Pharmaceutical composition for treating eye diseases or disorders

Abstract

The present invention provides a pharmaceutical composition, an intravitreal implant, and a particle suspension comprising a polymer matrix and at least one therapeutic agent that is released in a substantially linear manner over a specific period.

Description

Technology Field

[0001] Related applications

[0002] The present application claims priority to U.S. provisional application No. 62 / 814,198, filed on March 5, 2019, the entire contents of which are incorporated herein by reference.

[0003] Field of invention

[0004] The present invention relates to the field of pharmaceutical compositions, implants formed from pharmaceutical compositions, methods for forming implants, and methods for treating eye diseases and disorders. Background Technology

[0005] Inflammatory ocular diseases or disorders such as macular edema, retinal vein occlusion, and uveitis can cause blurred vision, double vision, floaters, eye pain, and vision loss, and in severe cases, lead to blindness.

[0006] For treatment, corticosteroids, such as dexamethasone (Ozurdex), are administered via intravitreal injection (IVT). ® ) or triamcinolone acetonide (TRIESENCE ® ) can be injected. Corticosteroids, for example, TRIESENCE ® Repeated bolus injections are associated with cataract formation, increased intraocular pressure, vitreous floaters, endophthalmitis, reduced vision, and retinal damage. Patients may receive multiple injections throughout the course of treatment. This therapy is burdensome for both patients and healthcare providers.

[0007] Intravitreal implants have been developed to deliver sustained concentrations of therapeutic agents over a set period. These implants are injected into or surgically implanted into the vitreous humor of the eye to release the therapeutic agent toward the back of the eye. For example, OZURDEX ®It is an intravitreal implant used for the extended release of dexamethasone to treat various ocular diseases or disorders. However, a sufficient level of therapeutic agent is released for only approximately 30 to 60 days, after which a new implant must be injected into the patient's eye. Repeated injections can lead to pain, headache, conjunctival hematoma, intraocular infection, ocular perforation, fibrosis of the extraocular muscles, vitreous detachment, reaction to the delivery vehicle, increased intraocular pressure, and the development of cataracts. Alternatively, Fluocinolone Acetoneide (ILUVIEN), which releases fluocinolone acetonide over a period of approximately 3 years, is used. ® Intravitreal implants containing ) have been developed. The duration of this corticosteroid exposure is often too extensive for many patients and can increase the risk of corticosteroid-related side effects, including cataract formation and increased intraocular pressure.

[0008] Various biodegradable polymers are used to manufacture these intravitreal implants. Specific examples of such polymers are poly(lactic acid-co-glycolic acid) (PLGA), and poly(lactic acid) or polylactic acid or polylactide (PLA), and various analogs or derivatives. For example, published PCT patent application WO201715604 (incorporated herein by reference) discloses a pharmaceutical composition for treating an ocular disease or disorder, comprising, in particular, a biodegradable polymer matrix and at least one therapeutic agent dispersed within the polymer matrix, wherein the polymer matrix may comprise a biodegradable poly(D,L-lactide) homopolymer, a biodegradable poly(D,L-lactide-co-glycolide), or a mixture thereof. Biodegradable polyester amide (PEA) polymers for use in biodegradable implants have already been described. PEA is based on amino acids and contains various peptide bonds. A synthetic method for producing PEA is described, for example, in U.S. Patent Application Publication No. 2008 / 0299174, the entire contents of which are incorporated herein by reference. The general structure of a polyester amide, particularly a polyester amide copolymer, is described in U.S. Patent No. 9789189, the entire contents of which are incorporated herein by reference, and is the chemical structure of the following formula (I):

[0009]

[0010] In the above formula,

[0011] m+p varies from 0.9 to 0.1, and a+b varies from 0.1 to 0.9;

[0012] m+p+a+b=1, where either m or p can be 0;

[0013] n varies from 5 to 300, a is at least 0.01, b is at least 0.015, the ratio of a to b (a:b) is from 0.1:9 to 0.85:0.15, wherein the m units and / or p units, and the a and b units are randomly distributed;

[0014] R 1 (C2-C 20 Independently selected from )alkyls;

[0015] R in a single skeletal unit m or p 3 and R 4 is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C 10 Each independently selected from aryl, (C1-C6)alkyl, -(CH2)SH, -(CH2)2S(CH)3, (CH3)2-CH-CH2-, -CH(CH3)2, -CH(CH3)-CH2-CH3, -CH2-C6H5, -(CH2)4-NH2, and mixtures thereof;

[0016] R 5 is (C2-C 20 )alkyl, (C2-C 20 Independently selected from alkenylene;

[0017] R 6 is selected from the cyclic fragment of 1,4:3,6-dianhydrohexitol of the following chemical formula (II):

[0018] ;

[0019] R 7 Silver (C6-C 10 Independently selected from the group consisting of aryl, (C1-C6)alkyl or protecting groups;

[0020] R 8 It is -(CH2)4-.

[0021] There is a great need in the medical field for pharmaceutical compositions formulated to serve as delivery systems for intravitreal implants with improved safety and efficacy profiles, which release therapeutic agents directly into the posterior part of the eye in a substantially linear manner over a period of at least three months. Such pharmaceutical compositions are likely to improve both the compliance and side effect profiles of current intravitreal implants.

[0022] Any citation of any reference herein shall not be deemed an acknowledgment that such reference may be used as prior art for the present invention.

[0023] Broadly, the present invention extends to a pharmaceutical composition for treating an ocular disease or disorder comprising a biodegradable polymer matrix comprising a mixture of a first polymer and a second polymer, wherein (1) the first polymer is a biodegradable polyester amide polymer; (2) the second polymer is selected from (i) a biodegradable poly(D,L-lactide) polymer; (ii) a biodegradable poly(D,L-lactide-co-glycolide) polymer; and (iii) any combination of (i) and (ii). At least one therapeutic agent, or an analog or derivative thereof, a pharmaceutically acceptable salt, amphoteric ion, polymorph, or solvate thereof is homogeneously dispersed within the polymer matrix. In certain embodiments, the pharmaceutical composition of the present invention is formulated to be administered intravitreally to the eye of a subject.

[0024] Current treatments for various eye diseases or disorders, such as increased intraocular pressure or eye inflammation, require the patient to receive daily eye drops or multiple steroid injections into the eye. The pharmaceutical composition of the present invention is designed to release at least one therapeutically effective dose in a substantially linear manner, thereby eliminating the need for daily drops and multiple steroid injections.

[0025] In certain embodiments, the pharmaceutical composition of the present invention is formulated to release at least one therapeutic agent in a substantially linear manner over a period of approximately 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.

[0026] In some embodiments, the present invention

[0027] (a) a biodegradable polymer matrix comprising a mixture of a first polymer and a second polymer; and

[0028] (b) at least one therapeutic agent or its analogue, derivative, pharmaceutically acceptable salt, zwitterionic, polymorph, or solvate homogeneously dispersed within the polymer matrix

[0029] A pharmaceutical composition for treating an eye disease or disorder comprising: (1) a first polymer is a biodegradable polyester amide polymer (PEA), and (2) a second polymer is a biodegradable poly(D,L-lactide) polymer (PLA), a biodegradable polyglycolide polymer (PGA), a biodegradable poly(D,L-lactide-co-glycolide) polymer (PLGA), or a combination thereof.

[0030] In some embodiments, the pharmaceutical composition provided herein is formulated to be administered into the vitreous humor of a subject's eye, and said pharmaceutical composition is formulated to release at least one therapeutic agent from the pharmaceutical composition in a substantially linear manner over a period of about 1 month to about 6 months.

[0031] (a) a therapeutic agent that modulates and particularly inhibits the activity of kinases such as Rho kinase, JAK kinase, vascular endothelial growth factor receptor (VEGF-R) or tyrosine kinase; (b) prostaglandins, (c) corticosteroids, or (d) any combination of (a) to (c) a number of therapeutic agents are applied to the pharmaceutical composition of the present invention.

[0032] In some embodiments, the therapeutic agent may include a therapeutic agent that modifies and particularly inhibits the activity of a kinase, such as IKK kinase.

[0033] Certain therapeutic agents, and their analogs or derivatives, their solvates, their pharmaceutically acceptable salts, their polymorphs, and their amphoteric ions include, but are not particularly limited to, the following substances:

[0034] Corticosteroids, e.g., dexamethasone, fluocinolone acetonide, budesonide, beclomethasone, beclomethasone (e.g., as a monopropionate or dipropionate ester), flunisolide, fluticasone (e.g., as a propionate or furoate ester), ciclesonide, mometasone (e.g., as a furoate ester), mometasone desonide, rofleponide, hydrocortisone, prednisone, prednisolone, methylprednisolone, naflocort, deflazacort, Halopredone acetate, fluocinolone acetonide, fluocinonide, clocortolone, tipredane, prednicarbate, alclometasone dipropionate, halomethasone, rimexolone, deprodone propionate, triamcinolone, betamethasone, fludrocortisone, desoxycorticosterone, ropreponide, etiprednol dichloroacetate, etc., or any combination thereof;

[0035] Prostaglandins, e.g., latanoprost, bimatoprost, travoprost, tafluprost, 3-hydroxy-2,2-bis(hydroxymethyl)propyl 7-((1r,2r,3r,5s)-2-((r)-3-(benzo[b]thiophene-2-yl)-3-hydroxypropyl)-3,5-dihydroxycyclopentyl)heptanoate having the following structure:

[0036]

[0037] Chlorprostenol isopropyl ester, 13,14-dihydrochloroprostenol isopropyl ester, latanoprostene bunod, unoprostone, PGF 1α Isopropyl ester, PGF 2α Isopropyl ester, PGF 3α Isopropyl ester, fluprostenol, or any combination thereof;

[0038] Rho kinase (ROCK) inhibitors, e.g., netarsudil or ripasudil or pharmaceutically acceptable salts thereof;

[0039] JAK kinase inhibitors, e.g., ruxolitinib for JAK1 / JAK2 (“JAKAFI” and “JAKAVI”), tofacitinib for JAK3 (“XELJANZ” and “JAKVINUS”), oclacitinib for JAK1 (“APOQUEL”), and baricitinib for JAK1 / JAK2 (“OLUMIANT”); and

[0040] Receptor tyrosine kinase inhibitors, e.g., gefitinib, lapatinib, erlotinib, sunitinib, sorafenib, regorafenib, afatinib, vandetanib, semaxanib, cediranib, neratinib, axitinib, lestaurtinib, tivozanib, or any combination thereof.

[0041] In some embodiments, the therapeutic agent includes dukeprost or tiaprost.

[0042] In some embodiments, the ROCK inhibitor of the therapeutic agent comprises 3-amino-N-(1-oxo-1,2-dihydroisoquinoline-6-yl)-2-(thiophene-3-yl)propanamide, (S)-3-amino-2-(4-(hydroxymethyl)phenyl)-N-(isoquinoline-6-yl)propanamide, (1R,2R)-N-(4-methylisoquinoline-6-yl)-2-(4-(N-(pyridine-2-yl)sulfamoyl)phenyl)cyclopropane-1-carboxamide, or pharmaceutically acceptable salts thereof.

[0043] In some embodiments, the therapeutic agent comprises a cyclopropylamide JAK inhibitor comprising CAS# 2246332-69-2 and its (R,R) isomers: 2246332-34-1, CAS# 2246331-96-2, CAS# 2246331-95-1, CAS# 2246331-94-0, CAS# 2246331-82-6.

[0044] In some embodiments, the therapeutic agent includes a prodrug of the described therapeutic agent.

[0045] In the pharmaceutical composition of the present invention, not only the ratio of the amounts of polymer 1 to polymer 2, but also the ratio of the amounts of the components used in polymer 2 when polymer 2 is a combination of polymers, is very important for the manipulation of a pharmaceutical composition having desired properties with respect to the amount of at least one therapeutic agent delivered in a substantially linear manner and the period during which such delivery occurs in a substantially linear manner. In a specific embodiment of the pharmaceutical composition of the present invention, the polymer matrix comprises 60 weight% of a biodegradable polyester amide polymer; 20 weight% of a biodegradable poly(D,L-lactide) polymer; and 20 weight% of a biodegradable poly(D,L-lactide-co-glycolide) polymer.

[0046] Furthermore, a specific embodiment of the pharmaceutical composition of the present invention comprises about 59 weight% of a polymer matrix; and about 41 weight% of at least one therapeutic agent, wherein about 60 weight% of the polymer matrix is ​​a biodegradable polyester amide polymer; about 20 weight% of the polymer matrix is ​​a biodegradable poly(D,L-lactide) polymer; and about 20 weight% of the polymer matrix is ​​a biodegradable poly(D,L-lactide-co-glycolide) polymer.

[0047] A specific therapeutic agent applied to this pharmaceutical composition of the present invention is dexamethasone.

[0048] The pharmaceutical composition of the present invention may be formulated to be administered into the vitreous humor of the eye of a subject, wherein the release of at least one therapeutic agent occurs in a substantially linear manner such that about 1% of the total amount of at least one therapeutic agent is released per day for about 3 months.

