Eye-protecting external preparation and preparation method thereof

Abstract

The invention discloses an eye protection external preparation and a preparation method thereof, and belongs to the technical field of ophthalmic preparations. The preparation method comprises the following steps: mixing a main agent solution A containing Ectoine and trehalose with a matrigel solution B containing chitosan quaternary ammonium salt; and then carrying out high-pressure microjet homogenization treatment on the mixed solution at 100-150 MPa so as to construct a supramolecular network structure. Through a specific high-pressure homogenization process, the obtained preparation has an excellent shear thinning characteristic, high viscosity is kept during standing to realize biological adhesion, the viscosity is instantaneously reduced during blinking to ensure comfort, and the problem of blurred vision of traditional gel is solved. Meanwhile, due to the network structure of the preparation, the active ingredients can be instantly released, the hypertonic state of the eyes can be rapidly relieved, and the preparation is adhered to the ocular surface for a long time.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to an eye-protecting external preparation and a preparation method thereof. BACKGROUND

[0002] At present, there are many kinds of eye-protecting external preparations on the market for relieving eye dryness and visual fatigue. One of them is ordinary eye drops, such as the eye drops whose main component is sodium hyaluronate. The viscosity of this kind of preparation is low, and the user feels comfortable when adding it, and it will not cause blurred vision. However, its disadvantage is that the preparation stays on the surface of the eyeball for a very short time, and is easily lost with the circulation of tears (see Figure 2 Control group 1). Therefore, the user needs to add it frequently to maintain eye wetness. Another kind is eye gel or eye ointment. In order to prolong the action time, this kind of preparation usually has very high viscosity. High viscosity indeed enables it to stay on the ocular surface for a long time, but at the same time it also brings obvious side effects, that is, it causes the user to have blurred vision, unclear vision, or a feeling of eyelid adhesion, and the use feels not good.

[0003] As can be seen, there has been a technical contradiction in the prior art for a long time: it is difficult to balance the long-acting effect brought by high viscosity and the comfort brought by low viscosity. In addition, eye dryness and fatigue are not only "water shortage", but also related to the imbalance of tear osmotic pressure, which leads to damage to the ocular surface cells. Many existing preparations only focus on physical water replenishment, and fail to provide effective protection to the ocular surface cells in a high-osmotic environment (see Figure 3 Control group). In addition, some long-acting technologies (such as microcapsule packaging technology) have their active ingredients coated inside the carrier, which are released slowly (see Figure 5 Control group), which causes the preparation to fail to take effect immediately after being added, and lacks immediate relief ability. SUMMARY

[0004] The technical problem to be solved by the present application is to provide an eye-protecting external preparation and a preparation method thereof, which can not only adhere to the surface of the eyeball for a long time to achieve long-acting protection, but also maintain low viscosity when blinking to ensure comfortable use and clear vision.

[0005] The above technical object of the present application is achieved by the following technical solution: a preparation method of an eye-protecting external preparation, comprising the following steps: (S1) preparing a main agent solution A: dissolving icodextrin and trehalose in a first part of water for injection; (S2) preparing a matrix glue solution B: dissolving chitosan quaternary ammonium salt in a second part of water for injection; (S3) complex homogenization: mixing the main agent solution A and the matrix glue solution B at low speed to obtain a mixed solution; (S4) supermolecular network construction: the mixed solution obtained in (S3) is subjected to high-pressure microfluidization homogenization treatment.

[0006] Further, the (S1) also includes dissolving sodium hyaluronate in the first part of the injection water.

[0007] Further, the first part of the injection water accounts for 80% of the total amount of water, and the second part of the injection water accounts for 20% of the total amount of water.

[0008] Further, the pressure of the high-pressure microfluidization homogenization treatment in (S4) is 100-150 MPa.

[0009] Further, after step (S4), it further includes the step of: (S5) adjusting the pH value of the preparation obtained in (S4) to 7.0, and performing 0.22 μm sterilization filtration.

[0010] Further, after step (S5), it further includes the step of: (S6) single-dose aseptic filling of the preparation filtered in (S5) by BFS process.

[0011] The application also provides an eye-protecting external preparation prepared by the above method. The preparation has shear thinning properties, and the apparent viscosity is greater than 8 Pa·s at a shear rate of 0.1 s -1 , and the apparent viscosity is less than 0.4 Pa·s at a shear rate of 100 s -1 . The preparation has bioadhesion, and the residual rate is greater than 70% after 60 minutes of in-vitro simulated tear flushing. The preparation has immediate release properties, and the cumulative release rate of the active ingredient is greater than 70% within 30 minutes in an in-vitro release model.

