Ophthalmic composition

Abstract

Disclosed herein is an ophthalmic composition of an active ingredient that is poorly soluble in water. The ophthalmic composition comprises cyclodextrin, axitinib, and water, and is a clear solution having a pH of less than about 5.5. In accordance with embodiments of the present disclosure, the ophthalmic composition is a clarified solution that does not contain any water-insoluble precipitates therein.

Description

BACKGROUND 1. TECHNICAL FIELD

[0002] The present disclosure relates to an ophthalmic composition of a poorly water-soluble active pharmaceutical ingredient (API). In particular, the disclosure relates to an ophthalmic composition characterized by a clear solution having a pH of less than about 5.5. 2. BACKGROUND

[0004] Axitinib is a tyrosine kinase inhibitor and is an API in an ophthalmic pharmaceutical composition for treating diseases such as age-related macular degeneration, diabetic retinopathy, and retinal vein occlusion. Ideally, the API in an ophthalmic pharmaceutical composition should be in a fully dissolved and stable condition, and the pH of the ophthalmic pharmaceutical composition should be close to the physiological pH to reduce the discomfort of the user. However, axitinib is poorly water-soluble, and thus, it is extremely challenging to use it as an API in an ophthalmic pharmaceutical composition due to its high hydrophobicity, which greatly limits its bioavailability.

[0005] Therefore, there is a need in the art to develop an improved ophthalmic composition containing a high concentration of a poorly water-soluble API (e.g., axitinib) that remains dissolved in the ophthalmic composition. SUMMARY

[0006] The summary is intended to provide a simplified abstract of the disclosure to convey a basic understanding of the disclosure to the reader. This summary is not an extensive overview of the disclosure, and it is not intended to identify key / critical elements of the present embodiments or to delineate the scope of the disclosure. Its sole purpose is to present some concepts of the present disclosure in a simplified form prior to the more detailed description thereof.

[0007] The present disclosure provides an ophthalmic composition containing axitinib. According to the disclosure, the ophthalmic composition is characterized by being a clear solution having a pH of less than about 5.5.

[0008] In one aspect, the disclosure relates to an ophthalmic composition comprising a cyclodextrin, axitinib, and water. The ophthalmic composition is typically a clear solution having a pH of between about 3 and 5.5.

[0009] According to non-essential embodiments of the disclosure, the ophthalmic composition further comprises a pharmaceutically acceptable excipient selected from the group consisting of a thickening agent, a stabilizing agent, a preservative, and combinations thereof.

[0010] According to certain embodiments of the present disclosure, the cyclodextrin, axitinib, and pharmaceutically acceptable excipients are present in the ophthalmic composition at concentrations of about 10-60% (w / v), 0.1-1.2% (w / v), and 0.001-12% (w / v), respectively.

[0011] According to preferred embodiments of the present disclosure, the pharmaceutically acceptable excipients are a combination of a thickening agent, a stabilizing agent, and a preservative, and the thickening agent, the stabilizing agent, and the preservative are present in the ophthalmic composition at concentrations of about 0.1-1.0% (w / v), 0.5-10% (w / v), and 0.001-1.0% (w / v), respectively.

[0012] According to certain embodiments of the present disclosure, the ophthalmic composition is a clear solution having a pH of about 3.5, and the cyclodextrin and the axitinib are present in the ophthalmic composition at concentrations of about 30% (w / v) and 1.2% (w / v), respectively, and the thickening agent, the stabilizing agent, and the preservative are present in the ophthalmic composition at concentrations of about 0.5% (w / v), 2.0% (w / v), and 0.02% (w / v), respectively.

[0013] According to certain embodiments of the present disclosure, the ophthalmic composition has a pH of about 4.0, the cyclodextrin and the axitinib are present in the ophthalmic composition at concentrations of about 40% (w / v) and 0.2-0.4% (w / v), respectively, and the thickening agent, the stabilizing agent, and the preservative are present in the ophthalmic composition at concentrations of about 0.25-0.5% (w / v), 1.0-2.0% (w / v), and 0.001-0.02% (w / v), respectively.

[0014] According to certain embodiments of the present disclosure, the ophthalmic composition has a pH of about 4.0, the cyclodextrin and the axitinib are present in the ophthalmic composition at concentrations of about 20% (w / v) and 0.4% (w / v), respectively, and the thickening agent, the stabilizing agent, and the preservative are present in the ophthalmic composition at concentrations of about 0.25% (w / v), 2.0% (w / v), and 0.02% (w / v), respectively.