[0049] A number of methods may be used by those skilled in the art to form the polymer matrix of the pharmaceutical composition of the present invention. A specific method is the mechanical blending of the first polymer and the second polymer. Other methods are described below.

[0050] Likewise, the amount of at least one therapeutic agent loaded into the pharmaceutical composition of the present invention may vary depending on the desired amount of therapeutic agent to be delivered in a substantially linear manner and the duration during which delivery occurs in a substantially linear manner. In a specific embodiment, the pharmaceutical composition of the present invention comprises (a) about 51 weight percent of a polymer matrix; and (b) about 49 weight percent of at least one therapeutic agent.

[0051] The biodegradable (D,L-lactide) polymer used in the pharmaceutical composition of the present invention may be an acid-terminated biodegradable poly(D,L-lactide) homopolymer or an ester-terminated poly(D,L-lactide) homopolymer.

[0052] Similarly, the poly(D,L-lactide-co-glycolide) polymer used in the pharmaceutical composition of the present invention may be an ester-terminated biodegradable poly(D,L-lactide-co-glycolide) copolymer or an acid-capped biodegradable poly(D,L-lactide-co-glycolide).

[0053] A number of types of polyester amide (PEA) polymers are applied to the pharmaceutical compositions of the present invention. Generally, these PEAs comprise the chemical structure of the following formula (I):

[0054]

[0055] In the above formula,

[0056] m+p varies from 0.9 to 0.1, and a+b varies from 0.1 to 0.9;

[0057] m+p+a+b=1, where m or p can be 0;

[0058] n varies from 5 to 300, a is at least 0.01, b is at least 0.015, the ratio of a to b (a:b) is from 0.1:9 to 0.85:0.15, wherein the m units and / or p units, and the a and b units are randomly distributed;

[0059] R 1 (C2-C 20 Independently selected from )alkyls;

[0060] R in a single skeletal unit m or p 3 and R 4 is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C 10 Each independently selected from aryl, -(CH2)SH, -(CH2)2S(CH)3, (CH3)2-CH-CH2-, -CH(CH3)2, -CH(CH3)-CH2-CH3, -CH2-C6H5, -(CH2)4-NH2, and mixtures thereof;

[0061] R 5 is (C2-C 20 )alkyl, (C2-C 20 Independently selected from alkenylene;

[0062] R 6 is selected from the cyclic fragment of 1,4:3,6-dianhydrohexitol of the following chemical formula (II):

[0063]

[0064] R 7 Silver (C6-C 10 Independently selected from aryl, (C1-C6)alkyl, or protecting groups;

[0065] R 8 It is -(CH2)4-.

[0066] The specific PEA applied to the pharmaceutical composition of the present invention has the chemical structure of the following formula (III):

[0067]

[0068] Other examples of PEA polymers applicable herein are disclosed in U.S. Patent No. 9,873,765 and U.S. Patent No. 9,789,189, the entire contents of which are incorporated herein by reference.

[0069] An intravitreal implant for treating ocular diseases or disorders, comprising the pharmaceutical composition of the present invention, is also provided. A number of methods may be used to produce the intravitreal implant of the present invention. A specific method applicable herein is PRINT ® It is the use of technology particle fabrication. PRINT ® The use of the technology enables the production of multiple intravitreal implants with highly consistent and predictable therapeutic release profiles that are custom-made and highly reproducible between implants, which was impossible with the use of other types of technology, e.g., extrusion. PRINT used to produce the intravitreal implants of the present invention ® In addition to the technology, the particles used in the particle suspension of the present invention are also described in PCT applications published by WO2007021762, WO2007024323, and WO2007030698, the entire contents of which are incorporated herein by reference. The mold cavity used to fabricate the intravitreal implant of the present invention may vary from the dimensions mentioned in various embodiments by ± 50 µm, or ± 40 µm, or ± 30 µm, or ± 20 µm, or ± 10 µm, or ± 5 µm.

[0070] PRINT ® The technology enables the creation of an intravitreal implant having variations in the release profile of a therapeutic agent that are not statistically significant. Consequently, at least one therapeutic agent release profile demonstrated by an embodiment of the implant is within a confidence interval and exhibits a coefficient of variation that does not affect the substantially linear manner in which the therapeutic agent is delivered. The ability to create the intravitreal implant of the present invention, which exhibits such highly consistent therapeutic agent loading or release, is an advancement beyond the latest technology.

[0071] In a specific embodiment of the present invention,

[0072] (a) A polymer matrix of about 59 weight% comprising (i) to (iii) below:

[0073] (i) About 60 wt% of a biodegradable polyester amide polymer having the structure of the following chemical formula (I):

[0074] ,

[0075] (ii) about 20 weight percent of biodegradable poly(D,L-lactide) homopolymer, and

[0076] (iii) about 20 wt% of biodegradable poly(D,L-lactide-co-glycolide) copolymer; and

[0077] (b) Approximately 41 wt% of dexamethasone homogeneously dispersed within the polymer matrix

[0078] Provides an intravitreal implant comprising a pharmaceutical composition including;

[0079] In the above formula,

[0080] m+p varies from 0.9 to 0.1, and a+b varies from 0.1 to 0.9;

[0081] m+p+a+b=1, where either m or p can be 0;

[0082] n varies from 5 to 300, a is at least 0.01, b is at least 0.015, the ratio of a to b (a:b) is from 0.1:9 to 0.85:0.15, wherein the m units and / or p units, and the a and b units are randomly distributed;

[0083] R 1 (C2-C 20 Independently selected from )alkyls;

[0084] R in a single skeletal unit m or p 3 and R 4 is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C 10Each independently selected from aryl, (C1-C6)alkyl, -(CH2)SH, -(CH2)2S(CH)3, (CH3)2-CH-CH2-, -CH(CH3)2, -CH(CH3)-CH2-CH3, -CH2-C6H5, -(CH2)4-NH2, and mixtures thereof;

[0085] R 5 is (C2-C 20 )alkyl, (C2-C 20 Independently selected from alkenylene;

[0086] R 6 is selected from the cyclic fragment of 1,4:3,6-dianhydrohexitol of the following chemical formula (II):

[0087] ;

[0088] R 7 Silver (C6-C 10 Independently selected from the group consisting of aryl, (C1-C6)alkyl or protecting groups;

[0089] R 8 is -(CH2)4- and;

[0090] (i), (ii) and (iii) are blended together to form a polymer matrix;

[0091] The above pharmaceutical composition is formulated to be administered into the vitreous humor of the eye of a subject;

[0092] Dexamethasone is released from the pharmaceutical composition in a substantially linear manner such that about 1% of the total dexamethasone contained in the pharmaceutical composition is released per day for about 3 months.

[0093] The present invention also provides a method for treating an eye disease or disorder in a human requiring treatment of the eye disease or disorder, comprising the step of administering at least one intravitreal implant of the present invention into the vitreous fluid of a human eye.

[0094] Ocular diseases or disorders treatable with the intravitreal implant of the present invention include, but are not limited to, ocular hypertension, ocular inflammatory diseases or disorders, glaucoma, neurodegenerative diseases or disorders, or any combination thereof.

[0095] Examples of ocular inflammatory diseases or disorders that can be treated with the pharmaceutical composition of the present invention as well as with the intravitreal implant of the present invention include, but are not limited to, uveitis, corneal ulcers, endophthalmitis, autoimmune diseases of the cornea or ocular surface, ophthalmic signs of HIV disease, or combinations thereof. In some embodiments, the ocular inflammatory disease or disorder is ocular herpes. Non-limiting examples of specific neurodegenerative diseases or disorders that can be treated with the present invention include diabetic eye disease, macular degeneration (wet or dry), inflammation, or dry eye syndrome.

[0096] These and other embodiments of the present invention will be better recognized by referring to the following drawings and detailed description. Brief explanation of the drawing

[0097] Figure 1 is a graph plotting the average daily release of dexamethasone from various pharmaceutical compositions (samples 8 to 15) of the present invention. Figure 2 is a graph of the cumulative percentage of dexamethasone released from intravitreal implant 7. Figure 3 is a graph of the average daily release rate of dexamethasone from intravitreal implant 7. Figure 4 is a graph of the cumulative percentage of therapeutic agent released over time from sample 16. Figure 5 is a graph of the cumulative percentage of therapeutic agent released over time from sample 17. Specific details for implementing the invention

[0098] The present invention provides novel pharmaceutical compositions and therapeutic delivery systems, namely intravitreal implants, as well as methods for manufacturing and using such systems to extend the release of at least one therapeutic agent into the eye in a substantially linear manner. A novel series of degradable polymer matrices was prepared by blending biodegradable poly(D,L-lactide) polymers, biodegradable poly(D,L-lactide-co-glycolide) polymers, and polyester amides. The pharmaceutical compositions of the present invention extend to a biodegradable therapeutic delivery system comprising a polymer matrix and a therapeutic agent contained in the polymer matrix. The intravitreal implant delivers a high concentration of at least one therapeutic agent sustained in a substantially linear manner over a period of up to 5 months in vitro. ® The present invention was developed from the pharmaceutical composition by utilizing technology. The present invention is further extended to biodegradable intravitreal implants having highly uniform, adjustable, and reproducible size, shape, loading, composition, and load distribution, and a desired extended therapeutic release profile, thereby making them useful for the treatment of various ocular diseases or disorders.

[0099] The present invention is based on the discovery that a polymer matrix comprising, surprisingly and unexpectedly, not only PEA polymers but also PLGA polymers and / or PLA polymers, or combinations thereof, and at least one therapeutic agent contained within this polymer matrix, causes at least one therapeutic agent to be released in a substantially linear manner over a period of at least 3 months, 4 months, 5 months, 6 months, or longer. Although there is no obligation to describe the amount of therapeutic agent released during the periods mentioned herein, or the substantially linear manner in which the therapeutic agent is released from the pharmaceutical composition of the present invention, and no particular desire to be bound by any description, it is presumed that when two or more different classes of polymers are mixed to create a unique novel polymer matrix, a blend of different degrees of phase separation may be obtained depending on the thermodynamic properties and compatibility of the polymers selected to form the polymer matrix. The hydrophobicity of the polymer matrix can be controlled by changing the ratio between the polymers used in the polymer matrix, namely the first polymer and the second polymer (as well as by controlling the amount of the component of the second polymer). Furthermore, the pharmaceutical composition having the claimed polymer matrix released at least one therapeutic agent in a substantially linear manner. This control of hydrophobicity, as well as the control of the amount of therapeutic agent contained in the polymer matrix, enables control of not only the amount of therapeutic agent released in a substantially linear manner, but also the duration during which such release occurs in a substantially linear manner. Accordingly, the present invention enables the design of a pharmaceutical composition to release a therapeutic agent in a substantially linear manner over a specific period.

[0100] Broadly, the present invention extends to pharmaceutical compositions for treating ocular diseases or disorders. Such pharmaceutical compositions of the present invention comprise a biodegradable polymer matrix comprising a mixture of a first polymer and a second polymer, wherein the first polymer is a biodegradable polyester amide, and the second polymer is selected from (a) a biodegradable poly(D,L-lactide) polymer, (b) a biodegradable poly(D,L-lactide-co-glycolide) copolymer, and (c) a combination of (a) and (b). The pharmaceutical compositions of the present invention further comprise at least one therapeutic agent homogeneously dispersed within the polymer matrix, wherein the pharmaceutical compositions are formulated to release at least one therapeutic agent from the pharmaceutical compositions in a substantially linear manner over a period of at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months, or a longer period. Optionally, the pharmaceutical compositions may be formulated as intravitreal implants for administration into the vitreous humor of a subject's eye. PRINT described and discussed below ® The technology can be used to create these intravitreal implants of the present invention.

[0101] Many terms and phrases are used throughout this specification and claims and are defined below.

[0102] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. Any method or material similar or equivalent to the method and material described herein may be used in the practice or testing of this invention.

[0103] It is also noted that the reagents described herein are merely examples, and equivalents thereof are known in the field.

[0104] As used herein, unless otherwise noted, the term "alkyl" itself or as part of another substituent refers to a specified number of carbon atoms (i.e., C 1-6 means a straight-chain or branched-chain hydrocarbon having 1 to 6 carbon atoms) and includes straight-chain, branched-chain, or cyclic substituents. Examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. (C 1-6 )alkyl, in particular ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl, and cyclopropylmethyl are most preferred.

[0105] As used herein, "alkenyl" refers to an unsaturated aliphatic hydrocarbon moiety comprising a straight-chain or branched-chain group. The alkenyl moiety must contain at least one alkene. "Alkenyl" may be exemplified by groups such as ethenyl, n-propenyl, isopropenyl, n-butenyl, etc. The alkenyl group may be substituted or unsubstituted. One or more substituents may be present. If substituted, the substituent is preferably an alkyl, halogen, or alkoxy. The substituent may substitute itself. The substituent may be placed on the alkene itself, on adjacent member atoms, or on the alkenyl moiety.

