WO2025044131A1

WO2025044131A1 - Methods for producing ophthalmic composition of poorly water-soluble drugs

Info

Publication number: WO2025044131A1
Application number: PCT/CN2024/080081
Authority: WO
Inventors: Wei-Hsiang Wang; Chi-Hsiang Chen; Cheng-Wen Lin; Sheng-Chieh Lin; Wei-Lin Chen; Jia-Rung Hu; Yen-Cheng Lin; Chi-Chih Chang; Chih-Yu Wu; Chieh-Ju Hu
Original assignee: Theratocular Biotek Co Ltd
Current assignee: Theratocular Biotek Co Ltd
Priority date: 2023-08-28
Filing date: 2024-03-05
Publication date: 2025-03-06
Anticipated expiration: 2026-02-28
Also published as: TW202508578A; WO2025044852A1; TW202508583A

Abstract

Disclosed herein are two methods for producing an ophthalmic composition of an active pharmaceutical ingredient (API) having a poor water-solubility. One method at least includes mixing the API and cyclodextrin in an aqueous vehicle placed in a heated bath at above 100 ℃, thereby producing a clear solution in which the API is completely dissolved. Another method at least includes mixing the API and cyclodextrin in an acidic solution having pH value of about 0 to 2.0, thereby producing the clear solution containing the API. The methods are characterized in not using any organic solvent.

Description

METHODS FOR PRODUCING OPHTHALMIC COMPOSITION OF POORLY WATER-SOLUBLE DRUGS

BACKGROUND OF THE INVENTION

1. FIELD OF THE INVENTION

The present disclosure relates to a method for producing an ophthalmic composition. More particularly, the disclosed invention relates to a method that is characterized in no using any organic solvent during producing the ophthalmic composition.

2. DESCRIPTION OF RELATED ART

Ophthalmic compositions are typically available in forms of solutions, suspensions, ointments, gels, or emulsions for direct application to the eyes. To produce ophthalmic compositions, in addition to determining the type of formulation based on the active pharmaceutical ingredient (API) , it is necessary to ensure the compatibility between excipients and other additives (e.g., preservatives, buffering agents, viscosity modifiers, tonicity agents, and antioxidants) for the chosen formulation. Furthermore, it is essential to guarantee the sterility and safety of the medication.

Due to the advantages of easy application, rapid drug delivery, uniform distribution, high compatibility and stability, and flexible dosing, ophthalmic compositions in a liquid form have become a popular choice. However, these formulations have their limitations when it comes to hydrophobic or poorly water-soluble APIs. To increase the solubility of hydrophobic or poorly water-soluble APIs in liquid ophthalmic compositions, the conventional approaches in the art involve dissolving the API in a solvent other than water, typically an organic solvent, before mixing it with other excipients.

However, ophthalmic composition prepared by such method would require additional treatments (e.g., to remove the organic solvent) before it may comply with guidelines set by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) . For example, in order for the ophthalmic composition prepared by Huang et al (Transl Vis Sci Technol. 2021; 10 (14) : 23) ) , which involved using glacial acetic acid as the solvent to dissolve the API, to meet the guidelines, the ophthalmic composition needed to be further desiccated under a vacuum oven at 120℃ for 24 hours, so as to ensure removal of all of the solvents. In the context of large-scale production, the process of removing organic solvents would adversely prolong the production time.

Further, even if the residual organic solvent levels meet the minimum standard, the potential impact of directly applying organic solvents to the eyes should not be overlooked and requires careful evaluation. In a long-term follow-up study published by de Oliveira et al, it was highlighted that chronic and prolonged exposure to organic solvents may affect eye movements and result in impaired visual tracking abilities (de Oliveira et al., Front. Neurosci. 11: 666; 2017) .

In view of the foregoing, there exists in the related art a need of an improved method to prepare an ophthalmic composition for hydrophobic or poorly water-soluble APIs.

SUMMARY

The following presents a simplified summary of the disclosure in order to provide a basic understanding to the reader. This summary is not an extensive overview of the disclosure and it does not identify key/critical elements of the present invention or delineate the scope of the present invention. Its sole purpose is to present some concepts disclosed herein in a simplified form as a prelude to the more detailed description that is presented later.

As embodied and broadly described herein, the purpose of the present disclosure is to provide a method for producing an ophthalmic composition of an active pharmaceutical ingredient (API) having a poor water-solubility. According to the present disclosure, the present method is characterized in not using any organic solvent.

In one aspect, the present disclosure is directed to a method for producing an ophthalmic composition of an API via thermal treatment. Typically, the method comprises steps of: (a) dissolving cyclodextrin in an aqueous vehicle to produce a cyclodextrin solution; (b) mixing and stirring the API with the cyclodextrin solution of step (a) until a suspension is formed; (c) subjecting the suspension of step (b) to a heated bath at about 100-150 ℃ until a clear solution is formed; and (d) cooling the clear solution of step (c) to about 20-30 ℃ to produce the ophthalmic composition of the API. Notably in the present method, the clear solution in steps (c) or (d) does not comprise any insoluble precipitates.

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

According to some embodiments of the present disclosure, the API is present in the suspension of step (b) in an amount of about 0.1%to about 1.6% (w/v) .

