Regorafenib in-situ gel preparation for treating ocular neovascular diseases

Abstract

The invention provides a regorafenib in-situ gel preparation for treating ocular neovascular diseases. The regorafenib in-situ gel preparation comprises regorafenib, a surfactant and an ion-sensitive in-situ gel material. According to the in-situ gel preparation disclosed by the invention, an in-situ gel preparation technology is combined with a particle drug carrier technology, and small molecules TKI are uniformly dispersed in an in-situ gel delivery carrier in the form of suspension particles by using suspension in-situ gel, or the small molecules TKI are encapsulated into nano-micelles and then dispersed in the in-situ gel delivery carrier, so that the in-situ gel preparation is prepared. The prepared particle in-situ gel ophthalmic preparation containing the micromolecule TKI is small in particle size, moderate in viscosity, stable in quality and free of irritation, and after the preparation is administrated in an eye drop mode, the eye tissue concentration and bioavailability of the preparation can be further remarkably improved, so that the intraocular curative effect of the preparation is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of medicines, and in particular to a regorafenib in situ gel preparation for treating ocular neovascularization diseases. Background Art

[0002] The eyeball is a closed structure. Once inflammation, trauma, infection or vascular disease occurs in important eye tissues such as the cornea, conjunctiva, iris, retina, choroid and optic nerve, it is easy to cause ocular neovascularization (NV). Among them, blinding diseases such as corneal neovascularization, neovascular glaucoma and choroidal neovascularization are particularly serious, and are also representative diseases of neovascularization located in the front, middle and posterior segments of the eye.

[0003] The abnormal growth of corneal neovascularization (CoNV) and increased vascular permeability can cause serious damage to the cornea and surrounding tissues and permanent vision loss. The global incidence of CoNV disease is as high as 4.1% to 10.4%, and the blindness rate of patients is 12% to 57.4%. Choroidal neovascularization (CNV) is mainly caused by insufficient blood supply to the choroidal capillaries. There are nearly 400 million patients worldwide, including diabetic retinopathy, macular edema, and age-related macular degeneration. Neovascular glaucoma (NVG) is a secondary glaucoma mainly caused by retinal vascular lesions. It has an acute onset and a blindness rate of up to 92.4%. Patients are extremely painful and the treatment is quite difficult.

[0004] Ocular neovascularization disease progresses rapidly, has a high blindness rate, and is seriously harmful. It is mainly caused by the imbalance between angiogenesis-promoting factors and angiogenesis-inhibiting factors. Vascular endothelial growth factor (VEGF) is one of the key regulators of angiogenesis. Although anti-VEGF drugs such as aflibercept and bevacizumab can treat ocular NV, repeated intraocular injections can cause physical and psychological trauma to patients. If it is administered by eye drops, it is large in size and highly polar, making it difficult to penetrate the cell membrane and inefficient. These defects affect the efficacy of biomolecules and limit their clinical research.

[0005] In contrast, most small-molecule tyrosine kinase inhibitors (TKIs) are highly lipophilic and can cross cell membranes to target and inhibit VEGF receptors VEGFR1, VEGFR2, VEGFR3, and multiple kinases (TIE-2, RAF1, EGFR, PDGFR, and FGFR, etc.), block downstream signal transduction, and work alone or together to control the growth of new blood vessels, the formation of the interstitial microenvironment, and disease progression. Many TKIs have good biological activity and selectivity for multiple tyrosine kinases and have been marketed for the treatment of cancer, so they may have great potential for the treatment of ocular NV diseases. The cornea, anterior chamber, iris, choroid, retina, optic nerve, etc. are the main sites of ocular NV and are also anatomical barriers to drug delivery. Blinking, tear renewal, nasolacrimal duct excretion, etc. cause a large amount of drug loss, so drugs must overcome these barriers to reach the lesions and take effect.

[0006] In the drug development of ocular NV diseases, many small molecule TKI drugs have made some progress, but there are still no marketed products. According to the method of administration, (1) intraocular injection of implants or suspensions such as axitinib, voronib, AR-13503, lenvatinib, and linifanib, which diffuse and metabolize quickly in the eye, is difficult to achieve the expected CNV efficacy. NVG still relies on intraocular injection of ranibizumab, aflibercept, etc. for treatment. (2) Eye drops are very convenient. The 0.5% pazopanib eye drops intended to treat CoNV have not made any progress since 2012, and KDR2-2 is still in Phase II clinical trials; 0.05% sunitinib or sorafenib, 0.1% regorafenib eye drops can effectively reduce CoNV in rat models; laquinimod, LHA510, regorafenib and other eye drops have poor efficacy on CNV, and 1.0% PAN90806 eye drops are still being promoted. Although eye drops are the most ideal route of administration for small molecule TKIs, their solubility, intraocular penetration and retention are key factors affecting their intraocular efficacy.

[0007] There have been many studies on small molecule TKI ocular delivery systems, but few have achieved significant results. Common solubilization methods include cyclodextrin inclusion compounds. PAN-90806 eye drops are made using hydroxypropyl-β-cyclodextrin and have completed Phase II clinical trials for the treatment of wet age-related macular degeneration; γ-cyclodextrin did not significantly improve the solubility of axitinib, regorafenib, motesanib, and pazopanib. Suspensions can disperse more drugs, and PAN-90806 suspension eye drops is one of them. The 2-3% regorafenib non-aqueous oily suspension eye drops prepared by invention WO2018 / 052053 have a concentration in the fundus of rabbits and monkeys lower than IC 50But it is ineffective; Regorafenib nanocrystals with a particle size of 97nm to 234nm can improve fundus distribution, but the dose is limited to 0.17% to 0.21%, and there are problems such as dispersibility, crystal transformation, and dissolution. Invention CN116251186A uses non-ionic surfactants and solubilizers to make 0.039% axitinib micelles with a concentration of 0.98 to 1.66ng / g in the rabbit fundus at 0.5h, and single-point eye tissue data is difficult to prove its effectiveness. Invention CN117598989A prepared 0.2% nintedanib emulsion eye drops in the rabbit cornea and conjunctiva reached 763ng / g to 1142ng / g, and its particle size and more intraocular distribution and pharmacokinetic behavior have not been disclosed. These drug delivery systems have been improved in terms of solubility, particle size, dosage, etc., but no response plans have been proposed for barriers such as eye membrane penetration performance and tear wash.

