Ophthalmic pharmaceutical composition and use thereof

Abstract

The present invention relates to an ophthalmic pharmaceutical composition, preferably an ophthalmic topical pharmaceutical composition, and preferably eye drops. The ophthalmic pharmaceutical composition comprises: 0.01-0.40% w / v, preferably 0.05-0.24% w / v of levocetirizine hydrochloride; 1.0-4.0% w / v, preferably 2.0-4.0% w / v of mannitol; optionally, 0-0.60% w / v, preferably 0-0.15% w / v of a pharmaceutically acceptable metal ion-containing osmotic pressure regulator, the pharmaceutically acceptable metal ion-containing osmotic pressure regulator being preferably selected from sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, or a combination of any two or more thereof; optionally, 0.05-1.0% w / v, preferably 0.2%-0.85% of a pharmaceutically acceptable buffer, the pharmaceutically acceptable buffer being preferably selected from a phosphate, a citrate, or any combination thereof, and preferably a citrate, which is preferably selected from sodium citrate and / or potassium citrate; and water as a solvent. The present invention also relates to use of the ophthalmic pharmaceutical composition in the preparation of eye drops, preferably eye drops for resisting allergy, especially allergic conjunctivitis.

Description

Ophthalmic pharmaceutical composition and use thereof

[0001] This application claims priority to Chinese Patent Application No. 202311824889.0 filed on December 27, 2023, and the contents of the above-mentioned Chinese patent application disclosure are hereby incorporated by reference in their entirety as a part of this application. Technical Field

[0002] The present invention generally relates to the field of medicine, and in particular to an ophthalmic pharmaceutical composition, in particular an ophthalmic pharmaceutical composition comprising levocetirizine hydrochloride, and use thereof in preparing eye drops, in particular eye drops for anti-allergic treatment, such as anti-allergic conjunctivitis. Background Art

[0003] Already on the market The active ingredient in the eye drops is cetirizine hydrochloride, a racemic form of levocetirizine hydrochloride and dextrocetirizine hydrochloride. Levocetirizine hydrochloride has an affinity for H1 receptors that is twice that of cetirizine hydrochloride and 30 times that of dextrocetirizine hydrochloride. As a new-generation histamine H1 receptor antagonist, levocetirizine hydrochloride offers superior safety, selectivity, and affinity. It is also a highly effective non-sedating antihistamine and has been widely used in clinical treatments for skin and respiratory problems. Levocetirizine hydrochloride is also FDA-approved for pediatric use. Currently, the only commercially available levocetirizine hydrochloride preparations are oral solution and drops; there are no topical formulations. Levocetirizine hydrochloride is readily soluble in water, but at low concentrations (<1%, w / v), it gradually forms insoluble substances, reducing the stability of its aqueous solution.

[0004] To address the stability issue of levocetirizine hydrochloride, researchers often use three methods.

[0005] The first approach is to add functional excipients such as polyethylene glycol (PEG)-based surfactants, such as polyethylene glycol 400, polysorbate 80, and other types of surfactants, to the formulation as solubilizers to increase the solubility of levocetirizine hydrochloride. For example, patent US11241426B2 uses polysorbate 80 as a surfactant to increase the solubility of levocetirizine hydrochloride, patent CN1166362C uses polyethylene glycol 400 to prevent chemical degradation of levocetirizine hydrochloride, and patent CN116437910A uses the novel excipient tocopherol to improve formulation stability. However, surfactants of this type often share some common characteristics: the polyethylene glycol structure forms hydrogen bonds with water molecules. Disruption of these hydrogen bonds (e.g., at elevated temperatures or physical interaction between the compound and the polyethylene glycol) can cause precipitation of the surfactant. Furthermore, the ether bonds in ethylene glycol or polyethylene glycol are susceptible to oxidation, leading to the formation of oxides during storage. This can lead to compatibility issues with easily oxidized drugs, such as those with piperazine structures or oxidizing properties, such as precipitation and N-oxide impurities. Furthermore, when the PEG segment is connected to the hydrophobic structure via an ester bond, it is susceptible to cleavage in the presence of strong acids and bases. While polyethylene glycol segments are generally non-toxic and non-toxic, they can be allergenic. Therefore, while polyethylene glycol-based surfactants can be used as solubilizers to increase the stability of levocetirizine hydrochloride, they also present quality and safety risks.

[0006] The second approach is to use molecular inclusion technology, namely, adding cyclodextrin excipients to the formulation to improve its stability. For example, patents CN114306227A and CN101795565A use cyclodextrin and its derivative inclusion technology to increase drug stability. However, cyclodextrin inclusion technology is complex, and the encapsulation efficiency remains to be determined. Furthermore, as levocetirizine hydrochloride is an FDA-approved medication for children, its formulation should also consider safety issues for children. Cyclodextrin has been suggested to pose potential safety risks to children.

[0007] The third approach is liposome technology, which involves adding phospholipids to the formulation to increase drug stability. However, liposome-encapsulated drug formulations are typically provided in a dry (e.g., freeze-dried) form and then reconstituted with an aqueous solution immediately before administration. This formulation is not ideal for patient handling, especially in children.

[0008] In addition, the prior art often uses surfactants in combination with water-soluble polymers to increase drug stability. For example, patent CN1166362C uses the surfactant poloxamer and the water-soluble polymer polyvinylpyrrolidone to improve the stability of the formulation. However, poloxamer is not biodegradable, so the safety of actual patients is not considered. Polyvinylpyrrolidone also increases impurities in the formulation and is mostly used in sustained-release formulations.

[0009] Therefore, there is a need in the art to provide a levocetirizine hydrochloride ophthalmic pharmaceutical composition with high stability (no precipitation or insoluble matter during long-term storage and low impurity content), simple dosage form, high safety, and few toxic and side effects. Summary of the Invention

[0010] The present invention is made in view of the above-mentioned problems existing in the prior art.

[0011] In a first aspect, the present invention provides an ophthalmic pharmaceutical composition having, for example, high stability (no insoluble matter and low impurity content during long-term storage), simple dosage form, high safety, and few toxic and side effects.

[0012] In a second aspect, the present invention provides use of the ophthalmic pharmaceutical composition in preparing eye drops, in particular eye drops for anti-allergy, such as anti-allergic conjunctivitis.

[0013] The applicant has found that the use of mannitol can improve the stability of levocetirizine hydrochloride ophthalmic pharmaceutical compositions, avoid the formation of insoluble substances and reduce the content of impurities formed during long-term storage.

[0014] The applicant also found that:

[0015] - When mannitol is used in combination with a pharmaceutically acceptable metal ion-containing osmotic pressure regulator such as sodium chloride, the amount of impurities formed during long-term storage can be further reduced.

[0016] - When a pharmaceutically acceptable buffer such as citrate is used, the amount of impurities formed during long-term storage can be further reduced, thereby further improving storage stability.

[0017] When a pharmaceutically acceptable thickening agent such as sodium hyaluronate is used, especially when used in combination with citrate, the content of impurities formed during long-term storage (eg, the content of individual impurities and the total content of impurities) can be reduced.

[0018] In particular, the present invention is achieved by:

[0019] 1. An ophthalmic pharmaceutical composition comprising:

[0020] 0.01-0.40% w / v, preferably 0.05-0.24% w / v levocetirizine hydrochloride;

[0021] 1.0-4.0% w / v, preferably 2.0-4.0% w / v mannitol; and

[0022] Water as solvent.

[0023] 2. The ophthalmic pharmaceutical composition according to item 1, further comprising 0-0.60% w / v, preferably 0-0.15% w / v, of a pharmaceutically acceptable metal ion-containing osmotic pressure regulator; preferably, the pharmaceutically acceptable metal ion-containing osmotic pressure regulator is selected from sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, or a combination of any two or more thereof.

