A powder composition for preventing and treating symblepharon, and a preparation method and use thereof

Abstract

This invention discloses a powder composition for the prevention and treatment of symblepharon (eyelid-eye-ball adhesion). The powder composition comprises a polymer material that cross-links with each other upon contact with an aqueous medium, forming a hydrogel isolation membrane in situ at the wound surface. This invention also discloses the application of the above-mentioned powder composition in the preparation of medicaments for the prevention and / or treatment of symblepharon. The powder composition provided by this invention, when applied to ocular surface wounds, rapidly forms a physical isolation layer in situ. This formed physical isolation layer exhibits good stability and can be gradually and gently degraded without the need for secondary surgical removal.

Description

Technical Field

[0001] This invention belongs to the interdisciplinary fields of biomedical engineering, ophthalmology and medical materials, and specifically relates to a powder composition for the prevention and treatment of symblepharon, its preparation method and application. Background Technology

[0002] Symblepharon is an abnormal fibrous adhesion between the palpebral conjunctiva and the bulbar conjunctiva, cornea, or sclera. It is a serious complication following ocular surface trauma or disease, leading to impaired eye movement, diplopia, and visual impairment. Its causes are diverse, primarily including physiochemical injuries such as chemical burns and thermal burns, ocular surface surgical trauma such as pterygium excision, and chronic inflammatory diseases such as Stevens-Johnson syndrome and ocular pemphigoid. The adhesions form during wound healing, where exposed matrix guides fibroblast migration and excessive collagen deposition, causing pathological connections between tissues that should be separated.

[0003] Currently, clinical methods for preventing and treating symblepharon mainly include amniotic membrane transplantation, silicone or polymeric membrane implantation, topical application of antimetabolites, and viscoelastic agents such as sodium hyaluronate. For example, Chinese patent CN118490870A discloses a sutureless decellularized biological amniotic membrane ocular surface composite material. This composite material includes an amniotic membrane matrix and a support structure supporting the amniotic membrane matrix. The amniotic membrane matrix is ​​derived from human amniotic membrane tissue, and the support structure includes animal cornea or non-biological cornea. The support structure is prepared to conform to the shape of a contact lens. In clinical use, the amniotic membrane composite material can be placed within the conjunctival sac and attached to the surface of the eyeball. The decellularized biological membrane matrix can effectively protect the corneal, bulbar conjunctiva, or palpebral conjunctiva wound, preventing adhesion between the wound and normal tissue, inhibiting the formation of corneal opacity, and eliminating the need to suture the wound with dressings. This facilitates ophthalmic clinical surgical procedures and subsequent dressing changes. For example, Chinese Patent Publication No. CN113631570A discloses an ophthalmic preparation comprising: one or more pharmaceutically acceptable excipients; a pharmaceutically active compound, such as IgG, capable of reducing the amount or harmful effects of autoantibodies on the ocular surface; and, in particular, said pharmaceutically active compound capable of treating clinical conditions selected from the group consisting of inflammatory, infectious, and immune ocular surface diseases or intraocular diseases that can cause the following symptoms: eye discomfort, keratitis, dry eye, symblepharon, fornix fluoroscopy shortening, palpebral / conjunctival keratosis, subconjunctival fibrosis, retinal gliosis, and glaucoma.

[0004] However, current clinical methods for preventing and treating symblepharon have significant limitations. Amniotic membrane transplantation, while commonly used, faces challenges such as limited donors, cumbersome procedures, difficulty in fixation, and early degradation. Silicone or polymeric membrane implantation requires surgical sutures, causes significant foreign body sensation, may damage the cornea, and often necessitates secondary removal. Topical application of antimetabolites (such as mitomycin C) can inhibit fibrosis, but its therapeutic window is narrow, and it carries serious toxic risks such as corneal dissolution, scleral softening, and delayed healing. Viscoelastic agents such as sodium hyaluronate have a short retention time on the ocular surface and their barrier function is not durable. Therefore, there is an urgent need for a novel barrier material that is easy to use, has a durable barrier, good biocompatibility, and requires no secondary surgery, to more effectively address this highly prevalent and disabling clinical challenge. Summary of the Invention