[0008] It can be seen that there are still many difficulties and pain points in the development of small molecule TKI ophthalmic preparations for the treatment of ocular neovascular diseases: (1) How to improve the selection of ophthalmic excipients and the stability of microparticle eye drops; (2) How to improve the solubility of small molecule TKIs and reduce the particle size of microparticles; (3) How to improve the permeability of the eye membrane; (4) How to reduce the impact of blinking and tear wash on its bioavailability. Therefore, selecting a suitable eye drop delivery system and improving the permeability of the eye membrane and ocular bioavailability are the key points in the development of small molecule TKI ophthalmic preparations. Summary of the invention

[0009] In view of the background technology, the inventors used the critical micelle concentration (CMC) value, an essential property of surfactants in forming micelles, as the theoretical basis for screening surfactant compositions, examined the solubility of small molecule TKIs therein, selected compositions with low CMC values, appropriate usage amounts and good solubilization effects, and then added viscosity-increasing matrices to prolong the intraocular retention time of the drug, and developed ophthalmic preparations that can improve the eye membrane permeability and intraocular exposure of small molecule TKIs.

[0010] The technical solution adopted by the present invention is:

[0011] A regorafenib in situ gel preparation for treating ocular neovascularization diseases, comprising regorafenib, a surfactant and an ion-sensitive in situ gel material.

[0012] Since a single surfactant cannot significantly increase the solubility of regorafenib and cediranib, and the solubility is closely related to the amount of surfactant used and the CMC value, the amount of many surfactants used in ophthalmic preparations does not exceed 5.0%, and their CMC values ​​are also very different. Therefore, the inventors designed and investigated a multi-surfactant composition, whose CMC value is lower than that of a single surfactant, and the quaternary combination and quinary combination are less than the ternary combination and less than the binary combination; there is an opposite trend for the solubility of regorafenib, which has never been mentioned in any published reports. For example, the lowest CMC value in the quaternary surfactant composition described in the present invention is 2.39μg / mL, and the solubility of regorafenib is also higher and more stable, which is better than each group of binary and ternary compositions. This is unexpected and has great value for the development of micellar formulations.

[0013] The particle size of the regorafenib nano-micelles is less than 20 nm, which is much smaller than the particle size of the regorafenib oily suspension (4.6-6.4 μm) and the regorafenib nanocrystals (97-234 nm) (invention US010894043B2).

[0014] The in situ gel preparation of the present invention further comprises one or more ion-sensitive in situ gel materials to increase the viscosity of the preparation. For example, deacetyl gellan gum (DGG, ) is a special gel matrix with good compatibility with the human body. After administration through eye drops, DGG and electrolytes (Na + , K + and Ca 2+ After the action of the eye drops, it can change from a liquid to a more viscous gel. Its viscosity is 10 to 20 times that of ordinary micelle solutions. It can withstand the shear force of blinking and enhance the ocular retention of small molecule TKIs, allowing the drug to be released slowly to increase bioavailability, reduce systemic absorption, reduce the frequency of medication, and thus improve patient compliance. This is also an important formulation technology to resist the physiological barrier of the eye.

[0015] The nano-micelle in-situ gel ophthalmic preparation for treating ocular neovascularization diseases provided by the present invention comprises small molecule TKI, surfactant, high molecular polymer, water for injection, osmotic pressure regulator, pH regulator, pH buffer, and / or gelling agent, and / or gelling regulator.

[0016] The nanomicelle in situ gel ophthalmic preparation for treating ocular neovascularization diseases of the present invention, wherein the small molecule TKI may be regorafenib, wherein regorafenib may be included in the preparation at a concentration of 0.01% w / w to 6.0% w / w suitable for the intended use.

[0017] The nanomicelle in situ gel ophthalmic preparation for treating ocular neovascularization diseases of the present invention, the osmotic pressure regulator includes mannitol, glucose, sorbitol, glycerol, polyethylene glycol, polypropylene glycol, propylene glycol or any combination thereof, which can be contained in the preparation at a concentration of 0.01% w / w to 10.0% w / w, and the osmotic pressure of the preparation can be 270mOsmol / kg to 400mOsmol / kg.

[0018] The nano-micelle in situ gel ophthalmic preparation for treating ocular neovascularization diseases of the present invention comprises a pH regulator including tromethamine, sodium hydroxide, hydrochloric acid, citric acid, boric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and all forms containing crystalline water or any combination thereof, which can be included in the preparation at a concentration of 0.01% w / w to 2.0% w / w, and the pH of the preparation is between 5.0 and 8.0.

[0019] The nano-micelle in situ gel ophthalmic preparation for treating ocular neovascularization diseases of the present invention comprises a pH buffer of sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium citrate, citric acid, sodium borate, boric acid and all its crystalline water-containing forms or any combination thereof, which can be included in the preparation at a concentration of 0.01% w / w and 2.0% w / w.

[0020] The nano-micelle in-situ gel ophthalmic preparation for treating ocular neovascularization diseases of the present invention comprises a gel regulator which is a compound containing monovalent or divalent cations, including sodium chloride, potassium chloride, zirconium chloride, magnesium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and all forms containing crystal water or any combination thereof, which can be included in the preparation at a concentration of 0.01% w / w to 2.0% w / w. Preferably, any combination of sodium dihydrogen phosphate and disodium hydrogen phosphate is included in the preparation at a concentration of 0.1% w / w to 0.5% w / w.

[0021] The nano-micelle in-situ gel ophthalmic preparation for treating ocular neovascularization diseases of the present invention comprises a gelling agent including deacetyl gellan gum, gellan gum, xanthan gum, carrageenan, guar gum, poloxamer, sodium alginate, polyvinyl alcohol, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose or any combination thereof, which can be included in the preparation at a concentration of 0.05% w / w to 5.0% w / w. Deacetyl gellan gum is preferably included in the preparation at a concentration of 0.1% w / w to 0.6% w / w.

[0022] At the same time, the inventors also constructed an in-situ gel ophthalmic preparation containing regorafenib suspension, in which the selected surfactant is polysorbate 80, and its concentration can be 0.02% w / w to 6.0% w / w; the selected suspending stabilizer composition includes glycerol, polyvinyl alcohol and hydroxypropyl methylcellulose, wherein the concentration of a single suspending stabilizer can be 0.02% w / w to 6.0% w / w; in this system, the regorafenib content can be 0.01-6.0%.

[0023] The inventors were surprised to find that the regorafenib suspension in situ gel ophthalmic preparation is a suspension system that is uniformly dispersed and can withstand hot pressure sterilization, and has in situ gel characteristics; its exposure in rabbit eyes is significantly better than that of the 3% regorafenib oily suspension, mainly due to smaller suspension particles, stabilizer-promoted penetration and in situ gel retention effect, which indicates that in situ gel also helps suspension eye drops improve drug bioavailability.

