Therapeutic substance-loaded zwitterionic eye drops and preparation method thereof

Abstract

The invention discloses a therapeutic substance-loaded zwitterionic eye drop which comprises a therapeutic substance, zwitterionic gel and a buffer solution, and the zwitterionic gel comprises a polymer containing a first structural unit and a second structural unit; the invention also discloses a preparation method of the zwitterionic eye drops. The preparation method comprises the following steps: step S100, premixing other components except the therapeutic substance; and step S200, adding the therapeutic substance to prepare the zwitterionic eye drops. According to the invention, the zwitterionic gel is used as a carrier, so that the zwitterionic gel not only has excellent biocompatibility and excellent adaptability to an ionic environment, but also can be better combined with a treatment object to achieve the effect of slow release of the medicine and improve the treatment effect.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a zwitterionic eye drop loaded with a therapeutic substance and a preparation method thereof. Background Art

[0002] Dry eye syndrome, also known as dysfunctional tear syndrome, refers to ocular surface damage and discomfort symptoms caused by an imbalance in the tear film's homeostasis, often manifested as dry eyes, easy fatigue, itchy eyes, blurred vision, fluctuating vision, foreign body sensation, painful and burning sensation, sticky secretions, fear of wind, fear of light, and sensitivity to external stimuli; sometimes the eyes are too dry and the basic tear production is insufficient, which stimulates reflex tear secretion and causes frequent tearing; in more serious cases, the eyes will become red, swollen, congested, keratinized, the corneal epithelium will be broken and filaments will adhere to it. This damage can cause corneal and conjunctival lesions over time and affect vision.

[0003] Existing treatments for dry eyes usually use gel eye drops, such as carbomer, PVA and other gel eye drops. Carbomer mainly destroys its gel through the ionic environment of the eye to release water to relieve dry eyes, but it cannot solve the dry eye problem from the source. At the same time, due to the extreme sensitivity of carbomer to the ionic environment, its residence time on the ocular surface is very short, which also makes it impossible to treat dry eyes through sustained release after drug loading; other materials such as PVA and other common ophthalmic materials will dissolve slowly in the gel state and cannot relieve dry eye symptoms at the appropriate time.

[0004] In addition, the raw materials of the eye drops currently on the market can easily destroy the stability of the tear film structure during the interaction between the eye drops and the tear film. The ability of the lipid layer in the tear film to resist tear evaporation is weakened, and while replenishing tears, it also destroys its "water retention" ability, thus treating the symptoms but not the root cause.

[0005] Existing eye drop products for treating dry eyes have poor drug loading and sustained-release capabilities. In order to achieve a certain therapeutic effect, users need to increase the frequency of eye drops, generally about 4 to 6 times a day. Frequent use will greatly reduce patients' medication compliance, resulting in poor treatment effects. Summary of the invention

[0006] In order to solve the above technical problems, the present application provides a zwitterionic eye drop loaded with a therapeutic substance, which not only has excellent biocompatibility and excellent adaptability to the ionic environment, but also can better combine with the therapeutic substance to achieve the effect of sustained drug release and enhance the therapeutic effect.

[0007] The present application provides a zwitterionic eye drop loaded with a therapeutic substance, comprising a therapeutic substance, a zwitterionic gel and a buffer solution, wherein the zwitterionic gel comprises a polymer containing a first structural unit and a second structural unit, wherein the general structural formula of the first structural unit is:

[0008]

[0009] The general structural formula of the second structural unit is:

[0010]

[0011] Wherein, the degree of polymerization is represented by y and x, wherein the value of y is 40 to 700, and the value of x is 100 to 2000;

[0012] R1 is nCH2, where n is a natural number from 1 to 10;

[0013] R2 is mCH2, m is a natural number of 1-10; M is a phosphorylcholine group or a sulfobetaine group;

[0014] R3 is zCH2, z is a natural number of 1-10; and M' is a carboxybetaine group.

[0015] Optionally, the polymer contains 5-15 mol% of the first structural unit and 85-95 mol% of the second structural unit. Optionally, the polymer contains 10 mol% of the first structural unit and 90 mol% of the second structural unit. Optionally, the value of the degree of polymerization y is 40-200, and the value of x is 100-500.

[0016] Optionally, the value of the degree of polymerization y is 40-60, and the value of x is 100-120.

[0017] Optionally, the first structural unit is:

[0018]

[0019] Optionally, the second structural unit is:

[0020]

[0021] Optionally, the zwitterion eye drops contain 6 to 15 wt % of zwitterion gel.

[0022] Optionally, the viscosity of the zwitterionic eye drops is 9 to 12 Pa·s.

[0023] Optionally, the molecular weight of the zwitterionic gel is 30,000 to 1,000,000.

[0024] Optionally, the charge percentage of the zwitterionic gel is 5-15%.

[0025] Optionally, in the zwitterionic eye drops, the therapeutic substance content is 2 to 4 wt%.

[0026] Optionally, the therapeutic agent is at least one of pilocarpine, cyclosporine A, diquafosol sodium, ofloxacin, tobramycin, gatifloxacin, acyclovir, ganciclovir, ribavirin, acetazolamide, dexamethasone, and indomethacin.

[0027] Optionally, the therapeutic substance is a therapeutic substance with an anionic charge.

[0028] Optionally, the therapeutic substance is diquafosol sodium, and in a simulated ocular surface tear environment, the release rate of the therapeutic substance of the zwitterionic eye drops in the first time is 99%-100%;

[0029] The first time is from T0 to T1, and the duration is 20 to 30 hours.

[0030] Optionally, the release rate of the zwitterion eye drops during the second time is 50% to 70%;

[0031] The second time is from T0 to T2, and the duration is 8 to 12 hours.

[0032] The present application also provides a method for preparing zwitterionic eye drops, comprising:

[0033] Step S100, premixing other components except the therapeutic substance;

[0034] Step S200, adding the therapeutic substance to prepare zwitterion eye drops.

[0035] Optionally, the step S100 specifically includes:

[0036] Step S110, preparing zwitterionic gel;

[0037] Step S120, mixing the prepared zwitterionic gel with the buffer solution;

[0038] The step S110 specifically includes:

[0039] Step S111, taking a zwitterionic monomer, methacryloyloxyethyl trimethylammonium chloride (MTAC monomer), and a reaction solvent and mixing them to form a premixed system, wherein the total mass concentration of the two monomers is 30-50%;

[0040] Step S112, reacting under oxygen isolation conditions to obtain the zwitterionic gel.

