A diquafosol composition, a pharmaceutical preparation containing the same and its application

Abstract

The present invention discloses a diquafosol composition, a pharmaceutical preparation containing the same and an application thereof. The present invention provides a diquafosol resin composition, which comprises diquafosol or a pharmaceutically acceptable salt thereof, an anion exchange resin and water. The diquafosol composition provided by the present invention has a high drug adsorption rate and drug loading, can achieve controlled release of the drug, improve the bioavailability of the drug, and is conducive to the drug exerting a stable and sustained therapeutic effect.

Description

Technical Field

[0001] The invention relates to an ophthalmic drug, in particular to a diquafosol composition, a pharmaceutical preparation containing the diquafosol composition and application thereof. Background Art

[0002] The chemical name of diquafosol is P',P4-di(5'-uridine)tetraphosphate, which has the following structure:

[0003]

[0004] Diquafosol is a P2Y2 receptor agonist that acts on the P2Y2 receptors on the conjunctival epithelium and goblet cell membranes, and by upregulating the intracellular calcium ion concentration, it promotes the secretion of water and mucin, thereby improving the symptoms of dry eye disease. Dry eye is a common ocular surface disease, which refers to a type of disease caused by abnormal tear quantity and / or quality, resulting in tear film instability and damage to the ocular surface, leading to ocular discomfort symptoms. In recent years, the incidence of dry eye has been increasing year by year, reaching 5% to 50%. Dry eyes, red eyes, foreign body sensation, photophobia and other ocular discomfort and / or visual impairment (visual fluctuations, etc.) are common symptoms. At present, the drug treatment of dry eyes is mainly artificial tears. Traditional artificial tears mainly improve patient discomfort through lubrication. Unlike traditional artificial tears, diquafosol eye drops can stabilize the tear film by promoting the secretion of mucin and tears. It is an artificial tear with a new mechanism of action. In October 2010, Santen Pharmaceutical developed an eye drop containing 3% (w / v) diquafosol tetrasodium salt (also referred to as "diquafosol sodium") Approved for marketing in Japan for the treatment of dry eye syndrome. In clinical use, 1 drop is applied to each eye 6 times a day. Its bioavailability is low, and it is used very frequently, resulting in poor patient compliance. In June 2022, Santen Pharmaceutical was approved to market diquafosol sodium 3% eye drops in Japan. LX, which is administered three times a day, is similar to Compared with eye drops, the frequency of administration is reduced, which reduces the burden on patients.

[0005] Patent document CN103282039 A is a product listed by Santen Pharmaceutical The corresponding preparation patent discloses an eye drop preparation containing diquafosol, which suppresses the production of insoluble precipitates in the preparation by adding ethylenediaminetetraacetate as a chelating agent to the eye drops, thereby improving the stability and shelf life of the eye drops.

[0006] Patent document CN111757742 A discloses an ophthalmic composition containing diquafosol or a pharmaceutically acceptable salt thereof and a cationic polymer (such as chitosan, chitosan derivatives, polyvinyl pyrrolidone, etc.), wherein the cationic polymer is used to improve the metabolic stability of diquafosol or a pharmaceutically acceptable salt thereof, so as to enhance the therapeutic effect on dry eye. The ophthalmic composition has the effect of increasing the amount of tears, does not show nerve irritation, and can improve the comfort of eye drops.

[0007] The diquafosol eye drops disclosed in the above prior art have low bioavailability, are administered multiple times a day, are used very frequently, and have poor patient compliance. Among them, CN111757742 A claims that it can reduce the number of eye drops, but it mainly improves the metabolic stability of diquafosol, fails to effectively delay the release of the drug, and has no significant improvement in efficacy.

[0008] Taking advantage of the easy ionization characteristics of some drug molecules, they can be combined with ion exchange resins to form drug-resin complexes through ion exchange or adsorption. For example, patent document CN106573066 A forms a complex for oral delivery of treprostinil with anion exchange resin, and adds a release retardant such as cellulose acetate to achieve a sustained release effect of 8-24 hours. M. Cun~a, JL Vila Jato et al. prepared a complex of terbutaline with a sulfonic acid cation exchange resin, and further used Eudragit RS / RL polymer to form microcapsules to control the drug release rate. If no release retardant is added, the drug release rate will be reduced. RS / RL releases the drug quickly in the complex (International Journal of Pharmaceutics, 199, 2000, 151-158). SH Jeong, K. Park et al. prepared a dextromethorphan-sodium polystyrene sulfonate cation exchange resin complex and proved that the sustained release of dextromethorphan could not be achieved by adjusting the particle size of the complex alone. Only after the complex was coated with a sustained release material (such as ethyl cellulose or polyvinyl acetate hydrocolloid dispersion) could the drug be released in a controlled manner, and the release rate mainly depended on the thickness of the coating (International Journal of Pharmaceutics, 353, 2008, 195-204). Y. Deng et al. prepared a complex of carbinoxamine and sodium polystyrene sulfonate cation exchange resin, but the complex released the drug too quickly and the controlled release was not ideal. After coating with polyvinyl acetate and microencapsulation, a certain degree of sustained release was achieved (International Journal of Pharmaceutics 588, 2020, Article 119779). It can be seen that most of the preparations containing drug-resin complexes provided in the prior art are administered orally, in which the resin mainly plays a role in drug adsorption. The complex itself cannot produce a good drug sustained release or controlled release effect, and other sustained release materials must be added to give the preparation the expected sustained release function; even if all the drug molecules in the complex for oral administration have been adsorbed on the resin, the drug-resin complex alone cannot achieve the expected sustained release effect. Summary of the invention

[0009] The technical problem to be solved by the present invention is that the existing diquafosol eye drops have the problems of short retention time and frequent administration, and provide a diquafosol composition, a pharmaceutical preparation containing the same and its application. The diquafosol composition provided by the present invention has a high drug adsorption rate and drug loading, and can achieve controlled release of the drug; the pharmaceutical preparation containing the diquafosol composition provided by the present invention has the function of significantly prolonging the retention time of the drug in the eye, effectively delaying the release of the drug, and thus improving the bioavailability of the drug, which is conducive to the drug exerting a stable and continuous therapeutic effect, reducing the number of administrations, and improving the compliance of eye medication.

[0010] The invention provides a diquafosol resin composition, which comprises diquafosol or a pharmaceutically acceptable salt thereof, an anion exchange resin and water.

[0011] The diquafosol or its pharmaceutically acceptable salt is preferably diquafosol sodium salt, more preferably diquafosol tetrasodium salt (diquafosol sodium for short).

[0012] The water can be conventional water in the art, preferably purified water.

[0013] The anion exchange resin may be a strongly basic anion exchange resin (e.g., a resin molecule containing a quaternary ammonium group -NR3 + ) or weakly basic anion exchange resin (for example, the resin molecule contains an organic amine group of a primary amine, a tertiary amine or a secondary amine, such as -NH2, -NHR or -NR2).

[0014] The skeleton of the anion exchange resin can be one or more of a polystyrene skeleton, a polystyrene-divinylbenzene skeleton, a polyacrylic acid skeleton or a polyethyleneimine skeleton.

[0015] Preferably, the polymerizable monomers of the anion exchange resin include one or more monomers selected from optionally substituted allylamine or derivatives thereof, optionally substituted styrene or derivatives thereof, or optionally substituted polyamine compounds or derivatives thereof.

[0016] When the polymerized monomer of the anion exchange resin comprises optionally substituted styrene or its derivatives, the anion exchange resin is preferably cholestyramine (CAS No.: 11041-12-6).

[0017] When the polymerizable monomers of the anion exchange resin include optionally substituted styrene or its derivatives, the anion exchange resin is preferably

[0018]

[0019] When the polymerized monomer of the anion exchange resin comprises an optionally substituted polyamine compound or a derivative thereof, the anion exchange resin is preferably colestipol (CAS No.: 26658-42-4).

[0020] When the polymerizable monomer of the anion exchange resin comprises an optionally substituted polyamine compound or a derivative thereof, the anion exchange resin is preferably

[0021]

[0022] When the polymerized monomer of the anion exchange resin comprises optionally substituted allylamine or its derivatives, the anion exchange resin is preferably colesevelam (CAS No.: 182815-43-6).

[0023] When the polymerizable monomer of the anion exchange resin comprises optionally substituted allylamine or its derivatives, the anion exchange resin is preferably

[0024]

[0025] Preferably, the anion exchange resin is one or more of cholestyramine, colestipol or colesevelam, more preferably colestipol.

[0026] Preferably, the diquafosol resin composition consists of diquafosol or a pharmaceutically acceptable salt thereof, anion exchange resin and water.

[0027] In a preferred embodiment, the diquafosol or its pharmaceutically acceptable salt is diquafosol sodium.

[0028] In a preferred embodiment, the diquafosol resin composition consists of diquafosol sodium, colesevelam and water.

[0029] In a preferred embodiment, the diquafosol resin composition consists of diquafosol sodium, cholestyramine and water.

[0030] In a preferred embodiment, the diquafosol resin composition consists of diquafosol sodium, colestipol and water.

[0031] In the composition, the mass concentration of diquafosol or its pharmaceutically acceptable salt may be 0.01-0.1 g / mL, preferably 0.01-0.08 g / mL, more preferably 0.02-0.05 g / mL, for example 0.03 g / mL.

[0032] In the diquafosol resin composition, the mass ratio (w / w) of the diquafosol or its pharmaceutically acceptable salt to the anion exchange resin may be 10:1-1:10, preferably 10:1-1:6, 10:1-1:3, 10:1-1:2, 10:1-1:1, 6:1-1:10, 6:1-1:6, 6:1-1:3, 6:1-1:2, 6:1-1:1, 3:1-1:10, 3:1-1:6, 3:1-1:3, 3:1-1: 1, 2:1-3:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1.

[0033] When the anion exchange resin is colesevelam, the mass ratio of the diquafosol or a pharmaceutically acceptable salt thereof to the colesevelam may be 10:1-1:1, preferably 9:1-1:1, 8:1-1:1, 7:1-1:1, 6:1-1:1, 5:1-1:1, 4:1-1:1, 3:1-1:1, 2:1-1:1 or 6:1-3:1; more preferably, the mass ratio of the diquafosol or a pharmaceutically acceptable salt thereof to the colesevelam is 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1.