[0024] The inventors conducted a rabbit ocular tissue distribution test on the regorafenib nano-micelle in situ gel preparation, the regorafenib suspension in situ gel ophthalmic preparation, and the 3% regorafenib non-aqueous oily suspension eye drops published in the invention WO2018 / 052053. The inventors found that the ocular penetration ability of the regorafenib suspension in situ gel ophthalmic preparation was better than that of the 3.0% regorafenib non-aqueous oily suspension. At the same time, a surprising discovery was that the ocular penetration ability of the nano-micelle in situ gel ophthalmic preparation of the present invention was significantly better than that of the 3.0% regorafenib non-aqueous oily suspension. The regorafenib dose in the test was 0.06%, which was only 1 / 50 of the 3.0% regorafenib oily suspension, indicating that the nano-micelle delivery system with a low CMC value can provide more free regorafenib, thereby significantly increasing its eye membrane penetration. The main reason is that the nanomicelle particle size is smaller and it is easier to penetrate the ocular barrier. At the same time, it is creatively combined with the in situ gel technology to increase the retention time in the eye. Therefore, the nanomicelle in situ gel preparation significantly improves the bioavailability of small molecule TKI, truly achieving the effect of low dose and good efficacy.

[0025] Compared with the prior art, the present invention has the following advantages:

[0026] The present invention provides a regorafenib in situ gel ophthalmic preparation for treating ocular neovascular diseases. The in situ gel preparation technology is used in combination with microparticle drug carrier technology. The small molecule TKI is uniformly dispersed in the in situ gel delivery carrier as suspended particles using a suspended in situ gel, or the small molecule TKI is loaded into nanomicelles and then dispersed in the in situ gel delivery carrier. The prepared microparticle in situ gel ophthalmic preparation containing small molecule TKI has a small particle size, moderate viscosity, stable quality, and no irritation. After administration in the form of eye drops, it can further significantly increase the ocular tissue concentration and bioavailability of the drug, thereby increasing its intraocular efficacy. The advantages of the suspended in situ gel and nanomicelle in situ gel ophthalmic preparations taking the small molecule TKI regorafenib as an example are summarized as follows:

[0027] (1) For regorafenib suspension in situ gel

[0028] The surfactant used in the preparation has a certain solubilizing effect on regorafenib, while reducing the interfacial tension between the suspended particles and the aqueous medium, thereby weakening the aggregation of particles.

[0029] The surfactant and suspending stabilizer composition used forms an aqueous suspension dispersion system that can achieve uniform particle size, good dispersibility and can withstand hot pressure sterilization, while the suspension system without high molecular weight polymer HPMC and only surfactant has particles that are agglomerated and uneven after high temperature sterilization, and the particle size increases by 5 to 6 times; the average particle sizes D90 and D50 of the preparation are 3 to 4 μm and 1 to 2 μm, respectively, which are smaller than those of the non-aqueous oily suspension of regorafenib (D50: 4.6 to 6.4 μm).

[0030] In addition to increasing viscosity, the DGG used in the in situ gelation technology has pseudoplasticity that allows the preparation to be converted into a semisolid gel when left standing for a long time, which significantly slows down the sedimentation of particles, making it difficult for suspended particles to aggregate or harden, which is different from the rapid precipitation and aggregation of regorafenib's non-aqueous oily suspension.

[0031] At the same dose of 3.0%, the exposure of regorafenib in the preparation in the rabbit cornea, aqueous humor and sclera was significantly higher than that of the non-aqueous oily suspension of regorafenib; the suspension in situ gel significantly improved the ocular bioavailability of regorafenib.

[0032] (2) For regorafenib nanomicelle in situ gel

[0033] The critical micelle concentration of the surfactant composition used in the preparation is as low as 5.09 μg / ml, and the regorafenib concentration is stable at around 0.6 mg / ml.

[0034] The average particle size of the preparation can reach below 20 nm, which is much smaller than the reported regorafenib oily suspension and nanocrystalline eye drops. The viscosity is 10 to 20 times that of ordinary micellar eye drops, which can improve the static and dynamic barriers of the eye, which is difficult to achieve with many other preparation technologies;

[0035] The preparation has stronger eye tissue penetration and absorption. Its exposure in the rabbit cornea, aqueous humor and sclera is comparable to that of the 3% regorafenib suspension in situ gel with micron-sized particles (there is no significant statistical difference between the two). Although the regorafenib content is only 0.06%, the more than 150-fold reduction in particle size fully enhances the eye membrane penetration ability and absorption efficiency of regorafenib.

[0036] A low dose of 0.06% regorafenib achieved greater exposure in the rabbit cornea, aqueous humor and sclera, which was significantly higher than the 3% regorafenib non-aqueous oily suspension; low-concentration regorafenib can achieve higher bioavailability, thereby reducing the input of large amounts of regorafenib raw materials, reducing the risk of side effects, increasing patient comfort, and avoiding transient blurring caused by suspended particles after eye drops. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 It is the Na of regorafenib nanomicelle in situ gel ophthalmic preparation + Concentration and viscosity investigation results diagram;

[0038] Figure 2 is the Na of regorafenib suspension in situ gel ophthalmic preparation + Concentration and viscosity investigation results diagram;

[0039] Figure 3 is the regorafenib concentration-time curve of samples A26, B23 and C1 in rabbit cornea;

[0040] Figure 4 is the regorafenib concentration-time curve of samples A26, B23 and C1 in rabbit aqueous humor;

[0041] Figure 5 The graph is a concentration-time curve of regorafenib in the sclera of rabbit eyes for samples A26, B23 and C1. DETAILED DESCRIPTION

[0042] Example 1: Solubility of Regorafenib and Cediranib in Ophthalmic Surfactants and Excipient Solvents Solubility test: According to the concentration in Table 1, take the material, add water to 5 g, and dissolve it completely; add 0.01 g of Regorafenib or Cediranib, mix well, shake in a 25°C water bath for 24 h, filter with a 0.22 μm polytetrafluoroethylene (PTFE) filter membrane, take 2 mL of the filtrate in a 10 mL volumetric flask, add acetonitrile to dilute to the scale, shake well, and detect the concentration of the compound therein by high performance liquid chromatography (HPLC).

[0043] HPLC method: chromatographic column Kinetex 2.6u Phenyl-Hexyl 100A (150×4.6mm, 2.6μm), mobile phase: phase A is 3% acetonitrile-0.1% trifluoroacetic acid, phase B is acetonitrile, mobile phase ratio: 0-10min is 57% phase A, 12min-16min is 45% phase A, 18min-23min is 57% phase A; flow rate: 1.0mL / min, column temperature: 50°C, wavelength: 232nm or 236nm.

[0044] Table 1 shows the solubility of regorafenib and cediranib in ophthalmic surfactants and solvents.

[0045] Table 1

[0046]

[0047]

[0048] Table 1 shows that among ophthalmic surfactants and solvents, the solubility of cediranib is slightly higher than that of regorafenib, but the overall solubilization effect is weak and not significant enough.

[0049] Example 2: Investigation and screening of CMC values ​​of multi-surfactant compositions

[0050] The surface tension method is a commonly used method for determining the CMC value. Its principle is based on the change in the surface tension of the surfactant solution. At low concentrations, the surface tension decreases with the increase in surfactant concentration until it reaches the CMC value and remains basically unchanged. Therefore, the turning point of the surface tension decrease is the CMC value.