[0041] Optionally, in the step S111, a zwitterionic surfactant is further added; wherein the zwitterionic surfactant is lauryl betaine, and based on the premixed system, the amount of the lauryl betaine is 0.02-2wt%.

[0042] Optionally, in the step S111, an initiator and a catalyst are also added; wherein the initiator is APS, and the amount of the initiator is 0.2-8 wt % based on the premixed system;

[0043] The catalyst is TEMED, and based on the premixed system, the amount of the catalyst is 0.2-8 wt %.

[0044] Optionally, in the step S111, after the reaction under oxygen-free conditions, unreacted monomers, initiators, catalysts and zwitterionic surfactants are separated and removed by post-treatment to obtain the zwitterionic gel.

[0045] Optionally, the molar ratio of the zwitterionic monomer to methacryloyloxyethyltrimethylammonium chloride (MTAC monomer) is 85:15 to 95:5.

[0046] Optionally, the reaction solvent is phosphate buffered saline (PBS).

[0047] Optionally, the buffer is phosphate buffered saline (PBS).

[0048] The reaction solvent is an auxiliary reagent in the process of preparing the zwitterionic gel, and the buffer is a diluent for the zwitterionic gel. The dosages of the reaction solvent and the buffer are independent of each other.

[0049] Optionally, the zwitterionic gel is formed by polymerizing a betaine zwitterionic monomer containing a phosphorylcholine group (MPC monomer) and methacryloyloxyethyl trimethylammonium chloride (MTAC monomer), and the structural formula of the betaine zwitterionic monomer containing a phosphorylcholine group is:

[0050]

[0051] Optionally, the zwitterionic gel is formed by polymerizing a carboxyl-containing betaine zwitterionic monomer (CB monomer) and methacryloyloxyethyl trimethylammonium chloride (MTAC monomer), and the structural formula of the carboxyl-containing betaine zwitterionic monomer is:

[0052]

[0053] Optionally, the zwitterionic gel is formed by polymerizing a betaine zwitterionic monomer (SB monomer) containing a sulfonic group and methacryloyloxyethyl trimethylammonium chloride (MTAC monomer), and the structural formula of the betaine zwitterionic monomer containing a sulfonic group is:

[0054]

[0055] The zwitterion eye drops of the present application have at least one of the following technical effects:

[0056] 1. The zwitterionic eye drops of the present application have excellent biocompatibility. Due to the presence of zwitterionic superhydrophilic groups in the eye drops, ionic crosslinking is formed through the action of charges, and the superhydrophilic groups are more firmly aggregated together, with excellent water binding ability, forming an ion hydration layer to prevent protein deposition, making the structure of the mucin layer, water layer and lipid layer of the tear film more stable, and the natural fusion effect of the material and the physiological structure is better;

[0057] 2. The zwitterionic eye drops of the present application are more suitable for ionic environments. Compared with the sensitivity of carbomer to ionic solutions and the slow dissolution of PVA under high viscosity, the present application has better adaptability to ionic environments. Although the zwitterionic gel is hydrophilic, its structure is sensitive to non-ionic environments. It will not be instantly destroyed when it comes into contact with tears, nor will it stay on the ocular surface for a long time without dissolving like PVA gel. The zwitterionic gel of the present application will gradually dissolve after staying on the ocular surface for a suitable period of time, with a longer water storage time and a stronger drug loading capacity;

[0058] 3. The zwitterionic eye drops prepared in the present application contain cationic polymer chains. The polymer structure can better combine with anionic charged therapeutic substances, especially diquafosol sodium, which has an excellent therapeutic effect on dry eye. It has a stronger and more effective adsorption effect (positive and negative charge attraction characteristics), and the drug sustained release ability is much better than other gel products and solutions with the same viscosity. It can also effectively reduce the number of medications, improve medication compliance, and improve the treatment effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 The present invention is a flow chart of the method for preparing the zwitterionic eye drops.

[0060] Figure 2 The drug release curves of fluorescein sodium for different products are shown;

[0061] Figure 3 The drug release curves of diquafosol sodium for different products are shown. DETAILED DESCRIPTION

[0062] The following will be combined with the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0063] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0064] In the present application, the dosage form of "eye drops" includes, for example, eye drop gel, eye drop ointment, eye drop solution, and eye drop. Eye drops for contact lenses are also included in the definition of eye drops.

[0065] The present application provides a zwitterionic eye drop loaded with a therapeutic substance, comprising a therapeutic substance, a zwitterionic gel and a buffer solution, wherein the zwitterionic gel comprises a polymer containing a first structural unit and a second structural unit, and the general structural formula of the first structural unit is:

[0066]

[0067] The general structural formula of the second structural unit is:

[0068]

[0069] Wherein, the degree of polymerization is represented by y and x, wherein the value of y is 40 to 700, and the value of x is 100 to 2000;

[0070] R1 is nCH2, n is a natural number of 1-10, preferably n=2;

[0071] R2 is mCH2, m is a natural number of 1-10, preferably m=2; M is a phosphorylcholine group or a sulfobetaine group;

[0072] R3 is zCH2, z is a natural number of 1-10, preferably z=3; M' is a carboxybetaine group.

[0073] The specific structural formulas of M are:

[0074]

[0075] The structural formula of M' is:

[0076]

[0077] The zwitterionic eye drops of the present application contain cationic polymer chains, which have positive and negative charge attraction properties with the loaded therapeutic substance, and can better combine with the anionic charged therapeutic substance, especially having a stronger and more effective adsorption effect on diquafosol sodium, which has an excellent therapeutic effect on dry eye, thereby achieving the effect of sustained drug release and improving the therapeutic effect. It can further effectively reduce the number of medication times, improve medication compliance, and improve the therapeutic effect.

[0078] The zwitterionic eye drops of the present application contain zwitterionic superhydrophilic groups, which can form ionic crosslinks through the action of charges. The superhydrophilic groups are more firmly aggregated together and have excellent ability to bind water, that is, excellent "water retention" properties, forming an ion hydration layer to prevent protein deposition, thereby making the structure of the mucin layer, water layer and lipid layer of the tear film more stable.

[0079] The amphiphilic characteristics of the zwitterionic gel provided in this application just meet the above requirements. When the tear film becomes thinner, the concentration of mucin in the lipid layer will increase accordingly, forming a dense polymer network. At this time, the "water retention" property of the zwitterionic gel will inhibit the evaporation of the aqueous layer of the tear film. It can be seen that the zwitterionic eye drops of this application can not only provide more sufficient water for the ocular surface of patients with dry eye, but also have the properties of the raw materials, resist protein adsorption, and maintain the stability of the tear film.

