Crystalline form of dexamethasone dimer and its use

Abstract

The present disclosure features polymorphs of dexamethasone prodrug dimers linked at the 21-C and 21'-C carbons via a carbonate-triethylene glycol-carbonate linker. Also disclosed are pharmaceutical compositions and articles comprising the polymorphs, and their use in treating diseases or conditions, such as by extended or controlled release of dexamethasone from the articles.

Description

Background Art

[0001] Dexamethasone is a drug useful in a variety of medical areas, such as for treating inflammatory diseases or conditions and reducing inflammation associated with surgery or other therapies. Summary of the invention

[0002] The present disclosure is characterized by a crystalline form of compound 1 (dexamethasone prodrug dimer) and an article formed from the crystalline form. The articles of the present disclosure can be machined, molded, emulsion processed, electrospun, electrosprayed, blown or extruded to form fibers, webs, woven fabrics, nonwoven fabrics, pellets, cylinders, microparticles (e.g., microbeads), nanoparticles (e.g., nanobeads) or any other type of shaped article, from which the dexamethasone prodrug dimer is released in a controlled manner. Alternatively, the crystalline form can be contained in a pharmaceutical composition (e.g., an oral dosage form or an injectable dosage form) formulated for administration to a subject.

[0003] In a first aspect, the invention features a solid crystalline form of Compound 1 (Form I), characterized in that a powder X-ray diffraction (PXRD) diffraction pattern (Cu, λ=1.54060) includes peaks expressed in 2θ (±0.2°) degrees at 3.8°, 7.6°, and 12.1°. In a specific embodiment, the solid crystalline form is further characterized by using Cu The PXRD diffraction pattern obtained by irradiation includes one, two, three or more peaks expressed in degrees 2θ (±0.2°) at 8.7°, 9.7°, 10.6°, 13.3° and 14.6°. In a particular embodiment, the solid crystalline form has a melting point of 159±2.5°C.

[0004] In another aspect, the invention features a solid crystalline form of Compound 1 (Form II) characterized by using Cu The powder X-ray diffraction (PXRD) diffraction pattern obtained by irradiation includes peaks expressed in 2θ (±0.2°) degrees at 3.9°, 7.9°, 11.9° and 15.8°. In certain embodiments, the solid crystalline form is further characterized by using Cu The PXRD diffraction pattern obtained by irradiation includes one, two, three or more peaks expressed in 2θ (± 0.2°) degrees at 4.8°, 5.7°, 6.6°, 8.6°, 9.7°, 13.4°, 14.5° and 17.2°. In a specific embodiment, the melting point of the solid crystalline form is 166±2.0°C.

[0005] In another aspect, the invention features a solid crystalline form of Compound 1 (Form III) characterized by using Cu The powder X-ray diffraction (PXRD) diffraction pattern obtained by irradiation includes peaks expressed in 2θ (±0.2°) degrees at 8.0°, 9.8°, 12.1° and 13.8°. In certain embodiments, the solid crystalline form is further characterized by using Cu The PXRD diffraction pattern obtained by irradiation comprises one, two, three or more peaks expressed in degrees 2θ (±0.2°) at 3.9°, 15.0°, 16.1° and 17.6°. In a particular embodiment, the solid crystalline form has a melting point of 172±2.0°C.

[0006] In another aspect, the invention features a solid crystalline form of Compound 1 (Form IV) characterized by using Cu The powder X-ray diffraction (PXRD) diffraction pattern obtained by irradiation includes peaks expressed in 2θ (±0.2°) degrees at 8.9°, 11.4°, 14.1° and 16.4°. In certain embodiments, the solid crystalline form is further characterized by using Cu The PXRD diffraction pattern obtained by radiation includes one, two, three or more peaks expressed in 2θ (± 0.2°) degrees at 7.0°, 17.1°, 17.9°, 19.1°, 19.8° and 20.3°. In a specific embodiment, the melting point of the solid crystalline form is higher than 225°C and the decomposition point is 225±2.0°C.

[0007] In another aspect, the invention features a solid crystalline form of Compound 1 (Form V) characterized by using Cu The powder X-ray diffraction (PXRD) diffraction pattern obtained by irradiation includes peaks expressed in 2θ (±0.2°) degrees at 5.6°, 6.5°, 8.1°, 12.7° and 15.2°. In certain embodiments, the solid crystalline form is further characterized by using Cu The PXRD diffraction pattern obtained by irradiation includes one, two, three or more peaks expressed in degrees 2θ (±0.2°) at 10.3°, 11.3°, 11.8°, 14.5° and 17.3°. In certain embodiments, the solid crystalline form has a melting point of 206±4.0°C.

[0008] In another aspect, the invention features a solid crystalline form of Compound 1 (Form VI) characterized by using Cu The powder X-ray diffraction (PXRD) diffraction pattern obtained by irradiation includes peaks expressed in 2θ (±0.2°) degrees at 3.7°, 7.4° and 16.7°. In certain embodiments, the solid crystalline form is further characterized by using Cu The PXRD diffraction pattern obtained by irradiation includes one, two, three or more peaks expressed in degrees 2θ (±0.2°) at 9.9°, 11.1°, 13.2° and 14.8°. In a particular embodiment, the solid crystalline form has a melting point of 152±4.0°C.

[0009] In another aspect, the invention features a solid crystalline form of Compound 1 (Form VII) characterized by using Cu The powder X-ray diffraction (PXRD) diffraction pattern obtained by irradiation includes peaks expressed in 2θ (±0.2°) degrees at 3.5°, 7.6°, 9.6° and 10.7°. In certain embodiments, the solid crystalline form is further characterized by using Cu The PXRD diffraction pattern obtained by irradiation includes one, two, three or more peaks expressed in degrees 2θ (±0.2°) at 7.1°, 12.7°, 14.5° and 15.2°. In a particular embodiment, the solid crystalline form has a melting point of 152±3.0°C.

[0010] In another aspect, the invention features a solid crystalline form of Compound 1 (Form VIII) characterized by using Cu The powder X-ray diffraction (PXRD) diffraction pattern obtained by irradiation includes peaks expressed in 2θ (±0.2°) degrees at 7.2°, 9.3°, 11.9°, 14.6° and 17.0°. In certain embodiments, the solid crystalline form is further characterized by using Cu The PXRD diffraction pattern obtained by irradiating includes one, two, three or more peaks expressed in degrees 2θ (±0.2°) at 6.7°, 15.9°, 18.0° and 18.6°.

[0011] In related aspects, the present invention is characterized in that a pharmaceutical composition comprises a solid crystalline form of the present invention and a pharmaceutically acceptable excipient. In a specific embodiment, the pharmaceutical composition is formulated for oral administration, for example as a tablet or capsule. In other embodiments, the crystal is suspended in a solution for injection into a subject's site (e.g., injection into a joint space). The pharmaceutically acceptable excipient used in the pharmaceutical composition can be any excipient described herein.

[0012] The invention features a method of making an article comprising Compound 1, the method comprising (a) heating a solid crystalline form of the invention to form a melt; and (b) heating the melt to form an article.

[0013] The invention further features a method of making an article comprising Compound 1, the method comprising (a) heating a solid crystalline form of the invention to form a melt; and (b) injection molding the melt to form the article.

[0014] The invention features a method of making an article comprising Compound 1, the method comprising (a) heating a solid crystalline form of the invention to form a melt; and (b) blow molding the melt to form the article.

[0015] The invention further features a method of making an article comprising Compound 1, the method comprising (a) dissolving a solid crystalline form of the invention to form a solution; and (b) evaporating the solvent to form the article.

[0016] The invention features a method of making an article comprising Compound 1, the method comprising (a) dissolving a solid crystalline form of the invention to form a solution; and (b) electrospinning or electrospraying the solution to form an article.

[0017] The invention further features a method of making an article comprising Compound 1, the method comprising (a) heating a solid crystalline form of the invention to form a melt; and (b) electrospinning or electrospraying the melt to form the article.

[0018] The invention features a method of making an article comprising Compound 1, the method comprising (a) heating a solid crystalline form of the invention to form a melt; and (b) extruding the melt to form an article.

[0019] In some embodiments of the above methods, the dexamethasone is released from the article by surface erosion.

[0020] In some embodiments of the above methods, the preparation releases less than 10% of the dexamethasone (as a percentage of the total dexamethasone present in the preparation as a prodrug) after 5 days in 100% bovine serum at 37°C; or less than 2% of the dexamethasone (as a percentage of the total dexamethasone present in the preparation as a prodrug) is released by surface erosion after 5 days in PBS at 37°C; or more than 20% of the dexamethasone (as a percentage of the total dexamethasone present in the preparation as a prodrug) is released by surface erosion after not less than 6 days in 100% bovine serum at 37°C; or more than 5.0% of the dexamethasone (as a percentage of the total dexamethasone present in the preparation as a prodrug) is released by surface erosion after not less than 6 days in PBS at 37°C; or the dexamethasone is released at a rate such that t 10 Greater than or equal to t 50 It is released from the product at a rate 1 / 10 of that of

[0021] In some embodiments of the above methods, the article further comprises 0.1% to 10% (w / w) of one or more additives, wherein the one or more additives are selected from plasticizers, antioxidants, binders, lubricants, radiopaque agents, and mixtures thereof.