[0005] The purpose of this invention is to provide a powder composition for the prevention and treatment of symblepharon, its preparation method and application. When the powder composition is applied to the ocular surface wound, it can quickly form a physical isolation layer in situ. The physical isolation layer formed has good stability and can be gradually and gently degraded without the need for secondary surgery to remove it.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution: A powder composition for the prevention and treatment of symblepharon, the powder composition comprising a polymer powder that cross-links with each other upon contact with an aqueous medium to form a hydrogel isolation membrane in situ at the wound site.

[0007] When in contact with a moist wound on the ocular surface, the powder composition provided by this invention can quickly form a hydrogel isolation film in situ, achieving physical isolation and preventing symblepharon; it also has the advantages of rapid film formation, good adhesion and good biocompatibility.

[0008] The powder composition provided by this invention aims to address the three major bottlenecks faced by existing symblepharon barrier materials: high operational complexity and invasiveness (e.g., requiring suture fixation), poor in-situ barrier stability, easy displacement or premature loss (e.g., easily washed away by tears), and poor safety and biocompatibility (e.g., cytotoxicity of antimetabolites). To address these issues, this invention innovatively proposes an "in-situ film-forming powder" strategy. This strategy provides a powder composition that, upon contact with a moist wound on the ocular surface, can rapidly (usually within seconds to one minute) form a stable, physiologically compliant physical barrier layer in situ. This barrier layer effectively blocks fibroblast migration and abnormal collagen fiber bridging. It exhibits good in-situ stability, is not easily washed away by tears or rapidly lost, effectively covers the critical window period of early wound healing (e.g., 1-3 days post-surgery), and then gradually and gently degrades as tissue repair progresses, requiring no secondary surgery for removal. The powder composition provided by this invention offers an integrated solution for the prevention and treatment of symblepharon caused by various factors such as surgical trauma, chemical burns, thermal burns, and chronic inflammation. This solution is extremely easy to operate (simply spray), minimally invasive, has excellent biocompatibility, and can be precisely applied to the target area.

[0009] The interaction mechanism between the powder composition and the aqueous medium is a physical interaction and / or a chemical group reaction; the physical interaction is selected from hydrogen bonding, electrostatic interaction, metal coordination or host-guest interaction, and the chemical group reaction is selected from the functional groups that react with each other, selected from carbon-carbon double bonds, alkynyl, active ester-amino, aldehyde-amino, borate ester-ortho-hydroxy, maleimide-thiol, epoxy-amino or aldehyde-hydroxy.

[0010] The polymer material is selected from one or more of natural polymers and their derivatives or synthetic polymers; the natural polymer is selected from at least one of hyaluronic acid (sodium), chondroitin sulfate, alginate, chitosan, carboxymethyl cellulose, gelatin, collagen or fibrinogen; the synthetic polymer is selected from at least one of polyacrylic acid and its salts (such as carbomer), polyethylene glycol (PEG), polyvinyl alcohol (PVA), poly(N-vinylpyrrolidone) (PNVP), polyethylene oxide (PEO), poly(hydroxyethyl methacrylate) (PHEMA) or polyethyleneimine.

[0011] The polymeric material may also be copolymers, graft copolymers, or interpenetrating network polymers of the aforementioned natural polymers and their derivatives or / and synthetic polymers.

[0012] The powder composition comprises polyacrylic acid and chitosan; or, the powder composition comprises aldehyde-modified hyaluronic acid and polyethyleneimine; or, the powder composition comprises sodium oxidized alginate and gelatin.

[0013] The average particle size of the powder composition is 0.1 μm-1000 μm, and the morphology of the powder composition is spherical, porous spherical, flake-like, fibrous, or irregular.