[0080] In addition, although the zwitterionic gel of the present application is hydrophilic, its structure is non-ionic and environmentally sensitive, and it will not be destroyed instantly when it contacts tears, nor will it stay on the ocular surface for a long time without dissolving like the existing PVA gel. It can be seen that the zwitterionic gel of the present application has good gel retention and gradually dissolves after staying on the ocular surface for a long time. It can be seen that the eye drops of the present application have a longer water storage time and a stronger drug loading capacity, further improving the drug utilization rate.

[0081] The polymer in the zwitterionic gel contains 5-15 mol% of the first structural unit and 85-95 mol% of the second structural unit. Preferably, the zwitterionic gel contains 10 mol% of the first structural unit and 90 mol% of the second structural unit.

[0082] The polymer preferably has a lower degree of polymerization, preferably, the value of y is 40-200, and the value of x is 100-500. More preferably, the value of y is 40-60, and the value of x is 100-120.

[0083] Preferably, when R1 is 2CH2, the first structural unit is:

[0084]

[0085] When R2 is 2CH2, the second structural unit is:

[0086] Hereinafter referred to as formula (1); or Hereinafter referred to as formula (2).

[0087] When R3 is 3CH2, the second structural unit is:

[0088] Hereinafter referred to as formula (3).

[0089] The main structural difference of the above-mentioned polymers is the anionic groups in the zwitterions, namely phosphorylcholine group (MPC), carboxybetaine group (CB) and sulfobetaine group (SB). All three zwitterionic polymers contain cationic charge polymerization structures and have stronger adsorption effects on anionic charged drugs such as diquafosol sodium.

[0090] Among them, SB has quaternary ammonium salt cations and sulfonic acid anions, and has better surface properties. The strongly alkaline quaternary ammonium salt ions are balanced with the equally strong acidic sulfonic acid ions, and no internal salt is formed. SB is acid and alkali resistant, anti-protein adsorption, bactericidal, anti-fungal and has good viscoelasticity. SB is more suitable for dry eye symptoms caused by an imbalanced intraocular environment and comprehensive etiology.

[0091] CB and MPC are more water-soluble because their strongly alkaline quaternary ammonium ions and weakly acidic carboxylic acid ions or phosphate ions form internal salts (slightly alkaline), making them more suitable for dry eye diseases that require rapid relief of dryness and have an acidic internal environment.

[0092] In some embodiments, the zwitterion eye drops contain 6-15 wt% of zwitterion gel, and the viscosity of the zwitterion eye drops is 9-12 Pa·s. Preferably, the molecular weight of the zwitterion gel is 30,000-1,000,000, and the charge percentage is 5%-15%.

[0093] The zwitterion eye drops also include 2-4 wt% of the therapeutic substance content, which is compatible with the dosage of the zwitterion gel and has a good loading effect. The remaining components in the zwitterion eye drops are buffer solutions, which play a role in dilution and concentration adjustment.

[0094] In some embodiments, the therapeutic agent may be at least one of pilocarpine, cyclosporine A, diquafosol sodium, ofloxacin, tobramycin, gatifloxacin, acyclovir, ganciclovir, ribavirin, acetazolamide, dexamethasone, and indomethacin.

[0095] In some embodiments, the therapeutic agent is an anionic therapeutic agent, and the adsorption effect on the zwitterionic gel with a cation charge is better.

[0096] Preferably, when the therapeutic substance loaded by the zwitterionic gel is diquafosol sodium (i.e., a small molecule with an anionic charge), in a simulated ocular surface tear environment, the release rate of diquafosol sodium in the zwitterionic eye drops within the first time is 99%-100%; the first time is T0 to T1, and the duration is 20 to 30 hours.

[0097] In the second time of the zwitterion eye drops, the release rate of diquafosol sodium is 50% to 70%; the second time is from T0 to T2, and the duration is 8 to 12 hours.

[0098] More specifically, the release rate of quafosol sodium from the zwitterion eye drops is 50%-60% within 0 to 8 hours; the release rate of quafosol sodium within 12 hours is 65%-70%; the release rate of quafosol sodium within 16 hours is 75%-80%; and the release rate of quafosol sodium within 24 hours is 99%-100%.

[0099] refer to Figure 1 The present application provides a method for preparing zwitterionic eye drops, comprising:

[0100] Step S100, premixing other components except the therapeutic substance, i.e., mixing and diluting the zwitterionic gel and the buffer;

[0101] Step S200, adding the therapeutic substance to prepare zwitterion eye drops.

[0102] In the above-mentioned mixed system, the amount of zwitterionic gel is 6-15wt%, the amount of therapeutic substance is 2-4wt%, and the rest is buffer solution. Preferably, the buffer solution is phosphate buffer solution (PBS) with a concentration of 0.1mol / L and a pH of 7.2±0.2.

[0103] Preferably, step S100 specifically includes:

[0104] Step S110, preparing zwitterionic gel;

[0105] Step S120, mixing the prepared zwitterionic gel with the above-mentioned buffer solution;

[0106] Preferably, the preparation of the zwitterionic gel in step S110 specifically includes the following steps:

[0107] Step S111, taking a zwitterionic monomer (providing the second structural unit), methacryloyloxyethyl trimethylammonium chloride (MTAC monomer, providing the first structural unit), and a reaction solvent and mixing them;

[0108] Step S112, reacting under oxygen isolation conditions to obtain the zwitterionic gel.

[0109] In step S111, the molar ratio of zwitterionic monomer to methacryloyloxyethyl trimethylammonium chloride (MTAC monomer) is 85:15 to 95:5. Zwitterionic monomers can be monomers with phosphorylcholine groups (MPC), carboxybetaine groups (CB) and sulfobetaine groups (SB), and the reaction solvent is phosphate buffer solution (PBS, concentration is 0.1 mol / L). The dosage can be obtained according to the feed ratio of other solutes and the total concentration. The structural formulas of MPC monomer, SB monomer and CB monomer are as follows:

[0110]

[0111] In step S111, a zwitterionic surfactant may be added, for example, lauryl betaine (LB) is selected. LB is a hydrophobic component with good compatibility and excellent thickening properties.

[0112] In step S111, an initiator and a catalyst may also be added; wherein the initiator is a PBS solution of ammonium persulfate (APS).

[0113] For example, during the mixing process, phosphate buffered saline (PBS) is added first, followed by ammonium persulfate (APS) in PBS. As an initiator for polymer synthesis, ammonium persulfate (APS) must be added after other solutes are evenly mixed in PBS. Otherwise, if ammonium persulfate is added directly, the raw materials will polymerize, so APS needs to be added later.