[0022] In further embodiments of the above methods, the article is in the form of a coating, a film, a fiber, a web, a woven fabric, a nonwoven fabric, a pellet, a cylinder, a hollow tube, a microparticle, a nanoparticle, or a shaped article. In other embodiments, the article is free of controlled release excipients, free of crystallization inhibiting excipients, free of mechanical integrity enhancing excipients, and / or free of binding excipients. In some embodiments, the article is in a glassy state.

[0023] In certain embodiments of the above methods, the controlled release is provided by any of the following: the size of the article, the composition of the article, the crystallinity of the article, the surface area of ​​the article, or a combination thereof.

[0024] In some embodiments of the above methods, at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) (w / w) of the preparation is Compound 1.

[0025] In further embodiments of the above methods, Compound 1 or dexamethasone is released from the preparation by surface erosion. In some embodiments, surface erosion releases less than 10% (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) of dexamethasone (as a percentage of the total drug dexamethasone present in the preparation as a prodrug) in 100% bovine serum at 37°C for 5 days; or less than 2% (e.g., less than 1.8%, less than 1.5%, less than 1.2%, less than 1.0%, or less than 0.5%) of dexamethasone (as a percentage of the total drug dexamethasone present in the preparation as a prodrug) in PBS at 37°C for 5 days. In yet other embodiments of any of the above articles, the surface erodes to release more than 20% (e.g., more than 22%, 24%, 26%, 28%, or 30%) of the dexamethasone (as a percentage of the total dexamethasone present in the article as a prodrug) in 100% bovine serum at 37°C for not less than 6, 8, 10, or 12 days (e.g., more than 24% of the dexamethasone in 100% bovine serum at 37°C for 10 days). In other embodiments of any of the above articles, the surface erodes to release more than 5.0% (e.g., more than 6.0%, 8.0%, 10%, 12%, or 15%) of the dexamethasone (as a percentage of the total dexamethasone present in the article as a prodrug) in PBS at 37°C for not less than 6, 8, 10, or 12 days (e.g., more than 5% of the dexamethasone in PBS at 37°C for 10 days). Dexamethasone can make t 10 Greater than or equal to t 50 In some embodiments, the article further comprises 0.1% to 10% (e.g., 0.1% to 5%, 0.1% to 2%, 0.5% to 2%, 1% to 10%) (w / w) of one or more additives, wherein the one or more additives are selected from plasticizers, antioxidants, adhesives, lubricants, radiopaque agents, and mixtures thereof.

[0026] In some embodiments of the above methods, the article is in the form of fibers having an average diameter of about 0.01 to 1 mm (e.g., 0.05 to 0.3 mm, 0.1 to 0.3 mm, 0.15 to 0.3 mm, 0.2 to 0.3 mm, 0.25 to 0.3 mm, 0.01 to 0.1 mm, 0.01 to 0.2 mm, 0.01 to 0.3 mm, 0.01 to 0.4 mm, 0.01 to 0.5 mm, 0.01 to 0.6 mm, 0.01 to 0.7 mm, 0.01 to 0.8 mm, or 0.01 to 0.9 mm). In other embodiments, the article is in the form of pellets having an average diameter of about 0.2 to 5 mm (e.g., about 0.2 to 1 mm, about 0.2 to 2 mm, about 0.3 to 3 mm, about 1.5 to 5 mm, about 2 to 5 mm, about 2.5 to 5 mm, about 3 to 5 mm, about 3.5 to 5 mm, about 4 to 5 mm, or about 4.5 to 5 mm). In further embodiments, the article is in the form of a cylinder having a diameter of about 0.01 to 1 mm (e.g., about 0.01 to 0.2 mm, about 0.1 to 0.3 mm, about 0.1 to 0.4 mm, about 0.2 to 0.5 mm, about 0.1 to 0.6 mm, about 0.1 to 0.7 mm, about 0.1 to 0.8 mm, or about 0.1 to 0.9 mm) and a length of 0.5 to 20 mm (e.g., about 0.5 to 1 mm, about 0.5 to 2 mm, about 0.5 to 4 mm, about 0.5 to 6 mm, about 0.5 to 8 mm, about 0.5 to 10 mm, about 0.5 to 12 mm, about 0.5 to 14 mm, about 0.5 to 16 mm, or about 0.5 to 18 mm). In some embodiments, the length of the cylinder is about 0.5 to 10 mm, or about 1 to 10 mm. In other embodiments, the article is in the form of microparticles having an average diameter of about 1 to 1000 μm (e.g., about 10 to 1000 μm, about 100 to 1000 μm, about 200 to 1000 μm, about 500 to 1000 μm, about 700 to 1000 μm, or about 900 to 1000 μm). In still other embodiments, the article is in the form of nanoparticles having an average diameter of about 0.01 to 1 μm (about 0.05 to 1 μm, about 0.1 to 1 μm, about 0.2 to 1 μm, about 0.3 to 1 μm, about 0.4 to 1 μm, about 0.5 to 1 μm, about 0.6 to 1 μm, about 0.7 to 1 μm, about 0.8 to 1 μm, or about 0.9 to 1 μm).

[0027] In some embodiments of the above methods, the article is a coating on a surface of an implantable medical device. In further embodiments of the above methods, the coating has a glassy state and is formed from a crystalline form of the present disclosure.

[0028] The crystalline form of the present invention can be used as a starting material in the manufacture of articles. The article can be made by a process comprising the following steps: (a) heating the crystalline form to form a melt; (b) cooling the melt to form a glassy composition; and (c) heating the glassy composition to a temperature above the glass transition temperature of the glassy composition, and forming the glassy composition to form a shaped article. Step (c) may include extruding, molding, blow molding, hot spinning, electrospinning or electrospraying the glassy composition to form a shaped article. In some embodiments, the method forms an article that is free of controlled release polymers, free of crystallization inhibiting excipients, free of mechanical integrity enhancing excipients and / or free of binding excipients; or the method forms an article that is optionally in a glassy state. In a further embodiment of the method, the article is in the form of a coating, a film, a fiber, a fiber web, a woven fabric, a nonwoven fabric, a pellet, a cylinder, a hollow tube, a microparticle, a nanoparticle or a shaped article.

[0029] In another embodiment of any of the above methods, the article comprises a solid crystalline form of the invention. In a particular embodiment, the article is a microparticle or a nanoparticle.

[0030] In a related aspect, the invention features a method of treating a subject suffering from an inflammatory condition, the method comprising administering to the subject a composition comprising a solid crystalline form of the invention. The inflammatory condition is osteoarthritis or any other inflammatory condition described herein. In a specific embodiment, the administering is by intra-articular injection.

[0031] In a related aspect, the invention features a microparticle or nanoparticle comprising a solid crystalline form of the invention. In certain embodiments, the microparticle or nanoparticle is formulated for oral administration, for example, as a tablet or capsule containing the microparticle or nanoparticle. In other embodiments, the microparticle or nanoparticle is suspended in a solution for injection into a site of a subject (e.g., injection into a joint space).

[0032] definition

[0033] The term "Compound 1" as used herein refers to the compound depicted in the following formula (I):

[0034]

[0035] The term "free of controlled release polymer" as used herein means that there is no amount of polymeric material greater than 10 KDa in the preparation produced by the method of the present disclosure, and the amount of polymeric material is sufficient to delay or slow the release of dexamethasone prodrug dimer from the preparation compared to the release profile observed for an otherwise identical preparation but without the polymeric material, wherein the release profile is measured at 37° C. in 100% fetal bovine serum (FBS).

[0036] As used herein, the term "free of a crystallization-inhibiting excipient" means that an amount of an excipient is not present in the article produced by the method of the present disclosure, the amount of the excipient being sufficient to reduce the amount of crystalline dexamethasone prodrug dimer in the article compared to the amount of crystalline dexamethasone prodrug dimer observed in an otherwise identical article but without the excipient. The level of crystallinity can be measured using DSC or XRD. In a specific embodiment, the article of the present disclosure is free of a crystallization-inhibiting excipient that is a polymeric material greater than 10 KDa.

[0037] As used herein, the term "free of mechanical integrity enhancing excipients" means that there is no amount of excipients in the article produced by the method of the present disclosure, which is sufficient to increase the mechanical integrity of the article compared to the mechanical integrity of the article that is otherwise identical but does not contain the excipient. For articles in the shape of rods, the mechanical integrity of the article can be tested using a three-point or four-point mechanical bending test (ASTM C1684-18) for the formulation containing or not containing the excipient in the dry state (before drug release), the wet state (before drug release), or the wet state after 15-30% drug release. For articles having a rectangular shape, the mechanical integrity can be tested using a three-point mechanical bending test (ASTM D790-17) or a four-point mechanical bending test (ASTM D6272) for the formulation containing or not containing the excipient in the dry state (before drug release), the wet state (before drug release), or the wet state after 15-30% drug release. A reduction in mechanical integrity causes the article to rupture faster, thereby increasing the total surface area of ​​the article of that amount and resulting in a faster release profile. In certain embodiments, the articles of the present disclosure are free of mechanical integrity enhancing excipients that are polymeric materials greater than 10 KDa.

[0038] The term "free of bound excipients" as used herein means that an amount of excipient is not present in the preparation produced by the method of the present disclosure, the amount of excipient being sufficient to delay or slow the release of dexamethasone prodrug dimer from the preparation compared to the release profile observed for an otherwise identical preparation but without the bound excipient, wherein the release profile is measured at 37° C. in 100% FBS.