[0024] 3. The ophthalmic pharmaceutical composition according to any one of items 1-2, further comprising 0.05-1.0% w / v, preferably 0.2%-0.85% of a pharmaceutically acceptable buffer, preferably selected from phosphate, citrate, or any combination thereof; preferably citrate, preferably selected from sodium citrate and / or potassium citrate;

[0025] 4. The ophthalmic pharmaceutical composition according to any one of items 1 to 3, further comprising 0-1.0% w / v, preferably 0-0.2% w / v, of a pharmaceutically acceptable surfactant.

[0026] 5. The ophthalmic pharmaceutical composition according to any one of items 1 to 4, further comprising 0.01-1.0% w / v, preferably 0.01-0.20% w / v, of a pharmaceutically acceptable thickener, preferably selected from sodium hyaluronate, polyvinyl alcohol, polyvinyl pyrrolidone, sodium sulfobutyl cyclodextrin, carbomer, hypromellose, or a combination of any two or more thereof, preferably sodium hyaluronate.

[0027] 6. The ophthalmic pharmaceutical composition according to any one of items 1 to 5, further comprising 0.01-0.1% w / v of a pharmaceutically acceptable stabilizer, preferably the stabilizer is selected from edetate disodium, edetate calcium sodium or any combination thereof, preferably edetate disodium.

[0028] 7. The ophthalmic pharmaceutical composition according to any one of items 1 to 6, which has a pH of 6.0-8.0, preferably 6.8-7.2; preferably, the ophthalmic pharmaceutical composition has been adjusted to a pH of 6.0-8.0, preferably 6.8-7.2, with a pharmaceutically acceptable pH adjuster, and the pH adjuster is preferably selected from sodium hydroxide, potassium hydroxide, HCl or any combination thereof.

[0029] 8. The ophthalmic pharmaceutical composition according to any one of items 1 to 7, which does not contain a preservative.

[0030] 9. The ophthalmic pharmaceutical composition according to any one of items 1 to 8, which has an osmotic pressure of 250-320, preferably 280-300 mOsm / kg.

[0031] 10. The ophthalmic pharmaceutical composition according to any one of items 1 to 9, which has a viscosity of 1 to 10.0, preferably 3.0 to 8.0 mPa·s, as measured by a Brookfield rotational viscometer at a temperature of 25°C.

[0032] 11. The ophthalmic pharmaceutical composition according to any one of items 1 to 10, which is an external ophthalmic pharmaceutical composition, preferably an eye drop.

[0033] 12. The ophthalmic pharmaceutical composition according to item 1-11, comprising:

[0034] 0.01-0.40% w / v, preferably 0.05-0.24% w / v levocetirizine hydrochloride;

[0035] 1.0-4.0% w / v, preferably 2.0-4.0% w / v mannitol;

[0036] 0-0.60% w / v, preferably 0-0.15% w / v of a pharmaceutically acceptable metal ion-containing osmotic pressure regulator;

[0037] 0.05-1.0% w / v, preferably 0.2%-0.85% of a pharmaceutically acceptable buffer;

[0038] 0-1.0% w / v, preferably 0-0.2% w / v of a pharmaceutically acceptable surfactant;

[0039] Optionally 0.01-1.0% w / v, preferably 0.01-0.20% w / v of a pharmaceutically acceptable thickening agent;

[0040] Optionally 0.01-0.1% w / v of a pharmaceutically acceptable stabilizer; and

[0041] Optionally, a pharmaceutically acceptable pH adjuster in an amount such that the ophthalmic pharmaceutical composition has a pH of 6.0-8.0, preferably 6.8-7.2;

[0042] The balance is water as solvent.

[0043] 13. Use of the ophthalmic pharmaceutical composition according to any one of items 1 to 12 in the preparation of eye drops, preferably eye drops for anti-allergy, especially anti-allergic conjunctivitis.

[0044] By combining levocetirizine hydrochloride with mannitol, the resulting ophthalmic pharmaceutical composition has very high long-term storage stability, does not form insoluble substances during long-term storage, and has a low impurity content. The most stringent standards for single and total impurity limits for levocetirizine hydrochloride API, tablets, and cetirizine hydrochloride API, oral solutions, tablets, and drops listed in existing pharmacopoeias (Chinese Pharmacopoeia, United States Pharmacopoeia, European Pharmacopoeia, and Japanese Pharmacopoeia) are: a maximum single impurity content of <0.1% w / v and a total impurity content of <0.5% w / v. The impurity content of the final formulation of the present invention is far below this limit. In addition, the ophthalmic pharmaceutical composition is simple to prepare, highly safe, and has few toxic and side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] The drawings described herein are used to provide a further understanding of the present invention and constitute a part of this application. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0046] FIG1 shows the evaluation results of the degree of ocular surface inflammation in the model group without levocetirizine hydrochloride and Examples 68-74 containing levocetirizine hydrochloride at different concentrations. DETAILED DESCRIPTION

[0047] In this application, unless otherwise specified, the temperature refers to room temperature (25° C.) and the pressure refers to atmospheric pressure.

[0048] In this application, unless otherwise specified, the expression "% w / v" used when referring to the content of a component in an ophthalmic pharmaceutical composition refers to the mass / volume percentage (g / ml), i.e., the grams of solute contained per 100 ml. The liquid preparations involved in the present invention have a relative density of approximately 1.0, so in actual preparation, they can be calculated as 100 grams per 100 ml. Therefore, the mass / volume (g / ml) percentage can also be approximately expressed as the mass / mass (g / g) percentage.

[0049] In the present application, unless otherwise specified, the expression "%" used in referring to the content or concentration of a component means "% w / v".

[0050] In this application, unless otherwise specified, even if the term "about" is not used to modify a numerical value, the numerical value should be understood to be modified by "about"; the term "about" includes a deviation of ±5% of the stated numerical value, that is, for a numerical value a, whether or not it is modified by "about", it should be understood to represent a range of a±5%a, that is, 0.95a to 1.05a.

[0051] In the present application, unless otherwise specified, N-oxide impurities or N-oxide impurities refer to cetirizine N-oxide impurities, namely 2-(2-{4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethoxy)acetic acid N1-oxide.

[0052] Ophthalmic pharmaceutical composition

[0053] The first aspect of the present invention provides an ophthalmic pharmaceutical composition comprising:

[0054] 0.01-0.40% w / v, preferably 0.05-0.24% w / v levocetirizine hydrochloride;

[0055] 1.0-4.0% w / v, preferably 2.0-4.0% w / v mannitol; and

[0056] Water as solvent.

[0057] In an embodiment, the ophthalmic pharmaceutical composition comprises 0.01-0.40% w / v, preferably 0.05-0.24% w / v levocetirizine hydrochloride. 38, 0.39, 0.40%, or a range defined by any two of the foregoing. Levocetirizine hydrochloride can be used for anti-allergic treatment, such as anti-allergic conjunctivitis treatment.

[0058] In an embodiment, the ophthalmic pharmaceutical composition comprises 1.0-4.0% w / v, preferably 2.0-4.0% w / v mannitol. For example, the ophthalmic pharmaceutical composition can comprise mannitol in an amount of 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% w / v, or a range defined by any two thereof. When the amount of mannitol is within the above range, for example, the preferred range, the long-term storage stability of the ophthalmic pharmaceutical composition can be improved, the formation of insoluble substances can be avoided, and the impurity content formed during long-term storage can be reduced. At the same time, the resulting ophthalmic pharmaceutical composition can have an osmotic pressure suitable for use in the human eye (250-320, preferably 280-300 mOsm / kg).