[0015] According to certain embodiments of the present disclosure, the ophthalmic composition has a pH of about 4.0, the cyclodextrin and the axitinib are present in the ophthalmic composition at concentrations of about 20% (w / v) and 0.4% (w / v), respectively, and the thickening agent, the stabilizing agent, and the preservative are present in the ophthalmic composition at concentrations of about 0.25% (w / v), 1.0% (w / v), and 0.02% (w / v), respectively.

[0016] According to certain embodiments of the present disclosure, the pH of the ophthalmic composition is about 4.0, the concentrations of the cyclodextrin and the axitinib in the ophthalmic composition are about 30% (w / v) and 0.8% (w / v), respectively, and the concentrations of the thickening agent, the stabilizing agent, and the preservative in the ophthalmic composition are about 0.25% (w / v), 1.0% (w / v), and 0.02% (w / v), respectively.

[0017] According to certain embodiments of the present disclosure, the pH of the ophthalmic composition is about 4.0, the concentrations of the cyclodextrin and the axitinib in the ophthalmic composition are about 40% (w / v) and 1.2% (w / v), respectively, and the concentrations of the thickening agent, the stabilizing agent, and the preservative in the ophthalmic composition are about 0.25% (w / v), 1.0% (w / v), and 0.02% (w / v), respectively.

[0018] According to certain embodiments of the present disclosure, the pH of the ophthalmic composition is about 5.0, the concentrations of the cyclodextrin and the axitinib in the ophthalmic composition are about 10% (w / v) and 0.1% (w / v), respectively, and the concentrations of the thickening agent, the stabilizing agent, and the preservative in the ophthalmic composition are about 0.5% (w / v), 2.0% (w / v), and 0.02% (w / v), respectively.

[0019] According to certain embodiments of the present disclosure, the pH of the ophthalmic composition is about 5.5, the concentrations of the cyclodextrin and the axitinib in the ophthalmic composition are about 60% (w / v) and 1.2% (w / v), respectively, and the concentrations of the thickening agent, the stabilizing agent, and the preservative in the ophthalmic composition are about 0.5% (w / v), 2.0% (w / v), and 0.02% (w / v), respectively.

[0020] According to certain embodiments of the present disclosure, the cyclodextrin is an alpha-cyclodextrin, a beta-cyclodextrin, or a gamma-cyclodextrin. Preferably, the cyclodextrin is a beta-cyclodextrin.

[0021] According to certain embodiments of the present disclosure, examples of the stabilizing agent suitable for use in the present application include, but are not limited to, a purine, a caffeine, a 3,7-dimethylxanthine, an isoquinoline, a xanthine, a hypoxanthine, and a uric acid. Preferably, the stabilizing agent is a caffeine.

[0022] According to some embodiments of the present disclosure, examples of thickening agents suitable for use in the present application include, but are not limited to, hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose, polyacrylic acid, polycarbophil, polyethylene glycol (PEG), and hyaluronic acid (HA). Preferably, the thickening agent is HPMC.

[0023] According to some embodiments of the present disclosure, examples of preservatives suitable for use in the present application include, but are not limited to, benzalkonium chloride (BAK), parabens, and chlorobutanol. Preferably, the preservative is BAK.

[0024] Upon reading the following embodiments, those skilled in the art will readily understand the basic spirit of the present application and other objectives of the present application, as well as the technical means and implementation modes adopted by the present application. DETAILED DESCRIPTION

[0025] In order to make the description of the present disclosure more detailed and complete, the following describes the implementation modes and specific embodiments of the present application; however, this is not the only form of implementing or using the specific embodiments of the present application. The embodiments include the features of the specific embodiments and the method steps and their order for constructing and operating the specific embodiments. However, other specific embodiments can also be used to achieve the same or equivalent functions and step orders.

[0026] 1. DEFINITIONS

[0027] For the sake of illustration, the terms used in the specification, embodiments, and patent claims will be uniformly described as follows. Unless otherwise specified, the definitions of all technical and scientific terms mentioned in this text are the same as understood by those skilled in the art.

[0028] Unless otherwise specified, the singular forms of the articles (a, an, the) used in this text cover their plural forms in this text.