[0039] As used herein, the term "cylinder" refers to the shape of the pharmaceutical composition of the present disclosure, which has parallel sides and a circular or elliptical cross-section, or a cross-section of a certain shape (e.g., a star-shaped cross-section). The average diameter of the cylinder can be in the range of about 0.01 to 1 mm in diameter, for example, about 0.01 to 0.2 mm, about 0.1 to 0.3 mm, about 0.1 to 0.4 mm, about 0.2 to 0.5 mm, about 0.1 to 0.6 mm, about 0.1 to 0.7 mm, about 0.1 to 0.8 mm, or about 0.1 to 0.9 mm. The average length of the cylinder can be in the range of about 0.05 to 20 mm, for example, about 0.05 to 1 mm, about 0.5 to 2 mm, about 0.5 to 4 mm, about 0.5 to 6 mm, about 0.5 to 8 mm, about 0.5 to 10 mm, about 0.5 to 12 mm, about 0.5 to 14 mm, about 0.5 to 16 mm, or about 0.5 to 18 mm. In some embodiments, the average diameter of the cylinder is in the range of about 0.01 to 1 mm, and the average length of the cylinder is about 0.1 mm to 4.0 mm. In some embodiments, the average length of the cylinder is about 0.5 to 10 mm or about 1 to 10 mm.

[0040] The term "fiber" as used herein refers to the shape of the pharmaceutical composition of the present disclosure, which is elongated or linear. The average diameter of the fiber can be in the range of about 0.01 to 1 mm, for example, 0.05 to 0.3 mm, 0.1 to 0.3 mm, 0.15 to 0.3 mm, 0.2 to 0.3 mm, 0.25 to 0.3 mm, 0.01 to 0.1 mm, 0.01 to 0.2 mm, 0.01 to 0.3 mm, 0.01 to 0.4 mm, 0.01 to 0.5 mm, 0.01 to 0.6 mm, 0.01 to 0.7 mm, 0.01 to 0.8 mm or 0.01 to 0.9 mm. The average length of the fibers can be in the range of about 20 to 20,000 mm, e.g., about 20 to 1000 mm, about 20 to 2,000 mm, about 100 to 2,000 mm, about 100 to 5,000 mm, about 1,000 to 8,000 mm, about 2,000 to 8,000 mm, about 2,000 to 10,000 mm, about 2,000 to 12,000 mm, about 2,000 to 15,000 mm, or about 5,000 to 18,000 mm.

[0041] As used herein, the term "fiber web" refers to a mesh or web having a plurality of attached or woven fibers. The fiber web can have aligned and unaligned morphologies.

[0042] As used herein, the term "glassy state" refers to an amorphous solid that includes greater than 70%, 80%, 90%, 95%, 98% or 99% (w / w) of Compound 1 and exhibits a glass transition temperature above 38° C. In the glassy state, the level of crystallinity is low, ranging from 0-15%, for example, 0-1%, 0-3%, 0-5%, 0-7%, 0-9%, 0-10% or 0-13%, as measured by DSC or XRD. One or more of the crystalline forms of the present invention may be thermally processed or solvent processed to form the glass formulations of the present disclosure.

[0043] The term "microparticles" as used herein refers to the shape of the pharmaceutical composition of the present disclosure, which may be regular or irregular in shape. The average diameter of the microparticles may be in the range of about 1 to 1000 μm, e.g., about 10 to 1000 μm, about 100 to 1000 μm, about 200 to 1000 μm, about 500 to 1000 μm, about 700 to 1000 μm, or about 900 to 1000 μm. As used herein, microbeads refer to spherical microparticles.

[0044] As used herein, the term "nanoparticle" refers to the shape of the pharmaceutical composition of the present disclosure, which can be a regular or irregular shape. The average diameter of the nanoparticle can be in the range of about 0.01 to 1 μm, for example, about 0.05 to 1 μm, about 0.1 to 1 μm, about 0.2 to 1 μm, about 0.3 to 1 μm, about 0.4 to 1 μm, about 0.5 to 1 μm, about 0.6 to 1 μm, about 0.7 to 1 μm, about 0.8 to 1 μm or about 0.9 to 1 μm. As used herein, "nano beads" refers to spherical nanoparticles.

[0045] As used herein, the term "nonwoven fabric" refers to a web-like structure of fibers bonded together by entanglement.

[0046] The term "pellet" as used herein refers to the shape of the pharmaceutical composition of the present disclosure, which is round, spherical or cylindrical or a combination thereof. The average diameter of the pellets can be in the range of about 0.2 to 5 mm, for example, about 0.2 to 1 mm, about 0.2 to 2 mm, about 0.3 to 3 mm, about 1.5 to 5 mm, about 2 to 5 mm, about 2.5 to 5 mm, about 3 to 5 mm, about 3.5 to 5 mm, about 4 to 5 mm, or about 4.5 to 5 mm.

[0047] As used herein, the term "surface erosion" refers to the process in which the pharmaceutical composition of the present disclosure gradually disintegrates and releases free drug from the dexamethasone prodrug dimer. Surface erosion can be customized to obtain the desired drug release rate. The surface erosion and release rate of a given drug from a dexamethasone prodrug dimer can also depend on the amount of the loaded dexamethasone prodrug dimer (accounting for the percentage of the final dexamethasone prodrug dimer preparation), the product size, the solubility of the dexamethasone prodrug dimer (e.g., by selecting an appropriate connector) and / or the surface area of ​​the product. For example, the surface erosion mechanism of drug release allows the drug delivery product to be customized to have specific physical characteristics (size, diameter, surface area, total mass, etc.) to achieve the desired drug release rate, and the drug release can be designed to start within minutes or hours, and can be continued for days, weeks, months or years.

[0048] As used herein, “t 50 " is the time at which 50% of the releasable drug is released from the article of the present disclosure. Time t 10 Correspondingly, it is the time when 10% of the releasable drug is released from the preparation of the present disclosure. When the release curve is completely linear, t 10 =t 50 When the drug is released in the initial burst, t 10 Much smaller than t 50 In the compositions and methods of the present disclosure, t 10 Can be equal to or greater than t 50 As described in Example 1, drug release from the preparations or compounds of the present disclosure can be measured in 100% bovine serum at 37°C or in PBS at 37°C.

[0049] The term "woven fabric" as used herein refers to a pharmaceutical composition similar to a material formed by weaving of fibers. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figures 1A-1C is a series of images and diagrams showing the formation of glassy pellets ( Figure 1B ) of compound 1 (dexamethasone-triethylene glycol-dexamethasone, Dex-TEG-Dex) ( Figure 1A ). Figure 1C is the result of powder X-ray diffraction (PXRD) of Compound 1 (Form III) crystallized from acetonitrile as described in Example 1 ( Figure 1C ).

[0051] Figure 2 is a graphical representation depicting the release of Compound 1 from glass pellets over time.

[0052] Figure 3is the powder X-ray diffraction (PXRD) diffraction pattern of the solid crystalline Form I of Compound 1 described in Example 2.

[0053] Figure 4 is the powder X-ray diffraction (PXRD) diffraction pattern of the solid crystalline Form II of Compound 1 described in Example 3.

[0054] Figure 5 is the powder X-ray diffraction (PXRD) diffraction pattern of the solid crystalline Form III of Compound 1 described in Example 4.

[0055] Figure 6 is a superposition of the solid crystalline Form III of Example 4 and the crystals of Example 1, corrected for the X-ray source. The superposition shows that the crystals of Example 1 and Example 4 are both Form III.

[0056] Figure 7 is the powder X-ray diffraction (PXRD) diffraction pattern of solid crystalline Form IV of Compound 1 described in Example 5.

[0057] Figure 8 is the powder X-ray diffraction (PXRD) diffraction pattern of solid crystalline Form V of Compound 1 described in Example 6.

[0058] Fig. 9 is the powder X-ray diffraction (PXRD) diffraction pattern of solid crystalline Form VI of Compound 1 described in Example 7.

[0059] Fig.10 is the powder X-ray diffraction (PXRD) diffraction pattern of solid crystalline Form VII of Compound 1 described in Example 8.

[0060] Fig.11 is the powder X-ray diffraction (PXRD) diffraction pattern of solid crystalline Form VIII of Compound 1 described in Example 9.

[0061] Fig.12 is a graphical representation depicting the release of Compound 1 from a crystalline powder suspended in phosphate buffered saline (PBS) containing 50% fetal bovine serum (FBS). As described in Example 10, the release of Compound 1 from different crystalline forms was quantified over time by HPLC. Compared to Form IV, Form I / II provides faster release. Forms I, II, or a mixture of Forms I / II are preferred where faster dissolution is desired, while Form IV is preferred where slower dissolution is desired.

[0062] Fig.13 is a graphical representation of the differential scanning calorimetry (DSC) curve of a mixture of Forms I and II. The melting point of Form I / II (mixture) is approximately 160-165°C.

[0063] Fig.14 is a graphical representation of the differential scanning calorimetry (DSC) curve of Form IV. The melting point of Form IV is 216-232°C.

[0064] Fig.15 is a graphical representation of the difference in solubility (mg / ml) of Form II and Form IV in 10% acetonitrile / water as a function of temperature. Form II is much more soluble in organic solvents than Form IV (see Example 13). DETAILED DESCRIPTION

[0065] Although the clinical importance of sustained drug release delivery systems in maintaining therapeutic drug concentrations over extended periods of time (e.g., days to weeks, months, and even years) has been recognized for decades, the number of successful commercialized products on the market is limited to date. It is recognized in the present disclosure that to develop a successful sustained drug delivery system, technical difficulties must be overcome, including drug degradation during formulation; lack of controlled release, including undesirable burst or incomplete release associated with diffusion or overall erosion mechanisms of drug release; low encapsulation efficiency; and formulation complexity.

