阅读说明：本技术 一种用于婴幼儿及儿童的医用眼贴及其制备方法 (Medical eye patch for infants and children and preparation method thereof ) 是由 韩熠 于 2019-11-20 设计创作，主要内容包括：本发明公开了一种医用眼贴,顺序包括防粘层(1)、微针阵列层(2)、眼药存储层(3)和粘贴层(4)。本发明还公开了所述医用眼贴的制备方法和用途。本发明医用眼贴使用和制备简单,对婴幼儿及儿童的眼睛无损伤。(The invention discloses a medical eye patch which sequentially comprises an anti-sticking layer (1), a microneedle array layer (2), an eye medicine storage layer (3) and a sticking layer (4). The invention also discloses a preparation method and application of the medical eye patch. The medical eye patch is simple to use and prepare, and has no damage to eyes of infants and children.)

1. The medical eye patch is characterized by sequentially comprising an anti-sticking layer (1), a microneedle array layer (2), an eye medicine storage layer (3) and an adhesive layer (4).

2. The medical eye patch according to claim 1, wherein the microneedle array layer (2) is made of lysozyme-sensitive hydrogel (6), the microneedles (2-1) on the microneedle array layer (2) are flat-head type, and the microneedles (2-1) are internally provided with microcatheters (2-2); the anti-sticking layer (1) is attached to the surface of the microneedle array layer (2) and used for protecting the microneedle (2-1) array on the microneedle array layer (2); the lysozyme sensitive hydrogel (6) is a hydrogel which can swell or dissolve in the presence of lysozyme (11), and is glutaraldehyde-crosslinked partially deacetylated chitin; the partially deacetylated chitin is 20-40% deacetylated chitin.

3. The medical eye patch according to claim 1, wherein the ophthalmic medicine storage layer (3) comprises an adhesive patch layer (3-1) and a thermal insulation layer (3-2), and an integrated medicine storage bin (3-3) is arranged in the middle of the adhesive patch layer (3-1); the lower surface of the heat insulation layer (3-2) is hermetically adhered to the upper end surface of the medicine storage bin (3-3), and the upper surface of the heat insulation layer (3-2) is adhered to the adhesion layer (4); a drug delivery system (5) is arranged in the drug storage bin (3-3); the drug delivery system (5) is a mixture of a drug (5-1) and a thermosensitive hydrogel (5-2).

4. The medical eye patch according to claim 1, wherein the adhesive layer (4) comprises an eyelid adhesive portion (4-1) and a nose bridge adhesive portion (4-2), the eyelid adhesive portion (4-1) comprises a central region (20) for applying the medicine and an extended region (21), and the ophthalmic storage layer (3) is adhered to the central region (20) for applying the medicine.

5. The medical eye patch as claimed in claim 4, wherein the adhesive layer (4) has an overall appearance of T-shape or H-shape, and when the T-shape is adopted, the central region (20) for applying medicine is one and located at the middle position of the top of the T-shape; when the medicine is H-shaped, the medicine applying central area (20) is two and is positioned at the middle position of two ends of the H-shaped.

6. A method for preparing a medical eye patch according to any one of claims 1 to 5, which comprises the steps of:

① adding a drug delivery system (5) into a drug storage bin (3-3) in the adhesive patch layer (3-1), and sealing and adhering the drug storage bin (3-3) with the thermal insulation layer (3-2) to form an eye drop storage layer 3;

②, pasting the surface of the microneedle array layer (2) with the microneedle (2-1) array on the anti-sticking layer (1), and then pasting the lower end surface of the sticky patch layer (3-1) of the eye drop storage layer (3) obtained in the step ① on the opposite end surface of the microneedle array layer (2) with the microneedle (2-1) array surface;

③, the upper end surface of the heat insulation layer (3-2) of the product obtained in the step ② is stuck to the medicine application central area (20) of the sticking layer (4), and the medical eye patch (100) is obtained.

7. The method for preparing according to claim 6, wherein the cartridge (3-3) is prepared by: preparing a material used for preparing the sticky patch layer (3-1) into a mixed solution (8), then casting the mixed solution (8) into a sticky patch mold (9), and drying to obtain the sticky patch layer (3-1) with a certain thickness; and cutting the middle part of one surface of the adhesive patch layer (3-1) to form an integrated medicine storage bin (3-3).

8. The production method according to claim 6, characterized in that the microneedle array layer (2) is produced by: and (2) placing the lysozyme sensitivity hydrogel (6) in a laser-drilled silicone mold (7), and preparing the microneedle array layer (2) with the microcatheter (2-2) in the microneedle (2-1) by adopting a micro injection molding process.

9. The method according to claim 8, wherein the lysozyme-sensitive hydrogel 6 is prepared by:

A. suspending chitin in 35-45 wt% alkali solution, soaking for 2-4h, adding ice to reduce the alkali concentration to 5-15 wt%, mixing at room temperature for 60-80h, filtering, neutralizing with acid, dialyzing to remove water, soaking in acid solution for 2-4 days, and neutralizing with alkali to neutrality to obtain partially deacetylated chitin with deacetylation content of 20-40%;

B. adding a certain volume of 20-30 wt% glutaraldehyde aqueous solution into the obtained partially deacetylated chitin aqueous solution, standing at room temperature for 20-30h, washing with glycine solution to remove residual glutaraldehyde, and washing with potassium phosphate buffer solution until the pH value is 5.5-6.5 to obtain the glutaraldehyde crosslinked partially deacetylated chitin, namely the lysozyme sensitive hydrogel; wherein the addition amount of the glutaraldehyde is 40-50 wt% of the chitin.