[0114] For example, a catalyst for catalyzing ammonium persulfate (APS), i.e., tetramethylethylenediamine (TEMED), may also be added. In step S111, after the reaction under oxygen-free conditions, unreacted monomers and auxiliary agents are separated and removed by post-treatment, wherein the auxiliary agents are initiators, catalysts, and zwitterionic surfactants, to obtain zwitterionic gel. In this case, when the catalyst is not completely reacted, the monomers are substantially all reacted.

[0115] In combination with the above preferred solution, the preparation of zwitterionic gel specifically includes the following steps:

[0116] Betaine zwitterion monomer and methacryloyloxyethyl trimethylammonium chloride (MTAC monomer) are dissolved in phosphate buffer solution (PBS), vortexed and ultrasonicated to clarify to form a premixed system, wherein the total mass concentration of the two monomers in the premixed system is 30%-50%, and the amount of PBS is calculated according to the total concentration of the two monomers. The amount relationship between the two monomers can be determined by a molar ratio, for example, the amount of the betaine zwitterion monomer is 85-95 mol%, and the amount of the MTAC monomer is 5-15 mol%.

[0117] Based on the premixed system (understood as the total weight of zwitterionic surfactant, initiator and catalyst before feeding), 0.02-2wt% of lauryl betaine (LB) was added;

[0118] Then add 0.2-8wt% ammonium persulfate (APS) solution in PBS and vortex mix evenly;

[0119] Then add 0.2-8wt% tetramethylethylenediamine (TEMED), vortex mix evenly, seal with sealing film to isolate oxygen, and fully react for 24 hours. During the reaction, the solution gradually turns yellow, and after the reaction is completed, it obviously changes from a solution state to a gel state;

[0120] Finally, the unreacted monomers, initiators, catalysts and zwitterionic surfactants were removed by dialysis purification to obtain zwitterionic gel.

[0121] Preferably, the zwitterionic gel can be formed by polymerizing a betaine zwitterionic monomer containing a phosphorylcholine group (MPC monomer) and methacryloyloxyethyltrimethylammonium chloride (MTAC monomer), and the polymer contains the second structural unit of the above formula (1) (hereinafter referred to as MPC polymer).

[0122] The zwitterionic gel can also be formed by polymerizing a betaine zwitterionic monomer (SB monomer) containing a sulfobetaine group and methacryloyloxyethyltrimethylammonium chloride (MTAC monomer), and the polymer contains the second structural unit of the above formula (2) (hereinafter referred to as SB polymer).

[0123] The polymer can also be formed by polymerizing a betaine zwitterionic monomer (CB monomer) containing a carboxy betaine group and methacryloyloxyethyl trimethyl ammonium chloride (MTAC monomer), and the polymer contains the second structural unit of the above formula (3) (hereinafter referred to as CB polymer).

[0124] The zwitterionic gel can also be formed by polymerizing any two or three of the above-mentioned MPC monomer, SB monomer, and CB monomer with MTAC monomer.

[0125] The specific synthetic routes of the above three types of polymers are as follows:

[0126] When the betaine zwitterion monomer adopts the above-mentioned MPC monomer, the synthesis route of the zwitterion gel is:

[0127]

[0128] When the betaine zwitterionic monomer is the above-mentioned CB monomer, that is, 3-{dimethyl[5,5,7-trimethyl-4,8-dioxy-1-(trimethyl nitrogen cation radical)-9-aza-3-oxadodecane-12-yl] nitrogen cation radical}propionate ion, the synthesis route of the zwitterionic gel is:

[0129]

[0130] When the betaine zwitterion monomer is the above-mentioned SB monomer, that is, 3-{dimethyl[5,5,7,7-tetramethyl-4,8-dioxy-11-(trimethyl nitrogen cation radical)-3,9-dioxaundecane-1-yl] nitrogen cation radical}propane-1-sulfonate ion, the synthesis route of the zwitterion gel is:

[0131]

[0132] Compared with the traditional synthesis method, the above synthesis method has the following advantages:

[0133] 1. This synthesis method does not require high temperature and high pressure treatment, and can be achieved by simple vortex mixing, which is simple and easy to operate;

[0134] 2. The raw materials used in this synthesis method can be purchased directly on the market, without the need for secondary synthesis, and are convenient and easy to obtain;

[0135] 3. This synthesis method does not require the use of large equipment, only vortex mixing facilities and molds are required;

[0136] 4. The raw materials used in this synthesis method are non-toxic and harmless, and the polymer materials produced have good stability and good repeatability, and there is a great possibility of mass production in the future.

[0137] Based on the fact that there are various types of polymers in the above-mentioned zwitterionic gel, preferably, in the process of preparing zwitterionic eye drops, 10wt%-12wt% of MPC polymer, or 12wt%-15wt% of CB polymer, or 6wt%-10wt% of SB polymer can be selected. The polymer is mixed and diluted with a buffer solution and a therapeutic substance, and the viscosity after dilution reaches 9 to 12 Pa·s.

[0138] In summary, the present application uses zwitterionic gel as a carrier, which can load therapeutic substances and has excellent drug sustained release effect, and can be well applied to the treatment of dry eye in the future. The present application achieves the following technical effects:

[0139] 1) The zwitterionic gel prepared in the present application is insensitive to the ionic environment on the surface of the eye and can remain in a gel state without dissolving within 24 hours after being dropped into the eye, effectively prolonging the residence time of the gel on the ocular surface, solving the problem that "eye drops" and carbomer gels cannot stay on the ocular surface for a long time;

[0140] 2) The gel component in the eye drops of the present application contains cationic polymer groups, which can enhance the loading capacity of anionic charged drugs and prolong the drug release time to achieve the effect of slow release of drugs, greatly improving the utilization rate of loaded therapeutic substances; in addition, based on the slow release of loaded therapeutic substances, the eye drops have little irritation to the ocular surface, effectively improving the comfort of eye drops (appropriate osmotic pressure, viscosity, slow drug release, etc.), which is conducive to improving patient compliance.

[0141] 3) The zwitterionic gel prepared in the present application has excellent amphiphilicity and anti-protein adsorption properties, which can enhance the stability of the tear film, thereby ensuring that the material does not destroy the anti-evaporation ability of the lipid layer of the tear film during use.

[0142] Examples 1 to 9 are preparation examples, and zwitterionic gels are prepared by referring to step 110 in the preparation method of the zwitterionic gel described above. The reaction solvent involved in the following examples is a PBS solution, and the concentration is 0.1 mol / L, and the pH is 7.2±0.2. The concentrations mentioned in the following examples are all mass concentrations unless otherwise specified.

