Preparation method of ophthalmic composition of low-solubility substances

Abstract

The present disclosure pertains to two methods for preparing ophthalmic compositions of active pharmaceutical ingredients (APIs) with low solubility. One method at least includes mixing API and cyclodextrin in an aqueous carrier placed in a heated bath above 100 DEG C, thereby producing a clarified solution in which the API completely solubilizes. Another method includes at least mixing API and cyclodextrin in an acidic solution having a pH of about 0 to 2.0, thereby producing a clarified solution containing API. The present disclosure is characterized by not using any organic solvent.

Description

Background of the Invention 1. Technical Field

[0002] This disclosure relates to a method for preparing an ophthalmic composition. More specifically, the disclosed invention is characterized by the fact that no organic solvents are used in the preparation of the ophthalmic composition. 2. Background Technology

[0004] Ophthalmic compositions are typically provided in the form of solutions, suspensions, ointments, gels, or emulsions for direct application to the eyes. In manufacturing ophthalmic compositions, in addition to determining the formulation type based on the active pharmaceutical ingredient (API), compatibility between excipients and other additives (such as preservatives, buffers, viscosity modifiers, tension agents, and antioxidants) must be ensured. Furthermore, ensuring the sterility and safety of the drug is also crucial.

[0005] Liquid ophthalmic compositions have become a popular choice due to their advantages such as ease of use, rapid drug delivery, uniform distribution, high compatibility and stability, and flexible administration. However, these formulations have limitations when dealing with hydrophobic or poorly soluble APIs. To increase the solubility of hydrophobic or poorly soluble APIs in liquid ophthalmic compositions, conventional methods in the art involve dissolving the API in a solvent other than water, typically an organic solvent, and then mixing it with other excipients.

[0006] However, ophthalmic compositions prepared using the aforementioned methods require additional processing (e.g., removal of organic solvents) before meeting the guidelines set by the International Council on Pharmaceutical Regulatory Affairs (ICH). For example, the ophthalmic composition prepared by Huang et al. (Transl Vis SciTechnol. 2021;10(14):23) involves the use of glacial acetic acid as a solvent to dissolve the API. To meet the guidelines, the ophthalmic composition also needs to be dried in a vacuum oven at 120 °C for 24 hours to ensure the removal of all solvents. In the case of large-scale production, the process of removing organic solvents can adversely extend the production time.

[0007] Furthermore, even if the residual organic solvent content meets the minimum standard, the potential impact of directly applying organic solvents to the eyes should not be ignored and requires careful evaluation. A long-term follow-up study published by de Oliveira et al. (de Oliveira et al., Front.Neurosci. 11:666; 2017) emphasized that long-term exposure to organic solvents may affect eye movements and lead to impaired visual tracking ability.

[0008] In view of this, there is an urgent need in the relevant field for an improved method to prepare ophthalmic compositions of hydrophobic or low-solubility APIs. Summary of the Invention

[0009] To provide readers with a basic understanding, a brief summary of the invention is provided below. This summary is not a broad overview of the invention, nor is it intended to identify key / essential components of the invention or to outline its scope. Its sole purpose is to present some concepts of the disclosure in a simplified conceptual form as an introduction to the more detailed description that follows.

[0010] As presented and broadly described herein, the purpose of this disclosure is to provide a method for preparing ophthalmic compositions containing low-solubility APIs. The method according to this disclosure is characterized by the absence of the use of any organic solvents.

[0011] Based on the present disclosure, this disclosure relates to a method for preparing an API ophthalmic composition by heat treatment. Typically, the method includes the following steps: (a) dissolving cyclodextrin in an aqueous carrier to produce a cyclodextrin solution; (b) mixing and stirring the API and the cyclodextrin solution from step (a) until a suspension is formed; (c) placing the suspension from step (b) in a heated bath at a temperature of about 100-150°C until a clear solution is formed; and (d) cooling the clear solution from step (c) to 20-30°C to form the API ophthalmic composition, wherein the clear solution from step (c) or (d) does not contain any insoluble precipitates.

[0012] According to some embodiments of this disclosure, cyclodextrin is present in the cyclodextrin solution of step (a) in an amount of about 20% to about 60% (w / v).

[0013] According to a partial embodiment of this disclosure, the API is present in the suspension of step (b) in an amount of about 0.1% to about 1.6% (w / v).

[0014] According to one embodiment of this disclosure, the API is selected from chlorpheniramine maleate ethyl carbonate, dexamethasone, prismin, prismin acetate, flumethasone cortisol, estradiol, ethinylestradiol, mesestrol, estriol, norethindrone, norethindrone acetate, methylnorethindrone, hydroxyprogesterone, 17α-methylprogesterone, progesterone, methyltestosterone, triamcinolone, testosterone, spironolactone, alfasalone, lanosterol, acrizanil, tevazanil, brigatinib, afatinib, erlotinib. The group consisting of neratinib, gefitinib, pyrotinib, icomitinib, amotinib, lapatinib, omamutinib, cimotinib, osimertinib, vandetanib, dacotinib, mobochetinib, lazazetinib, sorafenib, sunitinib, pazopanib, cabozantinib, axitinib, lenvatinib, ponatinib, regorafenib, dovitinib, folotinib, apatinib, nindine, sildenafil, carticinib, anlotinib, pirenoxine, methotrexate, lutein, and combinations thereof.

