Pharmaceutical composition for treating eye diseases or disorders

Abstract

To provide pharmaceutical compositions for treating ocular diseases or disorders, implants formed from the pharmaceutical compositions, methods of forming the implants, and methods of treating ocular diseases and disorders, which are designed for eliminating the need for daily drops and multiple steroidal injections.SOLUTION: Provided herein are pharmaceutical compositions, intravitreal implants and particle suspensions comprising a polymer matrix and at least one therapeutic agent that is released in a substantially linear manner for a particular duration.SELECTED DRAWING: None

Description

Technical Field

[0001] (Related Application) This application claims the benefit of priority based on U.S. Provisional Patent Application No. 62 / 814,198, filed on March 5, 2019, and the entire disclosure of which is hereby incorporated by reference herein.

[0002] (Technical Field) The present invention relates to pharmaceutical compositions, implants formed from the pharmaceutical compositions, methods of forming the implants, and methods of treating eye diseases and disorders.

Background Art

[0003] Ocular inflammatory diseases or disorders such as macular edema, retinal vein occlusion, and uveitis can cause blurred vision, double vision, floaters, eye pain, vision loss, and in severe cases, blindness.

[0004] Corticosteroids such as dexamethasone (Ozurdex®) or triamcinolone acetonide (TRIESENCE®) can be injected by intravitreal injection (IVT) for treatment. Repeated bolus injections of corticosteroids such as TRIESENCE® are associated with cataract formation, increased intraocular pressure, floaters, endophthalmitis, vision loss, and retinal damage. Patients may be administered a large number of injections during the treatment process. This regimen is burdensome to patients and healthcare providers.

[0005] Vitreous implants that deliver sustained concentrations of therapeutic agents over a period of time have been developed. These implants are injected or surgically implanted into the vitreous humor of the eye to release the therapeutic agent into the posterior segment. For example, OZURDEX® is a vitreous implant used to treat various eye diseases or disorders by releasing dexamethasone over a sustained period. However, sufficient levels of the therapeutic agent are released for only about 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, extraocular myofibrosis, vitreous detachment, reaction to the delivery medium, increased intraocular pressure, and cataract development. As an alternative, a fluocinolone acetonide-containing vitreous implant (ILUVIEN®) that releases fluocinolone acetonide over a period of about three years has also been developed. Corticosteroid exposure is often too long for many patients, which can lead to an increased risk of corticosteroid-related side effects, including cataract formation and increased intraocular pressure.

[0006] Various biodegradable polymers are used to manufacture such vitreous implants. Specific examples of such polymers include lactic acid-glycolic acid copolymers (PLGA) and polylactic acid (PLA), as well as various analogs or derivatives. For example, Patent Document 1 (incorporated herein by reference) discloses a pharmaceutical composition for treating an eye disease or disorder comprising 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 polyesteramide (PEA) polymers for use in biodegradable implants have been described above. PEA is amino acid-based and contains several peptide bonds. A synthetic method for preparing PEA is described, for example, in Patent Document 2, which is incorporated herein by reference in its entirety. The general structural formula of polyesteramides, particularly polyesteramide copolymers, is described in Patent Document 3, which is incorporated herein by reference in its entirety, and is shown in the following chemical structural formula (I). [ka] (I) (However, m+p is in the range of 0.9 to 0.1, and a+b is in the range of 0.1 to 0.9, m+p+a+b=1 (where either m or p may be zero), n is in the range of 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, and the m units and / or p units, as well as the a and b units, are randomly distributed. R 1 (C2-C 20 ) Selected from alkyl groups, R in m or p, which are single skeletal units 3 and R 4is, independently, hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C 10 )aryl, (C1-C6alkyl, -(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, R 5 is, independently, (C2-C 20 )alkyl, (C2-C 20 )alkenylene, R 6 is the bicyclic fragment of 1,4:3,6-dianhydrohexitol of the following structural formula (II),

Chemical formula

[0007] In the medical field related to treatments, for example, pharmaceutical compositions formulated in a delivery system, there is a great need for vitreous implants having an improved safety and efficacy profile that releases a therapeutic agent directly to the posterior eye substantially linearly over a period of at least 3 months. Such pharmaceutical compositions may improve both the compliance and the adverse event profile of current vitreous implants.

[0008] The citation of documents herein should not be construed as an admission that the documents are available as prior art to the present invention.​​​​​​​​​​​​​ [Patent Document 2] U.S. Patent Application Publication No. 2008 / 0299174 [Patent Document 3] U.S. Patent No. 9789189 [Overview of the project] [Problems that the invention aims to solve]

[0010] The present invention broadly relates to a pharmaceutical composition for treating a disease or disorder of the eye, comprising a biodegradable polymer matrix containing a mixture of a first polymer and a second polymer, wherein (1) the first polymer is a biodegradable polyesteramide polymer, and (2) the second polymer is (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), comprising the biodegradable polymer matrix. At least one therapeutic agent, or an analog or derivative thereof, a pharmaceutically acceptable salt, zwitterion, polymorph, or solvate thereof, is uniformly dispersed within the polymer matrix. In certain embodiments, the pharmaceutical composition of the present invention is formulated for intravitreous administration to the eye of a target.

[0011] For example, current treatments for various eye diseases or disorders, such as elevated intraocular pressure or inflammation, require patients to instill eye drops into their eyes daily or receive multiple steroid injections into their eyes. The pharmaceutical compositions of the present invention are designed to eliminate the need for daily eye drops and multiple steroid injections by releasing a substantially linearly therapeutically effective amount of at least one therapeutic agent.

[0012] In certain embodiments, the pharmaceutical compositions of the present invention are formulated to substantially linearly release a therapeutically effective amount of at least one therapeutic agent over approximately one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve months, or longer.

[0013] In some embodiments, a pharmaceutical composition for treating eye diseases or disorders, (a) A biodegradable polymer matrix comprising a mixture of a first polymer and a second polymer, (1) The first polymer is a biodegradable polyesteramide polymer (PEA), (2) The 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. Biodegradable polymer matrix, (b) At least one therapeutic agent, or an analog, derivative, pharmaceutically acceptable salt, zwitterion, polymorph, or solvate thereof, uniformly dispersed within a polymer matrix, A pharmaceutical composition containing the above is provided herein.

[0014] In some embodiments, the pharmaceutical compositions provided herein are formulated for intravitreous administration to the eye of interest, and the pharmaceutical compositions are formulated to release at least one therapeutic agent substantially linearly from the pharmaceutical composition over a period of about one to about six months.

[0015] Numerous therapeutic agents have applications in the pharmaceutical compositions of the present invention, including (a) those that modulate or particularly inhibit 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)-(c).

[0016] In some embodiments, therapeutic agents include those that modulate or particularly inhibit the activity of kinases such as IKK kinase.

[0017] Certain therapeutic agents, as well as their analogs or derivatives, solvates, pharmaceutically acceptable salts, polymorphs, and zwitterions, include, but are not limited to, the following: Corticosteroids, e.g., dexamethasone, fluocinolone acetonide, budesonide, beclomethasone, beclomethasone (e.g., as mono or dipropionate), flunisolide, fluticasone (e.g., as propionic acid or furoate), ciclesonide, mometasone (e.g., as furoate), mometasone desonide, lofreponide, hydrocortisone, prednisone, prednisolone, methylpredni Zolone, Naflocort, Deflazacort, Halopredone acetate, Fluocinolone acetonide, Fluocinonide, Crocoltolone, Chipredan, Prednicarbate, Alclomethasone dipropionate, Halomethasone, Rimexolone, Deprodone propionate, Triamcinolone, Betamethasone, Fludrocortisone, Deoxycorticosterone, Lofreponide, Ethiprednol dicloacetate, etc., or any combination thereof. Prostaglandins, for example, latanoprost, bimatoprost, travoprost, tafluprost, and 3-hydroxy-2,2-bis(hydroxymethyl)propyl7-((1r,2r,3r,5s)-2-((r)-3-(benzo[b]thiophen-2-yl)-3-hydroxypropyl)-3,5-dihydroxycyclopentyl)heptanoate having the following structural formula, [ka] Cloprostenol isopropyl ester, 13,14-dihydrocloprostenol isopropyl ester, latanoprostenbunod, unoprostone, PGF 1α Isopropyl ester, PGF 2α Isopropyl ester, PGF 3α Isopropyl ester, fluprostenol, or any combination thereof Rho kinase (ROCK) inhibitors, such as netalusdil or lipasudil or pharmaceutically acceptable salts thereof, JAK kinase inhibitors, such as ruxolitinib ("JAKAFI" and "JAKAVI") for JAK1 / JAK2, tofacitinib ("XELJANZ" and "JAKVINUS") for JAK3, oclacitinib ("APOQUEL") for JAK1, and baricitinib ("OLUMIANT") for JAK1 / JAK2, and Receptor tyrosine kinase inhibitors, such as gefitinib, lapatinib, erlotinib, sunitinib, sorafenib, regorafenib, afatinib, vandetanib, semaxanib, cediranib, neratinib, axitinib, restaurtinib, tivozanib, or any combination thereof.

[0018] In some embodiments, the therapeutic agent comprises dukeprost or tiaprost.

[0019] In some embodiments, the ROCK inhibitor of the therapeutic agent comprises 3-amino-N-(1-oxo-1,2-dihydroisoquinoline-6-yl)-2-(thiophen-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 a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, therapeutic agents, cyclopropylamide JAK inhibitors, include CAS#2246332-69-2 and its (R,R) isomers 2246332-34-1, CAS#2246331-96-2, CAS#2246331-95-1, CAS#2246331-94-0, and CAS#2246331-82-6.

[0021] In some embodiments, the therapeutic agent comprises a prodrug of the therapeutic agent described above.

[0022] In the pharmaceutical compositions of the present invention, the amount of polymer 1 to polymer 2, and the ratio of the amounts of components used in polymer 2 when polymer 2 is a combination of multiple polymers, are very important for designing a pharmaceutical composition having desired properties with respect to the amount of at least one therapeutic agent delivered substantially linearly and the duration over which such delivery occurs substantially linearly. In certain embodiments of the pharmaceutical compositions of the present invention, the polymer matrix is 60% by weight of biodegradable polyesteramide polymer, 20% by weight of biodegradable poly(D,L-lactide) polymer, and 20% by weight of biodegradable poly(D,L-lactide-co-glycolide) polymer, Includes.

[0023] Furthermore, specific embodiments of the pharmaceutical composition of the present invention are A polymer matrix comprising approximately 59% by weight, Approximately 60% by weight of the polymer matrix is ​​a biodegradable polyesteramide polymer. Approximately 20% by weight of the polymer matrix is ​​a biodegradable poly(D,L-lactide) polymer, and Approximately 20% by weight of the polymer matrix is ​​biodegradable poly(D,L-lactide-co-glycolide) polymer. polymer matrix and Approximately 41% by weight of at least one therapeutic agent, Includes.

[0024] One of the specific therapeutic agents that has applications in the pharmaceutical compositions of the present invention is dexamethasone.

[0025] The pharmaceutical composition of the present invention can be formulated for intravitreal administration to the eye of a subject in which the release of at least one therapeutic agent is substantially linear, such that about 1% of the total of at least one therapeutic agent is released per day over a period of about three months.

[0026] Numerous methods are available to those skilled in the art for forming the polymer matrix of the pharmaceutical composition of the present invention. In certain methods, the first polymer and the second polymer are mechanically blended. Other methods will be described later.

[0027] Similarly, the amount of at least one therapeutic agent to be filled into the pharmaceutical composition of the present invention may vary depending on the desired amount of therapeutic agent to be delivered substantially linearly and the duration over which the delivery is substantially linear. In certain embodiments, the pharmaceutical composition of the present invention comprises (a) about 51% by weight of a polymer matrix and (b) about 49% by weight of at least one therapeutic agent.

[0028] The biodegradable (D,L-lactide) polymer used in the pharmaceutical composition of the present invention may be an acid-end-capped biodegradable poly(D,L-lactide) homopolymer or an ester-end-capped poly(D,L-lactide) homopolymer.

[0029] 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-terminated biodegradable poly(D,L-lactide-co-glycolide).

[0030] Various polyesteramides (PEAs) have applications in the pharmaceutical compositions of the present invention. Generally, these PEAs include the following chemical structural formula (I). [ka] (I) (However, m+p is in the range of 0.9 to 0.1, and a+b is in the range of 0.1 to 0.9, m+p+a+b=1 (where either m or p may be zero), n is in the range of 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, and the m units and / or p units, as well as the a and b units, are randomly distributed. R 1 (C2-C 20 ) Selected from alkyl groups, R in m or p, which are single skeletal units 3 and R 4 These are, independently, hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, and (C6-C 10 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, R 5 (C2-C 20 )alkyl, (C2-C 20 ) Selected from alkenylenes, R 6 It is a bicyclic fragment of 1,4:3,6-dianehydrohexitol with the following structural formula (II): [ka] R 7 (C6-C 10 ) Selected from the group consisting of aryl, (C1-C6)alkyl, or protecting groups, R 8 (It is -(CH2)4-.)

