CN110787127A

CN110787127A - Eye temperature-sensitive gel and preparation method thereof

Info

Publication number: CN110787127A
Application number: CN201911267264.2A
Authority: CN
Inventors: 龚雁; 陈乐彤; 王正才; 王伟智
Original assignee: Individual
Current assignee: Individual
Priority date: 2019-12-11
Filing date: 2019-12-11
Publication date: 2020-02-14

Abstract

The invention provides an ophthalmic temperature-sensitive gel and a preparation method thereof. The ophthalmic temperature-sensitive gel comprises 0.05-0.2% of nintedanib and 18-20% of poloxamer. The preparation method of the ophthalmic thermosensitive gel comprises the steps of respectively preparing the nintedanib and the poloxamer, stirring, uniformly mixing the nintedanib and the poloxamer to fully dissolve the nintedanib and the poloxamer to be creamy, refrigerating, and measuring the gel temperature. The ophthalmic temperature-sensitive gel comprises 0.05-0.2% of nintedanib and 18-20% of poloxamer. The gel temperature was determined by a stirred cell method by artificially simulating tears. The gel temperature is close to the body temperature of a human body. The ophthalmic temperature-sensitive gel provided by the preparation method disclosed by the invention has the advantages of prominent temperature-sensitive property of nintedanib, prolonged administration time, increased drug effect, few raw materials, simple preparation method and low cost, and is suitable for large-scale production.

Description

Eye temperature-sensitive gel and preparation method thereof

[ technical field ] A method for producing a semiconductor device

The invention relates to the technical field of pharmacy, in particular to an ophthalmic temperature-sensitive gel and a preparation method thereof.

[ background of the invention ]

The current clinical ophthalmic preparations are mainly eye drops, eye ointments and eye gels, wherein the eye drops are mostly solutions of medicines. According to statistics, liquid eye drops account for about 70% of the marketed ophthalmic preparations, and are widely accepted by people due to convenient use, solution preparation and low cost. However, the liquid medicine stays in the eyes for a short time, the head needs to be raised when the liquid medicine is dripped into the eyes, the posture is kept as much as possible, and the liquid medicine cannot flow out to influence the medicine effect. When the eye drop is dropped into eyes, only 1% -10% of the medicine reaches the eyes to play a role due to blinking of eyelids and secretion of tears, and the administration frequency needs to be increased to improve bioavailability or stabilize curative effect. Meanwhile, the liquid medicine may flow into the throat or nasal cavity through eyes, and the medicine solution is easy to enter the nasal cavity and digestive tract through nasolacrimal ducts and is absorbed by the whole body to cause discomfort and unnecessary side effects, so that the eye medicine of the gel preparation is developed, and the eye gel mainly refers to that the medicine is mixed with auxiliary materials which can be prepared into gel to obtain suspension or semi-solid state, and emulsion-shaped viscous liquid of emulsion type.

The ophthalmic gel takes hydrophilic polymer as a carrier, has better biocompatibility, is in a semisolid state, can prolong the action time of the medicament and reduce the administration times, but is not convenient to administer as eye drops. The temperature-sensitive gel is one of gels, has critical phase transition temperature, can be subjected to expansion and contraction change due to change of environmental temperature, and is often used as one of drug controlled release carriers. The temperature-sensitive gel is in a liquid state at room temperature, and can be converted into a semisolid gel when the temperature is higher than the room temperature after being dripped into a body. The drug carrier can be adhered to and retained on the surface of an eye membrane and slowly releases the drug, and can improve the curative effect, reduce the administration frequency and increase the compliance of patients.

At present, the most commonly used temperature-sensitive material in the life science field is poloxamer, which is a block copolymer of Polyoxyethylene (PEO) -polyoxypropylene ether (PPO), spherical micelles with polyoxypropylene as an inner core and polyoxyethylene as an outer shell can be formed in water, and the micelles can be intertwined and stacked to form gel when the temperature reaches the gelation temperature along with the rise of the temperature. Among the poloxamer polymers, poloxamer 407(P407) has been studied most intensively.

Therefore, the invention provides an ophthalmic thermosensitive gel based on poloxamer 407 and a preparation method thereof.