[0015] According to some embodiments of this disclosure, the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and combinations thereof.

[0016] According to some embodiments of this disclosure, the β-cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin (HPβCD), methyl-β-cyclodextrin (MβCD), sulfobutyl ether-β-cyclodextrin (SBE-β-CD), random methylated β-cyclodextrin (RM-β-CD), carboxymethyl-β-cyclodextrin, and combinations thereof.

[0017] In a preferred embodiment, the β-cyclodextrin is hydroxypropyl-β-cyclodextrin.

[0018] According to some embodiments of this disclosure, the aqueous carrier is selected from the group consisting of water, saline, phosphate buffer (PBS), 2-amino-2-(hydroxymethyl)propane-1,3-diol buffer, and borate buffer. In a preferred embodiment, the aqueous carrier is water.

[0019] According to some embodiments of this disclosure, the method further includes adding a thickener and a stabilizer to the cyclodextrin solution in step (a) before step (b).

[0020] Examples of thickeners suitable for the methods of this disclosure include carboxymethyl cellulose (HPMC), sodium carboxymethyl cellulose, carbomer, polycarbamate calcium, polyethylene glycol (PEG), and hyaluronic acid (HA).

[0021] Examples of stabilizers suitable for the methods of this disclosure may be purines, purine derivatives, or combinations thereof. In one specific embodiment, the purine derivative is selected from the group consisting of caffeine, theobromine, isoguanine, xanthine, hypoxanthine, and uric acid.

[0022] According to some embodiments of this disclosure, the method further includes adding a preservative to the clarified solution in step (d).

[0023] Examples of preservatives suitable for use in this method include alkyl dimethyl benzyl ammonium chloride, p-hydroxybenzoate, and chlorobutanol.

[0024] According to another embodiment of this disclosure, this disclosure relates to another method for preparing an ophthalmic composition of an API by acidic dissolution. The method specifically includes the following steps: (a) dissolving cyclodextrin in an acidic solution with a pH of about 0-2.0 to produce an acidified cyclodextrin solution; (b) mixing and stirring the API with the acidified cyclodextrin solution from step (a) until a clear solution is formed; and (c) adjusting the pH of the clear solution from step (b) to a value of about 3.0 to 8.0 to produce an ophthalmic composition of the API, wherein the clear solution is free of any insoluble precipitates.

[0025] According to some embodiments of this disclosure, cyclodextrin is present in the clarified solution of step (b) in an amount of about 20% to about 60% (w / v).

[0026] According to a partial embodiment of this disclosure, the API is present in the clarified solution of step (b) in an amount of about 0.1% to about 1.6% (w / v).

[0027] According to one embodiment of this disclosure, the API is selected from chlorpheniramine maleate ethyl carbonate, dexamethasone, prismin, prismin acetate, flumethasone cortisol, estradiol, ethinylestradiol, mestriol, estriol, norethindrone, norethindrone acetate, norprogesterone, hydroxyprogesterone, 17α-methylprogesterone, progesterone, methyltestosterone, triamcinolone, testosterone, spironolactone, alfasalone, lanosterol, acrizaniol, tevozaniol, brigatinib, afatinib, erlotinib, and neratinib. The group consisting of tinib, gefitinib, pyrotinib, icotinib, amotinib, lapatinib, omamutinib, cimotinib, osimertinib, vandetanib, dacotinib, mobochetinib, lazazetinib, sorafenib, sunitinib, pazopanib, cabozantinib, axitinib, lenvatinib, ponatinib, regorafenib, dovitinib, folotinib, apatinib, nindine, sildenafil, carticinib, anlotinib, pirenoxine, methotrexate, lutein, and combinations thereof.

[0028] According to some embodiments of this disclosure, the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and combinations thereof.

[0029] According to some embodiments of this disclosure, examples of β-cyclodextrins applicable to the methods of this disclosure include hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, random methylated β-cyclodextrin, carboxymethyl-β-cyclodextrin, and combinations thereof.

[0030] According to some embodiments of this disclosure, the acidic solution is a hydrochloric acid solution of about 0.01 M to 1.0 M.

[0031] According to alternative or other embodiments of this disclosure, the method of this disclosure further includes adding a thickener, a stabilizer, a preservative, or a combination thereof to the clarified solution in step (c).

[0032] Examples of thickeners suitable for the methods of this disclosure include hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, carbomer, polycarbamate calcium, polyethylene glycol, and hyaluronic acid.

[0033] Examples of stabilizers suitable for the methods of this disclosure may be purines, purine derivatives, or combinations thereof. In one specific embodiment, the purine derivative is selected from the group consisting of caffeine, theobromine, isoguanine, xanthine, hypoxanthine, and uric acid.

[0034] Examples of preservatives suitable for use in the methods of this disclosure include alkyl dimethyl benzyl ammonium chloride, p-hydroxybenzoate, and chlorobutanol.

[0035] After reading the following embodiments, those skilled in the art will easily understand the basic spirit and other inventive objectives of the present invention, as well as the technical means and implementation methods adopted by the present invention.

[0036] Invention Description

[0037] To make the description of this disclosure more detailed and complete, illustrative descriptions of embodiments and specific examples of the present invention are provided below; however, these are not the only forms of implementing or utilizing the specific examples of the present invention. The embodiments cover features of multiple specific examples and methods and steps for constructing and operating these specific examples, as well as their order. However, other specific examples may also be used to achieve the same or equivalent functions and order of steps.