[0031] The specific PEA having applications in the pharmaceutical composition of the present invention has the following chemical structure formula (III). [ka] (III)

[0032] Other examples of PEA having the applications of the present invention are disclosed in U.S. Patent No. 9,873,765 and U.S. Patent No. 9,789,189, both of which are incorporated herein by reference.

[0033] Furthermore, vitreous implants for treating eye diseases or disorders comprising the pharmaceutical composition of the present invention are also provided. Numerous methods are available for manufacturing the vitreous implants of the present invention. One particular method having applications in the present invention is the production of PRINT® technology particles. The use of PRINT® technology makes it possible to mass-produce vitreous implants with highly reproducible, consistent, and predictable customized therapeutic agent release profiles for each implant, which is not possible with other technologies such as extrusion molding. PRINT® technology is used in the production of the vitreous implants of the present invention and in the production of particles used in the particle suspensions of the present invention, and is disclosed in International Publication Nos. 2007 / 021762, International Publication Nos. 2007 / 024323, and International Publication Nos. 2007 / 030698, which are incorporated herein by reference in their entirety. The mold bore used in the manufacture of the vitreous implant of the present invention may vary from the stated dimensions by ±50 μm, ±40 μm, ±30 μm, ±20 μm, ±10 μm, or ±5 μm in various embodiments.

[0034] PRINT® technology enables the creation of vitreous implants with therapeutic agent release profiles that exhibit statistically significant variability. As a result, the release profiles of at least one therapeutic agent exemplified in the implant embodiments are within confidence intervals and exhibit coefficients of variation that do not affect the substantially linear manner in which the therapeutic agent is released. The ability to manufacture vitreous implants of the present invention that exhibit a high degree of consistency in therapeutic agent filling and release represents a superior advantage over state-of-the-art technology.

[0035] In a particular embodiment of the present invention, A pharmaceutical composition, (a) A polymer matrix comprising approximately 59% by weight, (i) Approximately 60% by weight of a biodegradable polyesteramide polymer having the following structure: [ka] (I) (However, m+p is in the range of 0.9 to 0.1, and a+b is in the range of 0.1 to 0.9, m+p+a+b=1 (where either m or p may be zero), n is in the range of 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, and the m units and / or p units, as well as the a and b units, are randomly distributed. R 1 (C2-C 20 ) Selected from alkyl groups, R in m or p, which are single skeletal units 3 and R 4 These are, independently, hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, and (C6-C 10 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, R 5 (C2-C 20 )alkyl, (C2-C 20 ) Selected from alkenylenes, R 6 It is a bicyclic fragment of 1,4:3,6-dianehydrohexitol with the following structural formula (II): [ka] R 7 (C6-C 10 ) Selected from the group consisting of aryl, (C1-C6)alkyl, or protecting groups, R 8(It is -(CH2)4-.) (ii) Approximately 20% by weight of a biodegradable poly(D,L-lactide) homopolymer, and (iii) Approximately 20% by weight of biodegradable poly(D,L-lactide-co-glycolide) copolymer, Includes, (i), (ii), and (iii) are blended together to form the polymer matrix. polymer matrix and (b) Approximately 41% by weight of dexamethasone uniformly dispersed within the polymer matrix, Includes, The aforementioned pharmaceutical composition is formulated for intravitreous administration to the target eye, and Dexamethasone is released substantially linearly so that approximately 1% of the total amount of at least one of the therapeutic agents contained in the formulation is released per day over a period of approximately three months. Includes pharmaceutical compositions, A vitreous implant will be provided.

[0036] Furthermore, a method is also provided for treating an eye disease or disorder in a person requiring treatment, comprising administering at least one vitreous implant of the present invention into the vitreous fluid of a human eye.

[0037] The eye diseases or disorders that can be treated with the vitreous implant of the present invention include, but are not limited to, intraocular pressure, inflammatory eye diseases or disorders, glaucoma, neurodegenerative diseases or disorders, or combinations thereof.

[0038] Examples of ocular inflammatory diseases or disorders that can be treated with the pharmaceutical compositions and vitreous implants of the present invention include, but are not limited to, uveitis, corneal ulcers, endophthalmitis, autoimmune diseases of the cornea or ocular surface, ocular symptoms 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. [Brief explanation of the drawing]

[0039] To further understand the above-described and other embodiments of the present invention, please refer to the following drawings and detailed description.

[0040] [Figure 1] A graph plotting the average daily release of dexamethasone from various pharmaceutical compositions of the present invention (Samples 8-15). [Figure 2] Graph showing the cumulative percentage of dexamethasone released from vitreous implant 7. [Figure 3] Graph showing the average daily release rate of dexamethasone from vitreous implant 7. [Figure 4] Graph showing the cumulative percentage of therapeutic agent released over time from sample 16. [Figure 5] Graph showing the cumulative percentage of therapeutic agent released over time from sample 17. [Modes for carrying out the invention]

[0041] The present invention provides novel pharmaceutical compositions and therapeutic agent delivery systems, specifically vitreous implants, and methods for manufacturing and using such systems for substantially linear sustained release of at least one therapeutic agent into the eye. A novel system of biodegradable polymer matrices was prepared by mixing biodegradable poly(D,L-lactide) polymer, biodegradable poly(D,L-lactide-co-glycolide) polymer, and polyesteramide. The pharmaceutical compositions of the present invention extend to biodegradable therapeutic agent delivery systems comprising a polymer matrix and a therapeutic agent contained within the polymer matrix. Using PRINT® technology, a vitreous implant was developed from the pharmaceutical compositions of the present invention to deliver at least one therapeutic agent at a high sustained concentration substantially linearly over a period of up to 5 months in vitro. The present invention extends to biodegradable vitreous implants having high uniformity, adjustable and reproducible size, shape, fill volume, composition, and fill distribution, and a desired therapeutic agent sustained-release profile, which can be used to treat various eye diseases or disorders.

[0042] The present invention is based on the unexpectedly surprising discovery that by creating a polymer matrix comprising a PEA polymer, a PLGA polymer and / or a PLA polymer or a combination thereof, and at least one therapeutic agent contained within the polymer matrix, at least one therapeutic agent is released substantially linearly over a period of at least three, four, five, six months, or longer. While not obligatory, if the amount of therapeutic agent released, or the substantially linear manner in which the therapeutic agent is released from the pharmaceutical composition of the present invention over the period described herein, we do not wish to be bound by any description, but it is presumed that novel polymer matrices can be produced by mixing two or more different types of polymers, and that different degrees of phase separation blends can be obtained depending on the thermodynamic properties and miscibility of the polymers chosen to form the polymer matrix. The hydrophobicity of the polymer matrix can be adjusted by changing the ratio of polymers used in the polymer matrix, i.e., the ratio between the first polymer and the second polymer (and adjusting the amount of components of the second polymer). Furthermore, the pharmaceutical composition having the polymer matrix of the claims released at least one therapeutic agent substantially linearly. The control of hydrophobicity and the amount of therapeutic agent contained within the polymer matrix allows for the control of the amount of therapeutic agent released substantially linearly and the duration over which such substantially linear release occurs. Thus, the present invention makes it possible to design pharmaceutical compositions to release therapeutic agents substantially linearly over a specific period of time.

[0043] More broadly, the present invention extends to pharmaceutical compositions for treating eye 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 polyesteramide, 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 uniformly dispersed within the polymer matrix, and the pharmaceutical compositions are formulated to release at least one therapeutic agent substantially linearly from the pharmaceutical composition over a period of at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or longer. Optionally, the pharmaceutical compositions may be formulated as vitreous implants for intravitreal administration to the eye of interest. The PRINT® technology described and explained below can be used to manufacture such vitreous implants of the present invention.

[0044] Numerous terms and expressions are used throughout this specification and the claims, and these are defined below.

[0045] Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention pertains. Any methods and materials similar or equivalent to those described herein may be used in carrying out or testing the present invention.

[0046] Furthermore, it should be noted that the reagents described herein are merely examples, and their equivalents are also known in the art.

[0047] In this specification, unless otherwise specified, the term 'alkyl' refers to the number of carbon atoms indicated (e.g., C) either alone or as part of another substituent. 1-6(C) means a linear or branched hydrocarbon having 1 to 6 carbon atoms, and includes linear, branched, or cyclic substituents. Examples, but not limited to, include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. Most preferred is (C) 1-6 Alkyl compounds, particularly ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl, and cyclopropylmethyl.

[0048] In this specification, 'alkenyl' refers to an unsaturated aliphatic hydrocarbon moety containing linear and branched groups. An alkenyl moety always contains at least one alkene. 'Alkenyl' can be exemplified by groups such as ethenyl, n-propenyl, isopropenyl, and n-butenyl. The alkenyl group may be substituted or unsubstituted. Two or more substituents may be present. If substituted, the substituents are preferably alkyl, halogen, or alkoxy. The substituent itself may also be substituted. Substituents can be located on the alkene itself and on adjacent constituent atoms or on the alkenyl moety.

[0049] In this specification, 'alkynyl' refers to an unsaturated aliphatic hydrocarbon moety containing linear and branched groups. An alkynyl moety always contains at least one alkyne. 'Alkynyl' can be exemplified by groups such as ethynyl, propynyl, and n-butynyl. The alkynyl group may be substituted or unsubstituted. Two or more substituents may be present. If substituted, the substituents are preferably alkyl, amino, cyano, halogen, alkoxyl, or hydroxyl. The substituent itself may also be substituted. Substituents can be located on the alkyne itself and on adjacent constituent atoms or on the alkynyl moety.

[0050] In this specification, unless otherwise specified, 'aryl', alone or in combination with other terms, means a carbocyclic aromatic system comprising one or more rings (typically one, two, or three rings) which may be linked together in a pendant-like manner, such as biphenyl, or fused together, such as naphthalene. Examples of aryl groups include phenyl, anthrasyl, and naphthyl. Preferred examples are phenyl and naphthyl, with phenyl being the most preferred.

[0051] In this specification, the number of carbon atoms in a substituent is defined as 'C x-y 』 or 『C x -C y This can be shown by the prefix '', where x is the minimum number of carbon atoms in the substituent and y is the maximum number.

[0052] In this specification, “protecting group” refers to the protecting group moety described, for example, in “Protective Groups in Organic Synthesis” (T. Green and P. Wuts, 3rd edition, John Wiley and Sons, 1999). For example, a carboxylic acid group can be protected as an ester, for example, as an alkyl ester (e.g., methyl ester, t-butyl ester), a haloalkyl ester (e.g., haloalkyl ester), a trisalkylsilylalkyl ester, or an arylalkyl ester (e.g., benzyl ester, nitrobenzyl ester), or as an amide, for example, as a methylamide.

[0053] The term "treatment" refers to the application of one or more specific procedures used to improve a disease. In some embodiments, a specific procedure is the administration of one or more therapeutic agents. "Treatment" of an individual (e.g., a mammal such as a human) or cells is any type of intervention used in an attempt to alter the natural course of the individual or cells. Treatment includes, but is not limited to, the administration of pharmaceutical compositions and may be performed prophylactically or after the onset of a pathological event or contact with a pathogen. Treatment includes any desired effect on the symptoms and 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. Also included is "prophylactic" treatment, which may aim to reduce the rate of progression of the disease or condition being treated, delay the onset of the disease or condition, or reduce the severity at the time of onset. "Effective dose" or "therapeutic effective dose" refers to the amount of therapeutic agent effective to produce a desired therapeutic effect, administered to a subject that is a mammal, either as a single dose or as part of a series of doses.

[0054] In this specification, “pharmaceutically acceptable salt” refers to a derivative of the compound disclosed herein in which the parent compound is modified by converting an existing acid or base moiety to its salt form. A list of suitable salts is provided herein by reference in “Remington's Pharmaceutical Sciences, 17th ed.” (Mack Publishing Company, Easton, Pennsylvania, 1985, p. 1418) and the Journal of Pharmaceutical Science, vol. 66, no. 2 (1977).

[0055] In this specification, unless the context clearly indicates otherwise, a singular reference includes plural references.

[0056] In this specification, the term "including" means that the composition and method described comprises the elements described and does not exclude other elements.

[0057] "Approximately" and "about" are interchangeable and thereby limit a number, parameter, or property to a certain percentage (e.g., ±5%), which will be understood by those skilled in the art as appropriate in the scientific context in which the terms are used. Furthermore, all figures, values, and expressions referring to quantities used herein are subject to the various measurement uncertainties encountered in the art. Thus, unless otherwise noted, all values ​​expressed may be understood as being modified by the term "approximately."

[0058] Where a numerical range is disclosed herein, such ranges are continuous and include both the minimum and maximum values ​​of the range, as well as all values ​​between the minimum and maximum values. Furthermore, where a range refers to an integer, it includes all integers between the minimum and maximum values ​​of that range. Where multiple ranges are provided to describe a certain feature or property, these ranges may be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include all subranges that are contained within them. For example, a range described as "1 to 10" should be understood to include all subranges between the minimum value of 1 and the maximum value of 10.

