0.01-5.0% w / v, for example 0.01-4.0% w / v, for example 0.01-3.0% w / v, of phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof.

20. The composition according to any one of claims 16-19, further comprising a buffer, said buffer comprising, for example, or selected from one or more of: sodium dihydrogen phosphate and / or sodium citrate, preferably sodium dihydrogen phosphate, said buffer being in an amount of, for example, 0.01-2.0% w / v, such as 0.02-1.0% w / v, for example, the composition comprising 0.01-0.7% w / v, preferably 0.02%-0.7% w / v of sodium dihydrogen phosphate and / or 0.01-0.85% w / v of sodium citrate.

21. The composition according to any one of claims 16-20, further comprising an osmotic pressure regulator, said osmotic pressure regulator comprising, for example, one or more selected from: sodium chloride, glycerol, and / or mannitol.

22. The composition according to any one of claims 16-21, wherein the osmotic pressure of the composition is 260-400 mOsmol / kg, for example 260-340 mOsmol / kg.

23. The composition according to any one of claims 16-22, further comprising a pH adjuster, said pH adjuster comprising, for example, one or more selected from: HCl and / or NaOH.

24. The composition according to any one of claims 16-23, wherein the pH of the composition is 6.5-8.0, preferably 6.5-7.

5.

25. The composition according to any one of claims 16-24, further comprising hyaluronic acid or a pharmaceutically acceptable salt or ester thereof.

26. The composition of claim 25, wherein the hyaluronic acid or a pharmaceutically acceptable salt or ester thereof comprises or is sodium hyaluronate.

27. The composition according to any one of claims 25-26, wherein the composition comprises 0.01-1.0% w / v of hyaluronic acid or a pharmaceutically acceptable salt or ester thereof.

28. The composition according to any one of claims 25-27, wherein the weight-average molecular weight of the hyaluronic acid or its pharmaceutically acceptable salt or ester is 30,000 to 1,500,000, preferably 300,000 to 1,200,000.

29. The composition according to any one of claims 16-28, wherein the content of impurity A after storage at 60°C for 30 days is not more than 0.1%, for example not more than 0.09%, for example not more than 0.08%, for example not more than 0.07%, for example not more than 0.06%, for example not more than 0.05%, for example not more than 0.04%, for example not more than 0.03%, for example not more than 0.02%, relative to the mass of phenylbutyric acid or its pharmaceutically acceptable salt or ester initially contained in the composition.

30. The composition according to any one of claims 1-29, wherein it is an ophthalmic pharmaceutical composition, such as eye drops.

31. A method for preparing the composition according to any one of claims 1-30, comprising: The components are mixed evenly in water, and water is optionally added and the pH is adjusted. Water is then added to the full volume, and the mixture is optionally sterilized, filtered, and filled to provide the composition.

32. Use of the composition according to any one of claims 1-30 in the preparation of an formulation for treating eye diseases.

33. A method for improving the storage stability of a pharmaceutical composition, said pharmaceutical composition being an aqueous solution comprising phenylbutyric acid or a pharmaceutically acceptable salt or ester thereof, said method comprising: Add hyaluronic acid or a pharmaceutically acceptable salt or ester thereof to the aqueous solution; and / or No disodium ethylenediaminetetraacetate, ethylenediaminetetraacetic acid, or calcium sodium ethylenediaminetetraacetate is added to the aqueous solution. The content of impurity A in the obtained pharmaceutical composition after storage at 60°C for 30 days is not more than 0.1%, for example not more than 0.09%, for example not more than 0.08%, for example not more than 0.07%, for example not more than 0.06%, for example not more than 0.05%, for example not more than 0.04%, for example not more than 0.03%, for example not more than 0.02%, relative to the mass of phenylbutyric acid or its pharmaceutically acceptable salt or ester initially contained in the obtained pharmaceutical composition.

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