[0143] Example 1 Preparation of zwitterionic gel

[0144] Referring to step S110, a zwitterionic gel was prepared, and the specific operation was as follows: MPC monomer and methacryloyloxyethyl trimethyl ammonium chloride (MTAC monomer) were dissolved in phosphate buffer solution (PBS), vortexed and ultrasonicated to clarify, to form a premixed system, the total mass concentration of the two monomers was 41.7%, and the dosage relationship between the two monomers was: the dosage of MPC monomer was 85 mol%, and the dosage of MTAC monomer was 15 mol%;

[0145] Based on the premixed system, lauryl betaine (LB) was added in an amount of 0.02wt%;

[0146] Then add 0.2 wt % ammonium persulfate (APS) solution in PBS and vortex mix evenly;

[0147] Then add 0.2 wt% tetramethylethylenediamine (TEMED) and vortex mix evenly;

[0148] The premixed system was sealed with a sealing film to isolate oxygen from the reaction. After reacting for 24 hours, it was dialyzed and purified to remove unreacted monomers and monomers, initiators, catalysts and zwitterionic surfactants to obtain zwitterionic gel.

[0149] Example 2 Preparation of zwitterionic gel

[0150] Referring to step S110, a zwitterionic gel was prepared, and the specific operation was as follows: MPC monomer and methacryloyloxyethyl trimethyl ammonium chloride (MTAC monomer) were dissolved in phosphate buffer solution (PBS), vortexed and ultrasonicated to clarify to form a premixed system, the total mass concentration of the two monomers was 41.7%, wherein the amount of MPC monomer was 90 mol%, and the amount of MTAC monomer was 10 mol%;

[0151] Based on the premixed system, lauryl betaine (LB) was added in an amount of 0.2wt%;

[0152] Then add 4 wt % ammonium persulfate (APS) solution in PBS and vortex mix evenly;

[0153] Then add 4 wt % tetramethylethylenediamine (TEMED) and vortex mix evenly;

[0154] The premixed system was sealed with a sealing film to isolate oxygen from the reaction. After 24 hours of reaction, it was dialyzed and purified to remove unreacted monomers and monomers, initiators, catalysts and zwitterionic surfactants to obtain zwitterionic gel (hereinafter also referred to as MPC polymer).

[0155] Example 3 Preparation of zwitterionic gel

[0156] Referring to step S110, a zwitterionic gel was prepared, and the specific operation was as follows: MPC monomer and methacryloyloxyethyl trimethyl ammonium chloride (MTAC monomer) were dissolved in phosphate buffer solution (PBS), vortexed and ultrasonicated to clarify, to form a premixed system, the total mass concentration of the two monomers was 41.7%, wherein the amount of MPC monomer was 95 mol%, and the amount of MTAC monomer was 5 mol%;

[0157] Based on the premixed system, lauryl betaine (LB) was added in an amount of 2wt%;

[0158] Then add 8 wt % ammonium persulfate (APS) solution in PBS and vortex mix evenly;

[0159] Then add 8t% tetramethylethylenediamine (TEMED) and vortex mix evenly;

[0160] The premixed system was sealed with a sealing film to isolate oxygen from the reaction. After reacting for 24 hours, it was dialyzed and purified to remove unreacted monomers and monomers, initiators, catalysts and zwitterionic surfactants to obtain zwitterionic gel.

[0161] Example 4 Preparation of zwitterionic gel

[0162] Referring to step S110, a zwitterionic gel was prepared, and the specific operation was as follows: CB monomer and methacryloyloxyethyl trimethyl ammonium chloride (MTAC monomer) were dissolved in phosphate buffer solution (PBS), vortexed and ultrasonicated until clear, to form a premixed system, the total mass concentration of the two monomers was 37.4%, wherein the amount of CB monomer was 85 mol%, and the amount of MTAC monomer was 15 mol%;

[0163] Based on the premixed system, lauryl betaine (LB) was added in an amount of 0.02wt%;

[0164] Then add 0.2 wt % ammonium persulfate (APS) solution in PBS and vortex mix evenly;

[0165] Then add 0.2 wt% tetramethylethylenediamine (TEMED) and vortex mix evenly;

[0166] The premixed system was sealed with a sealing film to isolate oxygen from the reaction. After reacting for 24 hours, it was dialyzed and purified to remove unreacted monomers and monomers, initiators, catalysts and zwitterionic surfactants to obtain zwitterionic gel.

[0167] Example 5 Preparation of zwitterionic gel

[0168] Referring to step S110, a zwitterionic gel was prepared, and the specific operation was as follows: CB monomer and methacryloyloxyethyl trimethyl ammonium chloride (MTAC monomer) were dissolved in phosphate buffer solution (PBS), vortexed and ultrasonicated to clarify, to form a premixed system, the total mass concentration of the two monomers was 37.4%, wherein the amount of CB monomer was 90 mol%, and the amount of MTAC monomer was 10 mol%;

[0169] Based on the premixed system, lauryl betaine (LB) was added in an amount of 0.2wt%;

[0170] Then add 4 wt % ammonium persulfate (APS) solution in PBS and vortex mix evenly;

[0171] Then add 4 wt % tetramethylethylenediamine (TEMED) and vortex mix evenly;

[0172] The premixed system was sealed with a sealing film to isolate oxygen from the reaction. After 24 hours of reaction, it was dialyzed and purified to remove unreacted monomers and monomers, initiators, catalysts and zwitterionic surfactants to obtain zwitterionic gel (hereinafter also referred to as CB polymer).

[0173] Example 6 Preparation of zwitterionic gel

[0174] Referring to step S110, a zwitterionic gel was prepared, and the specific operation was as follows: CB monomer and methacryloyloxyethyl trimethyl ammonium chloride (MTAC monomer) were dissolved in phosphate buffer solution (PBS), vortexed and ultrasonicated to clarify, to form a premixed system, the total mass concentration of the two monomers was 37.4%, wherein the amount of CB monomer was 95 mol%, and the amount of MTAC monomer was 5 mol%;

[0175] Based on the premixed system, lauryl betaine (LB) was added in an amount of 2wt%;

[0176] Then add 8 wt % ammonium persulfate (APS) solution in PBS and vortex mix evenly;

[0177] Then add 8 wt % tetramethylethylenediamine (TEMED) and vortex mix evenly;

[0178] The premixed system was sealed with a sealing film to isolate oxygen from the reaction. After reacting for 24 hours, it was dialyzed and purified to remove unreacted monomers and monomers, initiators, catalysts and zwitterionic surfactants to obtain zwitterionic gel.