[0106] As used herein, "alkynyl" refers to an unsaturated aliphatic hydrocarbon moiety comprising a straight-chain group and a branched-chain group. The alkynyl moiety must contain at least one alkyne. "Alkynyl" may be exemplified by groups such as ethinyl, propynyl, n-butynyl, etc. The alkynyl group may be substituted or unsubstituted. One or more substituents may be present. When substituted, the substituent is preferably alkyl, amino, cyano, halogen, alkoxy, or hydroxyl. The substituent may substitute itself. The substituent is not on the alkyne itself but on an adjacent member atom of the alkynyl moiety.

[0107] As used herein, unless otherwise noted, the term “aryl,” used alone or in combination with other terms, refers to a carbon-cyclic aromatic system containing one or more rings (typically one, two, or three rings), wherein these rings may be attached together in a pendant manner, as in biphenyl, or fused, as in naphthalene. Examples of aryl groups include phenyl, anthracyl, and naphthyl. Preferred examples are phenyl and naphthyl, and phenyl is most preferred.

[0108] As used herein, the number of carbon atoms in a substituent is the prefix "C x-y " or "C x -C y It can be expressed as ", where x is the minimum number of carbon atoms in the substituent and y is the maximum number.

[0109] As used herein, “protecting group” refers to a protecting group moiety described, for example, in the literature [Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999)]. For example, the carboxylic acid group may be protected as an ester, for example, an alkyl ester (e.g., methyl ester; t-butyl ester); a haloalkyl ester (e.g., haloalkyl ester); a trisalkylsilylalkyl ester; or an aralkyl ester (e.g., benzyl ester; nitrobenzyl ester); or an amide, for example, methyl amide.

[0110] The term “treatment” refers to the application of one or more specific procedures used for the alleviation of a disease. In some embodiments, a specific procedure is the administration of one or more agents. “Treatment” of an individual (e.g., mammals, e.g., humans) or cell is any type of intervention used in an attempt to alter the natural processes of the individual or cell. Treatment includes, but is not limited to, the administration of a pharmaceutical composition and may be performed prophylactically or after the onset of a pathological event or contact with a pathogen. Treatment may include any desired effect on the symptoms or pathology of a disease or condition, and may include, for example, a minimal change or improvement in one or more measurable markers of the disease or condition being treated. “Prophylactic” treatment is also included, which may relate to a reduction in the rate of progression of the disease or condition being treated, a delay in the onset of the disease or condition, or a reduction in the severity of its onset. “Effective dose” or “therapeutic effective dose” refers to the amount of therapeutic agent administered to a mammalian subject as a single dose or as part of a series of doses that is effective in producing the desired therapeutic effect.

[0111] As used herein, “pharmaceutically acceptable salt” refers to a derivative of the disclosed compound in which the parent compound is modified by converting an existing acid or base moiety into its salt form. A list of suitable salts is found in the literature [Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418] and the literature [Journal of Pharmaceutical Science, 66, 2 (1977)], which are incorporated herein by reference in their entirety.

[0112] As used herein, unless the context otherwise specifies, the singular form includes the plural form.

[0113] As used herein, the term "comprising" is intended to mean that the composition and method include the mentioned elements but do not exclude other elements.

[0114] “Approximately” and “roughly” are interchangeable and refer to a plus or minus percentage (e.g., ±5%) of a number, parameter, or characteristic limited to what is understood by a person skilled in the art to be appropriate in the scientific context in which the terms are used. Furthermore, all numbers, values, and expressions referring to quantities used herein are subject to the various measurement uncertainties encountered in the art. Accordingly, unless otherwise indicated, all provided values ​​may be understood as modified by the term “approximately.”

[0115] Where a numerical range is disclosed herein, such range is a continuous range that includes both the minimum and maximum values ​​of the range, as well as all values ​​between the minimum and maximum values. Additionally, where a range refers to an integer, it includes all integers between the minimum and maximum values ​​of the range. Furthermore, where multiple ranges are provided to describe a feature or characteristic, such ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein should be understood to encompass any sub-ranges included therein. For example, the mentioned range “1 to 10” should be considered to include any sub-range between the minimum value 1 and the maximum value 10.

[0116] As used herein, "therapeutic agent" refers to a compound or substance in a pharmaceutical composition that exhibits biological activity and produces the effect of the pharmaceutical composition.

[0117] As used herein, the term "pharmaceutical composition" refers to a composition comprising a therapeutic agent, excipients, carriers, etc. Generally, a pharmaceutical composition is administered to a patient rather than the therapeutic agent alone.

[0118] As used herein, “eye disease or disorder” or “eye disease or disorder” may be used interchangeably and includes, but is not limited to, glaucoma, allergy, inflammatory eye disease or disorder, ocular hypertension, ocular cancer, neurodegenerative disease or disorder of the eye, e.g., diabetic macular edema (DME) and wet or dry age-related macular degeneration (AMD), uveitis, diabetic retinopathy, and dry eye disease.

[0119] As used herein, "kinase" is a type of enzyme that transfers the phosphate group of a high-energy donor, such as ATP, to a specific target molecule (substrate). The above process is referred to as phosphorylation.

[0120] As used herein, "receptor tyrosine kinase (RTK)" refers to a receptor protein selected from the RTK family of proteins described in the literature [Schlessinger, Cell, 103: 211-225 (2000)] that possesses intracellular kinase activity. "Receptor tyrosine kinase dimer" refers to a complex within the cell surface membrane comprising two receptor tyrosine kinase proteins. In some embodiments, a receptor tyrosine kinase dimer may comprise two covalently bonded receptor tyrosine kinase proteins. RTK dimers of particular interest are the Her receptor dimer and the VEGFR dimer. Receptor tyrosine kinases are an important class of receptors involved in many fundamental cellular processes, including cell proliferation, survival, metabolism, and migration (e.g., the literature [Schlessinger, Cell, 103: 211-225 (2000)]). A well-known family of this class includes the epidermal growth factor receptor (EGFR or Her1), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and vascular endothelial growth factor receptor (VEGFR). Receptor tyrosine kinases of this class are so named because, when activated by dimerization, the intracellular domain of the RTK requires tyrosine kinase activity capable of activating various signal transduction pathways. Consequently, RTKs are essential components of signal transduction pathways, mediating cell-to-cell communication and their function as relay points for signaling pathways. RTKs play a key role in numerous processes that control cell proliferation and differentiation, regulate cell growth and metabolism, and promote cell survival and apoptosis. Due to this property, many receptor tyrosine kinases are targets for drug development, and several promising clinical-phase therapeutics designed to inhibit RTK activity, such as IRESSA ® (Gepitinib) and TARCEVA ®It is being used as (erlotinib) (e.g., literature [Taxler, Expert Opin. Ther. Targets, 7: 215-234 (2003)]). The availability of convenient methods to measure pathway activation will lead to a better understanding of therapeutic mechanisms, and better therapeutic selection and disease management (Mirshafiey et al., Innov. Clin. Neursci. (11(7-8):23-26 (2014)).

[0121] As used herein, Janus kinase (JAK) refers to a cytoplasmic tyrosine kinase that transducts cytokine signaling from membrane receptors to STAT transcription factors. Four members of the JAK family, namely JAK1, JAK2, JAK3, and TYK2, are described. Upon binding of a cytokine to its receptor, JAK family members autophosphorylate and / or transphosphorylate each other prior to the phosphorylation of STAT, then translocate to the nucleus to regulate transcription. Intracellular JAK-STAT signaling is applicable to interferons and most interleukins, as well as various cytokines and endocrine factors, such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL (Vainchenker W. et al. (2008)).

[0122] The JAK family is involved in the introduction of intracellular signaling from over 70 different cytokines. Cytokines bind to their cell surface receptors, causing receptor dimerization and subsequent activation / phosphorylation of JAK tyrosine kinases. JAKs either bind to the receptor contemporaneously or are recruited upon cytokine binding. Subsequently, specific tyrosine residues on the receptor are phosphorylated by the activated JAK and used as docking sites for STAT proteins. After being phosphorylated and dimerized by JAK, STATs are translocated to the nucleus, where they bind to specific DNA elements and activate gene transcription. JAK1 signals along with all JAK isoforms in a cytokine-dependent manner.

[0123] JAK is essential for numerous physiological functions, and this essential function of JAK has been demonstrated by using genetically engineered mouse models deficient in specific JAKs. Jak1 - / - While mice die before and after birth, Jak2 - / - Mice are deficient in erythropoiesis and die around day E12. Jak3 - / - The mice are viable but have a SCID phenotype lacking T cells, B cells, and NK cells. TYK2 - / - Mice exhibit characteristics of high IgE syndrome. These phenotypes demonstrate the essential and non-redundant role of JAK activity in vivo (K. Ghoreschi, A. Laurence, JJ O'Shea, Immunol. Rev. 228, 273 (2009)).

[0124] Furthermore, mutations in JAK enzymes are associated with disease in humans. Inactivation mutations in JAK3 (or homologous gamma-chain cytokine receptor) cause a severe SCID phenotype (JJ O'Shea, M. Pesu, DC Borie, PS Changelian, Nat. Rev. Drug Discov. 3, 555 (2004)). Deletion of TYK2 causes high IgG syndrome and an increased risk of infection (Y. Minegishi et al., Immunity. 25, 745 (2006)). It has been reported that there are no inactivation mutations for JAK1 or JAK2, which is consistent with mouse data demonstrating that JAK1 and JAK2-deficient mice are non-viable. However, several mutations have been identified that cause myeloproliferative disorders by inducing congenitally active JAK2 and confirm the pivotal role of JAK2 in homeostasis (O. bdel-Wahab, Curr. Opin. Hematol. 18, 117 (2011)). JAK2 is the sole member of the JAK family involved in the induction of signaling of important hematopoietic cytokines IL-3, GMCSF, EPO, and TPO.

[0125] Additionally, JAKs play multiple roles downstream of cytokine signaling in both immune and non-immune cells. Autoimmunity is triggered by abnormal adaptive immune responses to autoantigens, and JAK-STAT (transduction agent and transcription activator) signaling is known to play a key role in this process. Therefore, JAK inhibitors may hold significant potential for the development of therapeutic agents to treat autoimmunity. JAK3 is a particularly interesting target because, unlike other JAKs, its expression is restricted to the immune system.

[0126] Because a significant amount of literature has accumulated linking the JAK / STAT pathway to various diseases and disorders, including hyperproliferative disorders and cancers, e.g., leukemia and lymphoma, immunological disorders and inflammatory disorders, e.g., transplant rejection, asthma, chronic obstructive pulmonary disease, allergies, rheumatoid arthritis, type 1 diabetes, amyotrophic lateral sclerosis, eye diseases or disorders, and multiple sclerosis, these have become targets for the development of numerous therapeutic agents that regulate, particularly inhibit, their activity.

[0127] As used herein, "Rho-related protein kinase" or "Rho kinase" (ROCK) is a key intracellular regulator of cytoskeletal kinetics and cell motility. Rho kinase regulates, through phosphorylation, a number of downstream targets of Rho A, including, for example, myosin light chain, myosin light chain phosphatase-binding subunit, and LIM kinase 2. These substrates regulate actin filament organization and contractility. In smooth muscle cells, Rho kinase mediates calcium sensitization and smooth muscle contraction. Inhibition of Rho kinase blocks muscle contraction induced by 5-HT and phenylephrine agonists. When introduced into non-smooth muscle cells, Rho kinase induces stress fiber formation and is required for cell transformation mediated by Rho A. Rho kinase participates in various cellular processes, including but not limited to cell adhesion, cell motility and migration, growth regulation, cell contraction, and cytokinesis. Rho kinase is involved in the activation of the Na / H exchange transport system, stress fiber formation, adducin activation, and physiological processes such as vasoconstriction, bronchial smooth muscle contraction, proliferation of vascular smooth muscle and endothelial cells, and platelet aggregation.

[0128] Inhibition of Rho kinase activity in animal models has demonstrated many benefits for the treatment of human diseases. These include cardiovascular diseases, e.g., hypertension, atherosclerosis, restenosis, cardiac hypertrophy, ocular hypertension, cerebral ischemia, cerebral vasospasm, penile erectile dysfunction; central nervous system disorders, e.g., neurodegeneration and spinal cord injury; and models of neoplasms. Inhibition of Rho kinase activity has been shown to inhibit tumor cell growth and metastasis, angiogenesis, arterial thrombotic disorders, e.g., platelet aggregation and leukocyte aggregation, asthma, intraocular pressure regulation, and bone resorption. In patients, inhibition of Rho kinase activity is beneficial for the control of cerebral vasospasm and ischemia following subarachnoid hemorrhage, reduction of intraocular pressure, increased aqueous humor outflow due to relaxation of the trabecular meshwork, improvement of blood flow to the optic nerve, treatment of glaucoma, reduction of intraocular pressure (IOP), and protection of healthy ganglion cells.