[0034] When the anion exchange resin is cholestyramine, the mass ratio of diquafosol or a pharmaceutically acceptable salt thereof to the cholestyramine may be 8:1-1:3, preferably 8:1-1:1, more preferably 7:1-1:1, 6:1-1:1, 5:1-1:1, 4:1-1:1, 3:1-1:1 or 2:1-1:1; more preferably, the mass ratio of diquafosol or a pharmaceutically acceptable salt thereof to the cholestyramine is 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1.

[0035] When the anion exchange resin is colestipol, the mass ratio of the diquafosol or its pharmaceutically acceptable salt to the colestipol may be 10:1-1:1, 9:1-1:1, 8:1-1:1, 7:1-1:1, 6:1-1:1, 5:1-1:1, 4:1-1:1, 3:1-1:1, 2:1-1:1 or 10:1-3:1; more preferably, the mass ratio of the diquafosol or its pharmaceutically acceptable salt to the colestipol is 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1.

[0036] Preferably, in the diquafosol resin composition, the diquafosol or a pharmaceutically acceptable salt thereof is adsorbed to the anion exchange resin.

[0037] Preferably, part of the diquafosol or a pharmaceutically acceptable salt thereof is adsorbed to the anion exchange resin.

[0038] Preferably, the adsorption is by ion exchange adsorption.

[0039] The adsorption rate of diquafosol or its pharmaceutically acceptable salt may be 1% to 100%, preferably 10% to 100%, 20% to 100%, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 90% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 100%. ~30%, 10%~20%, 20%~30%, 30%~40%, 40%~50%, 50%~60%, 60%~70%, 70%~80%, 80%~90%, 90%~100%, 20%~50%, 10%~40%, 15%~25%, 25%~35%, 35%~45%, 35%~50%, 45%~55%, 55%~65%, 65%~75%, 75%~85% or 85%~95%.

[0040] The particle size of the anion exchange resin is a conventional particle size in the art, and the particle size of the anion exchange resin may be 1-200 μm, preferably 1-50 μm, 1-30 μm, 1-20 μm, 1-10 μm, 1-5 μm, 3-50 μm, 3-30 μm, 3-20 μm, 3-10 μm, 3-5 μm, 5-50 μm, 5-30 μm, 5-20 μm, 5-10 μm, 10-50 μm, 10-30 μm, 10-20 μm, 20-50 μm, 20-30 μm, 30-50 μm, 5-15 μm, 15-25 μm, 25-35 μm or 35-45 μm;

[0041] Preferably, the particle size is selected from one or more of 1≤D90≤5μm, 5<D90≤10μm, 10<D90≤15μm, 15<D90≤20μm, 20<D90≤25μm, 25<D90≤30μm, 30<D90≤35μm, 35<D90≤40μm, 40<D90≤45μm and 45<D90≤50μm; more preferably, the particle size is selected from one or more of 1≤D90≤5μm, 5<D90≤10μm, 10<D90≤15μm, 15<D90≤20μm, 20<D90≤25μm or 25<D90≤30μm.

[0042] Preferably, the diquafosol resin composition comprises diquafosol or a pharmaceutically acceptable salt thereof, an anion exchange resin and water, the mass concentration of the diquafosol or a pharmaceutically acceptable salt thereof is 0.01-0.1 g / mL, and the mass ratio (w / w) of the diquafosol or a pharmaceutically acceptable salt thereof to the anion exchange resin is 10:1-1:10.

[0043] In a preferred embodiment, the diquafosol resin composition is composed of diquafosol sodium, colesevelam and water, the mass concentration of diquafosol sodium may be 0.01-0.1 g / mL; the mass ratio of diquafosol sodium to colesevelam is 10:1-1:1;

[0044] Preferably, the mass concentration of diquafosol sodium is 0.03 g / mL;

[0045] Preferably, the mass ratio of diquafosol sodium to colesevelam is 6:1-3:1 (e.g., 6:1, 5:1, 4:1 or 3:1), more preferably 6:1 or 3:1;

[0046] Preferably, the colesevelam has a particle size of 1-200 μm; more preferably 1-50 μm, more preferably 1-30 μm, most preferably 1-20 μm, for example 1≤D90≤5 μm, 5<D90≤10 μm, 10<D90≤15 μm or 15<D90≤20 μm;

[0047] Preferably, the adsorption rate of diquafosol sodium is 10% to 100%; more preferably 10% to 40%, more preferably 10% to 20% or 30% to 40%.

[0048] In a preferred embodiment, the diquafosol resin composition consists of diquafosol sodium, colesevelam and water, the mass concentration of the diquafosol sodium is 0.03 g / mL; the mass ratio of the diquafosol sodium to the colesevelam is 6:1; the particle size of the colesevelam is preferably 1-200 μm, more preferably 1-30 μm; the adsorption rate of the diquafosol sodium is preferably 10% to 20%.

[0049] In a preferred embodiment, the diquafosol resin composition consists of diquafosol sodium, colesevelam and water, the mass concentration of the diquafosol sodium is 0.03 g / mL; the mass ratio of the diquafosol sodium to the colesevelam is 3:1; the particle size of the colesevelam is preferably 1-200 μm, more preferably 1-30 μm; the adsorption rate of the diquafosol sodium is preferably 30% to 40%.

[0050] In a preferred embodiment, the diquafosol resin composition consists of diquafosol sodium, cholestyramine and water, the mass concentration of the diquafosol sodium is 0.01-0.1 g / mL; the mass ratio of the diquafosol sodium to the cholestyramine is 8:1-1:3, preferably 8:1-1:1.

[0051] In a preferred embodiment, the diquafosol resin composition is composed of diquafosol sodium, cholestyramine and water, the mass concentration of diquafosol sodium is 0.01-0.1 g / mL; the mass ratio of diquafosol sodium to cholestyramine is 8:1-1:3;

[0052] Preferably, the mass concentration of diquafosol sodium is 0.03 g / mL;

[0053] Preferably, the mass ratio of diquafosol sodium to cholestyramine is 3:1-1:3 (e.g., 3:1, 2:1, 1:1, 1:2, 1:3), more preferably 3:1-1:1 (e.g., 3:1, 2:1, 1:1), more preferably 3:1;

[0054] Preferably, the particle size of cholestyramine is 1-200 μm, more preferably 1-50 μm, more preferably 1-30 μm, for example 1≤D90≤5 μm, 5<D90≤10 μm, 10<D90≤15 μm, 15<D90≤20 μm, 20 μm<D90≤25 μm or 25<D90≤30 μm;

[0055] Preferably, the adsorption rate of diquafosol sodium is 10%-100%, more preferably 20%-100%, more preferably 20%-30%, 70%-80% or 90%-100%.

[0056] In a preferred embodiment, the diquafosol resin composition consists of diquafosol sodium, cholestyramine and water, the mass concentration of the diquafosol sodium is 0.03 g / mL; the mass ratio of the diquafosol sodium to the cholestyramine is 3:1; the particle size of the cholestyramine is preferably 1-200 μm, more preferably 1-30 μm; the adsorption rate of the diquafosol sodium is preferably 20%-30%.

[0057] In a preferred embodiment, the diquafosol resin composition consists of diquafosol sodium, cholestyramine and water, the mass concentration of the diquafosol sodium is 0.03 g / mL; the mass ratio of the diquafosol sodium to the cholestyramine is 1:1; the particle size of the cholestyramine is preferably 1-200 μm, more preferably 1-30 μm; the adsorption rate of the diquafosol sodium is preferably 70%-80%.

[0058] In a preferred embodiment, the diquafosol resin composition consists of diquafosol sodium, cholestyramine and water, the mass concentration of the diquafosol sodium is 0.03 g / mL; the mass ratio of the diquafosol sodium to the cholestyramine is 1:2; the particle size of the cholestyramine is preferably 1-200 μm, more preferably 1-30 μm; the adsorption rate of the diquafosol sodium is preferably 90%-100%.

[0059] In a preferred embodiment, the diquafosol resin composition consists of diquafosol sodium, cholestyramine and water, the mass concentration of the diquafosol sodium is 0.03 g / mL; the mass ratio of the diquafosol sodium to the cholestyramine is 1:3; the particle size of the cholestyramine is preferably 1-200 μm, more preferably 1-30 μm; the adsorption rate of the diquafosol sodium is preferably 90%-100%.

[0060] In a preferred embodiment, the diquafosol resin composition is composed of diquafosol sodium, colestipol and water, the mass concentration of diquafosol sodium is 0.01-0.1 g / mL; the mass ratio of diquafosol sodium to colestipol is 10:1-1:1;

[0061] Preferably, the mass concentration of diquafosol sodium is 0.03 g / mL;

[0062] Preferably, the mass ratio of diquafosol sodium to colestipol is 10:1-3:1 (e.g., 10:1 or 3:1), more preferably 3:1;

[0063] Preferably, the colestipol has a particle size of 1-200 μm, preferably 1-50 μm, more preferably 1-30 μm, most preferably 1-25 μm, for example 1≤D90≤5 μm, 5<D90≤10 μm, 10<D90≤15 μm, 15<D90≤20 μm or 20 μm<D90≤25 μm;

[0064] Preferably, the adsorption rate of diquafosol sodium is 10% to 100%, preferably 10% to 50%, and more preferably 35% to 50%.

[0065] In a preferred embodiment, the diquafosol resin composition consists of diquafosol sodium, colestipol and water, the mass concentration of the diquafosol sodium is 0.03 g / mL; the mass ratio of the diquafosol sodium to the colestipol is 10:1; the particle size of the colestipol is preferably 1-200 μm, more preferably 1-30 μm; the adsorption rate of the diquafosol sodium is preferably 10% to 20%.