[0029] Although the numerical ranges and parameters setting forth the broad scope of the application are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Herein, "about" or "approximately" means within 10%, 5%, 1%, or 0.5% of a given value or range. Alternatively, "about" or "approximately" means within an acceptable standard error of the mean when considered by one of ordinary skill in the art. Other than in the operating examples, or unless otherwise expressly specified, all ranges, amounts, values and percentages expressed herein should be understood as approximations. The application disclosed herein can be prepared in a manner substantially similar to the examples, excepting, of course, that the specific parameters set forth in the examples are not necessarily used. It is specifically intended that any and all parameters, including the amounts, weight, concentration, versions, forms and other like amounts, be interpreted broadly without undue experimentation with reference to the specification and figures. It will be clear to those of ordinary skill in the art that the application disclosed herein can be practiced without such specific details. In other instances, well-known methods have not been described in detail or have been described only generally in order not to unnecessarily obscure the application disclosed herein. Unless otherwise expressly specified, it is in the scope of the application to employ, now or in the future, yet-to-be-discovered equivalents and modifications of the application disclosed herein. The disclosure of the application is not limited to the specific examples described herein, but includes any alternatives, modifications, omissions, combinations (e.g., of aspects across different examples), and equivalents thereof within the scope of the application as defined by the appended claims.

[0030] In the present disclosure, the terms "poor water-solubility" and "poorly soluble in water" are used interchangeably to refer to a pharmaceutical compound having a solubility of less than 1 mg / mL at 20°C in water. + For example, axitinib has a solubility of about 0.2 μg / mL in solution media at pH 6.0 to 7.8 and is therefore considered a poorly soluble compound in water.

[0031] In the present disclosure, the term "clear solution" means a homogeneous mixture of a solute (e.g., axitinib) and a solvent, in which there are no visible particles or turbidity. The homogeneous mixture must appear clear, transparent, free of any haze, and light can pass directly through without scattering. In a clear solution, the solute molecules or ions are uniformly dispersed in the solvent and do not precipitate or come out of solution. In accordance with the present disclosure, the ophthalmic compositions of the present application are clear solutions free of any insoluble precipitates.

[0032] In the present disclosure, the term "pharmaceutically acceptable excipient" means an inert substance that can serve as a carrier for a pharmaceutical substance in the manufacture of a pharmaceutical dosage form. The pharmaceutically acceptable excipient is suitable for administration to a patient without causing undue discomfort or significantly interfering with the pharmaceutical activity of the pharmaceutical compound carried. In accordance with the present disclosure, pharmaceutically acceptable excipients suitable for use in liquid formulations include, but are not limited to, thickening agents, stabilizing agents, preservatives, and combinations thereof.

[0033] 2. DETAILED DESCRIPTION

[0034] The present disclosure is based, at least in part, on the discovery that the solubility of a poorly water-soluble API (e.g., axitinib) can be increased by acid dissolution (i.e., in an acidic solution). Accordingly, the present disclosure provides an ophthalmic composition of axitinib that is a clear solution having a pH of less than 5.5 (e.g., between 3.0 and 5.5). The ophthalmic composition provided herein contains a higher concentration of a more stable API than ophthalmic compositions containing axitinib made by published methods.

[0035] 2.1. Ophthalmic Composition of the Invention

[0036] In one aspect, the present disclosure provides an ophthalmic composition comprising a cyclodextrin, axitinib, and water, wherein the ophthalmic composition is a clear solution having a pH of about 3 to about 5.5, e.g., a pH of about 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5.

[0037] In accordance with embodiments of the present disclosure, the axitinib is present in the ophthalmic composition at a concentration of about 0.1-1.2% (w / v), e.g., about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, or 1.2% (w / v); and the cyclodextrin is present in the ophthalmic composition at a concentration of about 10-60% (w / v), e.g., about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% (w / v).

[0038] According to non-essential embodiments of the present disclosure, the ophthalmic composition further comprises at least one pharmaceutically acceptable excipient to improve the stability and / or bioavailability of axitinib. According to non-essential embodiments of the present disclosure, the pharmaceutically acceptable excipient is present in the ophthalmic composition at a concentration of between 0.001-12% (w / v), such as about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 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%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, or 12% (w / v). In general, the choice of pharmaceutically acceptable excipient depends on the pharmaceutical purpose, route of administration, or dosage form desired. According to embodiments of the present disclosure, the pharmaceutically acceptable excipient is selected from the group consisting of a thickening agent, a stabilizing agent, a preservative, and combinations thereof. According to certain embodiments of the present disclosure, the pharmaceutically acceptable excipient is a combination of a thickening agent, a stabilizing agent, and a preservative. According to other embodiments of the present disclosure, the pharmaceutically acceptable excipient is a combination of a thickening agent and a stabilizing agent.