[0129] In mammals, Rho kinase consists of two isoforms: ROCK1 (ROCKβ; p160-ROCK) and ROCK2 (ROCKα). ROCK1 and ROCK2 are differentially expressed and regulated in specific tissues. For example, ROCK1 is expressed ubiquitously at relatively high levels, whereas ROCK2 is preferentially expressed in the heart, brain, and skeletal muscle. These isoforms are also expressed in some tissues in a developmental stage-specific manner. ROCK1 is a substrate for cleavage by caspase-3 during apoptosis, whereas ROCK2 is not. Smooth muscle-specific basic calponins are phosphorylated exclusively by ROCK2.

[0130] Considering the involved cellular processes and the severity of the disease, compounds that selectively inhibit a single rho kinase or inhibit both ROCK1 and ROCK2 are required. Examples of rho kinase inhibitor therapeutics include netarsudil, used to lower IOP and treat glaucoma, or its pharmaceutically acceptable salts (e.g., "RHOPRESSA"). ®"), and rifasudil or its pharmaceutically acceptable salts used in the treatment of glaucoma and ocular hypertension (e.g., "GLANATEC ® Includes "). In some embodiments, a biologically active metabolite of such Rho kinase inhibitor is required.

[0131] As used herein, "prostaglandin" refers to any compound having a prostanic acid skeleton:

[0132]

[0133] (Prostanic acid skeleton).

[0134] Since these compounds, as well as their analogs or derivatives, possess ocular hypotensive activity, they are applied to treat or alleviate eye diseases or disorders.

[0135] Another type of therapeutic agent applied to the pharmaceutical composition of the present invention (e.g., intravitreal implant) is corticosteroids and their analogs or derivatives, or their salts or prodrugs. As used herein, "corticosteroids" refer to a class of steroid hormones produced in the adrenal cortex of vertebrates, and synthetic analogs and derivatives of these hormones. Two types of corticosteroids, e.g., glucocorticoids and mineralocorticoids, are involved in a wide range of physiological processes. Corticosteroids have been reported to be applied to the treatment of ocular diseases and disorders, particularly inflammatory ocular diseases and disorders.

[0136] As used herein, "therapeutic effective dose" means a level or amount of therapeutic agent necessary for the treatment of a disease or disorder, that is, a level or amount of therapeutic agent that produces a therapeutic response or a desired effect in a subject to whom the therapeutic agent is administered. In a specific embodiment of the present invention, the therapeutic effective dose means a level or amount of therapeutic agent necessary for the treatment of an ocular disease or disorder.

[0137] The present invention is further extended to an intravitreal implant prepared from the pharmaceutical composition of the present invention for placement in a human eye or in the posterior part of a human eye. In this embodiment, releasing the therapeutic agent from the implant in a substantially linear manner achieves a concentration of the therapeutic agent in the vitreous humor of the patient's eye that treats an ocular disease or disorder during the period in which the implant is designed to release the therapeutic agent in a substantially linear manner.

[0138] In some embodiments, the implants described herein are manipulated in size, shape, and composition to provide the maximum approximation of the implant to the iris-cornea angle of the human eye. In some embodiments, the implants are made of the pharmaceutical composition of the present invention comprising the polymer matrix described herein.

[0139] As used herein, the term "polymer" is intended to encompass homopolymers (polymers having only one type of repeating unit) and copolymers (polymers having more than one type of repeating unit).

[0140] "Biodegradable polymer" or "biocortic polymer" refers to a polymer that can be used interchangeably and degrades in vivo under physiological conditions. The release of at least one therapeutic agent occurs simultaneously with or after the degradation of the biodegradable polymer over time. The biodegradable polymer may be a homopolymer or a copolymer.

[0141] As used herein, the term “polymer matrix” refers to a homogeneous mixture of polymers. In other words, the matrix does not contain a mixture in which one part of the mixture differs from another part by composition, density, etc. Accordingly, the polymer matrix does not contain a composition containing a core and one or more outer layers, nor does it contain a composition containing a therapeutic reservoir and one or more parts surrounding the therapeutic reservoir. In the pharmaceutical composition of the present invention, the polymer matrix comprises a first polymer and a second polymer, wherein the first polymer comprises a polyester amide polymer (PEA), and the second polymer comprises a PLA polymer, a PLGA polymer, or a combination of a PLA polymer and a PLGA polymer, for example, (i) a biodegradable poly(D,L-lactide) polymer; (ii) a biodegradable poly(D,L-lactide-co-glycolide) polymer; or (iii) a combination of (i) and (ii).

[0142] The polymers used in the polymer matrix of the pharmaceutical composition of the present invention have independent properties associated with them, which provide the properties necessary to provide the release of a therapeutically effective amount of therapeutic agent in a substantially linear manner over a desired period when combined.

[0143] These polymers are often affected by enzymatic or hydrolytic instability. Water-soluble polymers can be crosslinked by hydrolytic or biodegradable instability to provide useful water-insoluble polymers. The degree of stability can vary widely depending on the choice of monomer, whether homopolymers or copolymers are used, the use of a mixture of polymers, and whether the polymer contains terminal acid groups.

[0144] The relative average molecular weight of the polymer matrix used in the intravitreal implant of the present invention is equally important for controlling the biodegradation of the polymer and the consequently extended release profile of the pharmaceutical composition of the present invention. To control the release profile of at least one therapeutic agent, the same or different polymer compositions of different molecular weights may be included.

[0145] A number of methods for forming a polymer matrix, including but not limited to melt blending, solution blending, partial block or graft copolymerization, and the preparation of an interpenetrating polymer network (IPN), are known to those skilled in the art. “Melt mixing” includes the step of mixing the first polymer and the second polymer together while they exist in a molten state. This involves the use of shear force, elongation force, compressive force, ultrasonic energy, electromagnetic energy, thermal energy, or a combination comprising at least one of the said forms of force or energy, and is performed in a processing device in which the said forms of force or energy are exerted by a single screw, multiple screws, a meshing idle or reverse screw, a non-meshing idle or reverse screw, a reciprocating screw, a screw with pins, a screw with screens, a barrel with pins, a roll, a ram, a helical rotor, or a combination comprising at least one of these.

[0146] The melt blending involving the aforementioned force may be performed in a machine such as a single or multi-screw extruder, a Buss mixer, a Henschel, a Helicon, a Ross mixer, a Banbury, a roll mill, a molding machine, such as an injection molding machine, a vacuum molding machine, a blow molding machine, etc., or a combination including at least one of the above machines.

[0147] Solution blending can also be used to prepare a polymer matrix, in which the polymer is added to a solution and blended. Solution blending may also utilize additional energy, such as shear, compression, or ultrasonic vibration, to promote the homogenization of quantum dots into the hydrogel. In one embodiment, the hydrogel is suspended in a fluid (e.g., water, alcohol, etc.) and introduced into an ultrasonic processor along with the quantum dots. The mixture can be solution blended by ultrasonic treatment for a time effective for dispersing the quantum dots into the hydrogel. Subsequently, the hydrogel containing the quantum dots can be dried, extruded, and molded if desired. During extrusion, the temperature of the hydrogel can be raised to facilitate crosslinking. The fluid used to swell the hydrogel can be removed during the extrusion process by using a vacuum over the extruder.

[0148] In certain embodiments, the polymer matrix of the present invention is produced from the mechanical mixing of polymers.

[0149] In an embodiment, the polymer matrix may be formed from any combination of polylactic acid, glycolic acid and copolymers thereof and polyester amides, providing the release of at least one therapeutic agent into the eye in a substantially linear manner over time. More importantly, a person skilled in the art may manipulate the polymer matrix used in the pharmaceutical composition of the present invention to deliver at least one therapeutic agent in a substantially linear manner for a period of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, or longer.

[0150] As used herein, the "substantially linear mode" refers to the first 90% of the therapeutic agent released from the pharmaceutical composition of the present invention having an R of 0.9 or higher. 2 This means that it will have a value. In some embodiments, the first 80% of the therapeutic agent released from the pharmaceutical composition of the present invention has an R value of 0.9 or higher.2 It will have a value.

[0151] Polymeric materials or compositions suitable for use in implants may be combined and may include materials that are biocompatible with the eye so as not to substantially interfere with the function or physiology of the eye. Such polymeric materials may be biodegradable or biocorrosive. Examples of useful polymeric materials include, but are not limited to, materials derived from and / or containing organic esters and organic ethers that produce physiologically acceptable degradation products when degraded. Additionally, polymeric materials derived from and / or containing anhydrides, amides, orthoesters, etc., alone or in combination with other monomers may also be used in the present invention. The polymeric materials may be addition or condensation polymers. The polymeric materials may be crosslinked or may not be crosslinked. In some embodiments, the polymer may contain at least one of oxygen and nitrogen in addition to carbon and hydrogen. Oxygen may be present as an oxy, e.g., hydroxy or ether, a carbonyl, e.g., a non-oxo-carbonyl, e.g., a carboxylic acid ester, etc. Nitrogen may exist as an amide, cyano, amino, or any combination thereof.

[0152] In one embodiment, a polymer of a hydroxyaliphatic carboxylic acid that is a homopolymer or copolymer, and a polysaccharide are useful for implants. The polyester may include polymers of D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, polycaprolactone, copolymers thereof, and combinations thereof.

[0153] Some characteristics of the polymer or polymer material to be used in embodiments of the present invention may include biocompatibility, compatibility with at least one selected therapeutic agent, ease of use of the polymer in the manufacture of the therapeutic agent delivery system described herein, a desired half-life in a physiological environment, and hydrophilicity.

[0154] Specific examples of polymers applied to the polymer matrix used in the preparation of the pharmaceutical composition of the present invention (e.g., intravitreal implant) are synthetic aliphatic polyesters, e.g., polymers of lactic acid and / or glycolic acid, and include poly-(D,L-lactide) (PLA), poly-(D-lactide), poly-(L-lactide), polyglycolic acid (PGA), and / or copolymer poly-(D,L-lactide-co-glycolide) (PLGA).

[0155] PLGA is synthesized through the random ring-opening copolymerization of cyclic dimers of glycolic acid and lactic acid. Consecutive monomer units of glycolic acid or lactic acid are joined together by ester bonds.

[0156] PLGA and PLA polymers are known to degrade through skeletal hydrolysis (bulk corrosion), and the final degradation products are lactic acid and glycolic acid, which are considered natural metabolic compounds that do not exhibit toxicity. Lactic acid and glycolic acid are safely eliminated through the Krebs cycle by conversion to carbon dioxide and water. The biocompatibility of PLA, PGA, and PLGA polymers has been further investigated in both non-ocular and ocular tissues of animals and humans. The results suggest that the polymers are well tolerated. Furthermore, PLA, PGA, and PLGA may contain terminal esters or acids.

[0157] Examples of PLA polymers that can be used in embodiments of the present invention are RESOMERs available from Evonik Industries, identified as, but not limited to, R207S, R202S, R202H, R203S, R203H, R205S, R208, R206, and R104. ®Product lines include. Examples of suitable PLA polymers include both acid-terminated polymers and ester-terminated polymers having an intrinsic viscosity of approximately 0.15 to approximately 2.2 dL / g when measured at 0.1% w / v in CHCl3 at 25°C with a Ubbelhode-sized Oc glass capillary viscometer.

[0158] PLAs of various molecular weights and various intrinsic viscosities can be synthesized. For example, but not limited to, in one embodiment, a PLA having an intrinsic viscosity of approximately 1.8 to approximately 2.2 dL / g, e.g., RESOMER ® R208S may be used. In another embodiment, PLA having an intrinsic viscosity of approximately 0.25 to approximately 0.35 dL / g, e.g., RESOMER ® R203S may be used. In another embodiment, PLA having an intrinsic viscosity of approximately 0.55 to approximately 0.75 dL / g, e.g., RESOMER ® You can use R205S.

[0159] Examples of PGA polymers that can be used in embodiments of the present invention include RESOMER available from Evonik Industries, identified as G205S but not limited thereto. ® Product lines are included. Other examples of suitable PGA polymers include both acid-terminated polymers and ester-terminated polymers. In some embodiments, the intrinsic viscosity of the PGA polymer is approximately 1.05 to approximately 1.25 dL / g when measured at 0.1% w / v in CHCl3 at 25°C using an Uberod size Oc glass capillary viscometer.

[0160] Examples of PLGA polymers that can be used in embodiments of the present invention include RESOMERs available from Evonik Industries, identified as, but not limited to, RG502, RG502S, RG502H, RG503, RG503H, RG504, RG504H, RG505, RG506, RG653H, RG752H, RG752S, RG753H, RG753S, RG755, RG755S, RG756, RG756S, RG757S, RG750S, RG858, and RG858S. ® Includes product lines. These PLGA polymers include both acid-terminated and ester-terminated polymers having an intrinsic viscosity of approximately 0.14 to approximately 1.7 dL / g when measured at 0.1% w / v in CHCl3 at 25°C using an Uberod-size Oc glass capillary viscometer. Exemplary polymers used in various embodiments of the present invention may include variations in the molar ratio of D,L-lactide to glycolide of approximately 50:50 to approximately 85:15, including but not limited to 50:50, 65:35, 75:25, and 85:15.

