An axitinib intraocular implant

Abstract

The present application provides an acesulfame implant which is stable, safe and can achieve at least 6 months of sustained release, can effectively treat various eye diseases including but not limited to glaucoma, cataract, retinal vein obstruction (RVO), uveitis, diabetic macular edema (DME) and age-related macular degeneration (wAMD and nAMD), etc., avoids repeated administration, reduces the formation of side effects, reduces the cost of drug use, and meets the high stability required by drug preparation in production, storage and transportation, has good application prospect, and meets the unmet clinical needs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation and relates to an axitinib intraocular implant and its preparation method. Background Technology

[0002] Eye diseases are mainly divided into two types: anterior eye diseases, including but not limited to glaucoma, cataracts, blepharospasm, conjunctival diseases, conjunctivitis, and corneal diseases, and posterior eye diseases, including but not limited to retinal vein occlusion (RVO), uveitis, diabetic macular edema (DME), and age-related macular degeneration (wAMD and nAMD). These inflammatory or degenerative eye diseases have affected millions of people worldwide and, if not treated properly, can lead to permanent visual impairment or blindness.

[0003] Systemic corticosteroid therapy has been used to treat severe uveitis. However, due to the blood-retinal barrier and other factors, only about 2% of the drug can reach the eye to exert its effect with systemic administration. This requires high-dose and frequent administration, which can cause various systemic adverse reactions. It is generally not suitable for other chronic retinal diseases (Cheng CK et al. (1995). Intravitreal sustained-release dexamethasone device in the treatment of experimental uveitis, Invest. Ophthalmol. Vis. Sci. 36: 442-53).

[0004] Direct ocular administration, such as intravitreal delivery, provides the most targeted drug delivery, ensuring effective drug concentrations while limiting systemic exposure. Vitreous implants have been developed, such as the marketed fluocinolone acetonide intravitreal implant. It is used to treat chronic non-infectious uveitis caused by infection of the posterior segment of the eye.

[0005] Axitinib is a tyrosine kinase inhibitor with the chemical name N-methyl-2-[3-((e)2-pyridin-2-yl-vinyl)-1H-indazole-6-ylthio]-benzamide, and has the following chemical structural formula (compound I):

[0006]

[0007] Currently, it is marketed in the United States as an oral coated tablet for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have failed prior treatment with a tyrosine kinase inhibitor or cytokine therapy. As a dual-target inhibitor of VEGF-R2 and PDGFR-B, axitinib has the expected activity to inhibit CNV formation (Giddabasappa Anand, Lalwani Kush, Norberg Rand, et al. Axitinib inhibits retinal and choroidalneovascularization in in vitro and in vivo models. Experimental Eye Research, 2016, 145).

[0008] Patent WO2014204791 discloses an axitinib eye drop; however, its drug loading capacity is small, and due to the drug barrier effect and tear dilution, it hinders sufficient drug from reaching the treatment site, requiring repeated administration and resulting in poor compliance. WO2017120600 discloses an axitinib ophthalmic injection, but it does not address the stability issues of the axitinib formulation.

[0009] The applicant of this invention discovered in experiments that axitinib is highly sensitive to light, and its content varies considerably under light conditions, which is detrimental to the stability of its pharmaceutical formulation. Furthermore, its low solubility also reduces the bioavailability of axitinib formulations. Summary of the Invention

[0010] In order to overcome the shortcomings of the prior art, the present invention aims to provide a stable, safe, and long-term release axitinib implant for the treatment of a variety of eye diseases, including but not limited to glaucoma, cataracts, retinal vein occlusion (RVO), uveitis, diabetic macular edema (DME), and age-related macular degeneration (wAMD and nAMD).

[0011] The present invention includes an intraocular implant containing axitinib and a biodegradable polymer.

[0012] In some embodiments, the biodegradable polymer is one or more of poly(lactic acid-co-glycolic acid) (PLGA) copolymer, polylactide (PLA), polyglycolic acid (PGA), and polyethylene glycol (PEG). In some embodiments, the biodegradable polymer is PLGA; in one embodiment, the biodegradable polymer is ester-terminated PLGA.

[0013] In some embodiments, the molecular weight of the ester-terminated PLGA is 15,000 to 100,000. In some embodiments, the molecular weight of the ester-terminated PLGA is 15,000 to 70,000. In a preferred embodiment, the molecular weight of the ester-terminated PLGA is 70,000. In a preferred embodiment, the molecular weight of the ester-terminated PLGA is 15,000.

[0014] In some embodiments, the ratio of glycolic acid to lactic acid monomers in the PLGA is 0:100 to 100:0; in some embodiments, the ratio of glycolic acid to lactic acid monomers is 15:85 to 85:15; and in some embodiments, the ratio of glycolic acid to lactic acid monomers is 50:50.

[0015] In some embodiments, the implant comprises 20%-90% axitinib by weight; in some embodiments, the implant comprises 30%-80% axitinib by weight; in some embodiments, the implant comprises 30%-70% axitinib by weight; in some embodiments, the implant comprises 40%-70% axitinib by weight; in some embodiments, the implant comprises 45%-70% axitinib by weight; in some embodiments, the implant comprises 40%-50% axitinib by weight; in some embodiments, the implant comprises 45%-50% axitinib by weight; in some embodiments, the implant comprises 50%-70% axitinib by weight; in some embodiments, the implant comprises 30%-80% axitinib and 20%-70% ester-capped PLGA by weight; in some embodiments, the intraocular implant comprises 50%-70% axitinib and 30%-50% ester-capped PLGA by weight. In some embodiments, the intraocular implant comprises 40%-70% axitinib and 30%-50% ester-capped PLGA by weight. In some embodiments, the intraocular implant comprises 40%-50% axitinib and 40%-50% ester-capped PLGA by weight. In some embodiments, the intraocular implant comprises 70% axitinib and 30% ester-capped PLGA by weight. In some embodiments, the intraocular implant comprises 50% axitinib and 40% ester-capped PLGA by weight. In some embodiments, the intraocular implant comprises 50% axitinib and 45% ester-capped PLGA by weight. In some embodiments, the intraocular implant comprises 50% axitinib and 50% ester-capped PLGA by weight. In some embodiments, the intraocular implant comprises 50% axitinib and 50% ester-capped PLGA by weight, wherein the molecular weight of the ester-capped PLGA is 70,000. In some embodiments, the intraocular implant comprises 50% axitinib and 50% ester-capped PLGA by weight, wherein the ester-capped PLGA has a molecular weight of 15,000.