10. Use of the medical eye patch according to any one of claims 1-5 for treating eye diseases in infants and children.

Technical Field

The invention belongs to the field of medical materials, and particularly relates to a medical eye patch suitable for infants and children and a preparation method thereof.

Background

The instillation of eye drops into the eye, commonly known as eye drops, is the most prominent route of administration for the treatment of eye diseases in infants and children, typically under the age of 10 years. For example, topical antibiotic eye drops are used for treating the obstruction of nasolacrimal duct caused by bacterial conjunctivitis and purulent secretion and preventing neonatal ophthalmia, and antiallergic eye drops are used for treating allergic conjunctivitis, and mydriatic agents, cycloplegic agents and the like are generally prepared into eye drops which are used for retina examination and pupil enlargement during refraction of children. Clinical results show that for children suffering from eye diseases, the traditional mode of directly dripping eye drops has the following defects: 1. when actually dropping eye drops, parents or guardians need to hold a child, break off eyelids, approach a dropper to an eyeball, and drop a drop of eye drops to a conjunctiva area, which is a way that the infant is usually not matched or even refused very much. 2. Eye drops are affected on the surface of the eyeball by tears, nasolacrimal duct inhalation, metabolic degradation, etc., and particularly, lacrimal secretion causes very little drug to be transported on the surface of the eyeball through intraocular barriers such as the cornea, conjunctiva and sclera. If the eye is stimulated by the mechanical force of topical application or slowly instilled eye drops, tear secretion increases and further dilutes the drug, and about 95% of the eye drops may be washed away from the eye surface by the tear within minutes, and these protective mechanisms result in poor absorption of the drug at the surface of the eye. Although infants and children have less tear fluid volume than adults, tear fluid volume is greater, resulting in more rapid dilution of the drug. If the child is administered while crying, the amount of the drug which really exerts curative effect is less. 3. Only 1-7% of the total amount of the final application is absorbed, except for the portion that is washed away by tears, and the remainder enters the systemic circulation. After the eye drops enter the systemic circulation, the blood volume of children patients, particularly infants is smaller than that of adults, so that the dosage diluted by the blood is very small. The relatively large dose and slow metabolism of the drug in the blood allows even one drop of eye drop to reach higher plasma concentrations and stay in the blood for longer periods of time, which increases the risk of systemic toxicity in infants and young children. 4. In addition to the inefficient drug concentration levels, the dosage of instilled drops is highly dependent on the administration process, such as the force of squeezing, the angle of application, and the ability to resist blinking, making it more difficult to control the dosage of the drops in a child patient than in an adult patient. Therefore, when the eye drops are topically applied to the eyes of infants and children, safety and effectiveness are considered, and it is desirable to obtain a therapeutic effect on the basis of the minimum dose.

In order to improve the delivery efficiency of the eye drops in the eye, the first way is to add a very small volume of eye drops, such as 11-15 μ L per drop, to prolong the residence time in the conjunctival sac, and even reduce the volume of each drop to 1-4 μ L to avoid the eye drops entering the nasal cavity, but changing the size and opening of the dropper head alone does not reduce the amount of each drop in the eye drops, and the change in surface tension of the drug formulation causes the volume of the drop to change; the second way is that the addition of viscosity enhancers to topical applications can keep the drug on the surface of the eye for a long period of time and reduce the rate of tear drainage, but the increase in viscosity can significantly interfere with vision; there is also a low-trauma method suitable for children to add eye drops, i.e. the infant is closed with his eyes in supine position, the eye drops are placed on the inner canthus anterior canthus and both eyes are closed tightly, once the eye drops are in place, the infant is guided to open his eyes, and the eye drops reach the tear film. The method has the advantages of reduced dosage of the medicine entering conjunctival sac compared with conventional eye drop method, and improved bioavailability. This approach is difficult to implement for young infants, as they are simply not able to cooperate.

In recent years, microneedles have been increasingly used to treat ophthalmic diseases. Advantages of microneedles over traditional hypodermic needles include: microneedles are typically of sufficient length, e.g., 25-2000 μm, to cross intraocular barriers such as epithelial cells and sclera, to allow local delivery of drug molecules in intraocular tissues, e.g., intrascleral and intrastromal delivery, to minimize pain and tissue damage, to reduce the risk of infection, to increase patient compliance due to the near invisibility of the microneedle, and to potentially achieve drug delivery of interest into the eye.