[0059] In this specification, "therapeutic agent" refers to a compound or substance within a pharmaceutical composition that is biologically active and produces the effect of the pharmaceutical composition.

[0060] In this specification, the term "pharmaceutical composition" refers to a composition that includes therapeutic agents, excipients, carriers, etc. Generally, a pharmaceutical composition, rather than a therapeutic agent alone, is administered to a patient.

[0061] In this specification, the terms "disease or disorder of the eye" or "disease or disorder of the eye" may be used interchangeably and are not limited to, but include, glaucoma, allergies, inflammatory eye diseases or disorders, intraocular hypertension, eye cancer, neurodegenerative diseases or disorders of the eye (such as diabetic macular edema (DME) and wet or dry age-related macular degeneration (AMD)), uveitis, diabetic retinopathy, and dry eye.

[0062] In this specification, "kinase" refers to a type of enzyme that transfers a phosphate group from a high-energy donor such as ATP to a specific target molecule (substrate). This process is called phosphorylation.

[0063] In this specification, “receptor tyrosine kinase (RTK)” refers to receptor proteins with intracellular kinase activity selected from the RTK family of proteins described in the paper by Schlessinger (Cell, Vol. 103, pp. 211-225, 2000). “Receptor tyrosine kinase dimer” refers to a complex within the cell surface membrane containing two receptor tyrosine kinase proteins. In some embodiments, a receptor tyrosine kinase dimer may contain two covalently linked receptor tyrosine kinase proteins. Of particular note 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., Schlessinger, Cell, Vol. 103, pp. 211-225, 2000). Well-known families in this class include 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). The class of receptor tyrosine kinases is so named because, upon activation by dimerization, the intracellular domain of RTKs acquires tyrosine kinase activity, which in turn can activate various signaling pathways. As a result, RTKs serve as relay points in signaling pathways, becoming crucial components of intercellular communication and the signaling pathways that mediate their functions. They play vital roles in numerous processes, including regulating cell proliferation and differentiation, controlling cell growth and metabolism, and promoting cell survival and apoptosis. Due to this property, many receptor tyrosine kinases are used as targets for drug development, and as several promising clinical-phase therapeutics, such as IRESSA® (gefitinib) and TARCEVA® (erlotinib), which are designed to inhibit RTK activity (e.g., Taxler, Expert Opin. Ther. Targets, Vol. 7, pp. 215-234, 2003).The availability of expedient methods for measuring pathway activation can lead to a deeper understanding of the mechanisms of therapeutic agents and improve therapeutic agent selection and disease management (Mirshafiey et al., Innov. Clin. Neursci. Vol. 11, Nos. 7-8, pp. 23-26, 2014).

[0064] In this specification, Janus kinase (JAK) refers to cytoplasmic tyrosine kinases that transmit cytokine signals from membrane receptors to STAT transcription factors. Four JAK family members are known: JAK1, JAK2, JAK3, and TYK2. When cytokines bind to their receptors, JAK family members transphosphorylate and / or autophosphorylate each other, subsequently phosphorylating STAT, which then translocates to the nucleus to regulate transcription. JAK-STAT intracellular signaling is suitable for interferons, most interleukins, and various cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL (Vainchenker W. et al., 2008).

[0065] The JAK family is involved in intracellular signaling from over 70 different cytokines. Cytokines bind to their cell surface receptors, triggering receptor dimerization and subsequent activation / phosphorylation of JAK tyrosine kinases. JAKs either constitutively associate with receptors or are recruited upon cytokine binding. Subsequently, specific tyrosine residues on the receptor are phosphorylated by activated JAK, acting as a docking site for the STAT protein. STAT, phosphorylated and dimerized by JAK, then translocates to the nucleus, where it binds to specific DNA factors and activates gene transcription. JAK1, along with all JAK isoforms, transmits signals in a cytokine-dependent manner.

[0066] JAKs are essential for several physiological functions, and these essential JAK functions have been demonstrated using genetically modified mouse models lacking specific JAKs. - / -The mice died during the perinatal period, while Jak2 - / - The mice exhibit erythropoiesis and die around E12. Jak3 - / - The mice are viable but exhibit the SCID phenotype, characterized by T cell, B cell, and NK cell deficiencies. TYK2 - / - The mice exhibit characteristics of hyper-IgE syndrome. This phenotype indicates an essential and non-superficial role of JAK activity in vivo (K. Ghoreschi, A. Laurence, JJ O'Shea, Immunol. Rev., vol. 228, p. 273, 2009).

[0067] Furthermore, mutations in the JAK enzyme have been linked to human diseases. Inactivating mutations in JAK3 (or the common γ-chain cytokine receptor) cause severe SCID phenotypes (JJ O'Shea, M. Pesu, DC Borie, PS Changelian, Nat. Rev. Drug Discov., Vol. 3, p. 555, 2004). TYK2 deletion leads to hyperIgG syndrome and increased risk of infection (Y. Minegishi et al., Immunity, Vol. 25, p. 745, 2006). No inactivating mutations have been reported for JAK1 and JAK2, consistent with mouse data showing that JAK1 and JAK2-deficient mice are unsustainable. However, several mutations resulting in constitutively active JAK2 have been identified, and these lead to myeloproliferative disorders, confirming the central role of JAK2 in hematopoiesis (O. bdel-Wahab, Curr. Opin. Hematol., Vol. 18, p. 117, 2011). JAK2 is the only member of the JAK family involved in the signaling of the critically important hematopoietic cytokines IL-3, GMCSF, EPO, and TPO.

[0068] Furthermore, JAKs play multiple roles in cytokine signaling granules in both immune and non-immune cells. Autoimmunity is caused by abnormal adaptive immune responses to autoantigens, and JAK-STAT (signal transducer and activator of transcription) signaling is known to play a crucial role in this process. Therefore, JAK inhibitors may hold considerable potential for the development of therapeutic agents to treat autoimmunity. JAK3 is a particularly attractive target because, unlike other JAKs, its expression is limited to the immune system.

[0069] A large amount of literature has accumulated linking the JAK / STAT pathway to various diseases and disorders, including hyperproliferative disorders, cancer (such as leukemia and lymphoma), immune and inflammatory disorders (such as 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 to modulate, and especially inhibit, the activity of these pathways.

[0070] In this specification, "Rho-related protein kinase" or "Rho kinase" (ROCK) is a major intracellular regulator of cytoskeletal dynamics and cell motility. Rho kinase regulates numerous downstream targets of Rho A, including, for example, myosin light chain, myosin light chain phosphatase binding subunit, and LIM kinase 2, via phosphorylation. These substrates regulate the organization and contractility of actin fibers. In smooth muscle cells, Rho kinase regulates calcium sensitization and smooth muscle contraction. Inhibition of Rho kinase blocks 5-HT and phenylephrine agonist-induced muscle contraction. When introduced into non-smooth muscle cells, Rho kinase induces stress fiber formation and is required for cell transformation regulated by Rho A. Rho kinase is involved in various cellular processes, including, but is not limited to, cell adhesion, cell motility and migration, growth regulation, cell contraction, and cytokines. Furthermore, Rho kinase is involved in the activation of the Na / H exchange transport system, stress fiber formation, adusin activation, and physiological processes (vasoconstriction, bronchial smooth muscle contraction, proliferation of vascular smooth muscle and endothelial cells, platelet aggregation, etc.).

[0071] Inhibition of Rho kinase activity in animal models has demonstrated that Rho kinase inhibition offers numerous benefits for the treatment of human diseases. These include models of cardiovascular diseases (hypertension, atherosclerosis, restenosis, cardiac hypertrophy, intraocular pressure, cerebral ischemia, cerebral vasospasm, penile erectile dysfunction, etc.), models of central nervous system disorders (neurodegeneration and spinal cord injury, etc.), and models of neoplasms. Inhibition of Rho kinase activity has been shown to inhibit tumor cell growth and metastasis, angiogenesis, arterial thromboembolism (platelet aggregation and leukocyte aggregation, etc.), asthma, intraocular pressure control, and bone resorption. In patients, inhibition of Rho kinase activity has benefits in controlling cerebral vasospasm and ischemia after subarachnoid hemorrhage, reducing intraocular pressure, increasing aqueous humor outflow due to relaxation of the trabecular meshwork, improving blood flow to the optic nerve, treating glaucoma, reducing intraocular pressure (IOP), and protecting healthy ganglion cells.

[0072] 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 at relatively high levels and broadly, while ROCK2 is preferentially expressed in the heart, blood vessels, and skeletal muscle. Furthermore, these isoforms are expressed in a developmental stage-specific manner in several tissues. ROCK1 is a substrate for caspase-3 cleavage during apoptosis, whereas ROCK2 is not. Smooth muscle-specific basic calponins are phosphorylated only by ROCK2.

[0073] In light of the range of related cellular processes and diseases, compounds that selectively inhibit one Rho kinase or inhibit both ROCK1 and ROCK2 are desirable. Examples of Rho kinase inhibitors include netaludil or its pharmaceutically acceptable salts (e.g., RHOPRESSA®) used to reduce IOP and treat glaucoma, and ripasudil or its pharmaceutically acceptable salts (e.g., GLANATEC®) used to treat glaucoma and intraocular hypertension. In some embodiments, biologically active metabolites of such Rho kinase inhibitors are desirable.

[0074] In this specification, 'prostaglandin' refers to any compound having the following prostanic acid skeleton. [ka] (Prostanic acid skeleton)

[0075] These compounds and their analogues or derivatives have intraocular pressure-lowering activity and, consequently, have applications in the treatment or improvement of eye diseases or disorders.

[0076] Another type of therapeutic agent having applications in the pharmaceutical compositions of the present invention (e.g., vitreous implants) is corticosteroids, and their analogs or derivatives, or their salts or prodrugs. Herein, 'corticosteroids' refers to a class of steroid hormones produced in the adrenal cortex of vertebrates, and also includes synthetic analogs and derivatives of these hormones. Two types of corticosteroids, such as glucocorticoids and mineralocorticoids, are involved in a wide range of physiological processes. Corticosteroids have been reported to have applications in the treatment of eye diseases or disorders, particularly inflammatory eye diseases or disorders.

[0077] In this specification, “therapeutic dose” means the level or amount of therapeutic agent necessary to treat a disease or disorder, i.e., the level or amount of therapeutic agent that produces a therapeutic response or desired effect in the subject to which the therapeutic agent is administered. In certain embodiments of the present invention, the therapeutic dose means the level or amount of therapeutic agent necessary to treat a disease or disorder of the eye.

[0078] The present invention further extends to vitreous implants manufactured from the pharmaceutical compositions of the present invention for placement in or within the posterior part of the human eye. In these embodiments, the substantially linear release of the therapeutic agent from the implant achieves a certain concentration of the therapeutic agent in the vitreous cavity of a patient's eye, treating an eye disease or disorder over a period of time for which the implant is designed to release the therapeutic agent substantially linearly.

[0079] In some embodiments, the implants described herein are designed with size, shape, and composition to provide the greatest possible approximation of the implant to the iris-corneal angle of the human eye. In some embodiments, the implant is manufactured from the pharmaceutical composition of the present invention, which comprises a polymer matrix as described herein.

[0080] In this specification, the term "polymer" is intended to encompass both homopolymers (polymers having only one type of repeating unit) and copolymers (polymers having two or more types of repeating units).

[0081] The terms "biodegradable polymer" or "biodegradable polymer" are interchangeable and refer to polymers that degrade 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.

[0082] In this specification, the term "polymer matrix" refers to a homogeneous mixture of polymers. In other words, the matrix does not include a mixture in which parts differ from other parts in terms of material, density, etc. Therefore, the polymer matrix does not include a composition comprising a core and one or more outer layers, nor a composition comprising a therapeutic agent reservoir and one or more parts surrounding the therapeutic agent reservoir. In the pharmaceutical composition of the present invention, the polymer matrix comprises a first polymer and a second polymer, the first polymer comprising a polyesteramide polymer (PEA), and the second polymer comprising a PLA polymer, a PLGA polymer, or a combination of a PLA polymer and a PLGA polymer, for example, (i) Biodegradable poly(D,L-lactide) polymer, (ii) Biodegradable poly(D,L-lactide-co-glycolide) polymer, or (iii) The combination of (i) and (ii), Includes.

[0083] The polymer used in the polymer matrix of the pharmaceutical composition of the present invention has independent properties associated with the polymer that, when combined, provide the properties necessary to produce a substantially linear release of a therapeutically effective amount of therapeutic agent over a desired period of time.

[0084] These polymers are often affected by enzymatic or hydrolytic instability. To obtain useful water-insoluble polymers, water-soluble polymers may be crosslinked with hydrolyzable or biodegradable unstable crosslinks. The degree of stability can vary widely depending on the selection of monomers, whether homopolymers or copolymers are used, the use of polymer mixtures, and whether the polymers contain terminal acid groups.