[0016] In some embodiments, the implant contains 200 micrograms to 1.5 milligrams of axitinib; in other embodiments, the implant contains 200 micrograms to 1 milligram of axitinib; and in still other embodiments, the implant contains 1 milligram to 1.5 milligrams of axitinib. In some embodiments, the intraocular implant weighs 200 micrograms, 400 micrograms, 500 micrograms, 600 micrograms, 700 micrograms, 1 milligram, or 150 milligrams.

[0017] In some embodiments, the implant includes a release modifier comprising one or more of hydroxypropyl methylcellulose, hyaluronic acid and its sodium salt, poloxamer, polyether, polyvinyl alcohol, polyvinylpyrrolidone, lactose, polyethylene glycol, mannitol, glucose, maltose, sodium chloride, potassium chloride, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, or sucrose. In some embodiments, the release modifier comprises one or more of polyethylene glycol, mannitol, sodium chloride, and polyvinylpyrrolidone. In some embodiments, the release modifier comprises one or more of mannitol, sodium chloride, and polyvinylpyrrolidone.

[0018] In some embodiments, the release regulator content is 0%-10% by weight; in some embodiments, the release regulator content is 2.5%-10% by weight; in some embodiments, the release regulator content is 5%-10% by weight; in some embodiments, the release regulator content is 0% by weight; and in some embodiments, the release regulator content is 10% by weight.

[0019] In some embodiments, the intraocular implant comprises: 50% axitinib, 40% ester-capped PLGA, and 10% mannitol by weight, wherein the ester-capped PLGA has a molecular weight of 15,000 or 70,000.

[0020] In some embodiments, the intraocular implant comprises: 50% axitinib, 40% ester-capped PLGA, and 10% polyvinylpyrrolidone by weight, wherein the ester-capped PLGA has a molecular weight of 15,000 or 70,000.

[0021] In some embodiments, the intraocular implant comprises: 50% axitinib, 45% ester-capped PLGA, and 5% sodium chloride by weight, wherein the ester-capped PLGA has a molecular weight of 15,000 or 70,000.

[0022] In some implementations, intraocular implants are used for vitreous delivery.

[0023] The present invention further provides a method for preparing the above-mentioned intraocular implant. In some embodiments, the preparation method employs a hot-melt extrusion method; in some embodiments, the preparation method employs a single extrusion or a double extrusion method; and in some embodiments, a single extrusion method is used.

[0024] In one embodiment, the preparation method may include the following specific steps: pulverizing axitinib, physically mixing it with a polymer and / or other optional excipients (e.g., release regulators, etc.), adding the mixture to a twin-screw hot melt extruder for extrusion, gradually heating the mixture within a temperature range of 90°C to 180°C, extruding the mixture, and cutting the extruded material to the desired length after extrusion.

[0025] In one embodiment, the preparation method may include the following specific steps: pulverizing axitinib and the polymer separately, physically mixing them with other optional excipients (such as release regulators), adding the mixture to a twin-screw hot melt extruder for extrusion, gradually heating the mixture within a temperature range of 90°C to 180°C, extruding the mixture, and cutting the extruded material to the desired length after extrusion.

[0026] In one embodiment, the preparation method includes the following steps: physically mixing axitinib with PLGA and / or a release regulator, adding the mixture to a twin-screw hot melt extruder, gradually heating the mixture within a temperature range of 90°C to 180°C, extruding the mixture, crushing the rod-shaped material formed in the first extrusion, adding it back to the twin-screw extruder for a second extrusion, and cutting the extruded material to the required length after extrusion.

[0027] This invention provides the use of the above-described implant in the preparation of a medicament for eye diseases, examples of which include, but are not limited to, glaucoma, cataracts, retinal vein occlusion, uveitis, diabetic macular edema, and age-related macular degeneration.

[0028] This invention provides a stable, safe axitinib implant that can achieve sustained release for at least 6 months. It can effectively treat a variety of eye diseases, including but not limited to glaucoma, cataracts, retinal vein occlusion (RVO), uveitis, diabetic macular edema (DME), and age-related macular degeneration (wAMD and nAMD). It avoids repeated dosing, reduces the formation of side effects, lowers medication costs, and meets the high stability required for drug formulations in production, storage, and transportation. It has good application prospects and meets unmet clinical needs. Attached Figure Description

[0029] Figure 1 In vitro release diagrams for prescriptions 1 to 3

[0030] Figure 2The images show intraocular fluorescein contrast imaging of monkeys treated with prescription 22 (A before modeling, B after modeling, C four weeks after drug administration). Detailed Implementation

[0031] The various aspects will now be described more fully below. However, these aspects may be implemented in many different forms and should not be construed as limited to the embodiments presented herein; rather, these embodiments are provided so that the disclosure is thorough and complete, and can fully demonstrate its scope to those skilled in the art.

[0032] definition

[0033] The following terms used in this article have the following meanings:

[0034] "Medicine" refers to any substance used to treat eye diseases.

[0035] "Intraocular" refers to the entire area of ​​the eye, including but not limited to the anterior chamber, posterior chamber, vitreous cavity, choroid, periocular region, ocular surface, pericortic space, conjunctiva, subconjunctival space, cornea, intracorneal space, extracorneal space, sclera, etc.

[0036] "Molecular weight" refers to the total relative molecular mass, which is the sum of the atomic weights of the atoms that make up the molecule.

