Ophthalmic pharmaceutical composition and application thereof

Abstract

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

Description

[0001] This application claims the priority of Chinese Patent Application No. 202311824889.0 filed on December 27, 2023, and the entire content of the above-mentioned Chinese patent application is incorporated herein by reference as part of this application. Technical Field

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

[0003] The active ingredient of the commercially available eye drops is cetirizine hydrochloride. Cetirizine hydrochloride is a racemate, containing levocetirizine hydrochloride and dexocetirizine hydrochloride. Among them, the affinity of levocetirizine hydrochloride for the H1 receptor is twice that of cetirizine hydrochloride and 30 times that of dexocetirizine hydrochloride. As a new generation of histamine H1 receptor antagonist, levocetirizine hydrochloride has high safety, selectivity and affinity, and is also a highly effective non-sedating antihistamine drug, which has been widely used in the clinical treatment of skin and respiratory systems. Levocetirizine hydrochloride is also one of the drugs approved by the FDA for use in children. Currently, the commercially available levocetirizine hydrochloride preparations are only levocetirizine hydrochloride oral solutions, drops, etc., and there is no topical administration preparation yet. Levocetirizine hydrochloride is easily soluble in water, but it will gradually form insoluble substances at low concentrations (<1%, w / v), reducing the stability of its aqueous solution.

[0004] Regarding the stability problem of levocetirizine hydrochloride, researchers often adopt three means.

[0005] The first method is to add functional excipients such as polyethylene glycol (PEG)-based surfactants, such as polyethylene glycol 400, polysorbate 80, and some other types of surfactants, as solubilizers in the prescription to improve the solubility of levocetirizine hydrochloride. For example, polysorbate 80 is used as a surfactant in Patent US11241426B2 to increase the solubility of levocetirizine hydrochloride, polyethylene glycol 400 is used in Patent CN1166362C to prevent the chemical degradation of levocetirizine hydrochloride, and a new excipient, tocopherol, is used in Patent CN116437910A to improve the stability of the preparation. However, these types of surfactant substances often have some commonalities: the PEG structure forms hydrogen bonds with water molecules, and once this hydrogen bond structure is disrupted (for example, when the temperature rises or the compound has a physical interaction with PEG), it may cause surfactant precipitation; at the same time, the ether bond structure in ethylene glycol or PEG is prone to oxidation, so these PEG-based surfactants are prone to generating oxides during storage and are prone to compatibility problems with some drugs that are easily oxidized, such as drugs with a piperazine structure or oxidizing drugs, such as generating precipitation, N-oxidation impurities, etc.; in addition, when the PEG chain segment is connected to the hydrophobic structure through an ester bond, it is prone to breakage under strong acids and bases. From a safety perspective, generally, the PEG chain segment has no toxic or side effects but has allergenicity. Therefore, although PEG-based surfactants can be used as solubilizers to increase the stability of levocetirizine hydrochloride, there are also quality and safety risks at the same time.

[0006] The second method is through molecular inclusion technology, that is, adding cyclodextrin-based excipients in the preparation to improve the stability of the preparation. For example, Patent CN114306227A and Patent CN101795565A use cyclodextrin and its derivative inclusion technology to increase the drug stability. However, the cyclodextrin inclusion technology process is complex, and the size of the encapsulation efficiency needs to be studied. Moreover, as a drug approved by the FDA for children, the preparation of levocetirizine hydrochloride should also consider the safety issues for children. Cyclodextrin has been shown to have potential safety risks for children.

[0007] The third method is liposome technology, that is, adding phospholipids in the preparation to increase the stability of the drug. However, drug preparations encapsulated in liposomes are usually provided in a dry form (such as freeze-drying) and then reconstituted with an aqueous solution immediately before administration. This preparation form is not conducive to patient operation, especially for pediatric patients.

[0008] In addition, surfactants and water-soluble polymers are usually used in combination in the prior art to increase the stability of drugs. For example, in Patent CN1166362C, the surfactant poloxamer and the water-soluble polymer polyvinylpyrrolidone are used to improve the stability of the preparation. However, poloxamer is not biodegradable, so the safety of actual patients is not considered. Moreover, polyvinylpyrrolidone will increase the impurities in the preparation and is mostly used in sustained-release and controlled-release preparations.

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

[0010] The present invention is precisely made in response to the above problems existing in the prior art.

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

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

[0013] The applicant has found that by using mannitol, the stability of the ophthalmic pharmaceutical composition of levocetirizine hydrochloride can be improved, the formation of insoluble substances can be avoided, and the impurity content formed under long-term storage can be reduced.

[0014] The applicant has 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 impurity content formed under long-term storage can be further reduced.

[0016] - When a pharmaceutically acceptable buffer such as citrate is used, the impurity content formed under long-term storage can be further reduced, and the storage stability can be further improved.

[0017] - When a pharmaceutically acceptable thickener such as sodium hyaluronate is used, especially when it is used in combination with citrate, the impurity content formed under long-term storage (such as the content of various single impurities and the total impurity content) can be reduced.

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

[0019] 1. An ophthalmic pharmaceutical composition, which comprises:

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

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

[0022] Water as a solvent.

[0023] 2. The ophthalmic pharmaceutical composition according to item 1, further comprising a pharmaceutically acceptable metal ion-containing osmotic pressure regulator at 0 - 0.60% w / v, preferably 0 - 0.15% w / v; 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.

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

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

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

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

[0028] 7. The ophthalmic pharmaceutical composition according to any one of items 1 - 6 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.

[0029] 8. The ophthalmic pharmaceutical composition according to any one of items 1 - 7 is free of preservatives.

[0030] 9. The ophthalmic pharmaceutical composition according to any one of Items 1-8, 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 1-9, which 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.

[0032] 11. The ophthalmic pharmaceutical composition according to any one of Items 1-10, which is an ophthalmic topical pharmaceutical composition, preferably eye drops.

[0033] 12. The ophthalmic pharmaceutical composition according to Items 1-11, which comprises:

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

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

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

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

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

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

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

[0041] 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;

[0042] The balance of water as a solvent.

