Formulation for treating ophthalmic conditions

Abstract

To provide a pharmaceutical composition for administration or use in the ocular region.SOLUTION: A pharmaceutical composition comprises (i) a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof and (ii) at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated as a suspension. The composition may be used to treat ophthalmic diseases and disorders caused by abnormal proliferation of angiogenesis.SELECTED DRAWING: Figure 4

Description

[Background technology]

[0001] Angiogenesis and neovascularization are the formation or growth of new or pre-existing capillaries or blood vessels and may be important in disease and health. Pathological ocular neovascularization or neovascularization occurs in the retina, choroid and cornea, resulting in severe visual impairment. It is associated with a wide range of disorders, including wet age-related macular degeneration (AMD), diabetic retinopathy, Retinal artery or vein occlusion, retinopathy of prematurity (ROP), neovascular glaucoma, and infectious processes or inflammation This includes corneal neovascularization secondary to the disease process. Summary of the Invention

[0002] In one aspect, the present disclosure provides a pharmaceutical composition, the pharmaceutical composition comprising: (i) Formula (I): JPEG2025004026000090.jpg2761(I) or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharma- ceutically acceptable excipient; The pharmaceutical composition is in a form for ophthalmic administration or use.

[0003] In some embodiments, the dosage form comprises a compound of formula (I), or an isotopic variant or tautomeric variant thereof. It is a suspension containing fine particles of the isomer, a pharma- ceutically acceptable salt, solvate or hydrate.

[0004] In one aspect, the present disclosure provides a pharmaceutical composition, the pharmaceutical composition comprising: (i) Formula (I): JPEG2025004026000091.jpg2761(I) or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharma- ceutically acceptable excipient; The pharmaceutical composition may be formulated as a suspension, gel or ointment.

[0005] In some embodiments, the particles are micronized.

[0006] In some embodiments, a compound of formula (I), or an isotopic variant or antagonism thereof, The particles of the variant, pharma- ceutically acceptable salt, solvate or hydrate are from about 0.1 μm to about 40 μm. It has a diameter.

[0007] In some embodiments, a compound of formula (I), or an isotopic variant or antagonism thereof, The particles of the variant, pharma- ceutically acceptable salt, solvate or hydrate are from about 0.1 μm to about 10 μm. It has a diameter.

[0008] In some embodiments, a compound of formula (I), or an isotopic variant or antagonism thereof, Particles of the variant, pharma- ceutically acceptable salt, solvate or hydrate have a diameter of about 0.3 μm to about 5 μm.

[0009] In some embodiments, at least about 10% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 20% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 30% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 40% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 50% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 60% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 70% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 80% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 90% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 95% of the particles have a diameter of about 0.1 μm to about 40 μm.

[0010] In some embodiments, the particles have a D10 value of less than about 0.5 μm. In some embodiments, the particles have a D10 value of less than about 1 μm. In some embodiments, the particles have a D10 value of less than about 1.5 μm.

[0011] In some embodiments, the particles have a D50 value of less than about 2.5 μm.

[0012] In some embodiments, the particles have a D50 value of less than about 5 μm. In the present invention, the particles have a D50 value of less than about 7.5 μm.

[0013] In some embodiments, the particles have a D90 value of less than about 5 μm. In some embodiments, the particles have a D90 value of less than about 10 μm. In some embodiments, the particles have a D90 value of less than about 15 μm.

[0014] In some embodiments, a compound of formula (I), or an isotopic variant or antagonism thereof, The variants, pharma- ceutically acceptable salts, solvates or hydrates may be crystallized, microcrystalline, amorphous or lyophilized.

[0015] In some embodiments, the dosage form is a modified release dosage form.

[0016] In some embodiments, the modified release dosage form is a delayed release dosage form, an extended release (ER) dosage form, or a targeted release dosage form.

[0017] In some embodiments, the ER dosage form is a sustained release (SR) dosage form or a controlled release (CR) dosage form.

[0018] In some embodiments, the composition comprises about 0.025% w / v to about 2.0% w / v of a compound of formula (I). In some embodiments, the composition comprises about 0.05% w / v to about 0.5% w / v of a compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises about 0.05% w / v to about 0.15% w / v of a compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof. ) or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0019] In some embodiments, the at least one pharma- ceutically acceptable excipient is a diluent, buffer, Batteries, suspending agents, solubilizers, emulsifiers, antioxidants, pH adjusters, preservatives, detackifiers, antifoaming agents, chelating agents, thickeners, viscosity adjusters, tonicifiers, colorants , an opacifier, an adhesive, a filler, a plasticizer, or any combination thereof.

[0020] In some embodiments, the at least one pharma- ceutically acceptable excipient is a suspending agent, a wetting agent, or a The additive may be a humectant, a pH adjuster, an antioxidant, an osmolality adjuster, or any combination thereof. In some embodiments, the suspending agent is a polymer.

[0021] In some embodiments, the suspending agent is a carbomer homopolymer, a carbomer copolymer, a carbomer interpolymer, a polycarbophil, a cellulose derivative. , polyvinyl alcohol, povidone, hyaluronic acid or its salts, chondroitin sulfate, natural gum, or any combination thereof.

[0022] In some embodiments, the cellulose derivative is hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, or any combination thereof.

[0023] In some embodiments, the hydroxypropyl methylcellulose (HPMC) is K100, K4M, K15M, K100M, E4M, E10M, or any combination thereof.

[0024] In some embodiments, the suspending agent is hydroxypropyl methylcellulose (HPMC).

[0025] In some embodiments, the hypromellose is HPMC E4M.

[0026] In some embodiments, the concentration of the suspending agent in the composition is up to about 1% w / w.

[0027] In some embodiments, the concentration of the suspending agent in the composition is up to about 0.5% w / w.

[0028] In some embodiments, the solubilizing agent is Kolliphor® ELP, Kolliphor® In some embodiments, the solubilizing agent is Kolliphor® HS 15, Kolliphor® HS 15, or a combination thereof.

[0029] In some embodiments, the concentration of the solubilizing agent in the composition is as high as about 5% w / w.

[0030] In some embodiments, the wetting agent is polyoxyl 15 hydroxystearate.

[0031] In some embodiments, the pH adjusting agent is a buffering agent. In some embodiments, the buffering agent is borate, a borate-polyol complex, a phosphate buffer, a citrate buffer, an acetic acid buffer, or the like. In some embodiments, the buffer is selected from a salt buffer, a carbonate buffer, an organic buffer, an amino acid buffer, or a combination thereof. In some embodiments, the buffer is a phosphate buffer or a hydrate thereof. In some embodiments, the phosphate buffer is potassium phosphate or a hydrate thereof. In some embodiments, the phosphate buffer is sodium dihydrogen phosphate dihydrate (NaH2PO4·2H2O), disodium hydrogen phosphate dodecahydrate (Na2HPO4·12H2O), or a combination thereof. do.

[0032] In some embodiments, the osmotic agent is a salt.

[0033] In some embodiments, the salt is sodium chloride.

[0034] In some embodiments, the concentration of the osmotic agent in the composition is up to about 0.5% w / w. .

[0035] In some embodiments, the antioxidant is thiosulfate.

[0036] In some embodiments, the thiosulfate is sodium thiosulfate.

[0037] In some embodiments, the concentration of the antioxidant in the composition is up to about 0.2% w / w.

[0038] In some embodiments, the compositions are stable at temperatures between about 20° C. and about 25° C. for up to 24 months.

[0039] In some embodiments, the composition is substantially free of impurities.

[0040] In some embodiments, the composition is at least about 90% pure by weight. In some embodiments, the composition is at least about 95% pure by weight. The composition is at least about 96% pure by weight. In some embodiments, the composition is at least In some embodiments, the compositions are at least about 97% pure by weight. In some embodiments, the compositions are at least about 98% pure by weight. In some embodiments, the compositions are at least about 99% pure by weight. In some embodiments, the composition comprises at least about 99.1%, about 99.2%, about 99.3%, It is about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9% or about 100% pure by weight.

[0041] In some embodiments, the composition includes up to about 2% w / w total impurities.

[0042] In some embodiments, the composition contains less than about 0.9% w / w, about 0.8% w / w, about 0.7% w / w, about 0.6% w / w, about 0.5% w / w, about 0.4% w / w, about 0.3% w / w, about 0.2% w / w, or about 0.1% w / w of total impurities. Included.

[0043] In some embodiments, the impurities are degradants.

[0044] In some embodiments, the impurity has formula (II): JPEG2025004026000092.jpg2649(II) The present invention includes compounds represented by the formula:

[0045] In some embodiments, the composition contains up to about 2.0% w / w of any individual impurity. Can be enjoyed.

[0046] In some embodiments, the composition has a pH of about 4.0 to about 9.0. In some embodiments, the composition has a pH of about 5.0 to about 8.0. In some embodiments, the composition has a pH of about 6.5 to about 8.0. In some embodiments, the composition has a pH of about 7.0 to about 8.0.

[0047] In one aspect, the present disclosure provides a method for treating or preventing a disorder or disease, the method comprising administering to a subject having a corresponding need a therapeutically effective amount of a pharmaceutical composition comprising: (i) Formula (I): JPEG2025004026000093.jpg2761(I) or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharma- ceutically acceptable excipient; The pharmaceutical composition is in a form for ophthalmic administration or use, The disorder or disease is a neovascular disorder or disease, an inflammatory disorder or disease, or cancer.

[0048] In one aspect, the present disclosure provides a method for treating or preventing a disorder or disease, the method comprising administering to a subject having a corresponding need a therapeutically effective amount of a pharmaceutical composition comprising: (i) Formula (I): JPEG2025004026000094.jpg2761(I) or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharma- ceutically acceptable excipient; The pharmaceutical composition is formulated as a suspension, The disorder or disease is a neovascular disorder or disease, an inflammatory disorder or disease, or cancer.

[0049] In one aspect, the present disclosure provides a method for treating or preventing an ocular disorder or disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising: (i) Formula (I): JPEG2025004026000095.jpg2761(I) or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharma- ceutically acceptable excipient; The pharmaceutical composition is in a form for ophthalmic administration or use.

[0050] In one aspect, the present disclosure provides a method for treating or preventing an ocular disorder or disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising: (i) Formula (I): JPEG2025004026000096.jpg2761(I) or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharma- ceutically acceptable excipient; The pharmaceutical composition is formulated as a suspension.

[0051] In some embodiments, the ocular disorder or disease is an impairment of the function, clarity and / or quality of the lens of the eye. or affect the structure.

[0052] In some embodiments, the ocular disorder or disease is wet macular degeneration, cataracts, presbyopia, nuclear sclerosis of the eye lens, Refsum disease, Smith-Lemli-Opitz syndrome (SLOS), Schnyder crystalline corneal dystrophy (SCCD), abetalipoproteinemia, familial hypobetalipoproteinemia, neovascularization, or cancer.

[0053] In some embodiments, the neovascularization is corneal neovascularization, iris neovascularization, or choroidal neovascularization.

[0054] In some embodiments, the ocular disorder or disease is corneal neovascularization.

[0055] In some embodiments, the subject has already undergone a surgical procedure to treat an ocular disorder or disease.

[0056] In some embodiments, about 0.005 mg / mL to about 5.0 mg / mL of a compound of formula (I). or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof is administered to the eye of a subject. About 4.0 mg / mL of a compound of formula (I), or an isotopic variant, tautomer, or derivative thereof. The pharmaceutical composition, which comprises a physiologically acceptable salt, solvate or hydrate, is administered to the eye of the subject.

[0057] In some embodiments, the composition is administered to a subject once daily, twice daily, three times daily, or four times daily.

[0058] In some embodiments, the composition is administered to the subject three times daily. In some embodiments, about 60 μL of a pharmaceutical composition comprising a compound of Formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof, is administered to the eye of the subject.

[0059] In some embodiments, administration is topical or by ocular injection, hi some embodiments, ocular injection is an intravitreal injection or a subconjunctival injection.

[0060] In one aspect, the present disclosure provides a method for preparing a pharmaceutical composition, the pharmaceutical composition comprising a compound of formula (I or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof, and at least one pharma- ceutically acceptable excipient, is formulated as a suspension, the method comprising: (i) micronizing a compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; (ii) a microparticulated compound of formula (I), or an isotopic variant or tautomer thereof; sterilizing the body, a pharma- ceutically acceptable salt, solvate or hydrate thereof, and (iii) a therapeutically effective amount of a compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof, and at least one pharma- ceutically acceptable The method includes mixing the composition with an excipient.

[0061] In one aspect, the present disclosure provides a method for preparing a pharmaceutical composition, the pharmaceutical composition comprising a compound of formula (I or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof, and at least one pharma- ceutically acceptable excipient, The pharmaceutical composition is in a form for ophthalmic administration or use, and the method comprises: (i) micronizing a compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; (ii) a microparticulated compound of formula (I), or an isotopic variant or tautomer thereof; sterilizing the body, a pharma- ceutically acceptable salt, solvate or hydrate thereof, and (iii) a therapeutically effective amount of a compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof, and at least one pharma- ceutically acceptable The method includes mixing the composition with an excipient.

[0062] In some embodiments, a compound of formula (I), or an isotopic variant or antagonism thereof, A suspension is formed containing particles of the variant, pharma- ceutically acceptable salt, solvate or hydrate.

[0063] In some embodiments, sterilization occurs prior to mixing. In some embodiments, sterilization occurs after mixing.

[0064] In some embodiments, sterilization is performed at a temperature of about 121° C. In this case, sterilization is carried out for about 20 to 30 minutes.

[0065] [Incorporation by Reference] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief description of the drawings]

[0066] [Figure 1] Figure 1 is a microscopic image (100x magnification) of KDR2-2 API, batch #CK0120554-02-03P-01-32-01. [Diagram 2] Figure 2 shows a microscope image (400x magnification) of KDR2-2 API after milling, batch #CK0120554-02-03P-01-32-01. [Diagram 3] FIG. 3 is a schematic depicting the manufacturing process for 0.1% w / v KDR2-2 eye drop suspension. [Figure 4] Figure 4 is a comparison of particle size distribution before and after milling of KDR2-2 API. [Figure 5A-5B] 5A-5B are chromatograms showing the purity of KDR2-2 API before and after milling. [Figures 6A-6E] 6A-6E are chromatograms depicting the increasing degradation of KDR2-2 formulations over a three month period at 40°C. [Figure 7] FIG. 7 is a chromatogram depicting the purity of KDR2-2 preparations. [Figure 8] FIG. 8 shows the results of RBC cell hemolysis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0067] The present disclosure provides compositions for treating and / or preventing, e.g., ophthalmic disorders or diseases. Further provided are methods for treating and / or preventing, for example, an ophthalmic disorder or disease.

[0068] I. Definition The abbreviations used herein have their usual meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to standard rules of chemical valency known in the chemical arts.

[0069] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are prone to conversion from one isomeric form to another. Refers to...

[0070] It will be apparent to one skilled in the art that some of the compounds of the present invention may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the invention.

[0071] Unless otherwise stated, structures depicted herein may further comprise the presence of one or more isotopically enriched atoms. Intentionally including compounds that differ only in planes, e.g., by substitution of hydrogen with deuterium or tritium, or 13 C enriched carbon or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this invention.

[0072] The compounds of the present invention contain unnatural proportions of atoms at one or more of the atoms that constitute such compounds. For example, the compound may contain tritium ( 3 H), Iodine-125( 125 I) Also is carbon 14 ( 14 The compound of the present invention may be radiolabeled with a radioisotope such as C). All isotopic variations, whether radioactive or not, are included within the scope of the present invention.

[0073] The term "isotopic variant" refers to an isotopic variant at one or more of the atoms that constitute such a compound. In some embodiments, an "isotopic variant" of a compound contains one or more isotopes in an unnatural proportion, such as hydrogen ( 1 H), deuterium ( 2 H), Tritium ( 3 H), Carbon 11 ( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen 13( 13 N), Nitrogen-14 ( 14 N), Nitrogen-15 ( 15 N), oxygen 14( 14 O), oxygen 15( 15 O), oxygen 16( 1 6 O), oxygen 17( 17 O), oxygen 18( 18 O), Fluorine 17( 17 F), Fluorine 18 ( 18 F), phosphorus 31 ( 31 P), phosphorus 32 ( 32 P), phosphorus 33 ( 33 P), sulfur 32( 32 S), Sulfur-33( 33 S), Sulfur 34( 34 S), Sulfur 35 ( 35 S), Sulfur 36( 36 S), Chlorine 35 ( 35 Cl), Chlorine 36 ( 36 Cl), Chlorine 37( 37 Cl), Bromine 79 ( 79 Br), Bromine 81 ( 81 Br), Iodine-123 ( 123 I), Iodine-125( 125 I), iodine-127( 1 27 I), Iodine-129( 129 I), and iodine-131 ( 131 I) including, but not limited to, In some embodiments, an "isotopic variant" of a compound is in a stable form, i.e., non-radioactive. In some embodiments, an "isotopic variant" of a compound contains one or more isotopes in non-naturally occurring proportions. It contains hydrogen (1 H), deuterium ( 2 H), Carbon-12 ( 12 C), carbon-13( 13 C), nitrogen 14( 14 N), Nitrogen-15 ( 15 N), oxygen 16( 16 O), oxygen 17( 17 O), oxygen 18( 18 O), Fluorine 17( 17 F), phosphorus 31 ( 31 P), sulfur 32( 32 S), Sulfur-33( 33 S), Sulfur 34( 34 S), Sulfur 36( 36 S), salt Elementary 35( 35 Cl), Chlorine 37( 37 Cl), Bromine 79 ( 79 Br), Bromine 81 ( 81 Br), and iodine-127 ( 127 In some embodiments, isotopic variants of the compounds include, but are not limited to, " is an unstable form, i.e., radioactive. In some embodiments, "isotopic variants" of a compound contain unnatural proportions of one or more isotopes, such as tritium ( 3 H), Carbon 11 ( 11 C), carbon-14( 14 C), nitrogen 13( 13 N), oxygen 14( 14 O), oxygen 15( 15 O), Fluorine 18 ( 18 F), N32( 32 P), phosphorus 33 ( 33 P), sulfur 35( 35 S), Chlorine 36 ( 36 Cl), Iodine-123 ( 123 I), Iodine-125( 125 I), Iodine-129( 129 I), and iodine-131 ( 131 I) but not limited to As will be understood, in the compounds according to the present invention, any hydrogen may be, if possible, replaced by, for example, 2H, or any carbon may be, for example, 13 In C or any nitrogen may be present, e.g. 15 N or any oxygen may be for example 18 In some embodiments, an "isotopic variant" of a compound may be non-O. Contains natural proportions of deuterium (D).

[0074] As noted, throughout this application, alternatives are written in Markush groups, i.e., each amino acid position contains more than one possible amino acid. Each member of a Markush group should be considered individually, thereby including other embodiments, and the Markush group should not be understood as a single unit.

[0075] As used herein, the term "a" or "an" refers to one or more. As used herein, the term "substituted by" means that the specified group may be replaced by one or more of any or all of the specified substituents. For example, a group such as an alkyl group or a heteroaryl group is an "unsubstituted C1-C 20 When "substituted by an alkyl group or an unsubstituted 2- to 20-membered heteroalkyl group," the group is one or more unsubstituted C1-C 20 It may contain alkyl groups and / or one or more unsubstituted 2-20 membered heteroalkyl groups.

[0076] As used herein, the term "acceptable" with respect to a formulation, composition or ingredient refers to having no continuing deleterious effects on the general health of the subject being treated.

[0077] The term "pharmaceutically acceptable salts" as used herein includes both acid addition salts and base addition salts, i.e., salts of active compounds prepared with relatively non-toxic acids or bases, as determined by the specific substituents found in the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, it is possible to obtain base addition salts by contacting a neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. When the compounds of the present invention contain relatively alkaline functional groups, it is possible to obtain acid addition salts by contacting a neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, lysine, nitric acid ... phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or thiophosphoric acid These include those derived from inorganic acids such as phosphoric acid and the like, and from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, and the like. Further included are amino acid salts such as arginine salts and the like, and salts of organic acids such as glucuronic acid or galacturonic acid and the like (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both alkaline and acidic functionalities that allow the compounds to be converted into either base or acid addition salts, or exist as zwitterions.

[0078] Thus, the compounds of the present invention may exist as salts, for example salts of pharma- ceutically acceptable acids. The present invention includes such salts. Non-limiting examples of such salts include hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, propionate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof, including racemic mixtures), succinate, benzoate, and salts with amino acids such as glutamic acid, as well as quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). These salts can be prepared by methods known to those skilled in the art.

[0079] Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in the usual manner. The parent form of the compound may differ from the salt forms in some physical properties (e.g., solubility in polar solvents). In some embodiments, the compounds of the invention contain both alkaline and acidic functional groups that can convert the compound into either a base addition salt or an acid addition salt. The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the usual manner. Although the parent form of the compound may differ from the salt forms in some physical properties (e.g., solubility in polar solvents), for purposes of the present invention, the salts disclosed herein are equivalent to the parent form of the compound, unless otherwise indicated.

[0080] In addition to salt forms, the present invention provides the compounds in the form of prodrugs. Prodrugs of the compounds described herein are compounds that are susceptible to chemical changes under physiological conditions to provide the compounds of the present invention ... in vivo after administration. Prodrugs can also be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, for example, when contacted with a suitable enzyme or chemical reagent.

[0081] Some compounds of the present invention may exist in unsolvated and solvated forms (including hydrated forms). In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present invention. Some compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be included within the scope of the present invention.

[0082] "Pharmaceutically acceptable excipient" and "pharmacologically acceptable carrier" refer to substances that contribute to the administration of a compound to and absorption by a subject and that do not cause significant toxicological effects in the patient and that may be included in the compositions of the present invention. Non-limiting examples of pharma-ceutically acceptable excipients include water, NaCl, saline solution, lactated Ringer's, normal sucrose, normal glucose, adhesives, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (e.g., Ringer's solution), alcohol, oils, gelatin, carbohydrates (e.g., lactose, amylose, or starch), fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and colors, etc. Such products can be sterilized and If necessary, it may be mixed with auxiliary substances, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants and / or aromatic substances. Substances such as acetaminophen, ...

[0083] The term "product" is intended to include formulations of active compounds with encapsulating materials, said encapsulating materials serving as carriers to provide a capsule in which the active ingredient, with or without other carriers, is surrounded by the carrier, thus binding the carrier to the active ingredient. Similarly, cachets and tablets are included. Tablets, powders, capsules, pills, cachets and tablets may be used as solid dosage forms suitable for oral administration.

[0084] The term "disease" or "condition" refers to an existing state or health condition of a patient or subject that can be treated with a compound or method according to the present invention. The disease can be an ophthalmic disease.

[0085] The term "treatment" refers to any indication of success in curing or ameliorating an injury, disease, pathology, or condition, including any objective or subjective parameter, such as abatement; remission; reduction in symptoms or making the injury, pathology, or condition tolerable to the patient; reduction in the rate of degeneration or decline; non-debilitating end points of degeneration; or improvement in the patient's physical or mental health. The treatment or amelioration of symptoms may be based on objective or subjective parameters, including the results of a physical exam, a neuropsychiatric exam, and / or a psychiatric evaluation. The term "treatment" and its verb forms may include prevention of an injury, pathology, condition, or disease. In some embodiments, treatment is prevention. In other embodiments, treatment does not include prevention.

[0086] "Treatment," "alleviation," or "relief" are used interchangeably herein. As used herein (and as understood in the art), these terms broadly include any manner of obtaining beneficial or desired results in a subject's condition, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether partial or complete, detectable or undetectable, reduction in the extent of disease, stabilization of the disease state (i.e., not worsening), prevention of the spread or spread of disease, delay or slowing of disease progression, improvement or remission of the disease state, reduction in recurrence of disease, and remission. In other words, as used herein, As such, "treatment" includes any cure, amelioration, or prevention of a disease. Treatment can prevent the onset of a disease, inhibit the spread of a disease, ameliorate symptoms of a disease (e.g., itching, swelling, burning, coughing, fever, chest pain, difficulty breathing), completely or partially eliminate the underlying cause of a disease, shorten the duration of a disease, or any combination of the above.

[0087] As used herein, "treatment" includes prophylactic treatment. The treatment method includes administering to a subject a therapeutically effective amount of a compound described herein. The administration step may consist of a single administration or may include a series of administrations. The length of the treatment period will depend on several factors, such as the severity of the condition, the age of the patient, the concentration of the compound, the activity of the composition used for treatment, or a combination thereof. It will also be understood that the effective amount of a therapeutic or prophylactic agent may increase or decrease during the course of a particular treatment or prophylactic regimen. Dose modifications may be obtained and accounted for by standard diagnostic measurements known in the art. In some cases, administration over an extended period of time may be necessary. For example, the composition is administered to a subject in an amount and for a period sufficient to treat the patient.

[0088] The term "prevention" refers to the reduction in the occurrence of a disease, condition, or condition in a patient. Prevention may be complete (no detectable symptoms) or partial, whereby fewer symptoms are observed than would occur in the absence of treatment. In some embodiments, prevention refers to slowing the progression of a disease, disorder, or condition, or preventing its progression to a harmful or otherwise undesirable state.

[0089] The term "patient" or "subject in need" refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administration of a pharmaceutical composition according to the present disclosure. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, dairy cows, deer, and other non-mammalian animals, including but not limited to fish and birds. In some embodiments, the patient is a human.

[0090] The treatment described herein further refers to the systemic delivery of the compounds disclosed herein to any type of plant, including trees, shrubs, flowering plants, ornamental plants, indoor plants, and the like. This includes potted plants, ground covers and grasses, and agricultural plants (including crops of agricultural plants).

[0091] As used herein, a "hydrate" is a compound that contains stoichiometric or non-stoichiometric amounts of water and, in some embodiments, is formed during crystallization with water.

[0092] As used herein, the term "agricultural plant" refers to any part or whole of a plant that is harvested or grown on a commercial scale, or that is used as a significant source of feed, food, fiber, or other chemical compounds.

[0093] An "effective amount" is the amount of the compound that achieves its stated purpose (e.g., achieving the effect of administration of the compound, treating a disease, decreasing enzyme activity, increasing enzyme activity, reducing a signal transduction pathway, or alleviating one or more symptoms of a disease or condition) relative to the absence of the compound. An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or amelioration of one or more symptoms of a disease. and may also be referred to as a "therapeutically effective amount." Equivalent terms refer to a reduction in the severity or frequency of a symptom, or the elimination of a symptom. A "prophylactically effective amount" of a drug is an amount of drug that, when administered to a subject, has a desired prophylactic effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology or condition or a symptom thereof. A complete prophylactic effect does not necessarily occur by administration of one dose, and may require the administration of a series of doses. The prophylactically effective amount may be administered in a single dose or multiple doses. As used herein, an "activity reducing amount" refers to the amount of antagonist required to reduce the enzyme activity relative to the absence of antagonist. As used herein, a "function disrupting amount" refers to the amount of antagonist required to disrupt the function of the enzyme or protein relative to the absence of antagonist. The exact amount depends on the therapeutic objectives and can be determined by one of skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). The therapeutically effective amount can be determined by measuring the relevant physiological effects and can be adjusted based on, for example, the administration plan and diagnostic analysis of the subject's condition. By way of example, at a specific time after administration, a compound of formula (I), or an isotopic variant, tautomer, or pharma- ceutically acceptable derivative thereof may be Measuring the serum levels of the corresponding salt, solvate or hydrate (or, for example, a metabolite thereof) can indicate whether a therapeutically effective amount has been administered.

[0094] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. The target concentration is the concentration of active compound that achieves the methods described herein, e.g., as determined using methods described herein or known in the art.

[0095] As is well known in the art, therapeutically effective amounts for humans can also be determined from animal models. For example, a dose for humans can be formulated to be a concentration found to be effective in animals. As described above, a dose in humans can be adjusted by monitoring the effectiveness of the compound and adjusting the dose upwards or downwards. It is within the capabilities of a person skilled in the art to adjust the dose based on the above and other methods to achieve maximum efficacy in humans. It is entirely within the capabilities of a person skilled in the art to adjust the dose based on the above and other methods to achieve maximum therapeutic window efficacy or toxicity in humans.

[0096] As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent sufficient to alleviate the above-mentioned disorder. For example, for a given parameter, a therapeutically effective amount may represent at least a 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90% or at least a 100% increase or decrease. The therapeutic efficacy may also be noted as a "-fold" increase or decrease. For example, a therapeutically effective amount may be It may have an effect of at least 1.2-fold, 1.5-fold, 2-fold, 5-fold or more relative to the control.