[0085] Equally important to controlling the biodegradability of the polymer and, consequently, the sustained-release profile of the pharmaceutical composition of the present invention, is the relative average molecular weight of the polymer matrix employed in the vitreous implant of the present invention. Different molecular weights of the same or different polymer compositions may be included to modulate the release profile of at least one therapeutic agent.

[0086] Numerous polymer matrix formation methods are known to those skilled in the art, and are not limited to these, but include melt mixing, solution mixing, partial block or graft copolymerization, and interpenetrating polymer network (IPN) preparation. "Melt mixing" involves mixing a first polymer and a second polymer together while they are in a molten state. This involves the use of shear force, extensional force, compressive force, ultrasonic energy, electromagnetic energy, thermal energy, or a combination of at least one of the aforementioned force or energy forms, and is performed in an apparatus in which the aforementioned force or energy form is exerted by a short-axis screw, multi-axis screw, meshing co-rotating or heterogeneous screw, non-meshing co-rotating or heterogeneous screw, reciprocating screw, pinned screw, screened screw, pinned barrel, roll, ram, helical rotor, or a combination of at least one of the aforementioned.

[0087] The aforementioned force-assisted melt mixing may be carried out using machines such as single-screw or multi-screw extruders, Bussneeders, Henschel, Helicone, Ross mixers, Banbury, and roll mills, molding machines such as injection molding machines, vacuum molding machines, and blow molding machines, or a combination including at least one of the aforementioned machines.

[0088] Solution mixing may also be used to produce the polymer matrix, in which case the polymer is placed in a solution and mixed. Additional energy, such as shear, compression, or ultrasonic vibration, may be used in the solution mixing to promote homogenization of the quantum dots by the hydrogel. In one embodiment, the hydrogel is suspended in a fluid (e.g., water, alcohol) and introduced into an ultrasonic device along with the quantum dots. The mixture may be a solution mixed by ultrasonic treatment for a time effective in dispersing the quantum dots within the hydrogel. The hydrogel with the quantum dots may then be dried, extruded, and molded as needed. The temperature of the hydrogel may be increased during extrusion to promote crosslinking. The fluid used to swell the hydrogel may be removed by using a vacuum on the extruder during the extrusion process.

[0089] In certain embodiments, the polymer matrix of the present invention is manufactured by mechanical mixing of polymers.

[0090] In several embodiments, the polymer matrix may be formed from polylactic acid, glycolic acid, and any combination of these copolymers with a polyesteramide, resulting in a substantially linear release of at least one therapeutic agent to the eye over time. More importantly, those skilled in the art can design the polymer matrix used in the pharmaceutical composition of the present invention to deliver at least one therapeutic agent substantially linearly over at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, or longer.

[0091] In this specification, "substantially linear" means that the first 90% of the therapeutic agent released from the pharmaceutical composition of the present invention has an R of 0.9 or higher. 2 This means that it should have a value. In one embodiment, 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 should have a value.

[0092] Examples of polymer materials or compositions suitable for use in implants include materials that are miscible and biocompatible with the eye, such as not substantially interfering with the function and physiology of the eye. Such polymer materials may be biodegradable or biodegradable. Examples of useful polymer materials include, but are not limited to, materials derived from and / or containing organic esters and organic ethers that produce physiologically acceptable degradation products upon degradation. Polymer materials derived from and / or containing anhydrides, amides, orthoesters, etc., may also be used in the present invention, either alone or in combination with other monomers. The polymer materials may be addition polymers or condensation polymers. The polymer materials may be crosslinked or uncrosslinked. In some embodiments, in addition to carbon and hydrogen, the polymer may contain at least one of oxygen and nitrogen. Oxygen may be present as oxy (e.g., hydroxy or ether), carbonyl (e.g., non-oxocarbonyl such as carboxylic acid esters), etc. Nitrogen may be present as amide, cyano, or any combination thereof.

[0093] In one embodiment, polymers of hydroxyaliphatic carboxylic acids (either homopolymers or copolymers) and polysaccharides are useful for implants. The polyester may include D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, polycaprolactone, copolymers thereof, and combinations thereof.

[0094] Some properties of polymers or polymer materials for use in embodiments of the present invention include biocompatibility, miscibility with at least one selected therapeutic agent, ease of use of the polymer when creating the therapeutic agent delivery system described herein, desired half-life in a physiological environment, and hydrophilicity.

[0095] Specific examples of polymers that have applications in polymer matrices used in the manufacture of pharmaceutical compositions of the present invention (e.g., vitreous implants) include synthetic aliphatic polyesters, such as polymers of lactic acid and / or glycolic acid, including poly-(D,L-lactide) (PLA), poly-(D-lactide), poly-(L-lactide), polyglycolic acid (PGA), and / or poly(D,L-lactide-co-glycolide) copolymer (PLGA).

[0096] PLGA is synthesized by random ring-opening copolymerization of cyclic dimers of glycolic acid and lactic acid. The consecutive monomer units of glycolic acid or lactic acid are linked by ester bonds.

[0097] PLGA and PLA polymers are known to degrade via skeletal hydrolysis (bulk erosion), with the final degradation products being lactic acid and glycolic acid, which are non-toxic and well-established natural metabolites. Lactic acid and glycolic acid are safely removed by conversion to carbon dioxide and water via the Krebs cycle. Furthermore, the biocompatibility of PLA, PGA, and PLGA polymers has been studied in both animal and human non-ocular and ocular tissues. Findings indicate that these polymers are well-tolerated. In addition, PLA, PGA, and PLGA may contain terminal esters or acids.

[0098] Examples of PLA polymers that can be used in embodiments of the present invention include, but are not limited to, the RESOMER® product line available from Evonik Industries, which includes those designated R207S, R202S, R202H, R203S, R203H, R205S, R208, R206, and R104. Suitable examples of PLA polymers include both acid-terminated and ester-terminated polymers having an inherent viscosity ranging from approximately 0.15 to approximately 2.2 dL / g when measured at 0.1% (w / v) in CHCl3 at 25°C using an Ubbelohde (size 0c) glass capillary viscometer.

[0099] It is possible to synthesize PLA with various molecular weights and various inherent viscosities. For example, in one embodiment, although not limited thereto, PLA such as RESOMER® R208S having an inherent viscosity of approximately 1.8 to approximately 2.2 dL / g can be used. In another embodiment, PLA such as RESOMER® R203S having an inherent viscosity of approximately 0.25 to approximately 0.35 dL / g can be used. In yet another embodiment, PLA such as RESOMER® R205S having an inherent viscosity of approximately 0.55 to approximately 0.75 dL / g can be used.

[0100] Examples of PGA polymers that can be used in embodiments of the present invention include, but are not limited to, the RESOMER® product line available from Evonik Industries, which is designated as G205S. Other examples of suitable PGA polymers include both acid-terminated and ester-terminated polymers. In some embodiments, the inherent viscosity of the PGA polymer is in the range of approximately 1.05 to approximately 1.25 dL / g when measured with an Ubbelohde (size 0c) glass capillary viscometer at 0.1% (w / v) in CHCl3 at 25°C.

[0101] Examples of PLGA polymers that can be used in embodiments of the present invention include, but are not limited to, the RESOMER® product line available from Evonik Industries, which includes RG502, RG502S, RG502H, RG503, RG503H, RG504, RG504H, RG505, RG506, RG653H, RG752H, RG752S, RG753H, RG753S, RG755, RG755S, RG756, RG756S, RG757S, RG750S, RG858, and RG858S. Such PLGA polymers include both acid-terminated and ester-terminated polymers having an inherent viscosity in the range of approximately 0.14 to approximately 1.7 dL / g when measured with an Ubbelohde (size 0c) glass capillary viscometer at 0.1% (w / v) in CHCl3 at 25°C. Exemplary polymers used in various embodiments of the present invention may include, but are not limited to, variations in the molar ratio of D,L-lactide to glycoside from approximately 50:50 to approximately 85:15, but examples include 50:50, 65:35, 75:25, and 85:15.

[0102] Other examples of PLGA polymers that can be used in embodiments of the present invention include, but are not limited to, those produced by Lakeshore Biomaterials, such as DLG 1A, DLG 3A, or DLG 4A. Such DLG polymers include both acid (A)-terminated and ester (E)-terminated polymers having an inherent viscosity in the range of approximately 0.0.5 to approximately 1.0 dL / g when measured at 0.1% (w / v) in CHCI3 at 25°C using an Ubbelohde (size 0c) glass capillary viscometer. Exemplary polymers used in various embodiments of the present invention may include, but are not limited to, variations in the molar ratio of D,L-lactide to glycoside from approximately 1:99 to approximately 99:1, such as 50:50, 65:35, 75:25, and 85:15.

[0103] RESOMERS® (registered trademark) products with "RG" or "DLG" in their product name (such as RG752S) are poly(D,L-lactide-co-glycolide) or PLGA having the following general structural formula (V). [ka] (V)

[0104] It is possible to synthesize DLGs of various molecular weights with various D,L-lactide-glycolide ratios. In one embodiment, DLG such as 1A, having an inherent viscosity of approximately 0.05 to approximately 0.15 dL / g, can be used. In another embodiment, DLG such as 2A, having an inherent viscosity of approximately 0.15 to approximately 0.25 dL / g, can be used.

[0105] Poly(D,L-lactide-co-glycolide) or PLGA copolymers can be synthesized in different ratios of lactide to glycolide (e.g., a lactide:glycolide ratio of 75:25). These copolymers may be ester-terminated PLGA copolymers, indicated by an 'S' at the end of the product name, or acid-terminated PLGA copolymers, indicated by an 'H' at the end of the product name.

[0106] Another biodegradable polymer with applications in the vitreous implant of the present invention is polyesteramide (PEA). PEA is disclosed in U.S. Patent No. 9,896,544 and U.S. Patent No. 9,789,189, both of which are incorporated herein by reference. An example of the general structural formula of PEA is shown in the following chemical structure (I). [ka] (I) (However, m+p is in the range of 0.9 to 0.1, and a+b is in the range of 0.1 to 0.9, m+p+a+b=1 (where either m or p may be zero), n is in the range of 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, and the m units and / or p units, as well as the a and b units, are randomly distributed. R 1 (C2-C 20 ) Selected from alkyl groups, R in m or p, which are single skeletal units 3 and R 4 These are, independently, hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, and (C6-C 10 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, R 5 (C2-C 20 )alkyl, (C2-C 20 ) Selected from alkenylenes, R 6 It is a bicyclic fragment of 1,4:3,6-dianehydrohexitol with the following structural formula (II): [ka] R 7 (C6-C 10 ) Selected from the group consisting of aryl, (C1-C6)alkyl, or protecting groups, R 8 (It is -(CH2)4-.)

[0107] A specific example of a PEA having applications in the present invention has the following chemical structure. [ka] (III)

[0108] The PEA polymer used in the pharmaceutical composition of the present invention (e.g., in vitreous implants) is hydrolyzed rather than enzymatically via bulk erosion and is completely biocompatible. Therefore, its degradation should not cause any substantial interference with the function or physiology of the eye.

[0109] In addition to the ratio of lactide and glycolide present in the implant of the present invention, the ratio of PEA to lactide and glycolide can be changed, thereby altering the biodegradability of the product and allowing those skilled in the art to adjust the polymer degradation time and the duration and amount of the therapeutic agent released. Thus, modifications and customizations of the biodegradable polymer matrix alter the therapeutic agent delivery profile according to the hypothetical theory discussed above, but such discussion is not an obligation provided by the inventors, and they are not bound in any way thereby.

[0110] Furthermore, the present invention also extends to compositions including liquid formulations and delivery systems. Therefore, the compositions of this application may be interpreted as including solutions, suspensions, or other liquid-containing compositions used in ophthalmic therapy.

[0111] Particle suspension As described above, the pharmaceutical composition of the present invention can be formulated into a particle suspension. In this specification, the particle suspension is a particulate pharmaceutical composition formulated as a suspension suspended in a liquid phase containing necessary additives such as a delivery medium.

[0112] Furthermore, the liquid formulation can also be in the form of a particle suspension. The particles are typically smaller than the vitreous implants disclosed herein, and their shape can vary. For example, some embodiments of the present invention use substantially cylindrical particles. The therapeutic agent delivery system of the present invention may include a population of the aforementioned particles having a predetermined particle size distribution. In some embodiments, the suspension may include a population of particles having a desired diameter measurement.

[0113] As discussed above, the polymer blends described herein can be used with particle suspensions. Therefore, in several embodiments, the PLA, PGA, PLGA, and PEA polymers discussed above can be formulated into the polymer matrices described herein, which can be formulated as particle suspensions for ocular administration in combination with at least one therapeutic agent. Additional agents, including but not limited to tocopherols (e.g., α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol), can be used in the particle suspensions described herein.