[0043] 13. Use of the ophthalmic pharmaceutical composition according to any one of Items 1-12 in the preparation of eye drops, preferably eye drops for anti-allergy, particularly for 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 content of formed impurities. The most stringent standards for the single impurity and total impurity limits of levocetirizine hydrochloride raw materials, tablets, and ceterizine hydrochloride raw materials, oral solutions, tablets, and drops included in the existing pharmacopoeias (Chinese Pharmacopoeia, United States Pharmacopoeia, European Pharmacopoeia, Japanese Pharmacopoeia) are: the maximum single impurity content < 0.1% w / v, and the total impurity < 0.5% w / v. However, the impurity situation of the final formulation of the present invention is far lower than this limit. Moreover, this ophthalmic pharmaceutical composition is simple to prepare, has high safety, and few toxic and side effects. Description of the Drawings

[0045] The drawings described herein are used to provide a further understanding of the present invention, form a part of this application, and the illustrative 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] Figure 1 To show the evaluation results of the degree of ocular surface inflammation in the model group without using levocetirizine hydrochloride and in Examples 68-74 containing different concentrations of levocetirizine hydrochloride. Detailed Description of the Invention

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

[0048] In this application, unless otherwise specified, when referring to the component content in the ophthalmic pharmaceutical composition, the expression "% w / v" means the mass / volume percentage (g / ml) content, that is, the number of grams of solute contained in every 100 ml of volume. The relative density of the liquid preparations involved in the present invention is about 1.0. Therefore, in the actual preparation process, it can be calculated as 100 grams per 100 ml. Therefore, the mass / volume (g / ml) percentage can also be approximately the mass / mass (g / g) percentage.

[0049] In this application, unless otherwise specified, when referring to the component content or concentration, the expression "%" means "% w / v".

[0050] In this application, unless otherwise specified, even if the term "about" is not used to modify the numerical expression, the value should be understood to be modified by "about"; the term "about" includes a deviation of ±5% of the stated value. That is, for the 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 impurity or N-oxidized impurity refers to the N-oxide impurity of cetirizine, i.e., N1-oxide of 2-(2-{4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethoxy)acetic acid.

[0052] Ophthalmic pharmaceutical composition

[0053] In a first aspect of the present invention, there is provided an ophthalmic pharmaceutical composition, comprising:

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

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

[0056] Water as a solvent.

[0057] In an embodiment, the ophthalmic pharmaceutical composition comprises levocetirizine hydrochloride at 0.01-0.40% w / v, preferably 0.05-0.24% w / v. For example, the ophthalmic pharmaceutical composition may comprise levocetirizine hydrochloride in the following amounts: 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% w / v, or a range defined by any two of them. Levocetirizine hydrochloride can be used for anti-allergy treatment, such as the treatment of allergic conjunctivitis.

[0058] In an embodiment, the ophthalmic pharmaceutical composition comprises 1.0 - 4.0% w / v, preferably 2.0 - 4.0% w / v of mannitol. For example, the ophthalmic pharmaceutical composition may comprise mannitol in the following amounts: 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 of them. 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 comprise 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 of them. 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 in consideration of 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 may include 0 - 0.60% w / v, preferably 0 - 0.15% w / v of the pharmaceutically acceptable metal ion-containing osmotic pressure regulator. For example, the ophthalmic pharmaceutical composition may include the following amounts of the 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 defined by any two of them. When the pharmaceutically acceptable metal ion-containing osmotic pressure regulator is a mixture of two or more components, the amounts 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 each independently be selected from the range of 0.01 - 0.59% w / v and each value in the above-mentioned range, and the sum of the amounts of each component 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 of them, preferably sodium chloride, sodium sulfate, or any combination thereof), compared with the case of using mannitol without using 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 of them, preferably sodium chloride, sodium sulfate, or any combination thereof, more preferably sodium chloride), 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 during long-term storage can be reduced.

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

[0063] In an embodiment, the ophthalmic pharmaceutical composition may further comprise 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 comprise a pharmaceutically acceptable buffer in the following amounts: 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, 0.75, 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 defined by any two of them.

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

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

[0066] The citrate may be selected from, for example, sodium citrate and / or potassium citrate (e.g., sodium citrate, potassium citrate, or a mixture of 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 amounts of the respective components (e.g., sodium citrate and potassium citrate in the case of a mixture of sodium citrate and potassium citrate) may each independently be 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 within the range of 0.05 - 0.99% w / v stated above), and their sum does not exceed 1.00% w / v.

[0068] In addition to using citrate and / or phosphate as buffers, the pharmaceutical composition may optionally further comprise one or more other pharmaceutically acceptable buffers, such as 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 potassium tetraborate), acetates (e.g., sodium acetate and / or potassium acetate), or any combination thereof. The pharmaceutical composition may comprise the other buffer in an amount of 0 - 0.5% w / v, such as 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, or a range defined by any two of them.

[0069] Preferably, the buffering agent only includes citrate and / or phosphate, and more preferably only includes citrate.

[0070] When citrate is used as the buffering agent, compared with the case of only using phosphate, carbonate, borate, or acetate as the buffering agent, the stability of the levocetirizine hydrochloride ophthalmic pharmaceutical composition can be improved, and the content of impurities formed during long-term storage (such as the content of single impurities and total impurities) can be reduced.

[0071] In one embodiment, the ophthalmic pharmaceutical composition may further include a pharmaceutically acceptable surfactant in an amount of 0 - 1.0% w / v, preferably 0 - 0.2% w / v, such as 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, 0.75, 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 defined by any two of them. When the surfactant is a mixture of two or more components, the amounts of the respective components can be independently selected from the values stated above in the range of 0.01 - 0.99% w / v, and the sum of the amounts of the respective components does not exceed 1.0% w / v.

[0072] The surfactant may be selected from polyethylene glycol-based surfactants, non-polyethylene glycol-based surfactants, or any combination thereof. For example, the surfactant may be selected from: polyethylene glycol-based surfactants such as polyethylene glycol (PEG) (e.g., polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, polyethylene glycol 1000), polyethylene glycol derivatives such as polyoxyethylene sorbitan esters (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 dodecahydroxystearate, non-polyethylene glycol-based surfactants such as sodium dodecyl sulfate (SDS), or any combination of two or more thereof.

