Implant for sustained-release drug delivery, preparation method thereof and eye drug

Abstract

The invention belongs to the technical field of medicines, and particularly relates to an implant for sustained-release drug delivery, a preparation method of the implant and an eye drug. Wherein the implant comprises a drug-loading matrix and active drugs discretely distributed in the drug-loading matrix, the drug-loading matrix comprises a degradable polymer, and mass transfer ducts of the active drugs are arranged in the drug-loading matrix and on the surface of the drug-loading matrix. According to the implant for sustained-release drug delivery, an active drug mass transfer pore channel is established, so that an active drug can be timely subjected to mass transfer and release, and meanwhile, the mass transfer pore channel can be used for timely exporting a degradation product of the drug, so that the degradation speed of the drug is controlled, drug burst release caused by an autocatalytic reaction in the degradation process of a degradable polymer is reduced, and the drug release rate is increased. The treatment effect is favorably improved.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical technology, and particularly relates to an implant for sustained-release drug delivery, a preparation method thereof, and an ophthalmic drug. Background Art

[0002] Currently, ophthalmic implants (rods or filaments) contain prostamide components (such as bimatoprost) and a biodegradable polymer matrix. After the implant is placed in the eye, a certain amount of prostamide component is slowly released into the eye within a certain period of time to reduce the intraocular pressure of the patient and treat glaucoma.

[0003] Traditional sustained-release ophthalmic polyester implants are generally of a dense structure without pores on the surface and inside. Due to this dense structure, such sustained-release implants do not establish a drug release channel in advance and only rely on the formation of channels during the degradation process. Their degradation rate is slow, and the internal moisture cannot be discharged in time, resulting in the inability of the drug component in the implant to be mass-transferred and released in time. In addition, during the degradation process, due to the autocatalytic effect, the internal acidic environment of the implant accelerates the degradation of the implant, resulting in an uncontrollable drug release rate and easily leading to the formation of a cortex on the loose surface inside the implant. Summary of the Invention

[0004] The purpose of this application is to provide an implant for sustained-release drug delivery, a preparation method thereof, and an ophthalmic drug, aiming to solve to a certain extent the problems that existing implants only rely on the channels formed during the degradation process, with slow mass transfer and release rates of drugs and uncontrollable release rates.

[0005] To achieve the above application purpose, the technical solutions adopted in this application are as follows:

[0006] In a first aspect, this application provides an implant for sustained-release drug delivery, including a drug-loaded matrix and active drugs discretely distributed in the drug-loaded matrix. Among them, the drug-loaded matrix includes a biodegradable polymer, and mass transfer pores for the active drugs are provided inside and on the surface of the drug-loaded matrix.

[0007] In some possible implementation manners, the porosity of the implant is 10% - 50%.

[0008] In some possible implementation manners, the pore diameter of the mass transfer pores is 0.1 μm - 10 μm.

[0009] In some possible implementation manners, the size of the implant is 0.1 mm - 6 mm.

[0010] In some possible implementation manners, the mass percentage content of the active drug in the implant is 5% - 50%.

[0011] In some possible implementation manners, the active drug includes an ophthalmic therapeutic drug.

[0012] In some possible implementation manners, the shape of the implant includes a rod shape, a bar shape, a sheet shape, or microspheres.

[0013] In some possible implementation manners, the implant is for intraocular drug delivery. When the shape of the implant is a bar shape, it is applied to the anterior chamber of the eye;

[0014] When the shape of the implant is a sheet shape, it is applied to the conjunctiva of the eye;

[0015] When the shape of the implant is a rod shape, it is applied to the lacrimal canaliculus of the eye.

[0016] In some possible implementation manners, the active drug is selected from at least one of bevacizumab, ranibizumab, pegaptanib, aflibercept, bimatoprost, latanoprost, travoprost, bepotastine, tafluprost, pilocarpine, atropine, scopolamine, betaxolol, metoprolol, bunolol, metipranolol, propranolol, timolol, benoxinate, acetazolamide, dorzolamide, brinzolamide, apraclonidine, brimonidine, dipivefrin, guanethidine, dapiprazole, and pharmaceutically acceptable salts thereof.

[0017] In some possible implementation manners, the degradable polymer is selected from at least one of polyester, polylactic acid, poly(lactic-co-glycolic acid), poly(p-dioxanone), polycaprolactone, polyethylene glycol, gelatin, collagen, hyaluronic acid, chitosan, and alginate.

[0018] In a second aspect, the present application provides a method for preparing an implant for sustained-release drug delivery, including the following steps:

[0019] Prepare a mixed slurry including a degradable polymer and an active drug;

[0020] Perform a solidification and shaping treatment on the mixed slurry to form a drug-loading matrix with the degradable polymer as the drug-loading matrix and the active drug as the distributed loading substance, and form pores inside and on the surface of the drug-loading matrix to obtain an implant for sustained-release drug delivery.

[0021] In some possible implementation manners, the method for preparing the mixed slurry includes the following steps:

[0022] Dissolve the degradable polymer and the active drug in a solvent to obtain the mixed slurry; or, melt and mix the degradable polymer and the active drug to obtain the mixed slurry.

[0023] In some possible implementation manners, the solidification and shaping treatment includes the following steps:

[0024] After coating the mixed slurry on a substrate to form a drug-loaded film, the drug-loaded film is processed into an implant of a desired shape; alternatively, the mixed slurry is directly poured into a mold with a fixed shape, and after curing and molding, it is demolded to obtain an implant of a desired shape.