[0059] In an embodiment, the ophthalmic pharmaceutical composition may optionally further include a pharmaceutically acceptable metal ion-containing osmotic pressure regulator. The pharmaceutically acceptable metal ion-containing osmotic pressure regulator may be selected from sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, or a combination of any two or more thereof. For example, the pharmaceutically acceptable metal ion-containing osmotic pressure regulator may be selected from: sodium chloride; potassium chloride; sodium sulfate; potassium sulfate; sodium chloride and potassium chloride; sodium chloride and sodium sulfate; sodium chloride and potassium sulfate; potassium chloride and sodium sulfate; potassium chloride and potassium sulfate; sodium sulfate and potassium sulfate; sodium chloride, potassium chloride, and sodium sulfate; sodium chloride, potassium chloride, and potassium sulfate; sodium chloride, sodium sulfate, and potassium sulfate; potassium chloride, sodium sulfate, and potassium sulfate; sodium chloride, potassium chloride, sodium sulfate, and potassium sulfate.

[0060] The amount of the pharmaceutically acceptable metal ion-containing osmotic pressure regulator can be appropriately selected taking into account the osmotic pressure and stability of the ophthalmic pharmaceutical composition (e.g., whether it will cause insoluble substances). In an embodiment, the ophthalmic pharmaceutical composition can include 0-0.60% w / v, preferably 0-0.15% w / v of a pharmaceutically acceptable metal ion-containing osmotic pressure regulator. For example, the ophthalmic pharmaceutical composition may include the following amounts of a pharmaceutically acceptable metal ion-containing osmotic pressure regulator: 0, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28 , 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60% w / v, or a range bounded by any two of them. When the pharmaceutically acceptable metal ion-containing osmotic pressure regulator is a mixture of two or more components, the amount of each component (sodium chloride, potassium chloride, sodium sulfate, and potassium sulfate) can be appropriately selected in consideration of the osmotic pressure of the resulting pharmaceutical composition, and can be each independently selected from the range of 0.01-0.59% w / v and the individual values ​​within this range stated above, and the sum of the components does not exceed 0.60% w / v.

[0061] When mannitol is used in combination with a pharmaceutically acceptable metal ion-containing osmotic pressure regulator (e.g., sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, or a combination of any two or more thereof, preferably sodium chloride, sodium sulfate, or any combination thereof), the long-term storage stability of the ophthalmic pharmaceutical composition can be further improved, and the content of impurities (single impurities and / or total impurities) formed under long-term storage conditions can be reduced, compared to the case where mannitol is used without a pharmaceutically acceptable metal ion-containing osmotic pressure regulator (e.g., sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, or a combination of any two or more thereof, preferably sodium chloride, sodium sulfate, or any combination thereof, more preferably sodium chloride).

[0062] When mannitol is used in combination with a pharmaceutically acceptable metal ion-containing osmotic pressure regulator (e.g., sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, or a combination of any two or more thereof, preferably sodium chloride, sodium sulfate, or any combination thereof), the amount of mannitol and the pharmaceutically acceptable metal ion-containing osmotic pressure regulator are each selected within the ranges described above, and in such an amount that the ophthalmic pharmaceutical composition can have an osmotic pressure (satisfying the isotonic requirement of the human body) of 250-320, preferably 280-300 mOsm / kg (e.g., 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320 mOsm / kg, or a range defined by any two thereof).

[0063] In an embodiment, the ophthalmic pharmaceutical composition may further include 0.05-1.0% w / v, preferably 0.2%-0.85% w / v of a pharmaceutically acceptable buffer. For example, the ophthalmic pharmaceutical composition may include the following amounts of a pharmaceutically acceptable buffer: 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 10. 5. 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0. 78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.00% w / v, or a range bounded by any two thereof.

[0064] Preferably, the buffer is selected from phosphate, citrate, or any combination thereof; preferably citrate.

[0065] The phosphate can be selected from, for example, disodium hydrogen phosphate, sodium monohydrogen phosphate, dipotassium hydrogen phosphate, and / or potassium monohydrogen phosphate (e.g., disodium hydrogen phosphate; sodium monohydrogen phosphate; dipotassium hydrogen phosphate; potassium monohydrogen phosphate; disodium hydrogen phosphate and sodium monohydrogen phosphate; disodium hydrogen phosphate and dipotassium hydrogen phosphate; disodium hydrogen phosphate and potassium monohydrogen phosphate; sodium monohydrogen phosphate and dipotassium hydrogen phosphate; sodium monohydrogen phosphate and potassium monohydrogen phosphate; dipotassium hydrogen phosphate and potassium monohydrogen phosphate; disodium hydrogen phosphate, sodium monohydrogen phosphate, and dipotassium hydrogen phosphate; disodium hydrogen phosphate, sodium monohydrogen phosphate, and potassium monohydrogen phosphate; disodium hydrogen phosphate, dipotassium hydrogen phosphate and potassium monohydrogen phosphate; sodium monohydrogen phosphate, dipotassium hydrogen phosphate and potassium monohydrogen phosphate).

[0066] The citrate salt may be selected from, for example, sodium citrate and / or potassium citrate (eg, sodium citrate, potassium citrate, or sodium citrate and potassium citrate).

[0067] When the buffer is a mixture of two or more buffers (e.g., a mixture of sodium citrate and potassium citrate), the amount of each component (e.g., sodium citrate and potassium citrate in the case of a mixture of sodium citrate and potassium citrate) can be independently selected from the range of 0.01-0.99% w / v (e.g., 0.01, 0.02, 0.03, 0.04% w / v and the values ​​stated above within the range of 0.05-0.99% w / v), and the sum thereof does not exceed 1.00% w / v.

[0068] In addition to using citrate and / or phosphate as a buffer, the pharmaceutical composition may optionally further include other pharmaceutically acceptable buffers, for example, one or more selected from the following: carbonates (e.g., sodium bicarbonate and / or potassium bicarbonate), boric acid, borates (e.g., sodium tetraborate and / or sodium tetraborate), acetates (e.g., sodium acetate and / or potassium acetate), or any combination thereof. The pharmaceutical composition may include 0-0.5% w / v, for example, the following amounts of the other buffers: 0, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23 , 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, or a range limited by any two of them.

[0069] Preferably, the buffer comprises only citrate, and / or phosphate, more preferably only citrate.

[0070] When citrate is used as a buffer, compared with the case where only phosphate, carbonate, borate, or acetate is used as a buffer, the stability of the levocetirizine hydrochloride ophthalmic pharmaceutical composition can be improved and the impurity content (e.g., single impurity content and total impurity content) formed during long-term storage can be reduced.

[0071] In one embodiment, the ophthalmic pharmaceutical composition may further include 0-1.0% w / v, preferably 0-0.2% w / v, for example, a pharmaceutically acceptable surfactant in the following amounts: 0, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16 , 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0 .46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0. % w / v, or a range defined by any two of the foregoing.

[0072] The surfactant can be selected from a polyethylene glycol-based surfactant, a non-polyethylene glycol-based surfactant, or any combination thereof. For example, the surfactant can be selected from a polyethylene glycol-based surfactant, such as polyethylene glycol (PEG) (e.g., polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, polyethylene glycol 1000), a polyethylene glycol derivative such as polyoxyethylene polysorbate (e.g., polysorbate 80), polyoxyethylene 40 hydrogenated castor oil (e.g., polyoxyethylene 40 hydrogenated castor oil), polyethylene glycol vitamin E succinate (e.g., polyethylene glycol 1000 vitamin E succinate), polyethylene glycol dodecyl stearate, a non-polyethylene glycol-based surfactant such as sodium dodecyl sulfate (SDS), or a combination of any two or more thereof.

[0073] The applicant has found that by adding mannitol, the level of impurities formed can be significantly reduced compared to the case where no mannitol is added.

[0074] In an embodiment, the ophthalmic pharmaceutical composition may further include 0.01-1.0% w / v, preferably 0.01-0.20% w / v, for example, a pharmaceutically acceptable thickener in an amount of 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 10. 6. 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75 % w / v, or a range defined by any two of the foregoing. When the thickener is a mixture of two or more components, the amount of each component can be independently selected from the values ​​listed above within the range of 0.01-0.99% w / v, and the sum of the amounts of the components does not exceed 1.00% w / v.