[0073] The applicant has found that by adding mannitol, the content of impurities formed can be significantly reduced compared to the case where mannitol is not added.

[0074] In an embodiment, the ophthalmic pharmaceutical composition may further comprise a pharmaceutically acceptable thickening agent in an amount of 0.01 - 1.0% w / v, preferably 0.01 - 0.20% w / v, such as the following amounts: 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, 0.75, 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 defined by any two of them. When the thickening agent is a mixture of two or more components, the amounts of the respective components may each independently be selected from the values listed above in the range of 0.01 - 0.99% w / v, and the sum of the amounts of the respective components does not exceed 1.00% w / v.

[0075] In one embodiment, the thickening agent may be selected from sodium hyaluronate, polyvinyl alcohol, polyvinylpyrrolidone, sodium sulfobutylcyclodextrin, carbomer, hydroxypropylmethylcellulose, or a combination of any two or more of them. Preferably, the thickening agent is selected from sodium hyaluronate.

[0076] By using a thickening agent, the ocular surface residence time of levocetirizine hydrochloride and the comfort of the preparation can be improved, and the therapeutic (anti-allergic, such as the treatment of allergic conjunctivitis) effect can be enhanced. When a part or all of the thickening agent (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 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% of the total mass of the thickening agent, or a range defined by any two of them) is sodium hyaluronate, compared with using other thickening agents (e.g., polyvinyl alcohol, polyvinylpyrrolidone, sodium sulfobutyl cyclodextrin, carbomer, hypromellose, or a combination of any two or more of them), the content of impurities formed during long-term storage (e.g., the content of various single impurities and the total impurity content) can be reduced; meanwhile, an equally excellent or better ocular surface residence time of levocetirizine hydrochloride can be obtained, thereby obtaining an equally excellent or better therapeutic (anti-allergic, such as the treatment of allergic conjunctivitis) effect.

[0077] In one embodiment, the ophthalmic pharmaceutical composition may further comprise 0.01 - 0.1% w / v of a pharmaceutically acceptable stabilizer. The stabilizer is not particularly limited and may be selected from stabilizers commonly used in the art. Preferably, the stabilizer is selected from disodium edetate, calcium disodium edetate, or any combination thereof, preferably disodium edetate. (In the art, the stabilizer may also be referred to as a metal ion chelator, which can effectively enhance the stability of the drug. The principle is that it can form stable water-soluble chelates with metal ions, preventing its own oxidation and being beneficial to improving the stability of the drug during preparation and storage. Since trace amounts of metal ions are contained in the raw materials, auxiliary materials, and packaging used in the preparation, the precipitation of metal ions during long-term storage poses a great quality risk to the drug. These metal ions may accelerate the oxidation process or other reactions during the stability study of the preparation, resulting in an increase in impurities. Therefore, adding a stabilizer such as disodium edetate, a metal chelator, to the preparation can increase the stability of the preparation). For example, the ophthalmic pharmaceutical composition may comprise the following amounts of stabilizer: 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 defined by any two of them.

[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 the following pH values: 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 of them.

[0079] In one embodiment, the ophthalmic pharmaceutical composition has been adjusted to a pH of 6.0 - 8.0, preferably 6.8 - 7.2 (such as 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 of them) 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), and the pH adjuster is preferably selected from sodium hydroxide, potassium hydroxide, HCl, or any combination thereof.

[0080] By using levocetirizine hydrochloride in combination with mannitol, the pharmaceutical composition of the present invention does not require the addition of preservatives (also known as bacteriostatic agents). Therefore, in an embodiment, the ophthalmic pharmaceutical composition may be free of preservatives. However, alternatively, the ophthalmic pharmaceutical composition may also contain a pharmaceutically acceptable preservative, for example, it may contain a preservative in an amount of 0 - 0.01% w / v, such as the following amounts: 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 may be selected from one or more of the following: quaternary ammonium salts (such as benzalkonium bromide, benzalkonium chloride), organic mercurials (such as thimerosal, phenylmercuric acetate, phenylmercuric nitrate), parabens bacteriostatic agents, polyquaternium salts, alcohols (such as chlorobutanol, benzyl alcohol), p-hydroxybenzoates (such as methylparaben, ethylparaben, propylparaben, etc.), acids and their salts (such as sorbic acid, chlorhexidine acetate, boric acid compounds). However, preferably, the ophthalmic pharmaceutical composition is free of preservatives.

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

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

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

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

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

[0086] A pharmaceutically acceptable metal ion-containing osmotic pressure regulator at 0 - 0.60% w / v, preferably 0 - 0.15% w / v. 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 of them, 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 phosphates, citrates, 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 polyethylene glycol-based surfactants, non-polyethylene glycol-based surfactants, or any combination 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, polyvinylpyrrolidone, sodium sulfobutyl cyclodextrin, carbomer, hypromellose, or any 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 disodium edetate, calcium disodium edetate or any combination thereof, preferably disodium edetate; 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 a solvent.

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

[0094] The above description of the components, amounts of components and properties of the ophthalmic pharmaceutical composition applies herein.

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

[0096] For example, the ophthalmic pharmaceutical composition of the present invention can be prepared as follows: Dissolve all components (optional pharmaceutically acceptable thickeners (such as sodium hyaluronate, polyvinyl alcohol, polyvinylpyrrolidone, sodium sulfobutyl cyclodextrin, carbomer, hypromellose, or a combination of any two or more thereof), optional pharmaceutically acceptable buffers (such as citrate), mannitol, optional pharmaceutically acceptable osmotic pressure regulators containing metal ions, optional pharmaceutically acceptable stabilizers, optional pharmaceutically acceptable surfactants, levocetirizine hydrochloride, optional pharmaceutically acceptable pH regulators (such as sodium hydroxide, potassium hydroxide, HCl, or any combination thereof)) simultaneously or sequentially in water. 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 carried out by stirring at room temperature.