[0014] Preferably, the powder composition consists of free-flowing solid microparticles with an average particle size between 1 μm and 500 μm. This particle size range ensures that the composition has good flowability, can be sprayed through instruments, and can fully interact with ocular surface tissue fluid to form a uniform and continuous isolation film in situ at the wound site.

[0015] Preferably, the powder composition comprises a polyacrylic acid derivative containing active ester groups and quaternized chitosan in a mass ratio of 1-3:1-3, and the average particle size of the powder composition is 10-200 μm. The above powder composition can form a uniform hydrogel film under moist conditions on the ocular surface and exhibits good adhesion and degradation properties.

[0016] More preferably, the mass ratio of the polyacrylic acid derivative containing active ester groups to the quaternized chitosan powder in the powder composition is 1:1. The above powder composition can form a uniform hydrogel film under moist conditions on the ocular surface and exhibits optimal adhesion and degradation properties.

[0017] The powder composition also includes one or more of a crosslinking agent, a pharmaceutically acceptable excipient, or a therapeutic agent.

[0018] The powder may further contain a crosslinking agent (such as genipin, calcium ions, etc.) or have reactive functional groups (such as aldehyde groups, succinimide esters, thiol groups, carbon-carbon double bonds, etc.) to achieve rapid in-situ crosslinking after contact with tissue fluid, thereby enhancing the mechanical strength and adhesion durability of the formed gel film. The crosslinking agent is selected from at least one of chemical crosslinking agents, ionic crosslinking agents, photocrosslinking agents, thermal crosslinking agents, or enzyme crosslinking agents.

[0019] The pharmaceutically acceptable excipients are selected from at least one of lubricants, preservatives, pH adjusters, osmotic pressure adjusters, antioxidants, humectants, thickeners, dispersants, emulsifiers, or colorants.

[0020] The powder composition, by loading a therapeutic drug, can achieve the dual functions of "physical barrier" and "drug therapy". The therapeutic drug is selected from at least one of the following: anti-inflammatory drugs (such as dexamethasone), antibiotics (such as moxifloxacin), antiviral drugs, antifungal drugs, antiproliferative drugs (such as low-concentration mitomycin C), immunosuppressants, anti-angiogenic drugs, analgesics, growth factors (such as epidermal growth factor EGF), cytokines, gene therapy vectors, stem cells, exosomes, antioxidants, vitamins, or trace elements.

[0021] The present invention also provides a method for preparing the above-mentioned powder composition, the method comprising: (1) Dissolve or disperse the polymeric material that forms a hydrogel in a solvent to form a dispersion; (2) After drying the dispersion, pulverize it to obtain a powder; (3) The powder is sieved to obtain powder within the target particle size range; (4) The powder is sterilized to obtain a powder composition.

[0022] The method for drying the powder can be spray drying, freeze drying, vacuum drying, fluidized bed drying, supercritical drying, pulverizing after solution casting, pulverizing after melt extrusion, pulverizing after electrospinning, mechanical pulverizing, grinding, or sieving; the sterilization method is selected from at least one of gamma-ray irradiation, electron beam irradiation, ultraviolet irradiation, moist heat sterilization, dry heat sterilization, gas sterilization (such as ethylene oxide gas sterilization), or filtration sterilization; in the preparation method provided by the present invention, the polymer material can be selectively mixed with at least one of crosslinking agent, excipient, and therapeutic drug, and the powder can be selectively sieved, mixed, surface modified, or functionalized.

[0023] The present invention also provides the use of the above-described powder composition in the preparation of a medicament for the prevention and / or treatment of symblepharon.

[0024] The present invention also provides the use of the above-mentioned powder composition in the preparation of a medicament for treating ocular surface repair.

[0025] The powder composition is suitable for ocular surface repair after ophthalmic surgery, chemical burns, thermal burns, radiation burns, infectious eye diseases, autoimmune eye diseases, or traumatic eye injuries.