From the infant and child ophthalmology perspective, the advantages of microneedles are represented by: since the microneedles only penetrate the top layer of the skin, they exhibit painless and minimally invasive immunity; the use method is relatively simple and is suitable for long-term use; the risk of needle puncture and cross infection is reduced; can be used for one time; the small dose of drug contained in the microneedles makes it easier for this particular population to reach therapeutic concentrations. However, the use of microneedles in infant and child ophthalmology presents risks and challenges, mainly as follows: for infants and children with relatively thin skin, the micro-needle transdermal drug injection mode can affect the pharmacokinetics of the delivered drug, and can generate undesirable toxicity while obtaining remarkable curative effect; for infants and children, biocompatibility of microneedle materials is particularly important because of the immaturity and gradual evolution of the skin barrier in this age group, typically 10 years and under, the strength of the material should puncture the skin to deliver the drug effectively, but not cause any side effects to the tissue, and the material must be neither systemically nor locally toxic. Therefore, selecting suitable microneedle materials faces significant challenges; although the microneedles are short in length, insertion of the microneedles causes a "feeling of pressure" and a "feeling of heaviness" to the eye, and as the volume of the drug released from the microneedles increases, the patient feels an increase in pain due to greater pressure required to disperse the drug; the accuracy of dosing is critical in infants and children because of the underdeveloped skin barrier function, which is more sensitive to excessive and unwanted drug exposure risks; proper microneedle use guidance and training for medical personnel, parents, and guardians, such as microneedle insertion depth and strength, is also a key and challenge for proper microneedle use. The micro-needles are mainly focused on hollow, soluble and coated micro-needles in the ophthalmic application, and because most of the micro-needles are made of stainless steel materials, the micro-needles can pierce the stratum corneum barrier and sometimes even penetrate into the active epidermis and the dermis in actual use, and the micro-needles still have great safety risks for the ophthalmology of infants and children.

The hydrogel is a polymer with a three-dimensional structure, swells when meeting water, keeps sufficient water in the structure, and has a volume which is increased by several times compared with the original volume. The hydrogel can be divided into natural hydrogel and synthetic hydrogel, wherein the former hydrogel comprises agarose, methylcellulose, hyaluronic acid, chitosan, starch, collagen and the like; the latter include polyvinyl alcohols containing a large number of hydrophilic groups, sodium polyacrylates, acrylate polymers and copolymers, and the like. Hydrogels can also be classified into conventional hydrogels, which have no significant volume change under the influence of external environments such as pH, temperature, light, ion concentration, solvent composition, and are generally prepared from hydrophilic monomers, and in-situ hydrogels; the volume of the in situ hydrogel changes dramatically with environmental changes, and specifically, the in situ hydrogel changes from a liquid state to a semi-solid state under environmental stimuli such as temperature, pH, pressure, and/or ionic strength. For ocular administration, the in situ hydrogel system can immediately gel under physiological conditions without obscuring the view, and is a viable intraocular drug delivery modality. The formed hydrogel increases viscosity and mucosa adhesiveness, prolongs the residence time of the medicine in eyes, and realizes the sustained release of the medicine so as to increase the bioavailability of the medicine. If a biocompatible hydrogel is selected, toxicity and irritation at the site of application will be minimized.

The hydrogel type microneedle overcomes the limitations of the traditional microneedle, namely a hollow, soluble and coated microneedle, such as insufficient drug loading capacity, difficulty in precise drug coating and difficulty in precisely controlling the drug release range and rate. Placing the active pharmaceutical ingredient in a separate drug depot has the opportunity to deliver more drug. The hydrogel microneedles can be made in various shapes, are easily sterilized, and can be absolutely completely separated from the skin. Hydrogel microneedles are easy to manufacture, inexpensive, and amenable to large-scale manufacture. With various polymeric materials, rapid swelling is possible while being sufficiently rigid to puncture the skin in the dry state. The gel microneedle is particularly suitable for fragile patients such as infants, children and the elderly. Nevertheless, even with topical intraocular application, hydrogel-type microneedles still puncture the eye, and similar to other microneedles, puncture-type ophthalmic applications still present discomfort and certain safety risks to extremely sensitive infants and children in ophthalmology.

Disclosure of Invention

The invention aims to provide a medical eye patch which is suitable for intraocular local administration of infants and children under the age of 10 years. The medical eye patch can effectively overcome or improve the defects of strong discomfort of children patients, poor drug compliance, low drug delivery efficiency and curative effect, obvious toxic and side effects, high difficulty in drug application operation and the like caused by the traditional eye drops and microneedle drug application mode in treating infant and child ophthalmic diseases, particularly eye anterior segment diseases.

The invention relates to a medical eye patch, which belongs to a non-puncture noninvasive hydrogel type patch for local drug delivery on the surface of an eyeball at the inner canthus of the eye.

The technical scheme of the invention is as follows:

the invention discloses a medical eye patch 100, which sequentially comprises an anti-sticking layer 1, a microneedle array layer 2, an eye medicine storage layer 3 and an adhesive layer 4.

Preferably, the microneedle array layer 2 is made of lysozyme sensitive hydrogel 6, the microneedles 2-1 on the microneedle array layer 2 are flat-head type, and the microneedles 2-1 are internally provided with microcatheters 2-2; the anti-sticking layer 1 is attached to the surface of the microneedle array layer 2 and used for protecting the microneedle 2-1 array on the microneedle array layer 2; the anti-sticking layer 1 is generally a transparent protective layer of Polycarbonate (PC) release paper, is a layer of polyester medical embossing plastic protective film attached to the surface of the microneedle array layer, and is removed before use; the lysozyme sensitive hydrogel 6 is hydrogel which can swell or dissolve in the environment with lysozyme 11 and is partially deacetylated chitin crosslinked by glutaraldehyde; the partially deacetylated chitin is 20-40% deacetylated chitin. The microneedle array layer 2 is made of lysozyme sensitive hydrogel 6, and the microneedle end which is contacted with the eyeball surface at the inner canthus, namely the junction of the inner ends (nasal side) of the upper eyelid margin and the lower eyelid margin is respectively in a common tip-shaped structure and is in a flat-head structure, so that the skin on the eyeball surface cannot be punctured.