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

[0099] (1) Dissolve the polymer components (such as pharmaceutically acceptable thickeners such as sodium hyaluronate, polyvinyl alcohol, polyvinylpyrrolidone, sodium sulfobutyl cyclodextrin, carbomer, hypromellose, or a combination of any two or more thereof) among all components except the surfactant in water to provide a first solution;

[0100] (2) Dissolve the remaining components (optional pharmaceutically acceptable buffers (such as citrate), mannitol, optional pharmaceutically acceptable osmotic pressure regulators containing metal ions, optional pharmaceutically acceptable stabilizers, optional pharmaceutically acceptable surfactants, levocetirizine hydrochloride) simultaneously or sequentially in water to provide a second solution;

[0101] (3) Combine the first solution and the second solution (such as 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, adjust the pH of the third solution (such as adjusting to 6.0 - 8.0, such as 6.8 - 7.2 or slightly lower) with a pharmaceutically acceptable pH regulator (such as sodium hydroxide, potassium hydroxide, HCl, or any combination thereof), and then add the remaining water (to the desired concentration of each component and the pH of the ophthalmic pharmaceutical composition is in the range of 6.0 - 8.0, such as 6.8 - 7.2) to obtain the ophthalmic pharmaceutical composition.

[0103] In one embodiment, step (4) can alternatively be carried out as follows: Add the remaining water (to the desired concentration of each component) to the third solution, and then optionally adjust the pH of the third solution (e.g., adjust to 6.0 - 8.0, such as 6.8 - 7.2) with a pharmaceutically acceptable pH regulator (such as sodium hydroxide, potassium hydroxide, HCl, or any combination thereof).

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

[0105] In the case where steps (1) and (2) each involve multiple solutes and their sequential dissolution, preferably, the latter component is added for dissolution after the dissolution of the previous component is completed.

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

[0107] By using levocetirizine hydrochloride in combination with mannitol, the ophthalmic pharmaceutical composition of the present invention has very high long - term storage stability, does not form insoluble substances during long - term storage, and has a low content of formed impurities. The most stringent standards for the single - impurity and total - impurity limits of levocetirizine hydrochloride raw materials, tablets, and cetirizine hydrochloride raw materials, oral solutions, tablets, and drops included in the existing pharmacopoeias (Chinese Pharmacopoeia, United States Pharmacopoeia, European Pharmacopoeia, Japanese Pharmacopoeia) are: the maximum single - impurity content < 0.1% w / v, and the total impurity < 0.5% w / v, while the impurity situation of the final formulation of the present invention is far lower than this limit. And this ophthalmic pharmaceutical composition is simple to prepare, has high safety, and few toxic and side effects. When mannitol is used in combination with a pharmaceutically acceptable osmotic pressure regulator containing metal ions such as sodium chloride, the content of impurities formed during long - term storage can be further reduced. When using a pharmaceutically acceptable buffer such as citrate, the content of impurities formed during long - term storage can be further reduced, further improving the storage stability. - When using a pharmaceutically acceptable thickening agent such as sodium hyaluronate, especially when used in combination with citrate, the content of impurities formed during long - term storage (such as various single - impurity contents and total - impurity contents) can be reduced, and at the same time, the residence time on the eye surface and the comfort of the preparation can be improved.

[0108] Examples

[0109] The embodiments of the present invention will be described in detail below in conjunction with the examples and the accompanying 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 regarded as limiting the scope of the present invention.

[0110] Raw materials and experimental instruments

[0111] The supplier information of the raw materials and experimental instruments used in the following examples is shown in Table 1 below:

[0112] Table 1: Raw Materials and Experimental Instruments

[0113]

[0114]

[0115]

[0116] Detection Method

[0117] (1) pH Measurement:

[0118] Use a pH meter of OHAUS (model FE28). After calibration according to the requirements of its instruction manual, measure the pH according to General Chapter 0631, Part IV of Chinese Pharmacopoeia (2020 Edition).

[0119] (2) Osmotic Pressure Measurement:

[0120] Use an osmometer of VOGEL (model Typ OM819.C) to measure the osmotic pressure according to General Chapter 0632, Part IV of Chinese Pharmacopoeia (2020 Edition).

[0121] (3) Impurity Detection:

[0122] Use a high performance liquid chromatograph of Waters (model Waters e2695) to detect impurities as follows according to General Chapter 0512, Part IV of Chinese Pharmacopoeia (2020 Edition).

[0123] Prepare the dilution solvent as follows: Prepare an aqueous solution containing 0.14% sodium dihydrogen phosphate and 0.27% disodium hydrogen phosphate heptahydrate, and adjust its pH value to 6.9 (±0.1) with 10% phosphoric acid solution, then mix the obtained product with acetonitrile in a volume ratio of 1:1.

[0124] Test Solution: Take an appropriate amount of the preparation prepared in each example.

[0125] Control Solution: Accurately measure 1 ml of the preparation prepared in each example, place it in a 100 - ml volumetric flask, dilute it to the mark with the above - mentioned dilution solvent, and shake well.

[0126] Control Solution of Impurity D: Take an appropriate amount of ceterizine impurity D reference substance, dissolve it with methanol and dilute it to a solution containing about 0.1 mg of impurity D per 1 ml.

[0127] Mixed Control Solution: Take appropriate amounts of ceterizine impurities B, C, E and ceterizine N - oxide impurity, and make a mixed solution containing about 0.1 mg of each of impurities B, C, E and ceterizine N - oxide impurity per 1 ml with the above - mentioned dilution solvent.

[0128] System suitability solution: Take appropriate amounts of levocetirizine hydrochloride reference substance, impurity D reference solution, and mixed reference solution, and prepare a mixed solution with the dilution solvent so that each 1 ml contains approximately 2.4 mg of levocetirizine hydrochloride and 0.012 mg each of impurities B, C, D, E, and cetirizine N-oxide impurity.

[0129] Sensitivity solution: Measure 1 ml of the reference solution and place it in a 20-ml volumetric flask. Dilute it to the mark with the dilution solvent and shake well.

[0130] Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler (Waters Symmetry Shield RP-18 column, 4.6 mm × 250 mm, 5 μm); use 0.2% ammonium hydrogen sulfate and 0.3% sodium dihydrogen phosphate monohydrate solution (adjust the pH value to 2.8 (±0.05) with 1 mol / L sodium hydroxide) as mobile phase A, and methanol as mobile phase B, and perform gradient elution according to Table 2 below; the column temperature is 40 °C; the detection wavelength is 232 nm; the injection volume is 10 μl.