[0039] According to certain embodiments of the present disclosure, the stabilizing agent is present in the ophthalmic composition at a concentration of between about 0.5-10% (w / v), such as about 0.5%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, or 10% (w / v).

[0040] According to certain embodiments of the present disclosure, the thickening agent is present in the ophthalmic composition at a concentration of between about 0.1-1.0% (w / v), such as about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1.0% (w / v).

[0041] According to certain embodiments of the disclosure, the preservative is present in the ophthalmic composition at a concentration of about 0.001-1.0% (w / v), e.g., about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 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% (w / v).

[0042] According to certain embodiments of the disclosure, the ophthalmic composition is a clear solution having a pH of about 3.5, and the cyclodextrin and the axitinib are present in the ophthalmic composition at a concentration of about 30% (w / v) and 1.2% (w / v), respectively, and the thickening agent, the stabilizing agent, and the preservative are present in the ophthalmic composition at a concentration of about 0.5% (w / v), 2.0% (w / v), and 0.02% (w / v), respectively.

[0043] According to certain embodiments of the disclosure, the ophthalmic composition has a pH of about 4.0, the cyclodextrin and the axitinib are present in the ophthalmic composition at a concentration of about 20% (w / v) and 0.4% (w / v), respectively, and the thickening agent, the stabilizing agent, and the preservative are present in the ophthalmic composition at a concentration of about 0.25% (w / v), 2.0% (w / v), and 0.02% (w / v), respectively.

[0044] According to certain embodiments of the disclosure, the ophthalmic composition has a pH of about 4.0, the cyclodextrin and the axitinib are present in the ophthalmic composition at a concentration of about 20% (w / v) and 0.4% (w / v), respectively, and the thickening agent, the stabilizing agent, and the preservative are present in the ophthalmic composition at a concentration of about 0.5% (w / v), 2.0% (w / v), and 0.02% (w / v), respectively.

[0045] According to certain embodiments of the disclosure, the ophthalmic composition has a pH of about 4.0, the cyclodextrin and the axitinib are present in the ophthalmic composition at a concentration of about 20% (w / v) and 0.4% (w / v), respectively, and the thickening agent, the stabilizing agent, and the preservative are present in the ophthalmic composition at a concentration of about 0.25% (w / v), 1.0% (w / v), and 0.02% (w / v), respectively.

[0046] According to certain embodiments of the present disclosure, the pH of the ophthalmic composition is about 4.0, the concentrations of the cyclodextrin and the axitinib in the ophthalmic composition are about 20% (w / v) and 0.2% (w / v), respectively, and the concentrations of the thickening agent, the stabilizing agent, and the preservative in the ophthalmic composition are about 0.5% (w / v), 1.0% (w / v), and 0.02% (w / v), respectively.

[0047] According to certain embodiments of the present disclosure, the pH of the ophthalmic composition is about 4.0, the concentrations of the cyclodextrin and the axitinib in the ophthalmic composition are about 30% (w / v) and 0.8% (w / v), respectively, and the concentrations of the thickening agent, the stabilizing agent, and the preservative in the ophthalmic composition are about 0.25% (w / v), 1.0% (w / v), and 0.02% (w / v), respectively.

[0048] According to certain embodiments of the present disclosure, the pH of the ophthalmic composition is about 4.0, the concentrations of the cyclodextrin and the axitinib in the ophthalmic composition are about 40% (w / v) and 1.2% (w / v), respectively, and the concentrations of the thickening agent, the stabilizing agent, and the preservative in the ophthalmic composition are about 0.25% (w / v), 1.0% (w / v), and 0.02% (w / v), respectively.

[0049] According to certain embodiments of the present disclosure, the pH of the ophthalmic composition is about 5.0, the concentrations of the cyclodextrin and the axitinib in the ophthalmic composition are about 10% (w / v) and 0.1% (w / v), respectively, and the concentrations of the thickening agent, the stabilizing agent, and the preservative in the ophthalmic composition are about 0.5% (w / v), 2.0% (w / v), and 0.02% (w / v), respectively.

[0050] According to certain embodiments of the present disclosure, the pH of the ophthalmic composition is about 5.5, the concentrations of the cyclodextrin and the axitinib in the ophthalmic composition are about 60% (w / v) and 1.2% (w / v), respectively, and the concentrations of the thickening agent, the stabilizing agent, and the preservative in the ophthalmic composition are about 0.5% (w / v), 2.0% (w / v), and 0.02% (w / v), respectively.

