CN112569187B - Tacrolimus nano eye emulsion and preparation method thereof - Google Patents
Tacrolimus nano eye emulsion and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Abstract
The invention discloses tacrolimus nano eye drops, which comprise the following components in percentage by mass: 0.05-0.2% of tacrolimus, 1880.1-0.5% of poloxamer, 0.1-0.5% of polycarbophil, 0.8-1.5% of medium-chain fatty glyceride, 1-2% of glycerol dioleate, 1.5-2.8% of glycerol, 0.5-4.0% of polyoxyethylene hydrogenated castor oil and the balance of deionized water. The eye drops are prepared by a shear dispersion method, have the average particle size of 160-220 nm, have the characteristics of slow release and pulse release, and can improve the treatment effect of local drug application to eyes.
Description
Technical Field
The invention belongs to the field of ophthalmic medicines, and particularly relates to tacrolimus nano ophthalmic emulsion and a preparation method thereof.
Background
Tacrolimus is a fermentation product isolated from Streptomyces by Taguze pharmacy, and in the field of ophthalmic drugs, its immunosuppressive action is stronger than that of cyclosporin A (CsA). The tacrolimus is locally applied to the eyes to treat the immunogenic inflammatory eye diseases, has excellent curative effects on corneal graft rejection and graft-versus-host disease, and is suitable for vernal keratoconjunctivitis patients with unobvious antiallergic treatment effects.
Tacrolimus is hardly soluble in water and is soluble in organic solvents such as ethanol, methanol and chloroform. In view of the problem of difficult solubility of the drug, the marketed product of Japan Qianshou pharmaceutical is tacrolimus suspension eye drops, the drug exists in a system in a granular state and needs to be shaken up before use, so that the drug is prevented from being unevenly distributed in the system and needs to be administered twice a day.
In the prior art, in the preparation method of tacrolimus ophthalmic gel preparation provided by patent CN101810563A, the drug is micronized or solid dispersion technology or cyclodextrin inclusion technology is adopted to significantly improve the solubility thereof, and then the tacrolimus ophthalmic gel preparation is prepared into an ophthalmic preparation which is in a liquid state in vitro and is in a gel state when dropped into eyes. The tacrolimus eye preparation prepared by the patent is dripped into eyes to form gel, and compared with eye drops, the tacrolimus eye preparation is not easy to be diluted by tears and is beneficial to enhancing the treatment effect.
Tacrolimus is used as an immunosuppressant, and has been clinically applied to various preparation forms. When the ophthalmic preparation is used as a local ophthalmic preparation, on one hand, the problem of the solubility of the ophthalmic preparation needs to be solved, the initial drug concentration needs to be higher and reaches the concentration above the effective drug, so that the drug can quickly take effect, the inflammation is inhibited, and meanwhile, irritant materials are avoided; on the other hand, the retention time of the medicine in the eyes is required to be prolonged as much as possible, the local medicine concentration is increased, and the treatment effect is further improved. The tacrolimus eye drops which can simultaneously meet the two performance requirements have good application prospect.
Disclosure of Invention
The invention provides tacrolimus nano eye drops, which can solve the problem of tacrolimus solubility, has the function of prolonging the drug release, has two rapid drug release peak values in an in vitro release test within 45min and 12h respectively, and has the characteristic of pulsed drug release, and the average particle size of the nano eye drops is 160-220 nm. Specifically, the following technique is used.
The tacrolimus nano eye emulsion comprises the following components in percentage by mass: 0.05-0.2% of tacrolimus, 1880.1-0.5% of poloxamer, 0.1-0.5% of polycarbophil, 0.8-1.5% of medium-chain fatty glyceride, 1-2% of glycerol dioleate, 1.5-2.8% of glycerol, 0.5-4.0% of polyoxyethylene hydrogenated castor oil and the balance of deionized water.