[0131] Table 2: Gradient elution conditions

[0132]

[0133] System suitability requirements: In the chromatogram of the system suitability solution, the elution order is successively 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 resolution 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 not less than 5000. In the chromatogram of the sensitivity solution, the signal-to-noise ratio of the main component peak height should be greater than 10.

[0134] Assay method: Precisely measure the test solution and the reference solution, and inject them into the liquid chromatograph respectively, and record the chromatogram.

[0135] (4) Viscosity determination:

[0136] Take the samples of the preparations formulated in each example, and according to General Chapter 0633 of the Fourth Part of the Chinese Pharmacopoeia 2020 Edition, use a Brookfield LV type rotational viscometer (model DV2TLVTJO) and a No. 18 rotor to determine the viscosity according to the law under the conditions of a rotation speed of 200 rpm and a temperature of 25 °C ± 0.5 °C.

[0137] Reference Example 1 (prescription of commercially available cetirizine hydrochloride eye drops)

[0138] Prepare the preparation of Reference Example 1 according to the formula listed in Table 3 as follows:

[0139] (1) Take water for injection, add hypromellose, and stir to dissolve at room temperature;

[0140] (2) Take an appropriate amount of water for injection, and sequentially add and dissolve glycerol, polyethylene glycol 400, polysorbate 80, disodium hydrogen phosphate, disodium edetate, and levocetirizine hydrochloride while stirring, and stir to mix evenly;

[0141] (3) Add the hypromellose solution obtained in step (1) to the solution obtained in step (2), and stir to mix evenly;

[0142] (4) Adjust the pH value of the solution obtained in the step to 7.0 with NaOH;

[0143] (5) Make up the volume to the full amount with water for injection, and stir evenly; filter the medicinal liquid and fill it.

[0144] Refer to Example 2 (US11241426 B2)

[0145] Prepare the preparation of Reference Example 2 according to the formula listed in Table 4 as follows:

[0146] (1) Take an appropriate amount of water for injection, and sequentially add and dissolve polysorbate 80, sodium citrate, sodium chloride, disodium edetate, and levocetirizine hydrochloride while stirring, and stir to mix evenly;

[0147] (2) Adjust the pH value of the solution obtained in step (1) to 7.0 with NaOH;

[0148] (3) Make up the volume to the full amount with water for injection, and stir evenly; filter the medicinal liquid and fill it.

[0149] Examples 1 - 10

[0150] Prepare the preparations of Examples 1 - 10 according to the formula listed in Table 3 as follows:

[0151] (1) Take an appropriate amount of water for injection, and sequentially add and dissolve disodium hydrogen phosphate, mannitol, disodium edetate, surfactant, and levocetirizine hydrochloride while stirring, and stir to mix evenly;

[0152] (2) Adjust the pH value of the solution obtained in step (1) to 7.0 with NaOH;

[0153] (3) Make up the volume to the full amount with water for injection, and stir evenly; filter the medicinal liquid and fill it.

[0154] Examples 11 - 16

[0155] Prepare the preparations of Examples 11 - 16 according to the formula listed in Table 4 as follows:

[0156] (1) Take an appropriate amount of water for injection, and sequentially add and dissolve sodium citrate, mannitol, disodium edetate, surfactant, and levocetirizine hydrochloride under stirring, and stir and mix evenly;

[0157] (2) Adjust the pH value of the solution obtained in step (1) to 7.0 with NaOH;

[0158] (3) Supplement water for injection to the full volume, stir evenly; filter the medicinal liquid and fill it.

[0159] Table 3

[0160]

[0161] Note: "To 100%" of water for injection in each table means that the amount of water is added to make each component reach the target value.

[0162] Table 4

[0163]

[0164]

[0165] Experimental Example 1

[0166] Measure the pH, osmotic pressure, and impurity content of the preparations of Reference Examples 1-2 and Examples 1-16 at 0 h (i.e., immediately measured after preparation at room temperature) and after being placed at 60 °C for 30 days. The results are shown in Table 5 below.

[0167] Note: The unknown impurities 1, 2, and 3 mentioned below refer to impurities with unknown structures whose relative retention times are 1.45, 0.23, and 1.83 respectively in terms of the peak emergence time in liquid chromatography (the same below).

[0168] Table 5

[0169]

[0170]

[0171]

[0172] For the preparations of Reference Examples 1-2 and Examples 1-16, none of the impurities B, C, D, E, and unknown impurity 1 were detected.

[0173] Taking the minimum of N-oxide impurities and total impurities as the main goal for comparison, the following conclusions can be drawn from the above table:

[0174] 1. When using mannitol as the osmotic pressure regulator as compared with using glycerol or sodium chloride as the osmotic pressure regulator, the contents of N-oxide impurities and total impurities are both significantly reduced.

[0175] 2. When sodium citrate is used instead of disodium hydrogen phosphate, except that the total impurity contents of Examples 3 and 13 using surfactant HS15 are basically the same, sodium citrate reduces the total impurity content of each system compared with disodium hydrogen phosphate.

[0176] Examples 17 - 22

[0177] Prepare the preparations of Examples 17 - 22 according to the formulations listed in Table 6 as follows:

[0178] (1) Take an appropriate amount of water for injection, and sequentially add and dissolve sodium citrate, osmotic pressure regulator, disodium edetate, and levocetirizine hydrochloride under stirring, and stir and mix evenly;

[0179] (2) Adjust the pH value of the solution obtained in step (1) to 7.0 with NaOH;

[0180] (3) Make up the volume to the full amount with water for injection, stir evenly; filter the medicinal liquid and fill it.

[0181] Table 6

[0182]

[0183]

[0184] Experimental Example 2

[0185] Measure the pH, osmotic pressure, and impurity content of the preparations of Examples 17 - 22 at 0 hour (i.e., immediately measured after preparation at room temperature) and after being placed at 60 °C for 30 days. The results are shown in Table 7 below.