[0179] Example 7 Preparation of zwitterionic gel

[0180] Referring to step S110, a zwitterionic gel was prepared, and the specific operation was as follows: SB monomer and methacryloyloxyethyl trimethyl ammonium chloride (MTAC monomer) were dissolved in phosphate buffer solution (PBS), vortexed and ultrasonicated until clear, to form a premixed system, the total mass concentration of the two monomers was 40.5%, wherein the amount of SB monomer was 85 mol%, and the amount of MTAC monomer was 15 mol%;

[0181] Based on the premixed system, lauryl betaine (LB) was added in an amount of 0.02wt%;

[0182] Then add 0.2 wt % ammonium persulfate (APS) solution in PBS and vortex mix evenly;

[0183] Then add 0.2 wt% tetramethylethylenediamine (TEMED) and vortex mix evenly;

[0184] The premixed system was sealed with a sealing film to isolate oxygen from the reaction. After reacting for 24 hours, it was dialyzed and purified to remove unreacted monomers and monomers, initiators, catalysts and zwitterionic surfactants to obtain zwitterionic gel.

[0185] Example 8 Preparation of zwitterionic gel

[0186] Referring to step S110, a zwitterionic gel was prepared, and the specific operation was as follows: SB monomer and methacryloyloxyethyl trimethyl ammonium chloride (MTAC monomer) were dissolved in phosphate buffer solution (PBS), vortexed and ultrasonicated until clear, to form a premixed system, the total mass concentration of the two monomers was 40.5%, wherein the amount of SB monomer was 90 mol%, and the amount of MTAC monomer was 10 mol%;

[0187] Based on the premixed system, lauryl betaine (LB) was added in an amount of 0.2wt%;

[0188] Then add 4 wt % ammonium persulfate (APS) solution in PBS and vortex mix evenly;

[0189] Then add 4 wt % tetramethylethylenediamine (TEMED) and vortex mix evenly;

[0190] The premixed system was sealed with a sealing film to isolate oxygen from the reaction. After 24 hours of reaction, it was dialyzed and purified to remove unreacted monomers and monomers, initiators, catalysts and zwitterionic surfactants to obtain zwitterionic gel (hereinafter also referred to as SB polymer).

[0191] Example 9 Preparation of zwitterionic gel

[0192] Referring to step S110, a zwitterionic gel was prepared, and the specific operation was as follows: SB monomer and methacryloyloxyethyl trimethyl ammonium chloride (MTAC monomer) were dissolved in phosphate buffer solution (PBS), vortexed and ultrasonicated to clarify, to form a premixed system, the total mass concentration of the two monomers was 40.5%, wherein the amount of SB monomer was 95 mol%, and the amount of MTAC monomer was 5 mol%;

[0193] Based on the premixed system, lauryl betaine (LB) was added in an amount of 2wt%;

[0194] Then add 8 wt % ammonium persulfate (APS) solution in PBS and vortex mix evenly;

[0195] Then add 8 wt % tetramethylethylenediamine (TEMED) and vortex mix evenly;

[0196] The premixed system was sealed with a sealing film to isolate oxygen from the reaction. After reacting for 24 hours, it was dialyzed and purified to remove unreacted monomers and monomers, initiators, catalysts and zwitterionic surfactants to obtain zwitterionic gel.

[0197] Parameter List

[0198] The preparation method of Examples 1 to 9 is used to prepare samples 1 to 9 corresponding to step 110, and the polymer solid content percentage and polymer charge percentage of each sample are measured and calculated respectively. The parameters of each sample are recorded in Table 1.

[0199] Table 1

[0200] sample Polymer solid content% Polymer charge percentage % Sample 1 41.7％ 15％ Sample 2 41.7％ 10％ Sample 3 41.7％ 5％ Sample 4 37.4％ 15％ Sample 5 37.4％ 10％ Sample 6 37.4％ 5％ Sample 7 40.5％ 15％ Sample 8 40.5％ 10％ Sample 9 40.5％ 5％

[0201] The percentage of polymer solid content is based on the mass of the input raw materials and the total mass of the synthesized polymer (including gel and PBS), to measure the percentage of solid content of the input raw materials to the total mass of the zwitterionic gel. The calculation formula is as follows:

[0202] Polymer solid content percentage (%) = (W1 + W2) / W3 * 100%;

[0203] W1 is the mass of zwitterionic monomer, W2 is the mass of MTAC, and W3 is the total mass of zwitterionic gel.

[0204] The polymer charge percentage is calculated based on the molar percentage of the zwitterionic monomer and the MTAC monomer. The calculation formula is as follows:

[0205] Polymer charge percentage (%) = M2 / (M1+M2)*100%;

[0206] Where: M1 is the molar percentage of zwitterionic monomer, M2 is the molar percentage of MTAC monomer. The percentage of charge in the polymer is the molar percentage of MTAC monomer in the total polymer, expressed as %. For example, a polymer containing 10% charge percentage means that the molar percentage of MTAC monomer in the synthesized polymer is 10%.

[0207] The molar percentage of each component can be calculated by the following formula:

[0208] Mole percentage (%) = n' / n*100%;

[0209] n' is the amount of substance corresponding to the zwitterion or MTAC monomer, and n is the total amount of substance of the polymer.

[0210] Example 10 Dilution of zwitterionic gel

[0211] The zwitterionic gels prepared in Example 2, Example 5 and Example 8 were diluted according to step 120, that is, the zwitterionic gels prepared in Example 2, Example 5 and Example 8 were mixed with buffer solution (PBS) and diluted to 6%, 8%, 10%, 12% and 15% (mass concentration), respectively, and the optimal viscosity value of the product was determined by measuring its viscosity.

[0212] The osmotic pressure of all diluted samples was adjusted to the osmotic pressure range of 260-310 mOsm. The viscosity test results of zwitterion gels of different mass concentrations are shown in Table 2 below.

[0213] Table 2

[0214]

[0215] Based on the test results, clinical data and literature reports, too low viscosity of ophthalmic gel is not conducive to drug loading and sustained release, and too high viscosity of gel will cause slow dissolution, slow release and discomfort to patients. Finally, the viscosity of the zwitterionic eye drops selected in this application is preferably 9 to 12 Pa·s. (This is the viscosity range after loading the therapeutic substance. The therapeutic substance is a small molecule and its content will not affect the viscosity)

[0216] Combined with the preferred viscosity range, the preferred range of the amount of the zwitterionic gel in the eye drops of the present application is as follows:

[0217] When the MPC polymer is used in the zwitterionic gel, the amount of the MPC polymer is 10 to 12 wt %;

[0218] When CB polymer is used in the zwitterionic gel, the amount of CB polymer is 12 to 15 wt %;

[0219] When SB polymer is used in the zwitterionic gel, the amount of SB polymer used is 8-10 wt%.