[0038] 1. Definition

[0039] For ease of explanation, specific terms set forth herein are described in a consistent manner in this specification, embodiments, and the appended claims. Unless otherwise defined herein, all technical and scientific terms herein have the same meaning as those known to those skilled in the art.

[0040] Unless the context clearly indicates otherwise, the singular forms “a” and “the” used in this article include the plural forms.

[0041] As used herein, the term "about" allows for a degree of variability in a numerical value or range, for example, within 10%, 5%, 1%, 0.5%, 0.1%, or 0.01% of a specified value or range. Alternatively, the term "about" means within an acceptable standard error of the average value when considered by a person skilled in the art. Therefore, unless indicated to the contrary, the numerical parameters set forth in this disclosure and the appended claims are approximate values ​​that can be varied as needed.

[0042] The terms “low solubility” or “poor solubility in water” used interchangeably in this document refer to pharmaceutical compounds with a solubility of less than 1 mg / mL at a temperature of 20 ± 5°C and a near-neutral pH (pH 6–8). For example, axitinib is a compound known to be poorly soluble in water, with a solubility of approximately 0.2 μg / mL in aqueous media over a pH range of 6.0 to 7.8.

[0043] As used herein, the term "aqueous carrier" refers to an aqueous carrier compatible with cyclodextrins (e.g., β-cyclodextrin) that allows cyclodextrins to be uniformly dispersed or dissolved within the aqueous carrier. According to this disclosure, examples of aqueous carriers include, but are not limited to, water, biocompatible buffers (e.g., phosphate-buffered saline (PBS) buffer), etc.

[0044] As used herein, the term "clarified solution" refers to a homogeneous mixture of a solute (e.g., an API with low solubility) and a solvent, which is free of visible particles or turbidity, appears transparent, and allows light to pass through without scattering, thus producing a clear and lucid appearance. In said clarified solution, solute molecules or ions are uniformly dispersed and do not precipitate or separate from the solvent. According to this disclosure, the clarified solution produced by the method of the present invention does not contain any undissolved precipitates.

[0045] Unless otherwise stated, the steps included in the method disclosed in this disclosure are not limited to a specific order. According to this disclosure, the individual steps listed in the method may be performed individually or in combination. For example, in some non-essential embodiments detailed in Section 2. Detailed Description below, steps (a) and (b) of the method of this disclosure may be combined. 2. Detailed Implementation

[0047] This disclosure is based, at least in part, on the discovery that the solubility of a poorly soluble drug can be enhanced by heating (e.g., at temperatures above 100°C) or by acid / base dissolution (e.g., dissolution in an acidic or acidic environment). Therefore, this disclosure provides a method for preparing ophthalmic compositions containing poorly soluble active pharmaceutical ingredients (APIs) without using any organic solvents, wherein the solubility of API in ophthalmic compositions prepared by the method of this disclosure is increased by approximately 8 to 12 times compared to the solubility of API in ophthalmic compositions prepared by currently known methods.

[0048] 2.1 Increasing the solubility of low-solubility APIs through heat treatment

[0049] Accordingly, one object of this disclosure relates to a method for increasing the solubility of a low-solubility API in an ophthalmic composition by heat treatment. For this purpose, the low-solubility API is first mixed with a binding agent (e.g., cyclodextrin), and then the mixture is heat-treated. Specifically, the method includes the following steps: (a) dissolving the cyclodextrin in an aqueous carrier to produce a cyclodextrin solution; (b) mixing and stirring the API and the cyclodextrin solution from step (a) until a suspension is formed; (c) placing the suspension from step (b) in a heating bath at a temperature of about 100-150°C until a clear solution is formed; and (d) cooling the clear solution from step (c) to 20-30°C to produce an ophthalmic composition of the API.

[0050] Examples of low-solubility APIs that can be dissolved by the methods described in this disclosure include, but are not limited to, chlorpheniramine ethyl carbonate, dexamethasone, prismin, prismin acetate, flumethasone cortisol, estradiol, ethinylestradiol, mesestrol, estriol, norethindrone, norethindrone acetate, methylnorethindrone, hydroxyprogesterone, 17α-methylprogesterone, progesterone, methyltestosterone, triamcinolone, testosterone, spironolactone, alfasalone, lanosterol, acrizaniol, tevozaniol, brigatinib, and alfasalone. The API includes nilotinib, erlotinib, neratinib, gefitinib, pyrotinib, icotinib, amotinib, lapatinib, omamutinib, cimotinib, osimertinib, vandetanib, dacotinib, mobochetinib, lazazetinib, sorafenib, sunitinib, pazopanib, cabozantinib, axitinib, lenvatinib, ponatinib, regorafenib, dovitinib, folotinib, apatinib, nintedine, sildenafil, carticinib, anlotinib, pirenoxine, methotrexate, lutein, and combinations thereof. According to some embodiments, the API is axitinib. According to alternative embodiments, the API is clotiprenoline ethyl carbonate.

[0051] Examples of cyclodextrins suitable for the methods of this disclosure include, but are not limited to, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and combinations thereof. In a preferred embodiment of this disclosure, the cyclodextrin is β-cyclodextrin.