[0066] In a preferred embodiment, the diquafosol resin composition consists of diquafosol sodium, colestipol and water, the mass concentration of the diquafosol sodium is 0.03 g / mL; the mass ratio of the diquafosol sodium to the colestipol is 3:1; the particle size of the colestipol is preferably 1-200 μm, more preferably 1-30 μm; the adsorption rate of the diquafosol sodium is preferably 35% to 50%.

[0067] The present invention provides a diquafosol preparation, which comprises the diquafosol resin composition as described above.

[0068] Preferably, in the diquafosol preparation, the diquafosol resin composition is one or more of the diquafosol sodium-colestipol composition (referring to the diquafosol resin composition whose anion resin is colestipol) as described above, the diquafosol sodium-colesevelam composition (referring to the diquafosol resin composition whose anion resin is colesevelam) as described above, or the diquafosol sodium-cholestyramine composition (referring to the diquafosol resin composition whose anion resin is cholestyramine) as described above, more preferably the diquafosol sodium-colestipol composition as described above.

[0069] Preferably, in the diquafosol preparation, the pH of the diquafosol preparation may be 4.5≤pH≤9, 5≤pH≤9, 5≤pH≤8, 5≤pH≤7, 5≤pH≤6, 7≤pH≤8, 8≤pH≤9, 7≤pH≤9 or 6≤pH≤7.

[0070] The pH of the diquafosol preparation can be obtained by a pH adjuster, and the type of the pH adjuster is not limited. Those skilled in the art can choose whether to add a pH adjuster and what pH adjuster to choose to obtain a suitable pH range according to the type of anion exchange resin used and the properties of the diquafosol resin composition and / or the diquafosol preparation.

[0071] Preferably, in the diquafosol preparation, the osmotic pressure (π) of the diquafosol preparation may be 250-350 mOsmol / kg; preferably 280-310 mOsmol / kg, for example 280≤π<290 mOsmol / kg, 290≤π<300 mOsmol / kg or 300≤π≤310 mOsmol / kg.

[0072] The osmotic pressure can be obtained by an osmotic pressure regulator, and the type of the osmotic pressure regulator is not limited. Those skilled in the art can choose whether to add an osmotic pressure regulator and which osmotic pressure regulator to choose to obtain a suitable osmotic pressure value range according to the type of anion exchange resin used and the properties of the diquafosol resin composition and / or the diquafosol preparation.

[0073] Preferably, the diquafosol preparation further comprises a pharmaceutically acceptable excipient.

[0074] The pharmaceutically acceptable excipients may be selected from one or more of conventional suspending agents, viscosity enhancers, solubilizing agents, mucosal adhesives, pH regulators, osmotic pressure regulators, preservatives and chelating agents in the art; preferably, the pharmaceutically acceptable excipients are selected from one or more of pH regulators, preservatives, osmotic pressure regulators and suspending agents.

[0075] The pH regulator is a conventional pH regulator in the art, and the pH regulator is selected from an acid, a base or a buffer salt.

[0076] The acid may be an organic acid or an inorganic acid, the organic acid may be selected from one or more of acetic acid, citric acid, citric acid, lactic acid and boric acid, and the inorganic acid may be selected from hydrochloric acid and / or phosphoric acid; preferably, the acidic regulator is one or more of acetic acid, citric acid, lactic acid and boric acid, most preferably acetic acid.

[0077] The base may be an inorganic base or an organic base. The inorganic base may be selected from one or more of sodium hydroxide, calcium hydroxide, potassium hydroxide and aqueous ammonia solution. The organic base may be selected from one or more of ethylenediamine, ethanolamine and basic amino acids. Preferably, the alkaline regulator is sodium hydroxide.

[0078] The buffer salt can be selected from one or more of boric acid-borax buffer salt, citric acid-sodium citrate buffer salt, phosphate-sodium phosphate buffer salt and acetic acid-sodium acetate buffer salt; preferably, the buffer salt is acetic acid-sodium acetate buffer salt.

[0079] The osmotic pressure regulator is a conventional osmotic pressure regulator in the art, and the osmotic pressure regulator can be selected from one or more of sodium chloride, potassium chloride, disodium hydrogen phosphate, sodium dihydrogen phosphate, boric acid, borax, mannitol, propylene glycol, sorbitol and glycerol; preferably, the osmotic pressure regulator is selected from one or more of sodium chloride, potassium chloride, disodium hydrogen phosphate, boric acid, mannitol and glycerol; more preferably, the osmotic pressure regulator is selected from one or more of boric acid, mannitol and glycerol, and most preferably glycerol and / or mannitol.

[0080] The suspending agent is a conventional suspending agent in the art, and the suspending agent can be selected from one or more of xanthan gum, carbomer, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, sodium hyaluronate (also known as sodium hyaluronate), polyvinyl alcohol, xyloglucan, povidone, hydroxyethyl cellulose, gellan gum and sodium alginate; preferably, the suspending agent is selected from one or more of xanthan gum, carbomer, hydroxypropyl methylcellulose, sodium hyaluronate and sodium alginate; more preferably, the suspending agent is selected from one or more of xanthan gum, hydroxypropyl methylcellulose and sodium hyaluronate; more preferably, hydroxypropyl methylcellulose and / or sodium hyaluronate.

[0081] The preservative is a conventional preservative in the art, and the preservative can be selected from one or more of sodium benzoate, potassium sorbate, edetate (also known as ethylenediaminetetraacetate or EDTA, such as disodium edetate), parabens (such as methyl paraben, ethyl paraben, propyl paraben or butyl paraben), sorbic acid, polyquaternium-1, chlorhexidine gluconate, chlorhexidine acetate, benzyl alcohol, phenethyl alcohol, benzalkonium chloride and benzalkonium bromide; preferably, the preservative is selected from one or more of ethylenediaminetetraacetate, methyl paraben, ethyl paraben, polyquaternium-1, chlorhexidine gluconate, chlorhexidine acetate and benzalkonium chloride; more preferably, the preservative is selected from one or more of polyquaternium-1, chlorhexidine gluconate or benzalkonium chloride, more preferably benzalkonium chloride.

[0082] Preferably, the diquafosol preparation is composed of the diquafosol resin composition as described above and the pharmaceutically acceptable excipients.

[0083] Preferably, in the aforementioned diquafosol preparation, the pharmaceutically acceptable excipient is the pH regulator.

[0084] Preferably, the diquafosol preparation consists of the diquafosol resin composition as described above and the pH regulator.

[0085] Preferably, the diquafosol preparation comprises the diquafosol resin composition as described above and the pH regulator, wherein the mass concentration of the diquafosol or a pharmaceutically acceptable salt thereof is 0.01-0.1 g / mL, the mass ratio of the diquafosol or a pharmaceutically acceptable salt thereof to the anion exchange resin is 10:1-1:1, and the pH of the diquafosol preparation is 4.5≤pH≤9.

[0086] Preferably, the diquafosol preparation comprises the diquafosol resin composition as described above and the pH regulator, wherein the mass concentration of the diquafosol or its pharmaceutically acceptable salt is 0.01-0.1 g / mL, the mass ratio of the diquafosol or its pharmaceutically acceptable salt to the anion exchange resin is 10:1-1:1, the adsorption rate of the diquafosol or its pharmaceutically acceptable salt is 10%-100%, the pH of the diquafosol preparation is 4.5≤pH≤9, and the particle size of the anion exchange resin is 1-30 μm.

[0087] In a certain embodiment, the diquafosol preparation is composed of the diquafosol sodium-colestipol composition and the pH regulator, the diquafosol sodium-colestipol composition is composed of the diquafosol sodium, the colestipol and the water, the mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the colestipol is 10:1-1:1, the particle size of the colestipol is 1-30 μm, the pH of the diquafosol preparation is 4.5≤pH≤9, and the adsorption rate of the diquafosol sodium is 10% to 100%.

[0088] In a preferred embodiment, the diquafosol preparation is composed of the diquafosol sodium-colestipol composition and the pH regulator (such as acetic acid), the diquafosol sodium-colestipol composition is composed of the diquafosol sodium, the colestipol and the water, the mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the colestipol is 3:1, the particle size of the colestipol is 1-30 μm, the pH of the diquafosol preparation is 5≤pH≤8, and the adsorption rate of the diquafosol sodium is 10% to 100%, preferably 20% to 50%.

[0089] In a preferred embodiment, the diquafosol preparation is composed of the diquafosol sodium-colesevelam composition and the pH regulator, the diquafosol sodium-colesevelam composition is composed of the diquafosol sodium, the colesevelam and the water, the mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the colesevelam is 10:1-1:1, the particle size of the colesevelam is 1-30 μm, the pH of the diquafosol preparation is 4.5≤pH≤9, and the adsorption rate of the diquafosol sodium is 10% to 100%.

[0090] In a preferred embodiment, the diquafosol preparation is composed of the diquafosol sodium-colesevelam composition and the pH adjuster (such as sodium hydroxide), the diquafosol sodium-colesevelam composition is composed of the diquafosol sodium, the colesevelam and the water, the mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the colesevelam is 3:1, the particle size of the colesevelam is 1-30 μm, the pH of the diquafosol preparation is 5≤pH≤8, and the adsorption rate of the diquafosol sodium is 10% to 100%, preferably 10% to 40%.

[0091] In a preferred embodiment, the diquafosol preparation is composed of the diquafosol sodium-cholestyramine composition and the pH regulator, the diquafosol sodium-cholestyramine composition is composed of the diquafosol sodium, the cholestyramine and the water, the mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the cholestyramine is 8:1-1:1, the particle size of the cholestyramine is 1-30 μm, the pH of the diquafosol preparation is 4.5≤pH≤9, and the adsorption rate of the diquafosol sodium is 10% to 100%.

[0092] In a preferred embodiment, the diquafosol preparation is composed of the diquafosol sodium-cholestyramine composition and the pH regulator (such as acetic acid or sodium hydroxide), the diquafosol sodium-cholestyramine composition is composed of the diquafosol sodium, the cholestyramine and the water, the mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the cholestyramine is 3:1, the particle size of the cholestyramine is 1-30 μm, the pH of the diquafosol preparation is 5≤pH≤8, and the adsorption rate of the diquafosol sodium is 10% to 100%, preferably 20% to 30%.