[0114] In several embodiments, the particles have a size of less than approximately 100 μm in any dimension. In several embodiments, the maximum dimension may be from approximately 10 μm to approximately 100 μm, or from approximately 12.5 μm to approximately 25 μm and up to approximately 50 μm. In another embodiment, the minimum dimension may be from approximately 10 μm to approximately 100 μm, or from approximately 12.5 μm to approximately 25 μm. PRINT® technology is readily available for producing the particles used in the particle suspensions described herein. The pharmaceutical composition of the present invention (for example, a vitreous implant and a particle suspension) contains a therapeutic agent content of 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%.

[0115] A delivery medium can be used for the administration of the particle suspension described herein by intravitreal injection. For example, hyaluronic acid (HA) delivery mediums, such as those described in U.S. Patents 7,582,311 and 7,651,703, can be used to formulate an injectable medium for delivering the particle suspension, which are incorporated herein by reference in their entirety. Hyaluronic acid (HA) is a polyanionic polysaccharide composed of N-acetyl-D-glucosamine and β-glucuronic acid. The unique viscoelasticity of HA, along with its biocompatibility and non-immunogenicity, has led to its use in numerous clinical applications, including synovial fluid replacement in arthritis, use as a surgical adjuvant in eye surgery, and use to promote the healing and regeneration of surgical wounds. Recently, HA has been investigated as a therapeutic agent delivery medium for various routes of administration, including ocular, nasal, pulmonary, parenteral, and topical.

[0116] In several embodiments, the particle suspension is delivered by an aqueous solution. In certain embodiments, the particle suspension of the present invention is delivered by an aqueous solution containing a sorbitol and hyaluronic acid (HA / sorbitol) medium. The aqueous solution contains 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 contains about 1% HA and about 50% sorbitol.

[0117] Manipulation of the therapeutic agent release profile The rate of therapeutic agent release from a vitreous implant or particle suspension (e.g., the pharmaceutical composition of the present invention) depends on several factors, but are not limited to, the surface area of ​​the implant, the therapeutic agent content, the water solubility of the therapeutic agent, and the rate of polymer degradation. As described above, a very important factor in determining the rate of therapeutic agent release is 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 a combination of (a) and (b), in addition to the duration, and also the PGLA:PLA ratio if the second polymer is a combination of PLA and PLGA. Other relevant factors include the lactide stereoisomer composition (i.e., the amount of L-lactide relative to DL-lactide) and molecular weight.

[0118] The versatility of PGA, PLA, PLGA, and PEA allows for the modification of therapeutic agent release in the construction of delivery systems to treat various eye diseases or disorders.

[0119] The versatility of PGA, PLA, PLGA, and PEA polymers, when combined with the manufacturing technology of the present invention, namely PRINT® technology particle manufacturing, allows for the creation of numerous customized, consistent, and highly predictable therapeutic agent release profiles, which were not possible with prior art such as extrusion molding. PRINT® technology is used in the manufacture of vitreous implants and particles used in the particle suspensions of the present invention, and is described in International Publications 2007 / 021762, 2007 / 024323, and 2007 / 030698, all of which are incorporated herein by reference.

[0120] The mold bore used in the manufacture of the vitreous implant of the present invention may vary from the described dimensions by ±50 μm, ±40 μm, ±30 μm, ±20 μm, ±10 μm, or ±5 μm depending on the various embodiments.

[0121] PRINT® technology enables the manufacture of vitreous implants of the present invention that exhibit highly reproducible drug release profiles for each implant. The drug release profiles exhibited by various implants of the present invention are consistent for each implant and show statistically insignificant variability. As a result, the drug release profiles exhibited by embodiments of the vitreous implants of the present invention are within confidence intervals and exhibit coefficients of variation that do not affect drug delivery. The ability to manufacture implants that exhibit a high degree of consistency in drug filling and release is an advantage that surpasses state-of-the-art technology.

[0122] Suitable therapeutic agents, and their analogs, derivatives, pharmaceutically acceptable salts, zwitterions, polymorphs, or solvates, uniformly dispersed within the polymer matrix described herein for use in various embodiments of the present invention may be those listed in the Orange Book published by the U.S. Food and Drug Administration, in particular the Orange Book which lists therapeutic agents approved for the treatment of eye diseases or disorders.

[0123] Examples of therapeutic agents having applications in the pharmaceutical composition of the present invention or in vitreous implants or particle suspensions made from the pharmaceutical composition of the present invention include the receptor tyrosine kinase (RTK) inhibitors discussed above. Specific examples of RTK inhibitors that have the uses described herein include, but are not limited to, gefitinib ("IRESSA®"), lapatinib ("TYKERB®" and "TYVERB®"), erlotinib ("TARCEVA®"), sunitinib malate ("SUTENT®"), sorafenib ("NEXAVAR"), regorafenib ("STIVARGA®"), vandetanib, afatinib ("GILOTRIF®"), axitinib ("INLYTA®"), semaxanib, cediranib ("RECENTIN"), neratinib ("NERLYNX®"), restaurtinib, and tivozanib ("FOTIVDA®").

[0124] Rho kinase inhibitors also have applications as described herein. Specific examples of such Rho kinase inhibitors that have applications in the pharmaceutical compositions of the present invention (e.g., the vitreous implants of the present invention) include, but are not limited to, netalusdil or a pharmaceutically acceptable salt thereof (e.g., RHOPRESSA®) used to reduce IOP and treat glaucoma, and ripasdil or a pharmaceutically acceptable salt thereof (e.g., GLANATEC®) used to treat glaucoma and intraocular hypertension.

[0125] Specific JAK inhibitors that have applications in the pharmaceutical compositions of the present invention (e.g., vitreous implants of the present invention) for the treatment of eye diseases or disorders include, but are not limited to, ruxolitinib for JAK1 / JAK2 ('JAKAFI' and 'JAKAVI'), tofacitinib for JAK3 ('XELJANZ' and 'JAKVINUS'), oclacitinib for JKA1 ('APOQUEL'), and baricitinib for JAK1 / JAK2 ('OLUMIANT').

[0126] Another example of therapeutic agents having applications as described herein is corticosteroids and their analogues and derivatives. Examples, though not limited to these, include dexamethasone, budesonide, beclomethasone, beclomethasone (e.g., as mono or dipropionate), flunisolide, fluticasone (e.g., as propionic acid or furoate), ciclesonide, mometasone (e.g., as furoate), mometasone desonide, lofreponide, hydrocortisone, prednisone, prednisolone, methylprednisolone, naflocort, deflazacort, halopredone acetate, fluocinolone acetonide, fluocinonide, crocoltolone, ticpredan, prednicarbate, alclomethasone dipropionate, halomethasone, rimexolone, deprodone propionate, triamcinolone, betamethasone, fludrocortisone, deoxycorticosterone, lofreponide, and etipredonol dicloacetate.

[0127] Examples of specific corticosteroids or their analogs or derivatives that have applications as described herein include the following: (a) Dexamethasone (has the chemical structure (V) immediately below) [ka] (V) IUPAC name: (8S,9R,10S,llS,13S,14S,16R,17R)-9-fluoro-n,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,ll,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one. (b) Fluocinolone acetonide (having the chemical structure (VI) immediately below) [ka] (VI) IUPAC name: (1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-II-hydroxy-8-(2-hydroxyacetyl)-6,6,9,13-tetramethyl-5,7-dioxapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-diene-16-one.

[0128] The prostaglandins and their analogs or derivatives that have therapeutic use in the pharmaceutical compositions of the present invention (e.g., vitreous 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]thiophen-2-yl)-3-hydroxypropyl)-3,5-dihydroxycyclopentyl)heptanoate (chemical structural formula (II)), cloprostenol isopropyl ester, 13,14-dihydrocloprostenol isopropyl ester, latanoprostenbunod, unoprostone, and PGF. 1α Isopropyl ester, PGF 2α Isopropyl ester, PGF 3α Examples include isopropyl esters, fluprostenol, or any combination thereof. In some embodiments, prostaglandins and their analogs or derivatives having therapeutic use include Dukeprost, thiaprost, or both. In some embodiments, prostaglandins and their analogs or derivatives having therapeutic use include free acids and pharmaceutically acceptable salts thereof of prostaglandins and their analogs or derivatives.

[0129] Other therapeutic agents that have use in the pharmaceutical compositions of the present invention for treating eye diseases or disorders such as glaucoma include, but are not limited to, beta-blockers, miotics, alpha-adrenergic receptor agonists, or carbonic anhydrase inhibitors, and antimetabolites such as 5-fluorouracil or mitomycin C.

[0130] Naturally, the pharmaceutical compositions of the present invention may include one therapeutic agent or a combination of two or more therapeutic agents, examples of which have been discussed above. Furthermore, analogs or derivatives, pharmaceutically acceptable salts, zwitterions, solvates, esters, and polymorphs of therapeutic agents, as discussed herein, have applications in the pharmaceutical compositions of the present invention. Herein, ‘analog’ is a compound that has a structure similar to that of another compound (its ‘parent’ compound) but differs from that other compound in a particular component. An analog may differ from its parent compound in that one or more atoms, functional groups, or substituents are substituted by another atom, group, or substituent. Similarly, an analog of a parent compound can also be formed by substituting a particular atom of the parent compound with a radioactive isotope of that particular atom. A ‘derivative’ is a compound that is thought to arise from or actually synthesized from a parent compound by substituting one atom with another atom or group of atoms.

[0131] In this specification, "pharmaceutically acceptable salt" refers to an ionotherapy agent that forms a neutral complex in combination with a counterion.

[0132] The term "zwitterion" refers to a molecule or ion that has a separate positive load group within it.

[0133] In this specification, "polymorphism" or "polymorphism" means that a solid material can exist in two or more forms or crystals. Crystal forms may be referred to herein as those characterized by graphic data. Such data include, for example, powder X-ray diffraction and solid-state NMR spectra. As is well known in the art, graphic data potentially provides additional technical information (so-called "fingerprints") that further define each solid, which cannot necessarily be described by reference to numerical values ​​or peak positions alone.

[0134] In the pharmaceutical compositions of the present invention (e.g., vitreous implants and particle suspensions), the therapeutic agent is mixed with a biodegradable polymer matrix to form the pharmaceutical composition. The amount of therapeutic agent used in the pharmaceutical composition depends on several factors, including, to name a few, the selection of the biodegradable polymer matrix, the selection of the therapeutic agent, the desired rate of substantially linear release, the duration of the desired rate of release, the composition of the pharmaceutical composition, and the pharmacokinetics of the eye.

[0135] For example, the total therapeutic agent content of the pharmaceutical composition of the present invention (e.g., a vitreous implant) may account for approximately 0.1% to approximately 60.0% by weight of the total pharmaceutical composition. In one embodiment, the therapeutic agent constitutes approximately 1% to 90%, or approximately 1% to 80%, or approximately 1% to 70%, or approximately 1% to 60%, or approximately 1% to 50%, or approximately 1% to 40%, or approximately 1% to 30%, or approximately 1% to 20%, or approximately 1% to 10%, or approximately 10% to 50%, or approximately 10% to 40%, or approximately 10% to 30%, or approximately 10% to 25%, or approximately 10% to 23%, or approximately 10% to 20%, or approximately 15% to 35%, or approximately 15% to 30%, or approximately 15% to 25%. These percentages are weight percentages. In certain embodiments, dexamethasone accounts for approximately 20.0% by weight of the pharmaceutical composition.

[0136] The pharmaceutical composition of the present invention is prepared by dissolving a polymer matrix and a therapeutic agent in a suitable solvent to create 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 possible. The solvent is then allowed to evaporate, leaving a homogeneous film. The solution can be aseptically filtered before the solvent evaporates.

[0137] Manufacturing of vitreous implants As described above, the present invention extends to the pharmaceutical compositions of the present invention, which are formulated as vitreous implants or particle suspensions. Various methods may be used to produce the implants or particle suspensions of the present invention. Such methods include, but are not limited to, solution casting, phase separation, interfacial methods, molding, compression molding, injection molding, extrusion, co-extrusion, thermal extrusion, demolition, heat compression, and combinations thereof. In some embodiments, the implants are preferably molded into a polymer mold.

[0138] In certain embodiments, the implants of the present invention are manufactured by PRINT® technology (Liquidia Technologies, Inc.) particle manufacturing. In particular, the implants are manufactured by molding the material intended to make up the implant into a mold hole.

[0139] The mold can be a polymer-based mold, and the mold bore can be formed to any desired shape and size. Characteristically, when the implants and particles are formed within the mold bore, the implants are highly uniform in shape, size, and composition. The consistency between the physical and compositional composition of each implant in the pharmaceutical composition results in a highly uniform release rate and dosing range for the pharmaceutical composition of the present invention. Furthermore, the method and materials for manufacturing the implants of the present invention have been granted U.S. Patent Nos. 9,545,737, 9,214,590, 9,205,594, 8,992,992, 8,662,878, 8,518,316, 8,444,907, 8,439,666, 8,420,124, 8,268,446, 8,263,129, and 8,15 As described and disclosed in U.S. Patent No. 8,728, U.S. Patent No. 8,128,393, and U.S. Patent No. 7,976,759, U.S. Patent Publication No. 2013-0228950, U.S. Patent Publication No. 2013-0011618, U.S. Patent Publication No. 2013-0256354, U.S. Patent Publication No. 2010-0003291, U.S. Patent Publication No. 2009-0165320, and U.S. Patent Publication No. 2008-0299174 (these are incorporated herein by reference in their entirety).