[0066] For topically administered sustained release delivery systems, it is recognized in the present disclosure that additional challenges may arise when the mass balance of the carrier or matrix of the drug impedes drug loading, or when the carrier and matrix produce undesirable effects (i.e., such as local inflammation). It is recognized in the present disclosure that there is an unmet need for a sustained release drug system that is formulated to release dexamethasone in a rate-controlled manner over an extended period of time (e.g., days to weeks, months, or even years) by a surface erosion process in the absence of or with a minimal amount of carrier and / or excipients, wherein the system primarily contains a dexamethasone prodrug and minimizes the side effects associated with the use of a carrier or matrix.

[0067] The present disclosure describes a crystalline form of a dexamethasone prodrug dimer that can be used to form a pharmaceutical composition produced by a viscous fluid such as a melt or solution to obtain a shaped article in which most of the material is in a glassy state. The shaped article can have the ability to release its prodrug / drug element from these shaped forms during surface-mediated degradation / dissolution. Due to the unique interactions present between molecules that are primarily amorphous, the shaped forms remain intact as the surface erodes, which can provide a controlled drug release rate over days, weeks, months, or years. The article formed by the crystalline form of the present disclosure can produce a sustained and uniform release of a dexamethasone prodrug without showing any burst release (e.g., t 10 Can be equal to or greater than t 50The high drug loading that can be present in the preparations of the present disclosure is suitable for producing local effective concentrations of dexamethasone over a period of days to weeks to months or even years.

[0068] Alternatively, the crystalline forms of the present disclosure may be incorporated into pharmaceutical compositions for administration to a subject (eg, for the treatment of inflammation).

[0069] Advantages associated with the use of the crystalline forms of the present invention may include: (i) increased storage stability, which may result in longer shelf life of the drug substance; (ii) increased thermal stability to allow high temperature processing with little or no detectable degradation; (iii) altered release profile in the presence of the crystalline form in the final drug product to be administered; (iv) reduced melting point to allow thermal processing at lower temperatures; (v) increased solubility in preferred solvents (e.g., Class 3 solvents, low boiling point solvents to obtain low residual solvents in the final product); (vi) reduced hygroscopicity; (vii) ease of manufacture / generation of crystals / particles of appropriate size to be retained in local tissues; and (viii) sufficient mechanical properties to allow resuspension and administration without changing the crystal / particle size.

[0070] Crystalline preparations

[0071] The pharmaceutical composition of the present invention comprising a crystalline form of Compound 1 may contain a pharmaceutically acceptable excipient, as used herein, including any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders and lubricants suitable for the particular dosage form desired. Remington's Pharmaceutical Sciences, 16th edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various excipients used to formulate pharmaceutical compositions and known preparation techniques thereof. Some examples of materials that can be used as pharmaceutically acceptable excipients include, but are not limited to, sugars such as lactose, glucose, mannitol, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; natural and synthetic phospholipids, such as soybean lecithin and egg yolk lecithin, lecithin, hydrogenated soybean lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, dioleoyl lecithin, hydroxylated lecithin, lysophosphatidylcholine, cardiolipin, sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, distearoylphosphatidylethanolamine (DSPE) and its polyethylene glycol esters, such as DSPE-PEG750 and DSPE-PEG2000, phosphatidic acid, phosphatidylglycerol and phosphatidylserine. Preferred commercial grade lecithin includes those available under the trade name or Lecithin obtained under the conditions of the present invention, including Phosal 53MCT, Phosal 50PG, Phosal 75SA, Phospholipon 90H, Phospholipon 90G and Phospholipon 90NG; particularly preferred are soybean-phosphatidylcholine (SoyPC) and DSPE-PEG2000; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solution, and other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives and antioxidants may also be present in the composition according to the judgment of the formulator.

[0072] Non-limiting examples of binders that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, hydroxyalkylcellulose, hydroxyalkylalkylcellulose, hydroxypropylmethylcellulose, or polyvinylpyrrolidone.

[0073] Non-limiting examples of osmotic agents that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sorbitol, mannitol, sodium chloride or other salts. Non-limiting examples of biocompatible polymers used in the intended dosage forms include, but are not limited to, poly(hydroxy acids), polyanhydrides, polyorthoesters, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinyl pyrrolidones, polysiloxanes, poly(vinyl alcohol), poly(vinyl acetate), polystyrenes, polyurethanes and copolymers thereof, synthetic celluloses, polyacrylic acids, poly(butyric acid), poly(valeric acid) and poly(lactide-co-caprolactone), ethylene vinyl acetate, copolymers thereof and blends thereof.

[0074] Non-limiting examples of hygroscopic polymers that can be used in the contemplated dosage forms include, but are not limited to, polyethylene oxide (e.g., having a molecular weight of 4,000,000 to 10,000,000). ), cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, cross-linked polyacrylic acid and xanthan gum.

[0075] Non-limiting examples of rate controlling polymers that can be used in the contemplated dosage forms include, but are not limited to, polymerized acrylate, methacrylate lacquers or mixtures thereof, polymerized acrylate lacquers, methacrylate lacquers, acrylic resins including copolymers of acrylic acid and methacrylate, or ammonium methacrylate lacquers containing a plasticizer.

[0076] The compositions described above, in any form described herein, can be used to treat a disease (e.g., an inflammatory disease, or any other disease or condition described herein). An effective amount refers to the amount of active compound / agent required to impart a therapeutic effect to the subject being treated. As will be appreciated by those skilled in the art, the effective dose will vary depending on the type of disease being treated, the route of administration, the use of excipients, and the possibility of co-use with other therapeutic treatments.

[0077] The pharmaceutical compositions of the present invention can be administered by any suitable route, such as parenteral, oral, nasal, rectal, topical, buccal, ocular administration or by inhalation. The term "parenteral" as used herein refers to subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional or intracranial injection.

[0078] The sterile injectable composition can be a suspension in a non-toxic parenterally acceptable diluent or solvent. Such diluents include, but are not limited to, 1,3-butanediol, mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, fixed oils are conventionally used as solvents or suspension media (e.g., synthetic monoglycerides or diglycerides). Fatty acids, such as, but not limited to, oleic acid and its glyceride derivatives, are useful in the preparation of injections, and natural pharmaceutically acceptable oils, such as, but not limited to, olive oil or castor oil, or their polyoxyethylated forms, are also useful. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as, but not limited to, carboxymethyl cellulose or similar dispersants. Other commonly used surfactants, such as, but not limited to, Tweens, Spans, or other similar emulsifiers or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solids, liquids, or other dosage forms, may also be used for formulation purposes.

[0079] The composition for oral administration can be any oral acceptable dosage form, including capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In some embodiments, the dosage form is an oral dosage form, such as a compressed tablet, a hard or soft gel capsule, an enteric coated tablet, an osmotic release capsule or a unique combination of excipients. In the case of tablets, conventional excipients include but are not limited to lactose, mannitol and corn starch. Lubricants are usually also added, such as but not limited to magnesium stearate. For oral administration in capsule form, useful diluents include but are not limited to lactose, mannitol, glucose, sucrose, corn starch, potato starch or cellulose. In other embodiments, the dosage form includes a capsule, wherein the capsule contains a mixture of materials to provide a desired sustained release formulation. When an aqueous suspension or emulsion is administered orally, the active ingredient can be suspended or dissolved in an oil phase combined with an emulsifier or suspending agent. If necessary, certain sweeteners, flavorings or coloring agents can be added.

[0080] The pharmaceutical composition for topical administration according to the invention can be formulated as a solution, ointment, cream, suspension, lotion, powder, paste, gel, spray, aerosol or oil. Alternatively, the topical preparation can be in the form of a patch or dressing impregnated with the active ingredient, which can optionally contain one or more excipients or diluents. In some preferred embodiments, the topical preparation contains a material that will enhance the absorption or penetration of Compound 1 through the skin or other affected area.

[0081] The topical composition contains a safe and effective amount of a dermatologically acceptable excipient suitable for application to the skin. A "cosmetic acceptable" or "dermatologically acceptable" composition or component refers to a composition or component suitable for contact with human skin without excessive toxicity, incompatibility, instability or allergic reaction. Excipients enable active agents and optional components to be delivered to the skin at appropriate concentrations. Therefore, excipients can act as diluents, dispersants, solvents, etc. to ensure that the active material is applied and evenly distributed on the selected target at appropriate concentrations. Excipients can be solid, semisolid or liquid. Excipients can be in the form of lotions, creams or gels, particularly in the form of sufficient thickness or yield points to prevent the active material from settling. Excipients can be inert or have dermatological benefits. It should also be physically and chemically compatible with the active ingredients described herein, and should not excessively impair stability, efficacy or other benefits of use associated with the composition.

[0082] Preparation of products

[0083] Pharmaceutical compositions of the present disclosure may include products in the form of fibers, fiber webs, woven fabrics, nonwoven fabrics, pellets, cylinders, hollow tubes, microparticles (e.g., microbeads), nanoparticles (e.g., nanobeads), or other shaped products. In some embodiments, pharmaceutical compositions of the present disclosure have a non-circular shape (e.g., extruded by a star die) that affects (e.g., increases) surface area. Suitable pharmaceutical compositions for the present disclosure may be small particles of regular or irregular shape, which may be solid, porous or hollow.