[0012] Compared with the prior art, the application has the following beneficial effects: 1. The application forms a special supermolecular network structure through the specific high-pressure microfluidization homogenization step (S4), which has excellent shear thinning properties. Specifically, it maintains high viscosity during simulated static state (such as 0.1 s -1 shear rate), thereby realizing long-acting bioadhesion; and the viscosity sharply decreases during simulated blinking (such as 100 s -1 shear rate), thereby ensuring that the eyes are not smeared and the body feels comfortable during use, and solving the technical problem of the contradiction between long-acting and comfort.

[0013] 2. The active ingredient (such as ikkis) of the preparation of the application is still in a free state while realizing long-acting adhesion, which can realize immediate release (such as more than 70% released within 30 minutes), and can quickly exert the cell osmotic pressure protection effect, thereby solving the technical problem that the slow-release preparation cannot take effect immediately.

[0014] 3. The method of the present invention also includes a BFS single-dose aseptic filling step (S6), and the resulting formulation is preservative-free, highly safe, and suitable for long-term use. Attached Figure Description

[0015] Figure 1 This is a process flow diagram of the preparation of an eye-protecting topical formulation according to the present invention; Figure 2 This is a graph showing the in vitro bioadhesion test curves of the formulation (experimental group) and the control group in the embodiments of the present invention; Figure 3 This is a bar chart showing the effect of the formulation (experimental group) and control group of the present invention on cell viability under hyperosmolar conditions. Figure 4 This is a comparison graph of the rheological properties (apparent viscosity-shear rate) of the formulation (experimental group) and the control group in the embodiments of the present invention; Figure 5 This is a comparison chart of the in vitro cumulative release curves of the active ingredients in the formulation of the present invention (experimental group) and the conventional sustained-release microcapsule formulation (control group). Detailed Implementation

[0016] The following will be combined with the appendix Figures 1-5 The present invention will be described in detail, clearly, and completely, along with specific embodiments. It should be understood that the embodiments described herein are merely illustrative and not intended to limit the scope of protection of the invention.

[0017] Example 1: Preparation of the topical eye care formulation of the present invention (refer to...) Figure 1 ) This embodiment provides a method for preparing an eye-protecting topical preparation, which follows the method described in this embodiment. Figure 1 The process flow is as shown. First, step (S1) is performed to prepare the main agent solution A: 80% of the total amount of water for injection is placed in a mixing tank, and low-speed stirring is started at room temperature. 1.5% (by weight, the same below) of ectoine, 2.0% of trehalose, and 0.1% of sodium hyaluronate are added sequentially, and stirring is continued until all materials are completely dissolved, resulting in a clear and transparent main agent solution A. Simultaneously, step (S2) is performed to prepare the matrix adhesive solution B: 20% of the total amount of water for injection is placed in another mixing tank, and stirring is started at room temperature. 0.3% of chitosan quaternary ammonium salt powder is slowly sprinkled into the water, and stirring is continued to allow it to fully swell, resulting in a uniform matrix adhesive solution B. The principle of preparing (S1) and (S2) separately is to avoid insufficient swelling or agglomeration of the polymer (chitosan quaternary ammonium salt) during the swelling process due to the presence of small molecules (such as ectoine and trehalose), ensuring that both materials reach their optimal dissolution and dispersion states.

[0018] Next, step (S3) homogenization is performed: while maintaining low-speed stirring, the main agent solution A is slowly pumped into the mixing tank containing the matrix adhesive solution B, and mixing continues at low speed for 15 minutes to allow the two solutions to be initially mixed and homogenized, resulting in a mixture. This step is a premixing process, preparing for the subsequent key steps.

[0019] Next, the core step (S4) of this invention, supramolecular network construction, is performed: the mixture obtained in step (S3) is pumped into a high-pressure microfluidic homogenizer. The homogenization pressure is set to 120 MPa (belonging to the appendix). Figure 1 (The preferred pressure range is 100-150 MPa), and the mixture is circulated and homogenized 8 times. This step is not a simple physical mixing; its working principle is to use extreme high pressure and strong mechanical shear force to force the long polymer chains of chitosan quaternary ammonium salt to fully untangle and extend, while simultaneously causing small molecules such as ectoine and trehalose, as well as water molecules, to rearrange under high energy. Through this high-energy treatment, the polymer backbone and small molecule protective agents interact through non-covalent bonds such as hydrogen bonds and van der Waals forces, constructing a highly uniform, stable supramolecular network structure with a specific topological conformation.