[0026] The powder composition can be applied by spraying, coating, dripping, injecting, brushing, dipping, or premixing into a paste or syrup before application. That is, the application can be performed directly with the powder in a dry state, or the powder can be premixed with a small amount of sterile water, balanced salt solution, or sodium hyaluronate solution to form a paste or syrup before application.

[0027] In a specific implementation, the powder composition described above can be sprayed or applied to areas of ocular surface wounds at risk of adhesion (such as conjunctival wounds at the end of surgery, exposed scleral beds, limbus, or areas damaged by chemical burns or injuries).

[0028] The present invention also provides a medical product comprising a sterile container and a powder composition as described above encapsulated therein. The product may be equipped with a dedicated powder spraying device, such as a sterile airbag with a narrow nozzle, a spiral propulsion powder sprayer, or a vibrating screen powder sprayer, to facilitate precise and uniform application during surgery.

[0029] Compared with the prior art, the advantages and beneficial effects of the present invention include: (1) Revolutionary simplification of operation: It is applied directly in powder form. After contact with ocular surface tissue fluid, it can quickly absorb water and swell and cross-link, forming a soft and adhesive hydrogel isolation film in situ on the wound. This film mechanically separates the conjunctival wound from the cornea or palpebral conjunctiva, preventing fibroblasts from crossing and collagen fibers from bridging, thereby preventing adhesion formation (or, physically isolating the eyeball from the eyelid tissue to prevent pathological adhesions); therefore, no sutures and fixation are required, greatly simplifying the surgical steps, shortening the operation time, and reducing the difficulty of the operation; (2) Excellent barrier adhesion and compliance: The powder forms a film in situ on the moist wound surface, which can perfectly fit the irregular ocular surface anatomy and form a uniform isolation layer without dead angles, which is difficult for pre-formed films to achieve. (3) High biocompatibility and safety: The materials are all biodegradable medical polymers, and the final degradation products are harmless, avoiding the use of antimetabolites with cytotoxicity; the hydrogel isolation membrane formed in situ has good biocompatibility and has the characteristics of being degradable or absorbed in the ocular surface environment, so that it does not need to be removed by a second surgery after the isolation function is completed. (4) Strong functional scalability: The powder is easy to load with a variety of drugs to achieve multifunctional integrated treatment such as anti-inflammatory, anti-infection, anti-proliferation or healing promotion; (5) High patient comfort: The formed hydrogel film is soft, with little foreign body sensation, and does not affect corneal metabolism; (6) Cost controllable and easy to promote: The powder preparation process is mature, the cost is low, and it is easy to store and transport. Attached Figure Description

[0030] Figure 1 The test results for the physicochemical properties of the hydrogel are shown in the storage modulus frequency curve and the adhesion force test curve. Figure 2 Comparative photographs of ocular surface healing and adhesion after using the powder of this invention in a rabbit ocular alkali burn model; Figure 3 A slit-lamp examination of the rabbit eye cornea (fluorescein staining and natural light show no edema, inflammation, and intact cornea); Figure 4 The in vitro release curve of curcumin-loaded powder; Figure 5 This is a comparison of the expression levels of inflammatory factors in vitro via qPCR (the figure shows the expression levels of TNF-α and IL-6 as examples). Detailed Implementation

[0031] The technical solution of the present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited to the following embodiments.