Tacrolimus suspension eye drops prepared by Japan Qianshou pharmacy are administrated twice a day, and the interval time of each time is about twelve hours. The tacrolimus nano eye emulsion can prolong the release time, has a second release peak value of about 12 hours, can closely link the effective drug treatment concentration in the local part of the eye, has the effect of pulsed release of the drug, and enhances the treatment effect while reducing the administration frequency.
Preferably, the tacrolimus nano eye milk comprises the following components in percentage by mass: tacrolimus 0.12%, poloxamer 1880.3%, polycarbophil 0.4%, medium-chain fatty glyceride 1.2%, glyceryl dioleate 1.2%, glycerol 2.2%, polyoxyethylene hydrogenated castor oil 1.6%, and the balance of deionized water.
More preferably, the polyoxyethylene hydrogenated castor oil is at least one of polyoxyethylene 35 hydrogenated castor oil and polyoxyethylene 40 hydrogenated castor oil.
The invention also provides a preparation method of the tacrolimus nano eye milk, which comprises the following steps:
s1, stirring tacrolimus, medium-chain fatty glyceride, glyceryl dioleate and polyoxyethylene hydrogenated castor oil at 45-70 ℃ for 20min to obtain a mixed solution I;
s2, stirring 60% of the total amount of the deionized water, poloxamer 188 and glycerol at normal temperature at 200-1000 rpm for 30-60 min to obtain a mixed solution II;
s3, adding the mixed solution II into the mixed solution I at the temperature of 60-75 ℃, shearing and emulsifying for 10-40 min at 8000-15000 rpm, and filtering with a 0.22 mu m filter membrane to obtain a mixed solution III;
s4, adding polycarbophil into the residual 40% of deionized water, stirring for 30-60 min at 40-60 ℃, and then sterilizing for 10min at 120 ℃ to obtain a mixed solution IV;
and S5, adding the mixed solution III into the mixed solution IV, stirring at 200-800 rpm for 10-30 min, and adjusting the pH value to 5.5-6.5 to obtain the eye milk. The pH value is adjusted by common pH regulator, such as NaOH solution and NaHCO3Solutions, and the like.
Preferably, in step S3, the conditions for shear emulsification are: shearing and emulsifying at 70 deg.C and 12000rpm for 25 min.
Preferably, in step S5, the pH is adjusted to 6.0.
Preferably, the average particle size of the prepared eye milk is 160-220 nm.
Compared with the prior art, the invention has the advantages that: the tacrolimus nano eye emulsion prepared by the invention can prolong the release time of the medicament in eyes, has two release peak values, has the characteristic of pulse release, can closely link the effective medicament treatment concentration in the local parts of the eyes, can reduce the administration frequency, improves the medication compliance and simultaneously has better treatment effect.
Drawings
FIG. 1 is a drug release profile of tacrolimus nano ophthalmic milk prepared in examples 1 and 5;
FIG. 2 is a drug release profile of tacrolimus nano ophthalmic milk prepared by comparative examples 1, 2, 4 and 5;
Detailed Description
The technical solutions of the present invention will be described clearly and completely below, and it should be understood 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.
In the following examples and comparative examples, the pH adjusting agent used for adjusting the pH was a 0.1mol/L NaOH solution.
Example 1
The tacrolimus nano eye milk provided by the embodiment comprises the following components in percentage by mass: tacrolimus 0.12%, poloxamer 1880.3%, polycarbophil 0.4%, medium-chain fatty glyceride 1.2%, glyceryl dioleate 1.2%, glycerol 2.2%, polyoxyethylene hydrogenated castor oil 1.6%, and the balance of deionized water.