[0025] In some possible implementation manners, in the step of preparing the mixed slurry by dissolving the degradable polymer and the active drug with the solvent, the total mass percentage content of the degradable polymer and the active drug in the mixed slurry is 5% to 30%.

[0026] In some possible implementation manners, the mass ratio of the degradable polymer to the active drug is 2:(0.1 - 1).

[0027] In some possible implementation manners, the drying conditions are vacuum drying at 50°C to 90°C.

[0028] In some possible implementation manners, the thickness of the drug-loaded film is 10 μm to 1000 μm.

[0029] In some possible implementation manners, the solvent includes at least one of dimethyl sulfoxide, N,N-dimethylformamide, acetone, chloroform, dichloromethane, ethyl acetate, and methanol.

[0030] In a third aspect, the present application provides an ophthalmic drug, which contains the implant for sustained-release drug delivery and / or the implant for sustained-release drug delivery prepared by the method.

[0031] An implant for sustained-release drug delivery provided in the first aspect of the present application originally has mass transfer channels composed of pores on its surface and inside. When in use, the moisture inside the implant can be timely discharged from the mass transfer channels, so that the active drug can be timely mass transferred and released; in addition, the pre-established mass transfer channels of the implant can timely discharge the acidic degradation products generated by the autocatalytic action of the degradable polymer, slow down the degradation rate of the drug-loaded matrix, reduce the formation of a cortex on the loose surface inside the implant, and thus reduce the sudden release of the drug caused by the autocatalytic reaction during the degradation of the degradable polymer.

[0032] A preparation method of an implant for sustained-release drug delivery provided in the second aspect of the present application, by mixing a degradable polymer and an active drug, and curing and molding to obtain an implant for sustained-release drug delivery, has the advantages of simple operation, low manufacturing cost, easy control of the uniform distribution of the active drug, and is conducive to controlling the formation of the mass transfer channels of the implant, and is conducive to ensuring the quality of the implant.

[0033] The ophthalmic drug provided in the third aspect of the present application can enable the active drug to be mass-transferred and released in a timely manner due to the pre-established mass transfer channels. At the same time, the mass transfer channels can export the degradation products of the ophthalmic drug in a timely manner, not only controlling the degradation rate of the ophthalmic drug, but also reducing the sudden release of the drug caused by the autocatalytic reaction during the degradation of the degradable polymer, which is beneficial to improving the therapeutic effect. Description of the Drawings

[0034] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the following will briefly introduce the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings in the following description are only some embodiments of the present application. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0035] Figure 1 It is a scanning electron micrograph of the surface of the implant provided in Embodiment 1 of the present application;

[0036] Figure 2 It is a scanning electron micrograph of the internal cross-section of the implant provided in Embodiment 1 of the present application;

[0037] Figure 3 It is a graph of the in vitro drug release performance of the implants provided in Embodiments 1 to 3 of the present application;

[0038] Figure 4 It is a scanning electron micrograph of the change in the internal holes of the implants provided in Embodiment 1 and Embodiment 3 of the present application;

[0039] Figure 5 It is a micrograph of the size change of the implants provided in Embodiment 1 and Embodiment 3;

[0040] Figure 6 It is a scanning electron micrograph of the surface of the implant provided in Embodiment 4;

[0041] Figure 7 It is a micrograph of the implant provided in Embodiment 4. Detailed Description of the Embodiments

[0042] In order to make the technical problems to be solved, the technical solutions and the beneficial effects of the present application more clear, the following further details the present application in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the present application.

[0043] In this application, the term "and / or" describes the association relationship of associated objects, indicating that there can be three relationships. For example, A and / or B can represent: A exists alone, A and B exist simultaneously, and B exists alone. Here, A and B can be singular or plural. The character " / " generally indicates that the associated objects before and after are in an "or" relationship.

[0044] In this application, "at least one" means one or more, and "a plurality" means two or more. "At least one of the following" or its similar expressions refer to any combination of these items, including any combination of single items or plural items. For example, "at least one of a, b, or c", or "at least one of a, b, and c" can both represent: a, b, c, a to b (i.e., a and b), a to c, b to c, or a to b to c, where a, b, and c can be single or plural respectively.

[0045] It should be understood that in various embodiments of this application, the magnitudes of the serial numbers of the above processes do not imply the order of execution. Some or all of the steps can be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation to the implementation process of the embodiments of this application.

[0046] The terms used in the embodiments of this application are only for the purpose of describing specific embodiments and are not intended to limit this application. The singular forms of "an implant for sustained-release drug delivery, its preparation method, and a medicament" and "the" used in the embodiments of this application and the appended claims are also intended to include the plural forms unless the context clearly indicates otherwise.

[0047] The weights of the relevant components mentioned in the embodiments of the specification of this application can not only refer to the specific contents of each component, but also represent the proportional relationship of the weights between the components. Therefore, as long as the contents of the relevant components in the embodiments of the specification of this application are scaled up or down in proportion, they are within the scope disclosed in the embodiments of the specification of this application. Specifically, the mass described in the embodiments of the specification of this application can be mass units well-known in the chemical industry such as μg, mg, g, kg, etc.

[0048] The terms "first" and "second" are only used for descriptive purposes to distinguish objects such as substances from each other, and cannot be understood as indicating or implying relative importance or implicitly indicating the quantity of the indicated technical features. For example, without departing from the scope of the embodiments of this application, the first XX can also be referred to as the second XX. Similarly, the second XX can also be referred to as the first XX. Thus, the features defined with "first" and "second" can explicitly or implicitly include one or more of such features.