[0093] Preferably, in the aforementioned diquafosol preparation, the pharmaceutically acceptable excipient further comprises the osmotic pressure regulator.

[0094] Preferably, the diquafosol preparation consists of the diquafosol resin composition as described above, the pH regulator and the osmotic pressure regulator.

[0095] Preferably, the diquafosol preparation comprises the diquafosol resin composition, the pH regulator and the osmotic pressure regulator, wherein the mass concentration of the diquafosol or its pharmaceutically acceptable salt is 0.01-0.1 g / mL, the mass ratio of the diquafosol or its pharmaceutically acceptable salt to the anion exchange resin is 10:1-1:1, the pH of the diquafosol preparation is 4.5≤pH≤9, and the osmotic pressure (π) of the diquafosol preparation is 250-350 mOsmol / kg.

[0096] In a preferred embodiment, the diquafosol preparation is composed of the diquafosol sodium-colestipol composition, the pH regulator and the osmotic pressure regulator, the diquafosol sodium-colestipol composition is composed of the diquafosol sodium, the colestipol and the water, the mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the colestipol is 10:1-1:1, and the particle size of the colestipol is 1-30 μm; the pH of the diquafosol preparation is 4.5≤pH≤9; the osmotic pressure (π) of the diquafosol preparation is 250-350 mOsmol / kg, and the adsorption rate of the diquafosol sodium is 10%-100%.

[0097] In a preferred embodiment, the diquafosol preparation is composed of the diquafosol sodium-colestipol composition, the pH regulator and the osmotic pressure regulator, the diquafosol sodium-colestipol composition is composed of the diquafosol sodium, the colestipol and the water, the mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the colestipol is 3:1, and the particle size of the colestipol is 1-30 μm; the pH of the diquafosol preparation is 6≤pH≤7; the osmotic pressure (π) of the diquafosol preparation is 250-350 mOsmol / kg, and the adsorption rate of the diquafosol sodium is 10%-100%, preferably 30%-50%.

[0098] In a preferred embodiment, the diquafosol preparation is composed of the diquafosol sodium-colestipol composition, the pH regulator and the osmotic pressure regulator, the diquafosol sodium-colestipol composition is composed of the diquafosol sodium, the colestipol and the water, the mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the colestipol is 10:1, and the particle size of the colestipol is 1-30 μm; the pH of the diquafosol preparation is 6≤pH≤7; the osmotic pressure (π) of the diquafosol preparation is 250-350 mOsmol / kg, and the adsorption rate of the diquafosol sodium is 10%-100%, preferably 10%-40%.

[0099] In a preferred embodiment, the diquafosol preparation is composed of the diquafosol sodium-colesevelam composition, the pH regulator and the osmotic pressure regulator. The diquafosol sodium-colesevelam composition is composed of the diquafosol sodium, the colesevelam and the water. The mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the colesevelam is 10:1-1:1, and the particle size of the colesevelam is 1-30 μm; the pH of the diquafosol preparation is 4.5≤pH≤9; the osmotic pressure (π) of the diquafosol preparation is 250-350 mOsmol / kg, and the adsorption rate of the diquafosol sodium is 10%-100%.

[0100] In a preferred embodiment, the diquafosol preparation is composed of the diquafosol sodium-colesevelam composition, the pH regulator and the osmotic pressure regulator, the diquafosol sodium-colesevelam composition is composed of the diquafosol sodium, the colesevelam and the water, the mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the colesevelam is 3:1, and the particle size of the colesevelam is 1-30 μm; the pH of the diquafosol preparation is 6≤pH≤7; the osmotic pressure (π) of the diquafosol preparation is 250-350 mOsmol / kg, and the adsorption rate of the diquafosol sodium is 10%-100%, preferably 30%-50%.

[0101] In a preferred embodiment, the diquafosol preparation is composed of the diquafosol sodium-cholestyramine composition, the pH regulator and the osmotic pressure regulator. The diquafosol sodium-cholestyramine composition is composed of the diquafosol sodium, the cholestyramine and the water. The mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the cholestyramine is 8:1-1:1, and the particle size of the cholestyramine is 1-30 μm; the pH of the diquafosol preparation is 4.5≤pH≤9; the osmotic pressure (π) of the diquafosol preparation is 250-350 mOsmol / kg, and the adsorption rate of the diquafosol sodium is 10%-100%.

[0102] In a preferred embodiment, the diquafosol preparation is composed of the diquafosol sodium-cholestyramine composition, the pH regulator and the osmotic pressure regulator. The diquafosol sodium-cholestyramine composition is composed of the diquafosol sodium, the cholestyramine and the water. The mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the cholestyramine is 3:1, and the particle size of the cholestyramine is 1-30 μm; the pH of the diquafosol preparation is 6≤pH≤7; the osmotic pressure (π) of the diquafosol preparation is 250-350 mOsmol / kg, and the adsorption rate of the diquafosol sodium is 10%-100%, preferably 20%-50%.

[0103] Preferably, in the aforementioned diquafosol preparation, the pharmaceutically acceptable excipient further comprises the suspending agent.

[0104] Preferably, the diquafosol preparation is composed of the diquafosol resin composition as described above, the pH regulator, the osmotic pressure regulator and the suspending agent.

[0105] The mass concentration of the suspending agent is 0.001-0.02 g / mL, preferably 0.005-0.01 g / mL, such as 0.005 g / mL or 0.01 g / mL.

[0106] Preferably, the diquafosol preparation comprises the diquafosol resin composition, the pH regulator, the osmotic pressure regulator and the suspending agent, the mass concentration of the diquafosol or its pharmaceutically acceptable salt is 0.01-0.1 g / mL, the mass ratio of the diquafosol or its pharmaceutically acceptable salt to the anion exchange resin is 10:1-1:1, the mass concentration of the suspending agent is 0.001-0.02 g / mL, the pH of the diquafosol preparation is 4.5≤pH≤9, and the osmotic pressure (π) of the diquafosol preparation is 250-350 mOsmol / kg.

[0107] In a preferred embodiment, the diquafosol preparation is composed of the diquafosol sodium-colestipol composition, the pH regulator (such as acetic acid), the osmotic pressure regulator (such as glycerol or mannitol) and the suspending agent (such as hydroxypropyl methylcellulose or sodium hyaluronate), the diquafosol sodium-colestipol composition is composed of the diquafosol sodium, the colestipol and the water, the mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the colestipol is 3:1, the mass concentration of the suspending agent is 0.001-0.02 g / mL, and the particle size of the colestipol is 1-30 μm; the pH of the diquafosol preparation is 6≤pH≤7; the osmotic pressure (π) of the diquafosol preparation is 250-350 mOsmol / kg, and the adsorption rate of the diquafosol sodium is 10%-100%, preferably 30%-50%.

[0108] Preferably, in the aforementioned diquafosol preparation, the pharmaceutically acceptable excipients further include a preservative.

[0109] Preferably, the diquafosol preparation consists of the diquafosol resin composition as described above, the pH regulator, the osmotic pressure regulator, the suspending agent and the preservative.

[0110] The mass concentration of the preservative is 0.000001-0.0001 g / mL, preferably 0.00001 g / mL.

[0111] Preferably, the diquafosol preparation refers to a pharmaceutical preparation used for the prevention, relief and / or treatment of eye diseases, etc. As its dosage form, it can be selected from liquid preparations for eyes (eye drops, eye washes, intraocular injection solutions, etc.), semi-solid preparations for eyes (eye ointments, eye creams, eye gels, etc.) and solid preparations for eyes (eye films, eye pills, intraocular inserts, etc.), etc., preferably liquid preparations for eyes, more preferably eye drops. It will be understood by those skilled in the art that eye drops have the same meaning as eye drops or eye drops, and eye drops for contact lenses are also included in the definition of eye drops.

[0112] Preferably, the usage of the ophthalmic preparation can be appropriately varied according to the dosage form, the severity of the symptoms of the patient to be administered, the age, weight, the doctor's judgment, etc. For example, when eye drops are selected as the dosage form, the eye drops can be administered 1-6 times a day, preferably 1-3 times a day, more preferably 1-2 times a day, and most preferably once a day.

[0113] The present invention provides a use of the above-mentioned diquafosol resin composition or the above-mentioned diquafosol preparation in preparing a medicine for preventing, alleviating and / or treating eye diseases.

[0114] The eye disease may be dry eye disease, and the dry eye disease may be reduced tears, insufficient tears, dry eyes, Sjogren's syndrome, keratoconjunctivitis sicca (KCS), allergic keratoconjunctivitis sicca (AKC), vernal keratoconjunctivitis (VKC), pemphigoid eye, marginal blepharitis, inability to close the eyelids or sensory nerve numbness, as well as dry eye disease associated with allergic conjunctivitis, dry eye disease after viral conjunctivitis, dry eye disease after corneal surgery, dry eye disease after secondary cataract surgery, or dry eye disease associated with contact lenses.

[0115] The present invention provides a method for preparing the diquafosol resin composition as described above, which comprises the following steps: mixing the diquafosol or a pharmaceutically acceptable salt thereof as described above and the anion exchange resin as described above in water to obtain the diquafosol resin composition.

[0116] Preferably, the diquafosol or a pharmaceutically acceptable salt thereof, the anion exchange resin and the water can be reacted by stirring; the stirring time is at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 75 minutes, at least 90 minutes, at least 120 minutes, at least 150 minutes, at least 180 minutes, at least 210 minutes, at least 240 minutes, at least 270 minutes, or at least 360 minutes.

[0117] The present invention also provides a method for preparing the diquafosol preparation as described above, which comprises the following steps: mixing the diquafosol resin composition as described above with the auxiliary materials as described above.

[0118] Preferably, the method for preparing the diquafosol preparation as described above comprises the following steps: mixing the diquafosol or a pharmaceutically acceptable salt thereof as described above and the anion exchange resin as described above in water to obtain a diquafosol resin composition.