[0140] The mold holes can be formed in various shapes and sizes. For example, the mold holes may be in the shape of a prism, square prism, triangular prism, pyramid, square pyramid, triangular pyramid, cone, cylinder, torus, or rod. The mold holes within the mold may be the same shape or different shapes. In some aspects of the present invention, the shape of the implant is a cylinder, square prism, or rod. In certain embodiments, the implant is a rod. The rod may have only 90° angles, may bulge along its long axis, or may taper so that one end is smaller than the other.

[0141] The mold holes can have dimensions ranging from nanometers to micrometers to millimeters and larger dimensions. In some embodiments of the present invention, the mold holes have dimensions in the micrometer and millimeter range. For example, the mold holes may have a minimum dimension between approximately 50 nanometers and approximately 750 μm. In one embodiment, the minimum mold hole dimension may be between approximately 100 μm and approximately 300 μm. In another embodiment, the minimum mold hole dimension may be between approximately 125 μm and approximately 250 μm. In yet another embodiment, the minimum mold hole dimension may be between approximately 10 μm and approximately 100 μm. In one embodiment, the minimum mold hole dimension may be between approximately 12.5 μm and approximately 50 μm, for example, between 25 μm and 30 μm. The mold holes may also have a maximum dimension between approximately 750 μm and approximately 10000 μm. In another embodiment, the maximum mold hole dimension may be between approximately 1000 μm and approximately 5000 μm. In another embodiment, the maximum die hole size may be between approximately 1000 μm and approximately 3500 μm. In yet another embodiment, the maximum die hole size may be between approximately 25 μm and approximately 100 μm. In one embodiment, the minimum die hole size may be between approximately 25 μm and approximately 50 μm, for example, between 25 μm and 30 μm.

[0142] In one embodiment, a mold hole with dimensions of approximately 12.5 μm × approximately 12.5 μm × approximately 25 μm (W × H × L) is used to produce particles of the particle suspension of the present invention.

[0143] In one embodiment, a mold hole with dimensions of approximately 25 μm × approximately 25 μm × approximately 25 μm (W × H × L) is used to produce the particles of the particle suspension of the present invention.

[0144] In one embodiment, a mold hole with dimensions of approximately 25 μm × approximately 25 μm × approximately 50 μm (W × H × L) is used to produce particles of the particle suspension of the present invention.

[0145] In one embodiment, a mold hole with dimensions of approximately 50 μm × approximately 50 μm × approximately 30 μm (W × H × L) is used to produce the particles of the particle suspension of the present invention.

[0146] In one embodiment, a mold hole with dimensions of approximately 50 μm × approximately 50 μm × approximately 50 μm (W × H × L) is used to produce particles of the particle suspension of the present invention.

[0147] In one embodiment, a mold hole generally having a rod shape with dimensions of approximately 140 μm × approximately 140 μm × approximately 1325 μm (W × H × L) is used to manufacture the vitreous implant of the present invention.

[0148] In further embodiments, a mold hole having a rod shape with dimensions of approximately 225 μm × approximately 225 μm × approximately 2965 μm (W × H × L) is used to manufacture the vitreous implant of the present invention.

[0149] In another embodiment, a mold hole generally having a rod shape with dimensions of approximately 395 μm × approximately 311 μm × approximately 6045 μm (W × H × L) is used to manufacture the vitreous implant of the present invention.

[0150] In one embodiment, a mold hole generally having a rod shape with dimensions of approximately 100 μm × approximately 100 μm × approximately 1500 μm (W × H × L) is used to manufacture the vitreous implant of the present invention.

[0151] In a further embodiment, a mold hole having a rod shape with dimensions of approximately 150 μm × approximately 150 μm × approximately 3150 μm (W × H × L) is used to manufacture the vitreous implant of the present invention.

[0152] In another embodiment, a mold hole generally having a rod shape with dimensions of approximately 180 μm × approximately 180 μm × approximately 3000 μm (W × H × L) is used to manufacture the vitreous implant of the present invention.

[0153] In one embodiment, a mold hole generally having a rod shape with dimensions of approximately 200 μm × approximately 200 μm × approximately 2000 μm (W × H × L) is used to manufacture the vitreous implant of the present invention.

[0154] In a further embodiment, a mold hole having a rod shape with dimensions of approximately 200 μm × approximately 200 μm × approximately 1000 μm (W × H × L) is used to manufacture the vitreous implant of the present invention.

[0155] In another embodiment, a mold hole generally having a rod shape with dimensions of approximately 225 μm × approximately 225 μm × approximately 2700 μm (W × H × L) is used to manufacture the vitreous implant of the present invention.

[0156] In another embodiment, a mold hole generally having a rod shape with dimensions of approximately 250 μm × approximately 250 μm × approximately 1500 μm (W × H × L) is used to manufacture the vitreous implant of the present invention.

[0157] In another embodiment, a mold hole generally having a rod shape with dimensions of approximately 200 μm × approximately 200 μm × approximately 4500 μm (W × H × L) is used to manufacture the vitreous implant of the present invention.

[0158] In another embodiment, a mold hole generally having a rod shape with dimensions of approximately 265 μm × approximately 265 μm × approximately 4500 μm (W × H × L) is used to manufacture the vitreous implant of the present invention.

[0159] In another embodiment, a mold hole generally having a rod shape with dimensions of approximately 255 μm × approximately 255 μm × approximately 4500 μm (W × H × L) is used to manufacture the vitreous implant of the present invention.

[0160] At the time of manufacture, the implants and particles may be left on a storage array or may be immediately collected for storage and / or use. The implants and particles described herein may be manufactured using a sterile process or may be sterilized after manufacture. Furthermore, the present invention also envisions a kit containing a storage array to which the manufactured implants and particles are attached. Such a storage array / implant kit provides a convenient method for the mass transport and distribution of manufactured implants.

[0161] In another embodiment, implants and particles can be manufactured by additive manufacturing techniques. Additive manufacturing methods, such as those described in U.S. Patent No. 9,120,270, can be used to create master templates or molds used in the PRINT® process, or to manufacture implants directly.

[0162] In certain embodiments, implants and particles are manufactured by the following steps: (i) dissolving polymers and therapeutic agents in a solvent (e.g., acetone); (ii) casting this solution to form a thin film; (iii) drying this film; (iv) folding this thin film on itself; (v) heating the folded thin film on the substrate to form a substrate; (vi) placing the thin film on the substrate onto a mold having a mold hole; (vii) applying pressure, and in some embodiments, heat, to the mold-thin film-substrate combination so that the thin film enters the mold hole; (viii) cooling; and (ix) removing the substrate from the mold to provide implants that substantially mimic the size and shape of the mold hole.

[0163] delivery device In several embodiments, a delivery device may be used to insert the vitreous implant or particle suspension of the present invention into one or both eyes for the treatment of an eye disease or disorder. Suitable devices include needles or needle-like applicators, such as those disclosed in International Publication No. 2018 / 045386, which is incorporated herein by reference in its entirety. In some embodiments, the minimum dimensions of the implant may range from approximately 50 μm to approximately 750 μm, and therefore needles or needle-like applicators in the range of approximately 15 gauge to approximately 30 gauge may be used. In some embodiments, the need gauges are 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 implants with a minimum dimension of 265 μm. In another embodiment, the device uses a 21 or 22 gauge needle for implants with a minimum dimension of 395 μm. In yet another embodiment, the device uses a 27 gauge needle for implants with a minimum dimension of 200 μm or for particle suspensions. The delivery implant may be a syringe with an appropriately sized needle, or a syringe-like implant with a needle-shaped applicator. In one embodiment, the device uses a 27 gauge ultra-thin wall needle with an inner diameter of 300 ± 10 micrometers.

[0164] In particular, delivery routes include puncture, intravitreous, subconjunctival, lens, scleral, fornix, subanterior Tenon's capsule, suprachoroidal, subposterior Tenon's capsule, subretinal, anterior chamber, and posterior chamber.

[0165] In some embodiments, one or more implants are delivered to the anterior chamber of the patient's eye to treat glaucoma and / or increased intraocular pressure.

[0166] In one embodiment, one or more implants are delivered to the anterior chamber of the patient's eye to treat uveitis.

[0167] kit The vitreous implant and delivery device may be provided as a kit for use. The implant may be packaged separately from the delivery device and filled into the delivery device immediately before use. Alternatively, the implant may be filled into the delivery implant before packaging. In this case, the delivery implant is ready for use when the kit is opened. The components may be sterilized individually and assembled as a kit, or sterilized after being assembled as a kit. Furthermore, as described above, the kit may include an array on which the implant is attached.

[0168] Use of the vitreous implant of the present invention for the treatment of eye diseases or disorders One aspect of the present invention provides a treatment for an eye disease or disorder, comprising placing a vitreous implant of the present invention in the eye of a patient suffering from the eye disease or disorder, disassembling the implant, and releasing a therapeutic agent substantially linearly over a period of at least about three months. The patient may be a human or an animal, such as a dog, cat, horse, cattle (or any agricultural livestock).

[0169] treatment process Throughout the treatment process, the biodegradable polymer matrix of the pharmaceutical composition of the present invention degrades and releases the therapeutic agent substantially linearly for at least about three months. By the time the therapeutic agent has been completely released, the polymer matrix has disintegrated. The complete degradation of the polymer matrix may take longer than the complete release of the therapeutic agent from the polymer matrix. The degradation of the polymer matrix may occur at the same rate as the release of the therapeutic agent.

[0170] Optionally, the pharmaceutical composition is administered repeatedly. This administration regimen results in the second administration of the pharmaceutical composition of the present invention being performed after the release of its therapeutic agent from the first administration. This administration regimen can be repeated 3, 4, 5, 6, 7, 8, 9, 10, or more times. In one embodiment, the vitreous implant of the present invention is to be completely disintegrated before re-administration is performed.

[0171] The present invention can be better understood by referring to the following non-limiting examples provided as illustrations of the invention. These examples are provided to better illustrate specific embodiments of the invention and should not be considered in any way as limiting the broad scope of the invention.

[0172] (Examples) (Example 1: Implant Manufacturing) A series of polymer matrix / therapeutic blends were prepared prior to the manufacture of the implant. A therapeutic agent was prepared by uniformly dispersing it throughout the implant body using a solution mixture. Each of the prepared blends contained PEA (polymer 1) and polymer 2 (including PLA polymer, PLGA polymer, or a combination of PLA and PLGA polymers) in different proportions. The PLA polymer used to manufacture the pharmaceutical composition was RESOMER® R203S PLA polymer (available from Evonik Industries). In this example, the PLGA polymer used to manufacture the pharmaceutical composition of the present invention was RESOMER® RG653H PLGA polymer (also available from Evonik Industries). The PEA used in the pharmaceutical composition had chemical structure III.

[0173] In the preparation of the pharmaceutical composition, polymers were mixed together in a specific ratio, and then chloroform was added directly, allowing the polymers to dissolve. The polymer / chloroform solution was then directly added to particulate dexamethasone. The chloroform was then evaporated on polyethylene terephthalate (PET) placed on a 60°C hot plate. After the removal of the chloroform, a thin film of homogeneous material remained.

[0174] (Example 2: Mold manufacturing) A template mold of a desired size for a rod shape with dimensions of 265 × 265 × 4500 μm was manufactured using the PRINT® process. Different pharmaceutical compositions of the present invention manufactured are shown in Column 2 of Table 1. If a polymer is not listed in Column 2 for a particular vitreous implant of the present invention, it means that the polymer was not used in the manufacture of the pharmaceutical composition used in that particular vitreous implant.

[0175] (Example 3: Manufacturing of a dexamethasone implant) A series of implants were fabricated using the polymer matrix / therapeutic blend from Example 1 and the mold from Example 2. The polymer matrix / therapeutic blend was spread on a PET sheet and heated. Once heated, the solvent was completely dried. The blend was covered with a mold of the desired dimensions. The blend was spread across the entire molding surface of the mold using light pressure with a roller. The mold / blend laminate was then passed through a commercially available thermal laminator using the parameters in the table below. The blend flowed into the mold cavity and took on the shape of the cavity. The blend was allowed to cool to room temperature, forming individual implants within the mold cavity. After removing the mold, a two-dimensional array of implants arranged on the film remained. The individual implants were removed from the PET film using forceps.