[ summary of the invention ]

Most of the prior art ophthalmic preparations are solutions, and when solution eye drops are dropped into eyes, only 1% -10% of the medicine reaches the eyes to play a role due to blinking of eyelids and secretion of tears, and the administration frequency needs to be increased to improve bioavailability or stabilize curative effect, so that the ophthalmic medicine of gel preparation is developed. However, the existing phase preparation process is relatively complex, and aiming at the problems, the invention provides the temperature-sensitive gel for the eyes and the preparation method thereof.

The invention provides an ophthalmic temperature-sensitive gel which comprises 0.05-0.2% of nintedanib, 18-20% of poloxamer and deionized water.

The invention provides a preparation method of an ophthalmic temperature-sensitive gel, which comprises the following steps:

weighing a certain amount of nintedanib medicine powder, slowly adding a certain volume of deionized water, and stirring on a magnetic stirrer until the medicine powder is completely dissolved;

weighing a certain amount of poloxamer, grinding the poloxamer into fine powder, slowly adding the fine powder into deionized water with a certain volume, and stirring the mixture while adding the deionized water;

adding the completely dissolved Nintedanib into the poloxamer solution, uniformly mixing, adding deionized water to complement the volume, and stirring on a magnetic stirrer to fully dissolve the Nintedanib into a creamy state;

refrigerating the solution for 24-48h until the poloxamer 407 is completely dissolved;

and measuring the gelation temperature of the prepared ophthalmic thermosensitive gel.

Preferably, the poloxamer is poloxamer 407.

Preferably, the ophthalmic temperature-sensitive gel comprises 0.05-0.2% of nintedanib, poloxamer and physiological water, wherein the mass fraction of the poloxamer is 18% -20%.

Preferably, the poloxamer is added slowly, and stirring is continued on a magnetic stirrer for more than ten seconds for each spoon of poloxamer to prevent excessive agglomeration.

Preferably, the pH value of the ophthalmic temperature-sensitive gel is 5-9.

Preferably, the gel temperature is measured by a stirrer method, and the stirrer method comprises the following steps:

putting about 7ml of gel matrix into a penicillin bottle with a fixed size of 4cm multiplied by 2cm, inserting a thermometer to enable a mercury bulb to be completely immersed into the solution, and meanwhile, placing a stirrer with a fixed size of 7mm multiplied by 3mm into the penicillin bottle, wherein the mercury bulb is close to the stirrer as much as possible and is prevented from contacting the bottom of the penicillin bottle;

placing the penicillin bottle in a low-temperature water bath, and adjusting and fixing the stirring speed to ensure that the water bath is slowly heated at a constant speed and continuously;

the temperature when the stirrer is close to stopping rotating is the gelling temperature T1, wherein the stirrer is considered to be close to stopping when the stirrer rotates for more than 3 seconds;

preparing artificial simulated tears, measuring 6ml of gel matrix, and measuring the volume of the gel matrix according to the temperature-sensitive gel for eyes: and (3) dripping the artificial simulated tear into the eye temperature-sensitive gel in an amount of 40:7, and repeating the measurement operation under the same condition to obtain the gelling temperature T2.

Preferably, the initial temperature T0 in the low-temperature water bath is about 20 ℃, the stirring speed is200 r/min, and the heating speed is 0.5 ℃/min.

Preferably, the artificial simulated tear comprises 6.78g of sodium chloride, 2.18g of sodium bicarbonate, 1.38g of potassium chloride and 0.084g of calcium chloride dihydrate in each liter of deionized water.

Compared with the prior art, the preparation method of the ophthalmic thermo-sensitive gel provided by the invention has the advantages of few raw materials, simple preparation process and low cost, and is suitable for large-scale production. The gel temperature of the ophthalmic temperature-sensitive gel provided by the invention is close to the body temperature of a human body, so that the state of the ophthalmic temperature-sensitive gel nintedanib is reversibly converted into a gel state when an administration part reaches the gel temperature after administration, the ophthalmic temperature-sensitive gel nintedanib is uniformly distributed and adhered to the administration part to form a sustained-release storage of a medicament, the action time of the medicament is prolonged, the local treatment effect is enhanced, and the toxic and side effects caused by systemic administration can be reduced.