[0037] "Biodegradable polymer" refers to a polymer that can be converted into non-toxic degradation products in the body over time, wherein the polymer needs to achieve the drug release kinetics according to the present invention as it degrades over time.

[0038] "Ester-terminated" refers to the presence of ester bonds at the ends of polymers. Common ester-terminated groups include, but are not limited to, alkyl esters and aromatic esters.

[0039] "Eye disease" refers to any illness, discomfort, or disorder that affects or involves the eye or a part of the eye, such as retinal disease. The eye includes the eyeball and the tissues and fluid that make up the eyeball, the muscles around the eye (such as the oblique and rectus muscles), and the portion of the optic nerve that is inside or adjacent to the eyeball.

[0040] "Implant" refers to a sterile preparation made from drugs and excipients for implantation into the body, including various forms of drug delivery such as subcutaneous implantation, intravitreal implantation, and intrauterine device (IUD) implantation. The term "implant" can be used interchangeably with "implantation."

[0041] Whenever the term "at least" precedes the first value in a series of two or more values, the term "at least" applies to each value in that series.

[0042] This invention provides an axitinib implant and method for treating ocular diseases. Typically, the implant continuously delivers axitinib to the ocular region for periods including, but not limited to, twelve months, nine months, six months, three months, or less than three months.

[0043] Axitinib intraocular implant

[0044] The implant of the present invention comprises axitinib dispersed in a biodegradable polymer for direct placement in the eye. In some embodiments, axitinib constitutes 20-90% of the implant weight; in some embodiments, axitinib constitutes 30-80% of the implant weight; in one embodiment, axitinib constitutes 50-70% of the implant weight; in one embodiment, axitinib constitutes 50% of the implant weight; and in one embodiment, axitinib constitutes 70% of the implant weight. In some embodiments, the implant contains 200 micrograms to 1.5 milligrams of axitinib; in some embodiments, the implant contains 200 micrograms to 1 milligram of axitinib; and in some embodiments, the implant contains 1 microgram to 1.5 milligrams of axitinib. In some embodiments, the implant contains 1.5 milligrams of axitinib; and in some embodiments, the implant contains 1 milligram of axitinib. In some embodiments, the implant contains 200 micrograms of axitinib. In some embodiments, the implant contains 400 micrograms of axitinib. In some embodiments, the implant contains 500 micrograms of axitinib. In some embodiments, the implant contains 600 micrograms of axitinib. In some embodiments, the implant contains 700 micrograms of axitinib, and in some embodiments, the implant contains 750 micrograms of axitinib.

[0045] In some embodiments, axitinib may be uniformly dispersed in a biodegradable matrix of the pharmaceutical composition. The choice of the biodegradable polymer matrix used may vary depending on factors such as desired release kinetics, patient tolerability, and the nature of the disease to be treated. Considered polymer properties include, but are not limited to, biocompatibility and biodegradability at the administration site, compatibility with axitinib, and processing temperature. In some embodiments, the biodegradable polymer matrix constitutes 20%–70% of the implant weight; in one embodiment, it typically constitutes 30%–50% of the implant weight; in another embodiment, it typically constitutes 50% of the implant weight; in another embodiment, it typically constitutes 30% of the implant weight; in another embodiment, it typically constitutes 40% of the implant weight; and in yet another embodiment, it typically constitutes 45% of the implant weight.

[0046] Available biodegradable polymer matrices include, but are not limited to, polymers made from monomers such as organic esters or organic ethers that produce physiologically acceptable degradation products upon degradation. Self-polymerization or polymerization with other monomers, such as acid anhydrides, amides, or orthoesters, can also be used. The polymers are typically condensation polymers. The polymers can be cross-linked or non-cross-linked.

[0047] For most polymers, in addition to carbon and hydrogen, oxygen and nitrogen are also present, especially oxygen, which can exist in the form of oxygen-containing groups, such as hydroxyl, carboxyl, ether, carbonyl, ester, etc. Nitrogen can exist in the form of amides, amino groups, etc. A description of a list of examples of available biodegradable polymers can be found in Heller, Biodegradable polymers in controlled drug delivery, in: "CRC critical reviews in therapeutic drug carrier systems", Vol. 1, CRC press, Boca Raton, FL (1987).

[0048] In some embodiments, the biodegradable polymer comprises at least one of the following: poly(lactic-co-glycolic acid) (PLGA), polylactide (PLA), polyglycolic acid (PGA), polyethylene glycol (PEG), D-lactide, D,L-lactide, L-lactide, D,L-lactide-co-ε-caprolactone, L-lactide-co-ε-caprolactone, D,L-lactide-co-glycolic acid-co-ε-caprolactone, poly(D,L-lactide-co-caprolactone), poly(L-lactide-co-caprolactone), poly(D-lactide-co-caprolactone), poly(D,L-lactide), poly(D-lactide), poly(L-lactide), poly(esteramide), or combinations thereof. In some embodiments, the biodegradable polymer comprises poly(lactide-co-glycolic acid) (PLGA).

[0049] Copolymers of glycolic acid and lactic acid are of particular interest, and the percentages of glycolic acid and lactic acid monomers in the PLGA can be 0-100%, 15-85%, 25-75%, or 35-65%. In a preferred embodiment, a PLGA with a glycolic acid to lactic acid monomer ratio of 50:50 is used.

[0050] On the other hand, the inventors discovered that using ester-terminated PLGA as a biodegradable polymer matrix can enhance the stability of axitinib drug compositions, including but not limited to stability under high temperature and humidity, light stability, and long-term stability. Ester-terminated PLGA has ester bonds at the polymer ends, and typical ester-termining groups include, but are not limited to, alkyl esters and aromatic esters. The molecular weight of ester-terminated PLGA is between 15,000 and 100,000; in a variation, the molecular weight of ester-terminated PLGA is between 15,000 and 70,000; in one embodiment, the molecular weight of ester-terminated PLGA is 70,000.