[0097] Dosage may vary depending on the needs of the patient and the compound used. In the context of the present invention, the dosage administered to the patient should be sufficient to achieve a beneficial therapeutic response in the patient over time. The amount of dosage will depend on the existence, nature and extent of any adverse side effects. It is within the skill of the art to determine the appropriate dosage for a particular case. Generally, treatment is initiated with relatively small dosages that are less than the optimal dosage of the compound. Thereafter, the dosage is increased in small increments until the optimal effect in such case is reached. The amount and interval of administration can be individually adjusted to provide a level of the administered compound that is effective for the particular clinical indication being treated. This provides a treatment plan that is appropriate to the severity of the individual's disease state.

[0098] As used herein, the term "administration" refers to parenteral or enteral administration. Thus, as used herein, "administration" includes, but is not limited to, oral administration, administration as a suppository, topical contact, intravenous administration, intraperitoneal administration, intramuscular administration, inhalation administration, aerosol administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, subcutaneous administration, or implantation of a sustained release device (e.g., a mini-osmotic pump) into a subject. Administration may be by any route, including transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal) administration. Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, liposomal formulations, intravenous infusion, use of transdermal patches, by ocular route, by ear route, and the like. "Concomitant administration" refers to administration of a composition described herein at the same time as, just before, or just after one or more other therapeutic methods are administered. The compounds of the present invention may be administered to a patient individually or in combination to a patient. Co-administration can refer to the administration of the compounds individually or in combination (the administration of more than one compound). The present invention is intended to include simultaneous, near-simultaneous, or sequential administration of the active substances or agents. Thus, the product may be combined with other active substances if desired (e.g., to reduce metabolic degradation). The compositions of the present invention may be delivered transdermally, may be delivered topically, and are formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Oral products include tablets, pills, powders, dragees, capsules, liquids, tablets, cachets, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by the patient. Solid form products include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form products include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. The compositions of the present invention are intended to include the administration of the active substances or agents at the same time. The composition may further comprise ingredients that provide sustained release and / or comfort. Such ingredients may be polymeric The compositions of the present invention include a granular, granular, and / or granular composition, such as a granular, granular, or ... For example, microspheres may be administered via intradermal injection of drug-containing microspheres for subcutaneous sustained release (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995), as biodegradable and injectable formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995), or as oral microspheres (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In other embodiments, formulations of the compositions of the present invention may be delivered using liposomes that fuse with cell membranes or liposomes that are endocytosed, i.e., by using receptor ligands attached to the liposomes. The receptor ligands bind to cell surface membrane protein receptors and cause endocytosis. The use of liposomes allows for the focus of delivery of the compositions of the invention to target cells in vivo, particularly if the liposome surface contains receptor ligands with specificity for the target cells or is otherwise directed preferentially to a particular organ. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989). The compositions of the invention may also be delivered as nanoparticles.

[0099] "Concomitant administration" refers to administration of a composition described herein in combination with one or more other therapeutic modalities. Concurrent administration of one or more other therapeutic methods may refer to administration just prior to or just after administration of one or more other therapeutic methods. The compounds of the present invention may be administered to a patient individually or concomitantly to a patient. Concomitant administration is intended to include administration of the compounds individually or in combination (more than one compound) simultaneously or sequentially. The compositions of the present invention may be They may be delivered transdermally, topically, or formulated as applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0100] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. The target concentration is the concentration of active compound that achieves the methods described herein, e.g., as determined using methods described herein or known in the art.

[0101] As is well known in the art, therapeutically effective amounts for humans can also be determined from animal models. For example, a dose for humans can be formulated to be a concentration found to be effective in animals. As described above, a dose in humans can be adjusted by monitoring the effectiveness of the compound and adjusting the dose upwards or downwards. It is within the ability of a person skilled in the art to adjust the dose based on the above and other methods to achieve maximum efficacy in humans.

[0102] Dosage may vary depending on the needs of the patient and the compound used. In the context of the present invention, the dosage administered to a patient should be sufficient to achieve a beneficial therapeutic response in the patient over time. The amount of dosage will be determined by the existence, nature and extent of any adverse side effects. It is within the skill of the art to determine the appropriate dosage for a particular case. Generally, treatment is initiated with a relatively small dosage that is less than the optimum dosage of the compound. Thereafter, the dosage is increased in small increments until the optimum effect in such case is reached.

[0103] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound that are effective for the particular clinical indication being treated, thereby providing a treatment regimen commensurate with the severity of the individual's disease state.

[0104] In accordance with the teachings herein, an effective prophylactic or therapeutic treatment regimen can be designed that does not cause substantial toxicity and effectively treats the clinical symptoms exhibited by a particular patient. Such regimens should involve careful selection of active compounds by considering factors such as compound potency, relative bioavailability, patient weight, the presence and severity of adverse side effects, suitable mode of administration, and the toxicity profile of the selected agent.

[0105] In some embodiments, the co-administration is within 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours, 2 days, 4 days, 1 week, or 1 month of the second active agent. Co-administration includes administering one active agent at a time. Co-administration includes administering two active agents simultaneously, about simultaneously (e.g., within about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration includes administering two active agents at a time. In other embodiments, the active agents may be formulated separately. In other embodiments, the active agents and / or adjuncts may be linked or combined with each other. It may be conjugated.

[0106] As used herein, a "cell" refers to a cell that has sufficient metabolic function to store or replicate its genomic DNA. A cell can be determined by methods well known in the art, including, for example, the presence of an intact membrane, staining with certain dyes, the ability to produce progeny, or, in the case of gametes, the ability to combine with a second gamete to produce viable progeny. The cells may include prokaryotic and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells, and cells of plant or animal origin, such as mammalian cells, insect (e.g., Spodoptera) cells, and human cells. The cells are useful if they are not naturally adherent or if they are treated (e.g., trypsinized) so that they do not adhere to a surface.

[0107] "Control" or "control experiment" is used in its ordinary sense to refer to an experiment in which an experimental subject or agent is treated as in a parallel experiment, except that an experimental step, agent, or variable is omitted. In some cases, a control is used as a standard for comparison in evaluating the efficacy of an experiment. In some embodiments, a control is measuring the activity of a protein in the absence of a compound described herein (including embodiments and examples).

[0108] "An amount sufficient to effect a change" refers to the presence of a detectable difference between the level of an indicator before (e.g., baseline level) and after administration of a particular treatment regimen, including any objective parameter (e.g., serum concentration) or subjective parameter (e.g., subject's sense of well-being).

[0109] "Substantially pure" means that an ingredient comprises more than about 75% of the total content of the composition, not including excipients. and typically comprises more than about 85% of the total content. Typically, "substantially pure" means that the total composition, excluding excipients, is at least 90%, preferably at least 90% pure. A composition that is at least 95%, at least 96%, at least 97% or more of the component of interest. In some cases, the ingredient of interest comprises more than about 90%, more than about 95%, or more than about 96% of the total content of the composition, excluding excipients (on a weight / weight basis). "Substantially pure" means that the composition has less than about 25%, 15%, 10%, 5%, or 4% It indicates that the product contains no or the following known or unknown impurities: Impurities do not include excipients (e.g., adhesives, fillers, diluents, glidants, lubricants, disintegrants, etc.).

[0110] As used herein, "angiogenesis" refers to the process of new blood vessels forming from pre-existing blood vessels. "Neovascularization" refers to the formation of new blood vessels that usually take the form of a functional microvascular network and are capable of being perfused by red blood cells, and serve as collateral circulation in response to local poor perfusion or ischemia. Neovascularization is generally distinguished from angiogenesis, because the main characteristic of angiogenesis is the protrusion and growth of capillary buds and capillary sprouts from pre-existing blood vessels.

[0111] As used herein, the terms "corneal neovascularization" and "corneal neovascularization" refer to the process by which new blood vessels form and grow from the limbus into the adjacent corneal stroma. Because the cornea is avascular and does not contain any blood vessels, any new blood vessels in the cornea typically result from blood vessels growing into the cornea from the limbal vascular plexus region of the eye.

[0112] "Choroidal neovascularization" refers to the formation of new blood vessels that originate from the choroid and can enter the subretinal space through rupture of Bruch's membrane in the retinal pigment epithelium.

[0113] "Retinal neovascularization" refers to the formation of new blood vessels that extend from the retinal surface into the vitreous.

[0114] "Iris neovascularization" is a medical condition of the iris of the eye in which new abnormal blood vessels (formed by neovascularization) are found on the surface of the iris. The condition is often associated with diabetes in late-stage proliferative diabetic retinopathy. Other conditions that can cause rubeosis iridis include central retinal vein occlusion, ocular ischemic syndrome, and chronic retinal detachment.

[0115] Macular degeneration, also called retinal degeneration, is an eye disease involving degeneration of the macula, which is the central portion of the retina. Unless specified, "macular degeneration" in this disclosure includes all forms of the disease.

[0116] "Wet macular degeneration," also called the neovascular or exudative form of macular degeneration, involves the formation of new blood vessels (i.e., neovascularization) that improves the blood supply of retinal tissue, especially beneath the macula, the part of the retina responsible for the sharp central vision. The new blood vessels are prone to damage and can rupture, causing bleeding and damage to surrounding tissue. Wet macular degeneration accounts for approximately 90% of blindness associated with macular degeneration. Neovascularization causes rapid loss of vision and eventually leads to scarring of the retinal tissue and bleeding in the eye. This scar tissue and blood produces dark, distorted areas in the field of vision, and invariably results in legal blindness. Wet macular degeneration typically begins with distortion of the central field of vision. Straight lines become wavy. Subjects with wet macular degeneration report blurred vision and the presence of blank spots (scotoma) in their field of vision.

[0117] "Dispersants" and / or "viscosity modifiers" are used in the liquid medium or in the granulation or mixing process. Materials that control the diffusion and uniformity of the drug are included. In some embodiments, these formulations further enhance the effect of a coating or disintegration matrix. Exemplary diffusion enhancers / dispersing agents are: For example, hydrophilic polymers; electrolytes; Tween® 60 or Tween® 80; PEG Polyvinylpyrrolidone (PVP, commercially known as Plasdone®); Carbohydrate-based dispersants such as hydroxypropylcellulose (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcellulose (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS); amorphous cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl alcohol (PVA); vinylpyrrolidone / vinyl acetate copolymer (S630); 4-(1,1,3,3-tetramethylbutyl)-phenol with ethylene oxide and formaldehyde; poloxamer (e.g., Pluronics F68 (registered trademark), Pluronics F88 (registered trademark) and Pluronics F108 (registered trademark), poloxamine (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ)); polyvinylpyrrolidone K12; polyvinylpyrrolidone K17; polyvinylpyrrolidone K25; or polyvinyl Pyrrolidone K30; Polyvinylpyrrolidone / vinyl acetate copolymer (S-630); Polyethylene glycol Cole (e.g., polyethylene glycol is about 300 to about 6000, or about 3350 to about 4000, or and combinations thereof. Examples of suitable cellulose acetate compositions include cellulose acetate or triethyl cellulose; ... Plasticizers such as cellulose may also be used as dispersing agents. Dispersing agents are particularly useful in liposomal dispersions, self-emulsifying dispersions are dimyristoyl phosphatidylcholine, natural phosphatidylcholine from eggs, natural phosphatidylglycerol from eggs, cholesterol and isopropyl myristate.

[0118] The term "diluent" refers to a chemical compound for diluting the compound of interest prior to delivery. Diluents may be used to stabilize the compound as they can provide a more stable environment. Salts that dissolve in buffer solutions (which can further provide pH control or maintenance) are used as diluents in the art, including, but not limited to, aqueous saline solutions buffered with phosphate. In some embodiments, diluents increase the volume of the composition, facilitating compression or creating sufficient volume for homogeneous mixing during capsule filling. Such compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®; calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugars such as Di-Pac® (Amstar); mannitol, hydroxypropyl methylcellulose, sorbitol, dextrose ... cellulose, hydroxypropyl methylcellulose acetate stearate, sucrose based diluents, confectioner's sugar; calcium sulfate monohydrate, sulfate Calcium dihydrate; calcium lactate trihydrate; dextrates; hydrolyzed These include: powdered cereals, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite and similar.

[0119] The term "water-insoluble diluents" typically refers to compounds used in the formulation of drugs, such as calcium phosphate, calcium sulfate, starch, modified starch, and microcrystalline cellulose, and microcellulose (e.g., about 0.45 g / cm 3 For example, Avicel, powdered cellulose ), indicating talc.

[0120] Examples of the "solubilizing agent" include triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium docusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-(2-hydroxyethyl)-2-pyrrolidone, polyacetamide, polyisobutene ... Rivinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, N-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, diethylene glycol mono Ethyl ether (transcutol), propylene glycol, dimethyl isosorbide, and similar.

[0121] "Stabilizers" include, for example, any antioxidants, buffers, acids, preservatives, and similar compounds.

[0122] "Suspension agents" include, for example, polyvinylpyrrolidone (e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K22, polyvinylpyrrolidone K32, polyvinylpyrrolidone K42, polyvinylpyrrolidone K52, polyvinylpyrrolidone K62, polyvinylpyrrolidone K72, polyvinylpyrrolidone K82, polyvinylpyrro Polyvinylpyrrolidone K17, Polyvinylpyrrolidone K25, or Polyvinylpyrrolidone K30); Vinylpyrrolidone / vinyl acetate copolymer (S630); polyethylene glycol (e.g., poly Ethylene glycol has a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400. may have an amount of 0.1 to 0.5% by mass; sodium carboxymethylcellulose; methylcellulose; hydroxypropyl methylcellulose; hydroxypropyl methylcellulose acetate stearate; polysorbate 80; hydroxyethylcellulose; sodium alginate; gums (e.g., tragacanth gum, gum arabic, guar gum, xanthan including xanthan gum); sugars; celluloses (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose); polyethoxylated sorbitan monolaurate; povidone, and similar compounds.

[0123] "Surfactants" include, for example, sodium lauryl sulfate, sodium docusate, Tween 60 or Tween 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glycerol monostearate, copolymers of ethylene oxide and propylene oxide (e.g., Pluronic® (BASF)), and similar compounds. Some other surfactants are , polyoxyethylene fatty acid glycerides and vegetable oils (e.g., polyoxyethylene (60) hydrogenated castor oil), and polyoxyethylene alkyl ethers and alkyl phenyl ethers (e.g., Octoxynol 10, Octoxynol 40). In some embodiments, a surfactant may be included to improve physical stability or for other purposes. Many nonionic surfactants are known that are acceptable for topical ophthalmic formulations. Such surfactants include tyloxapol; polyoxyethylene sorbitan esters (e.g., Polysorbate 80, Polysorbate 60, and Polysorbate 20); polyethoxylated castor oil (e.g., Cremophore EL); polyethoxylated hydrogenated castor oil (e.g., HCO-40), and poloxamer. Includes.

[0124] As used herein, the term "carrier" refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.

[0125] "Carrier materials" include any conventional excipients in pharmacy and should be selected based on compatibility with the compounds disclosed herein and the release profile properties of the desired dosage form. Exemplary carrier materials include, for example, adhesives, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. "Pharmaceutically compatible carrier materials" include gum arabic, gelatin, colloidal silicon dioxide, calcium glyceryl phosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol, cholesterol esters, sodium caseinate, Examples of suitable glycerols include, but are not limited to, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose complexes, sugars sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, HA and Lachman, L., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Vol. See seventh edition (Lippincott Williams & Wilkins 1999).

[0126] "Wetting agents" include, for example, oleic acid, glycerol monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate, triacetin, Tween 80, Vitamin E TPGS, ammonium salts, and similar compounds.

[0127] The compositions of the present invention are formulated to be isotonic with respect to natural tear fluid. Thus, the compositions are formulated to have an osmolality of about 280 to about 320 milliosmoles per kilogram of water ("mOsm / kg"). If necessary, the compositions may include an ophthalmologically acceptable tonicity adjuster, such as sodium chloride, potassium chloride, glycerin, sorbitol, or mannitol. In some embodiments, the ophthalmic composition further comprises a tonicity adjuster. In some embodiments, the tonicity adjuster is selected from sodium chloride, sodium nitrate, sodium sulfate, sodium hydrogen sulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dextrose, mannitol, sorbitol, sucrose, urea, propylene glycol, glycerin, or combinations thereof.

[0128] In some embodiments, the composition is stored in a plastic container. In some embodiments, the material of the plastic container comprises low density polyethylene (LDPE).

[0129] In some embodiments, the composition further comprises a pH adjusting agent. In some embodiments, the ophthalmically acceptable carrier further comprises at least one viscosity increasing agent. In some embodiments, The thickeners are cellulose-based polymers, polyoxyethylene-polyoxypropylene The polymer may be selected from lentotriblock copolymers, dextran-based polymers, polyvinyl alcohol, dextrin, polyvinylpyrrolidone, polyalkylene glycols, chitosan, collagen, gelatin, hyaluronic acid, or combinations thereof.

[0130] I. Composition In one aspect, the present disclosure provides a pharmaceutical composition, the pharmaceutical composition comprising: (i) Formula (I): JPEG2025004026000097.jpg2761(I) or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharma- ceutically acceptable excipient; The pharmaceutical composition is in a form for ophthalmic administration or use.

[0131] In some embodiments, the dosage form comprises a compound of formula (I), or an isotopic variant or tautomeric variant thereof. It is a suspension containing fine particles of the isomer, a pharma- ceutically acceptable salt, solvate or hydrate.

[0132] In one aspect, the present disclosure provides a pharmaceutical composition, the pharmaceutical composition comprising: (i) Formula (I): JPEG2025004026000098.jpg2761(I) or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharma- ceutically acceptable excipient; The pharmaceutical composition is formulated as a suspension, gel, or ointment, hi some embodiments, the pharmaceutical composition is formulated as a suspension.

[0133] In some embodiments, the particles are micronized.

[0134] In some embodiments, a compound of formula (I), or an isotopic variant or antagonism thereof, The particles of the variant, pharma- ceutically acceptable salt, solvate or hydrate are from about 0.1 μm to about 40 μm. In some embodiments, the compound of formula (I), or an isomer thereof, Particles of the isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate have a diameter of about 0.1 μm to about 10 μm. In some embodiments, particles of a compound of Formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof, have a diameter of about 0.3 μm to about 5 μm.

[0135] In some embodiments, at least about 10% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 20% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 30% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 40% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 50% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 60% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 70% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 80% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 90% of the particles have a diameter of about 0.1 μm to about 40 μm. In some embodiments, at least about 95% of the particles have a diameter of about 0.1 μm to about 40 μm.

[0136] In some embodiments, the particles have a D10 value of less than about 0.5 μm. In some embodiments, the particles have a D10 value of less than about 1 μm. In some embodiments, the particles have a D10 value of less than about 1.5 μm. In some embodiments, the particles have a D10 value of less than about 0.5 μm, about 0.6 μm, about 0.7 μm, about 0.8 μm, about 0.9 μm, about 1.0 μm, about 1.1 μm, about 1.2 μm, about 1.3 μm, about 1.4 μm, or about 1.5 μm.

[0137] In some embodiments, the particles have a D50 value of less than about 2.5 μm. In some embodiments, the particles have a D50 value of less than about 5 μm. In some embodiments, the particles have a D50 value of less than about 7.5 μm. In some embodiments, the particles have a D50 value of less than about 2.5 μm, about 2.6 μm, about 2.7 μm, about 2.8 μm, about 2.9 μm, about 3.0 μm, about 3.1 μm, about 3.2 μm, about 3.3 μm, about 3.4 μm, about 3.5 μm, about 3.6 μm, about 3.7 μm, about 3.8 μm, about 3.9 μm, about 4.0 μm, about 4.1 μm, about 4.2 μm, about 4.3 μm, about 4.4 μm, about 4.5 μm, about 4.6 μm, about 4.7 μm, about 4.8 μm, about 4.9 μm. , about 5.0 μm, about 5.1 μm, about 5.2 μm, about 5.3 μm, about 5.4 μm, about 5.6 μm, about 5.7 μm, about 5.8 μm, about 5.9 μm, about 6.0 μm, about 6.1 μm, about 6.2 μm, about 6.3 μm, about 6.4 μm, about 6.5 μm, about 6.6 μm, about 6.7 μm, about 6.8 μm, about 6.9 μm, about 7.0 μm, about 7.1 μm, about 7.2 μm, about 7.3 μm, about 7.4 μm or about 7.5 μm.

[0138] In some embodiments, the particles have a D90 value of less than about 5 μm. In some embodiments, the particles have a D90 value of less than about 10 μm. In some embodiments, the particles have a D90 value of less than about 15 μm. In some embodiments, the particles have a D90 value of less than about 4.0 μm, about 4.1 μm, about 4.2 μm, or about 4.3 μm. In some embodiments, the particles have a D90 value of less than about 5 μm, about 6 μm, about 7 μm, about 8 μm, about 9 μm, about 10 μm, about 11 μm, about 12 μm, about 13 μm, about 14 μm, or about 15 μm.

[0139] In some embodiments, a compound of formula (I), or an isotopic variant or antagonism thereof, The variants, pharma- ceutically acceptable salts, solvates or hydrates may be crystallized, microcrystalline, amorphous or lyophilized.

[0140] In some embodiments, the dosage form is a modified release dosage form. In some embodiments, the modified release dosage form is a delayed release dosage form, an extended release (ER) dosage form, or a targeted release dosage form. In some embodiments, the ER dosage form is a sustained release (SR) dosage form or a controlled release (CR) dosage form. In some embodiments, the composition comprises about 0.025% w / v to about 2.0% w / v of a compound of Formula (I), or In some embodiments, the composition comprises about 0.05% w / v to about 0.5% w / v of a compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises about 0.05% w / v to about 0.15% w / v of a compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof. The present invention includes compounds which are represented by the formula (I) or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0141] In some embodiments, the at least one pharma- ceutically acceptable excipient is a diluent, buffer, In some embodiments, the at least one drug may be a buffer, a suspending agent, a solubilizing agent, an emulsifying agent, an antioxidant, a pH adjusting agent, a preservative, a detackifying agent, an antifoaming agent, a chelating agent, a thickening agent, a viscosity adjusting agent, an isotonicity agent, a coloring agent, an opacifying agent, an adhesive, a filler, a plasticizer, or any combination thereof. The physiologically acceptable excipients are suspending agents, wetting agents, pH adjusting agents, antioxidants, osmolality adjusting agents, or any combination thereof.

[0142] In some embodiments, the suspending agent is a polymer. In some embodiments, the suspending agent is a carbomer homopolymer, a carbomer copolymer, a carbomer interpolymer, polycarbophil, a cellulose derivative, a polyvinyl alcohol, povidone, hyaluronic acid or a salt thereof, chondroitin sulfate, a natural gum, or any combination thereof. In some embodiments, the cellulose derivative is hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, or any combination thereof. In some embodiments, the hydroxypropyl methylcellulose (HPMC) is K100, K4M, K15M, K100M, E4M, E10M, or any combination thereof ...hydroxypropyl methylcellulose (HPMC) is K100, K4M, K15M, K100M, E4M, E10M, or any combination thereof. In some embodiments, the suspending agent is hydroxypropyl methylcellulose (HPMC). In some embodiments, the hypromellose is HPMC E4M.

[0143] In some embodiments, the concentration of the suspending agent in the composition is up to about 1% w / w. In an embodiment, the concentration of the suspending agent in the composition is up to about 0.5% w / w.

[0144] In some embodiments, the solubilizing agent is Kolliphor® ELP, Kolliphor® In some embodiments, the solubilizing agent is Kolliphor® HS 15, Kolliphor® HS 15, or a combination thereof.

[0145] In some embodiments, the concentration of the solubilizing agent in the composition is as high as about 5% w / w.

[0146] In some embodiments, the wetting agent is polyoxyl 15 hydroxystearate.

[0147] In some embodiments, the pH adjusting agent is a buffer. In some embodiments, the buffer is a phosphate buffer or a hydrate thereof. In some embodiments, the phosphate buffer is potassium phosphate or a hydrate thereof. In some embodiments, the phosphate buffer is sodium dihydrogen phosphate dihydrate (NaH2PO4·2H2O), disodium hydrogen phosphate dodecahydrate. solvate (Na2HPO4·12H2O), or a combination thereof.

[0148] In some embodiments, the tonicity adjusting agent is a salt, hi some embodiments, the salt is sodium chloride.

[0149] In some embodiments, the concentration of the osmotic agent in the composition is up to about 0.5% w / w. .

[0150] In some embodiments, the antioxidant is a thiosulfate, hi some embodiments, the thiosulfate is sodium thiosulfate.

[0151] In some embodiments, the concentration of the antioxidant in the composition is up to about 0.2% w / w.

[0152] In some embodiments, the compositions are stable at temperatures between about 20° C. and about 25° C. for up to 24 months.

[0153] In some embodiments, the composition is substantially free of impurities.

[0154] In some embodiments, the composition is at least about 90% pure. In some embodiments, the composition is at least about 95% pure. At least about 96% pure. In some embodiments, the composition is at least about 97% pure. In some embodiments, the composition is at least about 98% pure. In some embodiments, the composition is at least about 99% pure. The composition is at least about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, It is about 99.8%, about 99.9% or about 100% pure.

[0155] In some embodiments, the composition contains up to about 2% total impurities. In embodiments, the composition contains less than about 0.9% w / w, about 0.8% w / w, about 0.7% w / w, about 0.6% w / w, about 0.5% w / w, about 0.4% w / w, about 0.3% w / w, about 0.2% w / w, or about 0.1% w / w of total impurities. .

[0156] In some embodiments, the impurities are degradants.

[0157] In some embodiments, the impurity has formula (II): JPEG2025004026000099.jpg2549(II) The present invention includes compounds represented by the formula:

[0158] In some embodiments, the composition contains up to about 2.0% w / w of any individual impurity. Can be enjoyed.

[0159] In some embodiments, the composition has a pH of about 4.0 to about 9.0. In some embodiments, the composition has a pH of about 5.0 to about 8.0. In some embodiments, the composition has a pH of about 6.5 to about 8.0. In some embodiments, the composition has a pH of about 7.0 to about 8.0.

[0160] Antimicrobial agents, such as antibiotics and antifungals, may be added. Other substances may be added to the composition for the purpose of improving the stability of the composition. The materials may be stored at room temperature or at -20°C or at -40°C prior to use. may be packaged and stored at -80°C.

[0161] In some aspects, described herein are formulations that have no dose-to-dose variability.

[0162] In some embodiments, the temperature of the storage condition is between about 20° C. and about 70° C. In some embodiments, the temperature of the storage condition is between about 25° C. and about 65° C., between about 30° C. and about 60° C., between about 35° C. and about 55° C., or between about 40° C. and about 50° C. In some embodiments, the temperature of the storage condition is about 25° C. In some embodiments, the temperature of the storage condition is about 40° C. In some embodiments, the temperature of the storage condition is about 60° C.

[0163] In some embodiments, the relative humidity of the storage conditions is between about 50% and about 80%, or between about 60% and about 75%. In some embodiments, the relative humidity of the storage conditions is about 60%. In one embodiment, the storage conditions are at a relative humidity of about 75%.

[0164] In some embodiments, the composition has a pH of about 4.0 to about 9.0. In some embodiments, the composition has a pH of about 5.0 to about 8.0. In some embodiments, the composition has a pH of about 6.5 to about 8.0. In some embodiments, the composition has a pH of about 7.0 to about 8.0.

[0165] In some embodiments, the composition has a pH of less than about 9. In some embodiments, the composition has a pH of less than about 8.9. In some embodiments, the composition has a pH of less than about 8.8. In some embodiments, the composition has a pH of less than about 8.7. In some embodiments, the composition has a pH of less than about 8.6. In some embodiments, the composition has a pH of less than about 8.5. In some embodiments, the composition has a pH of less than about 8.4. In some embodiments, the composition has a pH of less than about 8.3. ... In some embodiments, the composition has a pH of less than about 8.2. In some embodiments, the composition has a pH of less than about 8.1.