[0051] The experimental implementation method of the surface tension method for investigating the CMC value is as follows: first, according to the surfactant ratio of each composition in Table 1, a solution of a certain initial total concentration is prepared, such as 0.32% w / w, and then it is diluted by 2 to 6400 times to obtain at least 12 gradient concentration sample groups, each sample is at least 40g; then a surface tension meter is used to detect the surface tension value (in mN / m) of each group of samples with different concentrations at room temperature (25°C ± 2°C), and a graph is drawn with the concentration of each group of samples as the abscissa and the surface tension value as the ordinate. According to the trend that the surface tension value of the sample from low to high concentration significantly decreases and then turns to a slowly decreasing trend, two linear curves with a large difference in the absolute value of the slope can be fitted, and the linear equation and slope of the two are obtained, and their intersection (sample concentration) is calculated, which is the CMC value (in μg / ml) of this surfactant composition.

[0052] Table 2 shows the results of the investigation and screening of the CMC values ​​of single, binary, ternary, quaternary and quinary surfactant compositions.

[0053] Table 2

[0054]

[0055]

[0056] The results in Table 2 show that:

[0057] (1) Three surfactants with relatively large solubilizing ability were used: polyethylene glycol 40 stearate, polysorbate 80 and polyoxyethylene castor oil 35. They were combined in different concentration ratios to form a series of binary surfactant compositions G1-G22. The surface tension method was used to measure that the CMC values ​​of 11 of the compositions were less than the minimum CMC value of a single surfactant (50 μg / ml for polysorbate 80). Among them, the CMC value of the combination numbered G22 (polyoxyethylene castor oil 35: polysorbate 80 = 1:8) was the smallest, which was 16.50 μg / ml.

[0058] (2) On the basis of a part of the binary composition, polyoxyethylene hydrogenated castor oil 40 or poloxamer 407 is added to form a ternary surfactant composition G23-34, wherein the CMC values ​​of the two compositions G23 (polyoxyethylene castor oil 35: polysorbate 80: polyoxyethylene hydrogenated castor oil 40 = 1:8:2) and G24 (polyoxyethylene castor oil 35: polyoxyethylene hydrogenated castor oil 40: poloxamer 407 = 5:1:2) are reduced to 13.59 μg / ml and 10.69 μg / ml, respectively, which are smaller than the CMC value of the binary composition.

[0059] (3) In this embodiment, a plurality of quaternary surfactant compositions containing polyoxyethylene hydrogenated castor oil 40 and poloxamer 407 were designed, and 7 groups of quaternary compositions with CMC values ​​less than 10 μg / ml were obtained, among which G38 (polysorbate 80: polyoxyethylene castor oil 35: polyoxyethylene hydrogenated castor oil 40: poloxamer 407 = 2:2:1:2), G46 (polyethylene glycol 40 stearate: polyoxyethylene castor oil 35: polyoxyethylene hydrogenated castor oil 40: poloxamer 407 = 2:2:1:2), and G48 (polyethylene glycol 40 stearate: polyoxyethylene castor oil 35: polyoxyethylene hydrogenated castor oil 40: poloxamer 407 = 3:2:1:2) were the best, with CMC values ​​of 5.09 μg / ml, 2.39 μg / ml, and 5.17 μg / ml, respectively.

[0060] (4) The results of the three groups of five-component surfactant compositions all failed to reach a composition with a CMC value less than 2.39 μg / ml.

[0061] The above results show that the CMC values ​​obtained from surfactant compositions of different types and numbers vary greatly, and their solubilization abilities for regorafenib are also different. This is not the conventional understanding that surfactant combinations have similar solubilization abilities for compounds, nor can it be inferred. It is necessary to carry out numerous experimental studies to explore surfactant compositions with better solubilization abilities for regorafenib.

[0062] Example 3: Correlation analysis between the CMC value, dosage of surfactant composition and regorafenib solubility

[0063] Several groups of multi-surfactant compositions with smaller CMC values ​​in Table 2 were selected and mixed with excess regorafenib. Nanomicelle solutions loaded with regorafenib were prepared by thin film dispersion method. The correlation between the surfactant dosage, CMC value and the obtained regorafenib dissolution concentration of each composition was compared and analyzed.

[0064] Implementation steps of the thin film dispersion method: according to the amount of surfactant composition used in Tables 2 and 3, take 0.01g of regorafenib and the surfactant composition in each proportion in an eggplant-shaped flask, add 25ml of an organic solvent, which can be ethanol, ethyl acetate or a combination in any proportion, and dissolve all the materials. Place it on a rotary evaporator and evaporate the organic solvent at 40-65°C to obtain a material film, cool it to room temperature, add water to elute it completely, add water to 10g, mix well, let it stand for 30min-1h, and filter it with a 0.22μm PTFE or nylon filter membrane to obtain it.

[0065] Table 3 shows the results of a correlation study between the CMC values, usage amounts and effects of the binary, ternary and quaternary surfactant compositions screened in Table 2 on the solubility of regorafenib.

[0066] Table 3

[0067]

[0068]

[0069] Table 3 shows that the more surfactants are used in the multi-surfactant composition and the smaller the CMC value is, the solubility of regorafenib tends to increase as a whole, and the highest solubility approaches about 600 μg / ml.

[0070] However, when the total amount of surfactants in ophthalmic preparations is 8%, it may cause certain irritation, and it is necessary to take into account both the solubilization effect of surfactants and the risk of irritation. Combining the amount of a single surfactant used in the above composition with the total amount of surfactants, CMC value and regorafenib solubility, samples A13 and A14 containing quaternary surfactant compositions G38 and G46 have more development potential. Based on this, further investigation is continued.

[0071] Example 4: Study on the stability of regorafenib content in nanomicelles

[0072] In order to better evaluate and compare the two groups of nanomicelle samples A13 and A14 in Table 3, new samples A19 and A20 of these two groups of formulations were prepared using the thin film dispersion method and the emulsification method, and their content stability was investigated.

[0073] Implementation steps of the emulsification method: According to the dosage of the surfactant composition of samples A13 and A14 in Table 3, take 0.02 g of regorafenib and 1.4 g of the surfactant composition, mix well, transfer to 50°C to 65°C water bath and stir for 10 to 20 hours, add water while keeping warm, stir and emulsify completely, take out and continue to stir, cool to room temperature, add water to 20 g, mix well, and filter with a 0.22 μm PTFE filter membrane to obtain.

[0074] Table 4 shows the results of the content stability test of the regorafenib-encapsulated nanomicelle composition.