[0119] the term

[0120] The "pharmaceutically acceptable salt" means that the salt is pharmaceutically acceptable and has the desired pharmaceutical activity. There are no particular restrictions on pharmaceutically acceptable salts, and examples include alkali metal or alkaline earth metal salts formed with lithium, sodium, potassium, calcium, magnesium, zinc, etc.; inorganic acid or organic acid salts formed with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, etc.

[0121] Ion exchange resin is a kind of insoluble macromolecular polymer with functional groups, with fixed ionizable functional groups (positively or negatively charged). Its unit structure consists of two parts, one is a cross-linked skeleton with a three-dimensional network structure and the other is active ions that can freely migrate between the cross-linked skeleton and the solution and exchange with other ions in the solution. According to the charge properties of the active ions that can be exchanged, ion exchange resins can be divided into cation exchange resins and anion exchange resins.

[0122] Anion exchange resin refers to a resin with basic groups in its molecules, such as quaternary ammonium groups (-NR3 + ) or an organic amine group (-NH2, -NHR or -NR2).

[0123] The anion exchange resin described in the present invention is a type of high molecular polymer that can capture or adsorb negatively charged drug molecules as a carrier or matrix, and can elute or desorb the drug molecules from the resin through anion exchange, thereby achieving controlled drug release. The process of the anion exchange resin as a carrier or matrix to capture or adsorb negatively charged drug molecules is called capture or adsorption, which is also an anion exchange process, and can be expressed as:

[0124] ReS-A1 - +D - =ReS-D - +A1 - (Formula 1);

[0125] The process of eluting or desorbing drug molecules from the resin by anion exchange is called elution or desorption, which can be expressed as:

[0126] ReS-D - +A2 - =ReS-A2 - +D - (Formula 2);

[0127] In Formula 1 or Formula 2, ReS represents a fixed group on an anion exchange resin, and A1 - 、A2 - Denotes anions that can exchange with negatively charged drug molecules, D - Represents a negatively charged drug molecule; A1 - 、A2 - can be the same or different, depending on the specific type of active anions that can be used for exchange in the anion exchange resin, and the specific environment in which the drug molecules are captured or adsorbed and eluted or desorbed. For example, in the present invention, A1 - It can be OH - , Cl - 、SO4 2- etc., A2 - It can be Cl - The ion exchange resin composition of the present invention is formed by capturing or adsorbing diquafosol with an anion exchange resin or is further prepared into an ophthalmic preparation. When the composition or preparation is applied to the eye, Cl in the tear fluid is reduced. - It can exchange with the negatively charged diquafosol again, causing it to be slowly desorbed or eluted from the resin, thereby achieving controlled and delayed release of the drug.

[0128] Diquafosol or its pharmaceutically acceptable salt is a dinucleotide derivative. The phosphate group of diquafosol carries more negative charges and can be adsorbed by positively charged anion exchange resin through ion exchange.

[0129] The cross-linked skeleton of the ion exchange resin may be, for example, a polystyrene skeleton (such as Mitsubishi Chemical DIAION TM Series of strong basic anion exchange resins type I, II and weak basic anion exchange resins WA20, WA21J, WA30; such as cholestyramine resin, PUROLITE TM A430MR resin; DOW Cholestyramine USP, Form No. 177-01877-204, The Dow Chemical Company; DUOLITE TM AP143 / 1083, Rohm and Haas, IE-566EDS), polystyrene-divinylbenzene skeleton (such as Thermo Fisher POROS AEX series), polyacrylic acid skeleton (such as Mitsubishi Chemical DIAION TMseries weakly basic anion exchange resin WA10); or, the N atom itself can also participate in forming a cross-linked skeleton. In this case, the quaternary ammonium, tertiary amine, secondary amine or primary amine group itself becomes part of the cross-linked skeleton, such as forming a polyethyleneimine skeleton (such as Nippon Catalyst series, SP series), etc.

[0130] The cholestyramine resin is a strong base type 1 anion exchange resin powder having a polystyrene matrix and quaternary ammonium functional groups. The exchangeable anion is usually chloride, which can be exchanged for another anionic substance or replaced by another anionic substance. A commercially available cholestyramine resin is PUROLITE TM A430MR resin, purchased from Purolite; another pharmaceutical grade cholestyramine resin is DUOLITE TM AP143 / 1094, purchased from Rohm and Haas Company.

[0131] The pharmaceutical preparation described in the present invention may include one or more of conventional suspending agents, viscosity enhancing agents, solubilizing agents, mucosal adhesives, pH regulators, osmotic pressure regulators, preservatives and chelating agents in the art, and is not limited to the combinations listed herein.

[0132] The mass concentration of each component in the present invention refers to the mass concentration of the component contained in the composition or preparation of the present invention calculated based on the total volume of the composition of the present invention or the total volume of the preparation of the present invention, and the unit is g / mL.

[0133] The particle size mentioned in the present invention refers to the D90 particle size, and D90 refers to the particle size corresponding to when the cumulative particle size distribution number of a sample reaches 90%.

[0134] It will be understood by those skilled in the art that, in the present invention, the particle size of the anion exchange resin will not have a substantial effect on the adsorption or release effect of the drug, but in order to enhance the comfort of ocular administration, the particle size of the anion exchange resin can be controlled within an appropriate range as needed.

[0135] stability

[0136] Stability refers to that the preparation disclosed in the present invention is chemically stable during, for example, storage, distribution, and product shelf life, and exhibits less degradation of the raw material and / or less degradation products. Stability studies can be conducted under certain temperature, humidity, and illumination conditions, and the degradation products of the preparation can be detected by, for example, HPLC with a UV detector after storage for at least one week, at least two weeks, at least one month, at least two months, at least three months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months. In certain embodiments, degradation products can be detected at time intervals of one month, three months, six months, nine months, twelve months, eighteen months, twenty-four months, thirty-six months, and / or forty-eight months. Storage conditions can be long-term, intermediate, or accelerated conditions. In certain embodiments, the storage conditions can be, for example, 25°C±2°C / 40% relative humidity (RH)±5%RH, 25°C±2°C / 60%RH±5%RH, 30°C±2°C / 35%RH±5%RH, 30°C±2°C / 65%RH±10%RH, 40°C±2°C / 45%RH±5%RH, 40°C±2°C / 75%RH±10%RH, 50°C±2°C / 75%RH±10%RH, 60°C±2°C / 50%RH±5%RH, 60°C±2°C / 40%RH±5%RH, 70°C±2°C / 50%RH±5%RH, 70°C±2°C / 75%RH±10%RH and / or 80°C±2°C / 40%RH±5%RH.

[0137] Irritant

[0138] Hemolysis test (or Red blood cell test) is used to evaluate the initial cell response caused by certain test substances. These test substances mainly damage the cell membrane and denature certain proteins, while non-irritating substances will not cause such reactions.

[0139] Membrane damage is usually evaluated by measuring the amount of hemoglobin leaked from red blood cells. This method uses spectrophotometry to measure the absorbance of red blood cell suspension after the action of chemicals, calculates the hemolysis rate, and obtains HC by curve fitting. 50 The HC value (i.e., the concentration of the test substance that causes 50% hemolysis of erythrocytes) is used as an indicator for evaluating the irritation of the test substance. 50 The larger the value, the less irritating the corresponding sample is. On the contrary, if HC 50 The smaller the value, the greater the irritation of the corresponding sample.

[0140] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0141] The reagents and raw materials used in the present invention are all commercially available. Among them, cholestyramine was purchased from Purolite, colesevelam was purchased from BOC Sciences, and colestipol was purchased from BOC Sciences.

[0142] The positive and progressive effects of the present invention are:

[0143] (1) The composition of the present invention and the pharmaceutical preparation containing the same can effectively delay the release time of the drug and improve the bioavailability. At the same time, they have good physical and chemical stability and are non-irritating or extremely low irritating to the eyes, thereby reducing the number of dosing times and improving the comfort and compliance of eye medication.

[0144] (2) The in vitro dissolution release time of the composition of the present invention and the pharmaceutical preparation containing the composition can reach at least 8-24 hours, preferably 8-12 hours, and more preferably 8-10 hours. The pharmacokinetic and efficacy test data in animals show that the preparation has a significant sustained-release effect, and can achieve a lower administration frequency of 1-3 times a day, preferably 1-2 times a day, and more preferably once a day while maintaining an excellent therapeutic effect. The sustained-release effect can reach at least 8-24 hours, preferably 8-12 hours, and more preferably 8-10 hours.

[0145] (3) The composition of the present invention and the pharmaceutical preparation containing the same have excellent physical and chemical stability. After the preparation is stored under accelerated conditions for at least one week, at least two weeks, or at least one month, the drug adsorption rate remains substantially unchanged. After the preparation is stored for at least one week, at least two weeks, at least one month, at least three months, at least six months, at least nine months, at least twelve months, at least eighteen months, or at least twenty-four months, it contains only, for example, less than 1% of impurities, or less than 0.5% of impurities, or less than 0.2% of impurities, or less than 0.1% of impurities. BRIEF DESCRIPTION OF THE DRAWINGS

[0146] Figure 1 : Changes in API adsorption rates of three anion exchange resins (CLYM / CLTP / CLVL) at different pH values.

[0147] Figure 2 : Prescription 4-1, 4-2, 4-3, chitosan eye drops, Eye drops and In vitro release profile of eye drops.

[0148] Figure 3 : Prescription 4-4, chitosan eye drops, Eye drops and In vitro release profile of eye drops.

[0149] Figure 4 : Prescription 4-5, chitosan eye drops, Eye drops and In vitro release profile of eye drops.

[0150] Figure 5 :Prescription 4-6, Eye drops and In vitro release profile of eye drops.

[0151] Figure 6 : Prescription 5-1, 5-2, 5-3, Eye drops and In vitro release profile of eye drops.