[0052] According to embodiments of this disclosure, the method begins by dissolving β-cyclodextrin in an aqueous carrier to generate a β-cyclodextrin solution (step (a)). Next, axitinib, as an API, is thoroughly mixed with the β-cyclodextrin solution until a suspension is formed (step (b)). According to embodiments of this disclosure, β-cyclodextrin is present in the β-cyclodextrin solution in an amount of about 20% to about 60% (w / v), for example, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% and 60% (w / v); and the API (e.g., axitinib) is present in the suspension in an amount of about 0.1% to 1.6% (w / v), for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5% or 1.6% (w / v). In one specific embodiment, β-cyclodextrin is present in the β-cyclodextrin solution at an amount of about 40% (w / v); while the API (e.g., axitinib) is present in the suspension at an amount of about 0.8% (w / v).

[0053] Examples of β-cyclodextrins suitable for the methods of this disclosure include, but are not limited to, hydroxypropyl-β-cyclodextrin (hereinafter referred to as HPβCD), methyl-β-cyclodextrin (MβCD), sulfonyl ether-β-cyclodextrin (SBE-β-CD), randomly methylated β-cyclodextrin (RM-β-CD), carboxymethyl-β-cyclodextrin, and combinations thereof. In one specific embodiment, the β-cyclodextrin used in the methods of this disclosure is hydroxypropyl-β-cyclodextrin.

[0054] The aqueous carriers suitable for use in this disclosure are water-based carriers that do not contain any organic solvents. Examples of aqueous carriers suitable for the methods of this disclosure include, but are not limited to, water, saline, PBS, 2-amino-2-(hydroxymethyl)propane-1,3-diol buffer, and borate buffer. In a preferred embodiment, the aqueous carrier is water; more preferably, it is sterile water.

[0055] It is worth noting that in some alternative embodiments, steps (a) and (b) can be combined. Specifically, the API and β-cyclodextrin are simultaneously mixed and dissolved in an aqueous carrier to form a mixture, and the mixture is stirred until a suspension is formed.

[0056] In steps (a) to (b), several conventional preparation methods can be used to accelerate dissolution and suspension, such as using a magnetic stirrer to help mix, dissolve and / or suspend.

[0057] Necessarily or selectively, a thickener and a stabilizer may be added to the β-cyclodextrin solution prior to step (b). According to some embodiments of this disclosure, the thickener present in the β-cyclodextrin solution is from about 0.1% to about 1% (w / v), for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, and 1% (w / v). In a preferred embodiment, the concentration of the thickener in the β-cyclodextrin solution is 0.5% (w / v). Furthermore, the stabilizer present in the β-cyclodextrin solution is from about 1% to 5% (w / v), for example, 1%, 2%, 3%, 4%, and 5% (w / v). According to one embodiment, the concentration of the stabilizer in the β-cyclodextrin solution is 2% (w / v).

[0058] Suitable thickeners and stabilizers can be selected based on general knowledge in the art and practical needs. Examples of thickeners suitable for this method include, but are not limited to, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, carbomer, polycarbofil, polyethylene glycol, hyaluronic acid, and combinations thereof. According to this disclosure, the stabilizer for the method of the present invention can be purine, purine derivatives, or combinations thereof. Examples of purine derivatives suitable as stabilizers of the present invention include, but are not limited to, caffeine, theobromine, isoguanine, xanthine, hypoxanthine, and uric acid. According to a preferred embodiment of this disclosure, hydroxypropyl methylcellulose and caffeine are added to the β-cyclodextrin solution and thoroughly mixed before the step of mixing with the API (i.e., axitinib).

[0059] Axitinib is mixed with a β-cyclodextrin solution to form a suspension (step (b)). Note that axitinib is not completely dissolved at this point. The resulting suspension is then placed in a heating bath until the axitinib is completely dissolved and the suspension becomes a clear solution (step (c)). As the temperature increases, the suspension gradually becomes clear, and even after heating is stopped, the solution remains clear without any precipitate forming. The heating time and temperature can be adjusted as needed, as long as the axitinib is completely dissolved. In some embodiments, the temperature of the heating bath (e.g., an oil bath) is about 100-150°C, such as 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, and 150°C; a preferred temperature is about 120°C. Furthermore, heating can last from about 5 minutes to several hours, for example, for 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, and 60 minutes, and for 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5 hours, preferably about 120 minutes. After heat treatment, a clear solution containing axitinib is produced (step c). Next, the clarified solution is cooled to 20-30°C, for example, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30°C. In a specific embodiment, the clarified solution is cooled to approximately 25°C, thereby producing the ophthalmic composition of the present invention containing axitinib. It should be noted that the clarified solution does not contain any insoluble precipitates, whether heated or cooled. In other words, the heat treatment in the method of the present invention enables the complete dissolution of axitinib in the ophthalmic composition. Even after cooling, axitinib remains soluble in the clarified solution.

[0060] According to this disclosure, preservatives may be added additionally or selectively to a cooled, clear solution. According to some embodiments of this disclosure, the preservative is present in the ophthalmic composition in an amount of about 0.001% to 2% (w / v), such as 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%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, and 2% (w / v). Examples of preservatives suitable for the methods of this disclosure include, but are not limited to, alkyl dimethyl benzyl ammonium chloride (BAK), parabens, and chlorobutanol. In one specific embodiment, the preservative, BAK, is present in the ophthalmic composition at an amount of 0.005% (w / v).