[0176] Table 1: Blend and mold design [Table 1]

[0177] (Example 4: Analysis of dexamethasone content) The implants prepared as described above were dissolved in acetonitrile, methanol, and water. The dexamethasone content of each implant was measured by RP-HPLC using a Phenyl-Hexyl HPLC column with a particle size of 3 μm and a 4.6 × 100 mm analytical column from Phenomenex Luna®. The mobile phase consisted of a gradient between a 0.1% purified aqueous trifluoroacetic acid (TFA) solution and acetonitrile at a rate of 1.0 mL / min for 4 minutes. The UV absorbance of dexamethasone was measured at 245 nm. Table 2 shows the dexamethasone content measured for each implant.

[0178] Table 2: Dexamethasone content [Table 2]

[0179] (Example 5: In vitro emission analysis of selected implants) The above single implants were placed in 4 mL glass screw-cap vials and incubated in 3 mL of 1 × PBS at 37°C. At each point in time of interest, the media was removed for analysis. The media was then replaced with 3 mL of fresh media. The removed media was analyzed for dexamethasone released by HPLC. Figure 1 shows the in vitro release of dexamethasone measured for each implant evaluated. Figure 2 shows the cumulative percentage of dexamethasone released from implant sample 7. The graph shows that the slope of the graph is substantially constant from day 0 to approximately day 90. Therefore, these data indicate that the pharmaceutical composition of the present invention (e.g., a vitreous implant) releases the therapeutic agent substantially linearly for at least 3 months.

[0180] Sample 7 is a vitreous implant of the present invention made from the pharmaceutical composition of the present invention, comprising: (a) a polymer matrix comprising (i) a biodegradable polyesteramide homopolymer having chemical structural formula (III) at a rate of approximately 60% by weight, (ii) a biodegradable poly(D,L-lactide) homopolymer at a rate of approximately 20% by weight, and (iii) a biodegradable poly(D,L-lactide-co-glycolide) copolymer at a rate of approximately 20% by weight, wherein (i), (ii), and (iii) are mixed together to form the polymer matrix; and (b) a vitreous implant of the present invention made from the pharmaceutical composition of the present invention.

[0181] Figure 3 is a graph of the average daily release rate of dexamethasone from sample 7 of the vitreous implant of the present invention. In Figure 3, the daily release amount of dexamethasone from day 0 to approximately day 90 is substantially constant, which also indicates that the pharmaceutical composition of the present invention (e.g., the vitreous implant) releases the therapeutic agent substantially linearly for at least 3 months.

[0182] Polymer matrices consisting solely of PEA exhibit an extremely slow and non-linear release profile. Polymer matrices consisting solely of PLGA / PLA exhibit a non-linear release profile after the initial rise.

[0183] Surprisingly, dexamethasone eluted from the combined PEA / PLGA matrix was observed to exhibit a high daily release and a substantially linear release profile (e.g., from initial administration to 90 days).

[0184] The scope of this invention is not limited by the specific embodiments described herein. Various modifications of the invention beyond those described herein will be apparent to those skilled in the art from the foregoing description and the accompanying drawings. Such modifications are intended to be included within the claims.

[0185] (Example 6: Storage and Stability of Compounds and Compositions) The compounds or compositions provided herein are prepared and placed in containers for storage at ambient temperature or high temperatures. When compounds or compositions are stored in polyolefin plastic containers, discoloration of the compounds or compositions is reduced compared to polyvinyl chloride plastic containers, whether dissolved or suspended in a liquid composition (e.g., aqueous solution or organic liquid) or as a solid. While not wishing to be bound by theory, such containers reduce the exposure of the container's contents to electromagnetic radiation, whether visible light (e.g., with wavelengths of about 380–780 nm) or ultraviolet (UV) light (e.g., about 190–320 nm (UV-B) or about 320–380 nm (UV-A)). Furthermore, some containers have the ability to reduce the exposure of the container's contents to infrared light, or contain a second component having such ability. Examples of containers used include those made from polyolefins, such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutene, or combinations thereof, particularly polyethylene, polypropylene, or combinations thereof. Furthermore, to further reduce the exposure of the contents of the container to UV light, visible light, or infrared light, the container may be placed inside a second container, for example, paper, cardboard, paperboard, metal film, or foil, or a combination thereof. Compounds and compositions that benefit from the reduction of fading, spoilage, or both during storage include eye drops or implants containing such compounds or compositions provided herein. Eye drops or implants may require storage for a period of up to three months or more, and in some cases, up to one year or more. The containers described herein may be containers for eye drops or implants. The containers may be in any form suitable for containing the contents, for example, bags, bottles, or boxes.

[0186] Other suitable containers and packaging are described, for example, in International Publication Nos. 2018 / 159700, 2018 / 159701, and 2018 / 159702, and Japanese Patent No. 6236167, the contents of which are incorporated herein by reference.

[0187] The composition placed in the container described may contain boric acid, D-mannitol, benzalkonium chloride, polyoxyl 40 stearate, polyethylene glycol 400, ethylenediaminetetraacetic acid, or a combination thereof, along with water or other suitable solvent medium or additives. In some cases, the medium is aqueous; in other cases, the medium is non-aqueous.

[0188] (Example 7: Polymer matrix / therapeutic agent mixture) A series of polymer matrix / therapeutic agent blends were prepared before implant fabrication. The therapeutic agent was uniformly dispersed throughout the implant body using high-temperature melt mixing. Polymers and small molecule JKA inhibitors were freeze-dried to produce fine powders. These powders were then melt-mixed using a 130°C hot plate to obtain a uniform paste.

[0189] (Example 8: Mold manufacturing) A templated mold with rod dimensions of 200 × 200 × 4500 μm was manufactured using the PRINT® process. Implants were manufactured using the JAK inhibitor (1R,2R)-N-(4-methylisoquinoline-6-yl)-2-(4-(N-(pyridine-2-yl)sulfamoyl)phenyl)cyclopropan-1-carboxamide.

[0190] (Example 9: Implant Manufacturing) A series of implants were fabricated using the polymer matrix and JAK inhibitor blend from Example 7 and the mold from Example 8 (see Table 3). The polymer matrix / therapeutic blend was spread on a PET sheet and heated. Once heated, the blend was covered with a mold of the desired dimensions. The blend was spread across the entire molding surface of the mold using light pressure with a roller. The mold / blend laminate was then passed through a commercially available thermal laminator using the parameters in Table 4 below. The blend flowed into the mold cavity and took on the shape of the cavity. The blend was allowed to cool to room temperature, forming individual implants within the mold cavity. After removing the mold, a two-dimensional array of implants arranged on the film remained. The individual implants were removed from the PET film using forceps.

[0191] Table 3: Blend composition and mold design [Table 3]

[0192] Table 4: Processing Parameters [Table 4]

[0193] To analyze the contents of the implants, the implants were first dissolved in 1 mL of DMSO. At this point, 3 mL of methanol was added to each sample and mixed. The small molecule JAK inhibitor content was measured by RP-HPLC using a Waters Atlantis T3, 3 μm particle size, 4.6 × 75 mm analytical column. The mobile phase consisted of a gradient of 0.1% TFA purified aqueous solution and acetonitrile at 1.0 mL / min for 5 minutes. The UV absorbance of the therapeutic agent was measured at 262 nm.

[0194] The in vitro release of the implant formulation was analyzed. A single implant was placed in a 4 mL glass screw-cap vial and incubated at 37° in 3 mL of 1× PBS containing 0.5% Tween 20. At each time point of interest, the media was removed for analysis. The media was then replaced with 3 mL of fresh media. The removed media was analyzed for the released therapeutic agent (i.e., (1R,2R)-N-(4-methylisoquinolin-6-yl)-2-(4-(N-(pyridin-2-yl)sulfamoyl)phenyl)cyclopropane-1-carboxamide) by HPLC. As can be seen from Figures 4 and 5, at least the first 80% of the therapeutic agent released from the implant had an R 2 value of 0.9 or greater.

[0195] [Appendix] [Appendix 1] A pharmaceutical composition for treating an eye disease or disorder, comprising (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 polymer, (2) the second polymer is a biodegradable poly(D,L-lactide) polymer, a biodegradable poly(D,L-lactide-co-glycolide) polymer, or a combination thereof, the biodegradable polymer matrix, and (b) at least one therapeutic agent, or an analog, derivative, pharmaceutically acceptable salt, zwitterion, polymorph, or solvate thereof, uniformly dispersed within the polymer matrix, comprising, the pharmaceutical composition being formulated for intravitreal administration to the eye of a subject, the pharmaceutical composition being formulated to release the at least one therapeutic agent substantially linearly from the pharmaceutical composition over about 1 month to about 6 months, pharmaceutical composition.

[0196] [Appendix 2] The pharmaceutical composition according to Appendix 1, wherein at least one therapeutic agent inhibits the activity of a kinase.

[0197] [Note 3] The pharmaceutical composition described in Appendix 2, wherein the kinase comprises Rho kinase, Janus kinase (JAK), vascular endothelial growth factor receptor (VEGF-R) kinase, or receptor tyrosine kinase.

[0198] [Note 4] The kinase is Rho kinase, and The at least one therapeutic agent is Netalusdil or a pharmaceutically acceptable salt thereof, Lipasdil or a pharmaceutically acceptable salt thereof, These combinations, including, The pharmaceutical composition described in Appendix 3.

[0199] [Note 5] The kinase is a JAK inhibitor, and The at least one therapeutic agent is Ruxolitinib, Tofacitinib, Oclacitinib, Baricitinib, or These combinations, including, The pharmaceutical composition described in Appendix 3.

[0200] [Note 6] The kinase is a receptor tyrosine kinase, and The at least one therapeutic agent is Gefitinib, Lapatinib, Erlotinib, Sunitinib, Sorafenib, Legorafenib, Afatinib, Vandetanib, Semaxanib, Cedilanib, Neratinib, Axitinib, Restaurtinib, Cediranib, or a combination thereof, comprising a pharmaceutical composition as described in Appendix 3.

[0201] [Appendix 7] The at least one therapeutic agent is prostaglandin, corticosteroid, or a combination thereof, being a pharmaceutical composition as described in Appendix 1.

[0202] [Appendix 8] The corticosteroid is dexamethasone, budesonide, beclomethasone, beclomethasone (e.g., as mono- or dipropionate ester), flunisolide, fluticasone (e.g., as propionate or furoate ester), ciclesonide, mometasone (e.g., as furoate ester), mometasone desonide, rofleponide, hydrocortisone, prednisone, prednisolone, methylprednisolone, naflocort, deflazacort, halopredone acetate, fluocinonide acetonide, fluocinonide, clocortolone, tipredane, prednicarbate, alclometasone dipropionate, halometasone, rimexolone, deprodone propionate, triamcinolone, betamethasone, fludrocortisone, desoxycorticosterone, rofleponide, etiprednol dicloacetate, or a combination thereof, being a pharmaceutical composition as described in Appendix 7.

[0203] [Appendix 9] The at least one therapeutic agent is Latanoprost, bimatoprost, travoprost, tafluprost, 3-hydroxy-2,2-bis(hydroxymethyl)propyl 7-((1r,2r,3r,5s)-2-((r)-3-(benzo[b]thiophen-2-yl)-3-hydroxypropyl)-3,5-dihydroxycyclopentyl)heptanoate (chemical structure (II)), cloprostenol isopropyl ester, 13,14-dihydrocloprostenol isopropyl ester, latanoprostenbunod, unoprostone, PGF 1α Isopropyl ester, PGF 2α Isopropyl ester, PGF 3α Isopropyl ester, fluprostenol, or a combination thereof Corticosteroids, or These combinations, That is, The pharmaceutical composition described in Appendix 1.

[0204] [Note 10] The at least one therapeutic agent is Latanoprost, Corticosteroids, Or, a combination of these, That is, The pharmaceutical composition described in Appendix 1.

[0205] [Note 11] The corticosteroid is dexamethasone. The pharmaceutical composition described in Appendix 8.

[0206] [Note 12] The at least one therapeutic agent is netalusdil or a pharmaceutically acceptable salt thereof. The pharmaceutical composition described in Appendix 4.

[0207] [Note 13] The polymer matrix is 60% by weight of biodegradable polyesteramide polymer, 20% by weight of biodegradable poly(D,L-lactide) polymer, and 20% by weight of biodegradable poly(D,L-lactide-co-glycolide) polymer, including, A pharmaceutical composition as described in any one of the appendices 1 to 12.

[0208] [Note 14] The polymer matrix is ​​a mechanical blend of the first polymer and the second polymer. A pharmaceutical composition as described in any one of the appendices 1 to 13.

[0209] [Note 15] A polymer matrix of approximately 51% by weight, and At least one therapeutic agent in an amount of approximately 49% by weight, including, A pharmaceutical composition as described in any one of the appendices 1 to 14.

[0210] [Note 16] The aforementioned biodegradable (D,L-lactide) polymer is an acid-terminated biodegradable poly(D,L-lactide) homopolymer or an ester-terminated poly(D,L-lactide) homopolymer. A pharmaceutical composition as described in any one of the appendices 1 to 15.