[0051] According to certain embodiments of the present disclosure, examples of cyclodextrins suitable for use in the compositions of the present application include, but are not limited to, a-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. Preferably, the cyclodextrin is β-cyclodextrin.

[0052] According to certain embodiments of the present disclosure, examples of thickening agents suitable for use in the present application include, but are not limited to, HPMC), sodium carboxymethylcellulose, polyacrylic acid, polycarbophil, PEG, and HA. According to a preferred embodiment, the thickening agent is HPMC. According to certain embodiments of the present disclosure, examples of stabilizing agents suitable for use in the present application include, but are not limited to, purine, caffeine, 3,7-dimethylxanthine, isoquinoline, xanthine, hypoxanthine, and uric acid. According to a preferred embodiment, the stabilizing agent is caffeine. According to certain embodiments of the present disclosure, examples of preservatives suitable for use in the present application include, but are not limited to, BAK, parabens, and chlorobutanol. According to a preferred embodiment, the preservative is BAK.

[0053] According to one working example of the present disclosure, the ophthalmic composition is a clear solution having a pH of 4.0 comprising beta-cyclodextrin, axitinib, caffeine, HPMC, and BAK, and the concentrations of beta-cyclodextrin, axitinib, caffeine, HPMC, and BAK in the ophthalmic composition are 40% (weight / volume), 1.2% (weight / volume), 1.0% (weight / volume), 0.25% (weight / volume), and 0.02% (weight / volume), respectively.

[0054] According to one working example of the present disclosure, the ophthalmic composition is a clear solution having a pH of 4.0 comprising beta-cyclodextrin, axitinib, caffeine, HPMC, and BAK, and the concentrations of beta-cyclodextrin, axitinib, caffeine, HPMC, and BAK in the ophthalmic composition are 30% (weight / volume), 0.8% (weight / volume), 1.0% (weight / volume), 0.25% (weight / volume), and 0.02% (weight / volume), respectively.

[0055] According to one working example of the present disclosure, the ophthalmic composition is a clear solution having a pH of 4.0 comprising beta-cyclodextrin, axitinib, caffeine, HPMC, and BAK, and the concentrations of beta-cyclodextrin, axitinib, caffeine, HPMC, and BAK in the ophthalmic composition are 20% (weight / volume), 0.4% (weight / volume), 2.0% (weight / volume), 0.25% (weight / volume), and 0.02% (weight / volume), respectively.

[0056] According to one operational example of the present disclosure, the ophthalmic composition is a clear solution having a pH of 4.0, which comprises beta-cyclodextrin, axitinib, caffeine, HPMC, and BAK, and the concentrations of beta-cyclodextrin, axitinib, caffeine, HPMC, and BAK in the ophthalmic composition are 20% (w / v), 0.4% (w / v), 1.0% (w / v), 0.25% (w / v), and 0.02% (w / v), respectively.

[0057] According to an embodiment of the present disclosure, the concentration of beta-cyclodextrin in the ophthalmic composition is at least 25 times the concentration of axitinib on a weight / volume (w / v) basis. For example, the concentration of beta-cyclodextrin is at least 31.25 times the concentration of axitinib, such as about 33.3 times, 37.5 times, 50 times, or 100 times.

[0058] 2.2 Preparation of the ophthalmic composition of the present disclosure

[0059] The ophthalmic composition of the present disclosure is prepared using an acid dissolution method, in which a weak acid solution is used as the initial solvent for a low-solubility API (e.g., axitinib). In addition, the method of the present disclosure does not use any organic solvent, and thus the final product (i.e., the ophthalmic composition) does not contain any organic solvent. In general, the ophthalmic composition of the present disclosure is manufactured using the following method. First, a cyclodextrin, preferably beta-cyclodextrin, is dissolved in an acidic solution having a pH of 0 to 2 to form an acidified cyclodextrin solution. Next, axitinib having a solubility of only 0.2 pg / mL is added to the acidified cyclodextrin solution, and the mixture is stirred until the solution is completely clear. If necessary, one or more pharmaceutically acceptable excipients, such as a thickening agent, a stabilizer, a preservative, and combinations thereof, are added to the clear solution to form a mixed solution. Next, the pH of the mixed solution is adjusted to 3.5 to 5.5 to obtain the ophthalmic composition of the present disclosure. It is understood that the axitinib in the obtained ophthalmic composition is in a completely dissolved state, that is, the ophthalmic composition of the present disclosure does not contain any undissolved material.

[0060] The above-described steps can be adjusted or combined as necessary. For example, axitinib and cyclodextrin can be simultaneously added to the acidic solution and stirred until the solution is completely clear.