[ description of the drawings ]

In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments are briefly introduced below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without inventive efforts, wherein:

FIG. 1 is a comparison of an ophthalmic temperature sensitive gel of the present invention before and after adding artificial tears;

FIG. 2 is a representative gross image of corneal neovascularization at various time points after alkali burn in each group of experimental rats shown in the present invention;

FIG. 3 is a representative gross image of hematoxylin-eosin staining of corneal tissue in rats in various experimental groups shown in the present invention;

FIG. 4 is a schematic representation of the results of the expression of Vascular Endothelial Growth Factor (VEGF) in rats in various experiments according to the present invention;

FIG. 5 is a schematic diagram showing the expression result of a platelet endothelial cell adhesion molecule (PECAM-1 or CD31) in rats in each experiment set according to the present invention;

[ detailed description ] embodiments

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The invention provides an ophthalmic temperature-sensitive gel which comprises 0.05-0.2% of nintedanib, 18-20% of poloxamer and deionized water. In other embodiments, the ophthalmic temperature-sensitive gel further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of: stabilizers, surfactants, polymer-based carriers, gelling agents, organic co-solvents, pH active ingredients, osmotic active ingredients, and with or without preservatives.

Example one

In this embodiment, the mass fraction of the nintedanib is 0.2%, and the mass fraction of the poloxamer is 20%. The poloxamer is poloxamer 407.

The preparation method of the ophthalmic temperature-sensitive gel comprises the following steps:

preparing and stirring nintedanib: weighing a certain amount of nintedanib medicine powder, slowly adding a certain volume of deionized water, and stirring on a magnetic stirrer until the medicine powder is completely dissolved;

poloxamer 407 was prepared and stirred: weighing a certain amount of poloxamer 407, grinding into fine powder, slowly adding into deionized water with a certain volume, and stirring while adding the deionized water;

mixing the stirred nintedanib and poloxamer 407 uniformly to dissolve them fully: adding the fully dissolved nintedanib into the poloxamer 407 solution, uniformly mixing, adding deionized water to complement the volume, and stirring on a magnetic stirrer to fully dissolve the nintedanib into a creamy state;

determination of the gelling temperature after refrigeration of the solution: and refrigerating the solution for 24-48h until the poloxamer 407 is completely dissolved, and measuring the gelling temperature.

Specifically, poloxamer 407 is added slowly, and stirring is continued on a magnetic stirrer for more than ten seconds every time a spoon of poloxamer is added, so that excessive agglomeration is prevented. The pH value of the eye temperature-sensitive gel is 5-9, and if the pH value is not in the range, a pH regulator is required to adjust the pH value of the eye temperature-sensitive gel.

The temperature-sensitive gel is determined by adopting a stirrer method, and the stirrer method comprises the following steps:

the preparation method comprises the steps of filling a penicillin bottle with a fixed size of 4cm multiplied by 2cm with about 7ml of gel matrix, inserting a thermometer to enable a mercury bulb to be completely immersed in a solution, and meanwhile placing a stirrer with a fixed size of 7mm multiplied by 3mm in the penicillin bottle, wherein the mercury bulb is close to the stirrer as possible and is prevented from contacting the bottom of the penicillin bottle. And (3) placing the penicillin bottle in a low-temperature water bath, and adjusting and fixing the stirring speed to ensure that the water bath is slowly heated at a constant speed and continuously. Specifically, the initial temperature T0 in the low-temperature water bath is about 20 ℃, the stirring speed is200 r/min, and the heating speed is 0.5 ℃/min. The temperature at which the rotor is near its stopped rotation is the gelation temperature T1, wherein a rotor rotation time of more than 3 seconds is considered near its stop.

Preparing artificial simulated tear, wherein the components of the artificial simulated tear comprise 6.78g of sodium chloride, 2.18g of sodium bicarbonate, 1.38g of potassium chloride and 0.084g of calcium chloride dihydrate in each liter of deionized water. Measuring 6ml of gel matrix, and measuring the volume of the ophthalmic temperature-sensitive gel: and (3) dripping the artificial simulated tear into the eye temperature-sensitive gel in an amount of 40:7, and repeating the measurement operation under the same condition to obtain the gelling temperature T2.

Example two

The concentration of the ophthalmic thermo-sensitive gel provided in this embodiment is 0.1%, wherein the poloxamer 407 has a mass component of 18%, and the preparation method is substantially the same as that in the first embodiment, and is not repeated herein.

EXAMPLE III

The concentration of the ophthalmic thermo-sensitive gel provided in this embodiment is 0.05%, wherein the poloxamer 407 has a mass component of 18%, and the preparation method is substantially the same as that in the first embodiment, and is not repeated herein.