[0075] In one embodiment, the thickener may be selected from sodium hyaluronate, polyvinyl alcohol, polyvinyl pyrrolidone, sodium sulfobutyl cyclodextrin, carbomer, hypromellose, or a combination of any two or more thereof. Preferably, the thickener is selected from sodium hyaluronate.

[0076] The use of a thickener can increase the ocular surface retention time of levocetirizine hydrochloride and the comfort of the preparation, thereby improving the therapeutic effect (anti-allergic, such as anti-allergic conjunctivitis treatment). 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110 When the thickener (e.g., polyvinyl alcohol, polyvinyl pyrrolidone, sodium sulfobutyl cyclodextrin, carbomer, hydroxypropyl methylcellulose, or a combination of any two or more thereof) is sodium hyaluronate, the impurity content (e.g., the content of various single impurities and the total impurity content) formed during long-term storage can be reduced compared to the use of other thickeners (e.g., polyvinyl alcohol, polyvinyl pyrrolidone, sodium sulfobutyl cyclodextrin, carbomer, hydroxypropyl methylcellulose, or a combination of any two or more thereof); at the same time, the ocular surface retention time of levocetirizine hydrochloride that is equally excellent or better can be obtained, thereby obtaining an equally excellent or better therapeutic (anti-allergic, such as anti-allergic conjunctivitis treatment) effect.

[0077] In one embodiment, the ophthalmic pharmaceutical composition may further include 0.01-0.1% w / v of a pharmaceutically acceptable stabilizer. The stabilizer is not particularly limited and can be selected from stabilizers commonly used in the art. Preferably, the stabilizer is selected from edetate disodium, edetate calcium sodium or any combination thereof, preferably edetate disodium. (In this art, stabilizers may also be referred to as metal ion chelators, which can effectively enhance the stability of drugs. The principle is that they can form stable water-soluble chelates with metal ions, which can prevent their own oxidation and help improve the stability of drugs during preparation and storage. Since the raw and excipient packages used in the preparations contain trace amounts of metal ions, the precipitation of metal ions during long-term storage poses a great quality risk to the drugs. These metal ions may accelerate the oxidation process or other reactions during the preparation stability test, thereby leading to an increase in impurities. Therefore, adding stabilizers such as metal chelators such as edetate disodium to the preparations can increase the stability of the preparations). For example, the ophthalmic pharmaceutical composition may include the stabilizer in an amount of 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10% w / v, or a range bounded by any two thereof.

[0078] In an embodiment, the ophthalmic pharmaceutical composition may have a pH of 6.0-8.0, preferably 6.8-7.2. For example, the ophthalmic pharmaceutical composition may have a pH of 6.0, 6.1, 6.2, 6.3, 6.4, 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 bounded by any two thereof.

[0079] In one embodiment, the ophthalmic pharmaceutical composition has been adjusted to a pH of 6.0-8.0, preferably 6.8-7.2 (e.g., 6.0, 6.1, 6.2, 6.3, 6.4, 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) with a pharmaceutically acceptable pH adjuster (in other words, the amount of the pH adjuster is such that the pharmaceutical composition has the above pH), preferably selected from sodium hydroxide, potassium hydroxide, HCl, or any combination thereof.

[0080] By combining levocetirizine hydrochloride with mannitol, the composition of the present invention does not require the addition of a preservative (also known as an antibacterial agent). Therefore, in an embodiment, the ophthalmic pharmaceutical composition may be preservative-free. However, alternatively, the ophthalmic pharmaceutical composition may also contain a pharmaceutically acceptable preservative, for example, 0-0.01% w / v, for example, the following amounts of preservative: 0, 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.010% w / v. For example, the preservative can be selected from one or more of the following: quaternary ammonium salts (e.g., benzalkonium bromide, benzalkonium chloride), organic mercuries (e.g., thimerosal, phenylmercuric acetate, phenylmercuric nitrate), paraben-type antibacterial agents, polyquaternium salts, alcohols (e.g., chlorobutanol, benzyl alcohol), parahydroxybenzoic acid esters (e.g., methylparaben, ethylparaben, propylparaben, etc.), acids and their salts (e.g., sorbic acid, chlorhexidine acetate, boric acid compounds). However, preferably, the ophthalmic pharmaceutical composition does not contain a preservative.

[0081] In an embodiment, the ophthalmic pharmaceutical composition (or the type and amount of each component contained in the ophthalmic pharmaceutical composition) can have an osmotic pressure of 250-320, preferably 280-300 mOsm / kg to meet the isotonic requirement of the human body. For example, the osmotic pressure can be 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320 mOsm / kg, or a range limited by any two thereof.

[0082] In one embodiment, the ophthalmic pharmaceutical composition may be an external ophthalmic pharmaceutical composition, such as eye drops.

[0083] In one embodiment, the present invention relates to an ophthalmic pharmaceutical composition comprising or consisting of:

[0084] 0.01-0.40% w / v, preferably 0.05-0.24% w / v levocetirizine hydrochloride;

[0085] 1.0-4.0% w / v, preferably 2.0-4.0% w / v mannitol;

[0086] 0-0.60% w / v, preferably 0-0.15% w / v of a pharmaceutically acceptable metal ion-containing osmotic pressure regulator, preferably the pharmaceutically acceptable metal ion-containing osmotic pressure regulator is selected from sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, or a combination of any two or more thereof, preferably sodium chloride, sodium sulfate, or any combination thereof, preferably sodium chloride;

[0087] 0.05-1.0% w / v, preferably 0.2%-0.85% of a pharmaceutically acceptable buffer, preferably the buffer is selected from phosphate, citrate, or any combination thereof; preferably citrate, which is preferably selected from sodium citrate and / or potassium citrate;

[0088] 0-1.0% w / v, preferably 0-0.2% w / v of a pharmaceutically acceptable surfactant, preferably the surfactant is selected from a polyethylene glycol-based surfactant, a non-polyethylene glycol-based surfactant, or any group thereof;

[0089] Optionally, 0.01-1.0% w / v, preferably 0.01-0.20% w / v of a pharmaceutically acceptable thickener, preferably the thickener is selected from sodium hyaluronate, polyvinyl alcohol, polyvinyl pyrrolidone, sodium sulfobutyl cyclodextrin, carbomer, hypromellose, or a combination of any two or more thereof, preferably sodium hyaluronate;

[0090] Optionally 0.01-0.1% w / v of a pharmaceutically acceptable stabilizer, preferably the stabilizer is selected from edetate disodium, edetate calcium sodium or any combination thereof, preferably edetate disodium; and

[0091] Optionally, a pharmaceutically acceptable pH adjuster, preferably sodium hydroxide, potassium hydroxide, HCl or any combination thereof, in an amount such that the ophthalmic pharmaceutical composition has a pH of 6.0-8.0, preferably 6.8-7.2;

[0092] The balance is water as solvent.

[0093] The ophthalmic pharmaceutical composition has an osmotic pressure of 250-320, preferably 280-300 mOsm / kg.

[0094] The above descriptions of the components, amounts and properties of the ophthalmic pharmaceutical composition are applicable here as well.

[0095] The ophthalmic pharmaceutical composition of the present invention may be prepared by any suitable method.