[0061] According to embodiments of the present disclosure, the acidified cyclodextrin solution can be prepared by adding an acid directly to a β-cyclodextrin solution until the pH is between 0 and 2. Examples of acids suitable for use in embodiments of the present application include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, citric acid, oxalic acid, and the like. According to certain embodiments of the present disclosure, the acid added to the β-cyclodextrin solution has a concentration greater than 0.1 M, and preferably between 0.02 M and 1.0 M. In one example, 0.1 M hydrochloric acid is added to a β-cyclodextrin solution until the pH is 1.0, thereby obtaining an acidified cyclodextrin solution.

[0062] Examples of β-cyclodextrins suitable for use in the methods of the present application include, but are not limited to, hydroxypropyl β-cyclodextrin (HPβCD), methyl-β- cyclodextrin (MβCD), sulfobutyl ether-β-cyclodextrin (SBE-β-CD), randomly methylated-β- cyclodextrin (RM-β-CD), carboxymethyl-β-cyclodextrin (MβCD), and combinations thereof. In one example, the pH of a HPβCD solution is adjusted to about 1.0 with hydrochloric acid, after which axitinib is added to the acidified HPβCD solution and stirred until a clear, transparent solution is obtained.

[0063] According to embodiments of the present disclosure, the pH of the clear solution is adjusted to between 3 and 5.5, such as about 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 4, or 5.5, thereby forming an ophthalmic composition of axitinib. Once a clear solution is obtained from the acidified cyclodextrin solution, a base can be used to adjust the pH of the solution to between 3 and 5.5. Examples of bases suitable for use in embodiments of the present application include, but are not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, and combinations thereof. According to one example, the base suitable for use in the methods of the present application is sodium hydroxide.

[0064] As described in paragraph 2.1 above, a pharmaceutically acceptable excipient, such as a thickening agent, a stabilizing agent, a preservative, or a combination thereof, can be added to the aforementioned clear solution having an adjusted pH, as desired. According to certain embodiments of the present application, the aforementioned clear solution having an adjusted pH further comprises a thickening agent, a stabilizing agent, and a preservative. According to other embodiments of the present application, the aforementioned clear solution having an adjusted pH further comprises a thickening agent and a stabilizing agent, but does not comprise a preservative.

[0065] Examples of suitable thickening agents for use in embodiments of the present application include, but are not limited to, hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose, polyacrylic acid, polycarbophil, polyethylene glycol (PEG), hyaluronic acid (HA), and combinations thereof. Examples of suitable stabilizing agents for use in the present application include, but are not limited to, purine, caffeine, 3,7-dimethylxanthine, isoquinoline, xanthine, hypoxanthine, uric acid, and combinations thereof. Examples of suitable preservatives for use in the present application include, but are not limited to, benzalkonium chloride (BAK), parabens, chlorobutanol, and combinations thereof. According to a preferred embodiment, the thickening agent is HPMC, the stabilizing agent is caffeine, and if a preservative is desired, the preservative is BAK.

[0066] According to embodiments of the present disclosure, the amount or ratio of β-cyclodextrin to axitinib in the ophthalmic compositions of the present application can be adjusted as desired, such that the concentration of β-cyclodextrin is between about 10% and 60% (w / v), and the concentration of axitinib is between about 0.1% and 1.2% (w / v), provided that the pH is maintained between 3.0 and 5.5 and no insoluble precipitates are present. According to embodiments of the present disclosure, the ratio of β-cyclodextrin to axitinib in the ophthalmic compositions is between about 25: 1 and 100: 1, such as about 25: 1, 31.25: 1, 33.3: 1, 37.5: 1, 50: 1, or 100: 1.

[0067] Optionally or in addition, the ophthalmic compositions of axitinib of the present application can be further sterilized, including, but not limited to, by autoclaving, dry heat sterilization, filtration sterilization, ethylene oxide sterilization, radiation sterilization, and chemical sterilization. The appropriate sterilization method can be selected based on the intended use and formulation form. In some embodiments, the ophthalmic compositions of the present application are sterilized by filtration, i.e., by passing the composition through a filter having a pore size of about 0.2 microns.

[0068] According to the descriptions of paragraphs 2.1 and 2.2 above, the present disclosure provides improved ophthalmic compositions and methods of making the same, which increase the solubility and stability of poorly soluble APIs (e.g., axitinib) in solution-based compositions.