[0166] In some embodiments, the composition has a pH of less than about 8.0. In some embodiments, the composition has a pH of less than about 7.9. In some embodiments, the composition has a pH of less than about 7.8. In some embodiments, the composition has a pH of less than about 7.7. In embodiments, the composition has a pH of less than about 7.6. The composition has a pH of less than about 7.5. In some embodiments, the composition has a pH of less than about 7.4. In some embodiments, the composition has a pH of less than about 7.3. In some embodiments, the composition has a pH of less than about 7.5. In some embodiments, the composition has a pH of less than about 7.2. In some embodiments, the composition has a pH of less than about 7.1. In some embodiments, the composition has a pH of less than about 7.0. In some embodiments, the composition comprises less than 2.0% primary degradants based on the concentration of the ophthalmic agent after an extended period of time at storage conditions. In some embodiments, the composition comprises less than 1.5% primary degradants based on the concentration of the ophthalmic agent after an extended period of time at storage conditions. In some embodiments, the composition comprises less than 1.0% primary degradants based on the concentration of the ophthalmic agent after an extended period of time at storage conditions. In some embodiments, the composition comprises less than 0.5% primary degradants based on the concentration of the ophthalmic agent after an extended period of time at storage conditions. In some embodiments, the composition comprises less than 0.4% primary degradants based on the concentration of the ophthalmic agent after an extended period of time at storage conditions. In some embodiments, the composition comprises less than 0.3% primary degradants based on the concentration of the ophthalmic agent after an extended period of time at storage conditions. In some embodiments, the composition comprises less than 0.2% primary degradants based on the concentration of the ophthalmic agent after an extended period of time at storage conditions. In some embodiments, the composition contains less than 0.1% primary degradants based on the concentration of the ophthalmic agent after an extended period of time at storage conditions.

[0167] Aqueous solution stability In some embodiments, the compositions described herein include a buffer. In some embodiments, the buffer is borate, a borate-polyol complex, a phosphate buffer, a citric acid buffer, or a combination thereof. The buffer may be selected from an acid salt buffer, an acetate buffer, a carbonate buffer, an organic buffer, an amino acid buffer, or a combination thereof.

[0168] In some cases, the borate salts include boric acid, salts of boric acid, other pharma- ceutically acceptable borate salts, and combinations thereof. In some cases, the borate salts include boric acid, sodium borate, potassium borate, calcium borate, magnesium borate, manganese borate, and other such borate salts.

[0169] As used herein, the term "polyol" includes any compound having at least one hydroxyl group on each of two adjacent carbon atoms that are not in trans configuration with respect to each other. The polyol may be linear or cyclic, substituted or unsubstituted, or a mixture thereof, so long as the resulting conjugate is water soluble and pharma- ceutically acceptable. In some cases, examples of polyols include sugars, sugar alcohols, sugar acids, and uronic acids. In some cases, polyols include, but are not limited to, mannitol, glycerin, xylitol, and sorbitol.

[0170] In some embodiments, the phosphate buffer is selected from the group consisting of phosphoric acid; alkali metal phosphates (e.g., disodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and tripotassium phosphate); alkaline earth metal phosphates (e.g., calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, monomagnesium phosphate, dimagnesium hydrogen phosphate, mono ... In some cases, the phosphate buffer includes an anhydride, an ammonium phosphate (e.g., diammonium hydrogen phosphate and ammonium dihydrogen phosphate), or a combination thereof. In some cases, the phosphate buffer is an anhydride. In some cases, the phosphate buffer is a hydrate.

[0171] In some embodiments, borate-polyol complexes include those described in U.S. Patent No. 6,503, 497. In some cases, the borate-polyol complexes include borate in an amount of about 0.01% w / v to about 2.0% w / v, and one or more polyols in an amount of about 0.01% w / v to about 5.0% w / v.

[0172] In some cases, the citrate buffer contains citric acid and sodium citrate.

[0173] In some cases, the acetate buffer includes acetic acid, potassium acetate, and sodium acetate.

[0174] In some cases, the carbonate buffer includes sodium bicarbonate and sodium carbonate.

[0175] In some cases, the organic buffer is a Good's buffer (e.g., 2-(N-morpholino)ethanesulfonic acid (MES), N-(2-acetamido)iminodiacetic acid, N-(carbamoylmethyl)iminodiacetic acid (ADA), piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES), N-(2-acetamido)-2-aminoethanesulfonic acid (ACES), β-hydroxy-4-morpholinepropanesulfonic acid, 3-morpholino-2-hydroxypropanesulfonic acid (MOPSO), cholamine chloride, 3-(N-morpholino)propanesulfonic acid (MOPS), N,N-bis(2-hydroxyethyl) 2-[(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid (TES), 4-(2-hydroxyethyl)-1-piperazine ethyl ethanesulfonic acid (HEPES), 3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxypropanesulfonic acid (DIPSO), acetamidoglycine, 3-[N-tris(hydroxymethyl)methylamino]-2-hydroxypropanesulfonic acid (TAPSO), piperazine-1,4-bis(2-hydroxypropanesulfonic acid), Propanesulfonic acid (POPSO), 4-(2-hydroxyethyl)piperazine-1-(2-hydroxypropyl) Propanesulfonic acid) hydrate (HEPPSO), 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid sulfonic acid (HEPPS), tricine, glycineamide, bicine or sodium N-tris(hydroxymethyl)methyl-3-aminopropanesulfonate (TAPS), glycine and diethanolamine (DEA).

[0176] In some cases, the amino acid buffering agents include taurine, aspartic acid and its salts (eg, potassium salts, etc.), E-aminocaproic acid, and analogs.

[0177] In some cases, the compositions described herein further comprise a tonicity adjusting agent. Tonicity adjusting agents are incorporated into products, such as ophthalmic compositions, to prevent osmotic shock at the application site. In some cases, buffers and / or pH adjusters that maintain ophthalmic solutions broadly at a particular ionic concentration and pH are considered tonicity adjusters. In some cases, the tonicity adjuster includes multiple salts, such as halide salts of monovalent cations. In some cases, the tonicity adjuster includes mannitol, sorbitol, dextrose, sucrose, urea, and glycerin. In some cases, suitable tonicity adjusters include sodium chloride, sodium nitrate, sodium sulfate, sodium hydrogen sulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dextrose, mannitol, sorbitol, sucrose, urea, propylene glycol, glycerin, or combinations thereof.

[0178] In some cases, the concentration of the tonicity adjusting agent in the compositions described herein is between about 0.5% and about 2.0%. In some cases, the concentration of the tonicity adjusting agent in the compositions described herein is between about 0.7% and about 1.8%, between about 0.8% and about 1.5%, or between about 1% and about 1.3%. In some cases, the concentration of the tonicity adjusting agent is about 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, or 1.9%. In some cases, the percentages are percentages by weight.

[0179] In some cases, the compositions described herein further comprise a pH adjuster. Acid or base pH adjusters can be used. The base can be an oxide, hydroxide, carbonate, bicarbonate, and the like. The oxide can be a metal oxide, such as calcium oxide, magnesium oxide, and the like. The hydroxide can be an alkali metal and alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and the like. The carbonate can be sodium carbonate, sodium bicarbonate, potassium bicarbonate, and the like. The acid can be an inorganic acid and an organic acid, such as hydrochloric acid, nitric acid, phosphoric acid, acetic acid, citric acid, fumaric acid, malic acid, tartaric acid, and the like. In some cases, the pH adjuster can include, but is not limited to, acetate, bicarbonate, ammonium chloride, citrate, phosphate, pharma- ceutically acceptable salts, and combinations or mixtures thereof.

[0180] As described elsewhere herein, the composition has a pH of about 4.0 to about 9.0. In some embodiments, the composition has a pH of about 5.0 to about 8.0. In some embodiments, the composition has a pH of about 6.5 to about 8.0. In some embodiments, the composition has a pH of about 7.0 to about 8.0.

[0181] In some embodiments, the composition has a pH greater than about 5.0. In some embodiments, the composition has a pH greater than about 4.9. The composition has a pH greater than about 4.8. In some embodiments, the composition has a pH greater than about 4.7. In some embodiments, the composition has a pH greater than about 4.6. In some embodiments, the composition has a pH greater than about 4.5. The composition has a pH greater than about 4.4. In some embodiments, the composition has a pH greater than about 4.3. In some embodiments, the composition has a pH greater than about 4.2. In some embodiments, the composition has a pH greater than about 4.1.

[0182] In some embodiments, the composition has a pH greater than about 6.0. In some embodiments, the composition has a pH greater than about 5.9. The composition has a pH greater than about 5.8. In some embodiments, the composition has a pH greater than about 5.7. In some embodiments, the composition has a pH greater than about 5.6. In some embodiments, the composition has a pH greater than about 5.5. The composition has a pH greater than about 5.4. In some embodiments, the composition has a pH greater than about 5.3. In some embodiments, the composition has a pH greater than about 5.2. In some embodiments, the composition has a pH greater than about 5.1.

[0183] In some embodiments, the composition has a pH greater than about 7.0. In some embodiments, the composition has a pH greater than about 6.9. The composition has a pH greater than about 6.8. In some embodiments, the composition has a pH greater than about 6.7. In some embodiments, the composition has a pH greater than about 6.6. In some embodiments, the composition has a pH greater than about 6.5. The composition has a pH greater than about 6.4. In some embodiments, the composition has a pH greater than about 6.3. In some embodiments, the composition has a pH greater than about 6.2. In some embodiments, the composition has a pH greater than about 6.1.

[0184] In some embodiments, the composition has a pH of less than about 9.0. In some embodiments, the composition has a pH of less than about 8.9. In some embodiments, the composition has a pH of less than about 8.8. In some embodiments, the composition has a pH of less than about 8.7. In embodiments, the composition has a pH of less than about 8.6. The composition has a pH of less than about 8.5. In some embodiments, the composition has a pH of less than about 8.4. In some embodiments, the composition has a pH of less than about 8.3. In some embodiments, the composition has a pH of less than about 8.5. In some embodiments, the composition has a pH of less than about 8.2. In some embodiments, the composition has a pH of less than about 8.1.

[0185] In some embodiments, the composition has a pH of less than about 8.0. In some embodiments, the composition has a pH of less than about 7.9. In some embodiments, the composition has a pH of less than about 7.8. In some embodiments, the composition has a pH of less than about 7.7. In embodiments, the composition has a pH of less than about 7.6. The composition has a pH of less than about 7.5. In some embodiments, the composition has a pH of less than about 7.4. In some embodiments, the composition has a pH of less than about 7.3. In some embodiments, the composition has a pH of less than about 7.5. In some embodiments, the composition has a pH of less than about 7.2. In some embodiments, the composition has a pH of less than about 7.1. In some embodiments, the composition has a pH of less than about 7.0.

[0186] In some cases, the compositions described herein further comprise a disinfectant. In some cases, the disinfectant is a polymeric biguanide, a polymeric quaternary ammonium compound, a chlorite, a bisbiguanide, a chlorite compound (e.g., potassium chlorite, sodium chlorite, etc.). chlorite, calcium chlorite, magnesium chlorite or mixtures thereof) and combinations thereof.

[0187] In some cases, the compositions described herein further comprise a preservative. In some cases, a preservative is added to the compositions described herein at a certain concentration to prevent the growth of or destroy microorganisms introduced into the composition. In some cases, the microorganisms may be bacteria (e.g., Proteus mirabilis, Serratia marcesens), viruses (e.g., Mycobacterium tuberculosis ... For example, herpes simplex virus, varicella zoster virus), fungi (for example, fungi from the genus Fusarium), yeasts (for example, Candida albicans), parasites (for example, Plasmodium, Gnathostoma), protozoa (for example, Giardia lamblia), nematodes (for example, Onchocercus volvulus), helminths (for example, Filarial The term refers to amoebas (e.g., Acanthamoeba spp.) and / or hamsters (e.g., Dirofilaria immitis) and / or amoebas (e.g., Acanthamoeba spp.).

[0188] In some cases, the concentration of the preservative is between about 0.0001% and about 1%, between about 0.001% and about 0.8%, between about 0.004% and about 0.5%, between about 0.008% and about 0.1%, and between about 0.01% and about 0.08%. In this case, the concentration of the preservative is about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.008%, 0.009%, 0.009%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0%.

[0189] In some embodiments, the preservative is selected from benzalkonium chloride, cetrimonium, sodium perborate, stabilized oxychloro complex, SofZia (Alcon), polyquaternium-1, chlorobutanol, edetate disodium, and polyhexamethylene biguanide.

[0190] In some embodiments, the compositions described herein are stored in a plastic container. In some embodiments, the material of the plastic container includes high density polyethylene (HDPE), low density polyethylene (LDPE), polyethylene terephthalate (PET), polyvinyl chloride (PVC), polypropylene (PP), polystyrene (PS), fluorinated HDPE, post-consumer recycled resin (PCR), K-resine (SBC), or bioplastic. In some cases, the plastic The container material includes LDPE.

[0191] In some embodiments, the compositions described herein are stored in a plastic container.

[0192] In some embodiments, the composition stored in the plastic container has a pH of about 4.0 to about 9.0. In some embodiments, the composition stored in the plastic container has a pH of about 5.0 to about 9.0. In some embodiments, the composition is stored in a plastic container. has a pH of about 6.5 to about 8.0. In some embodiments, the composition stored in the plastic container has a pH of about 7.0 to about 8.0.

[0193] In some embodiments, the composition stored in the plastic container has a pH of less than about 9.0. In some embodiments, the composition stored in the plastic container has a pH of less than about 8.9. In some embodiments, the composition stored in the plastic container has a pH of less than about 8.8. In some embodiments, the composition stored in the plastic container has a pH of less than about 8.8. has a pH of less than about 8.7. In some embodiments, the solution is stored in a plastic container. The composition has a pH of less than about 8.6. In some embodiments, the composition is stored in a plastic container. In some embodiments, the composition has a pH of less than about 8.5. The composition stored in the plastic has a pH of less than about 8.4. The composition stored in the plastic container has a pH of less than about 8.3. The composition stored in the stick container has a pH of less than about 8.2. The composition stored in the plastic container has a pH of less than about 8.1.

[0194] In some embodiments, the composition stored in the plastic container has a pH of less than about 8.0. In some embodiments, the composition stored in the plastic container has a pH of less than about 7.9. In some embodiments, the composition stored in the plastic container has a pH of less than about 7.8. In some embodiments, the composition stored in the plastic container has a pH of less than about 7.8. has a pH of less than about 7.7. In some embodiments, the solution is stored in a plastic container. The composition has a pH of less than about 7.6. In some embodiments, the composition is stored in a plastic container. In some embodiments, the composition has a pH of less than about 7.5. The composition stored in the plastic has a pH of less than about 7.4. The composition stored in the plastic container has a pH of less than about 7.3. The composition stored in the stick container has a pH of less than about 7.2. In some embodiments, the composition stored in the plastic container has a pH of less than about 7.1. In the present invention, the composition has a pH of less than about 7.0.

[0195] In some embodiments, the composition stored in the plastic container has at least 80% potency after an extended period of time at storage conditions. Compositions stored in containers have at least 85% efficacy after an extended period at storage conditions. In some embodiments, the composition stored in the plastic container has at least 90% potency after an extended period of time at storage conditions. Compositions stored in a container have an efficacy of at least 93% after an extended period at storage conditions. In some embodiments, the composition stored in the plastic container has a potency of at least 95% after an extended period of time at storage conditions. Compositions stored in plastic containers retain at least 97% of their original moisture content after extended periods at storage conditions. In some embodiments, the composition stored in the plastic container has a potency of at least 98% after an extended period of time at storage conditions. The composition stored in the plastic container has at least 99% potency after an extended period at storage conditions. The storage conditions include a temperature of about 25° C., about 40° C., or about 60° C. In some cases, The extended period of time may be at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months.

[0196] In some embodiments, the composition stored in the plastic container has at least 80% potency at a temperature of about 25° C., about 40° C., or about 60° C. The composition stored in the container has an efficacy of at least 85% at a temperature of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the plastic container has a potency of at least 90% at a temperature of about 25° C., about 40° C., or about 60° C. In some embodiments, The composition stored in the plastic container has a potency of at least 93% at a temperature of about 25° C., about 40° C., or about 60° C. In some embodiments, the composition stored in the plastic container has a potency of at least 93% at a temperature of about 25° C., about 40° C., or about 60° C. It has an efficacy of at least 95% at a temperature of about 25° C., about 40° C., or about 60° C. In some embodiments, In some embodiments, the composition stored in the plastic container has an efficacy of at least 97% at a temperature of about 25° C., about 40° C., or about 60° C. ... The composition has an efficacy of at least 98% at a temperature of about 25° C., about 40° C., or about 60° C. In embodiments, the composition stored in the plastic container has an efficacy of at least 99% at a temperature of about 25°C, about 40°C, or about 60°C.

[0197] In some embodiments, the composition stored in the plastic container can be stored for at least one week. , at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least In some embodiments, the composition has at least 80% potency within a period of at least 10 months, at least 12 months, at least 18 months, or at least 24 months. The composition may be used for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or In some embodiments, the compound has an efficacy of at least 85% over a period of at least 24 months. The composition stored in the plastic container may be used for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, In some embodiments, the composition stored in the plastic container has a potency of at least 90% within a period of at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, In some embodiments, the composition has a potency of at least 93% within a period of at least 10 months, at least 12 months, at least 18 months, or at least 24 months. The compositions have at least 95% efficacy within a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. The composition stored in the plastic container may be used for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, In some embodiments, the composition stored in the plastic container has a potency of at least 97% for a period of at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, In some embodiments, the composition has a potency of at least 98% within a period of at least 10 months, at least 12 months, at least 18 months, or at least 24 months. The compositions have at least 99% efficacy within a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months.

[0198] In some embodiments, the composition stored in the plastic container comprises less than 2.5% primary degradants based on the concentration of the ophthalmic agent after an extended period of time at the storage conditions. In some embodiments, the composition stored in the plastic container comprises less than 2.0% primary degradants based on the concentration of the ophthalmic agent after an extended period of time at the storage conditions. In some embodiments, the composition stored in the plastic container comprises less than 1.5% primary degradants based on the concentration of the ophthalmic agent after an extended period of time at the storage conditions. In some embodiments, the composition stored in the plastic container comprises less than 1.0% primary degradants based on the concentration of the ophthalmic agent after an extended period of time at the storage conditions. In some embodiments, the composition stored in the plastic container comprises less than 0.5% primary degradants based on the concentration of the ophthalmic agent after an extended period of time at the storage conditions. In some embodiments, the composition stored in the plastic container comprises less than 0.4% primary degradants based on the concentration of the ophthalmic agent after an extended period of time at the storage conditions. In some embodiments, the composition stored in the plastic container comprises less than 0.3% primary degradants based on the concentration of the ophthalmic agent after an extended period of time at the storage conditions. In some embodiments, the composition stored in the plastic container comprises less than 0.2% of a primary degradant based on the concentration of the ophthalmic agent after an extended period at the storage conditions. In some embodiments, the composition stored in the plastic container comprises less than 0.1% of a primary degradant based on the concentration of the ophthalmic agent after an extended period at the storage conditions. The storage conditions include a temperature of about 25° C., about 40° C., or about 60° C. In some cases, the extended period is at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 9 months, at least 10 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 21 months, at least 22 months, at least 23 months, at least 24 months, at least 25 months, at least 25 months, at least 26 months, at least 27 months, at least 28 months, at least 29 months, at least 30 months, at least 31 months, at least 32 months, at least 33 months, at least 34 months, at least 35 months, at least 36 months, at least 37 months, at least 38 months, at least 39 months, at least 40 ... months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months or at least 24 months It is the month.

[0199] In some embodiments, the composition stored in the plastic container comprises less than 2.5% primary degradants based on the concentration of the ophthalmic agent at a temperature of about 25° C., about 40° C., or about 60° C. In some embodiments, the composition stored in the plastic container comprises less than 2.0% primary degradants based on the concentration of the ophthalmic agent at a temperature of about 25° C., about 40° C., or about 60° C. In some embodiments, the composition stored in the plastic container comprises less than 1.5% primary degradants based on the concentration of the ophthalmic agent at a temperature of about 25° C., about 40° C., or about 60° C. In some embodiments, the composition stored in the plastic container comprises less than 1.0% primary degradants based on the concentration of the ophthalmic agent at a temperature of about 25° C., about 40° C., or about 60° C. In some embodiments, the composition stored in the plastic container comprises less than 0.5% primary degradants based on the concentration of the ophthalmic agent at a temperature of about 25° C., about 40° C., or about 60° C. In some embodiments, the composition stored in the plastic container comprises less than 0.4% primary degradants based on the concentration of the ophthalmic agent at a temperature of about 25° C., about 40° C., or about 60° C. In some embodiments, the composition stored in the plastic container comprises less than 0.3% primary degradants based on the concentration of the ophthalmic agent at a temperature of about 25° C., about 40° C., or about 60° C. In some embodiments, the composition stored in the plastic container comprises less than 0.2% primary degradants based on the concentration of the ophthalmic agent at a temperature of about 25° C., about 40° C., or about 60° C. In some embodiments, the composition stored in the plastic container comprises less than 0.1% primary degradants based on the concentration of the ophthalmic agent at a temperature of about 25° C., about 40° C., or about 60° C.

[0200] In some embodiments, the composition stored in the plastic container can be stored for at least one week. , at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least In some embodiments, the composition stored in the plastic container contains less than 2.5% primary degradants based on the concentration of the ophthalmic agent within a period of at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container contains less than 2.5% primary degradants based on the concentration of the ophthalmic agent within a period of at least 1 week, at least 2 weeks, at least 3 weeks at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, In some embodiments, the composition stored in the plastic container contains less than 2.0% primary degradants based on the concentration of the ophthalmic agent within a period of at least 18 months or at least 24 months. months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months or at least 24 months In some embodiments, the composition stored in the plastic container comprises less than 1.5% primary degradants based on the concentration of the ophthalmic agent within a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container comprises less than 0.5% primary degradants based on the concentration of the ophthalmic agent within a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container comprises less than 1.0% primary degradants based on the concentration of the ophthalmic agent within a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. At least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months In some embodiments, the composition stored in the plastic container comprises less than 0.4% primary degradants based on the concentration of the ophthalmic agent within a period of at least 1 month, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container comprises less than 0.4% primary degradants based on the concentration of the ophthalmic agent within a period of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. At least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 In some embodiments, the composition stored in the plastic container comprises less than 0.3% primary degradants based on the concentration of the ophthalmic agent within a period of at least 1 month, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container comprises less than 0.3% primary degradants based on the concentration of the ophthalmic agent within a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months , at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months In some embodiments, the composition stored in the plastic container contains less than 0.2% primary degradants based on the concentration of the ophthalmic agent within a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months. months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least Each formulation contains less than 0.1% of primary degradants based on the concentration of the ophthalmic agent within a period of at least 12 months, at least 18 months, or at least 24 months.

[0201] In some embodiments, the compositions described herein are stored in a glass container. In some embodiments, the glass container is a glass vial, e.g., a Type I glass vial. The glass vial may be a type II glass vial or a type III glass vial. In some embodiments, the glass container is a Type I glass vial. , Type I glass vials are borosilicate glass vials.

[0202] In some embodiments, the composition stored in the glass container has a pH of about 4.0 to about 9.0. In some embodiments, the composition stored in the glass container has a pH of about 5.0 to about 8.0. In some embodiments, the composition stored in the glass container has a pH of about 6.5 to about 8.0. In some embodiments, the composition stored in the glass container has a pH of about 7.0 to about 8.0.

[0203] In some embodiments, the composition stored in the glass container has a pH of less than about 9. In some embodiments, the composition stored in the glass container has a pH of less than about 8.9. In some embodiments, the composition stored in the glass container has a pH of less than about 8.8. In some embodiments, the composition stored in the glass container has a pH of less than about 8.7. In some embodiments, the composition stored in the glass container has a pH of less than about 8.6. In some embodiments, the composition stored in the glass container has a pH of less than about 8.5. In some embodiments, the composition stored in the glass container has a pH of less than about 8.4. In some embodiments, the composition stored in the glass container has a pH of less than about 8.3. In some embodiments, the composition stored in the glass container has a pH of less than about 8.2. In some embodiments, the composition stored in the glass container has a pH of less than about 8.1.

[0204] In some embodiments, the composition stored in the glass container has a pH of less than about 8.0. In some embodiments, the composition stored in the glass container has a pH of less than about 7.9. In some embodiments, the composition stored in the glass container has a pH of less than about 7.8. In some embodiments, the composition stored in the glass container has a pH of less than about 7.7. In some embodiments, the composition stored in the glass container has a pH of less than about 7.6. In some embodiments, the composition stored in the glass container has a pH of less than about 7.5. In some embodiments, the composition stored in the glass container has a pH of less than about 7.4. In some embodiments, the composition stored in the glass container has a pH of less than about 7.3. In some embodiments, the composition stored in the glass container has a pH of less than about 7.2. In some embodiments, the composition stored in the glass container has a pH of less than about 7.1. In some embodiments, the composition stored in the glass container has a pH of less than about 7.0. .

[0205] In some embodiments, the compositions described herein are formulated as an aqueous solution. In some embodiments, the aqueous solution is a stable aqueous solution. In some cases, the aqueous solution is stored in a plastic container as described above. In some cases, the aqueous solution is not stored in a glass container. In some cases, the aqueous solution is stored in the dark. In some cases, the aqueous solution is stored in the presence of light. In some cases, the aqueous solution is stable in the presence of light.

[0206] Other stabilizers useful in the ophthalmically acceptable formulations disclosed herein include, for example, fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidones, polyvinyl ethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers, moisture-absorbing polymers, and combinations thereof. In some embodiments, amide analogs of stabilizers are also used. In other embodiments, the stabilizer selected alters the hydrophobicity of the formulation, improves mixing of multiple components in the formulation, or controls the moisture level or phase flow in the process.

[0207] In other embodiments, the stabilizing agent is present in an amount sufficient to inhibit degradation of the ophthalmic agent. Examples of such stabilizing agents include, but are not limited to, glycerin, methionine, monothioglycerol, EDTA, ascorbic acid, polysorbate 80, polysorbate 20, arginine, heparin, dextran sulfate, cyclodextrin, pentosan polysulfate and other heparinoids, divalent cations (e.g., magnesium and zinc), or combinations thereof.

[0208] Other useful stabilizers for use in ophthalmically acceptable formulations include one or more anti-aggregation additives. It contains an anti-aggregation additive, which reduces the rate of protein aggregation. Enhances the stability of ophthalmic formulations. The anti-aggregation additive selected will be determined by the nature of the conditions to which the ophthalmic agent will be exposed. For example, some formulations that undergo agitation and thermal stress will require different anti-aggregation additives than formulations that undergo lyophilization and reconstitution. Examples of useful anti-aggregation additives include urea, guanidinium chloride, simple amino acids (e.g., glycine or arginine), sugars, polyalcohols, polysorbates, polymers (e.g., polyethylene glycol and dextran), alkyl sugars (e.g., alkyl glycosides), and surfactants.

[0209] Other useful formulations may contain one or more ophthalmically acceptable Examples of suitable antioxidants include ascorbic acid, methionine, sodium thiosulfate, and sodium metabisulfite. The oxidizing agent is selected from metal chelating agents, thiol-containing compounds and other common stabilizing agents.

[0210] Other useful compositions include compositions that are formulated to provide one or more ophthalmic solutions to improve physical stability or for other purposes. Suitable nonionic surfactants include, but are not limited to, polyoxyethylene fatty acid glycerides and vegetable oils (e.g., polyoxyethylene (60) hydrogenated castor oil), and polyoxyethylene alkyl ethers and alkyl phenyl ethers (e.g., Octoxynol 10, Octoxynol 40).

[0211] In some embodiments, the ophthalmically acceptable drug formulations described herein have a shelf life under storage conditions (e.g., room temperature) of at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 12 days, at least about 14 days, at least about 16 days, at least about 18 days, at least about 19 days, at least about 20 days, at least about 21 days, at least about 22 days, at least about 23 days, at least about 24 days, at least about 25 days, at least about 26 days, at least about 27 days, at least about 28 days, at least about 29 days, at least about 30 days, at least about 30 days, at least about 30 days, at least about 30 days at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months. In other embodiments, the formulations described herein are stable with respect to compound degradation for a period of at least about one week. The formulations described herein are stable with respect to compound degradation for a period of at least about one month (e.g., less than 30% degradation, less than 25% degradation, less than 20% degradation, less than 15% degradation, less than 10% degradation, less than 8% degradation, less than 5% degradation, less than 3% degradation, less than 2% degradation, or less than 1% degradation). In other embodiments, the formulations described herein are stable with respect to compound degradation for a period of at least about one week. Further described is a formulation that is stable with respect to degradation of the compound.