[0032] Example 1: Composition of polyacrylic acid derivatives containing active ester groups and quaternized chitosan powder 1.1 Raw Materials and Formulation (1) Component A: Polyacrylic acid derivative powder containing active ester groups (denoted as PAA-NHS), prepared by the following method: Acrylic acid (AA) and the active ester monomer N-hydroxysuccinimide ester (NHS) were dissolved in deionized water at a molar ratio of AA : NHS = 100 : 1 to form a homogeneous prepolymer solution. Add 0.1 wt% of photoinitiator Irgacure 2959, stir well, and then pour into the mold; Irradiation under 365 nm ultraviolet light for 30 minutes resulted in a photopolymerization reaction, forming a transparent hydrogel. The hydrogel was pre-frozen at -80°C for 24 hours, and then dried in a freeze dryer for 48 hours to obtain a porous sponge-like solid. The solid is mechanically crushed and sieved, and the powder with an average particle size between 10-200 μm is collected, which is PAA-NHS; (2) Component B: Quaternized chitosan powder (QCS), with an average particle size of 10-200 μm; (3) Mixing ratio: PAA-NHS and QCS are mixed at mass ratios of 1:1, 3:1 and 1:3 respectively.

[0033] 1.2 Preparation method (1) Pass PAA-NHS and QCS powder through a 200-mesh sieve respectively, and take the part with uniform particle size distribution.

[0034] (2) Mix thoroughly under sterile conditions according to the above proportions.

[0035] (3) Terminal sterilization is performed by γ-ray irradiation or ultraviolet irradiation to obtain a sterile powder composition.

[0036] 1.3 Performance Testing (1) Gel formation time test: Under simulated ocular surface wet conditions, all three ratios of powder formed a transparent continuous hydrogel film within 20s, with the 1:1 ratio forming the most uniform film. (2) Physicochemical property tests: The storage modulus (G') of the in-situ formed hydrogel was determined using a rotational rheometer. The results showed that the 1:1 ratio sample had the best mechanical compliance. The adhesion strength between the gel film and the simulated corneal surface was tested using the pull-off method. The adhesion force was moderate and stable, indicating that it has good adhesion properties (see Figure 1 ); (3) In vitro degradation behavior: In a simulated ocular surface fluid environment, the gel film gradually degraded within 7 days with no obvious residue.

[0037] Example 2: Powder compositions with various chemical crosslinking systems 2.1 Formula A: Aldehyde-modified hyaluronic acid and polyethyleneimine system Component A: Aldehyde-modified sodium hyaluronate powder (HA-CHO) Component B: Polyethyleneimine powder (PEI) The mixing ratio (mass ratio) is HA-CHO : PEI = 2 : 1.

[0038] The preparation method is the same as in Example 1. Upon contact with water, this system can rapidly crosslink to form a film via a Schiff base reaction.

[0039] 2.2 Formulation B: Sodium Oxygenated Alginate and Gelatin System Component A: Sodium oxidized alginate (ADA) Component B: Gelatin The mixing ratio (mass ratio) is ADA : Gelatin = 1 : 1.

[0040] The preparation method is the same as in Example 1. This system is cross-linked via a Schiff base reaction between the aldehyde group and the amino group.

[0041] Example 3: Application of the powder composition in a rabbit eyelid-bulbar adhesion model 3.1 Establishment of animal models A model of ocular surface alkali burn was prepared using New Zealand white rabbits to simulate the high-risk state of symblepharon.

[0042] 3.2 Grouping and Intervention Experimental group: The powder composition prepared in Example 1 was evenly sprayed onto the wound.

[0043] Blank control group: No material was applied.

[0044] 3.3 Observation Indicators The healing of the ocular surface, the degree of adhesion, and the condition of the cornea were observed on the 3rd, 7th, 14th, and 21st days after surgery.

[0045] 3.4 Observation Results (1) Macroscopic observation: No obvious symblepharon was observed in the experimental group, while obvious symblepharon was observed in the blank control group (see Figure 2 ).

[0046] (2) Corneal condition assessment: Slit-lamp examination showed that the corneal structure of the experimental group was intact, without edema or opacity, and the sodium fluorescein staining was negative, indicating that the powder composition did not damage the cornea (see Figure 3 ).

[0047] Example 4: Preparation and in vitro release of curcumin-loaded powder 4.1 Preparation of drug-loaded powder In Example 1, curcumin (1% of the total mass) was added to the 1:1 mixed powder and mixed evenly under light-protected conditions to obtain a curcumin-loaded powder composition.