[0051] In some embodiments, axitinib may be pulverized into particles or microparticles, wherein at least 90% of the axitinib particles or microparticles have a diameter of less than or equal to 20 micrometers, and in a variation, wherein at least 90% of the axitinib particles or microparticles have a diameter of less than or equal to 15 micrometers.

[0052] The biodegradable polymer of the present invention can optionally be pulverized into particles or microparticles. Regarding the size of the polymer particles or microparticles, in one variation, at least 90% of the polymer microparticles or particles have a diameter of 10-100 μm; in another variation, at least 90% have a diameter of 10-50 μm; and in yet another variation, at least 90% of the polymer microparticles or particles have a diameter of 20-40 μm.

[0053] In some embodiments, the implant of the present invention may optionally and / or preferably contain other excipients, such as release modifiers. The release modifier can be used to accelerate the release of axitinib while maintaining a smooth axitinib release profile. In one embodiment, the release modifier is one or more polysaccharides, such as cellulose-based materials, including: hydroxypropyl methylcellulose, hyaluronic acid, poloxamer, polyethers such as polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, and mixtures thereof. In one embodiment, the release modifier is a pore-forming agent and / or a stability enhancer, optionally lactose, mannitol, glucose, maltose, sodium chloride, potassium chloride, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, or sucrose, etc. In another embodiment, the release modifier is a mixture of two or more of the above modifiers. In one embodiment of the present invention, the pharmaceutical composition does not contain any release modifier. In one embodiment of the present invention, the release modifier is sodium chloride; in another embodiment of the present invention, the release modifier is polyvinylpyrrolidone; in another embodiment of the present invention, the release modifier is mannitol. In some embodiments of the present invention, the content of the release regulator is 0%-10% by weight; in some embodiments of the present invention, the content of the release regulator is 2.5%-10% by weight; in some embodiments of the present invention, the content of the release regulator is 5%-10% by weight; in some embodiments, the content of the release regulator is 0% by weight; in some embodiments, the content of the release regulator is 10% by weight; in some embodiments, the content of the release regulator is 5% by weight; and in some embodiments, the content of the release regulator is 2.5% by weight.

[0054] The intraocular implants described herein are typically solid and can be prepared in the form of granules, sheets, blocks, membranes, fibers, rods, discs, etc., or can be of any size or shape compatible with the selected implantation site, provided that the implant has the required release kinetics and can deliver a certain amount of drug that can treat the ocular disease. In some embodiments, depending on the drug dosage contained in the implant, the duration of continuous administration, and the clinical administration method, the implant of the present invention is preferably in the form of an elongated cylindrical or thin rod, 0.3 mm to 10 mm in length, 0.05 mm to 1 mm in diameter, and with a total weight of 100 to 5000 micrograms, typically 500 to 1500 micrograms. In some embodiments, the implant is 5 mm long, 0.5 mm in diameter, and has a total weight of 1000 micrograms. In some embodiments, the implant has a diameter of 0.5 mm, a length of 5-7 mm, and a weight of approximately 1.0-1.5 mg.

[0055] Preparation method

[0056] This invention provides a method for preparing an implant comprising the above-described axitinib pharmaceutical composition. The preparation method can be carried out by hot melt extrusion, for example, using a piston extruder, a single-screw hot melt extruder, or a twin-screw hot melt extruder to uniformly disperse and distribute axitinib in a biodegradable polymer. In some embodiments, the implant is prepared by single or double extrusion; in a preferred embodiment, single extrusion is used. Typically, the operating temperature for hot melt extrusion is approximately 25°C to 180°C; in some embodiments, the temperature is 90°C to 180°C; in some embodiments, the temperature is 130°C to 180°C; and in some embodiments, the temperature is 150°C to 180°C. In one embodiment, the single extrusion method may include the following steps: pulverizing axitinib, physically mixing it with a polymer and / or other optional reagents (e.g., release regulators), adding the mixture to a twin-screw hot melt extruder, gradually heating the mixture to a temperature between 90°C and 180°C, controlling the speed between 5 RPM and 30 RPM until the mixture melts and is fully mixed, extruding the mixture, and cutting the extrudate to the desired length, which is 5 mm in some embodiments.

[0057] In another embodiment, the preparation method may include the following steps: pulverizing axitinib and the polymer into granules or micropowders respectively; physically mixing the granules or micropowders with / or other optional reagents (e.g., release regulators); adding the mixture to a twin-screw hot melt extruder; gradually heating the mixture, setting the temperature between 90°C and 180°C, and controlling the speed between 5 RPM and 30 RPM until the mixture melts and is fully mixed; extruding the mixture; and cutting the extrudate to the desired length, which is 5 mm in some embodiments.

[0058] In another embodiment, the preparation method may include the following steps: physically mixing axitinib with PLGA and / or a release regulator; adding the mixture to a twin-screw hot melt extruder; gradually heating the mixture, with the temperature set between 90°C and 180°C and the speed controlled between 5 RPM and 30 RPM, until the mixture melts and is fully mixed; extruding the first extruded rod-shaped material; crushing the rod-shaped material and adding it back to the twin-screw hot melt extruder for a second extrusion; and cutting the extruded material to the required length, which is 5 mm in some embodiments.

[0059] Implantation method

[0060] Biodegradable implants can be placed into the eye using various methods, including through an incision in the iris followed by placement using forceps, a syringe, a cannula, or other types of drug delivery devices. In some cases, forceps, syringes, canns, or other types of drug delivery devices can be used without an incision. In a preferred variation, a handheld drug delivery device can be used to place one or more implants into the eye.

[0061] The implantation method typically involves first inserting a needle into the target area within the eye region. Once inside the target area, such as the vitreous cavity, the handle on a handheld delivery device is pushed to cause an advance mechanism that propels a plunger forward. As the plunger advances, it pushes the implant into the target area.