The gel temperatures for the three examples are shown in table 1:

TABLE 1 statistical table of gel temperatures for the examples

The data in the table 1 show that after the artificial simulated tears are added, the temperature of the ophthalmic gel is close to the body temperature of a human body, namely when the ophthalmic temperature-sensitive gel enters the eyes of the human body, the state of the ophthalmic temperature-sensitive gel, namely the nintedanib, is reversibly transformed into a gel state, is uniformly distributed and adhered to the eyes, becomes a slow-release storage of a medicament, prolongs the action time of the medicament and increases the medicament effect.

According to the prepared eye temperature-sensitive gel, an influence experiment on the neovascularization and related markers in the alkali burn cornea of a rat is carried out. The model experiment included the following steps:

step 1: preparation of alkali burn model in rat

30 male Wistar rats are prepared, purchased from Shanghai Schleger laboratory animal center, have the weight of 150-200 g, are healthy and free of eye diseases, and are subjected to adaptive feeding for one week to prepare an alkali burn model. A filter paper sheet having a diameter of 4mm was immersed in a 1mol/L NaOH solution for 1min to reach a saturated state, wherein the filter paper sheet was immersed in physiological saline for 1min in rats of the blank control group. After the rat is anesthetized by injecting chloral hydrate into the abdominal cavity, the rat is dropped with 0.5 percent lidocaine for local anesthesia for 10s, excess water is wiped off by a cotton swab, a filter paper sheet is placed in the center of the cornea of the rat eye and is maintained for 20s, the filter paper sheet is taken down, and the conjunctival sac is washed by normal saline for 1 min. The burned rats were then randomly divided into 5 groups of 6 rats each, of which:

the first group is a chloramphenicol model group, the second group is a 0.05% nintedanib group, the third group is a 0.1% nintedanib group, the fourth group is a 0.2% nintedanib group, the fifth group is a 1% dexamethasone group, and the left eye of the second group of rats is used as a blank control group. Wherein the second to fourth groups may be collectively referred to as a nintedanib group.

And smearing the nintedanib temperature-sensitive gel on the conjunctiva from the second group to the fourth group 1 day after the model is established every day, wherein the first group is given chloramphenicol eye drops, and the fifth group is given dexamethasone eye drops. ImageJ software for slit lamp photographing at 3, 7 and 14 days after respective operations calculates the proportion of the area proportion of the corneal neovascularization to the whole cornea. The eyeball was removed 14 days after the operation, the section was made, each group of animals was killed by removing the

neck

1, 4, and 7 days after the model was made, and the corneal tissue was immediately taken for observation.

Step 2: observation of new blood vessels

After 3, 7 and 14 days of burn, the condition of corneal neovascularization is observed by a slit lamp microscope, the condition of neovascularization is photographed and the area is calculated, the length of neovascularization growing from the corneoscleral edge in a centripetal manner is measured (based on the length of the neovascularization which is continuous, has small curvature and is perpendicular to the tangent line of the corneoscal edge), 5 values are measured in different quadrants of each picture, the average value is taken to obtain the lengths of different groups of corneal neovascularization in different periods, the data is substituted into a Rorbert computer digital model formula S ═ C/12 x × [ r2- (r-l)2], and S is the growth area of the corneal neovascularization. Wherein C is the number of the circle-spanning clock points of the corneal neovascular network, r is the corneal radius, and l is the neovascular length. The corneal neovascularization inhibitory rate was (1-Sx/Sd) × 100%, and when Sx was 14d, the blood vessel area in nintedanib group was large, and when Sd was 21d, the blood vessel area in group a was large. ImageJ software photographed with a slit lamp calculates the proportion of the area of corneal neovascularization in total cornea.

And step 3: immunofluorescence detection

The expression of VEGFR-2 and CD31 was detected by immunofluorescence. The eyeball is subjected to immunofluorescence staining after paraffin embedding, the growth condition of corneal neovascularization is observed under a fluorescence microscope, and the expression of VEGF is observed by an immunofluorescence section. 5 fields were taken from each section and HMAIS2000 images were analyzed to determine the relative values of immunofluorescent staining positive reactions to reflect the relative amounts of marker proteins in each group of specimens. The gray value is divided into 256 grades from 0 to 255, and the smaller the gray value is, the deeper the immunofluorescence staining is, and the higher the content of the positive reaction product is.