[0048] 4.2 In vitro release behavior The release behavior of curcumin in simulated ocular surface fluid was determined using the dialysis bag method. The results showed that curcumin was released rapidly initially, followed by a stable release phase, and the overall release behavior conformed to sustained-release characteristics (see [link to study]). Figure 4 ).

[0049] 4.3 In vitro functional verification Using an in vitro cellular inflammation model (LPS-stimulated human corneal epithelial cells) combined with qPCR detection, the curcumin-loaded powder group significantly inhibited the expression levels of inflammatory factors TNF-α and IL-6 (see [link to relevant data]). Figure 5 This result verifies that the powder composition of the present invention retains its rapid film-forming and physical isolation functions after being loaded with anti-inflammatory drugs, and can simultaneously achieve anti-inflammatory treatment, demonstrating the technical superiority and functional scalability of the present invention in the integrated design of "physical barrier + drug therapy".

Claims

1. A powder composition for the prevention and treatment of symblepharon, characterized in that, The powder composition comprises at least two polymer powders, which cross-link with each other when in contact with an aqueous medium to form a hydrogel isolation membrane in situ on the wound surface.

2. The powder composition for preventing and treating symblepharon according to claim 1, characterized in that, The interaction mechanism between the powder composition and the aqueous medium is a physical interaction and / or a chemical group reaction; the physical interaction is selected from hydrogen bonding, electrostatic interaction, metal coordination or host-guest interaction, and the chemical group reaction is selected from the functional groups that react with each other, selected from carbon-carbon double bonds, alkynyl, active ester-amino, aldehyde-amino, borate ester-ortho-hydroxy, maleimide-thiol, epoxy-amino or aldehyde-hydroxy.

3. The powder composition for preventing and treating symblepharon according to claim 1, characterized in that, The polymer material is selected from one or more of natural polymers and their derivatives or synthetic polymers; the natural polymer is selected from at least one of hyaluronic acid, chondroitin sulfate, alginate, chitosan, carboxymethyl cellulose, gelatin, collagen or fibrinogen; the synthetic polymer is selected from at least one of polyacrylic acid and its salts, polyethylene glycol, polyvinyl alcohol, poly(N-vinylpyrrolidone), polyethylene oxide, poly(hydroxyethyl methacrylate) or polyethyleneimine.

4. The powder composition for preventing and treating symblepharon according to claim 1, characterized in that, The powder composition comprises polyacrylic acid and chitosan; or, the powder composition comprises aldehyde-modified hyaluronic acid and polyethyleneimine; or, the powder composition comprises sodium oxidized alginate and gelatin.

5. The powder composition for preventing and treating symblepharon according to claim 1, characterized in that, The average particle size of the powder composition is 0.1 μm-1000 μm, and the morphology of the powder composition is spherical, porous spherical, flake-like, fibrous, or irregular.

6. The powder composition for preventing and treating symblepharon according to claim 1, characterized in that, The powder composition comprises a polyacrylic acid derivative containing active ester groups and quaternized chitosan in a mass ratio of 1-3:1-3, and the average particle size of the powder composition is 10-200 μm.

7. A method for preparing the powder composition according to any one of claims 1-6, characterized in that, The method includes: (1) Dissolve or disperse the polymeric material that forms a hydrogel in a solvent to form a dispersion; (2) After drying the dispersion, pulverize it to obtain a powder; (3) The powder is sieved to obtain powder within the target particle size range; (4) The powder is sterilized to obtain a powder composition.

8. Use of the powder composition according to any one of claims 1-6 in the preparation of a medicament for the prevention and / or treatment of symblepharon.

9. Use of the powder composition according to any one of claims 1-6 in the preparation of a medicament for treating ocular surface repair.

10. The application according to claim 8 or 9, wherein the powder composition is applied by spraying, coating, dripping, injecting, brushing, dipping, or premixing into a paste or gruel before application.

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