[0069] Examples

[0070] Example 1. Preparation and characterization of ophthalmic compositions of axitinib of the present application

[0071] 1.1. Preparation of ophthalmic compositions of axitinib of the present application

[0072] In this example, various formulations (i.e., Formulations 1-11) were prepared according to the formulation ratios listed in Table 1 and the following procedure.

[0073] To prepare an ophthalmic composition having a batch volume of 5 ml, HPβCD (0.5 g, 1 g, 1.5 g, 2 g, or 3 g) was mixed with axitinib (5 mg, 10 mg, 20 mg, 30 mg, 40 mg, or 60 mg) in 3 ml of a hydrochloric acid solution (0.1 M or 0.1 N) and continuously stirred (at a speed of about 200 rpm) until a clear, transparent, or light yellow solution was obtained. Next, caffeine (25 mg, 50 mg, or 100 mg), HPMC (12.5 mg or 25 mg), and BAK (1 mg) were added until a clear, transparent, or light yellow solution was again obtained, and the pH of the solution was adjusted to 3.5, 4.0, 5.0, or 5.5 using sodium hydroxide (1.0 N). The solution was diluted to a total volume of 5 ml with distilled water, sterilized by passing through a filter membrane having a pore size of about 0.2 μm, and thereby the desired ophthalmic axitinib composition was obtained.

[0074] 1.2 Analysis of the properties of the ophthalmic composition of Example 1

[0075] The ophthalmic composition of Example 1 was stored at 25°C for 1 month to perform a stability test, and the presence or absence of precipitates in the composition was observed periodically, and the results are summarized in Table 1.

[0076] Table 1 Composition and stability test results of Formulations 1 to 11

[0077] *This record is the number of days during which the composition solution maintained the absence of precipitates.

[0078] The results of Table 1 confirm that the ophthalmic composition of the present application has a high degree of stability and does not exhibit any precipitated material even after being stored for at least 1 month. In addition, Formulations No. 2, 3, 5, 6, and 9 exhibit better stability than other formulations, and do not exhibit any precipitated material even after being stored for more than 100 days.

[0079] In addition, the ophthalmic composition of the present application has an osmotic pressure similar to that of human fluids (e.g., tears), and thus can also effectively improve the willingness of patients to use it.

[0080] Example 2 Stability of the ophthalmic axitinib composition of the present application

[0081] The stability of the ophthalmic compositions prepared under different conditions was further investigated in this example. Comparative Formulations A to C were prepared in a similar manner as Example 1, but using the pH and / or HPβCD concentration listed in Table 2. In particular, the pH of Comparative Formulations A and B was greater than 5.5, and the HPβCD concentration of Comparative Formulation C was less than 10% (w / v). Comparative Formulations A to C were also stored at 25°C for 1 month to test their stability, and the presence of precipitates in the compositions was observed periodically. The results are summarized in Table 2.

[0082] Table 2. Stability test results for Comparative Formulations A to C

[0083] * This column records the number of days that the clear solution of the composition remained free of precipitates

[0084] The results in Table 2 demonstrate that all three Comparative Formulations developed precipitates within 1 month.

[0085] In particular, the HPβCD concentration in Comparative Formulation A was the same as in Formulations 4-6 of the present application, but once the pH exceeded 5.5 (i.e., 5.6), the formulation became unstable and developed precipitates after 2 weeks of storage. Similarly, in Comparative Formulation B, although the concentrations of HPβCD and axitinib were the same as in Formulation 2 of the present application, once the pH exceeded 5.5 (i.e., 5.9), the formulation became unstable and developed precipitates.

[0086] In addition, in Comparative Formulation C, the stability was also reduced when the HPβCD concentration was less than 10%, and precipitates developed after about 20 days of storage.

[0087] Although the foregoing embodiments of the present application have been disclosed, they are not intended to limit the present application. Various modifications and alterations of the present application are possible, without departing from the spirit and scope of the present application, and thus the scope of the present application is defined by the appended claims.

Claims

1. An ophthalmic composition comprising cyclodextrin, axitinib, and water, and being a clear solution with a pH between about 3 and 5.

5.

2. The ophthalmic composition of claim 1 further comprises a pharmaceutically acceptable excipient selected from the group consisting of thickeners, stabilizers, preservatives, and combinations thereof.

3. The ophthalmic composition of claim 2, wherein the concentrations of the cyclodextrin, the axitinib, and the pharmaceutically acceptable excipient in the ophthalmic composition are approximately 10-60% (weight / volume), 0.1-1.2% (weight / volume), and 0.001-12% (weight / volume), respectively.