[0096] For example, the ophthalmic pharmaceutical composition of the present invention can be prepared by dissolving all components (optional pharmaceutically acceptable thickener (e.g., sodium hyaluronate, polyvinyl alcohol, polyvinyl pyrrolidone, sodium sulfobutyl cyclodextrin, carbomer, hypromellose, or a combination of any two or more thereof), optional pharmaceutically acceptable buffer (e.g., citrate), mannitol, optional pharmaceutically acceptable metal ion-containing osmotic pressure regulator, optional pharmaceutically acceptable stabilizer, optional pharmaceutically acceptable surfactant, levocetirizine hydrochloride, optional pharmaceutically acceptable pH regulator (e.g., sodium hydroxide, potassium hydroxide, HCl, or any combination thereof)) in water simultaneously or sequentially in any order. In the case of sequential dissolution, preferably, the subsequent component is added for dissolution after the dissolution of the previous component is completed.

[0097] The dissolution can be performed by stirring at room temperature.

[0098] Alternatively, the ophthalmic pharmaceutical composition of the present invention can also be prepared as follows:

[0099] (1) dissolving a polymer component (e.g., a pharmaceutically acceptable thickener such as sodium hyaluronate, polyvinyl alcohol, polyvinyl pyrrolidone, sodium sulfobutyl cyclodextrin, carbomer, hypromellose, or a combination of any two or more thereof) among all components except a surfactant in water to provide a first solution;

[0100] (2) dissolving the remaining components (optional pharmaceutically acceptable buffer (e.g., citrate), mannitol, optional pharmaceutically acceptable metal ion-containing osmotic pressure regulator, optional pharmaceutically acceptable stabilizer, optional pharmaceutically acceptable surfactant, levocetirizine hydrochloride) simultaneously or sequentially in water to provide a second solution;

[0101] (3) combining the first solution with the second solution (e.g., adding the first solution to the second solution or adding the second solution to the first solution) to obtain a third solution;

[0102] (4) Optionally, the pH of the third solution is adjusted with a pharmaceutically acceptable pH adjusting agent (e.g., sodium hydroxide, potassium hydroxide, HCl, or any combination thereof) (e.g., to 6.0-8.0, e.g., 6.8-7.2, or slightly lower), and then the remaining water is added (to the desired concentration of each component and the pH of the ophthalmic pharmaceutical composition is in the range of 6.0-8.0, e.g., 6.8-7.2) to obtain the ophthalmic pharmaceutical composition.

[0103] In one embodiment, step (4) may alternatively be performed as follows: the remaining water is added to the third solution (to the desired concentration of each component), and then the pH of the third solution is optionally adjusted (e.g., to 6.0-8.0, e.g., 6.8-7.2) with a pharmaceutically acceptable pH adjusting agent (e.g., sodium hydroxide, potassium hydroxide, HCl, or any combination thereof).

[0104] The dissolution in each step can be carried out by stirring at room temperature.

[0105] In the case where steps (1) and (2) each involve a plurality of solutes and these are dissolved sequentially, preferably, the subsequent component is added for dissolution after the dissolution of the previous component is completed.

[0106] The second aspect of the present invention relates to use of the ophthalmic pharmaceutical composition of the first aspect of the present invention in the preparation of eye drops, preferably anti-allergic eye drops.

[0107] By combining levocetirizine hydrochloride with mannitol, the ophthalmic pharmaceutical composition of the present invention exhibits very high long-term storage stability, does not form insoluble matter during long-term storage, and exhibits low impurity levels. The most stringent standards for single and total impurity limits for levocetirizine hydrochloride API, tablets, and cetirizine hydrochloride API, oral solutions, tablets, and drops listed in existing pharmacopoeias (Chinese Pharmacopoeia, United States Pharmacopoeia, European Pharmacopoeia, and Japanese Pharmacopoeia) are: a maximum single impurity content of <0.1% w / v and a total impurity content of <0.5% w / v. However, the impurity content of the final formulation of the present invention is far below these limits. Furthermore, the ophthalmic pharmaceutical composition is simple to prepare, highly safe, and has minimal toxic and side effects. Combining mannitol with a pharmaceutically acceptable metal ion-containing osmotic pressure regulator, such as sodium chloride, can further reduce the impurity content formed during long-term storage. Using a pharmaceutically acceptable buffer, such as citrate, can further reduce the impurity content formed during long-term storage, further improving storage stability. - When a pharmaceutically acceptable thickener such as sodium hyaluronate is used, especially when used in combination with citrate, the impurity content formed during long-term storage (such as the content of various single impurities and the total impurity content) can be reduced, while at the same time improving the ocular surface retention time and the comfort of the preparation.

[0108] Example

[0109] The embodiments of the present invention will be described in detail below with reference to the examples and drawings. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention.

[0110] Raw materials and experimental instruments

[0111] The raw materials and experimental equipment suppliers used in the following examples are shown in Table 1 below:

[0112] Table 1: Raw materials and experimental instruments

[0113] Detection method

[0114] (1) pH determination:

[0115] The pH was measured using an OHAUS pH meter (model FE28) after calibration according to the instructions in its manual, in accordance with the General Chapter 0631 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0116] (2) Osmotic pressure measurement:

[0117] The osmotic pressure was measured using a VOGEL osmometer (model Typ OM819.C) according to the General Chapter 0632 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0118] (3) Impurity detection:

[0119] Using a Waters high performance liquid chromatograph (model Waters e2695), impurities were detected as follows according to the general rule 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0120] The dilution solvent was prepared as follows: an aqueous solution containing 0.14% sodium dihydrogen phosphate and 0.27% disodium hydrogen phosphate heptahydrate was prepared, the pH thereof was adjusted to 6.9 (±0.1) with 10% phosphoric acid solution, and the resultant was mixed with acetonitrile at a volume ratio of 1:1.

[0121] Test solution: Take an appropriate amount of the preparation prepared in each example.

[0122] Control solution: Accurately measure 1 ml of the preparation prepared in each example, place it in a 100 ml volumetric flask, dilute to the mark with the above-mentioned dilution solvent, and shake well.

[0123] Impurity D reference solution: Take an appropriate amount of cetirizine impurity D reference, dissolve it in methanol and dilute it to a solution containing approximately 0.1 mg of impurity D per 1 ml.

[0124] Mixed reference solution: Take appropriate amounts of cetirizine impurities B, C, E and cetirizine N-oxide impurities, add the dilution solvent to prepare a mixed solution containing approximately 0.1 mg of impurities B, C, E and cetirizine N-oxide impurities per 1 ml.

[0125] System suitability solution: Take appropriate amounts of levocetirizine hydrochloride reference substance, impurity D reference substance solution, and mixed reference substance solution, and add the dilution solvent to make a mixed solution containing approximately 2.4 mg of levocetirizine hydrochloride and 0.012 mg each of impurities B, C, D, E, and cetirizine N-oxide impurity per 1 ml.

[0126] Sensitivity solution: Measure 1 ml of the control solution and place it in a 20 ml volumetric flask. Dilute to the mark with the diluent solvent and shake well.

[0127] Chromatographic conditions: Octadecylsilane bonded silica gel was used as the filler (Waters Symmetry Shield RP-18 column, 4.6 mm × 250 mm, 5 μm); mobile phase A was 0.2% tetrabutylammonium hydrogen sulfate and 0.3% sodium dihydrogen phosphate monohydrate solution (pH adjusted to 2.8 (±0.05) with 1 mol / L sodium hydroxide), and mobile phase B was methanol, with gradient elution as shown in Table 2 below; column temperature was 40°C; detection wavelength was 232 nm; injection volume was 10 μl.

[0128] Table 2: Gradient elution conditions

[0129] System suitability requirements: In the system suitability solution chromatogram, the order of peaks is impurity C (RRT 0.70), impurity E (RRT 0.76), levocetirizine hydrochloride, impurity B (RRT 1.17), N-oxide impurity (RRT 1.27), and impurity D (RRT 2.66); the separation between the impurity C peak and the impurity E peak, and between the impurity B peak and the N-oxide impurity peak should be greater than 1.5; the number of theoretical plates calculated based on the levocetirizine hydrochloride peak should be no less than 5000; in the sensitivity solution chromatogram, the signal-to-noise ratio of the main component peak height should be greater than 10.