[0062] application

[0063] The implant of the present invention is used to treat eye diseases, examples of which include, but are not limited to, glaucoma, cataracts, retinal vein occlusion, uveitis, diabetic macular edema, and age-related macular degeneration.

[0064] Example

[0065] The present invention is further described in detail through the following embodiments, but these are not intended to limit the scope of protection of the present invention.

[0066] The following specific implementation methods use the following drugs, reagents, and instruments:

[0067] Instruments and equipment:

[0068]

[0069] Pharmaceuticals, excipients and reagents:

[0070] name Model / Specification company Axitinib pharmaceutical grade Zhejiang Jiuzhou Pharmaceutical Co., Ltd. PLGA RG502 Evonik Industries PLGA RG502H Evonik Industries PLGA RG505 Evonik Industries PLGA RG858S Evonik Industries PLA R205S Evonik Industries PEG 3350 Clariant methanol HPLC level Chengdu Kelong Chemical Co., Ltd. Acetonitrile HPLC level Chengdu Kelong Chemical Co., Ltd. Nacl AR level Sigma SDS AR level Sigma Mannitol 160C, pharmaceutical grade Roquette PVP VA64, pharmaceutical grade BASF

[0071] In vitro release experiment

[0072] Preparation method of release medium: Release medium: 0.9% NaCl + 0.3% SDS;

[0073] Weigh 9g of sodium chloride into 1000ml of degassed water, dissolve it, add 3g of sodium dodecyl sulfate, and sonicate for 30 minutes to obtain the final product.

[0074] The temperature of the isothermal shaker was set to 37.0±0.5℃, the rotation speed to 150RPM, and the operating mode to vortex. 4ml of a prepared 0.9% NaCl + 0.3% SDS solution was added to each 10ml vial as the release medium. The sample containing the release medium was added to the isothermal shaker for temperature equilibration. Once the liquid temperature reached 37℃, a piece of implant preparation with a diameter of 0.5mm and a length of approximately 5-7mm was added. The sample was shaken until it sank below the liquid surface and placed back into the isothermal shaker. The sample was kept at this temperature for operation. Samples were taken at predetermined times, and the concentration of API in the solution was determined by high-performance liquid chromatography (HPLC) (chromatographic conditions as follows). The sampling method involved transferring 3ml of the 4ml release medium from the sample vial and replacing it with 3ml of freshly prepared 0.9% NaCl + 0.3% SDS solution, then re-inserting the sample into the equipment for analysis. The single release amount and cumulative release amount were calculated to form the release behavior measurement results.

[0075] Stability test: The samples were left untreated for 5 days, 10 days or 30 days under three conditions: high temperature (60℃), high humidity (92.5%RH) and light (4500lx±500lx), while avoiding cross-influence from other conditions as much as possible.

[0076] Content detection method: determined by high performance liquid chromatography.

[0077] Chromatographic conditions and system suitability test: Octadecylsilane-bonded silica gel was used as the stationary phase, acetonitrile-water (50:50) was used as the mobile phase, the flow rate was 1.0 ml / min, the detection wavelength was 330 nm, and the column temperature was 35 ℃.

[0078] Example 1

[0079] Table 1 Formulation Composition

[0080]

[0081] Preparation process

[0082] Axitinib was pulverized using an air jet mill to a target particle size D90 ≤ 15 micrometers. The axitinib powder was then physically mixed with excipients and fed into a twin-screw hot-melt extruder at a controlled rate using a 0.5mm die. Heating was performed, with the temperature gradually increased within a range of 90℃-180℃ to prepare the extrudate, ensuring smooth extrusion. The extruded sample was stretched using a conveyor belt adapter, with the speed controlled between 5 RPM and 30 RPM to ensure smooth collection of the extruded rod-shaped material. All formulations used a total formulation amount of 7g, prepared according to the proportions listed in the formulation list. The extruded formulation sample had a diameter of 0.5mm, a length of 5mm, and a weight of approximately 1.0mg, making it suitable for implantation.

[0083] Release rate consideration:

[0084] Release rate results are shown in Figure 1 .

[0085] Stability assessment:

[0086] Stability studies were conducted on formulations 1, 2, and 3. They were exposed to high temperature (60℃), high humidity (92.5% RH), and light exposure (4500 lx ± 500 lx) for 5-10 days, respectively, while minimizing cross-influence from other conditions. The stability results are shown in Tables 2-4.

[0087] Table 2. Stability data over 5 days at high temperature

[0088]

[0089] Table 3. Stability data under high humidity for 5 days

[0090]

[0091] Table 4. Stability data for 5 days under illumination

[0092]

[0093] Example 2

[0094] Table 5 Formulation Composition

[0095]

[0096] Preparation process

[0097] API was pulverized using an air jet mill, and then the API powder was physically mixed with excipients. This mixture was then fed into a twin-screw hot-melt extruder at a controlled rate using a 0.5mm diameter circular die. The temperature was set between 150℃ and 180℃ to prepare the extrudate, ensuring smooth extrusion. The extruded sample was stretched using a conveyor belt adapter, with the speed controlled between 5 RPM and 30 RPM to ensure smooth collection of the extruded rod-shaped material. The formulation used a total dosage of 6g, prepared according to the proportions listed in the formulation list above. The extruded formulation sample was controlled to have a diameter of 0.5mm, a length of 5-6mm, and a weight of approximately 1.0-1.5mg per implant unit.

[0098] Stability assessment:

[0099] Stability studies were conducted on formulations 3 and 4 by exposing them to light (4500 lx ± 500 lx) for 5 days, minimizing cross-influence from other conditions. The stability results are shown in Table 6.