[0186] Table 7

[0187]

[0188] For the preparations of Examples 17 - 22, impurities B, C, D, E, and unknown impurity 1 are not detected.

[0189] Taking the clarity of the solution appearance, isotonicity of the osmotic pressure, and the minimum of N - oxide impurities and total impurities as the goals for comparison, the following conclusions can be drawn from Table 7 above: When no surfactant is used,

[0190] 1. Without using mannitol, when using sodium chloride as the osmotic pressure regulator (Example 17), when the optimal osmotic pressure is obtained (0.6% sodium chloride), precipitation occurs in the preparation and a clear appearance cannot be obtained; when using sodium sulfate as the osmotic pressure regulator (Example 18), at the maximum allowable dosage (0.15%), although a clear appearance is obtained, the osmotic pressure is low and cannot meet the isotonic requirement of ophthalmic preparations; when using glycerol as the osmotic pressure regulator (Example 19), it will cause an increase in the content of impurities such as N-oxide impurities and total impurities.

[0191] 3. When using mannitol, a clear solution appearance, optimal osmotic pressure, and low N-oxidation impurity and total impurity content can be obtained simultaneously; when mannitol is used in combination with sodium chloride or sodium sulfate, an impurity effect equivalent to or even better than that in the case of using mannitol alone can be achieved, and a better effect can be achieved when mannitol is used in combination with sodium chloride.

[0192] Examples 23 - 28

[0193] Prepare the preparations of Examples 23 - 28 according to the formulations listed in Table 8 below:

[0194] (1) Take an appropriate amount of water for injection, add a thickening agent, and stir at room temperature;

[0195] (2) Take an appropriate amount of water for injection, and sequentially add and dissolve sodium citrate, mannitol, sodium chloride, disodium edetate, and levocetirizine hydrochloride under stirring, and stir and mix evenly;

[0196] (3) Add the solution obtained in step (1) to the solution obtained in step (2), and stir and mix evenly;

[0197] (4) Adjust the pH value of the solution obtained in step (3) to 7.0 with NaOH;

[0198] (5) Make up the volume with water for injection to the full volume, and stir evenly; filter the medicinal liquid and fill it.

[0199] Table 8

[0200]

[0201] Experimental Example 3

[0202] Measure the pH, osmotic pressure, and impurity content of the preparations of Examples 23 - 28 at 0 °C (i.e., immediately measured after preparation at room temperature) and after being placed at 60 °C for 30 days. The results are shown in Table 9 below.

[0203] Table 9

[0204]

[0205] For the preparations of Examples 23-28, impurities B, C, D, E, and unknown impurity 1 were not detected.

[0206] As can be seen from Table 9 above, the addition of the thickener can not only change the viscosity of the system, thereby achieving the effect of increasing the residence time on the ocular surface: when the matrix is sodium hyaluronate and hypromellose, the viscosity is in the more preferred range of 3-8 mPa·s, and the effect is better; moreover, the addition of the thickener can also affect the impurity content: the examples with sodium hyaluronate have the fewest impurities. Considering the impurity content and viscosity comprehensively, sodium hyaluronate has the best effect.

[0207] Examples 29-39

[0208] Prepare the preparations of Examples 29-39 according to the formulations listed in Tables 10-11 below:

[0209] (1) Take an appropriate amount of water for injection, add the corresponding thickener (sodium hyaluronate or hypromellose), and stir to dissolve at room temperature;

[0210] (2) Take an appropriate amount of water for injection, and sequentially add and dissolve the buffer, mannitol, sodium chloride, disodium edetate, and levocetirizine hydrochloride under stirring, and stir and mix evenly;

[0211] (3) Add the thickener solution obtained in step (1) to the solution obtained in step (2), and stir and mix evenly;

[0212] (4) Adjust the pH value of the solution obtained in step (3) to 7.0 with NaOH;

[0213] (5) Make up the volume with water for injection to the full volume, and stir evenly; filter the medicinal liquid and fill it.

[0214] Table 10

[0215]

[0216] Table 11

[0217]

[0218] Experimental Example 4

[0219] Measure the pH, osmotic pressure, and impurity content of the preparations of Examples 29-39 at 0 h (i.e., immediately after preparation at room temperature) and after standing at 60 °C for 30 days. The results are shown in Tables 12-13 below.

[0220] Table 12

[0221]

[0222] Table 13

[0223]

[0224]

[0225] For the preparations of Examples 29 - 39, impurities B, C, D, and E were not detected.

[0226] As can be seen from Tables 12 - 13, whether sodium hyaluronate or hypromellose is used as the thickening agent, when sodium citrate is used as the buffer, the contents of N - oxide impurities and total impurities are the lowest and the effect is the best; and when sodium hyaluronate is used as the thickening agent compared to hypromellose, the types of impurities are fewer and the contents are lower, and the effect is better.

[0227] Examples 40 - 42

[0228] Prepare the preparations of Examples 40 - 42 according to the formula listed in Table 14 below:

[0229] (1) Take an appropriate amount of water for injection, add sodium hyaluronate, and stir to dissolve at room temperature;

[0230] (2) Take an appropriate amount of water for injection, and sequentially add and dissolve sodium citrate, mannitol, sodium chloride, disodium edetate, and levocetirizine hydrochloride while stirring, and stir to mix evenly;

[0231] (3) Add the sodium hyaluronate solution obtained in step (1) to the solution obtained in step (2);

[0232] (4) Adjust the pH value of the solution obtained in step (3) to 7.0 with NaOH;

[0233] (5) Make up the volume to the full amount with water for injection, and stir evenly; filter the medicinal liquid and fill it.

[0234] Table 14

[0235]

[0236]

[0237] Experimental Example 5

[0238] Measure the pH, osmotic pressure, and impurity content of the preparations of Examples 40 - 42 at 0 h (i.e., immediately after preparation at room temperature) and after being placed at 60 °C for 30 days. The results are shown in Table 15 below.

[0239] Table 15

[0240]

[0241] For the preparations of Examples 40 - 42, impurities B, C, D, E, N - oxide impurities, and unknown impurity 1 were not detected.

[0242] As can be seen from the above table, at a citrate concentration of 0.05 - 0.85% w / v, each preparation had a low total impurity content, and the total impurity content further decreased when the amount of sodium citrate was 0.1% - 0.85%.