[0049] In the first aspect of the embodiments of the present application, an implant for sustained-release drug delivery is provided, which includes a drug-loaded matrix and active drugs discretely distributed in the drug-loaded matrix. The drug-loaded matrix includes a degradable polymer, and mass transfer pores for the active drugs are provided inside and on the surface of the drug-loaded matrix.

[0050] For the implant for sustained-release drug delivery provided in the first aspect of the embodiments of the present application, the active drugs are discretely distributed in the drug-loaded matrix. This discrete distribution means that the active drugs are distributed in the drug-loaded matrix in a multi-point form, either uniformly or non-uniformly. The mass transfer pores inside and on the surface of the drug-loaded matrix provide mass transfer channels for the multi-point discretely distributed active drugs at the same time. On the one hand, the active drugs discretely distributed at multiple points in the drug-loaded matrix can achieve multi-point sustained release through different mass transfer pores, improving the uniformity and stability of the sustained release of the active drugs. This avoids the problems of limited release channels in the inner core of the core-shell coating structure, uneven release, poor stability, and easy burst release of the active drugs. On the other hand, the mass transfer pores provided inside and on the surface of the drug-loaded matrix are conducive to the timely exclusion of moisture inside the implant from the mass transfer pores during use, so that the active drugs can be mass-transferred and released in a timely manner. On the further hand, the pre-established mass transfer pores in the implant can timely discharge the acidic degradation products generated by the autocatalytic action of the degradable polymer, slow down the degradation rate of the drug-loaded matrix, reduce the formation of a cortex on the loose surface inside the implant, and further reduce the burst release of drugs caused by the autocatalytic reaction during the degradation of the degradable polymer.

[0051] In some possible implementation manners, the porosity of the implant is 10% - 50%. Exemplarily, the porosity of the implant can be 10%, 20%, 30%, 50%, etc., which are typical but non-limiting arbitrary point values or interval values between any two point values. Too high porosity will, to a certain extent, cause the mechanical strength of the implant to deteriorate, the drug loading to decrease, and the volume of the implant to increase under the same drug loading, which is not conducive to implantation. Too low porosity will affect the release rate of the active drugs. When the porosity of the implant is 10% - 50%, the implant has both good mechanical strength and suitable mass transfer pores for the active drugs, which is conducive to controlling the degradation rate of the drug-loaded matrix and the release rate of the active drugs, and is also conducive to maintaining the volume of the implant and facilitating implantation.

[0052] In some possible implementation manners, the pore diameter of the mass transfer pores is a typical but non-limiting arbitrary point value or interval value between any two point values, such as 0.1μm - 10μm. Exemplarily, the pore diameter of the mass transfer pores can be 0.1μm, 0.2μm, 0.5μm, 1μm, 2μm, 5μm, 7μm, 10μm, etc., which are typical but non-limiting arbitrary point values or interval values between any two point values. In this case, the pore diameter of the mass transfer pores is conducive to ensuring the structural stability of the implant and establishing suitable mass transfer pores for the active drugs, and is conducive to controlling the release rate of the active drugs.

[0053] In some possible implementations, the size of the implant is a typical but non-limiting arbitrary point value or an interval value between any two point values, such as 0.1 mm to 6 mm. Exemplarily, the size of the implant can be a typical but non-limiting arbitrary point value or an interval value between any two point values, such as 0.1 mm, 0.2 mm, 0.5 mm, 1 mm, 2 mm, 3 mm, 5 mm, 6 mm, etc. In this case, the size of the implant facilitates the implantation of the implant into the eye.

[0054] In some possible implementations, the mass percentage content of the active drug in the implant is 5% to 50%. Exemplarily, the mass percentage content of the active drug in the implant can be a typical but non-limiting arbitrary point value or an interval value between any two point values, such as 5%, 10%, 20%, 30%, 40%, 50%, etc. In this case, the mass percentage content of the active drug can ensure that the implant continuously and stably releases the drug during degradation, achieving the expected therapeutic effect; it can also ensure that the concentration of the drug in the body is at a safe and effective level, reducing the occurrence of side effects; at the same time, it can also ensure that the absorption, distribution, metabolism, and excretion processes of the drug in the body are more reasonable, thereby improving the bioavailability of the drug and enabling the drug to better exert its therapeutic effect; according to the different requirements of different diseases and treatment methods for the drug loading amount, by controlling the drug loading amount, specific treatment needs can be met, ensuring that the implant exerts the best effect during the treatment process.

[0055] In some possible implementations, the active drug includes an eye treatment drug, that is, the implant is a drug for treating eye diseases. Among them, the eye treatment drug can be a drug for reducing intraocular pressure, treating blepharitis, dry eye, macular degeneration, postoperative inflammation after cataract, uveitis, retinopathy, allergic conjunctivitis, protecting the optic nerve, refractive correction, etc.

[0056] In some possible implementations, when the implant is a drug for treating eye diseases, the implant is for intraocular drug delivery, and the implant treats eye diseases by being implanted into the eye.

[0057] In some possible implementations, the shape of the implant includes rod-shaped, bar-shaped, sheet-shaped, or microspherical. In this case, different shapes of the implant can be suitable for implantation in different parts. Specifically, the implantation position and the shape of the implant can be determined according to the use. The implantation position can be the anterior chamber, posterior chamber, vitreous cavity, choroid, suprachoroidal space, subretinal space, conjunctiva, subconjunctival space, episcleral space, intralamellar space of the cornea, supra corneal space, sclera, pars plana, avascular area caused by surgery, macula, retina, and sub-tenon's space of the eyeball.