And 4, step 4: statistical analysis

The statistical results are shown in Table 2

TABLE 2 corneal neocapillary area (mm) at different time points in rats after alkali burn²)

Statistical treatment: each group of data is expressed in x +/-s, SPSS11.5 statistical analysis software package is used for processing, single-factor variance analysis is adopted for overall mean comparison, q test is adopted for pairwise comparison among the groups of means, and the difference is considered to have statistical significance when P is less than 0.05.

And 5: analysis of results

Referring to fig. 1 and fig. 2 in combination, fig. 1 is a comparison chart of fig. 1 before and after adding artificial tears to an ophthalmic temperature-sensitive gel, fig. 2 is images of corneal neovascularization at different time points after alkali burn of experimental rats, and fig. 3 is a schematic diagram of calculating neovascularization areas of rats in a fifth group. Wherein, figure 1(A) is the eye temperature-sensitive gel without adding artificial tears, which is a liquid at 16 ℃, figure 1(B) is the eye temperature-sensitive gel with adding artificial tears, which is gelatinized at 37 ℃ after adding artificial tears. Fig. 2 is a representative gross image of the first, fourth, fifth and blank control groups on

days

1, 3, 7, 14 post-alkali burn.

Corneal epithelial edema in the damaged area and corneal scleral marginal vessel dilatation hyperemia were observed 1 day after the first group of injury; after 3 days, corneal neovascular buds at the corneal scleral edge are visible and extend into the transparent corneal region in a brush shape; after 7 days, the new blood vessels of the cornea grow vigorously, become remarkably long, the area is increased, the blood vessels extend out of branches and are partially anastomotic; after 14 days, the area of the corneal neovascularization reaches the maximum, the cornea is interwoven into a net shape, and the growth of the corneal neovascularization tends to be stable; by day 21, the corneal neovascularization was essentially stable and some of the blood vessels had regressed.

The new blood vessels in the fourth group grow slower than those in the model group, and have smaller range, are mostly limited to the corneoscleral margin and are not interwoven into a net shape. The fourth group of corneal neovessels not only have obviously smaller growth length and range than the first group, but also have obviously sparse density, tiny blood vessels, transparency and few branches at each time point.

Repeated measurement design data analysis of variance is carried out on the areas of the corneal neovessels of each group at 3, 7 and 14 days after the corneal alkali burn, the statistical significance of the overall difference at each time point is found (q14 is 154.20, P is less than 0.01), q test is carried out between groups, 0.2% of nintedanib groups at each time point are obviously lower than those of the model group, and the significance of the difference is significant (q14 is 24.02, P is less than 0.01).

Taking the fourth group of data as an example, the area ratios of the new blood vessels on

days

3, 7 and 14 are respectively as follows: 1043919/2245731-0.4648, 911316/3065586-0.2972 and 928394/3221272-0.2882. In 3 rd, 7 th and 14 th days, the fourth group is obviously lower than the model group, the difference is statistically significant (P <0.01), and in 3 rd, 7 th and 14 th days, the results indicate that the temperature-sensitive ophthalmic gel with different concentrations obviously inhibits the growth of corneal neovascularization, and the effect of the temperature-sensitive ophthalmic gel with the concentration of 0.2% is more obvious. The neovascular areas of the nintedanib groups were all significantly lower than the model group. On the third day, a certain effect can be observed in the third group, which shows that the ophthalmic temperature-sensitive gel can inhibit the formation of new blood vessels in the cornea for a long time after being administered, and the onset speed is high. The third group regressed the new blood vessels earlier and peaked lower than the fourth group.

Please refer to fig. 3. Fig. 3 shows representative gross images of hematoxylin-eosin staining of corneal tissue at the seventh day after alkali burn in rats, with groups of the first group (model group), the fourth group (0.2% nidanib group), the fifth group (1% dexamethasone group), and the blank control group, respectively. Each layer of the corneal tissue of the blank control group has complete structure and compact arrangement among cells, and no new blood vessel is found; the CNV at the corneal limbus of the model group is more, so that the CNV invades into a corneal stroma layer, a neovascular lumen is obviously visible in the superficial stroma layer, and a large amount of red blood cells are attached in the corneal stroma layer; dexamethasone and nintedanib dilate capillaries at the corneoscleral limbus and have fewer lumens for new blood vessels.