[0100] Table 6. Stability data for 5 days under illumination

[0101]

[0102] Example 3

[0103] Table 7 Formulation Composition

[0104]

[0105] Preparation process

[0106] API was pulverized using an air jet mill, and then the API powder was physically mixed with excipients. This mixture was then fed into a twin-screw hot-melt extruder at a controlled rate using a 0.5mm diameter circular die. The temperature was set between 90℃ and 180℃ to prepare the extrudate, ensuring smooth extrusion. The extruded sample was stretched using a conveyor belt adapter, with the speed controlled between 5 RPM and 30 RPM to ensure smooth collection of the extruded rod-shaped material. The formulation used a total dosage of 6g, prepared according to the proportions listed in the formulation list above. The extruded formulation sample had a diameter of 0.5mm, a length of 5-6mm, and a weight of approximately 1.0-1.5mg per implant unit.

[0107] Stability assessment:

[0108] Stability studies were conducted on formulations 6-8 by exposing them to light (4500 lx ± 500 lx) for 10 days without exposure, minimizing cross-influence from other conditions. The stability results are shown in Table 8.

[0109] Table 8. Stability data after 10 days under illumination

[0110]

[0111] Example 4

[0112] Table 9 Formulation Composition

[0113]

[0114] Preparation process

[0115] API was pulverized using an air jet mill, and then the API powder was physically mixed with excipients. This mixture was then fed into a twin-screw hot-melt extruder at a controlled rate using a 0.5mm diameter circular die. The temperature was set between 130℃ and 180℃ to prepare the extrudate, ensuring smooth extrusion. The extruded sample was stretched using a conveyor belt adapter, with the speed controlled between 5 RPM and 30 RPM to ensure smooth collection of the extruded rod-shaped material. The formulation used a total dosage of 6g, prepared according to the proportions listed in the formulation list above. The extruded formulation sample was controlled to have a diameter of 0.5mm, a length of 5-6mm, and a weight of approximately 1.0-1.5mg per implant unit.

[0116] Stability assessment:

[0117] A stability study was conducted on formulation 9-11. It was left untreated for 10 days under three different light conditions (4500 lx ± 500 lx), minimizing cross-influence from other conditions. The stability results are shown in Table 10.

[0118] Table 10 Stability data under illumination for 10 days

[0119]

[0120] Example 5

[0121] Table 11 Formulation Composition

[0122]

[0123] Preparation process

[0124] The API and excipients were pulverized in an air jet mill, and then the API powder and excipient powder were physically mixed and fed into a twin-screw hot melt extruder at a controlled rate. A 0.5mm diameter circular die was used, and the temperature was set between 150℃ and 180℃ to prepare the extrudate, ensuring smooth extrusion. The extruded sample was stretched using a conveyor belt adapter, with the speed controlled between 5 RPM and 30 RPM to ensure smooth collection of the extruded rod-shaped material. The formulation was prepared according to the proportions listed in the formulation list, with a total formulation amount of 6g. The extruded formulation sample was controlled to have a diameter of 0.5mm, a length of 5-6mm, and a weight of approximately 1.0-1.5mg per implant unit.

[0125] Stability assessment:

[0126] Stability studies were conducted on formulations 12-13 by exposing them to light (4500 lx ± 500 lx) for 10 days without exposure, minimizing cross-influence from other conditions. The stability results are shown in Table 12.

[0127] Table 12 Stability data for 10 days under illumination

[0128]

[0129] Example 6

[0130] Table 13 Formulation Prescription

[0131] Components Prescription 14 Axitinib 70 PLGA RG858S 30

[0132] Preparation process

[0133] Axitinib was added to an air jet mill and pulverized to a target particle size D90 ≤ 15 micrometers. The axitinib powder was then physically mixed with excipients and fed into a twin-screw hot-melt extruder at a controlled rate using a 0.5mm die. Heating was performed, with the temperature gradually increased within a range of 90℃-180℃ to prepare the extrudate, ensuring smooth extrusion. The extruded sample was stretched using a conveyor belt adapter, with the speed controlled between 5 RPM and 30 RPM to ensure smooth collection of the extruded rod-shaped material. The collected extrudate was a pale yellow rod-shaped material. The above formulation, with a total dosage of 7g, was prepared according to the proportions listed in the formulation list. The extruded formulation sample had a diameter of 0.5mm, a length of 5mm, and a weight of approximately 1.0mg, making it suitable for implantation.

[0134] Example 7

[0135] Table 14 Formulation Prescription

[0136]

[0137]

[0138] Preparation process

[0139] Axitinib was added to an air jet mill and pulverized to a target particle size D90 ≤ 15 micrometers. The axitinib powder was then physically mixed with excipients and fed into a twin-screw hot-melt extruder at a controlled rate using a 0.5mm die. Heating was performed, with the temperature gradually increased within a range of 90℃-180℃ to prepare the extrudate, ensuring smooth extrusion. The extruded sample was stretched using a conveyor belt adapter, with the speed controlled between 5 RPM and 30 RPM to ensure smooth collection of the extruded rod-shaped material. The collected extrudate was a pale yellow rod-shaped material. The above formulation, with a total dosage of 7g, was prepared according to the proportions listed in the formulation list. The extruded formulation sample was controlled to have a diameter of 0.5mm, a length of 5mm, and a weight of 1.0mg for implantation.

[0140] Example 8

[0141] Table 15 Formulation Prescription

[0142] Components Prescription 16 Axitinib 50 PLGA RG505 50

[0143] Preparation process

[0144] Axitinib powder (particle size D90 ≤ 76.6 μm) was physically mixed with excipients and added to a twin-screw hot melt extruder at a controlled rate using a 0.5 mm die. Heating was performed, with the temperature gradually increased within a range of 90℃-180℃ to prepare the extrudate, ensuring smooth extrusion. The extruded sample was stretched using a conveyor belt adapter, with the speed controlled between 5 RPM and 30 RPM to ensure smooth collection of the extruded rod-shaped material. The collected extrudate was a pale yellow rod-shaped material. The above formulation, with a total dosage of 7 g, was prepared according to the proportions listed in the formulation list. The extruded formulation sample was controlled to have a diameter of 0.5 mm, a length of 5 mm, and a weight of 1.0 mg for implantation.