[0058] In some possible implementation manners, the implant is for intraocular drug delivery, and the shape of the implant is rod-shaped. At this time, the implant can be implanted into the anterior chamber of the eye. It should be noted that the rod shape here refers to a slender linear structure, where the length is much greater than the diameter, emphasizing more on the slender ratio, and the shape is closer to a "line". Compared with a bar shape, the rod shape is more slender and has a smaller cross-section. In this case, the length of the implant can be 1 mm to 2 mm, the width can be 0.1 mm to 0.5 mm, and the height can be 0.1 mm to 0.5 mm. Exemplarily, the length of the implant can be any typical but non-limiting point value such as 1 mm, 1.5 mm, 2 mm, etc. or an interval value between any two point values, the width can be any typical but non-limiting point value such as 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, etc. or an interval value between any two point values, and the height can be any typical but non-limiting point value such as 0.1 mm, 0.15 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, etc. or an interval value between any two point values.

[0059] In some possible implementation manners, the implant is for intraocular drug delivery, and the shape of the implant is disc-shaped. At this time, the implant can be implanted under the conjunctiva. In this case, the diameter of the implant is 1 mm to 6 mm, and the thickness is 10 μm to 200 μm. Exemplarily, the diameter of the implant can be any typical but non-limiting point value such as 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, etc. or an interval value between any two point values, and the thickness can be any typical but non-limiting point value such as 10 μm, 20 μm, 30 μm, 50 μm, 100 μm, 150 μm, 200 μm, etc. or an interval value between any two point values.

[0060] In some possible implementation manners, the implant is for intraocular drug delivery, and the shape of the implant is bar-shaped. At this time, the implant can be implanted into the lacrimal duct. It should be noted that the bar shape here refers to a cross-section that is circular, square or polygonal, with a length greater than the diameter, and the shape is relatively thick and short. Compared with the rod shape, the bar shape is thicker and shorter, and has a larger cross-section. In this case, the diameter of the implant is 0.5 mm to 0.8 mm, and the length is 1 mm to 2 mm. Exemplarily, the diameter of the implant can be any typical but non-limiting point value such as 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, etc. or an interval value between any two point values, and the length can be any typical but non-limiting point value such as 1 mm, 1.5 mm, 2 mm, etc. or an interval value between any two point values.

[0061] In some possible implementation manners, the active drug is selected from at least one of bevacizumab, ranibizumab, pegaptanib, aflibercept, bimatoprost, latanoprost, travoprost, besifloxacin, tafluprost, pilocarpine, atropine, scopolamine, betaxolol, metoprolol, bunolol, metipranolol, propranolol, timolol, befunolol, acetazolamide, dorzolamide, brinzolamide, apraclonidine, brimonidine, dipivefrin, guanethidine, dapiprazole and pharmaceutically acceptable salts thereof. All of these active drugs can be applied to the treatment of eye diseases. Among them, anti-VEGF drugs such as bevacizumab, ranibizumab, pegaptanib sodium, aflibercept, etc. can be used for age-related macular degeneration, etc. Prostaglandin drugs such as bimatoprost, latanoprost, travoprost, besifloxacin, tafluprost, etc. can be used to reduce intraocular pressure and treat glaucoma. Pilocarpine belongs to miotics and can be used to treat glaucoma. Mydriatics such as atropine, scopolamine, etc. can be used for mydriasis and cycloplegia. β-blockers such as betaxolol, metoprolol, bunolol, metipranolol, propranolol, timolol, befunolol, etc. can be used to reduce intraocular pressure and treat glaucoma. Carbonic anhydrase inhibitors such as acetazolamide, dorzolamide, brinzolamide, etc. can be used to reduce intraocular pressure and treat glaucoma. α-agonists such as apraclonidine, brimonidine, etc. can be used to reduce intraocular pressure and treat glaucoma.

[0062] In some possible implementation manners, the active drug can also be a drug for treating other diseases, for example, chlorambucil, melphalan, cyclophosphamide, ifosfamide, carmustine, lomustine, semustine, chlorozotocin, cisplatin, carboplatin, oxaliplatin, fluorouracil, mitoxantrone, irinotecan, topotecan, vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, paclitaxel, docetaxel, bleomycin, methotrexate, gemcitabine, capecitabine, hydroxyurea, mitomycin, gefitinib, sunitinib, dexamethasone, dexamethasone acetate, prednisone, prednisone acetate, fluocinolone acetonide, fluocinolone acetonide acetate, triamcinolone acetonide, methylprednisolone, methylprednisolone aceponate, halobetasol propionate, cortisone, hydrocortisone, cyclosporine, rapamycin, tacrolimus, mycophenolic acid, fostriecin, mizoribine, sulfasalazine, azathioprine, methotrexate, dasatinib. These drugs can be used in the fields of cancer treatment, immunosuppression, anti-inflammation, hormone therapy, etc. In this case, the selectivity of the active drug in the implant is wide, and it can be applicable to the treatment of different diseases, and the application is flexible and convenient. For different treatment purposes, different active drugs can be loaded in the implant.

[0063] In some possible implementation manners, the degradable polymer includes a degradable synthetic polymer material or a degradable natural polymer material. Among them, the degradable synthetic polymer material can be polyester, polylactic acid, poly(lactic-co-glycolic acid), poly(p-dioxanone), polycaprolactone, polyethylene glycol; the degradable natural polymer material can be at least one of gelatin, collagen, hyaluronic acid, chitosan, alginate. These degradable polymers can be degraded in the eye, which is beneficial to form a mass transfer pore for releasing the active drug.