Preferably, the ophthalmic medicine storage layer 3 comprises an adhesive patch layer 3-1 and a heat insulation layer 3-2, and an integrated medicine storage bin 3-3 is arranged on the adhesive patch layer 3-1; the lower surface of the heat insulation layer 3-2 is hermetically adhered to the upper surface of the medicine storage bin 3-3, and the upper surface of the heat insulation layer 3-2 is adhered to the adhesion layer 4; a drug delivery system 5 is arranged in the drug storage bin 3-3; the drug delivery system 5 is a mixture of a drug 5-1 and a thermosensitive hydrogel 5-2. The drug storage bin 3-3 is stored with a microliter-scale drug delivery system 5, the volume of the drug delivery system is defined according to the age, the ocular anatomical structure and the pharmacokinetic characteristics of a child patient, and the volume of the drug delivery system is typically smaller than that of each drop of eye medicine of common eye drops, such as 1-15 muL; the administration system is an in-situ hydrogel system and is prepared by directly mixing thermosensitive hydrogel 5-2 and medicine 5-1. The bottom of the medicine storage bin 3-3 is provided with an adhesive patch layer 3-1, and an in-situ hydrogel medicine delivery system is injected into the medicine storage bin 3-3 in a micro-scale manner from the top of the medicine storage bin 3-3 and then is sealed by a heat insulation layer 3-2. The purpose of the heat-insulating layer 3-2 is to prevent the in-situ hydrogel drug delivery system 5 from changing its properties, particularly gelling, under the influence of the external environmental temperature, and thus affecting the ophthalmic drug delivery; the thermal insulation layer 3-2 is made of a flexible material having thermal insulation properties, such as aerogel material, especially silica aerogel film, and in order to improve its mechanical flexibility and to meet the requirements of eye application, fibrous material such as cellulose nanofibers can be added to improve its flexural modulus and flexural strength(ii) a To further improve the thermal insulation effect, opacifiers such as titanium dioxide and K can be doped ₂Ti ₆O ₁₃Whiskers, carbon, and the like.

The in-situ hydrogel drug delivery system 5 of the present invention can be prepared by directly mixing a thermosensitive hydrogel 5-2 with an ocular therapeutic drug 5-1, and the drug 5-1 can be combined with the thermosensitive hydrogel 5-2 to perform intraocular topical drug delivery, wherein the thermosensitive hydrogel for ocular drug delivery is a temperature sensitive polymer, is a free flowing solution at room temperature and becomes a non-flowing gel after contacting with the surface of the eyeball at a physiological temperature of 32-37 deg.C, the thermosensitive hydrogel can be a common thermosensitive natural polymer, such as a chitosan/β -glycerophosphate CS/GP mixture, cellulose, gelatin and derivatives thereof, and the thermosensitive hydrogel can be a commercial thermosensitive hydrogel commonly used for intraocular topical drug delivery, such as a commercial thermosensitive hydrogel commonly used for intraocular topical drug delivery

F-127PF-127, Poloxamer407, nonionic triblock copolymer PEO100/PPO65/PEO100, the thermosensitive hydrogel can also be thermosensitive synthetic polymers, including thermosensitive polymers such as polyisopropylacrylamide PNIPAAm and the like and thermosensitive amphiphilic triblock copolymers of polymers such as polyethylene oxide PEO, polypropylene oxide PPO, polylactic acid PLA, polylactic acid-glycolic acid copolymer PLGA, polyethylene glycol PEG, polycaprolactone PCL, poly (β -butyrolactone-lactic acid) PBLA and the like, such as PEO-PCL-PEO, PEG-PCL-PEG, PLGA-PEG-PLGA, PBLA-PEG-PBLA and the like, compared with PF-127 and chitosan hydrogels, the hydrogel generally has slower degradation rate and can have longer residence time in the eye.

The invention selects the thermosensitive hydrogel 5-2 with similar physicochemical properties such as water solubility and oil-water partition coefficient with the delivered drug as the delivery carrier of the drug 5-1 to combine with the drug. Typically as follows: small molecule drugs with high water solubility of 10mg/mL or more and low logD oil-water partition coefficient value of 3 or less can be combined with thermal sensitive hydrogel based on PF-127 and used for intraocular local drug delivery; whereas small molecule drugs with poor water solubility < 1mg/mL and high logD values of 3 or more are usually formulated in the form of nanosuspensions, such as drug nanoparticles, polymer micelles, solid lipid nanoparticles, liposomes or polymer microparticles, and then combined with thermosensitive hydrogels, such as nonionic triblock copolymers.

The release mechanism of the drug 5-1 loaded into the thermosensitive hydrogel 5-2 in the eye includes: control diffusion, control corrosion, and control swelling. Wherein, the drug release characteristics of the PF-127-based thermosensitive hydrogel are that burst release occurs in 1-2h at the beginning and then the release state is slow, while the drug release time of 5-1 is usually 6-24 h; the release time of the customized block copolymer and the chitosan thermosensitive hydrogel is obviously longer, and the customized block copolymer and the chitosan thermosensitive hydrogel can be completely released within several days to several weeks. The selection of a biocompatible, heat-sensitive hydrogel minimizes toxicity and irritation at the site of application.

In summary, depending on the type of eye disease, age group, drug release rate requirements, time per administration and treatment period of the infant and child, different types and ratios of drug and thermal hydrogel combinations can be selected to form in situ hydrogel drug delivery systems of different volumes, e.g., from 1 to 15 μ L.