[0061] Selectively or additionally, the cooled clarified solution (i.e., the final product of step (d)) may be further subjected to sterilization procedures well known in the art, including but not limited to, autoclaving, dry heat, filtration, ethylene oxide (ETO), radiation, and chemical sterilization. Appropriate sterilization treatments may be selected based on actual needs and the type of formulation. In some specific embodiments, the clarified solution of the present invention is sterilized by sequentially filtering it using filters with pore sizes of 0.45 µm and 0.2 µm, respectively.

[0062] 2.2 Increasing the solubility of low-solubility APIs through acid dissolution

[0063] Another object of this disclosure relates to a method for increasing the solubility of a low-solubility API in an ophthalmic composition by acid dissolution. Similar to the method described in Section 2.1 above, this method is characterized by the absence of any organic solvents. Specifically, the method comprises the following steps: (a) dissolving cyclodextrin in an acidic solution with a pH of approximately 0 to 2 to prepare an acidified cyclodextrin solution; (b) mixing the API with the acidified cyclodextrin solution from step (a) and stirring until a clear solution is formed; and (c) adjusting the pH of the clear solution from step (b) to approximately 3.0 to 8.0 to produce an ophthalmic composition of the API.

[0064] Examples of low-solubility APIs that can be dissolved using the acid dissolution method described in this disclosure include, but are not limited to, chlorpheniramine ethyl carbonate, dexamethasone, prismin, prismin acetate, flumethasone cortisol, estradiol, ethinylestradiol, mesestrol, estriol, norethindrone, norethindrone acetate, norprogesterone, hydroxyprogesterone, 17α-methylprogesterone, progesterone, methyltestosterone, triamcinolone, testosterone, spironolactone, alfasalone, lanosterol, acrizanil, tevozanil, brigatinib, etc. Afatinib, erlotinib, neratinib, gefitinib, pyrotinib, icomutinib, amotinib, lapatinib, omamutinib, cimotinib, osimertinib, vandetanib, dacotinib, mobochetinib, lazazetinib, sorafenib, sunitinib, pazopanib, cabozantinib, axitinib, lenvatinib, ponatinib, regorafenib, dovitinib, fotinib, apatinib, nintedine, sildenafil, carticinib, anlotinib, pirenoxine, methotrexate, lutein, and combinations thereof. According to some embodiments, the API is axitinib. According to alternative embodiments, the API is clotiprenoline ethyl carbonate.

[0065] Examples of cyclodextrins suitable for the methods of this disclosure include, but are not limited to, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and combinations thereof. In a preferred embodiment of this disclosure, the cyclodextrin is β-cyclodextrin.

[0066] According to embodiments of this disclosure, a water-soluble axitinib of about 0.2 μg / mL is thoroughly mixed with an acidified β-cyclodextrin solution with a pH between 0 and 2 (e.g., by stirring with a magnetic stirrer) until a clear solution is produced (steps (a) to (b)). An acidified β-cyclodextrin solution can be prepared by adding an acid to the β-cyclodextrin solution (e.g., the β-cyclodextrin solution described in Section 2.1 above) until the solution reaches the desired pH (e.g., 0 to 2). Examples of acids suitable for use in this disclosure include, but are not limited to, solutions of hydrochloric acid (HCl), sulfuric acid (H₂SO₄), nitric acid (HNO₃), phosphoric acid (H₃PO₄), citric acid (C₆H₈O₇), and oxalic acid (H₂C₂O₄). According to some embodiments of this disclosure, an acid is added to the β-cyclodextrin solution until the acid concentration of the solution is greater than 0.01 M, preferably about 0.01 to 1 M. In one specific embodiment, hydrochloric acid was added to the β-cyclodextrin solution until the pH of the solution was 1 (i.e., the concentration of the solution was 0.1 M). It should be noted that axitinib was completely dissolved in the resulting clear solution, and therefore the clear solution did not contain any insoluble precipitates.

[0067] According to embodiments of this disclosure, β-cyclodextrin is present in the clear solution at an amount of about 20% to about 60% (w / v), for example, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, and 60% (w / v), while axitinib is present in the clear solution of step (b) at an amount of about 0.1% to 1.6% (w / v), for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, and 1.6% (w / v). In a preferred embodiment of this disclosure, the concentration of β-cyclodextrin in the acidified β-cyclodextrin solution is about 40% (w / v), while the concentration of axitinib in the clear solution is about 0.8%.

[0068] Examples of β-cyclodextrins suitable for the methods of this disclosure include, but are not limited to, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, sulfonyl ether-β-cyclodextrin, randomly methylated β-cyclodextrin, carboxymethyl-β-cyclodextrin, and combinations thereof. In one specific embodiment, the API is mixed with an acidified hydroxypropyl-β-cyclodextrin solution having a pH of about 1.0, and the mixture is thoroughly mixed to obtain a clear solution.

[0069] It is worth noting that in some alternative embodiments, steps (a) and (b) can be performed together. Specifically, the API and cyclodextrin are mixed and simultaneously dissolved in an acidic solution to form a mixture, which is then stirred until a clear solution is formed.

[0070] Next, the pH of the resulting clear solution is readjusted to approximately 3.0 to 8.0, for example, pH values ​​of 3.0, 4.0, 5.0, 6.0, 7.0, or 8.0; preferably approximately 6.0, thereby forming an ophthalmic composition of an API (e.g., axitinib or other drugs). To readjust the clear solution derived from the acidified cyclodextrin solution, an alkaline solution may be added thereto. Examples of alkaline solutions suitable for the methods of this disclosure include, but are not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide solutions, and combinations thereof. In one specific embodiment, the alkaline solution used in step (c) is sodium hydroxide.