[0020] After homogenization, step (S5) is performed for adjustment and sterilization: the solution obtained in (S4) is transferred to a preparation tank, and an appropriate amount of PBS buffer is added to adjust its pH to 7.0 to ensure its mildness and compatibility with the physiological environment of the eye. Subsequently, the solution is filtered sequentially through 0.45μm and 0.22μm filter membranes for sterilization to obtain a sterile solution.

[0021] Finally, step (S6) aseptic filling is performed: the aseptic liquid from step (S5) is transferred to a BFS (blow-fill-seal) integrated aseptic filling machine in a clean environment. The BFS process continuously and automatically completes the blow molding of plastic bottles, the filling of aseptic liquid, and the melt sealing of the bottle neck in one station. In this embodiment, the filling volume is set to 0.4 mL / bottle. The principle of the BFS process is that the entire filling and sealing process is completed instantaneously under aseptic protection, eliminating external contamination. Therefore, the resulting formulation does not require the addition of any preservatives, greatly improving product safety.

[0022] Experiment Example 1: Bioadhesion Test To verify the long-term retention capability of the formulation of the present invention, an in vitro bioadhesion test was conducted. The experimental group consisted of the formulation prepared in Example 1 ( Figure 2 The invention is referred to as "the gel of this invention"). Control group 1 was a commercially available sodium hyaluronate eye drop without a polymer matrix. Control group 2 was a formulation prepared using the entire formulation of Example 1, but omitting the high-pressure homogenization process in step (S4) and only through low-speed mixing in step (S3). Figure 2(Referring to a formulation that has not undergone high-pressure homogenization). The experimental method involved applying equal volumes of sample onto a matrix simulating ocular surface mucin, followed by rinsing at a constant rate (simulating tear flow). The percentage of formulation remaining on the matrix was measured at 0, 10, 30, 60, 120, and 240 minutes. The experimental results are shown in the table below:

[0023] Experimental results are as follows Figure 2 As shown. Control group 1 (commercially available eye drops) was lost very quickly, with only 30.4% remaining after 10 minutes and almost completely lost after 60 minutes (1 hour) (5.2% remaining, not shown on the graph, but between 10.1% and 0.0%). Control group 2 (unhomogenized) had slightly better adhesion, but also lost more than half after 60 minutes (1 hour) (48.9% remaining, not shown on the graph, but between 65.3% and 30.2%). In contrast, the experimental group of this invention exhibited extremely strong bioadhesion, retaining 75.3% after 60 minutes (1 hour) (not shown on the graph, but between 88.5% and 60.1%), and still retaining 42.5% after 240 minutes (4 hours). This result confirms that it is the supramolecular network structure constructed by high-pressure homogenization in step (S4) that endows the formulation with superior adhesion properties, allowing it to remain on the ocular surface for a long time.

[0024] Experiment Example 2: Cell Osmotic Protection Test To verify the core efficacy of the formulation of this invention, a cell protection test was conducted. The experimental method involved placing human corneal epithelial cells in a hypertonic culture medium to simulate the hypertonic environment of dry eye syndrome. The experimental groups were as follows: normal control group (normal culture medium); hypertonic model group (hypertonic culture medium only); experimental group (hypertonic culture medium + formulation of Example 1); control group (hypertonic culture medium + commercially available sodium hyaluronate eye drops). After culture, the cell viability of each group was measured. The experimental results are shown in the table below:

[0025] Experimental results are as follows Figure 3 As shown, the cell survival rate in the hyperosmolar model group was only 48.2%, indicating that the hyperosmolar environment caused severe cell damage. The protective effect of the control group (commercially available eye drops) was limited, with a survival rate of only 55.8%. In contrast, the experimental group of this invention achieved a cell survival rate as high as 92.5%, almost recovering to the 100% level of the normal control group. Its working principle lies in the fact that the core active ingredients ectoine and trehalose in the formulation of this invention, as excellent osmolarity protectants, can form a hydration protective shell on the cell surface, locking in the water around the cells in a hyperosmolar environment, maintaining the normal osmotic pressure balance of the cells, thereby protecting the cells from damage.