[0075] Table 4

[0076]

[0077]

[0078] The results in Table 4 show that the regorafenib drug content in the nanomicelles prepared by the emulsification method is more stable than that prepared by the thin film dispersion method. At 2-8°C and 25°C, the regorafenib content in the nanomicelle sample A19 prepared by the emulsification method was maintained above 600 μg / ml. The surfactant composition G38 has a better solubilization effect and content stability on regorafenib than G46, which is unexpected by the inventors and has great value for the development of formulations.

[0079] Example 5: Particle size and gel properties analysis of regorafenib nanomicelle in situ gel ophthalmic preparation

[0080] Preparation of sample A21: Prepare micelles according to the formula of sample A21 and the emulsification method, add mannitol, disodium hydrogen phosphate and sodium dihydrogen phosphate, fully dissolve and mix, filter and obtain.

[0081] Preparation of samples A22 and A23-28: Prepare micelles according to the formula of sample A22 in Table 4 and the emulsification method, add mannitol, stir to dissolve, mix well, filter, and obtain micelle concentrate. Weigh 0.8g DGG, disperse it in an appropriate amount of water, stir well, stir in a 70℃ water bath for 1h, take out and cool, add water to 100g, filter, and obtain 0.8% DGG solution. Take the micelle concentrate and 0.8% DGG solution in proportion, mix well, add disodium hydrogen phosphate and sodium dihydrogen phosphate, fully dissolve and mix, and obtain. Prepare 6 groups of samples A23-28 according to the formula of sample A22 in Table 4 and Table 5, and examine their viscosity.

[0082] Table 5 shows the prescription of regorafenib nanomicelle and nanomicelle in situ gel ophthalmic preparations.

[0083] Table 5

[0084]

[0085]

[0086] Table 6 is the formula for sodium ion adjustment in the regorafenib nanomicelle in situ gel ophthalmic preparation.

[0087] Table 6

[0088]

[0089] Particle size and potential investigation: Take 0.1 mL of sample, dilute it with 0.9 mL of water, put it into the sample cell, and use a nanoparticle size and potential analyzer to detect its particle size (nm); take about 1 mL of sample and put it into the bent capillary sample cell to measure its potential (mV).

[0090] Viscosity test: (1) At 25°C, take 0.3 mL of the sample and spread it on the surface of the rheometer sample table. Lower the upper plate to 300 μm from the lower plate and wait for 3 to 10 minutes. Measure for 120 seconds at a shear rate of 18 / s. (2) At 34°C, take the sample and artificial tears in a ratio of 40:7, mix them well, and quickly take 0.3 mL and spread it on the surface of the lower plate. Measure its average viscosity value (mPa·s) using the same method at 25°C.

[0091] The average particle sizes of samples A21 and A22 were 14.65-16.02 nm and 14.91-16.73 nm, respectively, with PDI < 0.2 and good dispersibility, indicating that the addition of DGG has little effect on the particle size of regorafenib nanomicelles and the two have good compatibility.

[0092] Subsequently, the inventors investigated the viscosity of sample A21 and six groups of samples A23-28. Figure 1 As shown, sodium dihydrogen phosphate and disodium hydrogen phosphate can provide an appropriate amount of sodium ions to significantly increase the viscosity of DGG, and can also play a role in regulating pH and buffering the ophthalmic preparation system.

[0093] In addition, the viscosity of sample A21 at 25°C and 34°C (with AT) was 14.5 mPa·s and 14.6 mPa·s, respectively, which was only 1 / 10 of the in situ gel of regorafenib nanomicelles and had no in situ gel properties.

[0094] Example 6: Preliminary stability of nanomicelle ophthalmic formulations for treating ocular neovascularization diseases

[0095] Stability test: Inspect the appearance, properties, pH, osmotic pressure, content, particle size and Zeta potential of sample A26 at 2-8°C.

[0096] Table 7 shows the preliminary stability test results of sample A26.

[0097] Table 7

[0098]

[0099] The results in Table 7 show that the quality of the regorafenib nano-micelle in situ gel ophthalmic preparation of the present invention meets the requirements and has good stability, and it (sample A26) can be stored at 2-8°C.

[0100] Example 7: Investigation of surfactants in the aqueous suspension composition of regorafenib

[0101] The dispersed form of regorafenib in the aqueous suspension composition of regorafenib described in this example is suspended particles, and the surfactant and stabilizer composition contained therein jointly stabilize the particle size and suspensibility of the suspended particles. This example focuses on selecting polysorbate 80, polyoxyethylene castor oil 35 and a combination of the two as surfactants, and investigates their respective effects on the particle size of regorafenib, and the results are shown in Table 8.

[0102] Preparation plan for the sample of the aqueous suspension composition of regorafenib: according to the material ratio in Table 8, take regorafenib, surfactant, glycerol, polyvinyl alcohol, and hydroxypropyl methylcellulose, mix well, add appropriate amount of water, stir and mix quickly, place at a shear rate of 10000rpm for homogenization for 10 minutes, add water to fix the weight, mix well, and obtain three groups of samples B1, B2 and B3.

[0103] Particle size detection method: Use a laser particle distribution measuring instrument to detect the particle size of the sample. Add ultrapure water that meets the detection amount into the instrument sample cup and subtract its background signal. Take an appropriate amount of sample into the sample cup, start the test, and continue to add sample until the shading value is greater than 20%. At this time, measure three times continuously and collect the average value of the particle size D90 and span of each test result.

[0104] Table 8

[0105]

[0106] The results in Table 8 show that (1) Samples B1 and B2 use polysorbate 80 and polyoxyethylene castor oil 35 as particle stabilizers for regorafenib, respectively, to prepare aqueous suspension particles, wherein the average particle size of sample B1 is much smaller than that of sample B2, indicating that polysorbate 80 has a better stabilizing effect on regorafenib particles. (2) When the mixture of the two is used as a particle stabilizer, the particle size of the suspension particles increases instead of decreasing, indicating that mixed surfactants are not conducive to the stability of the particle size of the suspension particles. The use of polysorbate 80 alone can solve the stability of the particle size of aqueous regorafenib suspension particles, which is an unexpected discovery and an important technical support for promoting the development of this drug delivery system.

[0107] Example 8: Investigation of low molecular weight suspending stabilizers in regorafenib aqueous suspension compositions

[0108] Low molecular weight polyols are added to the aqueous suspension composition of regorafenib as suspending stabilizers, including glycerol, propylene glycol, and polyethylene glycol 400, which also have a wetting effect. Five groups of samples were prepared according to the sample preparation scheme of Example 7, and their particle sizes were tested.

[0109] Table 9 shows the results of investigating the wetting agent in the regorafenib aqueous suspension composition samples.

[0110] Table 9

[0111]

[0112] The results in Table 9 show that the average particle size of sample B4 without adding polyols is about 141 μm, while the particle size is significantly reduced after adding appropriate amounts of glycerol, propylene glycol or polyethylene glycol 400. The average particle sizes of samples B5 and B7 with 1.0% w / w glycerol or propylene glycol are both less than 10 μm, which is an unexpected result. Therefore, glycerol or propylene glycol is an indispensable low-molecular suspending stabilizer in regorafenib suspended particles, and the composition formed with polysorbate 80 has a significant effect on reducing and stabilizing the suspended particles.