[0071] According to the non-essential embodiments described in this disclosure, thickeners, stabilizers, preservatives, or combinations thereof may be additionally or selectively added to the clear solution produced in step (c). Preferably, all thickeners, stabilizers, and preservatives are added to the clear solution of step (c).

[0072] Examples of thickeners suitable for the methods of this disclosure include, but are not limited to, hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose, polyacrylic acid, polycarbamate, PEG, and hyaluronic acid and combinations thereof. According to some embodiments of this disclosure, the thickener is present in the clear solution of step (c) in an amount ranging from about 0.1% to 1% (w / v), for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, and 1% (w / v). According to one specific embodiment, the thickener is hydroxypropyl methylcellulose (HPMC) at a concentration of 0.5% (w / v) in the clear solution.

[0073] Examples of stabilizers suitable for the methods of this disclosure include, but are not limited to, purines, purine derivatives, or combinations thereof. Examples of purine derivatives suitable for the methods of this disclosure include, but are not limited to, caffeine, theobromine, isoguanine, xanthine, hypoxanthine, uric acid, etc. In specific embodiments of this disclosure, the stabilizer is present in the clear solution in an amount ranging from about 1% to 10% (w / v), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, and 10% (w / v). According to one specific embodiment, the stabilizer is caffeine, and it is present in the clear solution in an amount of 2.0% (w / v).

[0074] Examples of preservatives suitable for the methods of this disclosure include, but are not limited to, alkyl dimethyl benzyl ammonium chloride, parabens, and chlorobutanol. In some embodiments of this disclosure, the preservative is present in a clear solution in an amount of about 0.001% to 2% (w / v), for example, 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%, and 2% (w / v). In one specific embodiment, the concentration of the preservative alkyl dimethyl benzyl ammonium chloride in the clear solution is 0.005% (w / v).

[0075] Optionally or additionally, the product of step (c) (e.g., a clear solution or an ophthalmic composition containing axitinib) may be further subjected to sterilization procedures well known in the art, including but not limited to autoclaving, dry heat, filtration, ethane oxidation (ETO), radiation, and chemical sterilization. An appropriate sterilization method may be selected based on actual needs and formulation type. In some specific embodiments, the clear solution of this disclosure is sterilized by sequentially filtering it using filters with pore sizes of 0.45 µm and 0.2 µm.

[0076] By utilizing the features set forth in Sections 2.1 and 2.2 above, this disclosure provides an improved method for increasing the solubility of low-solubility APIs, thereby increasing their yield in aqueous ophthalmic compositions.

[0077] Example

[0078] Example 1: Preparation and characterization of an ophthalmic composition of axitinib

[0079] 1.1 Preparation of ophthalmic compositions

[0080] 1.1.1 Heat Treatment

[0081] Formulas suitable for small-batch manufacturing

[0082] Hydroxypropyl-β-cyclodextrin (HPβCD; 2 g), caffeine (100 mg), and hydroxypropyl methylcellulose (25 mg) were sequentially dissolved in 3.5 mL of distilled water and stirred (e.g., using a magnetic stirrer at 250 rpm) to produce a hydroxypropyl-β-cyclodextrin solution. Axitinib (60 mg) was added to the hydroxypropyl-β-cyclodextrin solution, and the mixture was stirred continuously until a suspension was formed. The suspension was placed in a heated oil bath at approximately 120°C for about 10 minutes. Subsequently, it was transferred to a water bath to cool to ambient temperature, resulting in a clear, transparent, or pale yellow solution. 0.25 mg of benzalkonium chloride (BAK) was added to the clarified solution and mixed thoroughly. The clarified solution was then diluted with distilled water to a total volume of 5 mL. The solution was then filtered sequentially through 0.45 µm and 0.2 µm filters to produce a liquid form of the axitinib ophthalmic composition (hereinafter referred to as Formulation I-1).

[0083] Formula suitable for multiple batches of mass production

[0084] To further verify the versatility of the heat treatment of this disclosure, different batches of ophthalmic compositions (i.e. formulations I-2 to I-7) were prepared using different proportions and heating conditions listed in Table 1 by following the same procedure as described above.

[0085] Table 1: Different preparation conditions for formulations I-1 to I-7

[0086] 1.1.2 Acidic dissolution

[0087] Hydroxypropyl-β-cyclodextrin (2 g) and axitinib (60 mg) were mixed in 3 mL of hydrochloric acid solution (0.1 N) and stirred continuously (200 rpm) until a clear, transparent or pale yellow solution was formed. The pH of the clear solution was then readjusted to 6 by adding sodium hydroxide (1.0 N). Caffeine (100 mg), hydroxypropyl methylcellulose (25 mg), and 0.25 mg of BAK were then added to the clear solution and stirred until completely dissolved. The solution was diluted with distilled water to approximately 5 mL and then filtered through 0.45 µm and 0.2 µm filters to produce a liquid form of the axitinib ophthalmic composition.

[0088] To further verify the versatility of the current acidic dissolution, various batches of ophthalmic compositions were prepared using different proportions and acid concentrations, following the same steps as described above.