[0026] Experiment Example 3: Rheological Property Testing To verify how the formulation of this invention resolves the contradiction between "long-lasting effect" and "comfort," rheological tests were conducted. The experimental group was the formulation of Example 1. The control group was Control Group 2 of Example 1 (formulation without high-pressure homogenization). The apparent viscosity of the formulation at different shear rates was measured using a rotational rheometer. The experimental results are shown in the table below:

[0027] Experimental results are as follows Figure 4 As shown. The experimental group of this invention exhibits relatively ideal shear thinning characteristics. Its working principle is as follows: at low shear rates (e.g., 0.1 s⁻¹), -1 (Simulating a static state), the supramolecular network structure formed by homogenization of (S4) remains intact and entangled, at which point the apparent viscosity of the formulation reaches as high as 8.5 Pa·s; it is this high static viscosity that leads to Figure 2 The strong bioadhesion shown is evident. However, when a high shear rate (e.g., 100 s⁻¹) is applied... -1 (Simulating a blinking motion), the network structure temporarily unwinds and orients, causing the viscosity to drop sharply to 0.35 Pa·s; at this point, the viscosity is close to that of water (the control group was 0.3 Pa·s). This characteristic allows the formulation of this invention to adhere to the ocular surface after being instilled into the eye, but instantly thins upon blinking, perfectly resolving the contradiction of existing technologies. In contrast, the unhomogenized control group had a viscosity of only 3.1 Pa·s when at rest, far from sufficient to achieve long-lasting adhesion.

[0028] Experiment Example 4: In vitro release characteristics test To verify how the formulation of this invention resolves the contradiction between "long-lasting effect" and "rapid-acting effect," an in vitro release test was conducted. The experimental group was the formulation of Example 1. The control group was a conventional sustained-release microcapsule formulation encapsulating the active ingredient. The cumulative release rate of the active ingredient (ectoine) was measured in a simulated tear environment. The experimental results are shown in the table below:

[0029] Experimental results are as follows Figure 5As shown. The control group (sustained-release microcapsules) released very slowly, with only 3.5% released after 30 minutes (0.5 hours) and only 7.0% after 1 hour, failing to achieve immediate effect. In contrast, the experimental group of this invention exhibited extremely rapid release, with 45.5% released in 6 minutes (0.1 hours), a cumulative release rate of 70.2% after 30 minutes (0.5 hours), and 85.1% after 1 hour. Its working principle lies in the fact that this invention constructs an open supramolecular network through homogenization (S4), rather than closed microcapsules. The active ingredient is freely dispersed within the network backbone; therefore, upon contact with the ocular surface (i.e., the release medium), the active ingredient can freely diffuse out, achieving immediate release and rapid efficacy. Figure 3 The cell protection effect shown is evident. Therefore, this invention simultaneously achieves both long-lasting adhesion and immediate onset of action.

[0030] This specific embodiment is merely an explanation of the present invention and is not intended to limit the invention. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they are within the scope of the claims of the present invention.

Claims

1. A method for preparing an eye-protecting topical preparation, characterized in that, Includes the following steps: (S1) Preparation of main agent solution A: Dissolve ectoine and trehalose in water for injection from Part I; (S2) Preparation of matrix adhesive solution B: Dissolve chitosan quaternary ammonium salt in the second part of the water for injection; (S3) Composite homogenization: The main agent solution A and the matrix adhesive solution B are mixed at a low speed to obtain a mixture; (S4) Construction of supramolecular network: The mixture obtained in (S3) is subjected to high-pressure microfluidic homogenization treatment.

2. The method according to claim 1, characterized in that, The process (S1) also includes dissolving sodium hyaluronate in the first portion of water for injection.

3. The method according to claim 1, characterized in that, The first part of the water for injection accounts for 80% of the total water consumption, and the second part of the water for injection accounts for 20% of the total water consumption.

4. The method according to claim 1, characterized in that, The pressure of the (S4) high-pressure microjet homogenization process is 100-150 MPa.

5. The method according to claim 1, characterized in that, The process includes the following step after step (S4): (S5) adjusting the pH of the preparation obtained in (S4) to 7.0 and performing 0.22 μm sterile filtration.

6. The method according to claim 5, characterized in that, The process includes a step (S6) after step (S5): the formulation filtered in (S5) is aseptically filled into single doses using the BFS process.

7. A topical eye care preparation, characterized in that, Prepared by the method as described in any one of claims 1 to 6.

8. The topical eye care preparation according to claim 7, characterized in that, The formulation exhibits shear-thinning properties, within 0.1 s. -1 At a shear rate, the apparent viscosity is greater than 8 Pa·s, and at 100 s⁻¹, it is greater than 8 Pa·s. -1 At the shear rate, the apparent viscosity is less than 0.4 Pa·s.

9. The topical eye care preparation according to claim 7, characterized in that, The formulation has bioadhesive properties, and after 60 minutes of simulated tear flushing in vitro, the residual rate is greater than 70%.

10. The topical eye care preparation according to claim 7, characterized in that, The formulation has an instant release characteristic, and in an in vitro release model, the cumulative release rate of the active ingredient is greater than 70% within 30 minutes.

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