The preparation method of the tacrolimus nano eye milk comprises the following steps:
s1, stirring tacrolimus, medium-chain fatty glyceride, glyceryl dioleate and polyoxyethylene hydrogenated castor oil at 65 ℃ for 20min to obtain a mixed solution I;
s2, stirring 60% of the total amount of the deionized water, poloxamer 188 and glycerol at 2800rpm at normal temperature for 45min to obtain a mixed solution II;
s3, adding the mixed solution II into the mixed solution I at 70 ℃, shearing and emulsifying for 25min at 12000rpm, and then filtering with a 0.22 mu m filter membrane to obtain a mixed solution III;
s4, adding polycarbophil into the residual 40% of deionized water, stirring for 45min at 50 ℃, and then sterilizing for 10min at 120 ℃ to obtain a mixed solution IV;
and S5, adding the mixed solution III into the mixed solution IV, stirring at 600rpm for 20min, and adjusting the pH value to 6.0 to obtain the eye milk.
Example 2
The tacrolimus nano eye milk provided by the embodiment comprises the following components in percentage by mass: tacrolimus 0.05%, poloxamer 1880.5%, polycarbophil 0.5%, medium-chain fatty glyceride 1.5%, glyceryl dioleate 2%, glycerol 2.8%, polyoxyethylene hydrogenated castor oil 4.0%, and the balance of deionized water.
The preparation method of tacrolimus nano ophthalmic milk in the embodiment is the same as that of the embodiment 1.
Example 3
The tacrolimus nano eye milk provided by the embodiment comprises the following components in percentage by mass: tacrolimus 0.2%, poloxamer 1880.1%, polycarbophil 0.1%, medium-chain fatty glyceride 0.8%, glycerol dioleate 1%, glycerol 1.5%, polyoxyethylene hydrogenated castor oil 0.5%, and the balance of deionized water.
The preparation method of tacrolimus nano ophthalmic milk in the embodiment is the same as that of the embodiment 1.
Example 4
The tacrolimus nano eye milk of the embodiment uses the same raw materials and the same mass percentage as the tacrolimus nano eye milk of the embodiment 1, and the preparation method is basically the same, except that: in step S3, the conditions of shear emulsification are: shearing and emulsifying at 70 deg.C and 8000rpm for 25 min.
Example 5
The tacrolimus nano eye milk of the embodiment uses the same raw materials and the same mass percentage as the tacrolimus nano eye milk of the embodiment 1, and the preparation method is basically the same, except that: in step S5, the pH was adjusted to 6.5.
Comparative example 1
The tacrolimus nano eye milk provided by the comparative example comprises the following components in percentage by mass: tacrolimus 0.12%, poloxamer 1880.3%, polycarbophil 0.4%, medium-chain fatty glyceride 1.2%, glycerol 2.2%, polyoxyethylene hydrogenated castor oil 1.6%, and the balance of deionized water.
The tacrolimus nano ophthalmic milk preparation method is basically the same as example 1 except that glycerol dioleate is not added in step S1.
Comparative example 2
The tacrolimus nano eye milk provided by the comparative example comprises the following components in percentage by mass: 0.12% of tacrolimus, 0.4% of polycarbophil, 1.2% of medium-chain fatty glyceride, 1.2% of glyceryl dioleate, 2.2% of glycerol, 1.6% of polyoxyethylene hydrogenated castor oil and the balance of deionized water.
The preparation method of the tacrolimus nano ophthalmic milk does not add poloxamer 188 in step S2, and other steps are basically the same as those in the example 1.
Comparative example 3
The tacrolimus nano eye milk provided by the comparative example uses the same raw materials and the same mass percentages as those of the tacrolimus nano eye milk in the embodiment 1, and the preparation method is basically the same, except that: in step S3, the conditions of shear emulsification are: shearing and emulsifying at 70 deg.C and 7000rpm for 25 min.
Comparative example 4
The tacrolimus nano eye milk provided by the comparative example uses the same raw materials and the same mass percentages as those of the tacrolimus nano eye milk in the embodiment 1, and the preparation method is basically the same, except that: in step S5, the pH is adjusted to 7.
Comparative example 5
The tacrolimus nano eye milk provided by the comparative example uses the same raw materials and the same mass percentages as those of the tacrolimus nano eye milk in the embodiment 1, and the preparation method is basically the same, except that: in step S5, the pH is adjusted to 5.