[0064] In some embodiments, the degradable polymer includes at least two of polyester, polylactic acid, poly(lactic-co-glycolic acid), poly(p-dioxanone), polycaprolactone, polyethylene glycol, gelatin, collagen, hyaluronic acid, chitosan, alginate and is used in combination. In this case, if the drug-loaded matrix is composed of multiple degradable materials, the drug release rate and the drug release amount can be adjusted by adjusting the types and proportions of different degradable materials, etc.

[0065] The implant for sustained-release drug delivery provided in the above embodiments of the present application can be prepared by the following example methods.

[0066] In a second aspect, an embodiment of the present application provides a preparation method for an implant for sustained-release drug delivery, including the following steps:

[0067] S10. Prepare a mixed slurry including a degradable polymer and an active drug;

[0068] S20. Perform a solidification and shaping treatment on the mixed slurry to form a drug-loaded matrix with a degradable polymer, an active drug as a distributed load, and form holes inside and on the surface of the drug-loaded matrix, so as to obtain an implant for sustained-release drug delivery.

[0069] The preparation method for an implant for sustained-release drug delivery provided in the second aspect of the present application prepares an implant for sustained-release drug delivery by making a mixed slurry of a degradable polymer and an active drug and then solidifying and shaping it. The method is simple and easy to operate, has a low manufacturing cost, and is easy to control the relatively uniform distribution of the active drug. At the same time, it is beneficial to form holes inside and on the surface of the drug-loaded matrix, facilitating the control of the formation of the mass transfer pore of the implant, so that the active drug can be mass-transferred and released in time. At the same time, the acidic degradation products generated by the autocatalysis of the degradable polymer are discharged in time, reducing the sudden release of the drug caused by the autocatalytic reaction during the degradation of the degradable polymer.

[0070] In the above step S10:

[0071] In some possible implementation manners, the preparation method of the mixed slurry includes the steps: first dissolve the degradable polymer and the active drug separately by a solvent, and then mix them to obtain the mixed slurry.

[0072] In some other possible implementation manners, the method for preparing the mixed slurry includes the steps of: dissolving a degradable polymer and an active drug together in a solvent to obtain the mixed slurry.

[0073] In some other possible implementation manners, the method for preparing the mixed slurry includes the steps of: directly heating and melting a polymer and then mixing it with an active drug to obtain the mixed slurry.

[0074] In some other possible implementation manners, the method for preparing the mixed slurry includes the steps of: heating and melting and mixing a degradable polymer and an active drug together to obtain the mixed slurry.

[0075] In some other possible implementation manners, the method for preparing the mixed slurry includes the steps of: grinding and oscillating and mixing a degradable polymer and an active drug, and then heating and melting to obtain the mixed slurry.

[0076] In some possible implementation manners, in the step of preparing the mixed slurry by dissolving the degradable polymer and the active drug in a solvent, the total mass percentage content of the degradable polymer and the active drug in the mixed slurry is 5% to 30%. Exemplarily, the total mass percentage content of the degradable polymer and the active drug in the mixed slurry is 5%, 10%, 20%, 30%, etc., which are typical but non-limiting arbitrary point values or interval values between any two point values. In this case, during the drying and forming process of the mixed slurry, holes are formed inside and on the surface of the drug-loaded matrix through the volatilization of the solvent, and an implant with a certain porosity is obtained, achieving good mechanical strength, being able to maintain the volume and shape change not obvious for a long time, being beneficial to controlling the degradation rate of the drug-loaded matrix and the release rate of the active drug.

[0077] In some possible implementation manners, the mass ratio of the degradable polymer to the active drug is 2:(0.1 - 1). Exemplarily, within this range of mass ratios, the drug loading amount in the implant can be 5%, 10%, 20%, 50%, etc., which are typical but non-limiting arbitrary point values or interval values between any two point values. In this case, by precisely controlling the drug loading amount, it can be ensured that the implant continuously and stably releases the drug during the degradation process, achieving the expected therapeutic effect; it can also ensure that the concentration of the drug in the body is at a safe and effective level, reducing the occurrence of side effects; at the same time, it can also ensure that the absorption, distribution, metabolism, and excretion processes of the drug in the body are more reasonable, thereby improving the bioavailability of the drug and enabling the drug to better play its therapeutic role; according to the different requirements of different diseases and treatment methods for the drug loading amount, by controlling the drug loading amount, specific treatment needs can be met, ensuring that the implant plays the best effect during the treatment process.

[0078] In the above step S20:

[0079] In some possible implementation manners, the curing and forming treatment includes the following steps:

[0080] The mixed slurry is coated on a substrate and dried to obtain a drug-loaded film, and then the drug-loaded film is processed into an implant of a desired shape. Among them, the thickness of the drug-loaded film is the thickness of the implant. The method of processing the drug-loaded film into an implant can be as follows: Cover the particle forming template on the drug-loaded film, place it in a flat hot press, apply a certain pressure to the two, and maintain a stable pressure for a period of time. After removing the pressure, remove the particle forming template to obtain neatly arranged drug-loaded particles on a substrate such as polyethylene glycol (PET). Finally, it is cut into the required shape by laser cutting or mechanical cutting to obtain the implant. Among them, the preparation method of the particle forming template is: Select fluorinated polydimethylsiloxane (PDMS), etc. as the template material, which has the function of easy demolding, and the forming method refers to the preparation method of microfluidic chips.

[0081] In some possible implementation manners, the drying condition of the drug-loaded film is vacuum drying at 50-90°C. Exemplarily, after a biodegradable polymer, an active drug, and a solvent are mixed to obtain a mixed slurry, and then through a coating process or directly introduced into a mold, the drying condition can be vacuum drying at 50°C, 60°C, 80°C, or 90°C. Under these drying conditions, it is beneficial to form the required pore size and porosity inside and on the surface of the implant through solvent volatilization, so as to ensure that the release rate of the active drug is within the required range and ensure the treatment effect.