[0084] Different forms of the pharmaceutical composition of the present disclosure (e.g., fibers, fiber meshes, woven fabrics, nonwoven fabrics, pellets, cylinders, hollow tubes, microparticles (e.g., microbeads), nanoparticles (e.g., nanobeads) or other shaped articles) can have the advantages of providing a controllable surface area, being easy to inject, not requiring removal after drug release is complete, and allowing adjustment of the drug release rate required for a given indication. When used as an injectable drug delivery device, the drug release rate and interaction with cells strongly depend on the size distribution of the pharmaceutical composition form.

[0085] Product processing method

[0086] A variety of methods can be used to form articles of the present disclosure, for example, thermal processing or solvent processing of a crystalline form of dexamethasone prodrug dimer Compound I. Thermal processing can include thermoforming, injection molding, extrusion, 3D printing, melt electrospinning, fiber spinning, fiber extrusion and / or blow molding. Solvent processing can include coating, microprinting, emulsion processing, dot printing, micropatterning, fiber spinning, solvent blowing, electrospraying and electrospinning.

[0087] Electrospray

[0088] In some embodiments, the crystalline form of the present disclosure is dissolved in a solvent (e.g., acetone) at a concentration of, for example, 10-30% w / v, and electrosprayed to form microbeads and nanobeads. The solution can be loaded into a syringe and can be injected onto a stationary collection plate at a specific rate, for example, 0.5 mL / h. Between the needle and the collection surface, a potential difference of, for example, 18 kV can be maintained. Nanoparticles are obtained using an exemplary concentration of 10% w / v. In other embodiments, microbeads are obtained using a concentration of 30% w / v.

[0089] Fiber Spinning

[0090] In some embodiments, the pharmaceutical composition of the present disclosure is prepared by electrospinning, for example, a fiber mesh with aligned and unaligned morphologies. The crystalline form of the present disclosure is dissolved in a solvent (e.g., THF or 1:1 ratio of DCM / THF). The solution can be injected from a syringe at a specific rate, for example, 0.5 mL / h, into a cylindrical mandrel rotating at a specific rotational speed, for example, 1150 rpm, to obtain aligned fibers, or injected onto a stationary collector surface to obtain unaligned fibers. For aligned and random fibers, a potential difference (e.g., 18 kV or 17 kV) can be maintained between a needle and a collection surface.

[0091] In other embodiments, fibers are prepared from a melt at elevated temperature, a glassy intermediate, or a solution formed by dissolving a pharmaceutical composition of the present disclosure in a solvent (e.g., DCM, THF, or chloroform). As used herein, melt spinning describes thermal processing from a molten state, hot spinning describes thermal processing from a glassy state, and wet spinning, dry spinning, and gel spinning describe solution processing.

[0092] Viscous melts, intermediates or solutions can be fed through a spinneret and can be formed into fibers when cooled (melt spinning or hot spinning) or after evaporating the solvent with warm air when compound 1 leaves the spinneret (dry spinning). Wet spinning and gel spinning according to methods known in the art can also be used to produce fibers of the present disclosure. Hot spinning describes a process substantially the same as the melt spinning process, but is performed with a glassy intermediate and heated to above the glass transition temperature (Tg) so that a viscous fluid rather than a melt is extruded / spinned. Alternatively, tweezers can be immersed in a molten material or concentrated solution and then slowly retracted to pull out the fiber. The pulling rate and pulling distance can be changed to produce fibers and columnar structures with different thicknesses.

[0093] Emulsion method

[0094] In some embodiments, microparticles or nanoparticles made of crystalline form can be formed using an emulsion method. The crystalline form can be dissolved in an organic solvent (e.g., DCM, THF, etc.), and a low percentage (e.g., 1%) of surfactant (e.g., SDS, PVA, etc.) can be added to the solution / mixture. The resulting mixture can be stirred at room temperature for an appropriate time to form an emulsion. The emulsion can then be added to Milli-Q water under stirring and kept for an appropriate time (e.g., 1 h) to remove residual solvent. The resulting microparticles or nanoparticles can be collected and dried by centrifugation to obtain the desired form.

[0095] Extrusion

[0096] In some embodiments, the injectable cylinder made of crystalline form can be formed by hot extrusion. The crystalline form can be loaded into a hot melt extruder, heated to a temperature higher than the melting point (for crystalline compositions) or the glass transition temperature (for pre-melted or amorphous compositions), and extruded using a light compressive force to push the material through a nozzle, and the material is pulled out of the extruder using a light pulling force. The extrudate can be cut into a desired length for appropriate administration for the indication of interest.

[0097] Bead Sizing and Grinding

[0098] In some embodiments, the size of the article of the present disclosure can be reduced using a grinding process to form particles, such as beads, of sizes in the micron (micron beads) to nanometer size range (nano beads). The grinding process can be performed using a grinder or other suitable equipment. Dry and wet grinding processes such as jet grinding, cryogenic grinding, ball milling, media grinding, ultrasonic treatment and homogenization are known and can be used in the methods described herein. Typically, in a wet grinding process, a suspension of the material to be used as the core is stirred with or without an excipient to reduce particle size. Dry grinding is a process in which the material to be used as the core of the article is mixed with a grinding medium with or without an excipient to reduce particle size. In a cryogenic grinding process, a suspension of the material to be used as the core is mixed with a grinding medium with or without an excipient at a cooling temperature. In some embodiments, the ground microparticles need to be subsequently heated to above the Tg to obtain a spherical shape, or particles with a non-spherical shape can be used for grinding.

[0099] Low temperature processing using intermediate glass products

[0100] In certain embodiments, the dexamethasone prodrug dimer has a limited thermal stability window (e.g., a short time range of a few seconds to a few minutes), thereby minimizing the effect on the purity of the dimer at elevated temperatures. In some embodiments, it is beneficial to prepare an intermediate glassy form (e.g., a film, pellet, microparticle, or other shaped article). This can be achieved by thermal processing or solvent processing to remove or reduce the crystallinity of the material to form a glassy composition. The glassy composition is then thermally processed at a lower temperature (e.g., just above the glass transition temperature (Tg) and processed below the melting temperature (Tm)). This can provide a longer time range for thermally processing the glassy material into a final shaped article while reducing the effect of processing conditions on the purity of the dexamethasone prodrug dimer in the article.

[0101] Exemplary processing details are provided in the Examples.

[0102] Powder X-ray Diffraction (PXRD) method

[0103] According to the method of preparing the embodiments of the present invention, the method and instrument used for PXRD analysis and the scale selected to display the results, Figure 1C-11 The intensity of a given peak observed in a PXRD diffraction pattern may vary when compared to the same peak in the representative PXRD diffraction pattern provided to illustrate embodiments of the invention provided herein. Figure 1C-11 The relative peak intensity differences between the peaks in the PXRD diffractogram of a given crystalline form can be observed by comparing the relative peak intensity of the peaks in the representative PXRD diffractogram of the crystalline form. Any such differences may be due in part to the preferred direction of the sample and its deviation from the ideal random sample direction, the preparation of the sample for analysis, and the method for analysis. Such variations are known and understood by those skilled in the art, and any such variations do not deviate from the invention disclosed herein.

[0104] In addition to Figure 1C-11 In addition to the relative peak intensity differences that can be observed when compared to the representative PXRD diffraction patterns provided in FIG. 1 , it should also be understood that the positions of the individual peaks can be compared to the Figure 1C-11 The values ​​observed in the representative PXRD diffraction patterns provided for the crystalline forms of the present invention or listed in the Examples vary by ±0.2° 2θ. Such variations are known and understood by those skilled in the art, and any such variations do not depart from the invention disclosed herein.

[0105] Furthermore, it should be understood that depending on the instrument used for X-ray analysis and its calibration, Figure 1C-11Compared to the representative PXRD diffraction pattern provided in , it can be observed that the peak position of each peak in the PXRD diffraction pattern is uniformly shifted by more than 0.2° 2θ. Thus, in some cases, the PXRD diffraction pattern of the crystalline form of the present invention may show a PXRD diffraction pattern that is similar to Figure 1C-11 The same relative peak positions are observed in the representative PXRD diffraction pattern provided in FIG. 1 , so that except for the uniform shift in the peak positions, the overall PXRD diffraction pattern is similar in appearance to that of FIG. Figure 1C-11 Considering the relative peak positions of the peaks in the PXRD diffraction pattern and the crystalline form of the present invention in Figure 1C-11 The relative peak positions observed in the PXRD diffraction pattern remain consistent, and any such uniform peak shifts observed in the PXRD diffraction pattern do not depart from the invention disclosed herein.

[0106] As used herein, the term "crystalline form" refers to a substance having a specific arrangement of molecular components in its crystal lattice, and which can be identified by physical characterization methods such as PXRD. As used herein, the term crystalline form is intended to include single-component and multi-component crystalline forms of Compound 1. Single-component forms of Compound 1 consist only of Compound 1 in the repeating units of the crystal lattice. Multi-component forms of Compound 1 include solvates of Compound 1 in which the solvent is also incorporated into the crystal lattice.

[0107] Drug delivery

[0108] When the pharmaceutical composition of the present invention releases dexamethasone from the article of the present invention in a controlled manner, such as by surface erosion, the pharmaceutical composition of the present invention provides optimal dexamethasone delivery. The surface erosion mechanism of drug release can keep the shaped article in its physical form (e.g., the shape / geometry of the article) while gradually reducing the size (e.g., like a soap bar) as the surface erodes, rather than the overall erosion that is unique to certain polymer-based drug release media (e.g., polylactic acid / glycolic acid). This can inhibit burst release and reduce the formation of inflammatory particles. The drug can be controlled to be delivered within a desired time period. A slower and more stable delivery rate can then lead to a reduction in the frequency with which the pharmaceutical composition must be applied to a subject, and improve the safety profile of the drug. Drug release can also be customized by modifying the article to provide stable release within a relatively short period of time to avoid the side effects of slow and longer release of the drug.