Application example 1: stability of Tacrolimus Nanoculars of examples 1-5 and comparative example 3
The average particle size of the Nano ophthalmic milks prepared in examples 1 to 5 and comparative example 3 was measured using a Nano-ZS90 malvern laser particle size analyzer, and the results are shown in table 1 below, while the Nano ophthalmic milks prepared in examples 1 to 5 and comparative example 3 were allowed to stand at room temperature for 1 month, and the appearance changes during observation, and the results are shown in table 2 below.
TABLE 1 average particle diameter of nano-ophthalmic milks of examples 1 to 5 and comparative example 3
| Group name | Average particle diameter of nm |
| Example 1 | 204.3 |
| Example 2 | 212.4 |
| Example 3 | 207.6 |
| Example 4 | 217.4 |
| Example 5 | 209.7 |
| Comparative example 3 | 268.5 |
TABLE 2 appearance of the nano-sized ophthalmic milks of examples 1 to 5 and comparative example 3 after standing at room temperature for 1 month
| Group name | Appearance after standing at room temperature for 1 month |
| Example 1 | Uniform milky white color, no oil drop and stratification on the liquid surface, and stability |
| Example 2 | Uniform milky white color, no oil drop and stratification on the liquid surface, and stability |
| Example 3 | Uniform milky white color, no oil drop and stratification on the liquid surface, and stability |
| Example 4 | Uniform milky white color, no oil drop and stratification on the liquid surface, and stability |
| Example 5 | Uniform milky white color, no oil drop and stratification on the liquid surface, and stability |
| Comparative example 3 | Milky white, oil-dripping on the surface, slight delamination, and instability |
As can be seen from the comparison of the detection results in table 1, the shearing force of the nano-sized ophthalmic milks of examples 1 to 5 and comparative example 3 has a great influence on the average particle size of the nano-sized ophthalmic milks during the preparation process. The shearing force is too small, resulting in too large a particle size of the eye emulsion. The results in table 2 show that the nano eye milk sample prepared by the technical scheme of the invention is stable, and the eye milk prepared by the comparative example 3 has a layering phenomenon after 1 month, and is not stable.
Application example 2: in vitro Release test for Tacrolimus NanoculiOpal emulsions prepared in examples 1 and 5 and comparative examples 1, 2, 4 and 5 the Tacrolimus NanoculiOpal emulsions prepared in examples 1 and 5 and comparative examples 1, 2, 4 and 5 were subjected to an in vitro Release test, and a drug Release test was performed in a diffusion cell using a 5 μm artificial fiber membrane as a permeation material, a 25% ethanol solution as a receiving medium, a feeding chamber for 0.2mL of an administration amount, a receiving cell volume of 7mL, and an effective permeation area of 3.14cm2. The diffusion cell is placed in a constant temperature water bath (37 +/-0.5 ℃), and a magnetic stirrer is placed under the constant temperature water bath at the stirring speed of 300 r/min. 5mL of receiving solution is taken out at 15min, 30min, 45min, 1h, 2h, 4h, 8h, 10h, 12h, 14h, 16h, 18h and 20h respectively, and simultaneously blank receiving solution with the same volume is supplemented. Centrifuging the obtained sample, collecting supernatant, analyzing the receiving solution by liquid chromatography, and dividing the drug release amount by the drug release time to obtain the drug release rate.
The specific calculation method of the drug release speed is as follows: assuming that the total amount of the drug is w, the release amount of the drug at 15min is w0The cumulative release amount of the drug at 30min is w1And the release rate of the drug at 15min is (w)0The release rate of the medicine is (w) at 30 min/0.251–w0)/0.25. In addition, (w)00.25 of/w)/0.25, is 15min, i.e. 0.25 h; (w)1–w0) 0.25 in/0.25 is 30 min-15 min, i.e. 0.25 h). The drug release profiles of the nano-sized ophthalmic milks of examples 1 and 5 and comparative examples 1, 2, 4 and 5 are plotted, as shown in fig. 1 and 2.