[0212] In another embodiment, the other surfactants (co-surfactants) and / or buffers are By combining with one or more of the pharma- ceutically acceptable vehicles, The active agent and / or buffer maintains the product at an optimal pH level for stability. The lipophilic agents include a) natural and synthetic lipophilic agents, such as phospholipids, cholesterol, cholesterol fatty acid esters and their derivatives; b) non-ionic surfactants, such as polyoxyethylene fatty alcohol esters, sorbitan fatty acid esters (Spans), polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene (20) sorbitan monooleate (Tween 80), polyoxyethylene (20) sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbitan monolaurate (Tween 20) and other Tweens, sorbitan fatty acids, e.g., polyoxyethylene (20) sorbitan monooleate (Tween 80), polyoxyethylene (20) sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbitan monolaurate (Tween 20), ... Vitamin Esters, Glycerol Esters (e.g. Myrj and triacetin), Poly triethylene glycol, cetyl alcohol, cetostearic alcohol, stearyl alcohol, polysorbate 80, poloxamer, poloxamine, polyoxyethylene castor oil derivatives (e.g., Cremophor® RH40, Cremphor A25, Cremphor A20, Cremophor (registered trademark) EL) and other Cremophor, sulfosuccinates, alkyl sulfates (SLS); PEG glyceryl fatty acid esters such as PEG-8 glyceryl caprylate / glyceryl caprate (Labrasol), PEG-4 glyceryl caprylate / glyceryl caprate (Labrafil Hydro WL 1219), PEG-32 glycerol laurate (Gelucire 444 / 14), PEG-6 glyceryl monooleate (Labrafil M 1944 CS), PEG-6 glyceryl linoleate (Labrafil M 2125 CS); propylene glycol Propylene glycol mono-fatty acid esters and propylene glycol di-fatty acid esters, such as propylene glycol laurate, propylene glycol caprylate / propylene glycol caprate Brij® 700, Ascorbyl-6-Palmitate, Stearylamine, Lauryl Ether, c) anionic surfactants (including calcium carboxymethylcellulose, sodium carboxymethylcellulose, dioctyl sodium sulfosuccinate, sodium alginate, polyoxyethylene glycerol triisopropyl ether, and any combination or mixture thereof); ethylene alkyl sulfates, sodium lauryl sulfate, triethanolamine stearate, potassium laurate, bile salts, and any combination or mixture thereof; and d) cationic surfactants (e.g., cetyltrimethylammonium bromide, lauryldimethylbenzyl-ammonium chloride).

[0213] In other embodiments, the one or more co-surfactants are present in the ophthalmically acceptable formulation of the present disclosure. When used, they are, for example, combined with a pharma- ceutically acceptable vehicle and present in the final formulation in an amount ranging, for example, from about 0.1% to about 20%, from about 0.5% to about 10%.

[0214] In one embodiment, the surfactant has an HLB value of 0 to 20. , the surfactants have HLB values ​​of 0-3, 4-6, 7-9, 8-18, 13-15, and 10-18.

[0215] Uniformity between aqueous solution doses Typical aqueous ophthalmic solutions are packaged in eye dropper bottles and administered as drops. For example, a single dose (i.e., a single dose) of the aqueous ophthalmic solution may contain one, two, three, or more drops. In some embodiments, the method may include administering a dose of the composition to an eye of a patient. The aqueous ophthalmic solution described herein is a single drop aqueous solution composition from an eye dropper.

[0216] In some cases, the present disclosure includes providing an ophthalmic aqueous composition with a uniform concentration between doses. In some cases, the uniform concentration between doses includes no significant difference in drug content from one dose to another. In some cases, uniform concentration between doses indicates no significant change from one dose to another. Ensures consistent drug content.

[0217] In some embodiments, the composition has a dose-to-dose concentration variation of the ophthalmic agent of less than 50%. In some embodiments, the composition has a dose-to-dose concentration variation of the ophthalmic agent of less than 40%. In some embodiments, the composition has a dose-to-dose concentration variation of the ophthalmic agent of less than 30%. In some embodiments, the composition has a dose-to-dose concentration variation of the ophthalmic agent of less than 20%. In some embodiments, the composition has a dose-to-dose concentration variation of the ophthalmic agent of less than 10%. In some embodiments, the composition has a dose-to-dose variation of the ophthalmic agent concentration of less than 5%.

[0218] In some embodiments, the change in concentration of the ophthalmic agent between doses is based on 10 consecutive doses. In some embodiments, the change in concentration of the ophthalmic agent between doses is based on 8 consecutive doses. In some embodiments, the change in concentration of the ophthalmic agent between doses is based on five consecutive doses. In some embodiments, the change in concentration of the ophthalmic agent between doses is based on three consecutive doses. In some embodiments, the change in concentration of the ophthalmic agent between doses is based on the doses of two Based on consecutive doses.

[0219] A non-settling formulation should not require shaking for uniform distribution of the drug. The shaking action for the patient is an easily major source of variability in the drug amount of the administered medication, and "no shaking" formulations have potential advantages over formulations that require shaking. Reports suggest that even with clearly marked shaking instructions on the label, patients do not always shake or forget to shake the ophthalmic composition, which must be shaken before administration of a dose. On the other hand, even for those patients who did shake the product, it is usually not possible to determine whether the strength and / or duration of shaking was sufficient for product homogeneity. In embodiments, the ophthalmic compositions described herein are "no shake" formulations that maintain the dose-to-dose uniformity described herein.

[0220] To assess dose-to-dose uniformity, drop bottles or drop tubes containing the ophthalmic (water-containing) compositions are stored upright for at least 12 hours prior to the start of testing. A given number of drops or strips are dispensed at a given time to mimic the recommended dosing of these products. At intervals, each commercial bottle or tube is assigned an extending period of time or until no product remains in the bottle or tube. All drops or strips are assigned to equilibrated glass vials, capped and stored at room temperature until analysis.

[0221] Viscosity of aqueous solutions In some embodiments, the composition is heated to about 20° C. for 1 s. -1 In some embodiments, the composition has a Brookfield RVDV viscosity of about 10 cps to about 50,000 cps at a shear rate of about 20° C. and 1 s. -1 At shear rates of about 100 cps to about 40,000 cps, the Brookfield RVDV viscosity is In some embodiments, the composition is heated to about 20° C. for 1 s. -1 In some embodiments, the composition has a Brookfield RVDV viscosity of about 500 cps to about 30,000 cps at a shear rate of about 100 cps. About 20℃ and 1s -1 In some embodiments, the composition has a Brookfield RVDV viscosity of about 1000 cps to about 20,000 cps at a shear rate of about 20° C. and 1 s. -1 At a shear rate of about 2000cps In some embodiments, the composition has a Brookfield RVDV viscosity of about 10,000 cps. The product is heated to about 20°C for 1s. -1 at a shear rate of about 4000 cps to about 8000 cps.

[0222] In some embodiments, the ophthalmic aqueous formulation has a viscosity between about 500 centipoise and 50,000 centipoise. Between about 750 centipoise and 50,000 centipoise, between about 1000 centipoise and 50,000 centipoise, between about 1000 centipoise and 40,000 centipoise, between about 2000 centipoise and In some embodiments, the viscosity of the composition may include sufficient thickening agent to provide a viscosity of between about 3000 and 30,000 centipoise, between about 3000 and 20,000 centipoise, between about 4000 and 10,000 centipoise, or between about 5000 and 8000 centipoise.

[0223] pH In some embodiments, the pH of the compositions described herein can be adjusted (e.g., by the addition of buffering agents and / or or a pH adjusting agent) to an ophthalmic compatible pH range of about 4.0 to about 9.0. In some embodiments, the ophthalmic composition has a pH of about 5.0 to about 8.0. In some embodiments, the ophthalmic composition has a pH of about 6.5 to about 8.0. In some embodiments, the ophthalmic composition has a pH of about 7.0 to about 8.0.

[0224] In some embodiments, useful formulations further comprise one or more pH adjusting or buffering agents. Suitable pH adjusting or buffering agents include, but are not limited to, acetates, bicarbonates, ammonium chlorides, citrates, phosphates, pharma- ceutically acceptable salts, and combinations or mixtures thereof.

[0225] In one embodiment, when one or more buffering agents are used in the formulations of the present disclosure, they are combined, for example, with a pharma- ceutically acceptable vehicle and may be present in a concentration of, for example, about 0.1% to about 20%, about 0.5%. In some embodiments of the present disclosure, the formulation is present in an amount ranging from about 10% to about 20%. Due to the amount of buffering agent included, the pH of the formulation does not interfere with the body's natural buffering system.

[0226] In one embodiment, the diluent is also used to stabilize the compound, which is This is because it can provide a more stable environment for the agent. Salts that dissolve in buffered solutions (which can further provide pH control or maintenance) are used as diluents in the art, including, but not limited to, phosphate buffered saline solutions.

[0227] In some embodiments, the ophthalmic compositions described herein have a viscosity of about 4.0 to about 9.0, about 5.0 The aqueous solution has a pH of about 7.0 to about 8.0, about 6.5 to about 8.0, about 6.5 to about 8.0, or about 7.0 to about 8.0.

[0228] In some embodiments, the ophthalmic compositions described herein have a viscosity of 6.0, about 6.1, about 6.2, About 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5 , about 8.6, about 8.7, about 8.8, about 8.9, about 9.0.

[0229] In some embodiments, the drug formulations described herein are administered for at least about one day. About 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, At least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 3 years, at least about 4 years, at least about 5 years, or In other embodiments, the compound is pH stable for any one of the following periods: In the present invention, the formulations described herein are stable with respect to pH for a period of at least about one week. In other embodiments, the formulations described herein have a pH that is consistent with that of the formulations described herein within a period of at least about two weeks. In other embodiments, the formulations described herein are stable for at least about 3 weeks. In other embodiments, the formulations described herein are pH stable for a period of at least about 1 month. Further described herein are formulations that are pH stable for a period of at least about 2 months or more.

[0230] Osmolarity In some embodiments, the compositions disclosed herein are formulated so as not to disrupt the ionic balance of the eye. In some embodiments, the compositions disclosed herein have the same or approximately the same ionic balance as the eye. In some embodiments, the compositions disclosed herein do not disrupt the ionic balance of the eye.

[0231] As used herein, "actual osmolality / osmolality" or "deliverable osmolality" refers to "Suitable osmolality / osmolality" refers to, for example, ophthalmic agents and gelling and / or thickening agents (e.g., polyoxyethylene-polyoxypropylene copolymers, carboxymethyl Measure the osmolality / osmolality of all excipients except cellulose or analogues. The term "osmolality" refers to the osmolality of a composition as determined by measuring the osmolality of the composition. The actual osmolality of the compositions disclosed herein is measured by a suitable method, such as the freezing point depression method described in Viegas et al., Int. J. Pharm., 1998, 160, 157-162. In some cases, the actual osmolality of the compositions disclosed herein is measured by a vapor pressure osmometry method (e.g., vapor pressure depression method), which allows for the determination of the osmolality of the composition at relatively high temperatures.

[0232] In some embodiments, the osmolality at the target site of action (e.g., the eye) is about the same as the osmolality of the delivery of the compositions described herein. In some embodiments, the compositions described herein have a deliverable osmolality of about 150 mOsm / L to about 500 mOsm / L, about 250 mOsm / L to about 500 mOsm / L, about 250 mOsm / L to about 350 mOsm / L, about 280 mOsm / L to about 370 mOsm / L, or about 250 mOsm / L to about 320 mOsm / L.

[0233] The actual osmolality of the ophthalmic compositions disclosed herein may be from about 100 mOsm / kg to about 1000 mOsm / kg, from about 200 mOsm / kg to about 800 mOsm / kg, from about 250 mOsm / kg to about 500 mOsm / kg, or from about 250 mOsm / kg to about 500 mOsm / kg. In some embodiments, the compositions described herein have a blood glucose concentration of about 100 mOsm / L to about 1000 mOsm / L. , has an actual osmolality of about 200 mOsm / L to about 800 mOsm / L, about 250 mOsm / L to about 500 mOsm / L, about 250 mOsm / L to about 350 mOsm / L, about 250 mOsm / L to about 320 mOsm / L, or about 280 mOsm / L to about 320 mOsm / L.

[0234] In some embodiments, suitable tonicity adjusters include, but are not limited to, any pharma- ceutically acceptable sugar, salt, or any combination or mixture thereof, such as, but not limited to, dextrose, glycerin, mannitol, sorbitol, sodium chloride, and other electrolytes. In some cases, the tonicity adjuster is selected from sodium chloride, sodium nitrate, sodium sulfate, sodium hydrogen sulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dextrose, mannitol, sorbitol, sucrose, urea, propylene glycol, glycerin, or combinations thereof.

[0235] In some embodiments, the ophthalmic compositions described herein include one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include sodium Suitable salts include those having a sodium, potassium or ammonium cation and a chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anion. Suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0236] sterility In some embodiments, the compositions are sterile. Included in the embodiments disclosed herein are means and processes for sterilizing the pharmaceutical compositions disclosed herein for human use. It is a goal to provide safe drug products that are relatively free of non-infectious microorganisms. The U.S. Food and Drug Administration provides regulatory guidance in "Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing," a publication available at http: / / www.fda.gov / cder / guidance / 5882fnl.htm, which is incorporated herein by reference in its entirety. Be absorbed.

[0237] As used herein, "sterilization" refers to a process for destroying or removing microorganisms present in a product or packaging. Any suitable method capable of sterilizing objects and compositions may be used. Methods that can be used to inactivate microorganisms include, but are not limited to, application of extreme heat, lethal chemicals, or gamma radiation. In some embodiments, the process for the preparation of an ophthalmic formulation includes subjecting the formulation to a sterilization method selected from heat sterilization, chemical sterilization, radiation sterilization, or filtration sterilization. The method used will be determined to a large extent by the nature of the device or composition to be sterilized. Details of many sterilization methods can be found in Chapter 40 of Remington: The Science and Practice of Pharmacy, published by Lippincott, Williams & Wilkins. and that subject matter is incorporated by reference.

[0238] Filtration Sterile filtration is a method of removing microorganisms from a solution without destroying them. Membrane filters are used for the filtration of heat-sensitive solutions. Such filters are thin, rigid homogeneous polymers of mixed cellulose esters (MCE), polyvinylidene fluoride (PVF, also called PVDF), or polytetrafluoroethylene (PTFE), and have pore sizes in the range of 0.1 μm to 0.22 μm. Solutions with different properties can be selectively filtered using different filtration membranes. For example, PVF and PTFE membranes are well suited for filtering organic solvents, and aqueous solutions can be filtered by PVF or MCE membranes. Filter devices are available at many scales, ranging from single-point-use disposable filters attached to syringes to commercial-scale filters used in manufacturing plants. Membrane filters are sterilized by autoclaving or chemical sterilization. Validation of membrane filtration systems is performed according to standardized protocols (Microbiological Evaluation of Filters for Sterilizing Liquids, Vol. 4, No. 3. Washington, DC: Health Industry Manufacturers Association, 1981) and involves the use of known volumes (approximately 10 7 / cm 2 ) an abnormally small microorganism For example, Brevundimonas diminuta (ATCC 19146) The use of membrane filters is challenging.

[0239] Pharmaceutical compositions are optionally sterilized by passage through a membrane filter. Formulations containing nanoparticles (U.S. Pat. No. 6,139,870) or multilamellar vesicles (Richard et al., International Journal of Pharmaceutics (2006), 312(1-2):144-50) can be sterilized by passage through a 0.22 μm filter. This allows sterilization without destroying tissue structures.

[0240] In some embodiments, the methods disclosed herein include sterilizing the formulation (or components thereof) by sterile filtration. For ophthalmic gel compositions containing a thermosetting polymer, filtration is performed at a temperature below the gel temperature (Tgel) of the formulation described herein (e.g., about 5° C.); and a viscosity that allows it to be filtered through a peristaltic pump in a reasonable time (e.g., greater than 100 cP). low theoretical value).

[0241] Thus, provided herein are methods of sterilizing ophthalmic formulations, preventing degradation of polymeric components (e.g., thermosetting and / or other thickening agents) and / or ophthalmic formulations during sterilization. In some embodiments, degradation of the ophthalmic agent is reduced or eliminated by a specific pH range of the buffer components and a specific ratio of thickening agent in the formulation. In some embodiments, the selection of a suitable thickening agent or thermosetting polymer allows the formulations described herein to be sterilized by filtration. In some embodiments, the combined use of a suitable thermosetting polymer or other thickening agent and a specific pH range of the formulation allows high temperature sterilization of the formulations described, with little or no degradation of the therapeutic agent or polymer excipients. Advantages of the sterilization methods according to the present invention are that, in some cases, the formulations have undergone terminal sterilization by high pressure sterilization, there is no loss of any ophthalmic agent and / or excipients and / or thickening agents during the sterilization process, and the formulations are substantially free of microorganisms and / or pyrogens.

[0242] Radiation sterilization One advantage of radiation sterilization is that it can sterilize many types of products without causing thermal degradation or other damage. The most commonly used radiation is 60 The primary sterilization sources are β-radiation from a Co source, or alternatively γ-radiation. The penetrating power of γ-radiation allows its use for sterilization of many product types, including solutions, compositions, and heterogeneous mixtures. The germicidal effect of radiation is due to the interaction of γ-radiation with biological macromolecules. Such interactions result in the generation of charged species and free radicals. Subsequent chemical reactions, such as rearrangement and cross-linking processes, cause these biological macromolecules to lose their normal function. The formulations described herein are optionally further sterilized using β-irradiation.

[0243] Sterilization by heat Many methods can be used to sterilize at high temperatures. One method is to use a saturated steam autoclave. In such a method, saturated steam at a temperature of at least 121°C and the object to be sterilized are Contact with the microorganisms is permitted. Heat is transferred to the microorganisms directly (in the case of the object to be sterilized) or indirectly by heating the bulk of the aqueous solution to be sterilized. Such methods are widely implemented due to their flexibility, safety and economy in the sterilization process.

[0244] microorganisms In some embodiments, the composition is substantially free of microorganisms. The acceptable level of bioburden or level of sterility is based on applicable standards that define a therapeutically acceptable composition, the applicable standards being the United States Pharmacopeia, Article 10. <1111> For example, acceptable sterility (e.g., bioburden) levels include about 10 colony forming units (cfu) / g of the formulation, about 50 cfu / g of the formulation, about 100 cfu / g of the formulation, about 500 cfu / g of the formulation, or about 1000 cfu / g of the formulation. In some embodiments, an acceptable bioburden level of a formulation may be about 1000 cfu / g of the formulation, about 1000 cfu / g of the formulation, or about 1000 cfu / g of the formulation. Bacterial or sterile: less than 10 cfu / mL of microbial agents, less than 50 cfu / mL of microbial agents, less than 500 cfu / mL of microbial agents Microbial agents, or less than 1000 cfu / mL of microbial agents. Alternatively, acceptable bioburden levels or sterility include the exclusion of specific harmful microbial agents. Examples of specific harmful microbial agents include, but are not limited to, Escherichia coli (E. coli), Salmonella sp., Pseudomonas aeruginosa (P. aeruginosa), and / or other specific microbial agents. No.

[0245] Sterility Assurance One important component of the quality control, quality assurance and validation process is sterility testing. The method of. Exemplarily, sterility testing is carried out in two ways. The first method is direct inoculation, where a sample of the composition to be tested is added to a growth medium and allowed to incubate for a long period of time, up to 21 days. Turbidity of the growth medium indicates contamination. The disadvantages of this method are the small sampling size of the bulk material, which reduces the sensitivity, and the detection of microbial growth based on visual observation. An alternative method is membrane filtration sterility testing. In this method, a volume of product is passed through a small membrane filter paper. The filter paper is then placed on a medium to promote microbial growth. This method has the advantage of being more sensitive when sampling the entire bulk product. The commercially available Millipore Steritest sterility testing system is alternatively used for the determination by membrane filtration sterility testing. For filtration testing of creams or ointments, the Steritest filtration system No. TLHVSL210 is used. For filtration testing of emulsions or viscous products, use Steritest filtration system No. TLAREM210 or TDAREM210. For filtration testing of prefilled syringes, use Steritest filtration system No. TTHASY210. Dispensed as aerosols or foams For filtration testing of materials, Steritest filtration system No. TTHVA210 is used. For filtration testing of soluble powders in ampoules or vials, Steritest filtration system No. TTHADA210 or TTHADV210 is used.

[0246] In some embodiments, the ophthalmic formulations described herein contain, per gram of formulation: Less than about 60 colony forming units (CFU), Less than about 50 colony forming units, Less than about 40 colony forming units 30 colony forming units of a microbial agent. In some embodiments, the ophthalmic formulations described herein are formulated to be isotonic with the eye.

[0247] Endotoxin Another aspect of the sterilization process is the by-products (hereinafter "products") resulting from the killing of microorganisms. The depyrogenation process removes pyrogens from a sample. Pyrogens are endotoxins or exotoxins that induce an immune response. An example of an endotoxin is the lipopolysaccharide (LPS) molecule found in the cell walls of gram-negative bacteria. During sterilization, bacteria are killed, for example by high pressure sterilization or ethylene oxide, but LPS residues induce proinflammatory immune responses, such as septic shock. Because endotoxins can vary widely in molecular size, their presence is measured in "endotoxin units" (EU). One EU is equivalent to 100 picograms of E. coli LPS. Humans have a maximum of 5EU / kg. Bioburden (e.g., microbial limits) and / or sterility (e.g., endotoxin levels) can be determined by any simple method known in the art. In some embodiments, the ophthalmic compositions described herein contain relatively low endotoxin levels (e.g., <4 EU / kg of subject's body weight) when compared to normally tolerated endotoxin levels (e.g., 5 EU / kg of subject's body weight). In some embodiments, the ophthalmic formulations have endotoxin levels of less than about 5 EU / kg of subject's body weight. In other embodiments, the ophthalmic formulations have endotoxin levels of less than about 4 EU / kg of subject's body weight. In other embodiments, the ophthalmic formulations have endotoxin levels of less than about 3 EU / kg of subject's body weight. In other embodiments, the ophthalmic formulations have endotoxin levels of less than about 2 EU / kg of subject's body weight.

[0248] In some embodiments, the ophthalmic formulation has an endotoxin level of less than about 5 EU / kg of formulation. In other embodiments, the ophthalmic formulation has an endotoxin level of less than about 4 EU / kg of formulation. In other embodiments, the ophthalmic formulation has an endotoxin level of less than about 3 EU / kg of formulation. In some embodiments, the ophthalmic formulation has an endotoxin level of less than about 5 EU / kg of product. In other embodiments, the ophthalmic formulation has an endotoxin level of less than about 1 EU / kg of product. In other embodiments, the ophthalmic formulation has an endotoxin level of less than about 0.2 EU / kg of product. In some embodiments, the ophthalmic formulation has an endotoxin level of less than about 5 EU / g of unit or product. Other embodiments In this embodiment, the ophthalmic preparation has an endotoxin level of less than about 4 EU / g (unit or product). In other embodiments, the ophthalmic formulation has an endosperm concentration of less than about 3 EU / g (unit or product). In some embodiments, the ophthalmic formulations have an endotoxin level of less than about 5 EU / mg (units or product). In other embodiments, the ophthalmic formulations have an endotoxin level of less than about 4 EU / mg (units or product). In other embodiments, the ophthalmic formulations have an endotoxin level of less than about 3 EU / mg (units or product). In some embodiments, the ophthalmic formulations described herein comprise an endotoxin level of about 1 EU / mL (formulation) to about 5 EU / mL (formulation). In some embodiments, the ophthalmic formulations described herein comprise an endotoxin level of about 2 EU / mL (formulation) to about 5 EU / mL (formulation), about 3 EU / mL (formulation) to about 5 EU / mL (formulation), or about 4 EU / mL (formulation) to about 5 EU / mL (formulation).

[0249] In some embodiments, the ophthalmic compositions described herein contain relatively low endotoxin levels (e.g., <0.5 EU / mL of formulation) when compared to normally tolerated endotoxin levels (e.g., 0.5 EU / mL of formulation). In some embodiments, the ophthalmic formulation has an endotoxin level of less than about 0.5 EU / mL of formulation. In other embodiments, the ophthalmic formulation has an endotoxin level of less than about 0.4 EU / mL of formulation. In other embodiments, the ophthalmic formulation has an endotoxin level of less than about 0.5 EU / mL of formulation. In the present invention, the ophthalmic formulation has an endotoxin level of less than about 0.2 EU / mL of the formulation.

[0250] Illustratively, pyrogen detection can be performed in a number of ways. Suitable sterility tests are described in the United States Pharmacopeia (USP). <71> Sterility Testing (23rd Edition, 1995) includes the tests described in Rabbit Pyrogen Test and the Horseshoe Crab Amebocyte Extraction Test are both based on the United States Pharmacopeia <85> Chapter and Article <151> Chapter (USP23 / NF 18, Biological Tests, The United States Pharmacopeial Convention, Rockville, MD, 1995). A selectable pyrogen assay has been developed based on the monocyte activation-kitkine assay. Homogeneous cell lines suitable for quality control applications have been developed and their ability to detect pyrogenicity in samples passing the rabbit pyrogen test and the Limulus amebocyte lysate test has been demonstrated (Taktak et al., J. Pharm Pharmacol. (1990), 43:578-82). In another embodiment, the ophthalmic formulation is depyrogenated. Other embodiments In some embodiments, the process for manufacturing the ophthalmic formulation includes testing the formulation for pyrogenicity. In some embodiments, the formulations described herein are substantially pyrogen-free.

[0251] Ophthalmic gel composition Gels are defined in several ways. For example, the United States Pharmacopeia defines a gel as a semi-solid system that consists of a suspension of small inorganic particles or large organic molecules interpenetrated by a liquid. Gels include single-phase or two-phase systems. Single-phase gels consist of large organic molecules dispersed evenly throughout a liquid, such that there is no clear boundary between the dispersed large molecules and the liquid. Some single-phase gels are prepared from synthetic polymers (e.g., carbomer) or natural gums (e.g., tragacanth gum). In some embodiments, single-phase gels typically contain water, although some are made using alcohols and oils. Two-phase gels consist of a network of small discrete particles.

[0252] Gels may be classified as hydrophobic or hydrophilic. In some embodiments, non-limiting examples of hydrophobic gel matrices include liquid paraffin with polyethylene, or fatty oils gelled with colloidal silica or aluminum or zinc soaps. In contrast, non-limiting examples of hydrophilic gel matrices include water, glycerin, or propylene glycol gelled with a suitable gelling agent (e.g., tragacanth gum, starch, cellulose derivatives, carboxyvinyl polymers, and magnesium aluminum silicate). In some embodiments, the rheology of the compositions disclosed herein is pseudoplastic, plastic, thixotropic, or dilatant.

[0253] In some embodiments, the ophthalmic composition is an ophthalmic gel, in which the ophthalmologically acceptable carrier comprises water and at least one thickening agent. The agent is a cellulose-based polymer, polyoxyethylene-polyoxypropylene rib. The polymer may be selected from the group consisting of lock copolymers, dextran-based polymers, polyvinyl alcohol, dextrin, polyvinylpyrrolidone, polyalkylene glycols, chitosan, collagen, gelatin, hyaluronic acid, or combinations thereof.

[0254] In some embodiments, the ophthalmic gel compositions described herein are semi-solid or liquid in a gelled state (e.g., at room temperature) prior to topical administration. Illustratively, suitable viscosity enhancing agents for use in such gels include gelling agents and suspending agents. In one embodiment, the viscosity enhancing agent is a suspending agent. In another embodiment, the enhanced viscosity formulation does not include a buffer. In another embodiment, the enhanced viscosity formulation includes a pharma- ceutically acceptable buffer. Optionally, sodium chloride or other tonicity agents are used to adjust tonicity, if necessary.

[0255] Exemplary ophthalmically acceptable viscosity agents include hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium chondroitin sulfate, and sodium hyaluronate. Other viscosity agents compatible with the target ocular site include gum arabic, agar, magnesium aluminum silicate, sodium alginate, sodium stearate, bladderwrack, bentonite, carbomer, carrageenan, carbopol, xanthan, cellulose, microcrystalline cellulose (MCC), ceratonia, chitin, carboxymethyl chitosan, chondrus, dextrose, furcellaran, zeolite, and the like. gelatin, ghatti gum, guar gum, hectorite, lactose, sucrose, maltodextrin, mannitol, sorbitol, honey, corn starch, wheat starch, rice starch, potato starch, sterculia gum, xanthum gum, tragacanth gum, ethyl cellulose, ethyl hydroxyethyl cellulose, ethyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, poly(hydroxyethyl methacrylate), oxypolygelatin, pectin, polygeline, povidone, propylene carbonate, methyl vinyl ether / maleic anhydride copolymer (PVM / MA), poly(methoxyethyl methacrylate), poly(hydroxy ... Poly(methoxyethoxyethyl methacrylate), Hydroxypropyl methylcellulose (HPMC), Sodium carboxymethylcellulose (CMC), Silicon dioxide Examples of viscosity enhancing excipients include, but are not limited to, polyvinylpyrrolidone (PVP: povidone), Splenda® (dextrose, maltodextrin and sucralose), or combinations thereof. In a specific embodiment, the viscosity increasing excipient is a combination of MCC and CMC. In another embodiment, the viscosity increasing agent is a combination of carboxymethylchitosan or chitin and alginate. The combination of chitin and alginate and the ophthalmic agent disclosed herein is used as a controlled release formulation to restrict the diffusion of the ophthalmic agent from the formulation. Additionally, the combination of carboxymethylchitosan and alginate selectively contributes to increased permeability of the ophthalmic agent through the eye.