[0211] [Note 17] The poly(D,L-lactide-co-glycolide) polymer is an ester-terminated biodegradable poly(D,L-lactide-co-glycolide) copolymer or an acid-terminated biodegradable poly(D,L-lactide-co-glycolide) copolymer. A pharmaceutical composition as described in any one of the appendices 1 to 16.

[0212] [Note 18] The biodegradable polyesteramide homopolymer has the following structure (I): A pharmaceutical composition as described in any one of the appendices 1 to 17. [ka] (I) (However, m+p is in the range of 0.9 to 0.1, and a+b is in the range of 0.1 to 0.9, m+p+a+b=1 (where either m or p may be zero), n is in the range of 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, and the m units and / or p units, as well as the a and b units, are randomly distributed. R 1 (C2-C 20 ) Selected from alkyl groups, R in m or p, which are single skeletal units 3 and R 4 These are, independently, hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, and (C6-C 10 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, R 5 (C2-C 20 )alkyl, (C2-C 20 ) Selected from alkenylenes, R 6 It is a bicyclic fragment of 1,4:3,6-dianehydrohexitol with the following structural formula (II): [ka] R 7 (C6-C 10 ) Selected from the group consisting of aryl, (C1-C6)alkyl, or protecting groups, R 8 (It is -(CH2)4-.)

[0213] [Note 19] The biodegradable polyesteramide homopolymer has the following structure (II): A pharmaceutical composition as described in any one of the appendices 1 to 18. [ka] (II)

[0214] [Note 20] The pharmaceutical composition comprises about 59% by weight of a polymer matrix and about 41% by weight of at least one therapeutic agent. A pharmaceutical composition as described in any one of the appendices 1 to 19.

[0215] [Note 21] The aforementioned pharmaceutical composition, (a) A polymer matrix comprising approximately 59% by weight, (i) Approximately 60% by weight of the polymer matrix is ​​a biodegradable polyesteramide homopolymer, (ii) Approximately 20% by weight of the polymer matrix is ​​a biodegradable poly(D,L-lactide) homopolymer, and (iii) Approximately 20% by weight of the polymer matrix is ​​a biodegradable poly(D,L-lactide-co-glycolide) copolymer. polymer matrix and (b) at least one therapeutic agent in an amount of about 41% by weight, The aforementioned at least one therapeutic agent is dexamethasone. At least one therapeutic agent, Includes, The aforementioned pharmaceutical composition is formulated for intravitreous administration to the target eye, and The pharmaceutical composition is formulated to release the at least one therapeutic agent substantially linearly, such that approximately 1% of the total amount of the at least one therapeutic agent contained in it is released per day over a period of approximately three months. The pharmaceutical composition described in Appendix 20.

[0216] [Note 22] A pharmaceutical composition, (a) A polymer matrix comprising approximately 59% by weight, (i) Approximately 60% by weight of a biodegradable polyesteramide homopolymer having the following structure (I), [Chemical formula] (I) (where m + p is in the range of 0.9 to 0.1, a + b is in the range of 0.1 to 0.9, m + p + a + b = 1 (where one of m or p may be zero), n is in the range of 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, the m units and / or p units and a and b units are randomly distributed, R [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ (ii) Approximately 20% by weight of a biodegradable poly(D,L-lactide) homopolymer, and (iii) Approximately 20% by weight of biodegradable poly(D,L-lactide-co-glycolide) copolymer, Includes, (i), (ii), and (iii) are blended together to form the polymer matrix. polymer matrix and (b) Approximately 41% by weight of dexamethasone uniformly dispersed within the polymer matrix, Includes, The aforementioned pharmaceutical composition is formulated for intravitreous administration to the target eye, and The pharmaceutical composition is formulated to release the dexamethasone substantially linearly, such that approximately 1% of the total amount of dexamethasone contained in the pharmaceutical composition is released from the pharmaceutical composition per day for approximately three months. Pharmaceutical composition.

[0217] [Note 23] The biodegradable polyesteramide homopolymer has the following structure (III): The pharmaceutical composition described in Appendix 22. [ka] (III)

[0218] [Note 24] A vitreous implant comprising a pharmaceutical composition described in any one of the appendices 1 to 23.

[0219] [Note 25] A vitreous implant for treating eye diseases or disorders, comprising a pharmaceutical composition described in any one of the appendices 1 to 24.

[0220] [Note 26] The aforementioned inflammatory diseases or disorders of the eye include uveitis, corneal ulcers, endophthalmitis, autoimmune diseases of the cornea or ocular surface, ocular manifestations of HIV disease, or combinations thereof. A pharmaceutical composition described in any one of the appendices 1 to 23, or a vitreous implant described in appendice 24 or 25.

[0221] [Note 27] The aforementioned inflammatory diseases or disorders of the eye include diabetic eye disease, wet age-related macular degeneration, dry age-related macular degeneration, inflammation, dry eye, or combinations thereof. A pharmaceutical composition described in any one of the appendices 1 to 23, or a vitreous implant described in appendice 24 or 25.

[0222] [Note 28] The aforementioned diseases or disorders of the eye include glaucoma, neurodegenerative diseases or disorders, intraocular hypertension, ocular inflammatory diseases or disorders, or combinations thereof. A pharmaceutical composition described in any one of the appendices 1 to 23, or a vitreous implant described in appendice 24 or 25.

[0223] [Note 29] The aforementioned neurodegenerative diseases or disorders include diabetic eye disease, wet age-related macular degeneration, dry age-related macular degeneration, inflammation, dry eye, or a combination thereof. The pharmaceutical composition described in Appendix 28.

[0224] [Note 30] A method for treating an eye disease or disorder in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described in any one of appendices 1 to 23 or a vitreous implant described in appendice 24 or 25.

[0225] [Note 31] The subject is a human. The method described in Appendix 30.

[0226] [Note 32] The administration to the subject includes administration into the vitreous fluid of the subject's eye. The method described in Appendix 30 or 31.

[0227] [Note 33] The aforementioned inflammatory diseases or disorders of the eye include uveitis, corneal ulcers, endophthalmitis, autoimmune diseases of the cornea or ocular surface, ocular manifestations of HIV disease, or combinations thereof. The method described in any one of the appendices 30 to 32.

[0228] [Note 34] The aforementioned inflammatory diseases or disorders of the eye include diabetic eye disease, wet age-related macular degeneration, dry age-related macular degeneration, inflammation, dry eye, or combinations thereof. The method described in any one of the appendices 30 to 32.

[0229] [Note 35] The aforementioned diseases or disorders of the eye include glaucoma, neurodegenerative diseases or disorders, intraocular hypertension, ocular inflammatory diseases or disorders, or combinations thereof. The method described in any one of the appendices 30 to 32.

[0230] [Note 36] The aforementioned neurodegenerative diseases or disorders include diabetic eye disease, wet age-related macular degeneration, dry age-related macular degeneration, inflammation, dry eye, or a combination thereof. The method described in Appendix 35.

[0231] [Note 37] A method for eluting a therapeutic agent from a depot in a subject requiring treatment, comprising administering a depot containing a pharmaceutical composition described in any one of Appendix 1 to 23 or a vitreous implant described in Appendix 24 or 25 to the subject once, wherein a certain amount of the therapeutic agent is eluted from the depot at a rate of about 1% per day of the initial amount of the therapeutic agent in the depot over a period of about one week to about three months after the administration of the depot.

[0232] [Note 38] A method for eluting a therapeutic agent from a depot in a subject requiring treatment, comprising administering a depot containing a pharmaceutical composition described in any one of Appendix 1 to 23 or a vitreous implant described in Appendix 24 or 25 to the subject once, wherein from the 7th to the 90th day after depot administration, an amount of approximately 10 to approximately 500 ng, approximately 500 to approximately 1500 ng, or approximately 1000 to approximately 2000 ng of the therapeutic agent is eluted from the depot daily.

[0233] [Note 39] A method for administering a therapeutic agent to a subject in need of treatment, comprising administering a depot containing a pharmaceutical composition described in any one of Appendix 1 to 23 to the subject once, wherein a certain amount of the therapeutic agent is eluted from the depot at a rate of about 1% per day for a period of about 1 week to about 3 months after the administration of the depot.

[0234] [Note 40] A method for administering a therapeutic agent to a subject in need of treatment, comprising administering a depot containing a vitreous implant as described in Appendix 24 or 25 to the subject once, wherein a certain amount of the therapeutic agent is eluted from the depot at a rate of about 1% per day for a period of about one week to about three months after the administration of the depot.

[0235] [Note 41] A method for administering a therapeutic agent to a subject in need of treatment, comprising administering a depot containing the pharmaceutical composition described in any one of Appendix 1 to 23 to the subject once, wherein, from the 7th to the 90th day after the administration of the depot, an amount of the therapeutic agent of about 10 to about 500 ng, about 500 to about 1500 ng, or about 1000 to about 2000 ng is eluted from the depot every day.

[0236] [Note 42] A method for administering a therapeutic agent to a subject in need of treatment, comprising administering a depot containing a vitreous implant as described in Appendix 24 or 25 to the subject once, wherein, from the 7th to the 90th day after administration of the depot, an amount of the therapeutic agent of about 10 to about 500 ng, about 500 to about 1500 ng, or about 1000 to about 2000 ng is eluted from the depot on a daily basis.

[0237] [Note 43] From the 7th to the 90th day after depot administration, approximately 750 to 1250 ng of the therapeutic agent is eluted from the depot on a daily basis. The method described in Appendix 38, 41, or 42.

[0238] [Note 44] Approximately 1000 ng of the therapeutic agent is eluted from the depot every day from the 7th to the 90th day after depot administration. The method described in Appendix 38, 41, or 42.

[0239] [Note 45] From approximately one week to approximately two months after depot administration, a certain amount of the therapeutic agent is leached from the depot at a rate of approximately 1% per day of the initial amount of the therapeutic agent in the depot. The method described in Appendix 37, 39, or 40.

[0240] [Note 46] From the 7th to the 60th day after depot administration, the aforementioned amount of the therapeutic agent is eluted from the depot every day. The methods described in Appendix 38, 41, 42, 43, or 44.

[0241] [Note 47] The administration is by injection into the eye of the subject. The method described in any one of the appendices 37 to 44.

Claims

1. A biodegradable polymer matrix comprising a mixture of a first polymer and a second polymer, (1) The first polymer is a biodegradable polyesteramide polymer, and the first polymer has the following structure: 【Chemistry 1】 (III) (2) The second polymer is a combination of an ester-terminated biodegradable poly(D,L-lactide-co-glycolide) polymer and an acid-terminated biodegradable poly(D,L-lactide-co-glycolide) polymer, 60 ± 5% by weight of the biodegradable polymer matrix is ​​the first polymer, and with respect to the second polymer, (i) 20 ± 5% by weight of the biodegradable polymer matrix is ​​an ester-terminated biodegradable poly(D,L-lactide-co-glycolide) copolymer, and 20 ± 5% by weight of the biodegradable polymer matrix is ​​an acid-terminated biodegradable poly(D,L-lactide-co-glycolide) copolymer, (ii) 30 ± 5% by weight of the biodegradable polymer matrix is ​​an ester-terminated biodegradable poly( (iii) a D,L-lactide-co-glycolide copolymer, wherein 10 ± 5% by weight of the biodegradable polymer matrix is ​​an acid-end-bound biodegradable poly(D,L-lactide-co-glycolide) copolymer, or (iii) 10 ± 5% by weight of the biodegradable polymer matrix is ​​an ester-end-bound biodegradable poly(D,L-lactide-co-glycolide) copolymer, and 30 ± 5% by weight of the biodegradable polymer matrix is ​​an acid-end-bound biodegradable poly(D,L-lactide-co-glycolide) copolymer. Biodegradable polymer matrix.

2. The biodegradable polymer matrix is ​​a mechanical blend of the first polymer and the second polymer. The biodegradable polymer matrix according to claim 1.

3. A method for preparing a biodegradable polymer matrix according to claim 1 or 2, comprising preparing a mixture of the first polymer and the second polymer by melt blending in order to prepare the biodegradable polymer matrix.

4. The method according to claim 3, wherein the molten blend comprises mechanically mixing the first polymer and the second polymer.

5. A method for preparing a biodegradable polymer matrix according to claim 1 or 2, comprising preparing a mixture of the first polymer and the second polymer by solution blending for the preparation of the biodegradable polymer matrix.

6. The method according to claim 5, wherein the solution blend comprises mechanically mixing the first polymer and the second polymer.

7. A vitreous implant comprising a biodegradable polymer matrix according to claim 1 or 2.

8. A pharmaceutical product comprising the biodegradable polymer matrix according to claim 1 or 2 or the vitreous implant according to claim 7.

9. The drug is injectable, The pharmaceutical product according to claim 8.

10. An injectable ophthalmic drug, The pharmaceutical product according to claim 8.

11. A device that releases the therapeutic agent substantially linearly over a period of at least three months. The pharmaceutical product according to any one of claims 8 to 10.

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