[0113] In order to further reduce the particle size of the suspended particles, the inventors used micronized regorafenib as a raw material, matched with the selected surfactant and stabilizer composition, and prepared samples according to the preparation method of Example 7. The dose of regorafenib was increased to 1.0% w / w to 3.0% w / w, or the surfactant and stabilizer composition were slightly adjusted, and the average particle size of each sample was examined.

[0114] Table 10 shows the results of investigating the regorafenib dosage and stabilizer composition in the regorafenib aqueous suspension composition samples.

[0115] Table 10

[0116]

[0117] The results in Table 10 show that in the aqueous suspension composition sample prepared using micronized regorafenib raw materials, the combined dosage of polysorbate 80 and glycerol remains unchanged, and when the dosage of regorafenib is increased to 1.0% w / w, 2.0% w / w, and 3.0% w / w, the average particle size of the three groups of samples is basically the same, all of which are about 6 μm. On the basis of sample B11 containing 3.0% w / w regorafenib, the ratio of polysorbate 80 to glycerol is adjusted to 2.5% w / w: 2.5% w / w, or 1% w / w propylene glycol is added, and when the total dosage of the two remains unchanged, the particle size of the obtained samples B12 and B13 also increases slightly and significantly. Moreover, as the dosage of glycerol in sample B12 increases, its osmotic pressure also increases, which has exceeded the osmotic pressure range of general eye drops of 270mOsmol / kg to 340mOsmol / kg; the osmotic pressure of sample B13 is appropriate, but the particle size and span are larger than sample B11. Therefore, the preferred combination ratio of polysorbate 80 to glycerol is 4.0% w / w:1.0% w / w.

[0118] Example 9: Investigation of polymer stabilizer and preparation process of regorafenib aqueous suspension composition

[0119] The aqueous suspension composition of regorafenib described in this example contains polymeric high molecular compounds as suspending stabilizers, including polyvinyl alcohol and hydroxypropyl methylcellulose, and the effect of hot pressing sterilization on its particle size is investigated.

[0120] Implementation plan for sample preparation: According to the composition ratio in Table 11, prepare each group of samples by the homogenization method of Example 7, and sterilize the samples by hot pressing. Put the samples into vials, add rubber stoppers and aluminum-plastic caps, sterilize at 115°C for 15 minutes, take them out, cool them to room temperature, and remix them. Finally, observe the appearance and properties of the samples, and use a laser particle distribution measuring instrument to detect the particle size of each sample.

[0121] Table 11 shows the results of investigation of the high molecular weight polymer suspending stabilizer in the regorafenib aqueous suspension composition sample.

[0122] Table 11

[0123]

[0124] The results in Table 11 show that the particle sizes of the four groups of samples before sterilization were all 6μm to 7μm. After hot-press sterilization, the suspensions of samples B14 and B15 were severely hardened into precipitates, the resuspension systems were uneven, and the average particle sizes of the two increased to 34 to 38μm, which were more than 5 times that of their respective non-sterilized samples. The particles of samples B16 and B17 containing HPMC were loose, easy to resuspend, and had little change in particle size, which was a very surprising discovery.

[0125] Although the combination of polysorbate 80 and glycerol can stabilize the particle size of regorafenib aqueous suspension particles, it cannot withstand the severe destruction of hot pressing sterilization. The addition of hydropropyl methylcellulose can maintain the looseness and particle size stability of the suspended particles at the same time, which solves the key problem of particle aggregation stability of the suspension system.

[0126] In order to obtain a smaller suspension particle size, the inventors adopted a grinding method, referring to the composition of sample B17 in Table 11, to prepare regorafenib aqueous suspension particles. The amount of polysorbate 80 in some of the newly prepared samples was slightly adjusted, and the average particle sizes of the samples before and after sterilization were compared.

[0127] Preparation method of sample B18: refer to the preparation scheme of sample B17 in Table 11 of this example.

[0128] Grinding method sample preparation and inspection plan: According to the combination formula in Table 12, take micronized regorafenib, add polyvinyl alcohol and hydroxypropyl methylcellulose, grind evenly, add polysorbate 80 and glycerol, continue to grind evenly, add appropriate amount of water, grind thoroughly for 10 minutes or 30 minutes, add water to fix the weight, mix well, and get it. Put part of the sample into a vial, add a rubber stopper and a pressed aluminum-plastic cap, sterilize at 115℃ for 15 minutes, take it out, cool to room temperature, and remix it to get the hot-pressed sterilized sample. Finally, test the particle size of each group of samples before and after sterilization.

[0129] Table 12 shows the results of the investigation of the preparation process of the regorafenib aqueous suspension composition samples.

[0130] Table 12

[0131]

[0132] The results in Table 12 show that the particle size of the regorafenib aqueous suspension granules sample prepared by the grinding method is reduced to about half of the sample prepared by the homogenization method, and the particle size of the sample sterilized by hot pressure does not increase significantly, indicating that this method is more effective in reducing the particle size of the sample, while prolonged grinding time will also increase the particle size, and the grinding time needs to be controlled.

[0133] When the amount of polysorbate 80 in sample B20 is reduced to 3.0% w / w, the particle size of the obtained sample B21 is basically the same as that of sample B20. Under the premise of ensuring particle stability, the more preferred amount of polysorbate 80 and glycerol used in combination is 3.0% w / w:1.0% w / w.

[0134] Example 10: Particle size study of regorafenib suspension in situ gel ophthalmic preparation

[0135] In this example, polysaccharides such as deacetyl gellan gum are introduced into the aqueous suspension particles of regorafenib to prepare a regorafenib suspension in situ gel ophthalmic preparation, which is intended to increase the viscosity of the drug delivery system and prolong the retention of regorafenib in the eye. We prepared a regorafenib aqueous suspension sample without acetyl gellan gum and a suspension in situ gel ophthalmic preparation with acetyl gellan gum, and examined and compared the appearance and particle size of the two.

[0136] Preparation method of regorafenib aqueous suspension granule sample: according to the combination formula in Table 13, take micronized regorafenib, add polyvinyl alcohol and hydroxypropyl methylcellulose, grind evenly, add polysorbate 80 and glycerol, continue to grind evenly, add appropriate amount of water, grind thoroughly for 10 minutes or 30 minutes, add sodium dihydrogen phosphate and disodium hydrogen phosphate, grind until all dissolved, add water to determine the weight, mix well, and obtain. Put the sample into a vial, add a rubber stopper and a pressure cap, sterilize at 115°C for 15 minutes, take out, cool to room temperature, and remix to obtain the hot press sterilization sample B22.