[0145] Example 9

[0146] Table 16 Formulation Prescription

[0147] Components Prescription 17 Prescription 18 Axitinib 50 50 PLGA RG502 50 / PLGA RG505 / 50

[0148] Preparation process

[0149] Axitinib was pulverized using an air jet mill to a target particle size D90 ≤ 15 micrometers. The axitinib powder was then physically mixed with excipient powder and fed into a twin-screw hot-melt extruder at a controlled rate using a 0.5mm die. Heating was performed, with the temperature gradually increased within a range of 90℃-180℃, to prepare the extrudate for smooth extrusion. The extruded sample was stretched using a conveyor belt adapter, with the speed controlled between 5 RPM and 30 RPM to ensure smooth collection of the extruded rod-shaped material. The rod-shaped material from the first extrusion was ground and pulverized, then fed back into the twin-screw hot-melt extruder for a second extrusion, and the extrudate was collected. The resulting extrudate was a pale yellow rod-shaped material. All formulations used a total dosage of 7g, prepared according to the proportions listed in the formulation list. The extruded formulation sample was controlled to have a diameter of 0.5mm, a length of 5mm, and a weight of 1.0mg for implantation.

[0150] Example 10: In vivo release experiment in monkey eyes

[0151] Sample: Axitinib implant, prepared according to prescriptions 19 and 20 (Table 17).

[0152] Preparation process: Axitinib is added to an air jet mill and pulverized to a target particle size D90 ≤ 15 micrometers. The axitinib powder is then physically mixed with excipients and fed into a twin-screw hot melt extruder at a controlled rate using a 0.5mm die. Heating is performed, with the temperature gradually increased within a range of 90℃-180℃ to prepare the extrudate, ensuring smooth extrusion. The extruded sample is stretched using a conveyor belt adapter, with the speed controlled between 5 RPM and 30 RPM to ensure smooth collection of the extruded rod. The extrudate is then cut to the desired length.

[0153] Table 17

[0154] prescription PLGA model Drug loading (%) 19 RG502 70 20 RG505 70

[0155] Animals: Two cynomolgus monkeys aged 2.5 to 6 years were purchased from Chengdu Huaxi Haiqi Pharmaceutical Technology Co., Ltd. The average weight at the time of purchase and modeling was 2.5 to 6.0 kg, and the individual weight values ​​were within ±20% of the average.

[0156] Animal grouping: One monkey was given prescription 19 as prescription 19 group, and another monkey was given prescription 20 as prescription 20 group.

[0157] Experimental drugs: 2 vials of Formula 19 (each vial measures 0.5mm x 7mm, with a total weight of approximately 1.42mg); 2 vials of Formula 20 (each vial measures 0.5mm x 7mm, with a total weight of approximately 1.45mg).

[0158] Administration process:

[0159] 1) After stabilizing and anesthetizing a monkey, and observing that there was no obvious physiological trunk activity, the monkey's eyes were disinfected with povidone-iodine solution;

[0160] 2) The implant was inserted into the vitreous body of the monkey's left eye by filling one vial of prescription 19 with a 22G needle. The implant was pushed into the monkey's vitreous body.

[0161] 3) The same procedure was used to implant the Prescription 20 implant into the left eye of another monkey.

[0162] Sampling and testing: For prescription 19, after the monkeys were raised for 1 month, they were euthanized, and vitreous fluid, lens, and residual drugs were collected from their eyes. After labeling, the concentration of each tissue was determined by high performance liquid chromatography. For prescription 20, after the monkeys were raised for 6 months, they were euthanized, and vitreous fluid, lens, and residual drugs were collected from their eyes. The results are shown in Tables 18-19.

[0163] Method for determining drug content in the lens: High performance liquid chromatography (General Chapter 0512, Chinese Pharmacopoeia 2020 Edition) was used. Animal plasma standard solutions with concentration gradients of 0.2, 1, 4, 10, 14, and 20 μg / mL were prepared. A standard curve was plotted by comparing concentration with peak area. The content of axitinib in the lens was calculated according to the following formula.

[0164] Determination of drugs in vitreous fluid: High performance liquid chromatography (General Chapter 0512, Chinese Pharmacopoeia 2020) was used for determination. Animal plasma standard solutions with six concentration gradients of axitinib (0.2, 1, 4, 10, 14, 20 ug / mL) were prepared. A standard curve was plotted by comparing concentration with peak area. The axitinib content in vitreous fluid was calculated according to the following formula.

[0165] Calculation formula:

[0166] Standard curve: Y = KX + b

[0167]

[0168]

[0169] In the formula:

[0170] Y: Peak area of ​​axitinib in the standard solution;

[0171] X: Concentration of axitinib in the standard solution;

[0172] Sample A: Area of ​​the axitinib peak in the sample to be tested;

[0173] V dilution volume: the dilution factor of the vitreous fluid to be tested.

[0174] Methods for determining residual drug content:

[0175] The axitinib content in the remaining drug was determined by high performance liquid chromatography (General Chapter 0512, Chinese Pharmacopoeia 2020 Edition), using axitinib raw material as a reference standard, and calculated by the external standard method. The calculation formula is as follows:

[0176]

[0177] In the formula:

[0178] A 样 Area of ​​the axitinib peak in the sample to be tested;

[0179] C 对照 : Control solution concentration;

[0180] Average peak area of ​​the control solution;

[0181] V 稀释体积: Dilution volume of the sample to be tested;

[0182] m 药段重量 Weight of the drug-eluting preparation.

[0183] Table 18. Release data of prescription 19 in monkey eyes after 1 month.