[0256] In some embodiments, the viscosity enhancing formulation comprises about 0.1 mM to about 100 mM of an ophthalmic agent, a pharma- ceutically acceptable viscosity agent, and water for injection. The concentration of the viscosity agent in the water is sufficient to provide the viscosity enhancing formulation with a final viscosity of about 100 cP to about 100,000 cP. In some embodiments, the viscosity of the gel is in the range of about 100 cP to about 50,000 cP, about 100 cP to about 1,000 cP, about 500 cP to about 1500 cP, about 1000 cP to about 3000 cP, about 2000 cP to about 8,000 cP, about 4,000 cP to about 50,000 cP, about 10,000 cP to about 500,000 cP, or about 15,000 cP to about 1,000,000 cP. In other embodiments, where a more viscous medium is required, the biocompatible gel may comprise at least about 35% by weight, at least about 45% by weight, or at least about 55% by weight , at least about 65% by weight, at least about 70% by weight, at least about 75% by weight, or at least Contains approximately 80% or more ophthalmic agent by weight. Highly concentrated samples are biocompatible. The viscosity enhancing formulation may comprise at least about 25% by weight, at least about 35% by weight, at least about 45% by weight , at least about 55% by weight, at least about 65% by weight, at least about 75% by weight, at least about 85% by weight %, at least about 90%, or at least about 95% or more by weight of an ophthalmic agent.

[0257] In one embodiment, a pharmacy acceptable enhanced viscosity ophthalmically acceptable The formulation comprises at least one ophthalmic agent and at least one gelling agent. Suitable gelling agents for the preparation of gel formulations include, but are not limited to, cellulose, cellulose derivatives, cellulose ethers (e.g., carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose), guar gum, xanthan gum, locust bean gum, alginates (e.g., alginic acid), silicates, starch, tragacanth gum, carboxyvinyl polymers, carrageenan, paraffin, petrolatum, and any combination or mixture thereof. In some other embodiments, hydroxypropylmethylcellulose (Methocel®) is used as a gelling agent. In some embodiments, the thickening agents described herein are further used as gelling agents in the gel formulations described herein.

[0258] In some embodiments, the ophthalmic gel compositions described herein are in situ gel formulations. In some cases, the in situ gel formulations are formulations based on increased precorneal residence time of the ophthalmic composition, improved ocular bioavailability, corneal mucoadhesion, lysosomal interactions and ionic gelation, improved corneal absorption, thermal gelation, or a combination thereof. In some cases, the in situ gel formulations are activated by pH, temperature, ions, UV, or solvent exchange.

[0259] In some cases, the ophthalmic gel composition includes one or more gelling agents. Agents include poloxamers (e.g., poloxamer 407), tetronics, ethyl (hydroxyethyl) cellulose, cellulose acetate phthalate (CAP), carbopol (e.g., Pall 1342P NF, Carbopol 980 NF), alginates (e.g., low acetyl gellan gum (Gelrite®), gellan gum, hyaluronic acid, pluronics (e.g., Pluronic F-127), chitosan, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), dextran, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), These include, but are not limited to, methylcellulose (MC), thiolated xyloglucan, polymethacrylic acid (PMMA), polyethylene glycol (PEG), pseudolatexes, xyloglucan, or combinations thereof.

[0260] In some cases, the in situ gel formulation further comprises a penetration enhancer, which in some cases includes surfactants (e.g., non-ionic surfactants), benzalkonium chloride, EDTA, surface active heteroglycosides, calcium chelators, hydroxypropyl-β-cyclodextrin (HPβCD), bile salts, and the like.

[0261] In some embodiments, the usefulness of other gel formulations will depend on the particular ophthalmic agent, other drug, or excipient / additive used, and for this reason are recognized to be within the scope of the present disclosure. For example, it is expected that other commercially available glycerin-based gels, glycerin-derived compounds, conjugated or crosslinked gels, matrices, hydrogels and polymers, gelatin and its derivatives, alginates and alginate-based gels, several natural and synthetic hydrogels and hydrogel-derived compounds may be used in the formulation of the ophthalmic agents described herein. In some embodiments, the ophthalmically acceptable gel is an alginate hydrogel SAF (R) Gel (ConvaTec, Princeton, NJ), Duoderm (R) Hydractive Gel (ConvaTec), Nu-gel® (Johnson & Johnson Medical, Arlington, Tex.), Carrasyn® (V) acemanan hydrogel (Carrington Laboratories, Inc., Irving, Tex.), glycerin gel Elta® hydrogel (Swiss-American Products, Inc., Dallas, Tex.), and KY® sterile (Johnson & Johnson). In certain embodiments, the biodegradable biocompatible gel further represents a compound present in the ophthalmically acceptable formulations disclosed and described herein.

[0262] In some embodiments, the thickening agent is a cellulose-based polymer selected from cellulose gum, alkyl cellulose, hydroxyalkyl cellulose, hydroxyl alkyl alkyl cellulose, carboxy alkyl cellulose, or combinations thereof. In some embodiments, the thickening agent is a hydroxyl alkyl alkyl cellulose. In some embodiments, the thickening agent is hydroxypropyl methyl cellulose.

[0263] In some embodiments, the viscosity enhanced formulation is characterized by a phase transition between room temperature and body temperature (including individuals with severe fever (e.g., up to about 42° C.). In some embodiments, the phase transition occurs at less than 1° C. body temperature, less than 2° C. body temperature, less than 3° C. body temperature, less than 4° C. body temperature, less than 6° C. body temperature, less than 8° C. body temperature, or less than 10° C. body temperature. In some embodiments, the phase transition occurs at less than about 15° C. body temperature, less than about 20° C. body temperature, or less than about 25° C. body temperature. In specific embodiments, the gelation temperature (Tgel) of the formulations described herein is about 20° C., about 25° C., or about 30° C. In specific embodiments, the gelation temperature (Tgel) of the formulations described herein is about 35° C. or about 40° C. The definition of body temperature includes the body temperature of a healthy individual or an unhealthy individual (including individuals with fever up to 42° C.). In some embodiments, the pharmaceutical compositions described herein are liquid at a temperature of about room temperature and are administered at or about room temperature.

[0264] Copolymers of polyoxypropylene and polyoxyethylene (e.g., polyoxyethylene-polyoxypropylene triblock copolymers) can be thermally cured when incorporated in aqueous solution. These polymers have the ability to change from a liquid state to a gel state at temperatures close to body temperature, allowing for useful formulations to be applied to the target ocular site. The phase transition from the liquid state to the gel state is determined by the concentration of the polymer and the components in the solution.

[0265] In some embodiments, the amount of thermosetting polymer in any formulation described herein is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer in any formulation described herein is about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 7.5% of the total weight of the formulation. The amount of thermosetting polymer (e.g., poloxamer 407) in any of the above formulations may vary depending on the formulation. In some embodiments, any of the formulations described herein may comprise about 10% by weight of the total formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 11% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 12% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 13% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 14% of the total weight of the formulation. In some embodiments, the total weight of the formulation is about 14%. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 15% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 16% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 17% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about About 18% by weight of the total formulation. In some embodiments, any of the formulations described herein may be The amount of thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 19% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 20% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 21% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about In some embodiments, any of the compositions described herein is about 23% by weight of the total formulation. The amount of thermosetting polymer (e.g., poloxamer 407) in the formulation is about 25% of the total weight of the formulation. In some embodiments, the amount of thickening agent (e.g., gelling agent) in any formulation described herein is about 1%, about 5%, about 10%, or about 15% of the total weight of the formulation. In some embodiments, the amount of thickening agent (e.g., gelling agent) in any formulation described herein is about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% of the total weight of the formulation.

[0266] In alternative embodiments, the thermogel is a PEG-PLGA-PEG triblock copolymer (Jeong et al., Nature (1997), 388:860-2; Jeong et al., J. Control. Tomoyuki Edition (2000), 63:155-63; Jeong et al., Adv. Drug Delivery Rev. (2002), 54:37-51). The polymer is present at a concentration of about 5% w / w to about 40% w / w. Depending on the desired properties, the lactate in the PLGA copolymer is The molar ratio of PEG / glycolide ranges from about 1:1 to about 20:1. The resulting copolymer is soluble in water and forms a free-flowing liquid at room temperature, but forms a hydrogel at body temperature. A commercially available PEG-PLGA-PEG triblock copolymer is RESOMER RGP t50106 manufactured by Boehringer Ingelheim. The material is a 50:50 poly(DL-lactide-co-glycolide) PLGA copolymer, 10% w / w PEG, and has a molecular weight of about 6000.

[0267] Other biodegradable thermoplastic polyesters include AtriGel® (provided by Atrix Laboratories, Inc.) and / or those disclosed in, for example, U.S. Pat. Nos. 5,324,519, 4,938,763, Nos. 5,702,716, 5,744,153, and 5,990,194, including, where appropriate, Suitable biodegradable thermoplastic polyesters are disclosed as thermoplastic polymers. Examples of suitable biodegradable thermoplastic polyesters include polylactide, polyglycolide, polycaprolactone, copolymers thereof, terpolymers thereof, and any combination thereof. In some such embodiments, suitable biodegradable thermoplastic polyesters include polylactide, polyglycolide, copolymers thereof, terpolymers thereof, or any combination thereof. In one embodiment, the biodegradable thermoplastic polyester is % to about 50,000. Alternatively, in another embodiment, the biodegradable thermoplastic polyester is a 75 / 25 poly(DL-lactide-co-glycolide) having no carboxy end groups, present at about 40 wt.% to about 50 wt.% of the composition, and having an average molecular weight of about 15,000 to about 24,000. In another or alternative embodiment, the method of polymerization results in the end groups of the poly(DL-lactide-co-glycolide) being hydroxyl groups. , carboxyl or ester. Condensation polymerization of lactic acid or glycolic acid provides a polymer with terminal hydroxyl and carboxyl groups. Ring-opening polymerization of cyclic lactide or glycolide monomers with water, lactic acid or glycolic acid provides a polymer with the same end groups. However, ring-opening polymerization of cyclic monomers with monofunctional alcohols such as methanol, ethanol or 1-dodecanol provides a polymer with one hydroxyl and one ester end group. Ring-opening polymerization of cyclic monomers with diols such as 1,6-hexanediol or polyethylene glycol provides a polymer with only hydroxyl end groups.

[0268] Since the polymer system of the thermosetting gel dissolves more completely at reduced temperatures, the dissolution aid method involves adding the required amount of polymer to the amount of water to be used at reduced temperatures. Typically, after wetting the polymer by shaking, the mixture is covered and stored in a cold room or at about 0°C to 10°C. The mixture is placed in a thermostatic container to allow the polymer to dissolve. The mixture is stirred or shaken to dissolve the thermosetting gel polymer faster. The ophthalmic agent and a number of additives, such as buffers, salts and preservatives, are then added and dissolved. In some cases, if the drug is not soluble in water, it is suspended. The pH is adjusted by adding a suitable buffer.

[0269] Ophthalmic ointment composition Ointments are homogeneous, viscous, semisolid products, most commonly thick greasy oils (e.g., 80% oil-20% water), intended for external application to the skin or mucous membranes. Ointments may contain It has a water number that defines the maximum amount of water that can be applied to the skin. It is used as an emollient or for the application of active ingredients to the skin for protective, therapeutic or preventative purposes and where a degree of occlusion is required. Ointments are used topically on several types of body surfaces. These include the skin and mucous membranes of the eye (eye ointment), vulva, anus, and nose.

[0270] The vehicle of an ointment is called an ointment base. The choice of base is determined by the clinical indication of the ointment. Different types of ointment bases include hydrocarbon bases (e.g., solid paraffin, soft paraffin, microcrystalline wax, and ceresin), absorbent bases (e.g., wool fat, beeswax), water-soluble bases (e.g., macrogol 200, 300, 400), emulsifying bases (e.g., emulsifying wax, cetrimide), vegetable oils (e.g., olive oil, coconut oil, sesame oil, almond oil, and peanut oil).

[0271] Ointments are formulated using hydrophobic, hydrophilic or water-emulsifiable matrices to provide products that are immiscible, miscible or emulsifiable with skin secretions. They may be derived from hydrocarbon (fatty) matrices, absorbent matrices, water-removable matrices or water-soluble matrices. The active agent is dispersed in the matrices, which then separate after the drug has penetrated the target site (e.g., membrane, skin, etc.).

[0272] As recognized in the present disclosure, it can be difficult to incorporate low concentrations of drugs with sufficient dose-to-dose uniformity into an ointment to effectively treat a disorder or disease. In some embodiments, poly(ethylene glycol), polyethoxylated castor oil (Cremophor® EL), alcohols having 12-20 carbon atoms, or mixtures of two or more of the foregoing, are used to disperse and / or dissolve effective amounts of ophthalmic drugs, particularly ascomycin derivatives and staurosporine derivatives, in an ointment matrix, particularly an ointment matrix that includes mostly oily and hydrocarbon components. It is used to disperse and / or dissolve the resulting ointment, which has excellent adhesion to the skin and eye tissue. It is an effective excipient that is well tolerated.

[0273] As further appreciated by the present disclosure, when the compositions are administered topically to the ocular surface, particularly the sclera, of said patient, ophthalmic drugs incorporated into the ointment compositions described herein, such as those of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof, is capable of effectively targeting the choroid and / or retina in a patient. In some embodiments, the ophthalmic ointment composition comprises an ophthalmic drug, an ointment base, and an agent for dispersing and / or dissolving the drug in the ointment base, the agent being poly(ethylene glycol). glycol), polyethoxylated castor oil, alcohols having 12 to 20 carbon atoms, and mixtures of two or more of the above ingredients.

[0274] In some embodiments, the ointment base comprises an ophthalmically acceptable oil or fatty base, such as natural waxes (e.g., white and yellow beeswax, carnauba wax, wool wax, refined lanolin, anhydrous lanolin), petroleum waxes (e.g., solid paraffin, microcrystalline wax), hydrocarbons (e.g., liquid paraffin, white soft paraffin, yellow soft paraffin, white petrolatum, yellow petrolatum), or combinations thereof.

[0275] The above mentioned oils and fat substrates are described in more detail in, for example, the British Pharmacopoeia 2001 Edition or the European Pharmacopoeia 3rd Edition. It is listed.

[0276] The ointment base may be present in an amount of about 50% to about 95% by weight, preferably 70% to 90% by weight, of the total weight of the composition.

[0277] A preferred ointment base comprises one or more of the natural waxes mentioned above, preferably wool wax (sheep's wool). hair sebum), and one or more of the above-mentioned hydrocarbons (preferably soft paraffin or petrolatum, more preferably Preferably in combination with liquid paraffin.

[0278] A particular embodiment of the ointment base includes, for example, 5 to 17 parts by weight of wool fat, 50 to 65 parts by weight of white petrolatum, and 20 to 30 parts by weight of liquid paraffin.

[0279] The agent for dispersing and / or dissolving the ophthalmic drug in the ointment matrix is ​​poly(ethylene glycol). The agent may be selected from the group consisting of polyethoxylated castor oil, alcohols having 12 to 20 carbon atoms, and mixtures of two or more of the above ingredients. is used in an amount of 1% by weight to 20% by weight, more preferably 1% by weight to 10% by weight, of the entire semisolid ophthalmic composition.

[0280] Alcohols having 12 to 20 carbon atoms are especially stearyl alcohols (C 18 H 37 OH), cetyl alcohol (C 16 H 33 OH) and mixtures thereof. Preferably, so-called cetostearic alcohols; mixtures of solid alcohols consisting essentially of stearyl alcohol and cetyl alcohol and preferably containing more than 40% by weight of stearyl alcohol and at least 90% by weight of the sum of stearyl alcohol and cetyl alcohol; more than 80% by weight of cetostearic alcohol. and emulsifiers (especially sodium cetostearyl sulfate and / or sodium lauryl sulfate, preferably or a composition containing an emulsifier in an amount of 7% by weight or more.

[0281] Polyethoxylated castor oil is a reaction product of natural or hydrogenated castor oil with ethylene glycol. Such a product may be obtained in a known manner, for example by reacting natural or hydrogenated castor oil or a fraction thereof with ethylene oxide in a molar ratio of, for example, about 1:30 to about 1:60, and selectively removing the free polyethylene glycol moieties from the product, for example by the methods disclosed in German Auslegeschriften 1,182,388 and 1,518,819. Particularly suitable and preferred is the commercially available Cremophor® EL, having a molecular weight of According to the steam osmometry method, the product has a viscosity index of about 1630, a saponification value of about 65-70, an acid value of about 2, an iodine value of about 28-32, and an nD25 of about 1.471. )HCO-60, which is a reaction product of hydrogenated castor oil and ethylene oxide, and has the following properties: acid value=about 0.3, saponification value=about 47.4, hydroxyl value=about 42.5, pH(5%)=about 4.6, color APHA=about 40, mp=about 36.0°C, freezing point=about 32.4°C, HO content(%, KF)=about 0.03.

[0282] In some embodiments, poly(ethylene glycol) is used as an agent to disperse and / or dissolve the ophthalmic drug in an ointment matrix according to the present disclosure. glycol) is typically represented by the general formula H-(OCH2-CH2) n It is a mixture of polymer compounds of OH, where the index n is typically in the range of 4 to 230, and the average molecular weight is from about 200 to about 10,000. Preferably, n is a value from about 6 to about 22, and the average molecular weight is between about 300 and about 1,000. More preferably, n is in the range of about 6 to about 13, and the average molecular weight is about 300 to about 600. Most preferably, n has a value of about 8.5 to about 9, and the relative molecular weight is about 400. Suitable poly(ethylene glycols) are readily available commercially, for example poly(ethylene glycols) having average molecular weights of about 200, 300, 400, 600, 1000, 1500, 2000, 3000, 4000, 6000, 8000, and 10000. (Roll).

[0283] Poly(ethylene glycol), particularly the preferred types mentioned above, is preferably used in an amount of 1% to 10% by weight, more preferably 1% to 5% by weight of the total semi-solid ophthalmic composition.

[0284] Particularly preferred embodiments of compositions according to the present disclosure include compositions in which the drug is dispersed and / or dissolved in an ointment matrix. The agent for preventing the formation of sebum is selected from poly(ethylene glycol), polyethoxylated castor oil, and mixtures of the above preferred ingredients.

[0285] Gel / ointment viscosity In some embodiments, the composition is heated to about 20° C. for 1 s. -1 In some embodiments, the composition has a Brookfield RVDV viscosity of about 10,000 cps to about 300,000 cps at a shear rate of about 10,000 cps to about 300,000 cps. is about 20℃ and 1s -1 Brookfield RVDV of about 15,000cps to about 200,000cps at shear rates of In some embodiments, the composition has a viscosity of about 20° C. and 1 s -1 In some embodiments, the composition has a Brookfield RVDV viscosity of about 50,000 cps to about 150,000 cps at a shear rate of about 100,000 cps. The composition is heated to about 20°C for 1 s. -1 At a shear rate of about 70,000cps to about 130,000cps, In some embodiments, the composition has a viscosity of about 20° C. and 1 s -1at a shear rate of about 90,000 cps to about 110,000 cps.

[0286] In some embodiments, the ophthalmic gel formulation has a viscosity of between about 500 and 1,000,000 centipoise, between about 750 and 1,000,000 centipoise, between about 1000 and 1,000,000 centipoise, between about 1000 and 400,000 centipoise, between about 2000 and 100,000 centipoise, between about 3000 and 50,000 centipoise, The ophthalmic gel formulation includes sufficient thickening agent to provide a viscosity between about 4000 and 25,000 centipoise, between about 5000 and 20,000 centipoise, or between about 6000 and 15,000 centipoise, hi some embodiments, the ophthalmic gel formulation includes sufficient thickening agent to provide a viscosity between about 50,0000 and 1,000,000 centipoise.

[0287] In some embodiments, the compositions described herein are low viscosity compositions at body temperature. In some embodiments, the low viscosity compositions contain about 1% to about 10% of a viscosity increasing agent (e.g., polyoxyethylene). In some embodiments, the gelling component is a propylene glycol-polyoxypropylene copolymer. In some embodiments, the low viscosity composition comprises about 2% to about 10% of a thickening agent (e.g., a gelling component such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low viscosity composition comprises about 5% to about 10% of a thickening agent (e.g., a gelling component such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low viscosity composition comprises about 10% of a thickening agent (e.g., a gelling component such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low viscosity ophthalmic compositions described herein provide an apparent viscosity of about 100 cP to about 10,000 cP. The low viscosity ophthalmic compositions described provide an apparent viscosity of about 500 cP to about 10,000 cP. In embodiments, the low viscosity ophthalmic compositions described herein provide an apparent viscosity of about 1000 cP to about 10,000 cP.

[0288] In some embodiments, the compositions described herein are viscous compositions at body temperature. In some embodiments, the viscous compositions include about 10% to about 25% of a viscosity enhancing agent (e.g., a gelling component such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, In the present invention, the viscous composition contains about 14% to about 22% of a thickening agent (e.g., polyoxyethylene-polyoxypropylene). In some embodiments, the viscous composition comprises about 15% to about 21% of a thickening agent (e.g., a gelling component such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the viscous ophthalmic compositions described herein provide an apparent viscosity of about 100,000 cP to about 1,000,000 cP. In some embodiments, the viscous ophthalmic compositions described herein provide an apparent viscosity of about 150,000 cP to about 500,000 cP. In some embodiments, the viscous ophthalmic compositions described herein provide an apparent viscosity of about 250,000 cP to about 300,000 cP. In some such embodiments, the viscous eye provides an apparent viscosity of about 500,000 cP. The ophthalmic composition is liquid at room temperature and gels between about room temperature and body temperature (including individuals with severe fevers (e.g., up to about 42° C.)). In some embodiments, the viscous ophthalmic composition is administered as a sole treatment method and is used to treat an ophthalmic disease or condition described herein.

[0289] In some embodiments, the viscosity of the gel formulations described herein is measured by any of the means described above. For example, in some embodiments, an LVDV-II+CP cone-plate viscometer and a cone-spindle CPE-40 are used to calculate the viscosity of the gel formulations described herein. In other embodiments, a Brookfield (spindle and cup) viscometer is used to calculate the viscosity of the gel formulations described herein. In some embodiments, the viscosity ranges described herein are measured at room temperature. In other embodiments, the viscosity ranges described herein are measured at body temperature (e.g., the average body temperature of a healthy human).

[0290] Dose-to-dose uniformity of gel / ointment Typically, eye gels are packaged in eye dropper bottles and administered as drops. For example, a single administration (i.e., a single dose) of eye gel may be one, two, three, or more drops administered to a patient. The method may include placing the ophthalmic ointment in the subject's eye. Typically, eye ointments are packaged in tubes or other squeezable containers with a dispensing nozzle, and strips of ointment are delivered by the dispensing nozzle. For example, a single administration (i.e., a single dose) of eye ointment may be one strip, or The method may include placing multiple strips of the eye gel into the patient's eye. In some embodiments, a dose of the eye gel described herein is a single drop of the gel composition from an eye dropper. In some embodiments, a dose of the eye ointment is dispensed by the nozzle of a dispensing tube. The ointment composition is one strip of the prescribed amount.

[0291] In some cases, the present disclosure includes providing an ophthalmic gel composition with a uniform concentration between doses. In some cases, the uniform concentration between doses is achieved without significant variation in drug content from one dose to another. In some cases, uniform concentration between doses indicates consistency from one dose to another. This ensures that the drug content is adequate.

[0292] In some cases, the present disclosure includes providing an ophthalmic ointment composition with a uniform concentration between doses. In some cases, the uniform concentration between doses is achieved without significant variation in drug content from one dose to another. In some cases, uniform concentration between doses indicates consistency from one dose to another. This ensures that the drug content is adequate.

[0293] In some embodiments, the composition has a dose-to-dose concentration variation of the ophthalmic agent of less than 50%. In some embodiments, the composition has a dose-to-dose concentration variation of the ophthalmic agent of less than 40%. In some embodiments, the composition has a dose-to-dose concentration variation of the ophthalmic agent of less than 30%. In some embodiments, the composition has a dose-to-dose concentration variation of the ophthalmic agent of less than 20%. In some embodiments, the composition has a dose-to-dose concentration variation of the ophthalmic agent of less than 10%. In some embodiments, the composition has a dose-to-dose variation of the ophthalmic agent concentration of less than 5%.

[0294] In some embodiments, the change in concentration of the ophthalmic agent between doses is based on 10 consecutive doses. In some embodiments, the change in concentration of the ophthalmic agent between doses is based on 8 consecutive doses. In some embodiments, the change in concentration of the ophthalmic agent between doses is based on five consecutive doses. In some embodiments, the change in concentration of the ophthalmic agent between doses is based on three consecutive doses. In some embodiments, the change in concentration of the ophthalmic agent between doses is based on the doses of two Based on consecutive doses.

[0295] A non-settling formulation should not require shaking for uniform distribution of the drug. The shaking action for the patient is an easily major source of variability in the drug amount of the administered medication, and "no shaking" formulations have potential advantages over formulations that require shaking. Reports suggest that even with clearly marked shaking instructions on the label, patients do not always shake or forget to shake the ophthalmic composition, which must be shaken before administration of a dose. On the other hand, even for those patients who did shake the product, it is usually not possible to determine whether the strength and / or duration of shaking was sufficient for product homogeneity. In embodiments, the ophthalmic gel and ophthalmic ointment compositions described herein are "no shake" formulations that maintain the dose-to-dose uniformity described herein.

[0296] To assess dose-to-dose uniformity, drop bottles or drop tubes containing the ophthalmic water-containing composition, ophthalmic gel composition, or ophthalmic ointment composition are stored upright for at least 12 hours prior to the start of testing. To mimic the recommended dosing of these products, a predetermined number of drops or strips are allocated from each commercially available bottle or tube at predetermined time intervals for an extended period of time or until no product remains in the bottle or tube. All drops or strips are allocated to equilibrated glass vials, capped, and stored at room temperature until analysis.

[0297] In some embodiments, milling processes are used to reduce the size of solid materials to form particles in the micrometer to nanometer size range. Dry milling and wet milling processes, such as jet milling, cryomilling, ball milling, media milling, and homogenization, are known and may be used in the methods described herein. Generally, in wet milling processes, a suspension of the material to be used as nanoparticles is mixed with milling media with or without excipients to reduce the particle size. Dry milling is a process in which a suspension of the material to be used as nanoparticles is mixed with milling media with or without excipients to reduce the particle size. In cryomilling processes, a suspension of the material to be used as nanoparticles is mixed with milling media with or without excipients at a cooled temperature. Any suitable milling media may be used for milling. In some embodiments, ceramic and / or polymeric materials and / or metals may be used. Examples of suitable materials include zirconium oxide, silicon carbide, silicon oxide, silicon nitride, zirconium silicate, yttrium oxide, glass, alumina, alpha-alumina, aluminum oxide, polystyrene, polyimide, polysilicon ... Examples of the milling media include silicon (methyl methacrylate), titanium, and steel. The milling media may have any suitable size. For example, the milling media may be at least about 0.1 mm, at least about 0.5 mm, at least about 0.5 mm, at least about 0.6 mm, at least about 0.8 mm, at least about 0.9 mm, at least about 1.2 mm, at least about 0.9 ... The milling media may have an average diameter of at least about 0.2 mm, at least about 0.5 mm, at least about 0.8 mm, at least about 1 mm, at least about 2 mm, or at least about 5 mm. In some cases, the milling media may have an average diameter of about 5 mm or less, about 2 mm or less, about 1 mm or less, about 0.8 mm or less, about 0.5 mm or less, or about 0.2 mm or less. Combinations of the above ranges are also possible (e.g., an average diameter of at least 0.5 mm and no more than about 1 mm). Other ranges are also possible.