[0137] Preparation method of regorafenib suspension in situ gel ophthalmic preparation: according to the combination formula in Table 13, take micronized regorafenib, add polyvinyl alcohol and hydroxypropyl methylcellulose, grind evenly, add polysorbate 80 and glycerol, continue to grind evenly, add appropriate amount of water, grind thoroughly for 10 minutes or 30 minutes, add water to fix weight, mix well, and obtain. Put part of the sample into a vial, add a rubber stopper and a gland, sterilize at 115°C for 15 minutes, take out, cool to room temperature, and remix to obtain a suspension sample concentrated solution. Take the suspension sample concentrated solution and 0.8% w / w deacetylated gellan gum filtered through a 0.22μm filter membrane in proportion, mix well, add sodium dihydrogen phosphate and disodium hydrogen phosphate, stir until completely dissolved, mix well, and obtain sample B23.

[0138] Table 13 shows the prescription of regorafenib aqueous suspension granules and suspension in situ gel ophthalmic preparations.

[0139] Table 13

[0140] Sample No. B22 B23 Composition Regorafenib Aqueous Suspension Granules Regorafenib suspension in situ gel Components Percentage (%w / w) Percentage (%w / w) Regorafenib 3.0 3.0 Polysorbate 80 3.0 3.0 glycerin 1.0 1.0 Deacetylated Gellan Gum - 0.3 Polyvinyl alcohol 0.2 0.2 Hydroxypropyl methylcellulose 0.2 0.2 Mannitol 0.8 0.8 Sodium dihydrogen phosphate 0.153 0.153 Disodium hydrogen phosphate 0.218 0.218 Add water for injection to 100 100

[0141] Table 14 shows the appearance and particle size inspection results of regorafenib aqueous suspension particles and suspension in situ gel ophthalmic preparations.

[0142] Table 14

[0143]

[0144]

[0145] Table 14 shows that the average particle size D90 of sample B22 and sample B23 is 3-5 μm, and D50 is 1-3 μm, with good dispersibility, indicating that DGG does not affect the dispersion stability of regorafenib suspended particles in the sample in the aqueous medium. The inventors also found that the suspended particles of sample B23 precipitated less, which may be due to the pseudoplasticity of DGG, which caused the sample to be converted into a semi-solid gel when standing for a long time and significantly slowed down the sedimentation of the particles, making it difficult for the suspended particles to aggregate or harden, which is a unique advantage of DGG.

[0146] Example 11: Study on the in situ gel properties of regorafenib suspension in situ gel ophthalmic preparation

[0147] In this embodiment, sodium dihydrogen phosphate and disodium hydrogen phosphate are used as buffers. + The total amount is the object of investigation, and Table 15 contains 4 groups of Na + The total concentration of regorafenib suspension in situ gel ophthalmic preparation was 0.070% w / w to 0.105% w / w, and the samples were prepared. Referring to the viscosity detection method of Example 6, the viscosity of each sample was examined.

[0148] Table 15 is the formula for sodium ion adjustment in regorafenib suspension in situ gel ophthalmic preparation

[0149] Table 15

[0150]

[0151] Figure 2 It was shown that the viscosity and in situ gel properties of the regorafenib suspension in situ gel ophthalmic preparation sample B23 were basically consistent with those of the regorafenib nanomicelle in situ gel sample A26.

[0152] Example 12: Preliminary stability study of regorafenib suspension in situ gel ophthalmic preparation

[0153] In order to further determine the quality and stability of the developed regorafenib in situ gel ophthalmic preparation, the inventors conducted a preliminary stability study on sample B23 in Example 10. The results are shown in Table 16.

[0154] Stability test plan: Test the stability of sample B23 at 25°C and 40% of the concentration. Test indicators include appearance, properties, pH, osmotic pressure, content, particle size, resuspension time, etc.

[0155] Table 16

[0156]

[0157] The results in Table 16 show that the quality of the regorafenib suspension in situ gel ophthalmic preparation of the present invention meets the requirements and has good stability. The regorafenib suspension in situ gel ophthalmic preparation (sample B23) can be stored at 25°C.

[0158] Comparative Example 1: Preparation and result analysis of regorafenib non-aqueous oily suspension

[0159] Preparation method: Weigh 0.3 g of micronized regorafenib, add it to light liquid paraffin, stir thoroughly, add light liquid paraffin to 10 g, mix well, and obtain 3.0% regorafenib oily suspension sample C1.

[0160] Stability study plan: The stability of comparative example C1 at 25°C was studied. The study indicators included appearance, properties, content, resuspensibility, viscosity, etc.

[0161] When placed at 25°C for a long time, sample C1 changes from a uniform suspension to a white precipitated oily liquid and can be resuspended within 60 seconds with a content of 95.2% to 99.2%. It has good overall stability. It is particularly noted that the viscosities of sample C1 at 25°C and 34°C (with AT) are 23.5 mPa·s and 26.9 mPa·s, respectively, which are 1 / 6 to 1 / 7 of sample A26 in Table 5 and sample B23 in Table 6, and have no in situ gel properties.

[0162] Example 13: Rabbit eye tissue distribution test study

[0163] Test plan: The three test groups were sample A26, sample B23 and sample C1 described in Comparative Example 1. New Zealand white rabbits were randomly divided into 3 groups, 6 rabbits in each group, and 2 rabbits at each time point; 40 μl of the sample was instilled into the rabbit eyelids and eyes, and the cornea, aqueous humor and sclera were collected at 0.5h, 1.5h and 4h after administration. After treatment, the concentration of regorafenib was detected by liquid chromatography tandem mass spectrometry (LC-MS / MS).

[0164] Table 17 shows the concentration of regorafenib distributed in rabbit eye tissues of each sample after instillation of sample A26, sample B23 and sample C1.

[0165] Table 17

[0166]

[0167] Table 17 shows that the nanomicelle sample A26 has stronger penetration in ocular tissues, and the in situ gel properties can maintain a higher concentration of regorafenib in ocular tissues. The ocular tissue distribution levels of sample A26 and sample B23 are comparable, showing the effect of micelle solubilization and nanoparticle size; while the concentration of sample B23 in each tissue is higher than that of sample C1, which is due to the membrane permeation effect of the composition and the long-term retention of DGG. These exciting results will greatly promote the development of therapeutic drugs for ocular neovascularization-related diseases.