[0152] Figure 7 : API adsorption rate change diagram of prescription 6-1 under different storage time. DETAILED DESCRIPTION

[0153] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0154] The abbreviations and Chinese full names of some technical terms in this invention are as follows:

[0155] abbreviation meaning API Diquafosol Sodium CLYM Cholestyramine CLTP Colestipol CLVL Colesevelam

[0156] The determination method adopted in the embodiment of the present invention is as follows:

[0157] Adsorption rate determination: The sample was centrifuged at 10000 rpm for 10 min to precipitate the resin that adsorbed the API. The absorbance of the free API in the supernatant was measured at a wavelength of 262 nm using an ultraviolet spectrophotometer to obtain the supernatant content. The resin API adsorption rate was calculated using the following formula:

[0158]

[0159] Particle size determination: After deducting the dispersed phase background with a laser particle size analyzer at a speed of 1000 rpm, take an appropriate amount of sample and drop it into the dispersed phase to make the optical detection concentration between 20-30%. Repeat the measurement twice and take the average value to determine the D90 particle size (D90 refers to the particle size corresponding to 90% of the cumulative particle size distribution number of a sample).

[0160] Osmotic pressure determination: Directly measured using a freezing point osmometer.

[0161] Viscosity measurement: Rotational rheometer, using a 2° cone-plate fixture with a diameter of 40 mm, at 25°C for 1 s -1 Shear rate determination.

[0162] Dissolution determination (reciprocating cylinder dissolution apparatus, USP3 method): select a dialysis bag with a molecular weight cutoff of 50kDa or 100kDa, sample volume 0.8g, temperature: 37℃, external medium artificial tears (6.78g NaCl, 2.18g NaHCO3, 0.084g CaCl2·2H2O and 1.38g KCl, dissolved in purified water to 1L) volume: 250mL; reciprocating cylinder speed 5Hz; sampling time points: 5min, 10min, 15min, 30min, 45min, 60min, 120min, 240min, 480min, 720min, 960min, 1200min, 1440min; sampling volume 5mL, and supplement with 5mL of fresh insulated medium at the same time.

[0163] Example 1: Preparation and adsorption rate test of diquafosol sodium and anion exchange resin

[0164] The unhomogenized anion exchange resin (CLYM / CLTP / CLVL) (original particle size of 100-200 μm) was evenly dispersed in 50 mL of purified water and magnetically stirred at room temperature. 3 g of diquafosol sodium (API) was added under stirring for adsorption. Stirring was continued at room temperature for 30 min, and finally the volume was adjusted to 100 mL with purified water.

[0165] Determination of API adsorption rate of resin: API was adsorbed with three anion exchange resins at the feed ratios described in Table 1, and the adsorption capacity of the resin for API was determined. The adsorption rate determination results are shown in Table 1:

[0166]

Table 1

[0167]

[0168] The results showed that the adsorption rates of API and resin in prescriptions 1-1 to 1-8 of Example 1 were all above 10%, showing good adsorption performance; when the resin content increased, the adsorption rate of API increased accordingly.

[0169] Example 2: Investigating the API adsorption rate of resins with different particle sizes

[0170] Resin pretreatment: The three anion exchange resins (CLYM / CLTP / CLVL) were homogenized by a high-pressure homogenizer at a certain homogenization pressure to reduce the resin particle size. The results are shown in Table 2:

[0171]

Table 2

[0172]

[0173] Determination of API adsorption rate of resin: According to the same preparation method as in Example 1, the API was adsorbed with three anion exchange resins with different particle sizes at a ratio of 3:1 (w / w), and the adsorption capacity of the resin for API was determined. The adsorption rate determination results are shown in Table 3:

[0174]

Table 3

[0175]

[0176] The results showed that the API adsorption rates of the three anion exchange resins showed strong API adsorption capacity at different particle sizes, and changes in particle size would not affect the API adsorption rate.

[0177] Example 3: Investigation of API adsorption rate of 5 μm resin under different pH conditions

[0178] The three anion exchange resins (CLYM / CLTP / CLVL) were homogenized in the manner of Example 2 to reduce the particle size to about 5 μm. The API was added to the stirred resin suspension at room temperature. After about 30 minutes of adsorption, a suitable pH adjuster (selected from organic acids such as acetic acid, citric acid, lactic acid, boric acid, or alkaline substances such as sodium hydroxide) was added in sufficient amount according to the measured initial pH value to adjust the pH value to about 5, about 6, about 7, or about 8 (see Table 4 for the measured values), and the adsorption rate was measured. The measurement results are detailed in Table 4 and the attached Figure 1 :

[0179]

Table 4

[0180]

[0181]

Table 4

[0182]

[0183]

[0184] Note: QS (quantity sufficient) means appropriate or sufficient quantity.

[0185] The results showed that CLTP and CLVL showed a certain pH-dependent adsorption rate. The adsorption rate decreased under neutral or weak alkaline conditions, but the adsorption rate was greater than 10% under each pH condition measured, which still met the requirements. The API adsorption rate of CLYM did not show pH dependence.

[0186] Example 4: In vitro release test of a formulation without a suspending agent

[0187] Sample preparation: Disperse 1g or 0.3g of anion exchange resin (CLYM / CLTP / CLVL) evenly in 50mL of purified water, homogenize under high pressure, and stir evenly at room temperature; add 3g of API under stirring, continue stirring at room temperature for 30min, adjust the pH value with acetic acid or sodium hydroxide, adjust the osmotic pressure to isotonic level (about 300mOsmol / kg) with appropriate amount of glycerol, and finally dilute to 100mL with purified water. The specific prescription (100mL) and adsorption rate test results are detailed in Table 5:

[0188]

Table 5

[0189]

[0190] The dissolution of formulations 4-1 to 4-5 was determined using a dialysis bag with a molecular weight cutoff of 100 kDa. The results are shown in Table 6 and Appendix. Figure 2-4 :

[0191]

Table 6

[0192]

[0193]

[0194] [1] Chitosan eye drops: Diquafosol eye drops containing chitosan polymer were prepared according to the method of Experiment 1-Eye Drops 1 described in Example 1 of Patent CN111757742 A (see paragraph

[0114] of the specification of CN111757742 A).

[0195] The dissolution of formulations 4-6 was determined using a dialysis bag with a molecular weight cut-off of 50 kDa. The results are shown in Table 7 and Appendix. Figure 5 :

[0196]

Table 7

[0197]

[0198] The results showed that: compared with the diquafosol sodium six-times-a-day eye drops marketed in Japan by Santen Pharmaceutical Eye drops three times a day ( Compared with the chitosan eye drops described in CN111757742A and CN111757742A, the composition of diquafosol sodium adsorbed with anion exchange resin in the present invention exhibits an obvious and excellent sustained release effect. When the feed ratio (w / w) of API to anion exchange resin is 3:1 or 10:1, it shows good dissolution characteristics, and the in vitro release time can reach at least 8-24 hours, which can meet the requirements of long-term retention in the patient's eyes and reducing the number of dosing times.

[0199] Example 5: In vitro release test of a formulation containing a suspending agent

[0200] Sample preparation: 3g of CLTP resin was evenly dispersed in 50mL of purified water, homogenized under high pressure, and stirred evenly under magnetic stirring at room temperature; 9g of API was added under stirring, and stirring was continued at room temperature for 30min. The pH value was adjusted with acetic acid, and the osmotic pressure was adjusted to a hypertonic level (~600mOsmol / kg) with an appropriate amount of glycerol. Finally, the volume was adjusted to 100mL with purified water to prepare a concentrated solution, which was recorded as solution A; 1g of sodium hyaluronate was slowly dispersed in 99g of purified water at room temperature, and stirred until it was completely swollen and dissolved to obtain a 1% (w / w) sodium hyaluronate concentrated solution, which was recorded as solution B; 2g of hydroxypropyl methylcellulose was slowly dispersed in 98g of purified water at room temperature, and stirred until it was completely swollen and dissolved to obtain a 2% (w / w) hydroxypropyl methylcellulose concentrated solution, which was recorded as solution C; 4mL of solution A was taken and added to 12mL of purified water at room temperature, and stirred evenly to obtain prescription 5-1; 4mL of solution A was taken and stirred at room temperature with 6g Mix with liquid B, add purified water to 12mL, and obtain prescription 5-2; take 4mL of liquid A, stir and mix with 6g of liquid C at room temperature, add purified water to 12mL, and obtain prescription 5-3.

[0201] The specific formulation prescription (12mL) and adsorption rate determination results are shown in Table 8:

[0202]

Table 8

[0203]

[0204] The dissolution test results of each prescription are shown in Table 9 and Appendix Figure 6 :

[0205]

Table 9

[0206]

[0207] The results showed that the sustained-release effect of the formulation with suspending agent was significantly better than that of the control formulation ( and LX), which can further delay the release of the drug compared to the formulation without a suspending agent.

[0208] Example 6: Accelerated stability test

[0209] Sample preparation: 3 g of CLTP resin was evenly dispersed in 50 mL of purified water, homogenized under high pressure in the manner of Example 2, and magnetically stirred at room temperature. 9 g of API was added for adsorption under stirring. After continuous stirring at room temperature for 30 min, 0.003 g of preservative benzalkonium chloride was added until completely dissolved. The pH value was adjusted to 6 with acetic acid, and the osmotic pressure was adjusted to a hypertonic level (~600 mOsmol / kg) with an appropriate amount of mannitol. Finally, the volume was adjusted to 100 mL with purified water to prepare a concentrated solution, recorded as solution A; 2 g of hydroxypropyl methylcellulose was slowly dispersed in 98 g of purified water at room temperature and stirred until completely swollen and dissolved to obtain a 2% (w / w) hydroxypropyl methylcellulose concentrated solution, recorded as solution B; 4 mL of solution A was taken and stirred at room temperature and mixed with 6 g of solution B, and purified water was added to 12 mL to obtain prescription 6-1.

[0210] A sufficient amount of the sample of prescription 6-1 was placed in a vial, which was capped and sealed and placed in a 40°C / 75% RH acceleration box to continuously monitor the changes in the API adsorption rate.

[0211] The specific formulation prescription (12mL) is shown in Table 10:

[0212]

Table 10

[0213]

[0214]

[0215] The adsorption rate stability test results are shown in Table 11 and Appendix Figure 7 :

[0216]

Table 11

[0217] prescription Day 0 7 days 14 days January 6-1 40.08％ 40.30％ 38.50％ 40.20％

[0218] The results showed that under the accelerated conditions of 40℃ / 75%RH, the API adsorption rate was relatively stable when the API resin preparation was stored for 0 days, 7 days, 14 days and 1 month.