[0243] Examples 43 - 62

[0244] Prepare the preparations of Examples 43 - 62 according to the formulations listed in Tables 16 - 19 below:

[0245] (1) Take an appropriate amount of water for injection, add sodium hyaluronate, and stir to dissolve at room temperature;

[0246] (2) Take an appropriate amount of water for injection, and sequentially add and dissolve sodium citrate, osmotic pressure regulator, disodium edetate, and levocetirizine hydrochloride while stirring, and stir to mix evenly;

[0247] (3) Add the sodium hyaluronate solution obtained in step (1) to the solution obtained in step (2), and stir to mix evenly;

[0248] (4) Measure the pH value of the solution obtained in step (3) to 7.0 with NaOH;

[0249] (5) Make up the volume with water for injection to the full volume, and stir evenly; filter the medicinal liquid and fill it.

[0250] Table 16

[0251]

[0252]

[0253] Table 17

[0254] Material Name Example 49 Example 50 Example 51 Example 52 Example 53 Levocetirizine Hydrochloride 0.20％ 0.20％ 0.20％ 0.20％ 0.20％ Sodium Citrate 0.85％ 0.85％ 0.85％ 0.85％ 0.85％ Mannitol 1.4％ 2.8％ 3.5％ 4.0％ 4.6％ Sodium Chloride / / / / / Sodium Sulfate / / / / / Disodium Edetate 0.020％ 0.020％ 0.020％ 0.020％ 0.020％ Sodium Hyaluronate 0.10％ 0.10％ 0.10％ 0.10％ 0.10％ Sodium Hydroxide Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Water for Injection Up to 100% Up to 100% Up to 100% Up to 100% Up to 100%

[0255] Table 18

[0256] Material Name Example 54 Example 55 Example 42 Example 56 Example 57 Levocetirizine Hydrochloride 0.20％ 0.20％ 0.20％ 0.20％ 0.20％ Sodium Citrate 0.85％ 0.85％ 0.85％ 0.85％ 0.85％ Mannitol 0.9％ 1.8％ 2.4％ 2.8％ 3.5％ Sodium Chloride 0.15％ 0.15％ 0.15％ 0.15％ 0.15％ Sodium Sulfate / / / / / Disodium Edetate 0.020％ 0.020％ 0.020％ 0.020％ 0.020％ Sodium Hyaluronate 0.10％ 0.10％ 0.10％ 0.10％ 0.10％ Sodium Hydroxide Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Water for Injection Up to 100% Up to 100% Up to 100% Up to 100% Up to 100%

[0257] Table 19

[0258]

[0259]

[0260] Experimental Example 6

[0261] Measure the appearance and osmotic pressure of the preparations in Examples 43 - 62 at 0 hour (i.e., immediately after preparation at room temperature) and after being placed at 60 °C for 30 days. The results are shown in Tables 20 - 23 below.

[0262] Table 20

[0263]

[0264] Table 21

[0265]

[0266] Table 22

[0267]

[0268] Table 23

[0269]

[0270] It can be seen from Tables 20 - 23 above that:

[0271] (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 - 320 mOsmol / kg that meets the isosmotic requirements of the human body.

[0272] (2) When mannitol is used, a colorless clear solution (i.e., no precipitation) and an osmotic pressure of 250 - 320 mOsmol / kg that meets the isosmotic requirements of the human body can be obtained, where:

[0273] - When mannitol is used alone as an osmotic pressure regulator, an osmotic pressure of 250 - 320 mOsmol / kg that meets the isosmotic requirements of the human body can be obtained with a mannitol dosage of 2.8 - 4.0% w / v;

[0274] - 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: in the case of 0.15% w / v sodium chloride, an osmotic pressure of 250 - 320 mOsmol / kg that meets the isosmotic requirements of the human body can be obtained with a mannitol dosage of 1.8 - 2.8% w / v; in the case of 0.15% w / v sodium sulfate, an osmotic pressure of 250 - 320 mOsmol / kg that meets the isosmotic requirements of the human body can be obtained with a mannitol dosage of 2.2 - 3.2% w / v.

[0275] Examples 63 - 67

[0276] Prepare the preparations in Examples 63 - 67 according to the formulations listed in Table 24 below:

[0277] (1) Take an appropriate amount of water for injection, add sodium hyaluronate, and stir to dissolve at room temperature;

[0278] (2) Take an appropriate amount of water for injection, and sequentially add and dissolve sodium citrate, mannitol, sodium chloride, disodium edetate, and levocetirizine hydrochloride while stirring, and stir to mix evenly;

[0279] (3) Add the sodium hyaluronate solution obtained in step (1) to the solution obtained in step (2);

[0280] (4) Adjust the pH value of the solution obtained in step (3) to 7.0 with NaOH;

[0281] (5) Supplement water for injection to the full volume, stir evenly; filter the medicinal liquid and fill it.

[0282] Table 24

[0283]

[0284]

[0285] Experimental Example 7

[0286] For the preparations of Examples 63 - 67, determine the impurity content and measure the ocular surface retention time through animal experiments. The results are shown in Tables 25 - 26 below.

[0287] The animal experiments are carried out as follows:

[0288] 1. Drop 50 μL of fluorescein sodium diluted to a 1% concentration with normal saline onto the ocular surface of New Zealand rabbits (New Zealand rabbits from Shenyang Tenghua Biotechnology Co., Ltd., 2 - 2.5 kg, half male and half female).

[0289] 2. Observe the time until the fluorescence completely disappears from the conjunctival sac and ocular surface, and record it.

[0290] 3. Rinse the eyeball with normal saline, and keep the experimental animals still for 10 min.

[0291] 3. Drop 50 μL of fluorescein sodium diluted to a 1% concentration with the test substance (the preparations of Examples 63 - 67) onto the ocular surface of the same New Zealand rabbit.

[0292] 4. Observe the time until the fluorescence completely disappears from the conjunctival sac and ocular surface, and record it.