[0220] In order to further observe the dissolution of the above-mentioned zwitterionic gel in a simulated tear environment, the zwitterionic gels prepared in Example 2, Example 5 and Example 8 were diluted to 10%, 12% and 8%, respectively, to obtain MPC polymer gel solution, CB polymer gel solution and SB polymer gel solution, respectively, and then 5g of each polymer gel solution was poured into 10mL, 20mL and 40mL of simulated tears (PBS solution was used in this test), that is, the dissolution of the zwitterionic gel was observed at a ratio of about 1:2, 1:4 and 1:8, respectively. The dissolution of zwitterionic gels with different end groups within 24 hours is shown in Table 3.

[0221] Table 3

[0222]

[0223] Note: The letters in the above figure represent the following meanings:

[0224] A: A large amount of gel is clearly seen; B: A lot of gel is present; C: Some gel is present; D: Very little gel is present; E: No gel is present.

[0225] As can be seen from the table above, the zwitterionic gel can be almost completely dissolved into liquid and dissolved in PBS within 24 hours. The CB polymer gel solution has a better hydrophilicity, so it takes a shorter time to dilute into a pure liquid. Under the conditions of 1:2 and 1:4, the MPC polymer gel solution and the SB polymer gel solution showed more durable performance.

[0226] Example 11 Preparation and release test of zwitterionic eye drops (including comparison)

[0227] Fluorescein sodium is a small molecule with an anionic charge. It is often used as a fluorescent marker for drugs and is widely used in medical clinical experiments (animal experiments) to observe the release of drugs.

[0228] In this example, the zwitterionic gels prepared in Example 2, Example 5 and Example 8 were diluted to 10%, 12% and 8% respectively to obtain MPC polymer gel solution, CB polymer gel solution and SB polymer gel solution respectively, and then mixed with sodium fluorescein. For every 1 ml of the polymer gel solution, 400 μg of sodium fluorescein was added accordingly.

[0229] 0.2% Carbomer gel, 14% PVA gel and 1.5% CMC gel with similar viscosity were selected as comparative proportions to eliminate the influence of different viscosities of the materials on the drug loading capacity.

[0230] Take the 6 groups of gel solutions prepared above (with the same sodium fluorescein loading concentration) and perform drug release test according to the drug release test method in the Chinese Pharmacopoeia. The specific operation is as follows:

[0231] Take 10 mL of the gel solution and transfer it to a dialysis bag with a molecular weight cutoff of 14,000. Then put the dialysis bag into a large beaker filled with 200 mL of PBS. Take 5 mL of the supernatant at 0.25 h, 0.5 h, 1 h, 4 h, 8 h and 24 h, and add 5 mL of PBS to the system.

[0232] The supernatant was taken out and measured by UV spectrophotometry at a wavelength of 485 nm, and a release rate curve was drawn based on the calculated results. Figure 2 As shown, since carbomer cannot exist stably in PBS solution, the gel structure is destroyed and thus there is no release effect.

[0233] Figure 2There are only the release rate curves of MPC polymer gel, CB polymer gel and SB polymer gel, and CMC gel and PVA gel. Through the release rate curve, it can be found that the release of PVA gel is the slowest, because the dissolution rate of PVA gel in PBS solution under the same viscosity as other gels is the slowest, and there is also a large amount of gel in 24h, so drug release is the slowest. The comparison of three kinds of polymer gels of the application with CMC gel can be found that the sudden release phenomenon of CMC gel is obvious in the first 1h, nearly 70%. Because CMC gel does not have amphipathicity, it can not be better fused between liquid and solid phase, so its ability to drug restraint is weaker, and the material charge is the same as the charge property of fluorescein sodium, and like repels each other, so the sudden release phenomenon is obvious in a short time.

[0234] The zwitterionic gel of the present application is amphiphilic, has better drug fusion, and the charge of the material is opposite to that of sodium fluorescein, has stronger adsorption, and therefore releases slowly.

[0235] In summary, this example preliminarily verifies that the three types of zwitterionic gels have a sustained-release effect on drugs containing anionic sodium fluorescein.

[0236] Among them, taking the release of 8h as an example, Figure 2 The five curves in the middle represent the drug release curves of CMC gel solution, CB polymer gel solution, SB polymer gel solution, MPC polymer gel solution, and PVA gel solution from top to bottom.

[0237] Example 12 Preparation of zwitterionic eye drops (loaded with diquafosol sodium) and drug release test (including comparison)

[0238] In order to further demonstrate the sustained release effect of zwitterionic gel on diquafosol sodium, diquafosol sodium was used as the drug for loading in this example.

[0239] Based on research, the concentration of commercially available diquafosol sodium is basically controlled at about 3%, and the concentration of the drug loading in the present application is 2-4%, preferably 2.5%-3.5%.

[0240] In this example, the zwitterionic gels prepared in Example 2, Example 5 and Example 8 were selected and diluted to 10%, 12% and 8% respectively to obtain MPC polymer gel solution, CB polymer gel solution and SB polymer gel solution respectively, and their viscosities were all around 9 Pa·s.

[0241] In this example, 0.2% carbomer gel, 14% PVA gel and 1.5% CMC gel with similar viscosity are selected for comparison, so as to eliminate the influence of different viscosities of materials on drug loading capacity.

[0242] Referring to step 200 of the present application, the diluted zwitterionic gel is mixed with diquafosol sodium to prepare zwitterionic eye drops, wherein the loading concentration of diquafosol sodium is 3%.

[0243] Take the above-prepared 6 groups of eye drops (with the same loading concentration of diquafosol sodium) and perform drug release test according to the drug release test method in the "Chinese Pharmacopoeia". The specific operation is as follows:

[0244] Take 5 mL of eye drops and transfer them to dialysis bags with a molecular weight cutoff of 14,000. Then put the dialysis bags into a large beaker filled with 1,500 mL of PBS. Take 5 mL of supernatant at 0.25 h, 0.5 h, 1 h, 4 h, 8 h and 24 h, and add 5 mL of PBS to the system.

[0245] The supernatant was taken out and measured by UV spectrophotometry at a wavelength of 260 nm, and a release rate curve was drawn based on the calculation results. Figure 3 As shown, since carbomer cannot exist stably in PBS solution, the gel structure is destroyed and thus there is no release effect.