Claims

1. A diquafosol resin composition, characterized in that It includes diquafosol or a pharmaceutically acceptable salt thereof, an anion exchange resin and water; The mass ratio (w / w) of the diquafosol or its pharmaceutically acceptable salt to the anion exchange resin is 10:1-1:

10.

2. The diquafosol resin composition according to claim 1, wherein It meets one or more of the following conditions: (1) The diquafosol or its pharmaceutically acceptable salt is diquafosol sodium salt; (2) The water is purified water; (3) The anion exchange resin is a strongly basic anion exchange resin or a weakly basic anion exchange resin; (4) The diquafosol resin composition is composed of diquafosol or a pharmaceutically acceptable salt thereof, anion exchange resin and water.

3. The diquafosol resin composition according to claim 2, characterized in that It meets one or both of the following conditions: (1) The diquafosol or its pharmaceutically acceptable salt is diquafosol tetrasodium salt; (2) The anion exchange resin is one or more of cholestyramine, colestipol or colesevelam.

4. The diquafosol resin composition according to claim 3, characterized in that The anion exchange resin is colestipol.

5. The diquafosol resin composition according to any one of claims 1 to 4, characterized in that It meets one or more of the following conditions: (1) The mass concentration of diquafosol or its pharmaceutically acceptable salt is 0.01-0.1 g / mL; (2) The mass ratio (w / w) of the diquafosol or its pharmaceutically acceptable salt to the anion exchange resin is 9:1-1:1; (3) The particle size of the anion exchange resin is 1-200 μm; (4) The adsorption rate of diquafosol or its pharmaceutically acceptable salt is 1% to 100%.

6. The diquafosol resin composition according to claim 5, characterized in that The mass ratio (w / w) of the diquafosol or its pharmaceutically acceptable salt to the anion exchange resin is 8:1-1:

1.

7. The diquafosol resin composition according to claim 6, characterized in that The mass ratio (w / w) of the diquafosol or its pharmaceutically acceptable salt to the anion exchange resin is 7:1-1:

1.

8. The diquafosol resin composition according to claim 7, characterized in that The mass ratio (w / w) of the diquafosol or its pharmaceutically acceptable salt to the anion exchange resin is 6:1-1:

1.

9. The diquafosol resin composition according to claim 8, characterized in that The mass ratio (w / w) of the diquafosol or its pharmaceutically acceptable salt to the anion exchange resin is 5:1-1:

1.

10. The diquafosol resin composition according to claim 9, characterized in that The mass ratio (w / w) of the diquafosol or its pharmaceutically acceptable salt to the anion exchange resin is 4:1-1:

1.

11. The diquafosol resin composition according to claim 10, characterized in that The mass ratio (w / w) of the diquafosol or its pharmaceutically acceptable salt to the anion exchange resin is 3:1-1:

1.

12. The diquafosol resin composition according to claim 11, characterized in that The mass ratio (w / w) of the diquafosol or its pharmaceutically acceptable salt to the anion exchange resin is 2:1-1:

1.

13. The diquafosol resin composition according to claim 5, characterized in that It meets one or more of the following conditions: (1) The mass concentration of diquafosol or its pharmaceutically acceptable salt is 0.01-0.08 g / mL; (2) The mass ratio (w / w) of the diquafosol or its pharmaceutically acceptable salt to the anion exchange resin is 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1; (3) The particle size of the anion exchange resin is selected from one or more of 1≤D90≤5μm, 5<D90≤10μm, 10<D90≤15μm, 15<D90≤20μm, 20<D90≤25μm, 25<D90≤30μm, 30<D90≤35μm, 35<D90≤40μm, 40<D90≤45μm and 45<D90≤50μm.

14. The diquafosol resin composition according to claim 13, characterized in that It meets one or both of the following conditions: (1) The mass concentration of diquafosol or its pharmaceutically acceptable salt is 0.02-0.05 g / mL; (2) The particle size of the anion exchange resin is selected from one or more of 1≤D90≤5μm, 5<D90≤10μm, 10<D90≤15μm, 15<D90≤20μm, 20<D90≤25μm or 25<D90≤30μm.

15. The diquafosol resin composition according to claim 14, characterized in that The mass concentration of diquafosol or its pharmaceutically acceptable salt is 0.03 g / mL.

16. The diquafosol resin composition according to claim 1, characterized in that The diquafosol resin composition comprises diquafosol or a pharmaceutically acceptable salt thereof, an anion exchange resin and water. The mass concentration of the diquafosol or a pharmaceutically acceptable salt thereof is 0.01-0.1 g / mL, and the mass ratio of the diquafosol or a pharmaceutically acceptable salt thereof to the anion exchange resin is 10:1-1:

10.

17. The diquafosol resin composition according to claim 16, characterized in that It is one of the following options: Scheme A: The diquafosol resin composition is composed of diquafosol sodium, colesevelam and water, the mass concentration of the diquafosol sodium is 0.01-0.1 g / mL; the mass ratio of the diquafosol sodium to the colesevelam is 10:1-1:1; Scheme B: The diquafosol resin composition is composed of diquafosol sodium, cholestyramine and water, the mass concentration of the diquafosol sodium is 0.01-0.1 g / mL; the mass ratio of the diquafosol sodium to the cholestyramine is 8:1-1:3; Scheme C: The diquafosol resin composition consists of diquafosol sodium, colestipol and water, the mass concentration of the diquafosol sodium is 0.01-0.1 g / mL; the mass ratio of the diquafosol sodium to the colestipol is 10:1-1:

1.

18. The diquafosol resin composition according to claim 17, characterized in that The scheme A satisfies one of the following conditions: (1) The mass concentration of diquafosol sodium is 0.03 g / mL; (2) The mass ratio of diquafosol sodium to colesevelam is 6:1-3:1; (3) The colesevelam has a particle size of 1-200 μm; (4) The adsorption rate of diquafosol sodium is 10% to 100%.

19. The diquafosol resin composition according to claim 18, characterized in that The scheme A satisfies one of the following conditions: (1) The mass ratio of diquafosol sodium to colesevelam is 6:1, 5:1, 4:1 or 3:1; (2) The colesevelam has a particle size of 1-50 μm; (3) The adsorption rate of diquafosol sodium is 10% to 40%.

20. The diquafosol resin composition according to claim 19, characterized in that The scheme A satisfies one of the following conditions: (1) The mass ratio of diquafosol sodium to colesevelam is 6:1 or 3:1; (2) The colesevelam has a particle size of 1-30 μm; (3) The adsorption rate of diquafosol sodium is 10% to 20% or 30% to 40%.

21. The diquafosol resin composition according to claim 20, characterized in that In the scheme A, the particle size of colesevelam is 1-20 μm.

22. The diquafosol resin composition according to claim 21, characterized in that In the scheme A, the particle size of colesevelam is 1≤D90≤5μm, 5<D90≤10μm, 10<D90≤15μm or 15<D90≤20μm.

23. The diquafosol resin composition according to claim 17, characterized in that The scheme B satisfies one of the following conditions: (1) The mass concentration of diquafosol sodium is 0.03 g / mL; (2) The mass ratio of diquafosol sodium to cholestyramine is 3:1-1:3; (3) The particle size of the cholestyramine is 1-200 μm; (4) The adsorption rate of diquafosol sodium is 10%-100%.

24. The diquafosol resin composition according to claim 23, characterized in that The scheme B satisfies one of the following conditions: (1) The mass ratio of diquafosol sodium to cholestyramine is 3:1, 2:1, 1:1, 1:2 or 1:3; (2) The particle size of the cholestyramine is 1-50 μm; (3) The adsorption rate of diquafosol sodium is 20%-100%.

25. The diquafosol resin composition according to claim 23, characterized in that The scheme B satisfies one of the following conditions: (1) The mass ratio of diquafosol sodium to cholestyramine is 3:1-1:1; (2) The particle size of the cholestyramine is 1-30 μm; (3) The adsorption rate of diquafosol sodium is 20%-30%, 70%-80% or 90%-100%.

26. The diquafosol resin composition according to claim 25, characterized in that The scheme B satisfies one of the following conditions: (1) The mass ratio of diquafosol sodium to cholestyramine is 3:1, 2:1 or 1:1; (2) The particle size of the cholestyramine is 1≤D90≤5μm, 5<D90≤10μm, 10<D90≤15μm, 15<D90≤20μm, 20<D90≤25μm or 25<D90≤30μm.

27. The diquafosol resin composition according to claim 26, characterized in that In the scheme B, the mass ratio of the diquafosol sodium to the cholestyramine is 3:

1.

28. The diquafosol resin composition according to claim 17, wherein The scheme C meets one of the following conditions: (1) The mass concentration of diquafosol sodium is 0.03 g / mL; (2) The mass ratio of diquafosol sodium to colestipol is 10:1-3:1; (3) The colestipol has a particle size of 1-200 μm; (4) The adsorption rate of diquafosol sodium is 10% to 100%.

29. The diquafosol resin composition according to claim 28, characterized in that The scheme C meets one of the following conditions: (1) The mass ratio of diquafosol sodium to colestipol is 10:1 or 3:1; (2) The colestipol has a particle size of 1-50 μm; (3) The adsorption rate of diquafosol sodium is 10%-50%.

30. The diquafosol resin composition according to claim 29, wherein The scheme C meets one of the following conditions: (1) The mass ratio of diquafosol sodium to colestipol is 3:1; (2) The colestipol has a particle size of 1-30 μm; (3) The adsorption rate of diquafosol sodium is 35%-50%.

31. The diquafosol resin composition according to claim 30, wherein The particle size of colestipol is 1-25 μm.

32. The diquafosol resin composition according to claim 31, wherein The particle size of colestipol is 1≤D90≤5μm, 5<D90≤10μm, 10<D90≤15μm, 15<D90≤20μm or 20<D90≤25μm.