[0161] Other examples of PLGA polymers that may be used in embodiments of the present invention include PLGA polymers produced by Lakeshore Biomaterials, identified as DLG 1A, DLG 3A, or DLG 4A, but not limited thereto. These DLG polymers include both acid (A)-terminated polymers and ester (E)-terminated polymers having an intrinsic viscosity of approximately 0.0.5 to approximately 1.0 dL / g when measured at 0.1% w / v in CHCl3 at 25°C using an Uberod-size Oc glass capillary viscometer. Exemplary polymers used in various embodiments of the present invention may include variations in the molar ratio of D,L-lactide to glycolide of approximately 1:99 to approximately 99:1, including but not limited to 50:50, 65:35, 75:25, and 85:15.

[0162] RESOMERS identified by "RG" or "DLG" in product names such as RG752S ® is a poly(D,L-lactide-co-glycolide) or PLGA having the general structure of the following chemical formula (V):

[0163]

[0164] DLGs of various molecular weights with various D,L-lactide-glycolide ratios can be synthesized. In one embodiment, DLG having an intrinsic viscosity of approximately 0.05 to approximately 0.15 dL / g, e.g. 1A, can be used. In another embodiment, DLG having an intrinsic viscosity of approximately 0.15 to approximately 0.25 dL / g, e.g. 2A, can be used.

[0165] Poly(D,L-lactide-co-glycolide) or PLGA copolymers can be synthesized at different ratios of lactide to glycolide, e.g., a lactide:glycolide ratio of 75:25. These copolymers may be ester-terminated PLGA copolymers identified by the terminal "S" in the product name, or acid-terminated PLGA copolymers identified by the terminal "H" in the product name.

[0166] Another biodegradable polymer applied to the intravitreal implant of the present invention is polyester amide (PEA). PEA is disclosed in U.S. Patents No. 9,896,544 and No. 9,789,189, which are incorporated herein by reference in whole. An example of the general structure of PEA is the chemical structure of the following formula (I):

[0167]

[0168] In the above formula,

[0169] m+p varies from 0.9 to 0.1, and a+b varies from 0.1 to 0.9;

[0170] m+p+a+b=1, where either m or p can be 0;

[0171] n varies from 5 to 300, a is at least 0.01, b is at least 0.015, the ratio of a to b (a:b) is from 0.1:9 to 0.85:0.15, wherein the m units and / or p units, and the a and b units are randomly distributed;

[0172] R 1 (C2-C 20 Independently selected from )alkyls;

[0173] R in a single skeletal unit m or p 3 and R 4 is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C 10 Each independently selected from aryl, (C1-C6)alkyl, -(CH2)SH, -(CH2)2S(CH)3, (CH3)2-CH-CH2-, -CH(CH3)2, -CH(CH3)-CH2-CH3, -CH2-C6H5, -(CH2)4-NH2, and mixtures thereof;

[0174] R 5 is (C2-C 20 )alkyl, (C2-C 20 Independently selected from alkenylene;

[0175] R 6 is selected from the cyclic fragment of 1,4:3,6-dianhydrohexitol of the following chemical formula (II):

[0176] ;

[0177] R 7 Silver (C6-C 10 Independently selected from the group consisting of aryl, (C1-C6)alkyl or protecting groups;

[0178] R 8 It is -(CH2)4-.

[0179] A specific example of PEA to be applied in the present invention has the chemical structure of the following formula (III):

[0180]

[0181] The PEA polymer applied to the pharmaceutical composition of the present invention (e.g., intravitreal implant) is degraded by hydrolysis through bulk corrosion and is not degraded by enzymes, and is completely biocompatible. Therefore, its degradation will not cause any substantial disturbance to the function or physiology of the eye.

[0182] By changing not only the ratio of PEA to lactide and glycolide, but also the ratio between the amount of lactide and the amount of glycolide present in the implant of the present invention, the biodegradability of the product is altered, thereby enabling adjustment of the self-polymer degradation time, as well as the duration and amount of sustained-release therapeutic agent, which are the subject of the art in the art. Accordingly, changes and customization of the biodegradable polymer matrix alter the therapeutic agent delivery profile due to the presumed theory discussed above, but the inventors are not obligated to provide said theory and are not bound by said theory in any way.

[0183] The present invention is further extended to compositions comprising liquid formulations and delivery systems. Accordingly, the present composition may be understood to include other liquid-containing compositions used in ophthalmic treatment, such as solutions, suspensions, and emulsions.

[0184] particle suspension

[0185] As previously described, the pharmaceutical composition of the present invention may be formulated as a particle suspension. As used herein, the particle suspension is a micronized pharmaceutical composition formulated as a suspension in an aqueous phase containing a necessary excipient, such as a delivery vehicle.

[0186] Furthermore, the liquid formulation may be a particle suspension. The particles may generally be smaller than the intravitreal implants disclosed herein and may vary in shape. For example, some embodiments of the present invention use substantially cylindrical particles. The therapeutic delivery system of the present invention may comprise a group of such particles having a predetermined size distribution. In an embodiment, the suspension may comprise a group of particles having a desired diameter measurement.

[0187] As discussed above, the polymer blends described herein may be used with particle suspensions. Accordingly, in the embodiments, the disclosed PLA, PGA, PLGA, and PEA polymers may be combined with at least one therapeutic agent and formulated into the polymer matrix described herein, which may be formulated as a particle suspension for ocular administration. Additional agents comprising, but not limited to, tocopherols (e.g., α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol) may be used in the particle suspension described herein.

[0188] In an embodiment, the particles have a size of less than about 100 µm at any dimension. In an embodiment, the largest dimension may be about 10 µm to about 100 µm, or about 12.5 µm to about 25 µm to about 50 µm. In another embodiment, the smallest dimension may be about 10 µm to about 100 µm, or about 12.5 µm to about 25 µm. PRINT ®The technology can be easily utilized to produce the particles used in the particle suspension of the present invention. The pharmaceutical composition of the present invention (e.g., intravitreal implants and particle suspensions) comprises about 1% to about 90%, or about 1% to about 80%, or about 1% to about 70%, or about 1% to about 60%, or about 1% to about 50%, or about 1% to about 40%, or about 1% to about 30%, or about 1% to about 20%, or about 1% to about 10%, or about 10% to about 50%, or about 10% to about 40%, or about 10% to about 30%, or about 10% to about 25%, or about 10% to about 23%, or about 10% to about 20%, or about 15% to about 35%, or about 15% to about 30%, or about 15% to about 25% of a therapeutic agent. Includes content.

[0189] The delivery vehicle may be used for the administration of the particle suspension described herein via intravitreal injection. For example, using a hyaluronic acid (HA) delivery vehicle, an injectable vehicle for administering the particle suspension may be formulated, such as the injectable vehicles described in U.S. Patents No. 7,582,311 and No. 7,651,703, which are incorporated herein by reference in their entirety. Hyaluronic acid (HA) is a polyvalent anionic polysaccharide composed of N-acetyl-D-glucosamine and beta-glucuronic acid. The intrinsic viscoelasticity of HA, along with its biocompatibility and non-immunogenicity, has enabled HA to be used in a number of clinical applications, including the replacement of synovial fluid in arthritis; use as a surgical adjuvant in eye surgery; and the promotion of healing and regeneration of surgical wounds. More recently, HA has been studied as a therapeutic agent for various routes of administration, including ocular, nasal, pulmonary, parenteral, and topical.

[0190] In an embodiment, the particle suspension is delivered by an aqueous solution. In a specific embodiment, the particle suspension of the present invention is delivered by an aqueous solution containing a sorbitol and hyaluronic acid (HA / sorbitol) vehicle. The aqueous solution comprises about 0.1% to 99% HA and about 1% to 99% sorbitol, or about 0.1% to 50% HA and about 20% to 90% sorbitol, or about 0.1% to 10% HA and about 40% to 60% sorbitol. In some embodiments, the aqueous solution comprises about 1% HA and about 50% sorbitol.

[0191] Manipulation of therapeutic release profiles

[0192] The release rate of the therapeutic agent from an intravitreal implant or particle suspension (e.g., a pharmaceutical composition of the present invention) is influenced by several factors, including but not limited to the surface area of ​​the implant, the content of the therapeutic agent and the water solubility of the therapeutic agent, and the polymer degradation rate. As described above, important aspects that determine not only the release rate of the therapeutic agent but also its duration are the ratio of the amount of the first polymer used, e.g., PEA, to the amount of the second polymer used, e.g., (a) PLA, (b) PLGA, or (c) a combination of (a) and (b), and the PGLA:PLA ratio when polymer 2 is a combination of PLA and PLGA. Other related factors include the lactide stereoisomer composition (i.e., the amount of L-lactide versus DL-lactide) and molecular weight.

[0193] The versatility of PGA, PLA, PLGA, and PEA enables the construction of delivery systems that coordinate the release of therapeutic agents to treat various ocular diseases or disorders.

[0194] The versatility of PGA, PLA, PLGA, and PEA polymers is the manufacturing technique of the present invention, namely PRINT ®When combined with the fabrication of technical particles, multiple customized, highly consistent, and predictable therapeutic release profiles can be generated, which was impossible with conventional technology, for example, based on extrusion. PRINT used to create the intravitreal implant of the present invention ® In addition to the technology, the particles used in the particle suspension of the present invention are also described in PCT applications published by reference No. WO2007021762, WO2007024323, and WO2007030698, which are incorporated herein by reference in their entirety.

[0195] The mold cavity used to fabricate the intravitreal implant of the present invention may vary from the dimensions mentioned in various embodiments by ± about 50 µm, or ± about 40 µm, or ± about 30 µm, or ± about 20 µm, or ± about 10 µm, or ± about 5 µm.

[0196] PRINT ® By utilizing the technology, it is possible to fabricate the intravitreal implants of the present invention, which exhibit therapeutic release profiles with highly reproducible characteristics between implants. The therapeutic release profiles exhibited by the various implants of the present invention show consistent and statistically insignificant variation between implants. Consequently, the therapeutic release profiles exhibited by embodiments of the intravitreal implants of the present invention are within a confidence interval and exhibit a coefficient of variation that does not affect therapeutic delivery. The ability to produce implants exhibiting such highly consistent therapeutic loading or release represents an advancement beyond the latest technology.

[0197] Suitable therapeutic agents homogeneously dispersed within the polymer matrix described herein for use in various embodiments of the present invention, as well as analogs, derivatives, pharmaceutically acceptable salts, amphoteric ions, polymorphs, or solvates thereof, may also be found in the Orange Book published by the Food and Drug Administration, which lists therapeutic agents approved for treating eye diseases or disorders in particular.

[0198] An example of a therapeutic agent applied to the pharmaceutical composition of the present invention, or to an intravitreal implant or particle suspension made from the pharmaceutical composition of the present invention, is an inhibitor of the receptor tyrosine kinase (RTK) discussed above. A specific example of an RTK inhibitor applied herein is gefitinib ("IRESSA ® "), Lapatinib ("TYKERB ® " and "TYVERB ® "), erlotinib("TARCEVA ® "), Sunitinib maleate("SUTENT ® "), sorafenib("NEXAVAR"), regorafenib("STIVARGA") ® "), vandetanib, apatinib("GILOTRIF ® "), axitinib("INLYTA ® "), semaxanib, cediranib("RECENTIN"), neratinib("NERLYNX") ® "), restaurtinib and tivoaznib ("FOTIVDA ® Includes, but not limited to, ")

[0199] Rho kinase inhibitors are also applicable herein. Specific examples of such Rho kinase inhibitors applicable to the pharmaceutical compositions of the present invention (e.g., the intravitreal implants of the present invention) are netarsudil or its pharmaceutically acceptable salts (e.g., "RHOPRESSA"), which are used to lower IOP and treat glaucoma. ®"), and rifasudil or its pharmaceutically acceptable salts used in the treatment of glaucoma and ocular hypertension (e.g., "GLANATEC ® Includes, but not limited to, ")

[0200] A specific JAK inhibitor applied to a pharmaceutical composition (e.g., the intravitreal implant of the present invention) used to treat ocular diseases or disorders is ruxolitinib for JAK1 / JAK2 ("JAKAFI ® " and "JAKAVI ® "); Tofacitinib for JAK3("XELJANZ ® " and "JAKVINUS"); oclacitinib for JAK1 ("APOQUEL ® "); and baricitinib for JAK1 / JAK2("OLUMIANT ® Includes, but not limited to, ")

[0201] Another example of a therapeutic agent applicable to this invention is corticosteroids, and their analogs and derivatives. Examples include dexamethasone, budesonide, beclomethasone, beclomethasone (e.g., as a monopropionate or dipropionate ester), flunisolide, fluticasone (e.g., as a propionate or furoate ester), ciclesonide, mometasone (e.g., as a furoate ester), mometasone desonide, rofleponide, hydrocortisone, prednisone, prednisolone, methylprednisolone, naflokort, deflazacort, halofredon acetate, fluocinolone acetonide, fluocinonide, clocortolone, tipredan, prednicarbate, alclomethasone dipropionate, halomethasone, rimexolone, deprodon propionate, triamcinolone, betamethasone, fludrocortisone, It includes, but is not limited to, desoxicorticosterone, rofleponide, etifrednol dichloroacetate, etc.