[0109] The rate at which a given drug is released from a pharmaceutical composition may also depend on the percentage of the amount of loaded drug dimer in the final drug dimer preparation, for example, by using a pharmaceutical excipient that acts as a filler. Another factor that can affect the rate at which a drug is released from, for example, microbeads is the size of the microbeads. In some embodiments, drug release is affected by changes in the surface area of ​​the preparation, for example, by changing the diameter of the microbeads. By adjusting the above factors, dissolution, degradation, diffusion, and controlled release can vary over a wide range. For example, release can be designed to start within minutes to hours, and can last for days, weeks, months, or years.

[0110] Uses and pharmaceutical compositions

[0111] In some embodiments, the crystalline form of the present disclosure is used to prepare a drug delivery device (or, for example, a drug reservoir) with minimal demand for additives. This can achieve local, sustained release and local biological effects while minimizing systemic reactions. In some embodiments, when present, the additive is a small amount and does not affect physical or bulk properties. In some embodiments, when present, the additive does not change the release properties of the drug from the pharmaceutical composition, but plays a role in improving the processing of the prodrug dimer into a shaped article. In some embodiments, the pharmaceutical composition includes additives, such as plasticizers (for example, to reduce thermal transition temperature), antioxidants (for example, to improve stability during thermal processing), adhesives (for example, to increase flexibility of the fiber), fillers (for example, to reduce total drug content), lubricants, radiopaque agents or mixtures thereof. The additive can be present in 30% (w / w), for example 20% (w / w), 10% (w / w), 7% (w / w), 5% (w / w), 3% (w / w), 1% (w / w), 0.5% (w / w) or 0.1% (w / w). Examples of plasticizers are polyols, for example glycerol, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, propylene glycol, triacetin, sorbitol, mannitol, xylitol, fatty acids, monosaccharides (e.g. glucose, mannose, fructose, sucrose), ethanolamine, urea, triethanolamine, vegetable oils, lecithin or waxes. Exemplary antioxidants are glutathione, ascorbic acid, cysteine ​​or tocopherol. Binders and fillers may be, for example, polyvinylpyrrolidone (PVP), starch paste, pregelatinized starch, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or polyethylene glycol (PEG) 6000.

[0112] Methods involving treating a subject may include preventing the disease, disorder, or condition in a subject who may be susceptible to, but has not yet been diagnosed as having, the disease, disorder, or condition; inhibiting the disease, disorder, or condition, e.g., arresting its progression; and alleviating the disease, disorder, or condition, e.g., causing regression of the disease, disorder, and / or condition. Treating a disease or condition includes ameliorating at least one symptom of a particular disease or condition, even if the underlying pathophysiology is not affected (e.g., treating pain in a subject by administering an agent, even if such agent does not treat the cause of the pain).

[0113] Pharmaceutical compositions comprising Compound 1 as described herein can be administered to a subject by any route known in the art. These routes include, but are not limited to, oral, sublingual, nasal, intradermal, subcutaneous, intramuscular, rectal, vaginal, intravenous, intraarterial, intracisternal, intraperitoneal, intravitreal, periocular, topical (such as powder, cream, ointment or drops), buccal and inhalation administration. Ideally, the products disclosed herein are administered parenterally (intravenously, intramuscularly or subcutaneously) as injections, or locally (intraocularly or in the interarticular space) as injections. The preparations are mixed under sterile conditions with a pharmaceutically acceptable carrier or suspending agent or resuspending agent (e.g., for microparticles and nanoparticles) and any desired preservatives or buffers that may be required.

[0114] The disclosed products comprising dexamethasone prodrug dimers described herein can be applied to the subject to be delivered in an amount sufficient to deliver a therapeutically effective amount of an incorporated agent as part of a preventive or therapeutic treatment or part of an adjuvant therapy to the subject to avoid the side effects of another drug or therapy. Generally, the effective amount of a medicament or component refers to the amount necessary to cause a desired biological response. The desired concentration of the medicament in the disclosed product will depend on many factors, including but not limited to the absorption, inactivation and excretion rate of the drug, and the delivery rate of dexamethasone dimer from the subject composition, the desired biological endpoint, the drug to be delivered, the target tissue, etc. It should be noted that the dosage value can also vary with the severity of the condition to be alleviated. It should also be understood that for any particular subject, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition. Generally, the administration will be determined using techniques known to those skilled in the art.

[0115] One of ordinary skill in the art can readily determine the concentration and / or amount of any pharmaceutical agent to be administered to a subject. Known methods can also be used to determine local tissue concentrations, diffusion rates from pharmaceutical compositions, and local blood flow before and after administration of the therapeutic formulation.

[0116] Sterilization of preparations

[0117] Generally, it is desirable that the preparation is sterile before or when it is applied to a subject. Sterile preparations are substantially free of pathogenic microorganisms, such as bacteria, microorganisms, fungi, viruses, spores, yeasts, molds, and other microorganisms generally associated with infection. In some embodiments, the products of the present disclosure may undergo aseptic processes and / or other sterilization processes. Aseptic processes generally include sterilizing the preparation, final formulation, and / or container closure of the drug product by processes such as heat, gamma radiation, ethylene oxide, or filtration, and then merging in a sterile environment. In some cases, aseptic processes are preferred. In other embodiments, terminal sterilization is preferred.

[0118] Treatment

[0119] The formulations of the present disclosure may be used in ophthalmology, oncology, laryngology, endocrinology and metabolic diseases, rheumatology, urology, neurology, cardiology, dental medicine, dermatology, otology, post-operative medicine, and orthopedics.

[0120] Ophthalmic applications

[0121] In certain embodiments, the articles of manufacture of the present disclosure may be used to prevent, treat, or manage diseases or conditions of the posterior portion of the eye, such as the retina, macula, choroid, sclera, and / or uvea.

[0122] In some embodiments, the articles of manufacture of the present disclosure are used as injectable drug delivery devices for ophthalmology (e.g., intravitreal injections, coatings on minimally invasive glaucoma surgery (MIGS) devices, or implanted blebs). During intravitreal injections, the drug is placed directly into the space behind the eye called the vitreous cavity, which is filled with a jelly-like fluid called the vitreous humor. Intravitreal injections can be used to treat retinal diseases such as diabetic retinopathy, macular degeneration, macular edema, uveitis, and retinal vein occlusion.

[0123] In certain embodiments, the articles of manufacture of the present disclosure may be used to treat, prevent, or control an ocular condition, i.e., a disease, discomfort, or condition that affects or involves the eye or one or more parts or regions of the eye. In some embodiments, the articles of manufacture of the present disclosure may be used to treat, prevent, or control an ocular condition in the front of the eye of a subject. Ocular conditions in the front of the eye include diseases, discomforts, or conditions such as post-surgical inflammation; uveitis; infection; aphakia; pseudophakia; astigmatism; blepharospasm; cataracts; conjunctival diseases; conjunctivitis; corneal diseases; corneal ulcers; dry eye syndrome; eyelid diseases; tear apparatus diseases; tear duct obstruction; myopia; presbyopia; pupil disorders; corneal neovascularization; refractive errors and strabismus. In some embodiments, the articles of the present disclosure may be used to treat, prevent, or control an ocular condition in the back of the eye of a subject. Ocular conditions at the back of the eye may include diseases, disorders or conditions such as intraocular melanoma; acute macular neuroretinopathy; Behcet's disease; choroidal neovascularization; uveitis; diabetic uveitis; histoplasmosis; infections, such as those caused by fungi or viruses; macular degeneration, such as acute macular degeneration, non-exudative age-related macular degeneration, and exudative age-related macular degeneration; edema, such as macular edema (e.g., cystoid macular edema (CME) and diabetic macular edema (DME)); multifocal choroiditis; ocular trauma affecting the posterior part or location of the eye; ocular tumors; retinal disorders, such as central retinal vein occlusion, diabetic retinopathy (including proliferative diabetic retinopathy), proliferative vitreoretinopathy (PVR), retinal artery occlusive disease, retinal detachment, uveitic retinal disease; sympathetic ophthalmia; Vogt's disease; Koyanagi-Harada (VKH) syndrome; uveitis diffuse; posterior eye conditions caused or affected by ocular laser treatment; posterior eye conditions caused or affected by photodynamic therapy, photocoagulation, radiation retinopathy, epiretinal membrane disorders, retinal branch vein occlusion, anterior ischemic optic neuropathy, non-retinopathy, diabetic retinopathy, retinitis pigmentosa, retinoblastoma and glaucoma. In some embodiments, the products of the present disclosure can be used to treat, prevent or control dry eye in a subject. In some embodiments, the products of the present disclosure can be used to treat, prevent or control inflammation in the eyes of a subject. Inflammation is associated with a variety of ocular conditions. Various ophthalmic surgical procedures (including cataract surgery) can also cause inflammation. In some embodiments, the agent delivered to the eye by the products and / or methods of the present disclosure described herein can be a corticosteroid. In some embodiments, the pharmaceutical compositions of the present disclosure are used as adjunctive therapies to reduce inflammation and fibrosis associated with devices (e.g., minimally invasive glaucoma surgery (MIGS) devices). In some embodiments, the articles of manufacture of the present disclosure may be used to treat, prevent, or manage age-related macular degeneration (AMD) in a subject.