[0082] In some possible implementation manners, the thickness of the drug-loaded film is 10μm - 1000μm. Exemplarily, the thickness of the drug-loaded film can be typical but non-limiting arbitrary point values or interval values between any two point values such as 10μm, 20μm, 30μm, 50μm, 100μm, 150μm, 180μm, 200μm, 500μm, 1000μm, etc. The thickness of these drug-loaded films is suitable for preparing implants for implantation in the eye.

[0083] In some possible implementation manners, the solvent includes at least one of dimethyl sulfoxide, N,N-dimethylformamide, acetone, chloroform, dichloromethane, ethyl acetate, and methanol. These solvents have good dissolution effects on both the biodegradable polymer and the active drug, facilitating the preparation of a mixed slurry with a specific concentration according to the actual application situation, and the application is flexible and convenient.

[0084] In some other possible implementation manners, the curing and forming treatment includes the following steps:

[0085] The mixed slurry is hot-melt coated on a substrate, and after cooling and curing, a drug-loaded film is obtained, and then the drug-loaded film is processed into an implant of a desired shape. Among them, the material of the substrate can be PET, etc., the temperature of the hot-melt coating can be 60°C - 150°C, and the coating thickness can be 10μm - 1000μm.

[0086] In some possible implementation manners, the solidification and shaping process includes the following steps:

[0087] The mixed slurry is directly poured into a mold with a fixed shape, and then dried and demolded to obtain an implant with the required shape.

[0088] In a third aspect, an embodiment of the present application provides an ophthalmic drug, which contains the above-mentioned implant for sustained-release drug delivery and / or the implant for sustained-release drug delivery prepared by the above method.

[0089] The ophthalmic drug provided in the third aspect of the embodiment of the present application contains the above-mentioned implant for sustained-release drug delivery. Since the implant has pre-established mass transfer channels, the active drug can be mass-transferred and released in a timely manner. At the same time, the mass transfer channels can export the degradation products of the ophthalmic drug in a timely manner, not only controlling the degradation rate of the ophthalmic drug, but also reducing the sudden release of the drug caused by the autocatalytic reaction during the degradation of the biodegradable polymer, which is beneficial to improving the treatment effect.

[0090] To enable those skilled in the art to clearly understand the above implementation details and operations of the present application, and to significantly reflect the advanced performance of the implant for sustained-release drug delivery and its preparation method in the embodiments of the present application, the following technical solutions are illustrated by multiple embodiments.

[0091] Example 1

[0092] A preparation method of an implant for sustained-release drug delivery includes the following steps:

[0093] Step 1: Weigh 30% of poly(lactic-co-glycolic acid) (PLGA), 50% of polylactic acid (PLA), and 20% of bimatoprost according to the mass percentage content, add them to acetone for dissolution, and configure a mixed slurry with a mass percentage concentration of bimatoprost of 2%, a mass percentage concentration of poly(lactic-co-glycolic acid) of 3%, and a mass percentage concentration of polylactic acid of 5%.

[0094] Step 2: Coat the mixed slurry on a PET substrate, and perform vacuum drying at 80 °C to obtain a drug-loaded film with a thickness of 200 μm.

[0095] Step 3: Cover the particle forming template on the drug-loaded film, put it into a flat hot press, apply a certain pressure to the two, and maintain a stable pressure for a period of time. After removing the pressure, remove the particle forming template, and obtain regularly arranged drug-loaded particles on the PET substrate. Finally, cut them into the required shape by laser to obtain a rectangular rod-shaped implant. The length, width, and height of the implant are: 1.8 mm × 0.2 mm × 0.2 mm, and the weight is 85 μg.

[0096] Example 2

[0097] A preparation method of an implant for sustained - release drug delivery, comprising the following steps:

[0098] Step 1: Weigh 80% of polylactic acid (PLA) and 20% of bimatoprost according to mass percentage content, add them to acetone for dissolution, and prepare a mixed slurry with a mass percentage concentration of 2% of bimatoprost and 8% of polylactic acid;

[0099] Step 2: Coat the mixed slurry onto a PET substrate, and dry it under vacuum at 80 °C to obtain a drug - loaded film with a thickness of 200 μm;

[0100] Step 3: Cover the particle - forming template on the drug - loaded film, put it into a flat hot press, apply a certain pressure to the two, and maintain a stable pressure for a period of time. After removing the pressure, remove the particle - forming template, and obtain regularly arranged drug - loaded particles on the PET substrate. Finally, cut them into the required shape by laser to prepare a rectangular rod - shaped implant. The length, width and height of the implant are: 1.8 mm×0.2 mm×0.2 mm, and the weight is 85 μg.

[0101] Example 3

[0102] A preparation method of an implant for sustained - release drug delivery, comprising the following steps:

[0103] Step 1: Weigh 85% of poly (lactic - co - glycolic acid) (PLGA) and 15% of bimatoprost according to mass percentage content, add them to acetone for dissolution, and prepare a mixed slurry with a mass percentage concentration of 1.5% of bimatoprost and 8.5% of poly (lactic - co - glycolic acid);

[0104] Step 2: Coat the mixed slurry onto a PET substrate, and dry it under vacuum at 80 °C to obtain a drug - loaded film with a thickness of 200 μm;

[0105] Step 3: Cover the particle - forming template on the drug - loaded film, put it into a flat hot press, apply a certain pressure to the two, and maintain a stable pressure for a period of time. After removing the pressure, remove the particle - forming template, and obtain regularly arranged drug - loaded particles on the PET substrate. Finally, cut them into the required shape by laser to prepare a rectangular rod - shaped implant. The length, width and height of the implant are: 1.5 mm×0.2 mm×0.2 mm, and the weight is 67 μg.