Preferably, the adhesive layer 4 includes an eyelid adhesive portion 4-1 and a nose bridge adhesive portion 4-2, the eyelid adhesive portion 4-1 includes a central application area 20 and an extension area 21, and the ophthalmic storage layer 3 is adhered to the central application area 20.

Preferably, the overall appearance of the adhesive layer 4 is T-shaped or H-shaped, and when the adhesive layer is T-shaped, the central application area 20 is one and is located at the middle position of the top of the T-shaped; when it is H-shaped, the drug application central area 20 is two and is located at the middle position of two ends of the H-shaped. Wherein the T-type is used for single-eye administration and the H-type is used for synchronous administration in two eyes.

The adhesive layer 4 includes an eyelid adhesive part 4-1 and a nose bridge adhesive part 4-2. The eyelid pasting part 4-1 comprises a medicine applying central area 20 and an extension area 21, the lower surface of the medicine applying central area is directly pasted on the upper surface of the heat insulation layer 3-2, and a strippable nontoxic protective layer is pasted on the lower surface of the extension area; the lower surface of the nose bridge sticking end is also adhered with a strippable nontoxic protective layer. The area of the central area for drug application is equal to or smaller than that of the inner canthus area, and can be a square or round area with the side length or the diameter being less than or equal to 1-2 mm. The adhesive layer 4 is made of adhesive base materials, wherein the base materials are medical breathable non-woven fabrics, elastic fabrics or PVC (polyvinyl chloride), and the adhesive is zinc oxide hot melt adhesive, acrylic adhesive or medical hot melt pressure-sensitive adhesive. The strippable nontoxic protective layer is made of anti-sticking release paper and the like. The T-shaped structure pasting layer determines that the appearance of the medical eye patch is T-shaped, and the medical eye patch is suitable for single-eye application; the adhesive layer can also be in an H-shaped structure, and the corresponding medical eye patch is H-shaped in appearance and is suitable for synchronous application of the medicine to both eyes.

The second aspect of the invention discloses a preparation method of the medical eye patch, which comprises the following steps:

① adding drug delivery system 5 into the drug storage bin 3-3 of the adhesive patch layer 3-1, and sealing and adhering the drug storage bin 3-3 with the thermal insulation layer 3-2 to form an eye drop storage layer 3;

②, pasting the surface of the microneedle array layer 2 with the microneedle 2-1 array on the anti-sticking layer 1, and then pasting the lower end face of the sticky patch layer 3-1 of the eyedrop storage layer 3 obtained in the step ① on the opposite end face of the microneedle array layer 2 with the microneedle 2-1 array;

③, the upper end surface of the heat insulation layer 3-2 of the product obtained in the step ② is stuck on the medicine application central area 20 of the sticking layer 4, and the medical eye patch 100 is obtained.

Preferably, the preparation method of the medicine storage bin 3-3 comprises the following steps: preparing a material used for preparing the sticky patch layer 3-1 into a mixed solution 8, then casting the mixed solution 8 into a sticky patch mold 9, and drying to obtain the sticky patch layer 3-1 with a certain thickness; and an integrated medicine storage bin 3-3 is formed in the middle of one surface of the adhesive patch layer 3-1 by micro-cutting or MEMS micro-cutting.

Preferably, the preparation method of the microneedle array layer 2 is as follows: placing lysozyme sensitive hydrogel 6 in a laser-drilled silicone mold 7, and preparing to obtain a microneedle array layer 2 with a microcatheter 2-2 in the microneedle 2-1 by adopting a micro injection molding process; and the microneedles 2-1 are of a flat head type. The method comprises the following specific steps: placing the crosslinked partially deacetylated chitin hydrogel in a laser-drilled silicone resin mold 7, and preparing by adopting a micro injection molding process; or directly adding the formula of the glutaraldehyde crosslinking agent and the partially deacetylated chitin hydrogel into a laser-drilled silicone resin mold, standing at room temperature for 24h, washing to remove residual crosslinking agent after the glutaraldehyde crosslinking agent and the partially deacetylated chitin hydrogel are subjected to crosslinking reaction in the mold to form hydrogel, and preparing the microneedle array layer by using a micro injection molding process. The micro injection molding process has the advantages that the polymer microneedle array with different shapes and the micro catheter 2-2 inside can be manufactured by adopting a centrifugal method and a vacuum method, and the micro injection molding process is low in cost and more suitable for batch manufacturing. The microneedle 2-1 is in an inverted frustum shape or a chamfered frustum shape, and the aperture of the contact end with the eyeball is narrowed and cannot puncture the surface of the eyeball.

The adhesive patch layer 3-1 is prepared by casting, i.e., casting a mixture 8 of 10% w/w of PMVE perfluoromethylvinylether/PMMA polymethylmethacrylate copolymer and 5 wt% of TPM tripropylene glycol methyl ether in a silicone mold 9, and standing and drying at room temperature for a period of time, e.g., 48 hours. And after the die is removed, a sticky patch layer 3-1 with a certain thickness is formed. The center of the sticky patch layer 3-1 is subjected to micro-cutting or MEMS micro-cutting to form the sticky patch layer of the integrated medicine storage bin 3-3. The volume of the drug storage bin 3-3 is typically 1-15 muL, and in order to enable the eye drug to stay in the conjunctival sac for a longer time, the volume of the drug storage bin can be controlled to be 1-4 muL, and then the eye drug can not enter the nasal cavity at all.