[0298] Any suitable solvent may be used for milling. The choice of solvent will depend, for example, on the solid material being milled, the particular type of stabilizer / mucus penetrant being used (e.g., a stabilizer that penetrates the mucus of the particles). The amount of the granules to be used is determined by the type of granules, the grinding material used, and other factors. A suitable solvent will not substantially dissolve the solid or ground material, but will provide a suitable amount of stabilizing / mucus penetrating agent. The solvent may be a solvent in which the drug dissolves to a sufficient degree. Non-limiting examples of solvents include water, buffers, other aqueous solutions, alcohols (e.g., ethanol, methanol, butanol) and mixtures thereof, and may optionally contain other ingredients, such as pharmaceutical excipients, polymers, drugs, salts, preservatives, viscosity modifiers, tonicity modifiers, flavorings, antioxidants, pH modifiers, and other pharmaceutical excipients. In other embodiments, organic solvents may be used. The drug may have any suitable solubility in these or other solvents, such as within one or more of the ranges for aqueous solubility or solubility in the coating solution described above. The resolution may be

[0299] Exemplary ophthalmically acceptable viscosity agents include hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium chondroitin sulfate, and sodium hyaluronate. Other viscosity agents suitable for the target ocular site include gum arabic, agar, magnesium aluminum silicate, sodium alginate, sodium stearate, bladderwrack, bentonite, carbomer, carrageenan, carbopol, xanthan, cellulose, microcrystalline cellulose (MCC), ceratonia, chitin, carboxymethyl chitosan, chondrus, decanol, glyceryl stearate ... Kistrose, Furcellan, Gelatin, Gum Ghatti, Guar Gum, Hectorite, Lactose, Sucrose, Maltodextrin, Mannitol, Sorbitol, Honey, Corn Starch, Wheat Starch, Rice Starch, Potato Starch, Araya Gum, Xanthan Gum, Tragacanth Gum, Ethyl Cellulose, Ethyl Hydroxyethyl Cellulose, Ethyl Methyl Cellulose, Methyl Cellulose, Hydroxyethyl Cellulose, Hydroxypropyl Cellulose, Poly(hydroxyethyl methacrylate), Oxypolygelatin, Pectin, Polygeline, Povidone, Propylene Carbonate, Methyl Vinyl Ether / Maleic Anhydride Copolymer (PVM / MA), Poly(methoxyethyl methacrylate), Poly(meth) (Toxoxyethoxyethyl methacrylate), Hydroxypropyl methylcellulose (HPMC), Sodium carboxymethylcellulose (CMC), Silicon dioxide, Polyvinylpyrrolidone (PVP: povidone), Splenda® (dextrose, maltodextrin and sucralose) or combinations thereof. In a specific embodiment, the viscosity increasing excipient is a combination of MCC and CMC. In another embodiment, the viscosity increasing agent is a combination of carboxymethylchitosan or chitin and alginate. The combination of chitin and alginate with the ophthalmic agent disclosed herein is used as a controlled release formulation to restrict the diffusion of the ophthalmic agent from the formulation. Additionally, the combination of carboxymethylchitosan and alginate selectively contributes to increased permeability of the ophthalmic agent through the eye.

[0300] In some embodiments, the viscosity enhancing formulation comprises about 0.1 mM to about 100 mM of an ophthalmic agent, a pharma- ceutically acceptable viscosity agent, and water for injection. The concentration of the viscosity agent in the water is sufficient to provide the viscosity enhancing formulation with a final viscosity of about 100 cP to about 100,000 cP. In some embodiments, the viscosity of the gel is in the range of about 100 cP to about 50,000 cP, about 100 cP to about 1,000 cP, about 500 cP to about 1500 cP, about 1000 cP to about 3000 cP, about 2000 cP to about 8,000 cP, about 4,000 cP to about 50,000 cP, about 10,000 cP to about 500,000 cP, or about 15,000 cP to about 1,000,000 cP. In other embodiments, where a more viscous medium is required, the biocompatible gel may comprise at least about 35% by weight, at least about 45% by weight, or at least about 55% by weight , at least about 65% by weight, at least about 70% by weight, at least about 75% by weight, or at least Contains approximately 80% or more ophthalmic agent by weight. Highly concentrated samples are biocompatible. The viscosity enhancing formulation may comprise at least about 25% by weight, at least about 35% by weight, at least about 45% by weight , at least about 55% by weight, at least about 65% by weight, at least about 75% by weight, at least about 85% by weight %, at least about 90%, or at least about 95% or more by weight of an ophthalmic agent.

[0301] In one embodiment, a pharmacy acceptable enhanced viscosity ophthalmically acceptable The formulation comprises at least one ophthalmic agent and at least one gelling agent. Suitable gelling agents for the preparation of the formulation include, but are not limited to, cellulose, cellulose derivatives, cellulose ethers (e.g., carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose), guar gum, xanthan gum, locust bean gum, alginates (e.g., alginic acid), silicates, starch, tragacanth gum, carboxyvinyl polymers, carrageenan, paraffin, petrolatum, and any combination or mixture thereof. In some other embodiments, hydroxypropylmethylcellulose (Methocel®) is used as the gelling agent.

[0302] In some cases, the ophthalmic composition includes one or more gelling agents. In some cases, the gelling agent is Poloxamers (e.g., poloxamer 407), tetronics, ethyl (hydroxyethyl) cellulose, cellulose acetate phthalate (CAP), carbopol (e.g., Gellan gum (e.g., Gellan 1342P NF, Carbopol 980 NF), alginates (e.g., low acetyl gellan gum (Gelrite®)), gellan gum, hyaluronic acid, pluronics (e.g., Pluronic F-127), chitosan, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), dextran, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), methylcellulose (Methylcellulose ... The present invention includes, but is not limited to, methylcellulose (MC), thiolated xyloglucan, polymethacrylic acid (PMMA), polyethylene glycol (PEG), pseudolatex, xyloglucan, or combinations thereof. This is not limited to:

[0303] In some embodiments, the thickening agent is a cellulose-based polymer selected from cellulose gum, alkyl cellulose, hydroxyalkyl cellulose, hydroxyl alkyl alkyl cellulose, carboxy alkyl cellulose, or combinations thereof. In some embodiments, the thickening agent is a hydroxyl alkyl alkyl cellulose. In some embodiments, the thickening agent is hydroxypropyl methyl cellulose.

[0304] Dose-to-dose uniformity Typically, ophthalmic formulations are packaged in an eye dropper and administered as drops. For example, a single administration (i.e., a single dose) of an ophthalmic formulation may be one, two, three, or more drops administered to a patient. In some embodiments, the method may include administering a dose of the present invention to an eye of a patient. The ophthalmic preparation described is a 3 drop composition from an eye dropper bottle.

[0305] In some cases, the present disclosure provides ophthalmic compositions with uniform concentration between doses. In some cases, uniform concentration between doses does not include significant changes in drug content from one dose to another. In some cases, uniform concentration between doses may be achieved by matching drug concentrations from one dose to another. Ensures proper content.

[0306] In some cases, the present disclosure includes providing an ophthalmic ointment composition with a uniform concentration between doses. In some cases, the uniform concentration between doses is achieved without significant variation in drug content from one dose to another. In some cases, uniform concentration between doses indicates consistency from one dose to another. This ensures that the drug content is adequate.

[0307] In some embodiments, the composition has a dose-to-dose concentration variation of the ophthalmic agent of less than 50%. In some embodiments, the composition has a dose-to-dose concentration variation of the ophthalmic agent of less than 40%. In some embodiments, the composition has a dose-to-dose concentration variation of the ophthalmic agent of less than 30%. In some embodiments, the composition has a dose-to-dose concentration variation of the ophthalmic agent of less than 20%. In some embodiments, the composition has a dose-to-dose concentration variation of the ophthalmic agent of less than 10%. In some embodiments, the composition has a dose-to-dose variation of the ophthalmic agent concentration of less than 5%.

[0308] In some embodiments, the change in concentration of the ophthalmic agent between doses is based on 10 consecutive doses. In some embodiments, the change in concentration of the ophthalmic agent between doses is based on 8 consecutive doses. In some embodiments, the change in concentration of the ophthalmic agent between doses is based on five consecutive doses. In some embodiments, the change in concentration of the ophthalmic agent between doses is based on three consecutive doses. In some embodiments, the change in concentration of the ophthalmic agent between doses is based on the doses of two Based on consecutive doses.

[0309] A non-settling formulation should not require shaking for uniform distribution of the drug. The shaking action for the patient is an easily major source of variability in the drug amount of the administered medication, and "no shaking" formulations have potential advantages over formulations that require shaking. Reports suggest that even with clearly marked shaking instructions on the label, patients do not always shake or forget to shake the ophthalmic composition, which must be shaken before administration of a dose. On the other hand, even for those patients who did shake the product, it is usually not possible to determine whether the strength and / or duration of shaking was sufficient for product homogeneity. In an embodiment, the ophthalmic compositions described herein are "no shake" formulations that maintain the dose-to-dose uniformity described herein. To assess dose-to-dose uniformity, the drop bottles or drop tubes containing the ophthalmic compositions are stored upright for at least 12 hours before the start of the study. To mimic the recommended dosing of these products, a set number of drops or strips are allocated from each commercially available bottle or tube at set time intervals for an ever-increasing period of time, or until no product remains in the bottle or tube. All drops or strips are allocated to equilibrated glass vials, capped, and stored at room temperature until analysis.

[0310] II.How to use In one aspect, the present disclosure provides a method for treating or preventing a disorder or disease, the method comprising administering to a subject having a corresponding need a therapeutically effective amount of a pharmaceutical composition comprising: (i) Formula (I): JPEG2025004026000100.jpg2761(I) or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharma- ceutically acceptable excipient; The pharmaceutical composition is in a form for ophthalmic administration or use, The disorder or disease is a neovascular disorder or disease, an inflammatory disorder or disease, or cancer.

[0311] In one aspect, the present disclosure provides a method for treating or preventing a disorder or disease, the method comprising administering to a subject having a corresponding need a therapeutically effective amount of a pharmaceutical composition comprising: (i) Formula (I): JPEG2025004026000101.jpg2761(I) or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharma- ceutically acceptable excipient; The pharmaceutical composition is formulated as a suspension, The disorder or disease is a neovascular disorder or disease, an inflammatory disorder or disease, or cancer.

[0312] In one aspect, the present disclosure provides a method for treating or preventing an ocular disorder or disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising: (i) Formula (I): JPEG2025004026000102.jpg2761(I) or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharma- ceutically acceptable excipient; The pharmaceutical composition is formulated as a suspension.

[0313] In one aspect, the present disclosure provides a method for treating or preventing an ocular disorder or disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising: (i) Formula (I): JPEG2025004026000103.jpg2761(I) or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharma- ceutically acceptable excipient; The pharmaceutical composition is in a form for ophthalmic administration or use.

[0314] In some embodiments, the ocular disorder or disease is an impairment of the function, clarity and / or quality of the lens of the eye. or affecting the structure of the ocular disorder or disease. In some embodiments, the ocular disorder or disease is wet macular degeneration, cataracts, presbyopia, nuclear sclerosis of the ocular lens, Refsum's disease, Smith-Lemli-Opitz syndrome (SLOS), Schneider's crystalline corneal dystrophy (SCCD), abetalipoproteinemia, familial hypobetalipoproteinemia, neovascularization, or cancer. In some embodiments, the neovascularization is corneal neovascularization, iris neovascularization, or choroidal neovascularization. In some embodiments, the ocular disorder or disease is corneal neovascularization. In some embodiments, the subject has already undergone a surgical procedure to treat the ocular disorder or disease.

[0315] In some embodiments, about 0.005 mg / mL to about 5.0 mg / mL of a compound of formula (I). or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof is administered to the eye of a subject. About 4.0 mg / mL of a compound of formula (I), or an isotopic variant, tautomer, or derivative thereof. The pharmaceutical composition, which comprises a physiologically acceptable salt, solvate or hydrate, is administered to the eye of the subject.

[0316] In some embodiments, the composition is administered to a subject once daily, twice daily, three times daily, or four times daily.

[0317] In some embodiments, the composition is administered to the subject three times daily. In some embodiments, about 60 μL of a pharmaceutical composition comprising a compound of Formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof, is administered to the eye of the subject.

[0318] In some embodiments, the composition is administered to the subject three times per day. In some embodiments, the composition is administered to the subject four times per day.

[0319] In some embodiments, administration is topical or by ocular injection, hi some embodiments, ocular injection is an intravitreal injection or a subconjunctival injection.

[0320] In some embodiments of the methods herein, the pharmaceutical composition is administered to the subject daily. In some embodiments of the methods herein, the pharmaceutical composition is administered to the subject once a day. In some embodiments of the methods herein, the compound is administered twice daily, three times daily, or four times daily. In some embodiments of the methods herein, the pharmaceutical composition is administered to the subject once daily. In some embodiments of the methods herein, the pharmaceutical composition is administered to the subject three times daily.

[0321] In some embodiments of the methods herein, the pharmaceutical composition continues to be administered to the subject for a period of about 12 weeks. In some embodiments of the methods herein, the pharmaceutical composition continues to be administered to the subject for a period of at least 1 week. In this embodiment, the pharmaceutical composition continues to be administered to the subject for a period of at least two weeks. In some embodiments of the method, the pharmaceutical composition is administered to the subject for a period of about two weeks. In some embodiments of the methods herein, the pharmaceutical composition continues to be administered to the subject for a period of 1 week, 2 weeks, 6 weeks, 12 weeks, 24 weeks, 48 ​​weeks, or 52 weeks.

[0322] In some embodiments, the ophthalmic aqueous formulations described herein are packaged in an eye dropper and administered as drops. For example, a single administration (i.e., a single dose) of the ophthalmic aqueous formulation may include placing one, two, three, or more drops in the patient's eye. In some embodiments, the eye gel formulations described herein are packaged in an eye dropper and administered as drops. For example, a single administration (i.e., a single dose) of eye gel may include placing one, two, three, or more drops in the patient's eye. In some embodiments, the eye ointment formulations described herein are packaged in a tube or other squeezable container having a dispensing nozzle, and the ointment strips are delivered by the dispensing nozzle. For example, a single administration (i.e., a single dose) of the eye ointment may be one strip, or multiple strips. In some embodiments, a dose of the ophthalmic aqueous formulation described herein is a drop of the aqueous composition from an eye dropper. In some embodiments, a dose of the ophthalmic gel described herein is a drop of the aqueous composition from an eye dropper. In some embodiments, one dose of eye ointment is one strip of the ointment composition dispensed by the nozzle of the dispensing tube.

[0323] In some embodiments, the ophthalmic aqueous formulation is administered as follows: The lower eyelid of the subject's eye is pulled down and a predetermined amount of the aqueous formulation (e.g., 1-3 drops) is applied to the inside of the eyelid. The ophthalmic tip of the dispensing mechanism is not allowed to come into contact with any surface to avoid contamination and / or damage. Do not touch.

[0324] In some embodiments, the ocular gel formulation is administered as follows: the lower eyelid of the recipient's eye is pulled down and a predetermined amount of gel (e.g., 1-3 drops) is applied to the inside of the eyelid. The ocular tip of the dispensing mechanism does not touch any surface to avoid contamination and / or damage.

[0325] In some embodiments, the eye ointment formulation is administered as follows: The lower eyelid of the recipient's eye is pulled down and a small amount of ointment (approximately 0.25 inches) is applied to the inside of the eyelid. The eye tip of the dispensing mechanism does not touch any surface to avoid contamination and / or damage.

[0326] In some embodiments, the ophthalmic composition is administered at predetermined time intervals for an extended period of time. In some embodiments, the ophthalmic composition is administered three times a day (i.e., 3 times a day). In some embodiments, the ophthalmic composition is administered within 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, or 12 to 15 years.

[0327] In some embodiments, the ophthalmic composition is administered in doses that have a concentration variation of the ophthalmic agent between doses of less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%.

[0328] The number of administrations of the composition to an individual in need thereof will be determined by the judgment of a medical professional, the disorder, the severity of the disorder, and the individual's response to the formulation. In some embodiments, the compositions disclosed herein are administered once to an individual in need thereof who suffers from mild acute symptoms. In some embodiments, the compositions disclosed herein are administered more than once to individuals suffering from moderate or severe acute symptoms and in need of treatment. If the condition is not improved, administration of the ophthalmic agent may be long-term, i.e., for an extended period of time, including for the life of the patient, at the discretion of the physician, to alleviate or otherwise control or limit the symptoms of the patient's disease or condition.

[0329] If the patient's condition does not improve, administration of the ophthalmic agent may be long-term, i.e., for an extended period of time, including the life of the patient, at the physician's discretion, to alleviate or otherwise control or limit the symptoms of the patient's disease or condition.

[0330] If the patient's condition has improved significantly, the physician may continue to administer the ophthalmic agent or, optionally, reduce or discontinue the administered dose of the drug for a period of time (i.e., a "drug holiday"). The length of the drug holiday may vary between 2 days and 1 year, and illustrative examples include 2 Days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction on the drug holiday may be 10% to 100%, and examples include 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0331] After improvement of the patient's ophthalmic condition occurs, administration of the ophthalmic agent at a dose is maintained, if necessary. Thereafter, as symptoms change, the dose or frequency of administration, or both, is optionally reduced such that the improved disease, disorder, or condition is maintained. In some embodiments, the patient requires long-term intermittent treatment following any recurrence of symptoms.

[0332] The amount of ophthalmic agent corresponding to such an amount will depend, for example, on factors such as the particular compound, the state and severity of the disease, and will vary according to the particular circumstances surrounding the disease history (including, for example, the particular ophthalmic agent being administered, the route of administration, the state being treated, the target area being treated, and the subject or host being treated). Desired doses include a single dose, or divided doses administered simultaneously (or within a short period of time) or at appropriate intervals.

[0333] In some embodiments, the initial administration is a particular ophthalmic agent and subsequent administrations are a different formulation or ophthalmic agent.

[0334] pH adjuster Sodium dihydrogen phosphate dihydrate (NaH2PO4·2H2O), disodium hydrogen phosphate dodecahydrate The monohydrate (Na2HPO4·12H2O) is used as a pH adjuster. Other alternatives include maleate, citrate, etc. Wetting agents include cationic or anionic surfactants and suspending agents include HPMC.

[0335] Suspension It is defined as a product containing finely divided drug particles (suspensions) somewhat unevenly distributed in a vehicle in which the drug exhibits the lowest degree of solubility. A suspension is the state of the drug when the drug particles are mixed with a fluid or solid but are not dissolved in the fluid or solid.

[0336] Polyoxyl 15 Hydroxystearate (Kolliphor® HS 15) Polyoxyl 15-hydroxystearate is a novel excipient with high dissolving capacity, low histamine release, low hemolytic activity, and good physiological tolerance, and has been approved for injection. Its safety is supported by marketed products and clinical study data.

[0337] HPMC Hypromellose (HPMC E4M) is widely used as a polymeric suspending agent for suspension formulations. Other commercial products with different viscosities and different degrees of substitution are also available.

[0338] Sodium thiosulfate Sodium thiosulfate is an antioxidant; its aqueous solution is neutral or slightly alkaline, and precipitates upon reaction with acid, making it suitable for alkaline drugs.

[0339] Administration In some embodiments, the pharmaceutical compositions herein are administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, The administration continues for about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days.

[0340] In some embodiments, the pharmaceutical compositions herein are administered daily, every other day, every other day three times each week, every two weeks, every three weeks, every four weeks, every five weeks, every three days, or every four days. every 5 days, every 6 days, every week, every 2 weeks, 3 times a week, 4 times a week, 5 times a week, 6 times a week In some embodiments, the compound is administered once every month, twice every month, three times every month, once every two months, once every three months, once every four months, once every five months, or once every six months. A compound (e.g., a compound of formula (I) or its isotopic variants, tautomers, pharmaceutical Methods for administration of the compounds of formula (I), (Is, I, II, III, IV ... The administration of the compounds may occur within 2 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, 15 minutes, or 10 minutes. In some cases, the compounds are administered simultaneously.

[0341] Angiogenesis and neovascularization Angiogenesis is the process by which new blood vessels grow from existing blood vessels. The process is associated with the migration and proliferation of vascular endothelial cells. Angiogenesis is associated with many serious human diseases, including malignant tumors. To date, ocular neovascular diseases have been widely reported, including age-related macular degeneration (AMD), diabetic retinopathy, neovascular glaucoma, etc. It was discovered that the common feature of these diseases is the abnormal proliferation of ocular neovascularization (Xiao Jin et al., “Research Progress on the Clinical Application and Basic Mechanism of Anti-VEGF Drug,” CHINA FOREIGN MEDICAL TREATMENT, 2012).

[0342] Both angiogenesis and neovascularization are regulated by a mixture of stimulators and inhibitors, which are balanced to ensure proper construction of blood vessels in the body.Miss-regulated angiogenesis or neovascularization is the root cause of many diseases and conditions.Inhibition of angiogenesis or neovascularization may be a useful treatment method for diseases such as macular degeneration, diabetic nephropathy, rheumatoid arthritis, arteriosclerotic plaque, endometriosis, Crohn's disease, uterine fibroids, benign prostatic hyperplasia, psoriasis, corneal neovascularization, iris neovascularization, choroidal neovascularization and cancer.

[0343] Several molecular mediators of angiogenesis have been identified, including basic and acidic fibroblast growth factors (aFGF, bFGF), transforming growth factors α and β (TGFα, TGFβ), platelet-derived growth factor (PDGF), angiogenin, platelet-derived endothelial growth factor (PD-ECGF), interleukin-1 (IL-1) and IL-2. Other stimulators involved in angiogenesis include angiopoietin 1, Del-1, follistatin, granulocyte-colony stimulating factor (G-CSF), hepatocyte growth factor (HGF), leptin, midkine, placental growth factor, pleiotrophin, and endothelial growth factor (VEGF). These include proliferin (PTN), progranulin, proliferin, and tumor necrosis factor-α (TNF-α). Control of angiogenesis is also mediated by a number of negative regulators of angiogenesis produced by the body, including angioarrestin, angiostatin (a plasminogen fragment), antiangiogenic factor (ATF), anti-angiogenic factor (AG ... Angiogenesis Antithrombin III, Cartilage-derived inhibitor (CDI), CD59 complement fragment, Endostatin (collagen XVIII fragment), Fibronectin fragment, gro-β, Heparin enzyme, heparin hexasaccharide fragment, human chorionic gonadotropin These include human chorionic gonadotropin (hCG), interferon alpha / beta / gamma, interferon-inducible protein (IP-10), interleukin-12, kringer 5 (plasminogen fragment), metalloproteinase inhibitors (TIMPs), 2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor 4 (PF4), prolactin 16 kD fragment, proliferin-related protein (PRP), retinoids, tetrahydrocortisol-S, thrombospondin 1 (TSP-1), vasculostatin, and vasostatin (calreticulin fragment). Of these angiogenic regulators, VEGF appears to play an important role as a positive regulator of the abnormal angiogenesis associated with tumor growth (reviewed in Brown et al. (1996) Control of Angiogenesis (Goldberg and Rosen), Birkhauser, Basel, and Thomas (1996) J. Biol. Chem. 271:603-606). The role of the PDGF-B member of the family of signaling molecules continues to be investigated, as it appears to play a role in the formation, expansion, and proper function of perivascular cells, which are sometimes called mural cells, e.g., vascular smooth muscle cells, mesangial cells, and pericytes.

[0344] Vascular endothelial growth factor receptor 2 (VEGFR2) (also called kinase insert domain receptor (KDR)) family members are receptor tyrosine kinases, e.g. VEGFR1, VEGFR2, etc. These receptors play important roles in the progression of diseases such as malignant tumor growth and metastasis, and vascular proliferative disorders (e.g. macular degeneration and tumors). EGFR2 / KDR / Flk-1 (vascular endothelial growth factor receptor 2 (VEGFR2)) is a member of the vascular endothelial growth factor receptor 2 (VEGFR2) family. VEGF-A and VEGF-C mediate angiogenesis. EGFR2 / KDR / Flk-1 is expressed primarily on vascular endothelial cells and endothelial cell precursor cells. EGFR2 / KDR / Flk-1 is also involved in endometrial epithelium, hematopoietic stem cells, hepatic sinusoidal endothelial cells, and Sertoli cells. It is expressed on cytoplasmic and Leydig cells, platelets and megakaryocytes, sensory and autonomic neurons, Schwann cells, Muller glial cells, retinal progenitor cells, and osteoblasts. VEGFR2 can bind to VEGFR1, and a soluble form of VEGFR2 can circulate in serum.

[0345] Platelet-derived growth factor receptor (PDGF-R) family members include receptor tyrosine kinases such as PDGFRα and PDGFRβ, colony-stimulating factor 1 receptor, stem cell growth factor receptor KIT, etc. These kinases have been found to be closely related to tumor initiation and progression. Abnormal expression of PDGFR is associated with various cancers including melanoma, meningioma, neuroendocrine tumors, ovarian cancer, prostate cancer, lung cancer, and pancreatic cancer. Abnormal activation of KIT is a direct trigger of the development and progression of many tumors. be.

[0346] FGFR (fibroblast growth factor receptor) family members are closely associated with cancer. FGFR1 , FGFR2, etc. For example, abnormal activation of FGFR2 has been found in endometrial cancer, cervical cancer, breast cancer, lung cancer and gastric cancer. The SRC kinase family is a tyrosine protein kinase The SRC kinase family includes proteins with oncogene activity. It was first discovered in the Rous sarcoma virus. As previously discovered, inhibition of SRC is a cancer or other diseases. The mitochondrial protein kinase (MAPK) pathway is an intracellular stress response signaling pathway that is closely related to inflammatory responses.

[0347] Macular degeneration is mainly divided into two types: dry and wet. AMD is characterized by the infiltration of new blood vessels from the choroid into the retina, followed by hemorrhage, exudation, and edema. and other pathological changes. Wet macular degeneration causes rapid loss of vision and is more serious than dry macular degeneration. At present, there has been good progress in the treatment of wet macular degeneration. Early laser cauterization was replaced by VEGF antagonists, but the latter was less effective and was soon replaced by photodynamic therapy. Photodynamic therapy has improved efficacy, but is still insufficient. Recently, a new VEGF antagonist, Lucentis, has been developed, which is a recombinant human-derived VEGF subtype monoclonal antibody fragment and can reduce angiogenesis. The drug was approved by the US FDA in 2006 for the treatment of wet macular degeneration and has been successfully used in the treatment of wet macular degeneration. It has been found that the anti-VEGF drug has excellent efficacy, and at the same time, the anti-VEGF drug also has therapeutic effects on diabetic retinopathy and neovascular glaucoma. However, Lucentis is an antibody drug with a very high price, so it cannot be popularized worldwide. Therefore, the development of small molecule angiogenesis inhibitor drugs with excellent efficacy and low price is the focus of fierce competition in the current international pharmaceutical industry.

[0348] Kits / Products The present disclosure further provides kits for treating diseases or disorders associated with angiogenic hyperproliferation. Such kits include one or more ophthalmic compositions disclosed herein, and The kit includes instructions for use. The present disclosure relates to an ophthalmic composition comprising one or more ophthalmic compositions for use in treating angiogenesis. Further contemplated is the use of the compound in the manufacture of a medicament for treating, alleviating, reducing or ameliorating the symptoms of a disease, dysfunction or disorder in a mammal, such as a human, suffering from a disease or disorder associated with abnormal proliferation of tissue, or at risk of suffering from or developing said disease or disorder.

[0349] In some embodiments, the kits include a single container, such as vials, tubes, and similar containers. and a carrier, package, or container partitioned to house the above containers, each of which contains one of the individual elements that are subject to use in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In other embodiments, the containers are made from a variety of materials, such as, for example, glass or plastic.

[0350] The articles of manufacture according to the present disclosure include packaging materials. The present disclosure further describes packaging materials for packaging drug products. See, for example, U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of drug packaging materials include drop bottles, These include, but are not limited to, tubes, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and anticipated mode of administration and treatment. A wide variety of ophthalmic compositions according to the present invention are anticipated to be therapeutic for a variety of diseases, disorders, or conditions that would benefit from controlled delivery of an ophthalmic agent to the eye.

[0351] In some embodiments, the kit comprises one or more separate containers, each of which is commercially available and / or commercially available. The formulations used herein may have one or more of a number of materials (e.g., rinses, wipes, and / or devices) that are desirable from a user's perspective. Such materials may further include a label listing the contents and / or instructions for use, and a package insert having instructions for use. In other embodiments, the label is on the container or In a further embodiment, the label is on the container when letters, numbers, or other characters forming the label are attached, molded, or etched onto the container itself, and the label is associated with the container when the label is present in a receptacle or carrier that also houses the container, e.g., a package insert. In other embodiments, the label is used to indicate that the contents are to be used for a particular therapeutic application. In a further embodiment, the label further indicates instructions for use of the contents, e.g., instructions for use in the methods described herein.