4. The ophthalmic composition of claim 3, wherein the pharmaceutically acceptable excipient is a combination of a thickener, a stabilizer, and a preservative, and the concentrations of the thickener, the stabilizer, and the preservative in the ophthalmic composition are approximately 0.1-1.0% (weight / volume), 0.5-10% (weight / volume), and 0.001-1.0% (weight / volume), respectively.

5. The ophthalmic composition of claim 4, wherein the pH of the ophthalmic composition is about 3.5, the concentrations of the cyclodextrin and the axitinib in the ophthalmic composition are about 30% (weight / volume) and 1.2% (weight / volume), respectively, and the concentrations of the thickener, the stabilizer and the preservative in the ophthalmic composition are about 0.5% (weight / volume), 2.0% (weight / volume) and 0.02% (weight / volume), respectively.

6. The ophthalmic composition of claim 4, wherein the pH of the ophthalmic composition is about 4.0, the concentrations of the cyclodextrin and the axitinib in the ophthalmic composition are about 20% (weight / volume) and 0.2-0.4% (weight / volume), respectively, and the concentrations of the thickener, the stabilizer, and the preservative in the ophthalmic composition are about 0.25-0.5% (weight / volume), 1.0-2.0% (weight / volume), and 0.001-0.02% (weight / volume), respectively.

7. The ophthalmic composition of claim 6, wherein the pH of the ophthalmic composition is about 4.0, the concentrations of the cyclodextrin and the axitinib in the ophthalmic composition are about 20% (weight / volume) and 0.4% (weight / volume), respectively, and the concentrations of the thickener, the stabilizer and the preservative in the ophthalmic composition are about 0.25% (weight / volume), 2.0% (weight / volume) and 0.02% (weight / volume), respectively.

8. The ophthalmic composition of claim 6, wherein the pH of the ophthalmic composition is about 4.0, the concentrations of the cyclodextrin and the axitinib in the ophthalmic composition are about 20% (weight / volume) and 0.4% (weight / volume), respectively, and the concentrations of the thickener, the stabilizer and the preservative in the ophthalmic composition are about 0.25% (weight / volume), 1.0% (weight / volume) and 0.02% (weight / volume), respectively.

9. The ophthalmic composition of claim 4, wherein the pH of the ophthalmic composition is about 4.0, the concentrations of the cyclodextrin and the axitinib in the ophthalmic composition are about 30% (weight / volume) and 0.8% (weight / volume), respectively, and the concentrations of the thickener, the stabilizer and the preservative in the ophthalmic composition are about 0.25% (weight / volume), 1.0% (weight / volume) and 0.02% (weight / volume), respectively.

10. The ophthalmic composition of claim 4, wherein the pH of the ophthalmic composition is about 4.0, the concentrations of the cyclodextrin and the axitinib in the ophthalmic composition are about 40% (weight / volume) and 1.2% (weight / volume), respectively, and the concentrations of the thickener, the stabilizer and the preservative in the ophthalmic composition are about 0.25% (weight / volume), 1.0% (weight / volume) and 0.02% (weight / volume), respectively.

11. The ophthalmic composition of claim 4, wherein the pH of the ophthalmic composition is about 5.0, the concentrations of the cyclodextrin and the axitinib in the ophthalmic composition are about 10% (weight / volume) and 0.1% (weight / volume), respectively, and the concentrations of the thickener, the stabilizer, and the preservative in the ophthalmic composition are about 0.5% (weight / volume), 2.0% (weight / volume), and 0.02% (weight / volume), respectively.

12. The ophthalmic composition of claim 4, wherein the pH of the ophthalmic composition is about 5.5, the concentrations of the cyclodextrin and the axitinib in the ophthalmic composition are about 60% (weight / volume) and 1.2% (weight / volume), respectively, and the concentrations of the thickener, the stabilizer, and the preservative in the ophthalmic composition are about 0.5% (weight / volume), 2.0% (weight / volume), and 0.02% (weight / volume), respectively.

13. The ophthalmic composition of claim 1, wherein the cyclodextrin is α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin.

14. The ophthalmic composition of claim 2, wherein the stabilizer is a purine, caffeine, 3,7-dimethylxanthine, isoquinoline, xanthine, hypoxanthine, or uric acid.

15. The ophthalmic composition of claim 2, wherein the thickener is hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyacrylic acid, polycarbohydrate, polyethylene glycol, or hyaluronic acid.

16. The ophthalmic composition of claim 2, wherein the preservative is phenylchlorocaine, paraben, or chlorobutanol.

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