[0202] Specific examples of corticosteroids, or analogs or derivatives thereof, applicable herein are as follows:

[0203] (a) Dexamethasone (having the chemical structure of the following chemical formula (V):

[0204]

[0205] IUPAC name: (8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-n,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one; and

[0206] (b) Fluosinolone acetonide (chemical structure of formula (VI) below):

[0207]

[0208] IUPAC Name: (1S,2S,4R,8S,9S,11S,12R,13S,19.3-4-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-6,6,9,13-tetramethyl-5,7-dioxapentacyclo[ 10.8.0.0<2,9>.0 <48> .0<13 18>]icosa-14,17-dien-16-on.

[0209] Prostaglandins and analogs or derivatives thereof applied as therapeutic agents in the pharmaceutical compositions of the present invention (e.g., intravitreal implants and particle suspensions) include latanoprost, bimatoprost, travoprost, tafluprost, 3-hydroxy-2,2-bis(hydroxymethyl)propyl 7-((1r,2r,3r,5s)-2-((r)-3-(benzo[b]thiophene-2-yl)-3-hydroxypropyl)-3,5-dihydroxycyclopentyl)heptanoate (chemical structure of formula (II)), chlorprostenol isopropyl ester, 13,14-dihydrochloroprostenol isopropyl ester, latanoprosten bunode, unoprostone, and PGF 1α Isopropyl ester, PGF 2αIsopropyl ester, PGF 3α It includes isopropyl ester, fluprostenol, or any combination thereof. In some embodiments, the prostaglandin and its analog or derivative applied as a therapeutic agent include dukeprost, tiaprost, or both. In some embodiments, the prostaglandin and its analog or derivative applied as a therapeutic agent include the free acid of the prostaglandin and its analog or derivative and a pharmaceutically acceptable salt thereof.

[0210] Other therapeutic agents applied to the pharmaceutical composition of the present invention for treating eye diseases or disorders, e.g., glaucoma, include, but are not limited to, beta-blockers, miotics, alpha-adrenergic agonists or carbonic anhydrase inhibitors, and antimetabolites, e.g., 5-fluorouracil or mitomycin C.

[0211] Naturally, the pharmaceutical compositions of the present invention may comprise a therapeutic agent or a combination of two or more therapeutic agents, examples thereof of which are discussed above. Furthermore, analogs or derivatives of therapeutic agents such as those discussed herein, pharmaceutically acceptable salts, amphoteric ions, solvates, esters, and polymorphs also apply to the pharmaceutical compositions of the present invention. As used herein, an "analogous agent" is a compound having a structure similar to that of another compound (its "parent" compound), but with certain components that differ from said other compound. An analogous agent may differ from its parent compound in that one or more atoms, functional groups, or substructures are substituted with other atoms, groups, or substructures. Likewise, an analogous agent of a parent compound may be formed by substituting a specific atom of the parent compound with a radioisotope of that specific atom. A "derivative" is a compound that may be conceived to be produced from or actually synthesized from a parent compound by substituting one atom with another atom or group of atoms.

[0212] As used herein, "pharmaceuticalally acceptable salt" refers to an ionizable therapeutic agent that combines with a counterion to form a neutral complex.

[0213] The term "amphoteric ion" refers to a molecule or ion that has a separate positively charged group and a negatively charged group within itself.

[0214] As used herein, “polymorph” or “polymorphism” is the ability of a solid material to exist in more than one form or crystal. Crystal forms may be referred to herein as those characterized by graphic data. Such data include, for example, powder X-ray diffraction patterns and solid-state NMR spectra. As is well known in the art, graphic data potentially provides additional technical information to further define each solid-state form (so-called “fingerprint”) that cannot necessarily be described by referring only to numerical values ​​or peak positions.

[0215] In the pharmaceutical composition of the present invention (e.g., intravitreal implants and particle suspensions), the therapeutic agent is blended with a biodegradable polymer matrix to form the pharmaceutical composition. The amount of therapeutic agent used in the pharmaceutical composition is determined by several factors, such as, to list a few, the selection of the biodegradable polymer matrix, the selection of the therapeutic agent, the desired release rate in a substantially linear manner, the duration of the desired release rate, the composition of the pharmaceutical composition, and ocular PK.

[0216] For example, the total therapeutic content of the pharmaceutical composition of the present invention (e.g., intravitreal implant) may account for approximately 0.1 to approximately 60.0 weight percent of the total pharmaceutical composition. In some embodiments, the therapeutic agent accounts for about 1% to about 90%, or about 1% to about 80%, or about 1% to about 70%, or about 1% to about 60%, or about 1% to about 50%, or about 1% to about 40%, or about 1% to about 30%, or about 1% to about 20%, or about 1% to about 10%, or about 10% to about 50%, or about 10% to about 40%, or about 10% to about 30%, or about 10% to about 25%, or about 10% to about 23%, or about 10% to about 20%, or about 15% to about 35%, or about 15% to about 30%, or about 15% to about 25%. All these percentages are weight percentages. In a specific embodiment, dexamethasone accounts for approximately 20.0 weight percent of the pharmaceutical composition.

[0217] The pharmaceutical composition of the present invention is prepared by dissolving a polymer matrix and a therapeutic agent in a suitable solvent to produce a homogeneous solution. For example, acetone, alcohol (e.g., methyl alcohol or ethyl alcohol), acetonitrile, tetrahydrofuran, chloroform, and ethyl acetate may be used as solvents. Other solvents known in the art are also considered. The solvent is then evaporated, leaving a homogeneous film. The solution may be aseptically filtered before the solvent evaporates.

[0218] Fabrication of intravitreal implants

[0219] As described above, the present invention extends to pharmaceutical compositions of the present invention formulated as intravitreal implants or particle suspensions. The implants or particle suspensions of the present invention can be produced using various methods. Such methods include, but are not particularly limited to, solvent casting, phase separation, interfacial methods, molding, compression molding, injection molding, extrusion, co-extrusion, thermal extrusion, die cutting, thermal compression, and combinations thereof. In certain embodiments, the implant is preferably molded in a polymeric mold.

[0220] In a specific embodiment, the implant of the present invention is PRINT ® It is manufactured through particle fabrication technology (Liquidia Technologies, Inc.). Specifically, the implant is manufactured by molding materials intended to constitute the implant in a mold cavity.

[0221] The mold is a polymer-based mold, and the mold cavity can be formed into any desired shape and dimensions. Uniquely, because the implants and particles are formed within the mold cavity, the implants are highly uniform in terms of shape, size, and composition. Due to the consistency between the physical and compositional configurations of each implant in the pharmaceutical composition, the pharmaceutical composition of the present invention provides a highly uniform release rate and dosage range. The method and material for producing the implant of the present invention are U.S. Patents No. 9,545,737, No. 9,214,590, No. 9,205,594, No. 8,992,992, No. 8,662,878, No. 8,518,316, No. 8,444,907, No. 8,439,666, No. 8,420,124, No. 8,268,446, No. 8,263,129, No. 8,158,728, No. 8,128,393 and No. 7,976,759; Further described and disclosed in U.S. Patent Application Publications No. 2013-0228950, No. 2013-0011618, No. 2013-0256354, No. 2010-0003291, No. 2009-0165320 and No. 2008-0299174 (each of which is incorporated herein by reference in its entirety).

[0222] The mold cavity can be formed in various shapes and sizes. For example, the cavity may have the shape of a prism, a rectangular prism, a triangular prism, a pyramid, a square pyramid, a triangular pyramid, a cone, a cylinder, a torus, or a rod. The cavity within the mold may have the same shape or different shapes. In a specific embodiment of the invention, the shape of the implant is cylindrical, a rectangular prism, or a rod. In a specific embodiment, the implant is a rod. The rod may have only a 90-degree angle, may bulge along its long axis, or may taper gradually so that one end is smaller than the other.

[0223] The mold cavity may have dimensions ranging from nanometers to micrometers to millimeters and larger dimensions. In certain embodiments of the present invention, the mold cavity has dimensions within the micrometer and millimeter range. For example, the cavity may have the smallest dimensions of approximately 50 nanometers to approximately 750 μm. In some embodiments, the smallest mold cavity dimensions may be approximately 100 μm to approximately 300 μm. In other embodiments, the smallest mold cavity dimensions may be approximately 125 μm to approximately 250 μm. In other embodiments, the smallest mold cavity dimensions may be approximately 10 μm to approximately 100 μm. In some embodiments, the smallest mold cavity dimensions may be approximately 12.5 μm to approximately 50 μm, for example, 25 μm to 30 μm. The mold cavity may have a maximum dimension of approximately 750 μm to approximately 10,000 μm. In another embodiment, the maximum mold cavity dimension may be approximately 1,000 μm to approximately 5,000 μm. In another embodiment, the maximum mold cavity dimension may be approximately 1,000 μm to approximately 3,500 μm. In another embodiment, the maximum mold cavity dimension may be approximately 25 μm to approximately 100 μm. In some embodiments, the minimum mold cavity dimension may be approximately 25 μm to approximately 50 μm, for example, 25 μm to 30 μm.

[0224] In one embodiment, particles of the particle suspension of the present invention are produced using a mold cavity having dimensions of about 12.5 μm x about 12.5 μm x about 25 μm (W x H x L).

[0225] In one embodiment, particles of the particle suspension of the present invention are produced using a mold cavity having dimensions of about 25 μm x about 25 μm x about 25 μm (W x H x L).

[0226] In one embodiment, particles of the particle suspension of the present invention are produced using a mold cavity having dimensions of about 25 μm x about 25 μm x about 50 μm (W x H x L).

[0227] In one embodiment, particles of the particle suspension of the present invention are produced using a mold cavity having dimensions of about 50 μm x about 50 μm x about 30 μm (W x H x L).

[0228] In one embodiment, particles of the particle suspension of the present invention are produced using a mold cavity having dimensions of about 50 μm x about 50 μm x about 50 μm (W x H x L).

[0229] In one embodiment, the intravitreal implant of the present invention is fabricated using a rod-shaped mold cavity having dimensions of approximately 140 μm x approximately 140 μm x approximately 1325 μm (W x H x L).

[0230] In a further embodiment, the intravitreal implant of the present invention is fabricated using a rod-shaped mold cavity having dimensions of about 225 μm x about 225 μm x about 2965 μm (W x H x L).

[0231] In another embodiment, the intravitreal implant of the present invention is fabricated using a rod-shaped mold cavity having dimensions of approximately 395 μm x approximately 311 μm x approximately 6045 μm (W x H x L).

[0232] In one embodiment, the intravitreal implant of the present invention is fabricated using a rod-shaped mold cavity having dimensions of approximately 100 μm x approximately 100 μm x approximately 1500 μm (W x H x L).

[0233] In a further embodiment, the intravitreal implant of the present invention is fabricated using a rod-shaped mold cavity having dimensions of about 150 μm x about 150 μm x about 3150 μm (W x H x L).

[0234] In another embodiment, the intravitreal implant of the present invention is fabricated using a rod-shaped mold cavity having dimensions of approximately 180 μm x approximately 180 μm x approximately 3000 μm (W x H x L).

[0235] In one embodiment, the intravitreal implant of the present invention is fabricated using a rod-shaped mold cavity having dimensions of approximately 200 μm x approximately 200 μm x approximately 2000 μm (W x H x L).

[0236] In a further embodiment, the intravitreal implant of the present invention is fabricated using a rod-shaped mold cavity having dimensions of about 200 µm x about 200 µm x about 1000 µm (W x H x L).

[0237] In another embodiment, the intravitreal implant of the present invention is fabricated using a rod-shaped mold cavity having dimensions of approximately 225 μm x approximately 225 μm x approximately 2700 μm (W x H x L).

[0238] In another embodiment, the intravitreal implant of the present invention is fabricated using a rod-shaped mold cavity having dimensions of approximately 250 μm x approximately 250 μm x approximately 1500 μm (W x H x L).

[0239] In another embodiment, the intravitreal implant of the present invention is fabricated using a rod-shaped mold cavity having dimensions of approximately 200 µm x approximately 200 µm x approximately 4500 µm (W x H x L).

[0240] In another embodiment, the intravitreal implant of the present invention is fabricated using a rod-shaped mold cavity having dimensions of approximately 265 μm x approximately 265 μm x approximately 4500 μm (W x H x L).

[0241] In another embodiment, the intravitreal implant of the present invention is fabricated using a rod-shaped mold cavity having dimensions of approximately 255 μm x approximately 255 μm x approximately 4500 μm (W x H x L).