As can be seen from fig. 1, the tacrolimus nano ophthalmic emulsions prepared in examples 1 and 5 have a first peak release rate within about 45min after administration and a second peak release rate within about 12h after administration, i.e. have two peak release rates at the same time. The existing tacrolimus eye drops on the market are administrated once every twelve hours, but the sample of the invention has a second drug release speed peak value about 12 hours after the administration, has the characteristic of pulse drug release, and can be closely connected with the effective drug treatment concentration in the local part of the eye.
As can be seen from fig. 2, the tacrolimus nano ophthalmic emulsions prepared in comparative examples 1, 2, 4 and 5 have only one peak value of the release rate after administration, and although the release amount at the peak value is high, the subsequent release amount is rapidly reduced, and the effect of pulse release cannot be achieved. The results in fig. 2 show that the pH of either the formulation or the system has a decisive influence on the pulsing effect of the drug release.
Application example 3: pharmacodynamic experiment for inhibiting rabbit eye cornea transplantation rejection reaction by tacrolimus nano eye emulsion prepared in examples 1, 4 and 5 and comparative examples 2 and 4
1. The rabbit is used for establishing an eye cornea transplantation operation model through an operation, and on the 3 rd day after the cornea transplantation operation, the situations of infection, hyphema, hypapheresis or postoperative iris incarceration, hyphema, crystal turbid eyes and the like caused by operation factors are eliminated. 15 rabbits were randomly divided into 5 groups of 3 rabbits each, and tacrolimus nano ophthalmic milk prepared in examples 1, 4 and 5 and comparative examples 2 and 4 was respectively added dropwise. Each group was administered 1 drop per day for 1 drop at the time starting on the third day after the operation for two weeks.
2. Observation method and index: on the 14 th day after operation, the corneal graft was observed under slit lamp, and the three indices of turbidity, edema and neovascularization were scored according to the scoring criteria shown in Table 3 below. The sum of the three scores is the Rejection Index (RI) of the day. The lower the total score, the better the graft effect and the weaker the immunological rejection.
TABLE 3 corneal transplantation postoperative rejection score criteria
| Clinical observations of corneal implants | Scoring |
| A. |
0 to 4 minutes |
| The corneal implant is completely transparent | 0 |
| Mild cloudiness of |
1 |
| Corneal implants were more turbid, but iris texture was still visible | 2 |
| The corneal iris has unclear texture but the pupil contour is visible | 3 |
| The corneal graft is totally turbid and unclear in the |
4 |
| B. Edema of |
0 to 4 minutes |
| Corneal implant without |
0 |
| Mild thickening of |
1 |
| Diffuse edema of |
2 |
| Diffuse edema of corneal stroma with small |
3 |
| |
4 |
| C. Cornea implant |
0 to 4 minutes |
| No new blood vessel of |
0 |
| The new blood vessel appears around the |
1 |
| Peripheral part of angiogenesis graft (da chuang yuan) | 2 |
| The new blood vessels reach the middle periphery of the |
3 |
| New blood vessel |
4 |
| Maximum total integral | 12 |
4. Scores of graft turbidity, edema and neovascularization of each group of rabbits at 14 days after the corneal transplantation are specifically shown in the following table 4.
TABLE 4 results of inhibition of rabbit eye corneal graft rejection by the nano-ocular milk of examples 1, 4, 5 and comparative examples 2, 4
As can be seen from table 4 above, the nano eye creams prepared by the technical solutions of examples 1, 4 and 5 have significantly better inhibitory effect on corneal graft rejection. The eye milk of the comparative examples 2 and 4 only has one peak value of drug release speed, lacks the characteristic of pulse drug release, does not form a second peak value of drug release speed 12-13 hours after the drug delivery, and may influence the effective drug concentration and further influence the treatment effect, so the immune rejection score result is obviously worse.