[0089] Table 2: Different preparation conditions for formulations II-1 to II-14

[0090] 1.2 Characteristic Analysis of the Ophthalmic Composition of Example 1.1

[0091] The amount of axitinib present in the final composition of Example 1.1 was measured by high-performance liquid chromatography (HPLC) to assess whether the method of this disclosure improves the solubility of axitinib in the ophthalmic composition of Example 1. Specifically, if the solubility of axitinib in the liquid increases, a higher amount of axitinib will be present in the final composition.

[0092] The results confirmed that the axitinib content in the ophthalmic compositions of Examples 1.1.1 and 1.1.2 was approximately 8 mg / mL to 12 mg / mL, which is significantly higher than the amount of axitinib compositions prepared by existing methods (i.e., approximately 1.8 mg / mL).

[0093] In addition, the stability of the ophthalmic compositions of Examples 1.1.1 and 1.1.2 was verified by storing them at 25°C and 40°C for one month each. The results are summarized in Tables 3 and 4, respectively.

[0094] Table 3: Stability results of the ophthalmic composition of Example 1.1.1, wherein Formulation I-3 is used as a representative example.

[0095]

[0096] Table 4: Stability results of the ophthalmic composition of Example 1.1.2, wherein Formulation II-4 is described as a representative example.

[0097]

[0098] The results in Tables 3 and 4 together indicate that the ophthalmic composition prepared by the method of the present invention has high stability.

[0099] Example 2: Comparison of characteristic parameters of axitinib compositions prepared by existing methods and known methods

[0100] For comparison, a control composition was prepared according to the method disclosed by Huang et al. (Transl Vis Sci Technol. 2021;10(14):23), in which axitinib was dissolved in glacial acetic acid, and the resulting solution was then sprayed and dried to produce the control composition. Characteristic parameters (including yield, impurity content, residual organic solvent, etc.) between the ophthalmic composition of Example 1.1 and the control composition were compared. The results are summarized in Table 5.

[0101] Table 5: Characteristic parameters of the ophthalmic composition of Example 1.1 and the control group composition

[0102] *Yield is obtained by dividing the filtered volume by the total batch volume.

[0103] The data in Table 5 collectively demonstrate that the ophthalmic composition prepared by the method of the present invention not only contains a larger amount of low-solubility API, but also, compared with the control group composition prepared by existing methods, can be prepared in a single reaction tank in a shorter time (i.e., <24 hours), with less impurity content, and without the use of any organic solvents, resulting in a higher yield.

[0104] Example 3: Preparation of an ophthalmic composition of chlorprednisolone ethyl carbonate

[0105] To test whether the method of the present invention is applicable to other low-solubility compounds, another ophthalmic composition was prepared by heat treatment using ethyl chlorteprenor carbonate as the API.

[0106] 3.1 Heat Treatment

[0107] Hydroxypropyl-β-cyclodextrin (2 g), caffeine (100 mg), and hydroxypropyl methylcellulose (25 mg) were sequentially dissolved in 3 mL of distilled water using a magnetic stirrer (500 rpm) to prepare a hydroxypropyl-β-cyclodextrin solution. Clotepenoethyl carbonate (40 mg) was added to the hydroxypropyl-β-cyclodextrin solution while continuously stirring until a suspension was formed. The suspension was placed in a heated oil bath at 120°C for approximately 5 minutes. Subsequently, it was transferred to a water bath and cooled to ambient temperature, resulting in a clear, transparent, or pale yellow solution. 0.25 mg of alkyl dimethyl benzyl ammonium chloride was added to the clear solution and mixed thoroughly. The solution was then diluted with distilled water to a total volume of approximately 5 mL and filtered through 0.45 µm and 0.2 µm filters to obtain a liquid form of clotepenoethyl carbonate ophthalmic composition.

[0108] 3.2 Characteristic analysis of the ophthalmic composition of Example 3.1

[0109] Measurements showed that the concentration of chlorpromazine ethyl carbonate in the ophthalmic composition of Example 3.1 was 8 mg / mL, which is significantly higher than the concentration of chlorpromazine ethyl carbonate compositions prepared by existing methods (data not shown).

[0110] It should be understood that the foregoing description of the embodiments is merely given by way of example, and various modifications can be made by those skilled in the art. The above specification, embodiments, and experimental results provide a complete description of the structure and use of exemplary embodiments of the present invention. Although various specific embodiments of the present invention are disclosed in the foregoing embodiments, they are not intended to limit the present invention. Those skilled in the art to which this invention pertains can make various modifications and alterations without departing from the principles and spirit of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

Claims

1. A method for preparing an eye-use composition of an active pharmaceutical ingredient (API) having low solubility, the method comprising: (a) Dissolve cyclodextrin in an aqueous carrier to produce a cyclodextrin solution; (b) Mix and stir the API and the cyclodextrin solution from step (a) until a suspension is formed; (c) Place the suspension from step (b) in a heating bath at a temperature of approximately 100-150°C until a clear solution is formed; and (d) Cool the clarified solution from step (c) to 20-30°C to produce the ophthalmic composition of the API. in, The clarified solution of step (c) or (d) does not contain any insoluble precipitate; and The method is characterized by the fact that it does not use any organic solvents.