[0352] In some embodiments, the ophthalmic composition is contained in a dispenser device, the dispenser device comprising one or more unit dosage forms, the unit dosage forms comprising a compound according to the present invention. In another embodiment, the dispenser device is accompanied by instructions for administration. In a further embodiment, the dispenser is further accompanied by a notice in a format prescribed by a governmental agency regulating the manufacture, use, or sale of the drug associated with the container, the notice reflecting the agency's approval of the format for human drugs or veterinary administration. In another embodiment, such notice is, for example, a label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. In a further embodiment, a composition comprising a compound according to the present invention formulated in a compatible pharmaceutical carrier is further prepared, the composition is placed in an appropriate container, and labeled for use in treating an indicated condition.

[0353] III.Synthesis method In one aspect, the present disclosure provides a method for preparing a pharmaceutical composition, the pharmaceutical composition comprising a compound of formula (I or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof, and at least one pharma- ceutically acceptable excipient, is formulated as a suspension, the method comprising: (i) micronizing a compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; (ii) a microparticulated compound of formula (I), or an isotopic variant or tautomer thereof; sterilizing the body, a pharma- ceutically acceptable salt, solvate or hydrate thereof, and (iii) a therapeutically effective amount of a compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof, and at least one pharma- ceutically acceptable The method includes mixing the composition with an excipient.

[0354] In one aspect, the present disclosure provides a method for preparing a pharmaceutical composition, the pharmaceutical composition comprising a compound of formula (I or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof, and at least one pharma- ceutically acceptable excipient, The pharmaceutical composition is in a form for ophthalmic administration or use, and the method comprises: (i) micronizing a compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; (ii) a microparticulated compound of formula (I), or an isotopic variant or tautomer thereof; sterilizing the body, a pharma- ceutically acceptable salt, solvate or hydrate thereof, and (iii) a therapeutically effective amount of a compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof, and at least one pharma- ceutically acceptable The method includes mixing the composition with an excipient.

[0355] In some embodiments, a compound of formula (I), or an isotopic variant or antagonism thereof, A suspension is formed containing particles of the variant, pharma- ceutically acceptable salt, solvate or hydrate.

[0356] In some embodiments, sterilization occurs prior to mixing. In some embodiments, sterilization occurs after mixing.

[0357] In some embodiments, sterilization is performed at a temperature of about 121° C. In this case, sterilization is carried out for about 20 to 30 minutes.

[0358] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes made in light of the same will occur to those skilled in the art and are within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are incorporated by reference in their entirety for all purposes.

[0359] IV. Working Examples Examples 1 to 5 summarize the development of a 0.1% w / v KDR2-2 eye drop suspension, which is an effective corneal nephropathy drug. It is used for the treatment of biovascular angiogenesis. Initially, a quality target product profile (QTPP) is defined based on the properties of the drug substance. Investigations during drug development focus on CQAs that may be affected by actual changes in the drug product formulation or manufacturing process. For KDR2-2 suspension eye drop, these CQAs include appearance, particle size, viscosity, osmolality, pH, assay, impurities, visible particles, and sterility. The drug substance used was from Asymchem Life Science (Tianjin) Co., Ltd. (No. 71, Seventh Avenue, Economic and Technological Development Zone, Tianjin, China, 300457). For the formulation development, the excipient grade selection was based on experience or supplier recommendations, and the grades of key excipients were optimized. For the process development, it included a micronization process, a sterilization process, a filtration process and a blending process. The micronization process, the sterilization process, the filtration process and the blending process were the critical process parameters (CPPs). During preparation, the acceptable ranges of content and particle size were determined. Scale-up principles and plans for expansion from lab scale to pilot scale (~50.0 kg of common mix) were discussed. A cGMP demonstration batch of ~50.0 kg was manufactured at pilot scale. Commercial scale operating ranges of the determined CPPs are proposed and typically qualified and continuously verified during commercial manufacturing. Finally, a control strategy is proposed that identifies process parameters as potentially high risk variables. Our control strategy further includes in-process controls and finished product specifications. The process is monitored during the product's life cycle and other knowledge gained is used to make appropriate adjustments to the control strategy.

[0360] Example 1: Target Product Quality Overview / Drug Product Based on the physicochemical properties exhibited by KDR2-2 during the early development stages, a target product profile was established to guide the development of KDR2-2 eye drop suspension.

[0361] Table 1. Target product quality overview of 0.1% w / v KDR2-2 eye drop suspension JPEG2025004026000104.jpg221150

[0362] Table 2 summarizes the quality attributes of KDR2-2 ophthalmic suspension and indicates which attributes are classified as critical quality attributes (CQAs) of the drug product. The product, particle size, sedimentation volume ratio, osmolality, viscosity, pH, sodium thiosulfate content, content uniformity, content and impurities are determined by formulation and / or process variables. The CQA subset that may be affected by

[0363] Table 2. Critical and non-critical quality attributes of 0.1% w / v KDR2-2 eye drop suspension JPEG2025004026000105.jpg131150

[0364] Chemical name: 2-(2-aminopyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)quinoline-5-carboxamide

[0365] Chemical structure: JPEG2025004026000106.jpg2761Molecular formula:C 21 H 14 F3N5O2 Molecular weight: 425.36 Physical description: White solid

[0366] Physicochemical properties of drug substances Water solubility: The solubility of KDR2-2 in different media was measured and is shown in Table 3.

[0367] Table 3. Solubility of KDR2-2 in different media JPEG2025004026000107.jpg66170

[0368] Particle size: KDR2-2 is a poorly soluble drug with large particle size. To meet the quality standard of KDR2-2 suspension eye drops, the drug substance should be micronized. The results of microscopic observation of KDR2-2 (batch #CK0120554-02-03P-01-32-01) in 1% Kolliphor® HS 15 are shown in Figure 1. The particle size of KDR2-2 (batch #CK0120554-02-03P-01-32-01) in 1% Kolliphor® HS 15 was measured by Malvern and is shown in Table 4.

[0369] Table 4, Granularity results for KDR2-2 API, batch #CK0120554-02-03P-01-32-01 JPEG2025004026000108.jpg28150

[0370] Example 2: Excipient compatibility studies The excipients used in the KDR2-2 eye drop suspension were selected based on excipient compatibility studies and the intention to prepare a simple eye drop suspension with acceptable physicochemical properties while providing good manufacturability in our process. Summary of excipient-drug substance compatibility studies, and A selection of each excipient grade is provided in this example.

[0371] With reference to the drug stability guiding principle, the pilot sample (batch #FNB190016-002) and blank excipient solution (batch #FNB190016-003) are kept stored at 60℃, 40℃ and illumination (4500Lx±500Lx) for 5, 10 and 30 days. The excipient-drug substance compatibility is evaluated according to the results of appearance, pH, viscosity, osmolality, particle size, content and impurities, and the results are summarized in Table 6. In the excipient compatibility study, common excipients used as polymeric suspending agents, solubilizing agents, pH adjusters, osmolality adjusters and antioxidants are evaluated.

[0372] Table 5. Summary of excipients for KDR2-2 eye drop suspension JPEG2025004026000109.jpg65150

[0373] Table 6. Excipient compatibility results for 0.1% w / v KDR2-2 eye drop suspension, batches #FNB190016-002 and FNB190016-003 JPEG2025004026000110.jpg180158 JPEG2025004026000111.jpg249156*If the impurity is less than 0.05%, it will be reported as "ND". Only if the impurity is greater than 0.05%, it will be calculated as total impurities.

[0374] After the samples were stored at 60°C for 10 days, white flocculent precipitate appeared in the KDR2-2 ophthalmic suspension, and some samples were close to clear after 30 days. After 30 days of storage at 40°C and illumination, the appearance, content and impurities of the KDR2-2 ophthalmic suspension and blank solution did not change significantly. Therefore, the excipients and drug substance are deemed to be compatible. The compatibility of the drug substance and excipients will be confirmed again by a stability study of the submitted batch. The results of such a study under accelerated conditions (40°C / NMT 25% RH) are summarized below. It can be seen.

[0375] Excipient Grade Selection Based on the results of the excipient compatibility study, hypromellose (HPMC E4M), polyoxyl 15 hydroxystearate (Kolliphor® HS 15), sodium dihydrogen phosphate dihydrate (NaH2PO4·2H2O), disodium hydrogen phosphate dodecahydrate (Na2HPO4·12H2O), sodium chloride were selected as excipients. Sodium thiosulfate and sodium thiosulfate were selected for product development. Selection of excipient grades and suppliers was based on previous formulation experience and knowledge of excipients in approved products that have been used successfully in manufacturing. Subsequent formulation development studies investigated the levels of excipients used in the formulation.

[0376] Table 7. Initial Selection of Excipient Type and Grade JPEG2025004026000112.jpg92150

[0377] Hypromellose (HPMC E4M): Hypromellose (HPMC E4M) is widely used as a polymeric suspending agent for suspension eye drops. The product name is METHOCEL TM It is.

[0378] Polyoxyl 15 Hydroxystearate (Kolliphor® HS 15): Polyoxyl 15-hydroxystearate is a novel excipient with high dissolving capacity, low histamine release, low hemolytic activity, and good physiological tolerance, and has been approved for injection. Its safety is supported by marketed products and clinical study data.

[0379] Sodium dihydrogen phosphate dihydrate (NaH2PO4·2H2O): It is widely used as a pH adjuster and is selected as an injection grade product from Merck. Residual solvent and microbial limits should meet requirements.

[0380] Disodium hydrogen phosphate dodecahydrate (Na2HPO4·12H2O): It is widely used as a pH adjuster and is selected as an injection grade product from Merck. Residual solvent and microbial limits should meet requirements.

[0381] Sodium chloride: Sodium chloride is widely used as an osmolality adjuster and is available in injectable grade from Merck. The product to be selected should meet the requirements for residual solvents and microbial limits.

[0382] Sodium thiosulfate: Sodium thiosulfate, an antioxidant, is from Sinopharm Chemical Reagent Co., Ltd. The quality should meet the requirements. The subsequent production will use Merck brand for clinical application.

[0383] Selection of excipient dosage Based on the initial formulation development, the excipient dosage is based on the Inactive Ingredients Database (IIG) and the National Drug Review Board. The usual doses of excipients published in the Clinical Trials Center's excipient database were confirmed to meet the dose limits and are shown in Table 8.

[0384] Table 8. Excipient dosages for 0.1% w / v KDR2-2 eye drop suspension JPEG2025004026000113.jpg66150*The daily dose is 3 drops, 3 times a day. **For the dose of IIG used in ophthalmic products, sodium thiosulfate IIG is used intravenously. Data show that the content of Kolliphor® HS 15 in the injectable product (Panitol) The abundance is 50%.

[0385] The dosages of excipients used in this product are based on the FDA-approved Drug Inactive Ingredients Database. The IIG dose is lower than that of ophthalmic or intravenous products.

[0386] Example 3: Drug Product Formulation Development Early Formulation Development Formulation development will start with a few small R&D batches (FNB180076-048-01~FNB180076-065-03). These batches were optimized by adjusting the amount of each excipient in the recipe to provide acceptable physical properties for our drug product. All these adjustments led to the prototype formulation FNB180076-065-03, which showed acceptable physical properties. Some bench scale tests are shown in Table 9. Table 10 provides the physical properties of the main bench scale formulations. The results showed that the base composition developed during the bench scale testing period could produce acceptable physical properties. By evaluating the physical properties of the above test batches, it was shown that the osmolality of the product could be influenced by disodium hydrogen phosphate dodecahydrate, sodium chloride, and sodium thiosulfate, and the concentration of hypromellose (HPMC E4M) affected the viscosity of the formulation. In order to reduce the sedimentation of the drug substance, FNB180076-065-03 is selected as the main bench scale formulation.

[0387] Table 9. Composition of Initial Formulation Testing, KDR2-2 Suspension Eye Drops 0.1% w / v, Batch #FNB180076-048-01, FNB180076-050-02, FNB180076-050-03, FNB180076-052-01, FNB180076-052-03, FNB180076-058-01, FNB180076-058-03, FNB180076-065-01, FNB180076-065-02 and FNB180076-065-03 JPEG2025004026000114.jpg136170

[0388] Table 10. Physical properties of selected bench-scale formulations of KDR2-2 ophthalmic suspension 0.1% w / v, batches #FNB180076-048-01, FNB180076-050-02, FNB180076-050-03, FNB180076-052-01, FNB180076-052-03, FNB180076-058-01, FNB180076-058-03, FNB180076-065-01, FNB180076-065-02 and FNB180076-065-03 JPEG2025004026000115.jpg66150

[0389] Initial stability study Another R&D batch (Batch #FNB180076-071-01, Batch: 2000 vials) containing the same levels of ingredients as FNB180076-065-03 is evaluated to determine stability at long-term conditions (25°C / 65%RH). No out-of-range pH, viscosity, osmolality, particle size, content and impurities were observed, leading to the conclusion that the formulation is stable and eligible for further development.

[0390] Table 11. Physical properties of KDR2-2 eye drop suspension under long-term conditions (25°C / 65% RH) JPEG2025004026000116.jpg63150*If the impurity is less than 0.05%, it will be reported as "ND". Only if the impurity is greater than 0.05%, it will be calculated as total impurities.

[0391] Based on the formulation development studies, the formulation composition is finally determined. The levels of hypromellose (HPMC E4M), disodium hydrogen phosphate dodecahydrate, sodium chloride and sodium thiosulfate are optimized. The finalized formulation of 0.1% w / v KDR2-2 ophthalmic suspension is shown in Table 12.

[0392] Table 12. JPEG2025004026000117.jpg77150

[0393] Example 4: Manufacturing Process Development Process parameters can potentially affect the quality attributes of the finished product. The process parameters used in a process step determined the quality attributes of the output material (intermediate) produced in that step. The process parameters of the intermediate from that step in the manufacturing process determined the quality attributes of the next intermediate, and finally the quality attributes of the finished drug product. The API micronization, API suspension sterilization process, hypromellose (HPMC E4M) preparation process, blank solution filtration and stirring / mixing processes were the CPPs of KDR2-2 suspension ophthalmic solution, and the CPPs of KDR2-2 suspension ophthalmic solution were studied to evaluate the product quality attributes.

[0394] Drug substance particle size selection for product development. In order to avoid excessive lacrimation, the drug particle size of the suspension eye drop should be reduced to a level <10 μm, and the micronization process of the drug substance was studied. For the jet micronization process parameters, the injection pressure is 5 bar and the grinding pressure is 3 bar. The particle size and distribution of KDR2-2 API before and after grinding were measured to determine whether the API can meet the formulation requirements after grinding. The results are shown in Figure 4 and Table 13.

[0395] Table 13, Particle size results after milling for KDR2-2 API, batch #CK0120554-02-03P-01-32-01 JPEG2025004026000118.jpg28150

[0396] API suspension sterilization process development The moist heat sterilization process aims to ensure the sterility of API and products. There are three types of sterilization of API: Sterilization methods were studied, namely moist heat sterilization with API, 0.1% Kolliphor® HS 15 and moist heat sterilization with HPMC E4M, moist heat sterilization with API and 0.1% Kolliphor® HS 15. The particle size of the products was evaluated and the results are shown in Table 14.

[0397] Table 14. Effect of API suspension sterilization process, batch # FNB180076-130-01, FNB180076-099-01 and FNB180076-101 JPEG2025004026000119.jpg77150

[0398] From the particle size results, it can be seen that the API-only moist heat sterilization resulted in a smaller particle size of the product than the other products. This applies to the production of

[0399] Development of hypromellose (HPMC E4M) preparation process HPMC E4M Preparation Process: (1) HPMC E4M was dissolved and then sterilized, cooled, and then added to the API suspension. The solution was sterilized together with other excipient solutions, and then dispersed by stirring. (2) After dissolving HPMC E4M, it was added to the API suspension and sterilized together with other excipient solutions, and then dispersed by stirring.

[0400] HPMC E4M was mixed with other excipient solutions, dissolved, and then filtered through 0.65 μm and 0.2 μm membranes. , and then added to the undispersed API suspension after sterilization.

[0401] Table 15. Effect of HPMC E4M preparation process, batches #FNB180076-071-01, FNB180076-088 and FNB180076-095 JPEG2025004026000120.jpg77150

[0402] For process (1), the particle size of the product is less than 10 μm, but the production line of Zhuhai ESSEX Bio-Pharmaceutical CO., Ltd. only has one sterilization tank, so the process is Concentrations of HPMC E4M for batches FNB180076-071-01 and FNB180076-088 The concentration of HPMC E4M was adjusted to 0.40% because the blank solution was difficult to filter when the viscosity of the product was 27.77 mPa·s. For process (3), the particle size of the product was 10 μm. Although larger, the particle size does not change significantly after the scale is expanded, and the blank solution can be successfully filtered and sterilized. This applies to production.

[0403] Blank solution filtration process development Filtration is a process of removing microorganisms in liquids or gases by physical retention to achieve the quality requirements related to sterile drugs. The effect of filtration on the product should be studied by filter adsorption experiments and compatibility experiments. PES and PVDF were selected, and the blank solution was sterilized by filtration through a 0.2 μm filter and evaluated for adsorption of the antioxidant sodium thiosulfate and impurities. The results are shown in Table 16.

[0404] Table 16, Effect of Blank Solution Filtration Process, Batch #FNB180076-079 JPEG2025004026000121.jpg79150

[0405] There was no significant change in the sodium thiosulfate content before and after filtration of the blank solution. After soaking, no related substances were detected. Filtration of PES and PVDF eliminated association and adsorption. It has been shown not to cause

[0406] Mixing / mixing process development The stirring / mixing process aims to obtain a suspension with a uniform particle size. The effect of mixing time on the particle size of the product was studied. The particle size results show that the longer the mixing time, the smaller the particle size of the obtained product.

[0407] Table 17. Effect of stirring / mixing time on product particle size, batch #FNB180076-130-01 JPEG2025004026000122.jpg32150

[0408] Example 5: Scale-up from lab scale to pilot scale The process was developed at lab scale (1.0 kg). This section describes the principles of scaling up the process to pilot scale (~50.0 kg) to produce an exhibit batch. Table 18 below summarizes the different process scales.

[0409] Table 18, Summary of process scales JPEG2025004026000123.jpg51150

[0410] Scale-up of KDR2-2 API micronization process A jet with the same mechanization as the jet used during the drug substance particle size selection period of the product development study is used for pilot scale production. The LODs of the pilot and scale-up batches are controlled to the same range as in the lab scale. The particle size of the API is evaluated.

[0411] Scale-up of sterilization processes in batch systems To ensure the quality of the filters, the filter elements were flow-tested before production. The first filter was equipped with a 0.65 μm polyethersulfone filter, and the second filter was equipped with a 0.65 μm polyethersulfone filter. A 0.2μm polyethersulfone filter was installed, and both were connected to the initial tank and vacuum tank. The batch system was subjected to moist heat sterilization at a temperature of 121℃ for 30 minutes. Sterilization was completed. Afterwards, the vacuum stirred tank was cooled to below 70°C.

[0412] Scale-up of HPMC E4M solution preparation process HPMC E4M was added to water for injection at 60°C to 70°C, then stirred at room temperature until a clear solution was obtained and cooled to below 30°C.

[0413] Scale-up of Kolliphor® HS 15 solution preparation process Kolliphor® HS 15 was dissolved in a water bath at 40°C to 50°C to a liquid state, and after uniform stirring, was accurately measured, and then water for injection was added at a temperature of less than 30°C and stirred.

[0414] Scale-up of API suspension sterilization process The scale-up of the API suspension sterilization process is summarized in Table 19.

[0415] Table 19. Scale-up of API suspension sterilization JPEG2025004026000124.jpg52150

[0416] Preparation of blank solutions and scale-up of the filtration process Sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dodecahydrate, sodium chloride and sodium thiosulfate were added individually to the Kolliphor® HS 15 solution and transferred to the HPMC E4M solution with stirring until the materials were completely dissolved, then the blank solution was mixed in. The blank solution was filtered through a 0.65 μm filter and a 0.2 μm filter into the API suspension, then the volume of the KDR2-2 suspension was fixed with water for injection at less than 30° C.

[0417] Scale-up of mixing / agitation processes The scale-up of the agitation / mixing process is summarized in Table 20.

[0418] Table 20, Scale-up of Agitation / Mixing JPEG2025004026000125.jpg71150

[0419] Scale-up of the filling process The KDR2-2 suspension was filled by BFS (blow fill and seal) integrated equipment.

[0420] Comparison of manufacturing equipment The manufacturing equipment for the proposed production of the pilot batch is shown in the table below.

[0421] Table 21, Manufacturing equipment JPEG2025004026000126.jpg49150

[0422] Display badge Based on the development research and scale-up principle, Zhuhai ESSEX Bio-Pharmaceutical CO.,Ltd. has developed 0.1% w / v (Bostal batch #FNB190016-002), 0.1% w / v (ESSEX batch #STH101-20190401) and 0.1% w / v (ESSEX batch #STH101-20190402) delivery batches were manufactured.

[0423] In this case, the micronization and sterilization of KDR2-2 API, preparation and filtration of blank solution and stirring / mixing process The process was successful and the formulation proved to perform as expected as documented in the batch records. After evaluation, acceptable physicochemical and stability properties were demonstrated.

[0424] The delivered batches were analyzed, evaluated, and released according to the corresponding protocols and standards. These evaluations were intended to demonstrate that the formula and manufacturing process for the production of KDR2-2 eye drop suspension produced a finished product that was within pre-specified standards. The results showed that the physicochemical attributes of the new product were acceptable and fell within the pre-defined specifications in the corresponding evaluation protocols.

[0425] Batch Formula for Critical Batches

[0426] Table 22. Batch recipes for KDR2-2 ophthalmic suspension 0.1% w / v, critical batches #FNB190016-002, STH101-20190401 and STH101-20190402 JPEG2025004026000127.jpg109150

[0427] Critical Process Parameters and In-Process Control

[0428] Table 23, Critical process parameters for critical batches of KDR2-2 Suspension Ophthalmic Solution, 0.1% w / v, Critical 0.1% w / v, Critical Batch #FNB190016-002, STH101-20190401 and STH101-20190402 JPEG2025004026000128.jpg189150

[0429] Test results for important batches The next section details the evaluation of the critical batches that were produced.

[0430] 1) Study of physical properties

[0431] Table A JPEG2025004026000129.jpg65150

[0432] The test results are summarized as follows:

[0433] Table 24. Physical properties of pH, particle size and osmolality of 0.1% w / v KDR2-2 eye drop suspension; batches #FNB190016-002, STH101-20190401 and STH101-20190402 JPEG2025004026000130.jpg45150

[0434] Table 25. Content, content uniformity and impurity properties of 0.1% w / v KDR2-2 eye drop suspension; Switch #FNB190016-002, STH101-20190401 and STH101-20190402 JPEG2025004026000131.jpg52150

[0435] Table 26. Sodium thiosulfate content of 0.1% w / v KDR2-2 eye drop suspension, batches #FNB190016-002, STH101-20190401 and STH101-20190402 JPEG2025004026000132.jpg32150

[0436] 2) In-process control

[0437] Table 27. Finished product testing results for KDR2-2 ophthalmic suspension 0.1% w / v; Batch #FNB190016-002 JPEG2025004026000133.jpg223161

[0438] Table 28, Finished Product Test Results for 0.1% w / v KDR2-2 Suspension Eye Drops; Batch # 0.1% w / v Suspension Eye Drops; Batch#STH101-20190401 JPEG2025004026000134.jpg222166

[0439] Table 29, Finished Product Test Results for 0.1% w / v KDR2-2 Suspension Eye Drops; Batch # 0.1% w / v Suspension Eye Drops; Batch#STH101-20190402 JPEG2025004026000135.jpg222165

[0440] Container Closure System The 0.1% w / v KDR2-2 eye drop suspension is packaged in the following container closure system:

[0441] Table 30. Packaging configuration of KDR2-2 ophthalmic suspension 0.1% w / v, batches #FNB190016-002, STH101-20190401 and STH101-20190402 JPEG2025004026000136.jpg90150

[0442] The proposed containers / closures for packaging our drug products comply with applicable USP <661> , <671> Meet the requirements.

[0443] Microbial attributes Materials and Methods Thioglycollate liquid medium, tryptic soy mash liquid medium, trypticase soy agar medium, pH 7.0 sterile sodium chloride-peptone buffer, 1% polysorbate 80-pH 7.0 sterile sodium chloride-peptone buffer, 0.9% sterile sodium chloride solution, and the like.

[0444] Equipment and Instruments HTY-601 type bacterial collection device, KAPY330 type bacterial culture incubator, sterile filter membrane (pore size 0.45 μm or less, diameter 50 mm), and membrane filter, suction filter bottle, Biochemical incubators etc. Sterile test tubes, sterile graduated straws, electronic turbidity meter or Maier turbidity meter, sterile pipettes , scissors, inoculation rings, etc.

[0445] Preparation of test solutions Sixty samples of KDR2-2 eye drop suspension were dissolved in 600 mL of 1% polysorbate 80, pH 7.0 sterile sodium chloride. The mixture is then pumped into sodium-peptone buffer and shaken until completely dissolved and a clear solution is obtained.

[0446] measurement KAPY330 Triple Colony Incubator, pH 7.0 Sterile Sodium Chloride-Peptone Buffer Using a centrifuge, aspirate the membrane at a speed of 150-200 rpm, then place the KDR2-2 solution in an incubator. Pump and filter the mixture, 300 mL each time, for two times. After washing, add 100 mL of thioglycolate. The culture liquid medium was pumped into each of the two incubators. For the 100 mL of tryptic soy mash liquid medium, 1 mL of thioglycollate liquid medium with less than 100 cfu / mL of Staphylococcus aureus was added as a positive control bacterium. and 1% polysorbate 80 in 100 mL of sterile sodium chloride-peptone buffer, pH 7.0 The same procedure was carried out using the test sample instead as a negative control. The thioglycollate liquid medium was cultured at 30°C to 35°C, and the pancreatic soybean meal liquid medium was cultured at 20°C to 25°C. The culture in the collection culture incubator should be observed daily for 14 days or more.

[0447] Cultivation and observation The incubator should be observed daily during the incubation period and bacterial growth should be recorded. If the medium is clear within the incubation detection period, or becomes turbid but no microbial growth is confirmed, the test KDR2-2 preparation is deemed to meet the requirements. If the medium becomes turbid during the incubation period, the presence or absence of microbial growth cannot be determined by appearance after 14 days of incubation. If the medium becomes turbid again, the medium should be transferred to the same fresh medium and kept for 3 days, or the original incubation solution should be sampled, smeared, stained, and examined under a microscope. Test to determine if bacteria are present.

[0448] result The positive control bacteria should grow well, and there should be no bacterial growth in the negative control. Otherwise, the experiment is invalid. If the KDR2-2 formulation medium is clear, or if it becomes cloudy but there is no bacterial growth, the test product is deemed to meet the requirements. If the medium in any culture material becomes cloudy and bacterial growth is confirmed, the test result is invalid, i.e., the test sample does not meet the regulations unless it can be proven that the grown microorganisms are not contained in the test sample.

[0449] Compatibility The product is a suspension eye drop. The results of the package compatibility study are presented in Tables 31 and 32.

[0450] Table 31, Content of relevant ingredients in packaging materials and products JPEG2025004026000137.jpg84150

[0451] Table 32: Determination of the content of each element in packaging materials JPEG2025004026000138.jpg55170*ND indicates detection value is less than 0.5μg / L

[0452] Five antioxidants (3114, 1010, 330, 1076, 168) and 2-mercaptobutene were removed from packaging materials and products. No 2-benzothiazole (2-MBT) was detected.

[0453] The contents of the lubricants methyl palmitate and methyl stearate in the packaging material were 40.7μg / g and 13.8μg / g, respectively, and the lubricants methyl palmitate and methyl stearate were not detected in the product. The volatile substances DBB, DBP, and DBHBA in the packaging material The contents of 0.08μg / g, 5.89μg / g and 0.09μg / g, respectively, and the volatile substances DBB, DBP and DBHBA were not detected in the product. The content of inorganic elements in the packaging material meets the requirements of the European Pharmacopoeia. Therefore, the selected single-dose eye dropper bottle and the product have good compatibility and can be used as the inner packaging of KDR2-2 eye drop suspension.