[0168] Example 14: Analysis of pharmacokinetic parameters in rabbit eye tissue distribution test

[0169] According to the test results shown in Table 17, the drug concentration-time curves of each group were drawn, as shown in Figure 3 to Figure 5 As shown in the figure, WinNonLin software (V8.1.0.3530) was used to perform statistical analysis and obtain the main pharmacokinetic parameters. (1) The peak time of the three groups of samples in the cornea, sclera and aqueous humor was basically the same, and the concentration of regorafenib in the sclera was much higher than that in the aqueous humor, indicating that they all diffused into the eye through the cornea-sclera pathway; (2) Overall, the ocular tissue bioavailability of regorafenib in the three groups of samples was ranked as follows: sample A26>sample B23>sample C1, that is, nanomicelle in situ gel>suspension in situ gel>suspension, while there was no significant difference between nanomicelle in situ gel and suspension in situ gel, but both were significantly higher than the suspension; because nanomicelle in situ gel has more free regorafenib, nanometer-scale particle size and gel intrinsic viscosity, it achieves a more efficient absorption and exposure (AUC) in ocular tissue.

[0170] It should be understood that these embodiments are included herein to illustrate rather than to limit the scope of the present invention. The experimental methods without specific conditions in the following examples are usually prepared according to the conventional conditions reported in the literature or the conditions recommended by the auxiliary material manufacturer. Unless otherwise specified, all percentages, ratios, proportions or fractions in the present invention are by weight. Unless specifically defined in the present invention, all professional and scientific terms used herein have the same meaning as the meaning that well-trained personnel may be familiar with. In addition, any method and material similar or equivalent to the method or material recorded in the present invention can be applied to the present invention. The preferred embodiments and materials described herein are for exemplary purposes only.

Claims

1. A regorafenib in situ gel preparation for treating ocular neovascularization diseases, characterized in that: The invention comprises regorafenib, a surfactant and an ion-sensitive in situ gelling material.

2. The regorafenib in situ gel preparation according to claim 1, characterized in that: The weight concentration of regorafenib in the preparation is 0.01% to 6.0%, preferably 0.06% to 3.0%.

3. The regorafenib in situ gel preparation according to claim 1 or 2, characterized in that: The regorafenib in situ gel preparation is a regorafenib nano-micelle in situ gel preparation.

4. The regorafenib in situ gel preparation according to claim 3, characterized in that: The micelle particle size of the regorafenib nano-micelle in situ gel preparation is 10 to 400 nm, preferably less than 20 nm.

5. The regorafenib in situ gel preparation according to claim 3, characterized in that: The surfactant is a surfactant composition formed by mixing multiple surfactants; the surfactant composition includes at least two of polyethylene glycol 40 stearate, polyoxyethylene castor oil series, polyoxyethylene hydrogenated castor oil series, polysorbate 80 and poloxamer 407.

6. The aqueous ophthalmic preparation of regorafenib according to claim 5, characterized in that: The surfactant composition is a quaternary composition: a combination of polysorbate 80, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated castor oil 40 and poloxamer 407, or a combination of polyethylene glycol 40 stearate, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated castor oil 40 and poloxamer 407, or a combination of polyethylene glycol 40 stearate, polysorbate 80, polyoxyethylene hydrogenated castor oil 40 and poloxamer 407.

7. The aqueous ophthalmic preparation of regorafenib according to claim 1 or 2, characterized in that: The ion-sensitive in situ gelling material is selected from any combination of one or more of deacetylated gellan gum, xanthan gum, carrageenan, carbomer, sodium hyaluronate, poloxamer, tragacanth gum, sodium alginate, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and carboxyethyl cellulose, and the ion-sensitive in situ gelling material is contained in the preparation at a concentration of 0.05% w / w to 5.0% w / w.

8. The regorafenib in situ gel preparation according to claim 3, characterized in that: It is prepared by an emulsification method.

9. The regorafenib in situ gel preparation according to claim 3, characterized in that: The invention also contains a gel regulator, which comprises a compound of monovalent or divalent cations and is selected from any combination of one or more of sodium chloride, potassium chloride, zirconium chloride, magnesium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and all their crystalline water-containing forms, and the gel regulator is contained in the preparation at a concentration of 0.01% w / w to 2.0% w / w.

10. The regorafenib in situ gel preparation according to claim 9, characterized in that: The gel regulator is any combination of sodium dihydrogen phosphate and disodium hydrogen phosphate, and is contained in the formulation at a concentration of 0.1% w / w to 0.5% w / w.

11. The regorafenib in situ gel preparation according to claim 3, characterized in that: An osmotic pressure regulator is also included, which includes mannitol, glucose, sorbitol, glycerol, polyethylene glycol, polypropylene glycol, propylene glycol or any combination thereof, contained in the preparation at a concentration of 0.01% w / w to 10.0% w / w, and the osmotic pressure of the preparation can be between 270mOsmol / kg and 400mOsmol / kg.

12. The regorafenib in situ gel preparation according to claim 3, characterized in that: Also included is a pH adjuster, which includes tromethamine, sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, boric acid, sodium borate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and all of their crystalline water-containing forms or any combination thereof, which are included in the preparation at a concentration of 0.01% w / w to 2.0% w / w, and the pH of the preparation is between 5.0 and 8.

0.

13. The regorafenib in situ gel preparation according to claim 1 or 2, characterized in that: It is a regorafenib suspension in situ gel formulation.

14. The regorafenib in situ gel preparation according to claim 14, characterized in that: The surfactant contained in the regorafenib suspension in situ gel preparation is a single type of surfactant.

15. The regorafenib in situ gel preparation according to claim 14, characterized in that: The surfactant is polysorbate 80 or polyoxyethylene castor oil 35.

16. The regorafenib in situ gel preparation according to claim 14 or 15, characterized in that: The invention also contains a low molecular weight suspension stabilizer, which is glycerol or propylene glycol.

17. The regorafenib in situ gel preparation according to claim 16, characterized in that: The combination ratio of polysorbate 80 and glycerol is 3.0% w / w:1.0% w / w.

18. The regorafenib in situ gel preparation according to claim 13, characterized in that: The invention also contains a high molecular polymer suspension stabilizer, which includes polyvinyl alcohol and hydroxypropyl methylcellulose.

19. The regorafenib in situ gel preparation according to claim 13, characterized in that: The average particle size of the suspension in situ gel preparation is: D90 is 3 to 5 μm, and D50 is 1 to 3 μm.

20. The regorafenib in situ gel preparation according to claim 19, characterized in that: The ion-sensitive in-situ gel material is deacetyl gellan gum.

21. The regorafenib in situ gel preparation according to claim 13, characterized in that: The suspension in situ gel formulation is prepared by a grinding method.

22. The regorafenib in situ gel preparation according to any one of claims 1 to 21, characterized in that: The described ocular neovascular diseases include: non-infectious ocular inflammation, corneal inflammation, corneal edema, corneal ulcer, inflammatory trachoma, pterygium, palpebral fissure, anti-rejection reaction after corneal transplantation, neovascular glaucoma, iris neovascularization, wet age-related macular degeneration, high myopia macular degeneration, macular edema, retinochoroiditis, uveitis, choroidal contusion, choroidal tumor, choroidal metastatic carcinoma, diabetic retinopathy, retinal vein occlusion, ocular ischemic syndrome and vascular streak sign.

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