2. The method of claim 1, wherein the API is selected from chlorpheniramine maleate ethyl carbonate, dexamethasone, prismin, prismin acetate, flumethasone cortisol, estradiol, ethinylestradiol, mesestrol, estriol, norethindrone, norethindrone acetate, methylnorethindrone, hydroxyprogesterone, 17α-methylprogesterone, progesterone, methyltestosterone, triamcinolone, testosterone, spironolactone, alfasalone, lanosterol, acrizanil, tevozanil, brigatinib, afatinib, erlotinib. The group consisting of nifedipine, neratinib, gefitinib, pyrotinib, icomitinib, amotinib, lapatinib, omamutinib, simotinib, osimertinib, vandetanib, dacotinib, mobochetinib, lazazetinib, sorafenib, sunitinib, pazopanib, cabozantinib, axitinib, lenvatinib, ponatinib, regorafenib, dovitinib, folotinib, apatinib, nindine, sildenafil, carticinib, anlotinib, pirenoxine, methotrexate, lutein, and combinations thereof.

3. The method of claim 1, wherein the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and combinations thereof.

4. The method of claim 3, wherein the β-cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin (HPβCD), methyl-β-cyclodextrin (MβCD), sulfobutyl ether-β-cyclodextrin (SBE-β-CD), random methylated β-cyclodextrin (RM-β-CD), carboxymethyl-β-cyclodextrin, and combinations thereof.

5. The method of claim 1, wherein the aqueous carrier is selected from the group consisting of water, saline, phosphate buffer (PBS), 2-amino-2-(hydroxymethyl)propane-1,3-diol buffer and borate buffer.

6. The method of claim 5, wherein the aqueous carrier is water.

7. The method of claim 1, further comprising, prior to step (b), adding a thickener and a stabilizer to the cyclodextrin solution of step (a).

8. The method of claim 7, wherein the thickener is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose, carbomer, polycarbamate, polyethylene glycol (PEG), and hyaluronic acid (HA).

9. The method of claim 7, wherein the stabilizer is a purine, a monopurine derivative, or a combination thereof.

10. The method of claim 9, wherein the purine derivative is selected from the group consisting of caffeine, theobromine, isoguanine, xanthine, hypoxanthine and uric acid.

11. The method of claim 1, further comprising adding a preservative to the clarified solution in step (d).

12. The method of claim 11, wherein the preservative is selected from the group consisting of alkyl dimethyl benzyl ammonium chloride (BAK), parabens, and chlorobutanol.

13. The method of claim 1, wherein the cyclodextrin is present in the cyclodextrin solution of step (a) in an amount of about 20% to about 60% (w / v).

14. The method of claim 1, wherein the API is present in the suspension of step (b) in an amount of about 0.1% to about 1.6% (w / v).

15. A method for preparing an eye-use composition having low solubility of an active pharmaceutical ingredient (API), the method comprising: (a) Dissolve cyclodextrin in an acidic solution with a pH of about 0-2.0 to produce an acidified cyclodextrin solution; (b) Mix and stir the API with the acidified cyclodextrin solution from step (a) until a clear solution is formed; and (c) Adjust the pH of the clarified solution from step (b) to a value of about 3.0 to 8.0 to produce the ophthalmic composition of the API. in, The clarified solution contains no insoluble precipitates, and The method is characterized by the fact that it does not use any organic solvents.

16. The method of claim 15, wherein the API is selected from chlorpheniramine maleate ethyl carbonate, dexamethasone, prednisolone, prednisolone acetate, fluorometholone, estradiol, ethinylestradiol, mestriol, estriol, norethindrone, norethindrone acetate, norprogesterone, hydroxyprogesterone, 17α-methylprogesterone, progesterone, methyltestosterone, triamcinolone, testosterone, spironolactone, alfasalone, lanosterol, acrizanil, tevozanil, brigatinib, afatinib, erlotinib. The group consisting of neratinib, gefitinib, pyrotinib, icomitinib, amotinib, lapatinib, omamutinib, cimotinib, osimertinib, vandetanib, dacotinib, mobochetinib, lazazetinib, sorafenib, sunitinib, pazopanib, cabozantinib, axitinib, lenvatinib, ponatinib, regorafenib, dovitinib, folotinib, apatinib, nindine, sildenafil, carticinib, anlotinib, pirenoxine, methotrexate, lutein, and combinations thereof.

17. The method of claim 15, wherein the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and combinations thereof.

18. The method of claim 17, wherein the β-cyclodextrin is selected from the group consisting of HPβCD, MβCD, SBE-β-CD, RM-β-CD, carboxymethyl-β-cyclodextrin, and combinations thereof.

19. The method of claim 15, wherein the acidic solution is about 0.01-0.1 M HCl solution.

20. The method of claim 15, further comprising adding a thickener, a stabilizer, a preservative, or a combination thereof to the clarified solution in step (c).

21. The method of claim 20, wherein the thickener is selected from the group consisting of HPMC, sodium carboxymethyl cellulose, carbomer, polycarbamate, PEG, and HA.

22. The method of claim 20, wherein the stabilizer is a purine, a monopurine derivative, or a combination thereof.

23. The method of claim 22, wherein the purine derivative is selected from the group consisting of caffeine, theobromine, isoguanine, xanthine, hypoxanthine and uric acid.

24. The method of claim 20, wherein the preservative is selected from the group consisting of alkyl dimethyl benzyl ammonium chloride, p-hydroxybenzoate and chlorobutanol.

25. The method of claim 15, wherein the cyclodextrin is present in the clarified solution of step (b) in an amount of about 20% to about 60% (w / v).

26. The method of claim 15, wherein the API is present in the clarified solution of step (b) in an amount of about 0.1% to about 1.6% (w / v).

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