[0130] Determination method: Accurately measure the test solution and control solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0131] (4) Viscosity measurement:

[0132] Take a sample of the preparation prepared in each example, and measure it according to the law according to the general rule 0633 of the fourth part of the 2020 edition of the Chinese Pharmacopoeia, using a Brookfield LV rotational viscometer (model DV2TLVTJO) and a No. 18 rotor at a speed of 200 rpm and 25°C ± 0.5°C.

[0133] Reference Example 1 (Prescription of commercially available cetirizine hydrochloride eye drops)

[0134] According to the formulation listed in Table 3, the preparation of Reference Example 1 was prepared as follows:

[0135] (1) Add hydropropyl methylcellulose to water for injection and stir at room temperature to dissolve;

[0136] (2) Take an appropriate amount of water for injection, add dissolved glycerol, polyethylene glycol 400, polysorbate 80, disodium hydrogen phosphate, disodium edetate, and levocetirizine hydrochloride in sequence while stirring, and stir to mix evenly;

[0137] (3) adding the hydroxypropyl methylcellulose solution obtained in step (1) to the solution obtained in step (2), stirring and mixing uniformly;

[0138] (4) adjusting the pH of the solution obtained in step 1 to 7.0 with NaOH;

[0139] (5) Add water for injection to the full amount and stir evenly; filter the liquid and fill it.

[0140] Reference Example 2 (US11241426 B2)

[0141] According to the formulation listed in Table 4, the preparation of Reference Example 2 was prepared as follows:

[0142] (1) Take an appropriate amount of water for injection, add polysorbate 80, sodium citrate, sodium chloride, edetate disodium, and levocetirizine hydrochloride in sequence while stirring, and stir to mix evenly;

[0143] (2) adjusting the pH of the solution obtained in step (1) to 7.0 with NaOH;

[0144] (3) Add water for injection to the full amount and stir evenly; filter the liquid medicine and fill it.

[0145] Examples 1-10

[0146] According to the formulations listed in Table 3, the formulations of Examples 1-10 were prepared as follows:

[0147] (1) Take an appropriate amount of water for injection, add disodium hydrogen phosphate, mannitol, disodium edetate, surfactant, and levocetirizine hydrochloride in sequence while stirring, and stir to mix evenly;

[0148] (2) adjusting the pH of the solution obtained in step (1) to 7.0 with NaOH;

[0149] (3) Add water for injection to the full amount and stir evenly; filter the liquid medicine and fill it.

[0150] Examples 11-16

[0151] According to the formulations listed in Table 4, the formulations of Examples 11-16 were prepared as follows:

[0152] (1) Take an appropriate amount of water for injection, add and dissolve sodium citrate, mannitol, disodium edetate, surfactant, and levocetirizine hydrochloride in sequence while stirring, and stir to mix evenly;

[0153] (2) adjusting the pH of the solution obtained in step (1) to 7.0 with NaOH;

[0154] (3) Add water for injection to the full amount and stir evenly; filter the liquid medicine and fill it.

[0155] Table 3 Note: In each table, "to 100%" of water for injection means that the amount of water added is such that each component reaches the target value.

[0156] Table 4

[0157] Experimental Example 1

[0158] The pH, osmotic pressure, and impurity content of the preparations of Reference Examples 1-2 and Examples 1-16 were measured at 0 o'clock (i.e., immediately after preparation at room temperature) and after being placed at 60°C for 30 days. The results are shown in Table 5 below.

[0159] Note: The unknown impurities 1, 2 and 3 mentioned below refer to impurities with unknown structures whose relative retention times in liquid chromatography are 1.45, 0.23 and 1.83 respectively (the same below).

[0160] Table 5

[0161] For the preparations of Reference Examples 1-2 and Examples 1-16, impurities B, C, D, E, and unknown impurity 1 were not detected.

[0162] Taking the minimization of N-oxide impurities and total impurities as the main objectives for comparison, the following conclusions can be drawn from the above table:

[0163] 1. Compared with using glycerol or sodium chloride as an osmotic pressure regulator, the content of N-oxide impurities and total impurities are significantly reduced when mannitol is used as an osmotic pressure regulator.

[0164] 2. When sodium citrate was used instead of disodium hydrogen phosphate, except for Examples 3 and 13 using surfactant HS15, in which the total impurity contents were substantially the same, sodium citrate reduced the total impurity contents of each system relative to disodium hydrogen phosphate.

[0165] Examples 17-22

[0166] According to the formulations listed in Table 6, the formulations of Examples 17-22 were prepared as follows:

[0167] (1) Take an appropriate amount of water for injection, add and dissolve sodium citrate, osmotic pressure regulator, edetate disodium, and levocetirizine hydrochloride in sequence while stirring, and stir to mix evenly;

[0168] (2) adjusting the pH of the solution obtained in step (1) to 7.0 with NaOH;

[0169] (3) Add water for injection to the full amount and stir evenly; filter the liquid medicine and fill it.

[0170] Table 6

[0171] Experimental Example 2

[0172] The pH, osmotic pressure and impurity content of the preparations of Examples 17-22 were measured at time 0 (i.e., immediately after preparation at room temperature) and after storage at 60°C for 30 days. The results are shown in Table 7 below.

[0173] Table 7

[0174] For the preparations of Examples 17-22, impurities B, C, D, E, and unknown impurity 1 were not detected.

[0175] The comparison is based on the objectives of clear solution appearance, isotonic osmotic pressure, and minimum N-oxide impurities and total impurities. The following conclusions can be drawn from Table 7: When no surfactant is used,

[0176] 1. When sodium chloride was used as an osmotic pressure regulator (Example 17) without mannitol, precipitation occurred in the preparation when the optimal osmotic pressure (0.6% sodium chloride) was obtained, and a clear appearance could not be obtained. When sodium sulfate was used as an osmotic pressure regulator (Example 18), at the maximum allowable usage amount (0.15%), although a clear appearance was obtained, the osmotic pressure was low and the isotonic requirement for ophthalmic preparations could not be met. When glycerol was used as an osmotic pressure regulator (Example 19), the content of impurities such as N-oxygen impurities and the total impurity content increased.

[0177] 3. When mannitol is used, a clear solution appearance, optimal osmotic pressure, and low N-oxide impurities and total impurity content can be obtained simultaneously; when mannitol is used in combination with sodium chloride or sodium sulfate, an impurity reduction effect comparable to or even better than that of mannitol alone can be achieved, wherein the combination of mannitol and sodium chloride can achieve a better effect.

[0178] Examples 23-28

[0179] According to the formulations listed in Table 8 below, the formulations of Examples 23-28 were prepared as follows:

[0180] (1) Take an appropriate amount of water for injection, add thickener, and stir at room temperature;

[0181] (2) Take an appropriate amount of water for injection, add and dissolve sodium citrate, mannitol, sodium chloride, disodium edetate, and levocetirizine hydrochloride in sequence while stirring, and stir to mix evenly;

[0182] (3) adding the solution obtained in step (1) to the solution obtained in step (2) and stirring to mix uniformly;

[0183] (4) adjusting the pH of the solution obtained in step (3) to 7.0 with NaOH;

[0184] (5) Add water for injection to the full amount and stir evenly; filter the liquid and fill it.

[0185] Table 8

[0186] Experimental Example 3

[0187] The pH, osmotic pressure and impurity content of the preparations of Examples 23-28 were measured at time 0 (i.e., immediately after preparation at room temperature) and after storage at 60°C for 30 days. The results are shown in Table 9 below.

[0188] Table 9

[0189] For the preparations of Examples 23-28, impurities B, C, D, E, and unknown impurity 1 were not detected.