Referring to fig. 4, fig. 4 is a representative general graph showing the expression results of Vascular Endothelial Growth Factor (VEGF) on the seventh day of rat alkali burn in each experiment of the present invention, which is respectively set as a first group (model group), a fourth group (0.2% nintedanib group), a fifth group (1% dexamethasone group) and a blank control group. . In the model group, 1 day after injury, scattered inflammatory cell infiltration can be seen at the corneoscleral margin, intracytoplasmic VEGF staining is not obvious, and 3 days after injury, inflammatory cell intracytoplasmic VEGF staining is seen to be green fluorescence with certain intensity. After 7 days of injury, VEGF expression was seen in the shallow 1/3 stroma and inflammatory cell cytoplasm at the corneoscleral limbus, which was dark green, with significant inflammatory changes in the corneal stroma. VEGF expression was seen as dark green fluorescence in inflammatory cell cytoplasm throughout the stromal layer 14 days after injury, but inflammatory changes in the cornea were slightly mild.

In the fourth group, corneal inflammatory cell infiltration was mostly limited to the corneoscleral limbus and superficial basal layers, and the number of corneal inflammatory cells was significantly reduced compared to the model group, the intra-cytosolic VEGF staining was lighter, the inflammatory response was significantly reduced at day 7, and the grey scale measurements showed that at each time point, the nintedanib group was significantly smaller than the model group. The differences were statistically significant at all other time points (P < 0.05).

Referring to FIG. 5, FIG. 5 is a schematic representation showing the expression of platelet endothelial cell adhesion molecule (CD31) on day seven of rat alkali burn in each experiment. CD31 is an intra-Platelet CD31 also known as Platelet endothelial cell adhesion molecule (PECAM-1), a member of the immunoglobulin superfamily, expressed on the surfaces of vascular endothelial cells, platelets, monocytes, neutrophils and a variety of other cells, indicating neovascularization. The blood vessel fluorescence level is further evaluated through immunofluorescence, and the result shows that the rat retinal tissue CD31 expression level in the blank control group is the lowest, the expression in the nintedanib group and the dexamethasone group is also obviously reduced, and the expression in the blank control group is obviously increased, so that the green fluorescence intensity is increased.

In conclusion, the area of the new blood vessels is obviously reduced under the action of the nintedanib eye temperature-sensitive gel with different concentrations compared with a new blood vessel model group, wherein the inhibition effect is more obvious when the concentration of the fourth group is 0.2%.

While the foregoing is directed to embodiments of the present invention, it will be understood by those skilled in the art that various changes may be made without departing from the spirit and scope of the invention.

Claims

1. The ophthalmic temperature-sensitive gel is characterized by comprising 0.05-0.2% of nintedanib, and 18-20% of poloxamer.

2. The preparation method of the temperature-sensitive gel for the eyes is characterized by comprising the following steps:

3. The method for preparing the ophthalmic temperature-sensitive gel according to claim 1, wherein the poloxamer is poloxamer 407.

4. The preparation method of the ophthalmic temperature-sensitive gel according to claim 1, wherein the ophthalmic temperature-sensitive gel comprises 0.05-0.2% of nintedanib, poloxamer and physiological water, and the mass fraction of the poloxamer is 18-20%.

5. The method for preparing temperature-sensitive ophthalmic gel according to claim 1, wherein the poloxamer is added slowly, and stirring is continued for more than ten seconds on a magnetic stirrer every time a spoon of the poloxamer is added, so as to prevent excessive agglomeration.

6. The method for preparing the ophthalmic temperature-sensitive gel according to claim 1, wherein the pH of the ophthalmic temperature-sensitive gel is 5 to 9.

7. The method for preparing the ophthalmic temperature-sensitive gel according to claim 1, wherein the gel temperature is measured by a stirrer method, and the stirrer method comprises the following steps:

8. The method for preparing the ophthalmic temperature-sensitive gel according to claim 7, wherein the initial temperature T0 in the low-temperature water bath is about 20 ℃, the stirring rate is200 r/min, and the heating rate is 0.5 ℃/min.

9. The method for preparing eye temperature-sensitive gel according to claim 7, wherein the artificial simulated tear comprises 6.78g of sodium chloride, 2.18g of sodium bicarbonate, 1.38g of potassium chloride and 0.084g of calcium chloride dihydrate per liter of deionized water.