Statistics were recorded on the survival time of corneal grafts from each group of rabbits, and the total observation time of the experiment was 60 days, and the observation period was 1 dose and 1 drop per day, and the specific results are shown in table 5 below.
TABLE 5 survival time of rabbit corneal grafts from examples 1, 4, 5 and comparative examples 2, 4 groups
| Group name | Survival time of corneal graft (d) | Average survival time (d) | Memory survival rate during observation period |
| Example 1 | 60、60、60 | 60 | 100％ |
| Example 4 | 60、60、60 | 60 | 100％ |
| Example 5 | 60、60、60 | 60 | 100％ |
| Comparative example 2 | 45、52、60 | 52.3 | 33.3％ |
| Comparative example 4 | 37、60、49 | 48.7 | 33.3％ |
As can be seen from Table 5, when the nano eye drops prepared in examples 1, 4 and 5 were used for rabbit corneal transplantation, the corneal graft survived in the observation period, while the rabbit survival periods of comparative examples 2 and 4 were significantly lower than the examples of the present invention, indicating that the tacrolimus eye drops having sustained-release prolonged release time and two drug release peaks provided by the present invention have better clinical effects, not only reducing the frequency of drug administration and improving the compliance of drug administration, but also have better clinical treatment effects, and have good clinical application prospects.
Claims (6)
1. The tacrolimus nano eye drops are characterized by comprising the following components in percentage by mass: 0.05-0.2% of tacrolimus, 1880.1-0.5% of poloxamer, 0.1-0.5% of polycarbophil, 0.8-1.5% of medium-chain fatty glyceride, 1-2% of glycerol dioleate, 1.5-2.8% of glycerol, 0.5-4.0% of polyoxyethylene hydrogenated castor oil and the balance of deionized water;
the tacrolimus nano eye milk comprises the following steps:
s1, stirring tacrolimus, glyceryl dioleate, medium-chain fatty glyceride and polyoxyethylene hydrogenated castor oil at 45-70 ℃ for 20min to obtain a mixed solution I;
s2, stirring 60% of the total amount of the deionized water, poloxamer 188 and glycerol at normal temperature at 200-1000 rpm for 30-60 min to obtain a mixed solution II;
s3, adding the mixed solution II into the mixed solution I at the temperature of 60-75 ℃, shearing and emulsifying for 10-40 min at 8000-15000 rpm, and filtering with a 0.22 mu m filter membrane to obtain a mixed solution III;
s4, adding polycarbophil into the residual 40% of deionized water, stirring for 30-60 min at 40-60 ℃, and then sterilizing for 10min at 120 ℃ to obtain a mixed solution IV;
and S5, adding the mixed solution III into the mixed solution IV, stirring at 200-800 rpm for 10-30 min, and adjusting the pH value to 5.5-6.5 to obtain the eye milk.
2. The tacrolimus nano eye milk according to claim 1, which is characterized by comprising by mass percent: tacrolimus 0.12%, poloxamer 1880.3%, polycarbophil 0.4%, medium-chain fatty glyceride 1.2%, glyceryl dioleate 1.2%, glycerol 2.2%, polyoxyethylene hydrogenated castor oil 1.6%, and the balance of deionized water.
3. The tacrolimus nano eye milk according to claim 1 or 2, wherein the polyoxyethylene hydrogenated castor oil is at least one of polyoxyethylene 35 hydrogenated castor oil and polyoxyethylene 40 hydrogenated castor oil.
4. The tacrolimus nano ophthalmic milk according to the claim 1, wherein in the step S3, the shearing and emulsifying conditions are as follows: shearing and emulsifying at 70 deg.C and 12000rpm for 25 min.
5. The tacrolimus nano ophthalmic milk according to the claim 1, wherein in the step S5, the pH value is adjusted to 6.0.
6. The tacrolimus nano eye milk according to claim 1, wherein the average particle size of the prepared eye milk is 160-220 nm.
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