33. A diquafosol preparation, characterized in that: It includes the diquafosol resin composition as described in any one of claims 1 to 32; the diquafosol preparation also includes a pharmaceutically acceptable excipient, and the pharmaceutically acceptable excipient is one or more of a suspending agent, a viscosity increasing agent, a solubilizing agent, a mucosal adhesive, a pH adjusting agent, an osmotic pressure adjusting agent, a preservative or a chelating agent.

34. The diquafosol preparation according to claim 33, characterized in that It satisfies one or more of the following conditions: (1) The diquafosol resin composition is one or more of a diquafosol sodium-colestipol composition, a diquafosol sodium-colesevelam composition or a diquafosol sodium-cholestyramine composition; (2) The pH of the diquafosol preparation is 4.5 ≤ pH ≤ 9; (3) The osmotic pressure of the diquafosol preparation is 250-350 mOsmol / kg; (4) In the diquafosol preparation, the pharmaceutically acceptable excipient is selected from one or more of a pH regulator, an osmotic pressure regulator and a suspending agent.

35. The diquafosol preparation according to claim 34, characterized in that The pH of the diquafosol preparation is 5≤pH≤9.

36. The diquafosol preparation according to claim 35, characterized in that The pH of the diquafosol preparation is 5≤pH≤8.

37. The diquafosol preparation according to claim 36, characterized in that The pH of the diquafosol preparation is 5≤pH≤7.

38. The diquafosol preparation according to claim 37, characterized in that The pH of the diquafosol preparation is 5≤pH≤6.

39. The diquafosol preparation according to claim 34, characterized in that The pH of the diquafosol preparation is 7≤pH≤8.

40. The diquafosol preparation according to claim 34, characterized in that The pH of the diquafosol preparation is 8≤pH≤9.

41. The diquafosol preparation according to claim 34, characterized in that The pH of the diquafosol preparation is 7≤pH≤9.

42. The diquafosol formulation of claim 34, wherein The pH of the diquafosol preparation is 6≤pH≤7.

43. The diquafosol preparation according to claim 34, characterized in that It satisfies one or more of the following conditions: (1) The diquafosol resin composition is a diquafosol sodium-colestipol composition; (2) The osmotic pressure of the diquafosol preparation is 280-310 mOsmol / kg; (3) The pH of the diquafosol preparation is 5≤pH≤8.

44. The diquafosol preparation according to claim 43, characterized in that It satisfies one or more of the following conditions: (1) The osmotic pressure of the diquafosol preparation is 280≤π<290mOsmol / kg, 290≤π<300mOsmol / kg or 300≤π≤310mOsmol / kg; (2) The pH of the diquafosol preparation is 6≤pH≤7.

45. The diquafosol formulation according to claim 33, characterized in that The invention comprises the diquafosol resin composition as claimed in claim 1 and the pH regulator, wherein the pH regulator is an acid, a base or a buffer salt, the mass concentration of the diquafosol or a pharmaceutically acceptable salt thereof is 0.01-0.1 g / mL, the mass ratio of the diquafosol or a pharmaceutically acceptable salt thereof to the anion exchange resin is 10:1-1:1, the adsorption rate of the diquafosol or a pharmaceutically acceptable salt thereof is 10%-100%, the pH of the diquafosol preparation is 4.5≤pH≤9, and the particle size of the anion exchange resin is 1-30 μm.

46. ​​The diquafosol formulation according to claim 45, characterized in that The diquafosol preparation is composed of the diquafosol sodium-colestipol composition and the pH regulator, the pH regulator is acetic acid, the diquafosol sodium-colestipol composition is composed of the diquafosol sodium, the colestipol and the water, the mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the colestipol is 3:1, the particle size of the colestipol is 1-30 μm, the pH of the diquafosol preparation is 5≤pH≤8, and the adsorption rate of the diquafosol sodium is 20%~50%; Or, the diquafosol preparation is composed of the diquafosol sodium-colesevelam composition and the pH regulator, the pH regulator is sodium hydroxide, the diquafosol sodium-colesevelam composition is composed of the diquafosol sodium, the colesevelam and the water, the mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the colesevelam is 3:1, the particle size of the colesevelam is 1-30 μm, the pH of the diquafosol preparation is 5≤pH≤8, and the adsorption rate of the diquafosol sodium is 10%~40%; Or, the diquafosol preparation is composed of the diquafosol sodium-cholestyramine composition and the pH regulator, the pH regulator is acetic acid or sodium hydroxide, the diquafosol sodium-cholestyramine composition is composed of the diquafosol sodium, the cholestyramine and the water, the mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the cholestyramine is 3:1, the particle size of the cholestyramine is 1-30 μm, the pH of the diquafosol preparation is 5≤pH≤8, and the adsorption rate of the diquafosol sodium is 20%~30%.

47. The diquafosol formulation of claim 45, wherein It also includes an osmotic pressure regulator, which is glycerol and / or mannitol. The osmotic pressure of the diquafosol preparation is 250-350 mOsmol / kg.

48. The diquafosol formulation according to claim 47, characterized in that The diquafosol preparation is composed of the diquafosol sodium-colestipol composition, the pH regulator and the osmotic pressure regulator. The diquafosol sodium-colestipol composition is composed of the diquafosol sodium, the colestipol and the water. The mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the colestipol is 3:1, and the particle size of the colestipol is 1-30 μm. The pH of the diquafosol preparation is 6≤pH≤7; the osmotic pressure of the diquafosol preparation is 250-350 mOsmol / kg, and the adsorption rate of the diquafosol sodium is 30%-50%. Or, the diquafosol preparation is composed of the diquafosol sodium-colestipol composition, the pH regulator and the osmotic pressure regulator, the diquafosol sodium-colestipol composition is composed of the diquafosol sodium, the colestipol and the water, the mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the colestipol is 10:1, and the particle size of the colestipol is 1-30 μm; the pH of the diquafosol preparation is 6≤pH≤7; the osmotic pressure of the diquafosol preparation is 250-350 mOsmol / kg, and the adsorption rate of the diquafosol sodium is 10%-40%; Or, the diquafosol preparation is composed of the diquafosol sodium-colesevelam composition, the pH regulator and the osmotic pressure regulator, the diquafosol sodium-colesevelam composition is composed of the diquafosol sodium, the colesevelam and the water, the mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the colesevelam is 3:1, and the particle size of the colesevelam is 1-30 μm; the pH of the diquafosol preparation is 6≤pH≤7; the osmotic pressure of the diquafosol preparation is 250-350 mOsmol / kg, and the adsorption rate of the diquafosol sodium is 30%-50%; Or, the diquafosol preparation is composed of the diquafosol sodium-cholestyramine composition, the pH regulator and the osmotic pressure regulator, the diquafosol sodium-cholestyramine composition is composed of the diquafosol sodium, the cholestyramine and the water, the mass concentration of the diquafosol sodium is 0.03g / mL, the mass ratio of the diquafosol sodium to the cholestyramine is 3:1, and the particle size of the cholestyramine is 1-30μm; the pH of the diquafosol preparation is 6≤pH≤7; the osmotic pressure of the diquafosol preparation is 250-350mOsmol / kg, and the adsorption rate of the diquafosol sodium is 20%-50%.

49. The diquafosol formulation according to claim 47, wherein The invention also comprises a suspending agent, which is hydroxypropylmethylcellulose and / or sodium hyaluronate, and the mass concentration of the suspending agent is 0.001-0.02 g / mL.

50. The diquafosol formulation according to claim 49, wherein The mass concentration of the suspending agent is 0.005-0.01 g / mL.

51. The diquafosol preparation according to claim 50, characterized in that The mass concentration of the suspending agent is 0.005 g / mL or 0.01 g / mL.

52. The diquafosol formulation of claim 49, wherein The diquafosol preparation is composed of the diquafosol sodium-colestipol composition, the pH regulator, the osmotic pressure regulator and the suspending agent, wherein the pH regulator is acetic acid, the osmotic pressure regulator is glycerol or mannitol, the suspending agent is hydroxypropyl methylcellulose or sodium hyaluronate, the diquafosol sodium-colestipol composition is composed of the diquafosol sodium, the colestipol and the water, the mass concentration of the diquafosol sodium is 0.03 g / mL, the mass ratio of the diquafosol sodium to the colestipol is 3:1, the mass concentration of the suspending agent is 0.001-0.02 g / mL, and the particle size of the colestipol is 1-30 μm; the pH of the diquafosol preparation is 6≤pH≤7; the osmotic pressure of the diquafosol preparation is 250-350 mOsmol / kg, and the adsorption rate of the diquafosol sodium is 30%-50%.

53. The diquafosol formulation of claim 49, wherein The invention also comprises a preservative, wherein the preservative is selected from one or more of polyquaternium-1, chlorhexidine glucose or benzalkonium chloride; and the mass concentration of the preservative is 0.000001-0.0001 g / mL.

54. The diquafosol preparation according to claim 53, characterized in that It satisfies one or more of the following conditions: (1) The preservative is benzalkonium chloride; (2) The mass concentration of the preservative is 0.00001 g / mL.

55. The diquafosol formulation of claim 53, wherein The diquafosol preparation consists of the diquafosol resin composition, the pH regulator, the osmotic pressure regulator, the suspending agent and the preservative.

56. Use of the diquafosol resin composition according to any one of claims 1 to 32 or the diquafosol preparation according to any one of claims 33 to 55 in the preparation of a medicament for preventing, alleviating and / or treating eye diseases.

57. The use according to claim 56, characterized in that The eye disease is dry eye.

58. The use according to claim 57, characterized in that The dry eye disease is tear reduction, tear deficiency, dry eyes, Sjögren's syndrome, keratoconjunctivitis sicca, allergic keratoconjunctivitis sicca, vernal keratoconjunctivitis, pemphigoid eye, marginal blepharitis, inability to close the eyelids or sensory nerve numbness, as well as dry eyes associated with allergic conjunctivitis, dry eyes after viral conjunctivitis, dry eyes after corneal surgery, dry eyes after secondary cataract surgery or dry eyes associated with contact lenses.

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