[0242] Once fabricated, the implants and particles may remain on an array for storage or be immediately retrieved for storage and / or use. The implants and particles described herein may be fabricated using a sterilization process or sterilized after fabrication. Accordingly, the present invention envisions a kit comprising a storage array having fabricated implants and particles attached thereto. This storage array / implant kit provides a convenient method for the mass transport and distribution of fabricated implants.

[0243] In other embodiments, implants and particles may be produced through the application of additive manufacturing techniques. For example, the additive manufacturing disclosed in U.S. Patent No. 9,120,270 is PRINT ® Manufacture of the master mold used in the process, PRINT disclosed herein ® It can be used for the manufacture of molds used in the process, or for the direct fabrication of implants.

[0244] In certain embodiments, the implant and particles are produced through a process of (i) dissolving a polymer and a therapeutic agent in a solvent, e.g., acetone; (ii) casting the solution into a thin film; (iii) drying the film; (iv) folding the thin film; (v) heating the folded thin film on a substrate to form a substrate; (vi) placing the thin film on the substrate in a mold having a mold cavity; (vii) applying pressure and, in some embodiments, heat to the mold-thin film-substrate combination so that the thin film enters the mold cavity; (viii) cooling; and (ix) removing the substrate from the mold to provide an implant substantially similar in size and shape to the mold cavity.

[0245] delivery device

[0246] In an embodiment, a delivery device may be used to insert the intravitreal implant or particle suspension of the present invention into an eye or eyes to treat an ocular disease or disorder. Suitable devices may include, for example, a needle or needle-like applicator disclosed in PCT Application Publication No. WO2018045386, which is incorporated herein by reference in its entirety. In some embodiments, since the smallest dimension of the implant may be approximately 50 µm to approximately 750 µm, a needle or needle-like applicator having a gauge of approximately 15 to approximately 30 may be used. In certain embodiments, the needle gauge is approximately 15, approximately 16, approximately 17, approximately 18, approximately 19, approximately 20, approximately 21, approximately 22, approximately 23, approximately 24, approximately 25, approximately 26, approximately 27, approximately 28, approximately 29, or approximately 30. In one embodiment, the device uses a 25-gauge needle for an implant having a minimum dimension of 265 µm. In another embodiment, the device uses a 21 or 22 gauge needle for an implant having a minimum dimension of 395 µm. In another embodiment, the device uses a 27 gauge needle for a particle suspension or implant having a minimum dimension of 200 µm. The delivery implant may be a syringe with a needle of appropriate size or a syringe-like implant with a needle-like applicator. In one embodiment, the device uses a 27 gauge ultrathin-walled needle with an inner diameter of 300 + / - 10 micrometers.

[0247] Delivery routes include, in particular, puncture, intravitreal, subconjunctival, crystalline, sclera, perforation, anterior subtenon, supracorbital, posterior subtenon, subretinal, anterior chamber, and posterior chamber.

[0248] In an embodiment, an implant or implants are delivered to the anterior chamber of a patient's eye to treat glaucoma and / or elevated intraocular pressure.

[0249] In some embodiments, an implant or implants are delivered to the anterior chamber of a patient's eye to treat uveitis.

[0250] Kit

[0251] The intravitreal implant and the delivery system can be combined and provided as a kit for use. The implant can be packaged separately from the delivery device and loaded into the delivery device immediately before use. Alternatively, the implant can be loaded into the delivery implant before packaging. In this case, once the kit is opened, the delivery implant is ready for use. The components can be sterilized individually and combined into a kit, or sterilized after being combined into a kit. Additionally, as mentioned above, the kit may include an array to which the implants are combined.

[0252] Use of the intravitreal implant of the present invention for the treatment of eye diseases or disorders

[0253] In one aspect of the present invention, a method for treating an eye disease or disorder is provided, comprising the steps of placing the intravitreal implant of the present invention into the eye of a patient suffering from an eye disease or disorder, disassembling the implant, and releasing a therapeutic agent in a substantially linear manner over a period of at least about three months. The patient may be a human or an animal, for example, a dog, cat, horse, cow (or any agricultural livestock).

[0254] Treatment process

[0255] Over the course of treatment, the biodegradable polymer matrix of the pharmaceutical composition of the present invention degrades and releases the therapeutic agent in a substantially linear manner for at least about 3 months. Once the therapeutic agent is fully released, the polymer matrix disintegrates. Complete degradation of the polymer matrix may take longer than the complete release of the therapeutic agent from the polymer matrix. Polymer matrix degradation may occur at the same rate as the release of the therapeutic agent.

[0256] Optionally, the pharmaceutical composition is administered in a repetitive manner. The administration method provides a method in which a second dose of the pharmaceutical composition of the present invention is administered after the release of a first dose of its therapeutic agent. This administration method may be repeated 3, 4, 5, 6, 7, 8, 9, 10, or more times. In one embodiment, the intravitreal implant of the present invention must be completely decomposed before re-administration occurs.

[0257] The present invention may be better understood by referring to the following non-limiting embodiments provided as examples of the invention. The following embodiments are provided to more fully illustrate specific embodiments of the invention. However, they should by no means be construed as limiting the broad scope of the invention.

[0258] Examples

[0259] Example 1: Fabrication of an implant

[0260] A series of polymer matrix / therapeutic blends were prepared prior to the fabrication of the implant. Solvent mixing was used to produce a therapeutic agent homogeneously dispersed throughout the entire implant body. Each prepared blend contained different ratios of PEA (Polymer 1) to Polymer 2, which contained PLA polymer, PLGA polymer, or a combination of PLA polymer and PLGA polymer. The PLA polymer used to produce the pharmaceutical composition was RESOMER, which is available from Evonik Industries. ®The R203S PLA polymer was used. For this example, the PLGA polymer used to produce the pharmaceutical composition of the present invention was a RESOMER, which is also available from Evonik Industries. ® RG653H was a PLGA polymer. The PEA used in the pharmaceutical composition had the chemical structure of formula (III).

[0261] In the preparation of the pharmaceutical composition, polymers were mixed together in a specific ratio, and then chloroform was added directly to dissolve the polymers. Next, the polymer / chloroform solution was added directly to micronized dexamethasone. Subsequently, the chloroform was evaporated onto a polyethylene terephthalate (PET) sheet placed on a hot plate at 60°C. After the chloroform was removed, a thin film of homogeneous material remained.

[0262] Example 2: Fabrication of a mold

[0263] PRINT ® A rod-shaped mold of the desired dimensions with dimensions of 265x265x4500 μm was produced using a process. The different pharmaceutical compositions of the present invention produced are listed in the second column of Table 1. If a polymer for a specific intravitreal implant of the present invention is not mentioned in the second column, it means that the polymer was not used in the manufacture of the pharmaceutical composition used for that specific intravitreal implant.

[0264] Example 3: Fabrication of a Dexamethasone Implant

[0265] A series of implants were fabricated using the polymer matrix / therapeutic blend of Example 1 and the mold of Example 2. The polymer matrix / therapeutic blend was spread out on a PET sheet and heated. Once heated, the solvent was completely dried. The blend was covered with a mold of desired dimensions. Light pressure was applied using a roller to spread the blend over the entire surface of the mold. Subsequently, the mold / blend laminate was passed through a commercially available thermal laminate using the parameters in the table below. The blend flowed into the mold cavity and took the shape of the mold cavity. The blend was cooled to room temperature, and individual implants were formed in the mold cavity. Afterward, the mold was removed, leaving a two-dimensional array of implants on the film. The individual implants were removed from the PET film using forceps.

[0266]

[0267]

[0268] Example 4: Analysis of Dexamethasone Content

[0269] The implant prepared as described above was dissolved in acetonitrile, methanol, and water. Phenomenex Luna ® The dexamethasone content of each implant was measured by RP-HPLC using a phenyl-hexyl HPLC 3 µm particle size and a 4.6 x 100 mm analytical column. The mobile phase consisted of a gradient of 0.1% trifluoroacetic acid (TFA) and acetonitrile in purified water at 1.0 ml / min over 4 minutes. The UV absorbance of dexamethasone was measured at 245 nm. Table 2 lists the measured dexamethasone content in each implant.

[0270]

[0271] Example 5: In vitro release analysis of selected implants

[0272] The aforementioned single implant was placed in a 4 mL glass screw-top vial and incubated in 3 mL of 1X PBS at 37°C. At each point of interest, the medium was removed for analysis. Then, the medium was replaced with 3 mL of fresh medium. The removed medium was analyzed for released dexamethasone using the HPLC method. Figure 1 shows the measured in vitro release of dexamethasone per evaluated implant. Figure 2 shows the cumulative percentage of dexamethasone released from implant sample 7. The graph shows that the slope of the graph remained substantially constant from day 0 to approximately day 90. Therefore, this data demonstrates that the pharmaceutical composition of the present invention (e.g., an intravitreal implant) releases the therapeutic agent in a substantially linear manner for at least 3 months.

[0273] Sample 7 is an intravitreal implant of the present invention made from a pharmaceutical composition of the present invention comprising (a) about 59 weight% of a polymer matrix comprising (i) about 60 weight% of a biodegradable polyester amide homopolymer having the chemical structure of formula (III), (ii) about 20 weight% of a biodegradable poly(D,L-lactide) homopolymer, and (iii) about 20 weight% of a biodegradable poly(D,L-lactide-co-glycolide) copolymer; and (b) about 41 weight% of dexamethasone homogeneously dispersed within the polymer matrix, wherein (i), (ii) and (iii) are blended together to form a polymer matrix.

[0274] FIG. 3 is a graph of the average daily dexamethasone release rate from sample 7 of the intravitreal implant of the present invention. In FIG. 3, the daily dexamethasone release amount is substantially constant from day 0 to approximately day 90, which also demonstrates that the pharmaceutical composition of the present invention (e.g., intravitreal implant) releases the therapeutic agent in a substantially linear manner for at least 3 months.

[0275] The PEA homopolymer matrix exhibits a very slow nonlinear emission profile. The PLGA / PLA homopolymer matrix exhibits a nonlinear emission profile followed by an initial burst.

[0276] Surprisingly, it was observed that dexamethasone released from the combination PEA / PLGA matrix exhibited a high daily release rate and a substantially linear release profile (e.g., for up to 90 days from the first administration).

[0277] The scope of the present invention should not be limited by the specific embodiments described herein. Various variations of the present invention other than those described herein will be obvious to those skilled in the art from the foregoing description and the accompanying drawings. Such variations fall within the scope of the appended claims.

[0278] Example 6: Storage and Stability of Compounds and Compositions

[0279] A compound or composition provided herein is prepared and placed in a container for storage at ambient temperature or elevated temperature. When the compound or composition is stored in a polyolefin plastic container compared to a polyvinyl chloride plastic container, the discoloration of the compound or composition is reduced, whether it is dissolved or suspended in a liquid composition (e.g., an aqueous or organic liquid solution) or exists as a solid. Without being bound by theory, the container reduces the exposure of the container contents to electromagnetic radiation, whether visible light (e.g., having a wavelength of about 380 to 780 nm) or ultraviolet (UV) radiation (e.g., having a wavelength of about 190 to 320 nm (UV-B light) or about 320 to 380 nm (UV-A light)). Some containers also include a performance that reduces the exposure of the container contents to infrared radiation, or a second component having such performance. The container used comprises a container made from polyolefin, e.g., polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutene, or a combination thereof, in particular polyethylene, polypropylene, or a combination thereof. To further reduce the exposure of the container contents to UV, visible light, or infrared light, a second container, e.g., paper, cardboard, paperboard, metallic film or foil, or a combination thereof, may be placed inside the container. Compounds and compositions that benefit from reduced discoloration, degradation, or both during storage include eye drops or implants containing the compounds or compositions provided herein. The eye drops or implants may require storage for up to three months or longer; in some cases, up to one year or longer. The container described herein may be an eye drop or implant container. The container may be any form suitable for containing the contents, e.g., a bag, a bottle, or a box.

[0280] Other suitable containers and packaging are described, for example, in International Publications No. WO 2018 / 159700, WO 2018 / 159701 and WO 2018 / 159702, the contents of which are incorporated herein by reference, and Japanese Patent No. 6236167(B2).

[0281] The composition disposed inside the described container may comprise boric acid, D-mannitol, benzalkonium chloride, polyoxyl 40 stearate, polyethylene glycol 400, ethylenediaminetetraacetic acid, or a combination thereof; and water or another suitable solvent vehicle or excipient. In some cases, the vehicle is an aqueous vehicle. In other cases, the vehicle is a non-aqueous vehicle.

[0282] Example 7: Polymer Matrix / Therapeutic Agent Blending

[0283] A series of polymer matrix / therapeutic agent blends were prepared prior to the fabrication of the implant. A therapeutic agent homogeneously dispersed throughout the body of the implant was produced using hot melt mixing. A fine powder was prepared by cryo-grinding the polymer and small molecule JAK inhibitor. A homogeneous paste was provided by heating and melting the powder using a hot plate at 130°C.