[0454] Control Strategies The control strategy is a combination of input material control, process control and monitoring, design space associated with single or multiple unit operations, and final product specifications to ensure consistent quality. For this product, the proposed pilot scale process control strategy is shown in the table below, where the different elements of the control strategy are shown in the third column. The operating ranges of the critical process parameters are Determined by scale-up and validation. Specifications and in-process controls are regulatory commitments for the proposed commercial process.

[0455] Table 33. Control measures for common KDR2-2 eye drop suspensions of 0.1% w / v JPEG2025004026000139.jpg185150 JPEG2025004026000140.jpg148150

[0456] Table 34. Published specifications for KDR2-2 ophthalmic suspension, 0.1% w / v JPEG2025004026000141.jpg165150

[0457] KDR2-2 API micronization The particle size of KDR2-2 API is controlled by injection pressure and grinding pressure.

[0458] Batch System Sterilization The control strategy for batch system sterilization is to maintain the sterilization temperature and sterilization time.

[0459] HPMC E4M preparation The control strategy for HPMC E4M preparation is to control the temperature of the WFI when adding HPMC E4M. .

[0460] Kolliphor® HS 15 Solution Preparation The control strategy for the preparation of the Kolliphor® HS 15 solution is to maintain the temperature as the Kolliphor® HS 15 melts. The temperature of the WFI is controlled to avoid the formation of micelles. It should be.

[0461] API Suspension Sterilization The control strategy for API suspension sterilization is to maintain the sterilization temperature, sterilization time, and post-sterilization temperature. be.

[0462] Filtration The time of blank solution filtration is controlled by pressure filtration.

[0463] filling The filling time is controlled by the filling volume.

[0464] Example 6: Study the stability of KDR2-2 suspensions using sodium sulfite or sodium thiosulfate as antioxidants. material HPMC K15M Kolliphor® ELP, BASF KDR2-2 API Other reagents were of commercial analytical grade.

[0465] device Laser diffraction particle size analyzer, Mastersizer 3000, Malvern, UK Osmometer, Osmomat 030, Gonotec, Germany PH Monitor, S20P, Mettler Toledo, Switzerland Balance, BSA124S, Sartorius, Germany UPLC, Agilent, USA

[0466] Experimental Method Stability test of KDR2-2 suspension formulation Prepare HPMC solution (8g / 900g) Add 8g of HPMC E4M to a blue cap bottle, add water to make 900g, heat in a water bath at 60-70℃ for dissolution, stir at room temperature until clear, cool to below 30℃, and hold at 121℃ for 30min or filter sterilize before final product.

[0467] HPMC:K15M / E4M Prepare the Wet Reagent Solution Dissolve Kolliphor® HS 15 in a water bath at 40°C to 50°C until it becomes liquid, and then accurately measure it after uniform stirring. Then add water, phosphate buffer, osmotic pressure regulator and antioxidant, and filter through a 0.22 μm membrane for sterilization.

[0468] Wetting agent / non-ionic solubilizer: Kolliphor ELP / HS15

[0469] Table 35, Salt solutions JPEG2025004026000142.jpg56161

[0470] Preparation of suspension Add 30mL of water and KDR2-2 micronized powder into a blue cap bottle and sterilize at 121℃ for 30min. Cool the temperature to below 70℃, then add 60g of salt solution to completely dissolve the materials. Accelerated experiments and influencing factor experiments are carried out to determine the potential, osmotic pressure, particle size, pH, content and purity.

[0471] Table 36 JPEG2025004026000143.jpg73163

[0472] JPEG2025004026000144.jpg81161

[0473] Results and Discussion Stability of suspensions containing sodium sulfite. 1.1. Test results on day 0 Standard curve: Y=70925X+466.51, R 2 = 0.9994, mean labeled amount percentage (%) = 100.19%, SD = 0.69% JPEG2025004026000145.jpg57170

[0474] 1.2, Light of KDR2-2 suspension (5000Lux / 90uw / cm 2 ) Test results for the fifth day Mean labeling percentage (%) = 102.17%, SD = 2.13% JPEG2025004026000146.jpg46170

[0475] 1.3. KDR2-2 suspension test results on the fifth day at high temperature Mean labeling percentage (%) = 86.42%, SD = 0.50% JPEG2025004026000147.jpg46170

[0476] 2. Stability of Suspensions Containing Sodium Thiosulfate 2.1. Test results on day 0 Standard curve: 70925X+466.51, R 2 = 0.9994, mean labeled amount percentage (%) = 101.65%, SD = 2.38% JPEG2025004026000148.jpg61170

[0477] 2.2, Light of KDR2-2 suspension (5000Lux / 90uw / cm 2 ) Test results for the fifth day Mean labeling percentage (%) = 102.75%, SD = 2.23% JPEG2025004026000149.jpg61170

[0478] 2.3. Test results of KDR2-2 suspension at high temperature for 5 days Mean labeling percentage (%) = 100.67%, SD = 0.69% JPEG2025004026000150.jpg61170

[0479] 2.4, Light of KDR2-2 suspension (5000Lux / 90uw / cm 2 ) Test results for the 10th day Mean labeling percentage (%) = 101.28%, SD = 1.48% JPEG2025004026000151.jpg61170

[0480] 2.5. Test results of KDR2-2 suspension at high temperature for 10 days Mean labeling percentage (%) = 100.92%, SD = 1.42% JPEG2025004026000152.jpg61170

[0481] 3.1 Suspension without antioxidants results within 3 months in accelerated testing JPEG2025004026000153.jpg57170

[0482] Example 7: Micronization of drug substance To meet the quality standards for KDR2-2 suspension formulations, the drug substance should be micronized. Based on the results of the excipient compatibility study, the following excipients were selected: hypromellose (HPMC E4M), polyoxyl 15 hydroxystearate (Kolliphor® HS 15), sodium dihydrogen phosphate dihydrate (NaH2PO4·2H2O), disodium hydrogen phosphate dodecahydrate (Na2HPO4·12H2O), sodium chloride. Sodium thiosulfate and sodium thiosulfate were selected for product development. Selection of excipient grades and suppliers was based on previous formulation experience and knowledge of excipients in approved products that have been used successfully in manufacturing. Subsequent formulation development studies investigated the levels of excipients used in the formulation.

[0483] Critical Process Parameters (CPP) Particle size: fine particle size of raw materials In order to avoid excessive lacrimation, the drug particle size of the suspension eye drop should be reduced to a level <10 μm, and the micronization process of the drug substance was studied. A certain amount of KDR2-2 API was taken and fed into a jet mill. For the jet micronization process parameters, the injection pressure is 5 bar, the grinding pressure is 3 bar, and the micronization medium is air. A dry method (Mastersizer 3000, Malvern) was used to measure the particle size and distribution of KDR2-2 API before and after grinding. , to determine whether the API meets the formulation requirements after grinding. The results are as follows: As shown in Figure 4.

[0484] JPEG2025004026000154.jpg29161

[0485] The API content is determined by liquid chromatography, Diamonsil®plus-C18 column (4.6×150 mm, 5 μm), mobile phase: acetonitrile (with 0.2‰ trifluoroacetic acid): water (with 0.2‰ trifluoroacetic acid), acetonitrile gradient 5%-95%, time: 17 min, column temperature 20° C., detection wavelength 254 nm. The results are as follows and are shown in Figures 5A-5B.

[0486] JPEG2025004026000155.jpg45161 Impurity 1 and Impurity 2 correspond to intermediate A and intermediate B shown in Scheme 1 of Example 8.

[0487] Hypromellose preparation process development: Selection of suspending agent, use appropriate pharmaceutical polymer excipient as suspending agent

[0488] Accurately weigh 0.15g of hypromellose (HPMC E4M) and add 30mL of water (WFI, 60℃~70℃), then stir at room temperature to obtain a clear solution. Cool to below 30℃ for further use. The solution is then transferred to a 10mL stoppered cylinder and mixed by inversion 3 times. Observations and photographs were taken at 0h, 3h, 8h, 12h, and 24h.

[0489] JPEG2025004026000156.jpg45161

[0490] JPEG2025004026000157.jpg15153

[0491] Wetting agent / non-ionic solubilizer: Kolliphor ELP / HS15 Add 0.9g of HPMC to a blue cap bottle, add water to make 150mL, and heat in a water bath at 60-70°C for dissolution. Accurately weigh out 4.5g of Kolliphor HS15, add 30mL of water (WFI, 60-70°C), and then stir at room temperature to obtain a clear solution. Cool to below 30°C for further use. The solution is then transferred to a 10mL stoppered cylinder and mixed by inversion 3 times. Observations and photographs were taken at 0h, 3h, 12h, and 24h.

[0492] JPEG2025004026000158.jpg39161

[0493] Osmolality and pH adjusters Sodium dihydrogen phosphate dihydrate (NaH2PO4·2H2O): widely used as a pH adjuster, choose the product with injection grade from Merck, its residual solvent and microbial limits should meet the requirements.

[0494] Disodium hydrogen phosphate dodecahydrate (Na2HPO4·12H2O): widely used as a pH adjuster, we selected an injection grade product from Merck, whose residual solvent and microbial limits meet the requirements. should be satisfied.

[0495] Sodium chloride: Sodium chloride is widely used as an osmolality adjuster and is available from Merck Select the product with injection grade, and its residual solvent and microbial limits should meet the requirements.

[0496] Sterilization Process A, KDR2-2 drug substance was micronized, added into brown vial, sealed, and then sterilized by steam sterilization at 121℃ for 30 minutes. At the same time, dispersion medium solution (excipient solution) was prepared according to the formula, and the excipient solution was filtered through a 0.2μm polyethersulfone (PES) micropore filter. After filtration and sterilization were completed, the KDR2-2 drug substance and the dispersion medium solution (excipient solution) were mixed under aseptic conditions. B, KDR2-2 drug substance was micronized and all excipient substances except HS 15 were added to a brown vial (total mass solution is 50 g) and sealed, then HS 15 was added which was sterilized by steam sterilization at 121°C for 30 min and filtered through 0.2 μm polyethersulfone. C. Micronize the KDR2-2 drug substance and prepare HS 15 according to the prescription (dissolve in water, total weight is 50g), then add them to a beaker. Add the remaining prescription ingredients by stirring and seal. After that, it was sterilized by steam at 121°C for 20 minutes.

[0497] Production process 1 description: 1. Add HPMC to 1 L of water (WFI) at 60℃ to 70℃ to expand it, then stir at room temperature until it becomes a clear liquid, and add another 2 L of WFI. 2. Sterilize the HPMC by steam sterilization at 121℃ for 30 minutes. Cool to room temperature while stirring, and mix with solution A. Write down. 3. Accurately weigh out 0.15g of Kolliphor® HS 15 and add WFI, then leave at room temperature. The mixture was stirred at rt to obtain a clear solution, which was designated as solution B. 4. Accurately measure out NaH2PO4·2H2O, Na2HPO4·12H2O, sodium chloride, and sodium thiosulfate according to the recipe, add 1L of WFI, and then stir at room temperature to obtain a clear solution, which is called solution C. 5. Mix solution B and solution C and filter through a 0.2 μm polyethersulfone (PES) micropore filter to obtain solution D. 6. Accurately weigh out KDR2-2, add 1L of WFI, and sterilize by steam sterilization at 121℃ for 30 minutes. This is called API solution E. 7. Add solution D to solution E and stir until clear, then add solution A and dilute to 10 L. Add WFI so that the mixture becomes uniform. 8. Sampling to determine pH, osmotic pressure, particle size and distribution, microbial limit, drug content, and sedimentation ratio , viscosity, etc. 9. Use a filling machine to fill the bottle. The filling volume is 0.4mL per bottle.

[0498] Production process 2 description: 1. Add HPMC to 1 L of water (WFI) at 60℃ to 70℃ to swell, then stir at room temperature until it becomes a clear liquid, and add 2 L of WFI. This is called solution A. 2. Accurately weigh out Kolliphor® HS 15 according to the requirement of the formulation, add 2L of WFI, then stir at room temperature to get a clear solution, which is marked as solution B. 3. Accurately measure out NaH2PO4·2H2O, Na2HPO4·12H2O, sodium chloride, and sodium thiosulfate according to the recipe, add 1L of WFI, and then stir at room temperature to obtain a clear solution, which is called solution C. 4. Mix solutions A, B and C and form a 0.2 μm polyethersulfone (PES) micropore filter. Filter the solution through a filter and designate it as solution D. 5. Accurately weigh out KDR2-2, add 1L of WFI, and sterilize by steam sterilization at 121℃ for 30 minutes. This is called API solution E. 6. Add solution D to solution E and stir until clear, then add solution A and dilute to 10 L. Add WFI so that the mixture becomes uniform. 7. Sampling to measure pH, osmotic pressure, particle size and distribution, microbial limit, drug content, sedimentation ratio , viscosity, etc. 8. Use a filling machine to fill the bottle. The filling volume is 0.4mL per bottle.

[0499] Description of production process 3: Preparation of micelles 1. Add HPMC to 1 L of water (WFI) at 60℃ to 70℃ to swell, then stir at room temperature until it becomes a clear liquid, and add 2 L of WFI. This is called solution A. 2. Accurately weigh out Kolliphor® HS 15 according to the requirement of the formulation, add 2L of WFI, then stir at room temperature to get a clear solution, which is marked as solution B. 3. Accurately measure out NaH2PO4·2H2O, Na2HPO4·12H2O, sodium chloride, and sodium thiosulfate according to the recipe, add 1L of WFI, and then stir at room temperature to obtain a clear solution, which is called solution C. 4. Mix solutions A, B and C and form a 0.2 μm polyethersulfone (PES) micropore filter. Filter the solution through a filter and designate it as solution D. 5. Accurately weigh out KDR2-2, add 1L of WFI, and sterilize by steam sterilization at 121℃ for 30 minutes. This is called API solution E. 6. Add solution D to solution E and stir until clear, then add solution A and dilute to 10 L. Add WFI so that the mixture becomes uniform. 7. Sampling to measure pH, osmotic pressure, particle size and distribution, microbial limit, drug content, sedimentation ratio , viscosity, etc. 8. Use a filling machine to fill the bottle. The filling volume is 0.4mL per bottle.

[0500] Qualitative and quantitative composition of KDR2-2 suspension formulation JPEG2025004026000159.jpg62131

[0501] Example 8: Stability studies of formulations As can be seen from the chromatograms in Figures 6A to 6E and Figure 7, the KDR2-2 formulation was unstable at 40°C. Initially, the main chromatogram had a small decomposition peak, but the KDR2-2 content changed from 99.7% to about 97% after the first month, and to 93% or 94% after the second month. At the first month, the mean KDR2-2 purity (%) was 97.93%, which is consistent with a 2% KDR2-2 formulation. It is shown that it has close resolution.

[0502] High-throughput analysis confirmed that KDR2-2 formulations (solution or suspension) were unstable at 40° C. The degradation products were intermediate A (impurity 1) and intermediate B (impurity 2) as shown in Scheme 1.

[0503] Scheme 1 JPEG2025004026000160.jpg99153

[0504] Based on the eye drop preparation requirements or formulation quality requirements, the normal function of the eye can withstand an osmolarity value of about 200mOsmol / kg to about 500mOsmol / kg (about 300mOsmol / kg is considered the optimal value). For the hemolysis test, 300μL of 1*PBS was added to 300μL of RD171207 formulation, the total volume was 600μL, the osmolarity value was 350mOsmol / kg, the pH value was 7.65, and 400μL of RD171207 formulation was added with 200mOsmol / kg. Add 1 μL of ddHO to obtain an osmolality value of 560 mOsmol / kg and a pH value of 7.77.

[0505] As seen from the RBC cell hemolysis test, dilution with water or PBS could reduce the osmolarity value, leading to a decrease in red blood cell hemolysis, compared to the RD171207 formulation (Figure 8).

[0506] Although the present specification has shown and described preferred embodiments of the present disclosure, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous changes, modifications, and substitutions will occur to those skilled in the art without departing from the present disclosure. As will be appreciated, multiple alternatives to the embodiments of the present disclosure described herein may be adopted in implementing the present disclosure. The appended claims define the scope of the present disclosure, and it is intended to cover methods, structures, and equivalents within the scope of these claims.

Claims

1. (i) Formula (I): （I） or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharma- ceutically acceptable excipient, The pharmaceutical composition is in a form for ophthalmic administration or use.

2. 10. The composition of claim 1, wherein the dosage form is a suspension comprising fine particles of a compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof.

3. (i) Formula (I): （I） or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharma- ceutically acceptable excipient, The pharmaceutical composition is formulated as a suspension.

4. The composition of claim 2 or 3, wherein the particles are micronized.

5. 5. The composition of any one of claims 2 to 4, wherein the particles of the compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof, have a diameter of about 0.1 μm to about 40 μm.

6. 6. The composition of any one of claims 2 to 5, wherein the particles of the compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof, have a diameter of about 0.1 μm to about 10 μm.

7. 7. The composition of any one of claims 2 to 6, wherein the particles of the compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof, have a diameter of about 0.3 μm to about 5 μm.

8. The composition of claim 4 or 5, wherein at least about 10% of the particles have a diameter of about 0.1 μm to about 40 μm.

9. 9. The composition of claim 4, 5, or 8, wherein at least about 20% of the particles have a diameter of about 0.1 μm to about 40 μm.

10. 10. The pharmaceutical composition of any one of claims 4, 5, 8, or 9, wherein at least about 30% of the particles have a diameter of about 0.1 μm to about 40 μm.

11. 11. The composition of any one of claims 4, 5, 8 to 10, wherein at least about 40% of the particles have a diameter of about 0.1 μm to about 40 μm.

12. 12. The composition of any one of claims 4, 5, 8 to 11, wherein at least about 50% of the particles have a diameter of about 0.1 μm to about 40 μm.

13. 13. The composition of any one of claims 4, 5, 8 to 12, wherein at least about 60% of the particles have a diameter of about 0.1 μm to about 40 μm.

14. 14. The composition of any one of claims 4, 5, 8 to 13, wherein at least about 70% of the particles have a diameter of about 0.1 μm to about 40 μm.

15. 15. The composition of any one of claims 4, 5, 8 to 14, wherein at least about 80% of the particles have a diameter of about 0.1 μm to about 40 μm.

16. 16. The composition of any one of claims 4, 5, 8 to 15, wherein at least about 90% of the particles have a diameter of about 0.1 μm to about 40 μm.

17. 17. The composition of any one of claims 4, 5, 8 to 16, wherein at least about 95% of the particles have a diameter of about 0.1 μm to about 40 μm.

18. The composition of any one of claims 1 to 4, wherein the particles have a D10 value of less than about 1 μm.

19. The composition of any one of claims 1 to 4, wherein the particles have a D50 value of less than about 5 μm.

20. The composition of any one of claims 1 to 4, wherein the particles have a D90 value of less than about 10 μm.

21. The composition according to any one of claims 1 to 20, wherein the compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof, is crystallized, microcrystallized, amorphized or lyophilized.

22. The composition of any one of claims 1 to 21, wherein the dosage form is a modified release dosage form.

23. 23. The composition of claim 22, wherein the modified release dosage form is a delayed release dosage form, an extended release (ER) dosage form, or a targeted release dosage form.

24. 24. The composition of claim 23, wherein the ER dosage form is a sustained release (SR) dosage form or a controlled release (CR) dosage form.

25. 26. The composition of any one of claims 1 to 25, wherein the composition comprises about 0.025% w / v to about 2.0% w / v of a compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof.

26. 26. The composition of any one of claims 1 to 25, wherein the composition comprises about 0.05% w / v to about 0.5% w / v of a compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof.

27. 26. The composition of any one of claims 1 to 25, wherein the composition comprises about 0.05% w / v to about 0.15% w / v of a compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof.

28. 28. The composition of any one of claims 1 to 27, wherein the at least one pharma- ceutically acceptable excipient is a diluent, a buffer, a suspending agent, a solubilizing agent, an emulsifying agent, an antioxidant, a pH adjusting agent, a preservative, a detackifying agent, an antifoaming agent, a chelating agent, a thickening agent, a viscosity adjusting agent, an isotonicity agent, a colorant, an opacifying agent, an adhesive, a filler, a plasticizer, or any combination thereof.

29. 30. The composition of claim 28, wherein the at least one pharma- ceutically acceptable excipient is a suspending agent, a wetting agent, a pH adjusting agent, an antioxidant, an osmolality adjusting agent, or any combination thereof.

30. 30. The composition of claim 29, wherein the suspending agent is a polymer.

31. 31. The composition of claim 29 or 30, wherein the suspending agent is a carbomer homopolymer, a carbomer copolymer, a carbomer interpolymer, polycarbophil, a cellulose derivative, a polyvinyl alcohol, povidone, hyaluronic acid or a salt thereof, chondroitin sulfate, a natural gum, or any combination thereof.

32. 32. The composition of claim 31, wherein the cellulose derivative is hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, or any combination thereof.

33. 33. The composition of claim 32, wherein the hydroxypropyl methylcellulose (HPMC) is K100, K4M, K15M, K100M, E4M, E10M, or any combination thereof.

34. 34. The composition of any one of claims 30 to 33, wherein the suspending agent is hydroxypropyl methylcellulose (HPMC).

35. 35. The composition of claim 34, wherein the hypromellose is HPMC E4M.

36. The composition of any one of claims 30 to 35, wherein the concentration of the suspending agent in the composition is up to about 1% w / w.

37. The composition of any one of claims 30 to 36, wherein the concentration of the suspending agent in the composition is up to about 0.5% w / w.

38. The composition of any one of claims 28 to 37, wherein the solubilizing agent is Kolliphor® ELP, Kolliphor® HS 15, or a combination thereof.

39. 39. The composition of claim 38, wherein the solubilizing agent is Kolliphor® HS 15.

40. 40. The composition of claim 38 or 39, wherein the concentration of the solubilizing agent in the composition is up to about 5% w / w.

41. The composition according to any one of claims 28 to 40, wherein the wetting agent is polyoxyl 15 hydroxystearate.

42. The composition of any one of claims 28 to 31, wherein the pH adjusting agent is a buffering agent.

43. 43. The composition of claim 42, wherein the buffer is a phosphate buffer or a hydrate thereof.

44. 44. The composition of claim 43, wherein the phosphate buffer is potassium phosphate or a hydrate thereof.

45. The phosphate buffer is sodium dihydrogen phosphate dihydrate (NaH 2 PO 4 ・2H 2 O), disodium hydrogen phosphate dodecahydrate (Na 2 HPO 4 ・12H 2 O), or a combination thereof.

46. The composition of any one of claims 28 to 45, wherein the osmolality modifying agent is a salt.

47. 47. The composition of claim 46, wherein the salt is sodium chloride.

48. 48. The composition of claim 46 or 47, wherein the concentration of the osmotic agent in the composition is up to about 0.5% w / w.

49. The composition of any one of claims 28 to 48, wherein the antioxidant is a thiosulfate.

50. 50. The composition of claim 49, wherein the thiosulfate is sodium thiosulfate.

51. 51. The composition of claim 49 or 50, wherein the concentration of the antioxidant in the composition is up to about 0.2% w / w.

52. The composition of any one of claims 1 to 51, wherein the composition is stable at a temperature of about 20°C to about 25°C for up to 24 months.

53. The composition of any one of claims 1 to 52, wherein the composition is substantially free of impurities.

54. The composition of any one of claims 1 to 53, wherein the composition is at least about 90% pure.

55. The composition of any one of claims 1 to 54, wherein the composition is at least about 95% pure.

56. The composition of any one of claims 1 to 55, wherein the composition is at least about 96% pure.

57. The composition of any one of claims 1 to 56, wherein the composition is at least about 97% pure.

58. The composition of any one of claims 1 to 57, wherein the composition is at least about 98% pure.

59. The composition of any one of claims 1 to 58, wherein the composition is at least about 99% pure.

60. 60. The composition of any one of claims 1-59, wherein the composition is at least about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9% or about 100% pure.

61. 60. The composition of any one of claims 1 to 59, wherein the composition contains up to about 2% w / w total impurities.

62. 60. The composition of any one of claims 1 to 59, wherein the composition contains less than about 0.9% w / w, about 0.8% w / w, about 0.7% w / w, about 0.6% w / w, about 0.5% w / w, about 0.4% w / w, about 0.3% w / w, about 0.2% w / w or about 0.1% w / w of total impurities.

63. 63. The composition of claim 61 or 62, wherein the impurity is a degradant.

64. The impurity has the formula (II): (II) The composition of any one of claims 61 to 63, comprising a compound represented by the formula:

65. 60. The composition of any one of claims 1 to 59, wherein the composition contains up to about 2.0% w / w of any individual impurity.

66. The composition of any one of claims 1 to 65, wherein the composition has a pH of about 4.0 to about 9.

0.

67. The composition of any one of claims 1 to 65, wherein the composition has a pH of about 5.0 to about 8.

0.

68. The composition of any one of claims 1 to 62, wherein the composition has a pH of about 6.5 to about 8.

0.

69. The composition of any one of claims 66 to 68, wherein the composition has a pH of about 7.0 to about 8.

0.

70. A method for preparing a composition according to any one of claims 1 to 69, comprising the steps of: (i) microparticulating the compound represented by formula (I) or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; (ii) sterilizing the micronized compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof; and (iii) the method, comprising mixing a therapeutically effective amount of a compound represented by formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof, with at least one pharma- ceutically acceptable excipient.

71. 71. The method of claim 70, wherein a suspension is formed comprising particles of the compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof.

72. 72. The method of claim 70 or 71, wherein the sterilization occurs prior to the mixing.

73. 72. The method of claim 70 or 71, wherein the sterilization occurs after the mixing.

74. The method according to any one of claims 70 to 73, wherein the sterilization is carried out at a temperature of about 121°C.

75. The method of any one of claims 70 to 74, wherein the sterilization is carried out for about 20 minutes to about 30 minutes.

76. A method for treating a disease or disorder associated with abnormal angiogenic proliferation comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 69.

77. 77. The method of claim 76, wherein the disease or disorder associated with abnormal angiogenic proliferation is due to an abnormality in VEGFR2.

78. 77. The method of claim 76, wherein the neovascular hyperplasia is ocular neovascularization.

79. 77. The method of claim 76, wherein the neovascular hyperplasia is choroidal neovascularization.

80. 20. The method of claim 19, wherein the disease or disorder is wet macular degeneration, diabetic retinopathy or neovascular glaucoma, and the disease associated with abnormal angiogenesis is wet macular degeneration, diabetic retinopathy or neovascular glaucoma.

81. 70. A method of treating an abnormal protein kinase disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-69.

82. 82. The method of claim 81, wherein the protein kinase is VEGFR2, PDGFR-β, KIT, AURORA-B, FGFR2, SRC, JAK2 or p38-α.

83. 83. The method of claim 82, wherein the protein kinase is VEGFR2, KIT or PDGFR-β.

84. 70. A method for treating or preventing a disorder or disease comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 69, wherein said disorder or disease is a neovascular disorder or disease, an inflammatory disorder or disease, or a cancer.

85. 70. A method of treating or preventing an ocular disorder or disease comprising administering to the eye of a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-69.

86. 86. The method of claim 85, wherein the ocular disorder or disease affects the function, clarity and / or structure of the lens of the eye.

87. 86. The method of claim 85, wherein the ocular disorder or disease is wet macular degeneration, cataract, presbyopia, nuclear sclerosis of the lens of the eye, Refsum's disease, Smith-Lemli-Opitz syndrome (SLOS), Schneider's crystalline corneal dystrophy (SCCD), abetalipoproteinemia, familial hypobetalipoproteinemia, neovascularization, or cancer.

88. 88. The method of claim 87, wherein the neovascularization is corneal neovascularization, iris neovascularization, or choroidal neovascularization.

89. 89. The method of claim 88, wherein the ocular disorder or disease is corneal neovascularization.

90. 90. The method of any one of claims 76 to 89, wherein the subject has already undergone a surgical procedure to treat an ocular disorder or disease.

91. 91. The method of any one of claims 76 to 90, wherein a pharmaceutical composition comprising about 0.005 mg / mL to about 5.0 mg / mL of the compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof, is administered to the eye of the subject.

92. 91. The method of any one of claims 76 to 90, wherein a pharmaceutical composition comprising about 0.01 mg / mL to about 4.0 mg / mL of the compound of formula (I), or an isotopic variant, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof, is administered to the eye of the subject.

93. 93. The method of any one of claims 76-92, wherein the composition is administered to the subject once per day, twice per day, three times per day, or four times per day.

94. 94. The method of any one of claims 76-93, wherein the composition is administered to the subject three times daily.

95. 95. The method of any one of claims 76 to 94, wherein the administration is topical or by injection.

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