[0124] Treatment of osteoarthritis

[0125] In some embodiments, the products of the present disclosure are used to treat osteoarthritis (OA). For OA of the knee, if other conservative treatments are ineffective, intra-articular (IA) injections (e.g., steroids) are preferred as a last non-surgical approach. Steroids can be used to reduce inflammation of the tendons and ligaments of osteoarthritic joints. IA steroid injections result in short-term relief of OA pain and can be considered an adjunct to core treatment for relieving moderate to severe pain in OA patients. Dexamethasone can be used to treat OA. In some embodiments, microspheres of the present disclosure consisting of Compound 1 are injected into the knee joint to treat OA.

[0126] Surgery

[0127] In some embodiments, the articles of manufacture of the present disclosure are used in conjunction with surgical procedures. For example, the articles of manufacture of the present disclosure may be implanted at a surgical site to reduce the risk of inflammation treated by the surgical procedure, or may be used as an adjunct to reduce the risk of infection.

[0128] Example

[0129] The following examples are put forth to provide one of ordinary skill in the art with instructions for how to use, prepare, and evaluate the compositions and methods described herein and are purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure.

[0130] Example 1: Compound 1 (dexamethasone-triethylene glycol-dexamethasone) can be synthesized, processed into glassy pellets by thermoforming, and the drug released from the intact pellets by surface erosion

[0131] Dexamethasone (1 mol equivalent) was suspended in dichloromethane on an ice bath, and triethylamine (2 mol equivalent) and triethylene glycol bis(chloroformate) (0.6 mol equivalent) were added to the mixture. The ice bath was allowed to warm to room temperature, and the reaction was stirred overnight. The solvent was removed, and the solid residue was purified by column chromatography. The product was recrystallized twice from acetonitrile to give compound 1 ( Figure 1A ).

[0132] PXRD patterns were recorded using a Bruker D8 Discover with a Davinci Design diffractometer. X-rays were obtained using a cobalt sealed tube source (λ = 400 nm) at 35 kV and 45 mA. ). A Vantec 500 (MiKroGap Technology) area detector was used with 6 frames at 600 s per frame at a distance of 20.0 cm from the sample. The raw data were integrated using Diffrac.Eva (version 4.2.1) and displayed in Topas software (version 4.2; Bruker-AXS). The PXRD diffraction pattern of the solid crystalline form III of compound 1 is Figure 1C , having peaks expressed in 2θ (±0.200°) degrees at 9.316°, 11.501°, 14.019°, 15.982°, 17.268°, 17.685°, 18.658°, 20.440°, 21.782°, 23.472°, 29.816° and / or 33.150°.

[0133] Compound 1: HPLC (mobile phase: H2O / TFA and MeCN / TFA) 31.7 min; elemental analysis: for C 52 H 68 F2O 16 Analysis calculated: C, 63.27; H, 6.94; N, 0.00; Cl, ​​0.00 Found: C, 62.62; H, 6.84; N, <0.50; Cl <100 ppm. 1H NMR (400MHz, DMSO-d6) δ (ppm) 0.80 (d, J = 7Hz, 6H, 2×C16α-CH3); 0.90 (s, 6H, 2×C18-CH3); 1. 08(m,2H,2×C16-H);1.35(m,2H,2×C14-H);1.49(s,6H,2×C19-CH3);1.54(q,J=13Hz,2H,2× C13-H); 1.64 (q, J=11Hz, 2H, 2×C15-CH2); 1.77 (m, 2H, 2×C15-CH2); 2.15 (m, 4H, 2×C6-CH2); 2.32(m,4H,2×C7-CH2); 2.62(m,2H,2×C12-CH2); 2.89(m,2H,2×C12-CH2); 3.57(s,4H,2×TEG OCH2); 3.65(m,4H,2×TEG OCH2); 4.15(m,2H,2×OCH); 4.22(m,4H,2×TEG OCH2); 4.79 (d, 2H, AB, J = 18.5 Hz, 2H, C21-CH2O-); 5.09 (d, 2H, AB, J = 18.5 Hz, 2H, C21-CH2O-); 5.18 (s, 2H, C17-OH); 5.40 (d, 2H, J = 4.5 Hz, C11-OH); 6.01 (d, 2H, J = 1.9 Hz, 2x olefin C4-CH); 6.23 (dd, 2H, J = 10.1 and 1.9 Hz, CH, 2× olefin C2-CH); 7.29 (d, 2H, C1-CH2× olefin CH, 10.1 Hz, 2H). MS (ESI+) m / z: [M+H]+, for C 52 H 69 F2O 16 The calculated value is 987.46; the measured value is 987.46.

[0134] Compound 1 was formed into glassy pellets by thermoforming ( Figure 1B The crystalline powder was melted at 185°C and formed into pellets from a 1 mm x 1 mm cylindrical die. The starting powder and the thermally processed pellets were characterized by powder X-ray diffraction (PXRD; Figure 1C ) were tested to confirm the thermal processing transformation of compound 1 from a crystalline state to a glassy state.

[0135] Thermoformed pellets (approximately 1 mm x 1 mm) from Compound 1 were then placed in a 20 mL glass vial and 2 mL of release buffer (100% phosphate buffered saline (PBS), PBS containing 1% fetal bovine serum (FBS), or 100% FBS) was added. The samples were incubated at 37°C on a shaker rotating at 115 rpm. After 1 day, 3 days, 7 days, and then at alternating intervals of 3 and 4 days (i.e., 1, 3, 7, 10, 14 days, etc.), the release buffer was sampled directly (PBS) or syringe filtered, the protein was precipitated with acetonitrile, and the drug release product was extracted. The samples were analyzed by high performance liquid chromatography (HPLC) to quantify the drug product. The cumulative drug release was calculated and plotted as the percentage of total drug in each pellet released over time ( Figure 2 ).

[0136] Example 2: Form I - Solid Crystals of Compound 1

[0137] The PXRD diffraction patterns generated for Examples 2 to 9 used a copper X-ray source, as opposed to the cobalt X-ray source used in Example 1. Two machines were used to collect the PXRD diffraction patterns:

[0138] 1. Some PXRD diffractograms were recorded on a Bruker D8 Discover powder X-ray diffractometer (Bruker-AXS, Karlsruhe, Germany). The sample holder was oscillated along the X-axis and Y-axis during the measurement. The generator was an Incoetec IμS copper X-ray source (IMSTub: For each sample, one frame was collected using a still scan at a distance of 134.2 mm from the sample using an Eiger2R_500K detector. The raw data were evaluated using the program EVA (Bruker-AXS, Karlsruhe, Germany).

[0139] 2. Other PXRD diffractograms were recorded on a Bruker D2 Phaser powder X-ray diffractometer (Bruker-AXS, Karlsruhe, Germany). The sample holder rotated during the measurement. The generator was a SIEMENS KFL Cu 2K X-ray source (IMSTube: Copper tube). A source slit of 0.2 mm, an air scattering screen of 1 mm and a detector slit of 3 mm were used. For each sample, one scan was performed using a LynxEye detector at a distance of 141 mm from the sample using coupled theta-twotheta scanning. The raw data were evaluated using the program EVA (Bruker-AXS, Karlsruhe, Germany).

[0140] The PXRD diffraction pattern of the solid crystalline form I of compound 1 is Figure 3 The PXRD diffraction pattern peaks of Form I expressed in 2θ (±0.20°) degrees are listed in the table below.

[0141]

[0142] Crystals of Form I were prepared as follows: A suspension of Compound 1 (11 g) in acetonitrile (110 ml) was stirred magnetically and heated to obtain a solution. The solution was cooled to room temperature and stirred for 16 hours. The white solid was filtered and dried (approximately 54% yield, mp 157.1-161.3° C.).

[0143] Example 3: Form II - Solid crystals of Compound 1.

[0144] The PXRD diffraction pattern was recorded as described in Example 2. The PXRD diffraction pattern of the solid crystalline Form II of Compound 1 is Figure 4 The PXRD diffraction pattern peaks of Form II expressed in 2θ (±0.20°) degrees are listed in the table below.

[0145]

[0146] Crystals of Form II were prepared as follows: A suspension of Compound 1 (30.4 g) in acetonitrile (455 ml) was stirred magnetically and heated to 70°C to obtain a solution. The solution was cooled to room temperature and allowed to stand for several days. The white solid was filtered and dried. Recrystallization was repeated under the same conditions (yield of about 77%, mp 164.2–167.7°C).

[0147] Example 4: Form III - Solid crystals of Compound 1.

[0148] The PXRD diffraction pattern was recorded as described in Example 2. The PXRD diffraction pattern of the solid crystalline Form III of Compound 1 is Figure 5 The PXRD diffraction peaks of Form III expressed in 2θ (±0.20°) degrees are listed in the table below.

[0149]

[0150] The PXRD diffraction pattern in Example 1 is also Form III, but was captured using a cobalt X-ray source rather than the copper X-ray source used in this example. Due to the different X-ray sources, the 2θ values ​​are different despite the same form (Form III). Figure 6 An overlay of the PXRD diffraction patterns from two different X-ray sources from Example 1 and this example is shown, with the 2θ values ​​converted to d values ​​to demonstrate that both are Form III.