[0106] Example 4

[0107] A preparation method of an implant for sustained - release drug delivery, comprising the following steps:

[0108] Step 1: Weigh 80% of poly (lactic-co-glycolic acid) (PLGA) and 20% of dexamethasone by mass percentage, add them to acetone for dissolution, and prepare a mixed slurry with a mass percentage concentration of 2% of dexamethasone and 8% of poly (lactic-co-glycolic acid).

[0109] Step 2: Coat the mixed slurry onto a PET substrate, and dry it under vacuum at 80 °C to obtain a drug-loaded film with a thickness of 200 μm.

[0110] Step 3: Cover the particle forming template on the drug-loaded film, put it into a flat hot press, apply a certain pressure to the two, and maintain a stable pressure for a period of time. After removing the pressure, remove the particle forming template, and neat drug-loaded particles are obtained on the PET substrate. Finally, cut them into the required shape by laser to prepare rectangular rod-shaped implants.

[0111] In order to verify the progressiveness of the embodiments of the present application, the following experimental performance tests were respectively carried out on the implants prepared in the above embodiments:

[0112] 1. The pore conditions inside and on the surface of the implant in Example 1:

[0113] As shown in the attached Figure 1 and Figure 2 figures, where the attached Figure 1 is the scanning electron microscope image of the surface of the implant in Example 1, and the attached Figure 2 is the internal cross-sectional scanning electron microscope image of the implant in Example 1. From the attached Figure 1 and the attached Figure 2 figures, it can be seen that mass transfer pores with a size of 300 nm to 1500 nm are distributed on the surface and inside of the implant. On the one hand, the active drugs discretely distributed at multiple points in the drug-loaded matrix can achieve multi-point slow release through these different mass transfer pores, improving the slow release uniformity and stability of the active drugs. This avoids the problems of limited release channels in the inner core, uneven release, poor stability, and easy burst release of the active drugs in the core-shell coating structure. In addition, these pre-established mass transfer pores in the implant can enable the active drugs to be mass-transferred and released in a timely manner. At the same time, the mass transfer pores can export the degradation products of the drugs in a timely manner, not only controlling the degradation rate of the drugs, but also reducing the burst release of the drugs caused by the autocatalytic reaction during the degradation of the degradable polymer, which is beneficial to improving the treatment effect. And, with the continuous progress of subsequent degradation, these pores can further establish mass transfer channels for drug release.

[0114] 2. In vitro drug release performance:

[0115] Simulate the conditions before implanting into the anterior chamber of the eye, and soak it in PBS (phosphate buffer solution) at 32 °C. The experimental results are shown in the attached Figure 3 figure, and the attached Figure 3In vitro drug release performance curves of the implants of Examples 1 to 3. From the experimental results, it can be seen that the weights of the implants of Examples 1, 2, and 3 are 85 μg, 85 μg, and 67 μg respectively, and the drug loadings are 17 μg, 17 μg, and 10 μg respectively.

[0116] The implant of Example 1 released 8.7%, approximately 1.5 μg, in the first 7 days. The cumulative release in the first 28 days was 11.6%, and the cumulative release amount was 2 μg. By the 182nd day, an additional 11.5 μg was released, with an average daily release of 74 ng. By the 231st day, approximately 3 μg was released, with an average daily release of approximately 61 ng, and the cumulative release by the 231st day was approximately 97%.

[0117] The implant of Example 2 released 10%, approximately 1.7 μg, in the first 7 days. The cumulative release in the first 28 days was 20%, and the cumulative release amount was 3.4 μg. By the 189th day, an additional 9.7 μg was released, with an average daily release of 60 ng.

[0118] The implant of Example 3 released 9.5% in the first 7 days and then hardly released any drug. By the 91st day, the cumulative release rate was 9.65%, and the cumulative release amount was 0.965 μg.

[0119] From the above test results, it can be seen that the implants of Examples 1 and 2 have a long slow-release period for the active drug and a balanced slow-release rate, which are suitable for the drug application requirements with a long slow-release period for the active drug. The slow release of the active drug in the implant of Example 3 is mainly concentrated in the early stage, with a balanced slow-release rate, which is suitable for the drug application requirements with a short slow-release period for the active drug. In addition, in Example 1, the drug-loaded matrix uses a combination of PLA and PLGA. Among them, an increase in the proportion of acid-terminated PLA and a decrease in the molecular weight of ester-terminated PLGA are beneficial to improving the release rate of the bimeprazole drug. Therefore, the implant of Example 1 shows a better slow-release effect.

[0120] 3. Changes in internal pores during the in vitro drug release performance test:

[0121] As shown in the attached Figure 4 Scanning electron micrographs of the changes in internal pores of Example 1 and Example 3 are shown. At the initial state, the interiors of Example 1 and Example 3 are filled with pores. The pore range of Example 1 is 2 μm to 4 μm, and the pore range of Example 3 is 300 nm to 2 μm.

[0122] With the progress of degradation, the number of pores in Examples 1 and 3 gradually increased, and the pore size became larger. During the entire degradation process of Example 1, the internal pores gradually filled the entire implant, and obvious pore collapse was observed at 224 days. After 84 days in Example 3, the change of internal pores was no longer obvious. It can be seen that Example 1 uses a degradable polymer of poly (lactic-co-glycolic acid) (PLGA) + polylactic acid (PLA) as the drug-loading matrix, and the drug-loading matrix has a more significant and continuous degradation effect during the subsequent slow-release process, which is beneficial to the continuous and long-term slow release of the active drug. The drug-loading matrix of Example 3 only uses poly (lactic-co-glycolic acid) (PLGA) as the degradable polymer, and the degradation rate is slow. The slow-release effect of the active drug is mainly concentrated in the early stage of degradation.