[0293] Table 25

[0294] Residence Time / min Irritation Filtration Condition Example 21 8 Non-irritating Easy Example 63 9 Non-irritating Easy Example 64 15 Non-irritating Easy Example 42 23 Non-irritating Easy Example 65 30 Blinking Frequency Increased Filtration Slowed Down Example 66 54 Eyes Do Not Open after Administration Difficult Example 67 120 Eyes Do Not Open and Rub after Administration Unable to Filter

[0295] To achieve better therapeutic effects, it is desirable for the drug to have a long residence time on the ocular surface after administration. According to the above table, considering the residence time of the drug on the ocular surface and the actual physiological responses of rabbits after administration, the dosage of sodium hyaluronate can be 0 - 0.20%, and the effect is better when it is 0.05% - 0.20% (the residence time is longer, more than 10 minutes, without irritation, and easy to filter).

[0296] Table 26

[0297]

[0298] In the above Table 26, impurities B, C, D, E, and unknown impurity 1 were not detected in the preparations of each example.

[0299] It can also be seen from the above table that the addition of sodium hyaluronate will not cause precipitation, and can further reduce the total impurity content, and the impurity conditions are better than those of Reference Example 1 and Reference Example 2.

[0300] Taking into comprehensive consideration the residence time of the drug on the ocular surface, and combining with the comfort of patients after use and the prescription stability (impurity content and precipitation formation), the dosage of sodium hyaluronate is preferably 0.01 - 0.20% w / v.

[0301] Examples 68 - 74

[0302] According to the formulations listed in the following Table 27, the preparations of Examples 68 - 74 were prepared as follows.

[0303] (1) Take an appropriate amount of water for injection, add sodium hyaluronate, and stir to dissolve at room temperature;

[0304] (2) Take an appropriate amount of water for injection, and sequentially add and dissolve sodium citrate, mannitol, sodium chloride, disodium edetate, and levocetirizine hydrochloride while stirring, and stir to mix evenly;

[0305] (3) Add the sodium hyaluronate solution obtained in step (1) to the above solution, and stir to mix evenly;

[0306] (4) Adjust the pH value of the solution obtained in the step to 7.0 with NaOH;

[0307] (5) Make up the volume to the full amount with water for injection, and stir evenly; filter the medicinal liquid and fill it into containers.

[0308] Table 27

[0309]

[0310]

[0311] Experimental Example 8

[0312] The preparations of Examples 68 - 74 were evaluated through animal experiments. The animal experiments were conducted as follows:

[0313] On Day 0 and Day 7, aluminum adjuvant (Lianmai Biologics) was added dropwise into an equal volume of 10 mg / mL OVA (ovalbumin, Sigma) with continuous mixing to obtain a 5 mg / mL OVA solution. Each female Balb / c mouse (Shenyang Tenghua Biotechnology Co., Ltd., Balb / c mouse; 18 - 22 g; female) was intraperitoneally injected with 0.2 mL of the above OVA solution for sensitization.

[0314] From Day 15 to Day 18, 5 μL of 50 mg / mL OVA solution was dropped into the conjunctival sac of the mice for eye challenge. 30 minutes before the challenge, the preparation (preparations of Examples 68 - 74) was administered into the conjunctival sac. 30 minutes after the challenge, a slit - lamp microscope was used to take pictures and score. The drug was administered twice a day for four consecutive days.

[0315] After OVA allergic challenge, the severity of ocular surface inflammation was evaluated under a slit - lamp. The scoring criteria are shown in Table 28 below. At the same time, 10 minutes after the challenge, the scratching actions of each group of mice within 10 minutes were observed and the number of times was recorded. The experimental results are shown in Figure 1 , where Figure 1 the model group in

[0316] Table 28

[0317]

[0318] Among them, mild, moderate, and severe are defined as shown in Table 29 below:

[0319] Table 29

[0320]

[0321]

[0322] It can be seen from Figure 1 that levocetirizine hydrochloride at a concentration of 0.01 - 0.40% w / v all has a certain therapeutic effect. When the concentration is 0.05 - 0.24% w / v, the score is higher and the effect is better. When the concentration is 0.12% w / v, the score is the best and the effect is optimal.

[0323] Although the specific embodiments of the present invention have been described in detail, those skilled in the art will understand that, based on all the teachings that have been disclosed, various modifications and substitutions can be made to those details, and these changes are all within the protection scope of the present invention. The entire scope of the present invention is given by the appended claims and any equivalents thereof.

Claims

1. An ophthalmic pharmaceutical composition, preferably an ophthalmic external pharmaceutical composition, preferably an eye drop; comprising: 0.01-0.40% w / v, preferably 0.05-0.24% w / v levocetirizine hydrochloride; 1.0-4.0% w / v, preferably 2.0-4.0% w / v 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 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, which is preferably selected from phosphate, citrate, or any combination thereof; preferably citrate, which is preferably selected from sodium citrate and / or potassium citrate; and Water as solvent.

2. The ophthalmic pharmaceutical composition according to claim 1, further comprising 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 to 2, further comprising 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, hydroxypropyl methylcellulose, or a combination of any two or more thereof, preferably sodium hyaluronate.

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

5. The ophthalmic pharmaceutical composition according to any one of claims 1 to 4, having 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 adjusting agent, and the pH adjusting agent 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 to 5, which does not contain a preservative.

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

8. The ophthalmic pharmaceutical composition according to any one of claims 1 to 7, 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.

9. The ophthalmic pharmaceutical composition according to claims 1 to 8, comprising: 0.01-0.40% w / v, preferably 0.05-0.24% w / v levocetirizine hydrochloride; 1.0-4.0% w / v, preferably 2.0-4.0% w / v mannitol; 0-0.60% w / v, preferably 0-0.15% w / v of a pharmaceutically acceptable metal ion-containing osmotic pressure regulator; 0.05-1.0% w / v, preferably 0.2%-0.85% of a pharmaceutically acceptable buffer; 0-1.0% w / v, preferably 0-0.2% w / v of a pharmaceutically acceptable surfactant; Optionally 0.01-1.0% w / v, preferably 0.01-0.20% w / v of a pharmaceutically acceptable thickener; Optionally 0.01-0.1% w / v of a pharmaceutically acceptable stabilizer; and 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; The balance is water as solvent.

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

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