[0190] As shown in Table 9 above, the addition of a thickener not only modifies the viscosity of the system, thereby increasing ocular surface retention time—when the matrix is ​​sodium hyaluronate and hypromellose, a viscosity within the preferred range of 3-8 mPa·s yields even better results—but also influences impurity content: the sodium hyaluronate example exhibits the lowest impurities. Taking both impurity content and viscosity into account, sodium hyaluronate exhibits the best results.

[0191] Examples 29-39

[0192] According to the formulations listed in Tables 10-11 below, the formulations of Examples 29-39 were prepared as follows:

[0193] (1) Take an appropriate amount of water for injection, add the corresponding thickener (sodium hyaluronate or hydroxypropyl methylcellulose), and stir to dissolve at room temperature;

[0194] (2) Take an appropriate amount of water for injection, add dissolution buffer, mannitol, sodium chloride, disodium edetate, and levocetirizine hydrochloride in sequence while stirring, and stir to mix evenly;

[0195] (3) adding the thickener solution obtained in step (1) to the solution obtained in step (2), stirring and mixing uniformly;

[0196] (4) adjusting the pH of the solution obtained in step (3) to 7.0 with NaOH;

[0197] (5) Add water for injection to the full amount and stir evenly; filter the liquid and fill it.

[0198] Table 10

[0199] Table 11

[0200] Experimental Example 4

[0201] The pH, osmotic pressure and impurity content of the preparations of Examples 29-39 were measured at time 0 (i.e., immediately after preparation at room temperature) and after storage at 60°C for 30 days. The results are shown in Tables 12-13 below.

[0202] Table 12

[0203] Table 13

[0204] For the preparations of Examples 29-39, impurities B, C, D, and E were not detected.

[0205] As can be seen from Tables 12-13, regardless of whether sodium hyaluronate or hypromellose is used as the thickener, the N-oxide impurities and total impurities contents are the lowest when sodium citrate is used as the buffer, and the effect is the best; and compared with using hypromellose as the thickener, the use of sodium hyaluronate has fewer types of impurities, lower contents, and better effects.

[0206] Examples 40-42

[0207] According to the formulations listed in Table 14 below, the formulations of Examples 40-42 were prepared as follows:

[0208] (1) Take an appropriate amount of water for injection, add sodium hyaluronate, and stir to dissolve at room temperature;

[0209] (2) Take an appropriate amount of water for injection, add and dissolve sodium citrate, mannitol, sodium chloride, disodium edetate, and levocetirizine hydrochloride in sequence while stirring, and stir to mix evenly;

[0210] (3) adding the sodium hyaluronate solution obtained in step (1) to the solution obtained in step (2);

[0211] (4) adjusting the pH of the solution obtained in step (3) to 7.0 with NaOH;

[0212] (5) Add water for injection to the full amount and stir evenly; filter the liquid and fill it.

[0213] Table 14

[0214] Experimental Example 5

[0215] The pH, osmotic pressure and impurity content of the preparations of Examples 40-42 were measured at time 0 (i.e., immediately after preparation at room temperature) and after storage at 60°C for 30 days. The results are shown in Table 15 below.

[0216] Table 15

[0217] For the preparations of Examples 40-42, impurities B, C, D, E, N-oxide impurities, and unknown impurity 1 were not detected.

[0218] As can be seen from the table above, at a citrate concentration of 0.05-0.85% w / v, each preparation has a lower total impurity content, and the total impurity content is further reduced when the amount of sodium citrate is 0.1%-0.85%.

[0219] Examples 43-62

[0220] According to the formulations listed in Tables 16-19 below, the formulations of Examples 43-62 were prepared as follows:

[0221] (1) Take an appropriate amount of water for injection, add sodium hyaluronate, and stir to dissolve at room temperature;

[0222] (2) Take an appropriate amount of water for injection, add and dissolve sodium citrate, osmotic pressure regulator, edetate disodium, and levocetirizine hydrochloride in sequence while stirring, and stir to mix evenly;

[0223] (3) adding the sodium hyaluronate solution obtained in step (1) to the solution obtained in step (2), and stirring to mix uniformly;

[0224] (4) The solution obtained in step (3) was measured with NaOH to a pH value of 7.0;

[0225] (5) Add water for injection to the full amount and stir evenly; filter the liquid medicine and fill it.

[0226] Table 16

[0227] Table 17

[0228] Table 18

[0229] Table 19

[0230] Experimental Example 6

[0231] The appearance and osmotic pressure of the preparations of Examples 43-62 were measured at time 0 (i.e., immediately after preparation at room temperature) and after storage at 60°C for 30 days. The results are shown in Tables 20-23 below.

[0232] Table 20

[0233] Table 21

[0234] Table 22

[0235] Table 23

[0236] From Tables 20-23 above, we can see that:

[0237] (1) When mannitol is not used as an osmotic pressure regulator, it is impossible to simultaneously obtain a colorless clear solution (i.e., no precipitation) and an osmotic pressure of 250 to 320 mOsmol / kg that meets the human body's isotonic requirement.

[0238] (2) When mannitol is used, a colorless, clear solution (i.e., no precipitation) and an osmotic pressure of 250 to 320 mOsmol / kg, which meets the human body's isotonic requirements, can be obtained simultaneously, wherein:

[0239] When mannitol is used alone as an osmotic pressure regulator, a dosage of 2.8-4.0% w / v mannitol can achieve an osmotic pressure of 250-320 mOsmol / kg, which meets the human body's isotonic requirement.

[0240] When mannitol is used in combination with 0.15% w / v sodium chloride or 0.15% w / v sodium sulfate, the dosage of mannitol can be reduced: with 0.15% w / v sodium chloride, a dosage of 1.8-2.8% w / v mannitol can achieve an osmotic pressure of 250-320 mOsmol / kg, which meets the human body's isotonic requirement; with 0.15% w / v sodium sulfate, a dosage of 2.2-3.2% w / v mannitol can achieve an osmotic pressure of 250-320 mOsmol / kg, which meets the human body's isotonic requirement.

[0241] Examples 63-67

[0242] According to the formulations listed in Table 24 below, the formulations of Examples 63-67 were prepared as follows:

[0243] (1) Take an appropriate amount of water for injection, add sodium hyaluronate, and stir to dissolve at room temperature;

[0244] (2) Take an appropriate amount of water for injection, add and dissolve sodium citrate, mannitol, sodium chloride, disodium edetate, and levocetirizine hydrochloride in sequence while stirring, and stir to mix evenly;

[0245] (3) adding the sodium hyaluronate solution obtained in step (1) to the solution obtained in step (2);

[0246] (4) adjusting the pH of the solution obtained in step (3) to 7.0 with NaOH;

[0247] (5) Add water for injection to the full amount and stir evenly; filter the liquid and fill it.

[0248] Table 24

[0249] Experimental Example 7

[0250] For the preparations of Examples 63-67, the impurity content was determined and the ocular surface retention time was determined by animal experiments. The results are shown in Tables 25-26 below.

[0251] The animal experiments were carried out as follows:

[0252] 1. Add 50 μL of fluorescein sodium diluted to 1% concentration with normal saline to the ocular surface of New Zealand rabbits (Shenyang Tenghua Biotechnology Co., Ltd., New Zealand rabbits, 2-2.5 kg, half male and half female).

[0253] 2. Observe and record the time until the fluorescence in the conjunctival sac and ocular surface completely disappears.

[0254] 3. Rinse the eyeballs with normal saline and keep the experimental animals still for 10 minutes.

[0255] 3. Add 50 μL of sodium fluorescein diluted to 1% concentration with the test substance (preparation of Examples 63-67) to the eye surface of the same New Zealand rabbit.

[0256] 4. Observe and record the time until the fluorescence in the conjunctival sac and ocular surface completely disappears.