The in situ hydrogel drug delivery system 5 is injected into the drug storage 3-3 of the adhesive patch layer 3-1 by a microinjection process or microinjection process in a sterile environment at room temperature, e.g., 20 ℃, the volume of the injected in situ hydrogel drug delivery system being typically 1-15 μ L, preferably 1-4 μ L. After the in-situ hydrogel drug delivery system is injected, a thermal insulation layer 3-2 is sealed on the upper end surface of the drug storage bin, and the thermal insulation layer and the adhesive patch layer 3-1 of the integrated drug storage bin form an eye drop storage layer 3 together. The lower surface of the adhesive patch layer 3-1 of the ophthalmic medicine storage layer 3 is slightly pressed on the opposite end surface of the lysozyme hydrogel microneedle array layer 2 with the microneedle 2-1 array surface, so that the two are adhered together. The upper end face of the heat insulation layer 3-2 of the eye drop storage layer 3 is directly adhered with the medicine application central area 20 of the adhesive layer 4, and the anti-sticking layer 1 is adhered on the surface of the hydrogel micro-needle array layer 2 with the micro-needle 2-1 array, so that the complete medical eye drop is prepared.

Preferably, the lysozyme-sensitive hydrogel 6 is prepared by the following method:

A. suspending chitin in 35-45 wt% alkali solution, soaking for 2-4h, adding ice to reduce the alkali concentration to 5-15 wt%, stirring at room temperature for 60-80h, filtering, neutralizing with acid, dialyzing to remove water, soaking in acid solution for 2-4 days, and neutralizing with alkali to neutrality to obtain partially deacetylated chitin with deacetylation content of 20-40%;

B. adding a certain volume of 20-30 wt% glutaraldehyde aqueous solution into the obtained partially deacetylated chitin aqueous solution, standing at room temperature for 20-30h, washing with glycine solution to remove residual glutaraldehyde, and washing with potassium phosphate buffer solution until the pH value is 5.5-6.5 to obtain the glutaraldehyde crosslinked partially deacetylated chitin, namely the lysozyme sensitive hydrogel; wherein the addition amount of the glutaraldehyde is 40-50 wt% of the chitin.

Human tears contain a large amount of lysozyme, the average concentration of lysozyme in tears of infants and children under 10 years old exceeds 1000mg/L, lysozyme 11 is an endoprotease with good properties, and can hydrolyze (l → 4) glycosidic bonds of chitin and some bacterial cell wall peptidoglycans, but peptidoglycans are a crosslinking material which cannot be made, and cannot make membranes or gels against lysozyme, chitosan, although easily forming membranes and gels, cannot be degraded by lysozyme 11, chitin β - (1,4) -2-acetamido-2-deoxy-D-glucan is a biopolymer widely distributed in nature, is a highly hydrophobic material, and is not easy to make into fibers and membranes because it is itself insoluble in water and most commonly used solvents, and in order to increase the hydrophilicity of chitin, its N-acetylglucosamine glucose unit can be deacetylated in strong alkali, and about 50% of chitin is easily deacetylated in water and dilute acid solvents, therefore, partially deacetylated chitin can make 11 degradable chitin hydrogels.

The preparation steps of the lysozyme sensitivity hydrogel microneedle array layer 2 are as follows in sequence: preparing partial deacetylated chitin, preparing glutaraldehyde cross-linked partial deacetylated chitin hydrogel, and preparing blunt end hydrogel microneedles.

The preparation method of the partially deacetylated chitin comprises the following steps: suspending chitin in 40 wt% NaOH solution, reducing pressure for 3 hr, and adding ice to reduce NaOH concentration to 10 wt%. Next, the mixture was stirred at room temperature for 75 hours, filtered, neutralized with concentrated hydrochloric acid and dialyzed to remove water. At this point approximately 31% deacetylated chitin was obtained, which was then kept in dilute acid solution for 3 days and then neutralized with NaOH to ph7.0 or so.

The preparation method of the glutaraldehyde crosslinking partially deacetylated chitin hydrogel comprises the following steps: adding 25 wt% glutaraldehyde solution with certain volume as cross-linking agent into the above partially deacetylated chitin solution, and standing the solution at room temperature for 24 h. Washing the gel with glycine with a certain concentration to remove residual glutaraldehyde, and washing with a potassium phosphate buffer solution until the pH value of the buffer solution is maintained at 6.0 to obtain the glutaraldehyde crosslinked partially deacetylated chitin; wherein the addition amount of the glutaraldehyde is 45 wt% of the chitin.

The chitin hydrogel with different deacetylation degrees can be obtained by adjusting the reaction conditions, so that the reaction rate of lysozyme 11 and partially deacetylated chitin can be adjusted, the swelling time of the hydrogel can be further adjusted, and the typical swelling time is from several hours to tens of hours. In particular, the rate of hydrogel swelling, and thus the rate of drug release, can be controlled by varying the crosslink density. The partially deacetylated chitin hydrogel did not swell or dissolve in the absence of lysozyme 11.

The third aspect of the invention discloses the application of the medical eye patch in treating eye diseases of infants and children under the age of 10 years old.