[0151] Crystals of Form III are prepared as follows: a suspension of Compound 1 (6.83 g) in acetonitrile (683 ml) is formed. The solution is heated to 40° C. for 30 minutes under ultrasonic treatment to obtain a fine suspension, which is filtered through Whatman 40 filter paper to obtain a clear yellow solution. The solution is placed in a refrigerator (-20° C.) and allowed to stand for 4 hours. The white solid (4.66 g) is collected by filtration and suspended in acetonitrile (466 ml), heated to 40° C. for 30 minutes under ultrasonic treatment to obtain a fine suspension, and filtered through Whatman 40 filter paper to obtain a clear light yellow solution. The solution is placed in a refrigerator (-20° C.) and allowed to stand for 4 hours. The white solid (4.16 g) is filtered and dried. (About 61% yield, mp 172° C.).

[0152] Example 5: Form IV - Solid crystals of Compound 1.

[0153] The PXRD diffraction patterns were recorded as described in Example 2. The PXRD diffraction pattern of the solid crystalline Form IV of Compound 1 is Figure 7 The PXRD diffraction pattern peaks of Form IV expressed in 2θ (±0.20°) degrees are listed in the table below.

[0154]

[0155] Crystals of Form IV were prepared as follows: A suspension of Compound 1 (4 g) in 1,4-dioxane (30 ml) was stirred magnetically and heated to 40°C to obtain a solution. The solution was cooled to room temperature. The white solid was filtered and dried under vacuum at 50°C. The recrystallization was repeated under the same conditions (yield of about 90%, mp 223.2–226.4°C (decomposition)).

[0156] Example 6: Form V - Solid crystals of Compound 1.

[0157] The PXRD diffraction patterns were recorded as described in Example 2. The PXRD diffraction pattern of the solid crystalline Form V of Compound 1 is Figure 8 The PXRD diffraction pattern peaks of Form V expressed in 2θ (±0.20°) degrees are listed in the table below.

[0158]

[0159]

[0160] Crystals of Form V were prepared by magnetically stirring a suspension of compound 1 (19.6 mg) in 1,4-dioxane (1.6 ml), heating to 60° C. for approximately 4 hours, cooling to 20° C. at a rate of 0.02° C. / min, and storing at 5° C. for several days. A white solid was isolated (mp 203.4-210.1° C.).

[0161] Example 7: Form VI - Solid crystals of Compound 1.

[0162] The PXRD diffraction pattern was recorded as described in Example 2. The PXRD diffraction pattern of the solid crystalline Form VI of Compound 1 is Fig. 9 The PXRD diffraction peaks of Form VI expressed in 2θ (±0.20°) degrees are listed in the table below.

[0163]

[0164]

[0165] Crystals of Form VI were prepared as follows: A suspension of Compound 1 (1.12 g) in acetonitrile-water 10% v / v (18 ml) was stirred magnetically and heated to 60°C for approximately 1 hour. Another portion of acetonitrile-water 10% v / v (6 ml) was added to obtain a clear solution. The solution was filtered while hot to remove undissolved particles. Water (16.5 ml) was added dropwise to the solution. The solution was removed from the heat and stirred magnetically at room temperature for 3 hours. The white solid was filtered (approximately 80% yield, mp 148.7–155.3°C).

[0166] Example 8: Form VII - Solid crystals of Compound 1.

[0167] The PXRD diffraction pattern was recorded as described in Example 2. The PXRD diffraction pattern of the solid crystalline Form VII of Compound 1 is Fig.10 The PXRD diffraction pattern peaks of Form VII expressed in 2θ (±0.20°) degrees are listed in the table below.

[0168]

[0169] Crystals of Form VII were prepared as follows: A suspension of Compound 1 (160 mg) in acetonitrile (2.3 ml) was stirred magnetically and heated to 60 ° C for about 1.5 hours. Another portion of acetonitrile (0.75 ml) was added to obtain a clear solution. Water (5.25 ml) was added dropwise to the solution. The solution was removed from the heat and stirred magnetically at room temperature for 3 hours. The white solid was filtered (approximately 80% yield, mp 150.5–154.7 ° C).

[0170] Example 9: Form VIII—Solid crystals of Compound 1.

[0171] The PXRD diffraction patterns were recorded as described in Example 2. The PXRD diffraction pattern of the solid crystalline Form VIII of Compound 1 was Fig.11 The PXRD diffraction pattern peaks of Form VIII expressed in 2θ (±0.20°) degrees are listed in the table below.

[0172]

[0173] Crystals of Form VIII were prepared as follows: A suspension of Compound 1 (9 mg) in tetralin (800 μL) was magnetically stirred and heated at 50° C. for 1 hour. A portion of the suspension (250 μL) was filtered and 400 μL of heptane was added to the filtrate. A white solid was obtained after removal of the solvent.

[0174] Alternatively, crystals of Form VIII were prepared as follows: A suspension of Compound 1 (9 mg) in 2-methyl-2-propanol (800 μL) was magnetically stirred and heated at 50° C. for 1 hour. A portion of the suspension (250 μL) was filtered and 400 μL of heptane was added to the filtrate. A white solid was obtained after removal of the solvent.

[0175] Example 10: Drug release from Form I / II and Form IV of Compound 1.

[0176] Compound 1, Form I / II (mixture) and Form IV were formed from acetonitrile and ethanol, respectively. The crystalline powder was suspended in phosphate buffered saline (PBS) containing 50% fetal bovine serum (FBS), and the drug release of the different crystalline forms was quantified over time by HPLC (see Fig.12 ). Compared with crystalline form IV, crystalline form I / II provides faster release. Where faster dissolution is required, crystalline form I, II or a mixture of crystalline form I / II is preferred, while crystalline form IV is preferred where slower dissolution is required.

[0177] Example 11: Melting points of Form I / II and Form IV.

[0178] like Fig.13 As observed from the differential scanning calorimetry (DSC) curve shown in , the melting point of Form I / II (mixture) is about 160-165°C, thus having the advantage of being capable of thermal processing. Form IV has a significantly higher melting point of 216-232°C, as Fig.14 as shown, and decomposes upon heating.

[0179] Example 12: Stability of Forms II and IV.

[0180] Form IV is the most thermodynamically stable polymorph observed, and most other polymorphs are observed to convert to Form IV over time or upon slow heating. For example, stability testing of Form VIII and the amorphous form showed conversion to Form IV by PXRD after 14 days at room temperature and / or 14 days of cooling at 0°C. Finally, under the conditions tested, no conversion of Form IV to any other polymorph was observed. Thus, Form IV in solid form has the advantage of a longer shelf life without interconversion to another crystalline form.

[0181] It was also observed that Form II has high thermodynamic stability and no conversion to Form IV was observed under the conditions tested. Since Form II has a low melting point, it is a crystalline form with high stability and can also be used for high temperature processing into the articles of the present invention.

[0182] Example 13: Solubility of Forms II and IV.

[0183] The solubility of Form II and Form IV was measured in 90% acetonitrile-10% water as a function of temperature (see Fig.15 ). It was observed that Form II exhibited higher solubility, especially at higher temperatures.

[0184] It was also observed that Form IV exhibited significantly lower solubility (approximately 10 times lower) than Form II in organic solvents (e.g., acetonitrile, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, isobutyl acetate, acetone, butyl acetate, ethyl acetate, isopropyl acetate, and methanol). This observation has implications for coating applications because it is more practical to make high concentration coating solutions (e.g., for coating surfaces by dipping or spraying a solution of Compound 1 onto the surface) from Form II than from Form IV.

[0185] Other Implementations

[0186] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 883,170, filed on August 6, 2019, and PCT Application No. PCT / CA2019 / 050136, filed on February 1, 2019, each of which is incorporated herein in its entirety.

[0187] Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, these descriptions and examples should not be construed as limiting the scope of the disclosure. The disclosures of all patents and scientific literature cited herein are expressly incorporated by reference in their entirety.

Claims

1. A solid crystalline form of a compound represented by the following formula: The solid crystalline form is characterized by a powder X-ray diffraction (PXRD) pattern including peaks at 8.9°±0.2°2θ, 11.4°±0.2°2θ, 14.1°±0.2°2θ, and 16.4°±0.2°2θ.

2. The solid crystalline form according to claim 1, characterized in that The PXRD pattern further included peaks at 7.0°±0.2°2Θ, 17.1°±0.2°2Θ, 17.9°±0.2°2Θ, 19.1°±0.2°2Θ, 19.8°±0.2°2Θ, and 20.3°±0.2°2Θ.

3. A solid crystalline form of a compound represented by the following formula: Features The PXRD pattern included peaks at 3.8°±0.2°2θ, 7.6°±0.2°2θ, 8.7°±0.2°2θ, 9.7°±0.2°2θ, and 12.1°±0.2°2θ.

4. The solid crystalline form of claim 3, further characterized by The PXRD pattern further included peaks at 10.6°±0.2° 2Θ, 13.3°±0.2° 2Θ, and 14.6°±0.2° 2Θ.

5. A pharmaceutical composition comprising the solid crystalline form of any one of claims 1 to 4 and a pharmaceutically acceptable excipient.

6. Use of a solid crystalline form according to any one of claims 1 to 4 in the preparation of a medicament for treating a subject suffering from an inflammatory condition.

7. Use according to claim 6, wherein the inflammatory condition is an ocular condition.

8. The use according to claim 6, wherein the medicament is formulated for intraocular injection.

9. The use according to claim 6, wherein the inflammatory condition is osteoarthritis.

10. The use according to claim 6, wherein the medicament is formulated for injection into a joint space.

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