[0284] Example 8: Fabrication of a mold

[0285] PRINT ® A rod-shaped mold with dimensions of 200x200x4500 µm was fabricated using a process. An implant was fabricated using the JAK inhibitor (1R,2R)-N-(4-methylisoquinoline-6-yl)-2-(4-(N-(pyridine-2-yl)sulfamoyl)phenyl)cyclopropane-1-carboxamide.

[0286] Example 9: Implant fabrication

[0287] A series of implants were fabricated using the polymer matrix and JAK inhibitor blend of Example 7 and the mold of Example 8 (see Table 3). The polymer matrix / therapeutic blend was spread out on a PET sheet and heated. Once heated, the blend was covered with a mold of desired dimensions. Light pressure was applied using a roller to spread the blend over the entire surface of the mold. Subsequently, the mold / blend laminate was passed through a commercially available thermal laminate using the parameters of Table 4 below. The blend flowed into the mold cavity and took on the shape of the mold cavity. The blend was cooled to room temperature, and individual implants were formed in the mold cavity. Then, the mold was removed, leaving a two-dimensional array of implants on the film. The individual implants were removed from the PET film using forceps.

[0288]

[0289]

[0290] To analyze the implant content, the implant was first dissolved in 1 mL of DMSO. Once dissolved, 3 mL of methanol was added to each sample and mixed. The content of small molecule JAK inhibitors was measured by RP-HPLC using a Waters Atlantis T3, 3 µm particle size, 4.6 x 75 mm analytical column. The mobile phase consisted of a gradient of 0.1% TFA and acetonitrile in purified water at 1.0 mL / min over 5 minutes. The UV absorbance of the therapeutic agent was measured at 262 nm.

[0291] The in vitro release of the implant formulation was analyzed. A single implant was placed in a 4 mL glass screw-top vial and incubated at 37°C in 3 mL of 1X PBS containing 0.5% Tween 20. At each time point of interest, the medium was removed for analysis. Subsequently, the medium was replaced with 3 mL of fresh medium. The removed medium was analyzed via HPLC for the released therapeutic agent (i.e., (1R,2R)-N-(4-methylisoquinoline-6-yl)-2-(4-(N-(pyridine-2-yl)sulfamoyl)phenyl)cyclopropane-1-carboxamide). As shown in Figures 4 and 5, at least the first 80% of the therapeutic agent released from the implant had an R value of 0.9 or higher. 2 It had a value.

Claims

Claim 1 As a pharmaceutical composition for the treatment of an eye disease or disorder, the pharmaceutical composition comprises (a) a biodegradable polymer matrix comprising a mixture of a first polymer and a second polymer, wherein (1) the first polymer is a biodegradable polyester amide homopolymer, and the biodegradable polyester amide homopolymer comprises the following structure (III); (2) a biodegradable polymer matrix in which the second polymer is a biodegradable poly(D,L-lactide-co-glycolide) polymer or a combination of biodegradable poly(D,L-lactide-co-glycolide) polymers, and the biodegradable poly(D,L-lactide-co-glycolide) polymer comprises an ester-terminally capped biodegradable poly(D,L-lactide-co-glycolide) polymer, an acid-terminally capped biodegradable poly(D,L-lactide-co-glycolide) polymer, or a combination thereof; and (b) at least one therapeutic agent or a pharmaceutically acceptable salt thereof homogeneously dispersed within the biodegradable polymer matrix; Comprising, at least one therapeutic agent or a pharmaceutically acceptable salt thereof comprises a corticosteroid, a therapeutic agent inhibiting kinase activity, or a combination thereof, wherein the corticosteroid is dexamethasone, and the therapeutic agent inhibiting kinase activity is gefitinib; sunitinib; sorafenib; regorafenib; vandetanib; semaxanib; cediranib; axitinib; tivozanib;Selected from the group consisting of (1R,2R)-N-(4-methylisoquinoline-6-yl)-2-(4-(N-(pyridine-2-yl)sulfamoyl)phenyl)cyclopropane-1-carboxamide, or combinations thereof; the pharmaceutical composition is formulated for intravitreal administration to the eye of a subject and is formulated to release at least one therapeutic agent or a pharmaceutically acceptable salt thereof from the pharmaceutical composition in a linear manner over a period of 1 to 6 months; the pharmaceutical composition comprises 59 wt% ±5% of a biodegradable polymer matrix and 41 wt% ±5% of at least one therapeutic agent or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprises 51 wt% ±5% of a biodegradable polymer matrix and 49 wt% ±5% of at least one therapeutic agent or a pharmaceutically acceptable salt thereof; and the ocular disease or disorder is uveitis, corneal ulcer, endophthalmitis, wet age-related macular degeneration, dry age-related macular degeneration A pharmaceutical composition selected from degeneration, ocular inflammation, dry eye, glaucoma, ocular hypertension, or a combination thereof. Claim 2 A pharmaceutical composition according to claim 1, wherein the biodegradable polymer matrix is ​​a mechanical blend of a first polymer and a second polymer. Claim 3 A pharmaceutical composition comprising particles having dimensions of (200 µm ± 5%) x (200 µm ± 5%) x (4500 µm ± 5%) in claim 1. Claim 4 A pharmaceutical composition according to claim 1, wherein the poly(D,L-lactide-co-glycolide) polymer is an ester-terminated biodegradable poly(D,L-lactide-co-glycolide) copolymer or an acid-capped biodegradable poly(D,L-lactide-co-glycolide) copolymer. Claim 5 A pharmaceutical composition according to claim 1, wherein the second polymer is a combination of biodegradable poly(D,L-lactide-co-glycolide) polymers, and the combination of biodegradable poly(D,L-lactide-co-glycolide) polymers comprises an ester-terminally capped biodegradable poly(D,L-lactide-co-glycolide) copolymer and an acid-terminally capped biodegradable poly(D,L-lactide-co-glycolide) copolymer. Claim 6 A pharmaceutical composition according to claim 1, wherein the second polymer is a combination of biodegradable poly(D,L-lactide-co-glycolide) polymers comprising an ester-terminated biodegradable poly(D,L-lactide-co-glycolide) copolymer having a biodegradable polymer matrix of 20 wt% ±5% and an acid-terminated biodegradable poly(D,L-lactide-co-glycolide) copolymer having a biodegradable polymer matrix of 20 wt% ±5%. Claim 7 In claim 1, the biodegradable polymer matrix of 60 wt% ±5% is a biodegradable polyester amide homopolymer; the biodegradable polymer matrix of 20 wt% ±5% is a biodegradable ester-terminated poly(D,L-lactide-co-glycolide) homopolymer; the biodegradable polymer matrix of 20 wt% ±5% is a biodegradable acid-terminated poly(D,L-lactide-co-glycolide) copolymer; or the biodegradable polymer matrix of 60 wt% ±5% is a biodegradable polyester amide homopolymer; and the biodegradable polymer matrix of 30 wt% ±5% is a biodegradable ester-terminated poly(D,L-lactide-co-glycolide) homopolymer; A biodegradable polymer matrix of 10 wt% ±5% is a biodegradable acid-terminated poly(D,L-lactide-co-glycolide) copolymer; a biodegradable polymer matrix of 60 wt% ±5% is a biodegradable polyester amide homopolymer; a biodegradable polymer matrix of 10 wt% ±5% is a biodegradable ester-terminated poly(D,L-lactide-co-glycolide) homopolymer; a biodegradable polymer matrix of 30 wt% ±5% is a biodegradable acid-terminated poly(D,L-lactide-co-glycolide) copolymer; or a biodegradable polymer matrix of 40 wt% ±5% is a biodegradable polyester amide homopolymer; and a biodegradable polymer matrix of 30 wt% ±5% is a biodegradable ester-terminated poly(D,L-lactide-co-glycolide) homopolymer; A pharmaceutical composition in which the biodegradable polymer matrix of 30 wt% ±5% is a biodegradable acid-terminated poly(D,L-lactide-co-glycolide) copolymer. Claim 8 A pharmaceutical composition according to claim 1, comprising 59 wt% ±5% of a biodegradable polymer matrix and 41 wt% ±5% of at least one therapeutic agent or a pharmaceutically acceptable salt thereof. Claim 9 In claim 1, at least one therapeutic agent or a pharmaceutically acceptable salt thereof is a pharmaceutical composition comprising axitinib. Claim 10 The pharmaceutical composition of claim 1 comprises (a) 59 wt% ±5% of a biodegradable polymer matrix; and (b) 41 wt% ±5% of at least one therapeutic agent or a pharmaceutically acceptable salt thereof, wherein at least one therapeutic agent or a pharmaceutically acceptable salt thereof is axitinib. Claim 11 A pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is used to treat an eye disease or disorder, and the eye disease or disorder comprises uveitis, corneal ulcer, endophthalmitis, or a combination thereof. Claim 12 A pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is used to treat an eye disease or disorder, and the eye disease or disorder comprises wet age-related macular degeneration, dry age-related macular degeneration, ocular inflammation, dry eye syndrome, or a combination thereof. Claim 13 A pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is used to treat an eye disease or disorder, and the eye disease or disorder comprises glaucoma, ocular hypertension, or a combination thereof. Claim 14 An intravitreal implant comprising a pharmaceutical composition according to any one of claims 1 to 10. Claim 15 A pharmaceutical composition in the form of an intravitreal implant in claim 11. Claim 16 A pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is intended for use in a method for dissolving at least one therapeutic agent or a pharmaceutically acceptable salt thereof from a depot in a subject requiring the dissolution of at least one therapeutic agent or a pharmaceutically acceptable salt thereof from a depot, said method comprising the step of administering a depot containing the pharmaceutical composition to said subject once, wherein a certain amount of at least one therapeutic agent or a pharmaceutically acceptable salt thereof is dissolved from the depot at a rate of 1% of the at least one therapeutic agent or a pharmaceutically acceptable salt thereof in the initial depot per day for 1 week to 3 months after administration of the depot. Claim 17 A pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is intended for use in a method for dissolving at least one therapeutic agent or a pharmaceutically acceptable salt thereof from a depot in a subject requiring the dissolution of at least one therapeutic agent or a pharmaceutically acceptable salt thereof from a depot, the method comprising the step of administering a depot containing the pharmaceutical composition to the subject once, wherein an amount of at least one therapeutic agent or a pharmaceutically acceptable salt thereof in the amount of 10 to 500 ng, 500 to 1,500 ng, or 1,000 to 2,000 ng is dissolved from the depot daily from the 7th day after administration of the depot until the 90th day. Claim 18 A pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is intended for use in a method of administering at least one therapeutic agent or a pharmaceutically acceptable salt thereof to a subject requiring administration of at least one therapeutic agent or a pharmaceutically acceptable salt thereof, said method comprising the step of administering a depot containing the pharmaceutical composition to said subject once, said subject, wherein a certain amount of at least one therapeutic agent or a pharmaceutically acceptable salt thereof is eluted from the depot at a rate of 1% of the at least one therapeutic agent or a pharmaceutically acceptable salt thereof in the initial depot per day for 1 week to 3 months after administration of the depot. Claim 19 A pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is intended for use in a method of administering at least one therapeutic agent or a pharmaceutically acceptable salt thereof to a subject requiring administration of at least one therapeutic agent or a pharmaceutically acceptable salt thereof, said method comprising the step of administering a depot containing the pharmaceutical composition to said subject once, said subject, wherein an amount of at least one therapeutic agent or a pharmaceutically acceptable salt thereof in an amount of 10 to 500 ng, 500 to 1,500 ng, or 1,000 to 2,000 ng is eluted from the depot daily from the 7th day after administration of the depot until the 90th day. Claim 20 A pharmaceutical composition according to claim 17, wherein at least one therapeutic agent or a pharmaceutically acceptable salt thereof in an amount of 750 to 1,250 ng is released from the depot daily from day 7 to day 90 after administration of the depot. Claim 21 A pharmaceutical composition according to claim 16, wherein a certain amount of at least one therapeutic agent or a pharmaceutically acceptable salt thereof is released from the depot at a rate of 1% per day of at least one therapeutic agent or a pharmaceutically acceptable salt thereof in the initial depot for 1 week to 2 months after administration of the depot. Claim 22 A pharmaceutical composition according to claim 17, wherein a certain amount of at least one therapeutic agent or a pharmaceutically acceptable salt thereof is released from the depot daily from day 7 to day 60 after administration of the depot. Claim 23 In paragraph 16, a pharmaceutical composition in which administration is by injection into the eye of the subject. Claim 24 In paragraph 16, a pharmaceutical composition in the form of an intravitreal implant. Claim 25 A pharmaceutical composition according to claim 17, wherein an amount of at least one therapeutic agent or a pharmaceutically acceptable salt thereof is released from the depot daily from day 7 to day 90 after administration of the depot. Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 delete Claim 33 delete Claim 34 delete Claim 35 delete Claim 36 delete Claim 37 delete Claim 38 delete Claim 39 delete Claim 40 delete Claim 41 delete Claim 42 delete Claim 43 delete Claim 44 delete Claim 45 delete Claim 46 delete Claim 47 delete Claim 48 delete Claim 49 delete Claim 50 delete Claim 51 delete

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