The invention relates to a medical eye patch implementation mode and a drug application principle:

after the infants and children sleep, the infants and children are in a supine posture, the anti-sticking layer 1 of the medical eye patch 100 is uncovered, the lysozyme sensitive hydrogel micro-needle array layer 2 is aligned to the inner canthus of the infants and is in contact with the surface 10 of the eyeball at the inner canthus, the strippable nontoxic protective layer on the lower surface of the sticking layer 4 is uncovered, the eyelid sticking part 4-1 of the sticking layer is stuck to the inner sides of the upper eyelid and the lower eyelid, and the nose bridge sticking part 4-2 is stuck to the nose bridge. At this time, the flat microneedle 2-1 end of the lysozyme sensitive hydrogel microneedle array layer 2 contacts with the eyeball surface 10 at the inner canthus to trigger the very thin tear film in the inner canthus to secrete a trace amount of tears, the microneedle 2-1 in the original state is swelled under the action of lysozyme 11 contained in the trace amount of tears to trigger the in-situ hydrogel drug delivery system 5 to flow and diffuse from the drug storage bin 3-3 through the adhesive patch layer 3-1 and then flow to the eyeball surface 10 at the inner canthus through the swelled microcatheter 2-2, the thermal hydrogel 5-2 in the drug delivery system is gelated in the physiological temperature range of the eyeball surface to lose fluidity and adhere to the eyeball surface 10 at the inner canthus, the drug 5-1 loaded in the thermal hydrogel 5-2 is released in a controlled manner through different mechanisms, so as to prolong the retention time of the drug 5-1 in the eye, sustained drug release is achieved to increase the bioavailability of drug 5-1. After the application, the adhesive layer 4 is gently peeled off from the eyelids and the bridge of the nose and the patch 100 is removed without any substance remaining on the surface of the eyeball.

The invention has the beneficial effects that:

1. the application of the medical eye patch is carried out after infants and children are asleep, the medial canthus application is not needed to be matched, the operation of parents or guardians is only to paste the medical eye patch and align the central application area with the medial canthus, and the application is very simple. After the application of the medicine is finished, the medical eye patch is only needed to be removed.

2. The medicine dosage in each medical eye patch is constant, and the medicine application amount is not highly dependent on the medicine application process.

3. The contact end of the micro needle of the medical eye patch and the surface of the eyeball is designed to be flat, so that the surface of the eyeball cannot be punctured completely, the medical eye patch belongs to noninvasive drug delivery, and the pain and safety risk of drug delivery are greatly reduced.

4. The medicine application central area of the medical eye patch is smaller and only acts on inner canthus, the mechanical acting force on the whole eye in the medicine application process is smaller, the discomfort of a child patient can be reduced, the eye stimulation is greatly reduced, the tear secretion caused by conditioned reflex is greatly reduced, and the quantity of medicine diluted by tears is greatly reduced; the microneedle array can be quickly swelled under the action of a small amount of tear film lysozyme, and the medicine in the trace thermosensitive hydrogel can quickly reach the surface of the eyeball and quickly gelate, so that the action time of the medicine on the surface of the eyeball is prolonged, and the bioavailability of the local medicine is improved. In addition, the medicine storage amount and the medicine application amount are very small, so that the toxic and side effects caused by the medicine entering the systemic circulation are greatly reduced.

5. The micro-needle array prepared from the lysozyme sensitive hydrogel for the medical eye patch is very stable in an environment without lysozyme, and the quality guarantee period of the eye patch is effectively prolonged. Meanwhile, the microneedle array prepared from the lysozyme-sensitive hydrogel is easily sterilized and can be completely separated from the surface of the eyeball without remaining on the surface of the eyeball after application.

6. The medical eye patch disclosed by the invention achieves the purposes of controlling the release of the medicine and obtaining the controllable medicine release rate by cooperatively controlling the swelling rate of the lysozyme sensitive hydrogel microneedle and the gelation rate of the thermosensitive hydrogel in a drug delivery system.

7. The medical eye patch disclosed by the invention is made of flexible medical or biocompatible materials, is soft in application process, and cannot cause hard injury to the skin and eyeballs of a child patient; while also minimizing toxicity and irritation at the site of application.

8. The medical eye patch has the advantages of simple manufacturing method, low cost and easy batch production.

Drawings

Fig. 1 is a top view of the T-shaped medical eye patch of the present invention.

Fig. 2 is a top view of the appearance of the H-shaped medical eye patch of the present invention.

Fig. 3 is a sectional view of an application region of the medical eye patch of the present invention.

Fig. 4 is a sectional exploded view of the application area of the medical eye patch of the present invention.

Fig. 5 is a schematic diagram of the preparation of a microneedle array for a medical eye patch of the present invention.

Fig. 6 is a schematic diagram of the preparation of the adhesive patch layer of the medical eye patch integrated drug storage bin of the invention.

Fig. 7 is a schematic view showing the state of application of the medical eye patch of the present invention.

Fig. 8 is a schematic view of the medical eye patch of the present invention just after being attached.

Fig. 9 is a schematic view of the process of applying the medical eye patch of the present invention.

The reference signs are: 1. an anti-sticking layer; 2. a microneedle array layer; 2-1, microneedles; 2-2, microcatheter; 3-an ophthalmic drug reservoir layer; 3-1, a sticky patch layer; 3-2, a heat insulation layer; 3-3, a medicine storage bin; 4-a sticking layer; 4-1, eyelid adhesive; 4-2 nose bridge adhesive part; 5. a drug delivery system; 5-1, medicaments; 5-2, thermosensitive hydrogel; 6. a lysozyme sensitive hydrogel; 7. laser drilling a silicone mold; 8. mixing the solution; 9. a sticky patch mold; 10. the surface of the eyeball; 11. lysozyme; 20. a drug application central area; 21. an epitaxial region; 100. a medical eye patch.