[0257] Table 25

[0258] To achieve better therapeutic effects, it is desirable for the drug to have a longer residence time on the ocular surface after administration. Based on the table above, combined with the drug's ocular surface residence time and the actual physiological responses of rabbits after administration, the dosage of sodium hyaluronate can be 0-0.20%, with 0.05%-0.20% achieving the best results (longer residence time, over 10 minutes, non-irritation, and easy filtration).

[0259] Table 26

[0260] In Table 26 above, impurities B, C, D, E, and unknown impurity 1 were not detected in the preparations of each example.

[0261] It can also be seen from the above table that the addition of sodium hyaluronate does not cause precipitation, and can further reduce the total impurity content, and the impurity situation is better than that of Reference Example 1 and Reference Example 2.

[0262] Taking into account the drug's retention time on the ocular surface, combined with the patient's comfort after use and the stability of the prescription (impurity content and precipitation formation), the effect is better when the dosage of sodium hyaluronate is 0.01-0.20% w / v.

[0263] Examples 68-74

[0264] According to the formulations listed in Table 27 below, the formulations of Examples 68-74 were prepared as follows.

[0265] (1) Take an appropriate amount of water for injection, add sodium hyaluronate, and stir to dissolve at room temperature;

[0266] (2) Take an appropriate amount of water for injection, add and dissolve sodium citrate, mannitol, sodium chloride, disodium edetate, and levocetirizine hydrochloride in sequence while stirring, and stir to mix evenly;

[0267] (3) adding the sodium hyaluronate solution obtained in step (1) to the above solution and stirring to mix evenly;

[0268] (4) adjusting the pH of the solution obtained in step 1 to 7.0 with NaOH;

[0269] (5) Add water for injection to the full amount and stir evenly; filter the liquid medicine and fill it.

[0270] Table 27

[0271] Experimental Example 8

[0272] The preparations of Examples 68-74 were evaluated by animal experiments. The animal experiments were conducted as follows:

[0273] On days 0 and 7, aluminum adjuvant (Lianmai Bio) was added dropwise to an equal volume of 10 mg / mL OVA (ovalbumin, Sigma) with continuous mixing to prepare a 5 mg / mL OVA solution. Each Balb / c female mouse (Shenyang Tenghua Biotechnology Co., Ltd., Balb / c mice; 18-22 g; female) was sensitized by intraperitoneal injection of 0.2 mL of the above OVA solution.

[0274] On days 15 to 18, mice were challenged by dropping 5 μL of 50 mg / mL OVA solution into the conjunctival sac. Drugs (preparations of Examples 68-74) were administered intraconjunctival sac 30 minutes before challenge, and photographed and scored under a slit lamp microscope 30 minutes after challenge. Drug administration was continued twice daily for four days.

[0275] After OVA allergic challenge, the severity of ocular surface inflammation was assessed under a slit lamp using the scoring criteria shown in Table 28. Furthermore, 15 minutes after challenge, the mice in each group were observed for 10 minutes and the number of eye scratchings was recorded. The experimental results are shown in Figure 1. The model group in Figure 1 refers to the group that received no drug administration; all other procedures were the same.

[0276] Table 28

[0277] Among them, mild, moderate, and severe are defined as follows in Table 29:

[0278] Table 29

[0279] As can be seen from Figure 1, levocetirizine hydrochloride concentrations of 0.01-0.40% w / v all have certain therapeutic effects, with higher scores and better effects at concentrations of 0.05-0.24% w / v, and the best score and effect at a concentration of 0.12% w / v.

[0280] Although specific embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that various modifications and substitutions may be made to those details in light of all the teachings disclosed herein, and such modifications are within the scope of the present invention. The full scope of the present invention is given by the appended claims and any equivalents thereof.

Claims

1. An ophthalmic pharmaceutical composition, preferably an ophthalmic topical pharmaceutical composition, preferably eye drops; it comprises: 0.01 - 0.40% w / v, preferably 0.05 - 0.24% w / v of levocetirizine hydrochloride; 1.0 - 4.0% w / v, preferably 2.0 - 4.0% w / v of mannitol; Optionally, 0 - 0.60% w / v, preferably 0 - 0.15% w / v of a pharmaceutically acceptable metal ion-containing osmotic pressure regulator; preferably, the pharmaceutically acceptable metal ion-containing osmotic pressure regulator is selected from sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, or any combination of two or more thereof; Optionally, 0.05 - 1.0% w / v, preferably 0.2% - 0.85% of a pharmaceutically acceptable buffer, which is preferably selected from phosphates, citrates, or any combination thereof; preferably citrate, which is preferably selected from sodium citrate and / or potassium citrate; and Water as a solvent.

2. The ophthalmic pharmaceutical composition according to claim 1, which further comprises 0 - 1.0% w / v, preferably 0 - 0.2% w / v of a pharmaceutically acceptable surfactant.

3. The ophthalmic pharmaceutical composition according to any one of claims 1 - 2, which further comprises 0.01 - 1.0% w / v, preferably 0.01 - 0.20% w / v of a pharmaceutically acceptable thickening agent, preferably the thickening agent is selected from sodium hyaluronate, polyvinyl alcohol, polyvinylpyrrolidone, sodium sulfobutyl cyclodextrin, carbomer, hypromellose, or any combination of two or more thereof, preferably sodium hyaluronate.

4. The ophthalmic pharmaceutical composition according to any one of claims 1 - 3, which further comprises 0.01 - 0.1% w / v of a pharmaceutically acceptable stabilizer, preferably the stabilizer is selected from disodium edetate, calcium disodium edetate or any combination thereof, preferably disodium edetate.

5. The ophthalmic pharmaceutical composition according to any one of claims 1 - 4, which has a pH of 6.0 - 8.0, preferably 6.8 - 7.2; preferably, the ophthalmic pharmaceutical composition has been adjusted to a pH of 6.0 - 8.0, preferably 6.8 - 7.2 with a pharmaceutically acceptable pH regulator, and the pH regulator is preferably selected from sodium hydroxide, potassium hydroxide, HCl, or any combination thereof.

6. The ophthalmic pharmaceutical composition according to any one of claims 1 - 5 does not contain preservatives.

7. The ophthalmic pharmaceutical composition according to any one of claims 1 - 6 has an osmotic pressure of 250 - 320, preferably 280 - 300 mOsm / kg.

8. The ophthalmic pharmaceutical composition according to any one of claims 1 - 7 has a viscosity of 1 - 10.0, preferably 3.0 - 8.0 mPa·s, and the viscosity is measured by a Brookfield rotational viscometer at a temperature of 25°C.

9. The ophthalmic pharmaceutical composition according to claims 1 - 8 comprises: 0.01 - 0.40% w / v, preferably 0.05 - 0.24% w / v of levocetirizine hydrochloride; 1.0 - 4.0% w / v, preferably 2.0 - 4.0% w / v of mannitol; A pharmaceutically acceptable metal ion-containing osmotic pressure regulator in an amount of 0 - 0.60% w / v, preferably 0 - 0.15% w / v; A pharmaceutically acceptable buffer in an amount of 0.05 - 1.0% w / v, preferably 0.2% - 0.85% w / v; A pharmaceutically acceptable surfactant in an amount of 0 - 1.0% w / v, preferably 0 - 0.2% w / v; Optionally, a pharmaceutically acceptable thickening agent in an amount of 0.01 - 1.0% w / v, preferably 0.01 - 0.20% w / v; Optionally, a pharmaceutically acceptable stabilizer in an amount of 0.01 - 0.1% w / v; And Optionally, a pharmaceutically acceptable pH regulator in an amount such that the ophthalmic pharmaceutical composition has a pH of 6.0 - 8.0, preferably 6.8 - 7.2; The balance being water as a solvent.

10. Use of the ophthalmic pharmaceutical composition according to any one of claims 1 - 9 in the preparation of eye drops, preferably eye drops for anti-allergy, especially for anti-allergic conjunctivitis.

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