[0246] Figure 3 There are only release rate curves of MPC polymer gel, CB polymer gel, SB polymer gel, CMC gel and PVA gel. It can be found from the release rate curve that PVA gel releases the slowest, because PVA gel has the slowest dissolution rate in PBS solution with the same viscosity as other gels, and there is still a lot of gel after 24 hours, so the drug release is the slowest and the drug is not completely dissolved.

[0247] Comparison of the three polymer gels of the present application with the CMC gel shows that the drug loaded by the polymer gel of the present application is released more slowly. This is because at the same viscosity, due to the positive charge of zwitterions, the adsorption capacity for the negatively charged diquafosol sodium is stronger, while the CMC gel itself is not amphiphilic and is negatively charged, and the loading and adsorption capacity for diquafosol sodium are both weak, so an extremely obvious burst release phenomenon of nearly 65% ​​is presented within 1 hour. Therefore, zwitterions are overall superior to CMC gel in terms of release capacity.

[0248] At 24 hours of release, since the polymer gel solution of the present application and the CMC gel solution were mostly completely dissolved, the release rates were close.

[0249] Based on the fact that diquafosol sodium can be slowly released under this experimental condition and the release rate is greater than 90% within 24 hours, the release effect of the polymer gel solution of the present application is comprehensively judged to be better than that of carbomer gel solution, PVA gel solution and CMC gel solution.

[0250] Among them, taking the release of 8h as an example, Figure 3The five curves in the middle represent the drug release curves of CMC gel solution, SB polymer gel solution, CB polymer gel solution, MPC polymer gel solution, and PVA gel solution from top to bottom.

[0251] In summary, in combination with Example 11 and Example 12, the drug sustained release test results of the two anionic compounds are consistent, which fully demonstrates that the zwitterionic eye drops of the present application have excellent drug sustained release function. If used as a carrier for dry eye treatment, the zwitterionic eye drops can release the drug well, and can achieve a sustained sustained release effect within one day. Not only is it better than CMC gel in terms of sustained release speed, the treatment is more stable, and it is more suitable for the tear environment than PVA gel, and it is basically dissolved after 24 hours. At the same time, it is more suitable for the ionic environment, and the gel system will not be quickly destroyed in PBS like carbomer gel.

[0252] The technical features of the above-mentioned embodiments can be combined arbitrarily. To make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification. When the technical features in different embodiments are embodied in the same figure, it can be regarded that the figure also discloses the combination examples of the various embodiments involved.

[0253] The above-mentioned embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the patent application. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application.

Claims

1. A zwitterionic eye drop loaded with a therapeutic substance, characterized in that: The invention comprises a therapeutic substance, a zwitterionic gel and a buffer, wherein the zwitterionic gel comprises a polymer containing a first structural unit and a second structural unit, wherein the general structural formula of the first structural unit is: The general structural formula of the second structural unit is: Wherein, the degree of polymerization is represented by y and x, wherein the value of y is 40 to 700, and the value of x is 100 to 2000; R1 is nCH2, where n is a natural number from 1 to 10; R2 is mCH2, m is a natural number of 1-10; M is a phosphorylcholine group or a sulfobetaine group; R3 is zCH2, z is a natural number of 1-10; and M' is a carboxybetaine group.

2. The zwitterion eye drops according to claim 1, characterized in that The polymer contains 5-15 mol% of the first structural unit and 85-95 mol% of the second structural unit.

3. The zwitterion eye drops according to claim 2, characterized in that The first structural unit is:

4. The zwitterion eye drops according to claim 2, characterized in that The second structural unit is:

5. The zwitterion eye drops according to claim 1, characterized in that The zwitterion eye drops contain 6 to 15 wt % of zwitterion gel.

6. The zwitterion eye drops according to claim 5, characterized in that The viscosity of the zwitterion eye drops is 9 to 12 Pa·s.

7. The zwitterion eye drops according to claim 5, characterized in that The molecular weight of the zwitterionic gel is 30,000 to 1,000,000.

8. The zwitterion eye drops according to claim 5, characterized in that The charge percentage of the zwitterionic gel is 5%-15%.

9. The zwitterion eye drops according to claim 1, characterized in that In the zwitterionic eye drops, the therapeutic substance content is 2-4 wt%.

10. The zwitterion eye drops according to claim 9, characterized in that The therapeutic agent is at least one of pilocarpine, cyclosporine A, diquafosol sodium, ofloxacin, tobramycin, gatifloxacin, acyclovir, ganciclovir, ribavirin, acetazolamide, dexamethasone, and indomethacin.

11. The zwitterion eye drops according to claim 9, characterized in that: The therapeutic substance is a therapeutic substance with an anionic charge.

12. The zwitterion eye drops according to claim 11, characterized in that The therapeutic substance is diquafosol sodium, and in a simulated ocular surface tear environment, the release rate of the therapeutic substance of the zwitterion eye drops in the first time is 99%-100%; The first time is from T0 to T1, and the duration is 20 to 30 hours.

13. The zwitterion eye drops according to claim 12, characterized in that: The release rate of the zwitterion eye drops during the second time period is 50% to 70%; The second time is from T0 to T2, and the duration is 8 to 12 hours.

14. The method for preparing the zwitterionic eye drops according to any one of claims 1 to 13, characterized in that: include: Step S100, premixing other components except the therapeutic substance; Step S200, adding the therapeutic substance to prepare zwitterion eye drops.

15. The preparation method according to claim 14, characterized in that: The step S100 specifically includes: Step S110, preparing zwitterionic gel; Step S120, mixing the prepared zwitterionic gel with the buffer solution; The step S110 specifically includes: Step S111, taking a zwitterionic monomer, methacryloyloxyethyl trimethyl ammonium chloride, and a reaction solvent and mixing them to form a premixed system, wherein the total mass concentration of the two monomers is 30-50%; Step S112, reacting under oxygen isolation conditions to obtain the zwitterionic gel.

16. The preparation method according to claim 15, characterized in that: In the step S111, a zwitterionic surfactant is also added; wherein the zwitterionic surfactant is lauryl betaine.

17. The preparation method according to claim 15, characterized in that: In the step S111, an initiator and a catalyst are also added; wherein the initiator is APS; The catalyst is TEMED.

18. The preparation method according to claim 15, characterized in that: In the step S111, after the reaction under oxygen-free conditions, unreacted monomers, initiators, catalysts and zwitterionic surfactants are separated and removed by post-treatment to obtain the zwitterionic gel.

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