Detailed Description

The invention is further illustrated by the following examples and figures, which are only intended to provide a better understanding of the present invention and are not intended to be limiting.

FIG. 1 is a top view of the T-shaped medical eye patch of the present invention for single eye application, with one central application area 20 located at the middle of the top of the T-shape; fig. 2 shows the H-shape of the present invention for synchronous binocular application, and the central region 20 for application is two and located at the middle of the two ends of the H-shape. Wherein the non-application areas in the adhesive layer 4 are the extension area 21 and the nose bridge adhesive portion 4-2. When the medical eye patch is attached to eyes for applying medicine, the left image shows that the medicine is applied by a single eye, and the right image shows that the medicine is applied by two eyes synchronously as shown in fig. 7.

FIG. 3 is a cross-sectional view of the application area of a medical eye patch of the present invention; fig. 4 is a sectional exploded view of the application area of the medical eye patch of the present invention. As shown in fig. 3, the medical eye patch of the present invention sequentially comprises a release layer 1, a microneedle array layer 2, an ophthalmic storage layer 3, and an adhesive layer 4. As shown in fig. 4, the anti-sticking layer 1 is generally a transparent protective layer of polycarbonate PC release paper, and is a layer of polyester medical embossed plastic protective film attached to the surface of the microneedle array layer 2, and is used for protecting the microneedles 2-1 on the microneedle array layer 2 and is removed before use; the micro-needle 2-1 on the micro-needle array layer 2 is in a flat head shape with an inverted truncated cone, and the micro-catheter 2-2 is arranged in the micro-needle 2-1; the sticky patch layer 3-1 has a certain thickness, and an integrated medicine storage bin 3-3 is formed in the middle of the upper surface of the sticky patch layer; the drug storage bin 3-3 is provided with a drug delivery system 5, and the drug delivery system 5 is a mixture of thermosensitive hydrogel 5-2 and eye treatment drugs 5-1.

Fig. 5 is a schematic diagram of the preparation of a microneedle array for a medical eye patch of the present invention. The preparation steps are as follows: the lysozyme sensitivity hydrogel 6 is placed in a laser punching silicone mold 7, and a micro injection molding process is adopted to prepare a micro needle array layer 2 with micro catheters 2-2 in micro needles 2-1; and the microneedles 2-1 are of a flat head type. The method comprises the following specific steps: placing the crosslinked partially deacetylated chitin hydrogel in a laser-drilled silicone resin mold 7, and preparing the microneedle array layer 2 by adopting a micro-injection molding process; or directly adding the formula of glutaraldehyde crosslinking and partial deacetylated chitin hydrogel into a laser-drilled silicone resin mold, standing at room temperature for 24h to allow crosslinking reaction to occur in the mold, and simultaneously preparing the microneedle array layer 2 by a micro injection molding process. The micro injection molding process is a centrifugal and vacuum method, and the shape of the obtained microneedle 2-1 is an inverted frustum shape.

Fig. 6 is a schematic diagram of the preparation of the adhesive patch layer with the integrated drug storage chamber of the medical eye patch of the present invention. The preparation steps are as follows: preparing a material used for preparing the sticky patch layer 3-1 into a mixed solution 8, then casting the mixed solution 8 into a sticky patch mold 9, and drying to obtain the sticky patch layer 3-1 with a certain thickness; then, cutting is carried out on the middle part of one surface of the adhesive patch layer 3-1 by adopting a micro-cutting or MEMS micro-cutting method to form an integrated medicine storage bin 3-3, and a medicine delivery system 5 can be placed in the medicine storage bin 3-3.

Fig. 7 is a schematic view showing the state of application of the medical eye patch of the present invention. Fig. 8 and 9 are schematic diagrams of the application of the medical eye patch of the present invention, wherein fig. 8 is a diagram of the application process of the medical eye patch immediately after the application of the medical eye patch, and fig. 9 is a diagram of the application process of the medical eye patch after the application of the medical eye patch. Generally, after a patient is asleep, the patient is in a supine position, the anti-adhesion layer 1 of the medical eye patch 100 is uncovered, the microneedle array layer 2 is aligned to the inner canthus of the infant and is in contact with the surface 10 of the eyeball at the inner canthus, the peelable non-toxic protective layer on the lower surface of the adhesive layer 4 is uncovered, and the nose bridge adhesive end 4-2 is adhered to the nose bridge. At this time, the flat-headed microneedle 2-1 end of the microneedle array layer contacts with the eyeball surface 10 at the inner canthus to trigger the very thin tear film at the inner canthus to secrete a trace amount of tears, under the action of lysozyme 11 contained in trace amount of tears, the microneedle which is harder in the initial state swells, as shown in figure 8, a drug delivery system 5 is triggered to flow and diffuse from a drug storage bin 3-3 through a sticky patch layer 3-1 and then flow to an eyeball surface 10 at an inner canthus through a swollen microcatheter 2-2, as shown in figure 9, a thermosensitive hydrogel 5-2 in the drug delivery system is gelatinized at the physiological temperature range of the eyeball surface to lose fluidity and adhere to the eyeball surface at the inner canthus, and the drug 5-1 loaded in the thermosensitive hydrogel 5-2 is released under control of different mechanisms, so that the retention time of the drug 5-1 in the eyes is prolonged, and the sustained drug release is achieved to increase the bioavailability of the drug.

After the application, the adhesive layer 4 is gently peeled off from the eyelids and the bridge of the nose and the patch 100 is removed without any substance remaining on the surface of the eyeball.