[0184]

[0185] Table 19 Release data of prescription 20 in monkey eyes after 6 months

[0186]

[0187] Example 11 Pharmacodynamic Experiment

[0188] The pharmacodynamics of the above prescription 20 were validated using a monkey CNV model, as detailed below:

[0189] Modeling method:

[0190] This study investigated the efficacy of a single intravitreal injection of Prescription 20 implant on laser-induced choroidal neovascularization leakage and growth in cynomolgus monkeys. The experiment employed laser photocoagulation around the fovea of ​​the cynomolgus monkey's retina to induce choroidal angiogenesis, establishing an animal model similar to human choroidal neovascularization. Fluorescein fundus angiography was performed before photocoagulation and 21 and 28 days after photocoagulation to assess the model's formation.

[0191] Grouping method:

[0192] Take one male crab-eating macaque as the prescription for 20 groups.

[0193] Application and testing methods:

[0194] Twenty-one days after photocoagulation, one vial of Prescription 20 was injected into each eye of the 20-group model. Fundus photography, fluorescein fundus angiography, and OCT were performed on the animals in the 20-group model before modeling, before grouping, and on days 7, 14, and 28 after administration to observe the inhibitory effect of the test product on choroidal neovascularization. Fundus examinations were performed every two weeks starting 29 days after administration, and gross dissections were performed on day 51 and day 204 of the experiment.

[0195] The experimental results are summarized as follows:

[0196] (1) General situation

[0197] From the start of the modeling process to the end of the experiment, the 20 groups of monkeys treated with the prescription were in good mental condition, had normal spontaneous activity, and showed no abnormalities in appearance.

[0198] (2) AMD modeling

[0199] Before laser modeling, color fundus photography of all eyes in the 20 groups of monkeys treated with the prescription showed no abnormalities in the retina and retinal vessels. Fundus fluorescein angiography revealed no fluorescein leakage. OCT scans of the fundus showed a smooth and even retinal pigment layer with uniform thickness across all retinal layers. Twenty days after laser modeling (before medication), color fundus photography of both eyes in the 20 groups of monkeys treated with the prescription showed nine laser spots around the macula in each eye. These laser spots exhibited high fluorescence around the macula, with significant fluorescein leakage extending beyond the edge of the laser spots.

[0200] (3) Fluorescence contrast examination

[0201] Twenty-eight days after administration of the prescription to the monkeys in group 20, the area of ​​the fluorescein spot in the left eye decreased, and the reduction in the area of ​​fluorescein leakage was 10.821 mm. 2 The area of ​​the fluorescein spot in the right eye decreased 28 days after drug administration, with a reduction of 7.193 mm in the fluorescein leakage area. 2 The number of grade 4 fluorescent spots was 5 and 3 on days 14 and 28 after administration, respectively, which was a decrease compared to 12 before administration.

[0202] Table 20: Fluorescent Spot Area (mm) 2 )

[0203]

[0204] Note: A fluorescein leakage area of ​​0 indicates that no fluorescein leakage was detected during FFA examination.

[0205] (4) Fundus examination

[0206] On days 65, 79, 93, 107, 121, 135, 149, 163, 177, 191, and 204 of the 20-group monkey experiment, the optic disc was faintly visible in the fundus; on days 136, 149, 163, 177, 191, and 204 of the experiment, anterior chamber cells were visible.

[0207] In summary, under the conditions of this experiment, in cynomolgus monkeys using a laser-induced CNV model, a single intravitreal injection of Prescription 20 showed that Prescription 22 implant inhibited CNV in the monkeys, as demonstrated by retinal fluorescein angiography, OCT examination, and fundus examination. The axitinib implant proposed in this application can achieve a sustained-release therapeutic effect of no less than 6 months, exhibits stability, and is expected to reduce the frequency of administration, extend the dosing interval, lower medication costs, and improve patient compliance.

Claims

1. An intraocular implantable axitinib, characterized in that... The implant comprises 50% axitinib and 50% PLGA by weight, wherein the PLGA is PLGA RG505 or PLGA RG502.

2. The intraocular implant according to claim 1, characterized in that... The ratio of glycolic acid to lactic acid monomers in the PLGA is 50:

50.

3. The intraocular implant according to claim 1, characterized in that... The implant contains axitinib in a weight of 200 micrograms to 1 milligram.

4. The intraocular implant according to claim 3, characterized in that... The implant contains axitinib in amounts of 200 micrograms, 400 micrograms, 500 micrograms, 600 micrograms, 700 micrograms, or 1 milligram.

5. The implant according to any one of claims 1-4, characterized in that... The implant is used for intravitreal drug delivery.

6. A method for preparing an intraocular implant comprising any one of claims 1-5, characterized in that... The preparation method includes the following steps: physically mixing axitinib and PLGA, adding the mixture to a twin-screw hot melt extruder, gradually heating the mixture within a temperature range of 90℃-180℃, extruding the mixture, and cutting the extruded material to the required length after extrusion.

7. The preparation method according to claim 6, characterized in that... The preparation method includes the following steps: physically mixing axitinib and PLGA, adding the mixture to a twin-screw hot melt extruder, gradually heating the mixture within a temperature range of 90℃-180℃, extruding the mixture, crushing the rod-shaped material formed in the first extrusion, adding it back to the twin-screw extruder for a second extrusion, and cutting the extruded material to the required length after extrusion.

8. The preparation method according to claim 6, characterized in that... The preparation method includes the following steps: pulverizing axitinib, physically mixing it with PLGA, adding the mixture to a twin-screw hot melt extruder, gradually heating it, with the temperature set between 90℃ and 180℃, extruding it, and cutting the extruded material to the required length after extrusion.

9. The preparation method according to claim 6, characterized in that... The preparation method includes the following steps: crushing axitinib and PLGA separately, physically mixing them, adding the mixture to a twin-screw hot melt extruder, gradually heating it, with the temperature set between 90℃ and 180℃, extruding it, and cutting the extruded material to the required length after extrusion.

10. Use of any one of the intraocular implants according to claims 1-5 in the preparation of a medicament for treating an eye disease, said eye disease being glaucoma, cataract, retinal vein occlusion, uveitis, diabetic macular edema, and age-related macular degeneration.

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