[0123] 4. Size change during in vitro drug release performance test:

[0124] As shown in the appendix Figure 5 are the microscopic images of the size changes of Example 1 and Example 3. The size of Example 1 was observed to increase significantly starting from the 84th day, and by the 224th day, the implant lost its regular shape and the volume decreased significantly compared to the 168th day. The size of Example 3 did not change significantly within 224 days. It can be seen that the implants prepared in Examples 1 and 2 have a long degradation duration, which is beneficial to the long-term slow release of the loaded active drug. The implant prepared in Example 3 has a slow degradation rate and a slow slow-release rate of the loaded active drug.

[0125] 5. Experimentally test the surface pore condition of the implant obtained in Example 4 above:

[0126] As shown in the appendix Figure 6 shown, Figure 6 is the scanning electron microscope image of the surface of the implant in Example 4. It can be seen from Figure 6 that a large number of pores are distributed on the surface of the implant. With the continuous progress of degradation, these pores are beneficial to the establishment of mass transfer channels for drug release.

[0127] 6. Observe the overall morphology of the implant obtained in Example 4 above:

[0128] As shown in the appendix Figure 7 shown, Figure 7 is the microscopic image of the implant in Example 4. It can be seen from the figure that the shape of the implant in Example 4 is a rectangular rod.

[0129] The above are only the preferred embodiments of the present application and are not intended to limit the present application. Any modifications, equivalent replacements, and improvements made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. An implant for sustained-release drug delivery, characterized in that: The invention comprises a drug-carrying matrix and active drugs discretely distributed in the drug-carrying matrix, wherein the drug-carrying matrix comprises a degradable polymer and has mass transfer channels for the active drugs inside and on the surface of the drug-carrying matrix.

2. The implant according to claim 1, characterized in that The porosity of the implant is 10% to 50%; And / or, the pore size of the mass transfer channel is 0.1 μm to 10 μm; And / or, the size of the implant is 0.1 mm to 6 mm.

3. The implant according to claim 1 or 2, characterized in that The mass percentage of the active drug in the implant is 5% to 50%; and / or, the active drug comprises an ocular therapeutic drug; And / or, the shape of the implant includes rod, bar, sheet or microsphere.

4. The implant according to claim 3, characterized in that The implant is for intraocular administration, and when the implant is in the shape of a rod, it is applied to the anterior chamber of the eye; When the implant is in the shape of a sheet, it is applied to the conjunctiva of the eye; When the implant is in the shape of a rod, it is applied to the lacrimal canaliculus of the eye.

5. The implant according to any one of claims 1, 2 or 4, characterized in that The active drug is selected from at least one of bevacizumab, ranibizumab, pegaptanib, aflibercept, bimatoprost, latanoprost, travoprost, bimetaprost, tafluprost, pilocarpine, atropine, scopolamine, betaxolol, metoprolol, bunolol, metipranolol, propranolol, timolol, benfuranolol, acetazolamide, dorzolamide, brinzolamide, alaclonidine, brimonidine, dipivefrin, guanethidine, dapprazole and pharmaceutically acceptable salts thereof.

6. The implant according to any one of claims 1, 2 or 4, characterized in that The degradable polymer is selected from at least one of polyester, polylactic acid, polylactic acid-glycolic acid copolymer, polydioxanone, polycaprolactone, polyethylene glycol, gelatin, collagen, hyaluronic acid, chitosan and alginate.

7. A method for preparing an implant for sustained-release drug delivery, characterized in that: The following steps are involved: preparing a mixed slurry including a degradable polymer and an active drug; The mixed slurry is solidified and molded to form an implant with the degradable polymer as a drug-carrying matrix and the active drug as a distributed load, and holes are formed inside and on the surface of the drug-carrying matrix to obtain a sustained-release drug delivery implant.

8. The preparation method according to claim 7, characterized in that: The preparation method of the mixed slurry comprises the following steps: Dissolving the degradable polymer and the active drug in a solvent to obtain the mixed slurry; or, melt-mixing the degradable polymer and the active drug to obtain the mixed slurry; And / or, the curing and molding process comprises the following steps: After the mixed slurry is coated on a substrate to form a drug-loaded film, the drug-loaded film is processed into an implant of a desired shape; alternatively, the mixed slurry is directly poured into a mold with a fixed shape, and demolded after solidification to obtain an implant of a desired shape.

9. The preparation method according to claim 8, characterized in that: In the step of using the solvent to dissolve the degradable polymer and the active drug to prepare the mixed slurry, the total mass percentage of the degradable polymer and the active drug in the mixed slurry is 5% to 30%; and / or, the mass ratio of the degradable polymer to the active drug is 2:(0.1-1); And / or, the drug-loaded film is dried under vacuum conditions at a temperature of 50° C. to 90° C.; And / or, the thickness of the drug-loaded film is 10 μm to 1000 μm; And / or, the solvent includes at least one of dimethyl sulfoxide, N,N-dimethylformamide, acetone, chloroform, dichloromethane, ethyl acetate, and methanol.

10. An ocular drug, characterized in that: The ocular medicine comprises the implant for sustained-release drug delivery as claimed in any one of claims 1 to 6 and / or the implant for sustained-release drug delivery prepared by the method as claimed in any one of claims 7 to 9.

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