According to one embodiment of the present disclosure, the API is selected from the group consisting of dexamethasone, prednisolone, prednisolone acetate, fluorometholone, estradiol, ethinylestradiol, mestranol, estriol, norethindrone, norethindrone acetate, norgestrel, ethisterone, 17α-methylprogesterone, progesterone, methyltestosterone, triamcinolone, testosterone, spironolactone, alfaxalone, lanosterol, acrizanib, tivozanib, brigatinib, afatinib, erlotinib, neratinib, gefitinib, pyrotinib, icotinib, almonertinib, lapatinib, olmutinib, simotinib, osimertinib, vandetanib, dacomitinib, mobocertinib, lazertinib, sorafenib, sunitinib, pazopanib, cabozantinib, axitinib, lenvatinib, ponatinib, regorafenib, dovitinib, foretinib, apatinib, nintedainb, cediranib, catequentinib, anlotinib, pirenoxine, loteprednol etabonate, methotrexate, lutein, and a combination thereof.

According to some embodiments of the present disclosure, the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and a combination thereof.

According to some embodiments of the present disclosure, the β-cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin (HPβCD) , sulfobutylether-β-cyclodextrin (SBE-β-CD) , randomly methylated β-cyclodextrin (RM-β-CD) , methyl-β-cyclodextrin (MβCD) , carboxymethyl-β-cyclodextrin, and a combination thereof.

In one preferred embodiment, the β-cyclodextrin is HPβCD.

According to some embodiments of the present disclosure, the aqueous vehicle is selected from the group consisting of water, saline, phosphate-buffered saline, 2-Amino-2- (hydroxymethyl) propane-1, 3-diol (tris-) buffer, and borate buffered saline. In one preferred embodiment, the aqueous vehicle is water.

According to some embodiments of the present disclosure, the present method further comprises adding a thickening agent and a stabilizer to the β-cyclodextrin solution of step (a) prior to step (b) .

Example of the thickening agent suitable for use in the present method includes hydroxypropyl methylcellulose (HPMC) , sodium carboxymethylcellulose, carbomer, polycarbophil, polyethylene glycol (PEG) , and hyaluronic acid (HA) .

Example of the stabilizer suitable for use in the present method may be purine, a derivative of purine, or a combination thereof. In one working example, the derivative of purine is selected from the group consisting of caffeine, theobromine, isoguanine, xanthine, hypoxanthine, and uric acid.

According to some embodiments of the present disclosure, the present method further comprises adding a preservative to the clear solution of step (d) .

Example of the preservative suitable for use in the present method includes benzalkonium chloride (BAK) , alkyl parabens, and chlorobutanol.

In another aspect, the present disclosure is directed to another method for producing an ophthalmic composition of an API via acidic dissolution. Typically, the method comprises steps of: (a) dissolving cyclodextrin in an acidic solution having a pH value of about 0 to 2.0, to produce an acidified cyclodextrin solution; (b) mixing and stirring the API with the acidified cyclodextrin solution of step (a) until a clear solution is formed; and (c) adjusting the pH of the clear solution of step (b) to a value of about 3.0 to 8.0, thereby producing the ophthalmic composition of the API, wherein the clear solutions does not comprises any insoluble precipitates.

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

According to some embodiments of the present disclosure, the API is present in the clear solution of step (b) in an amount of about 0.1%to about 1.6% (w/v) .

According to some embodiments of the present disclosure, examples of the β-cyclodextrin suitable for use in the present method include hydroxypropyl-β-cyclodextrin (HPβCD) , sulfobutylether-β-cyclodextrin (SBE-β-CD) , randomly methylated β-cyclodextrin (RM-β-CD) , methyl-β-cyclodextrin (MβCD) , carboxymethyl-β-cyclodextrin, and a combination thereof.

According to some embodiments of the present disclosure, the acidic solution is an HCl solution about 0.01 to 1.0 M.

According to alternative or additional embodiments of the present disclosure, the method further comprises adding a thickening agent, a stabilizer, a preservative, or a combination thereof to the clear solution of step (c) .

Many of the attendant features and advantages of the present disclosure will becomes better understood with reference to the following detailed description.

DESCRIPTION

The detailed description provided below in connection with the appended drawings is intended as a description of the present examples and is not intended to represent the only forms in which the present example may be constructed or utilized. The description sets forth the functions of the example and the sequence of steps for constructing and operating the example. However, the same or equivalent functions and sequences may be accomplished by different examples.

1. Definition

For convenience, certain terms employed in the specification, examples and appended claims are collected here. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of the ordinary skills in the art to which this invention belongs.

The singular forms “a” , “and” , and “the” are used herein to include plural referents unless the context clearly dictates otherwise.

The term “about” as used herein allows for a degree of variability in a value or range, for example, within 10%, within 5%, within 1%, within 0.5%, within 0.1%, or within 0.01%of a stated value or of a stated limit of a range. Alternatively, the term “about” means within an acceptable standard error of the mean when considered by one of ordinary skill in the art. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present disclosure and attached claims are approximations that can vary as desired.

The terms “poor water-solubility” or “poorly soluble in water” as interchangeably used herein refer to a pharmaceutical compound having a solubility that is less than 1 mg/mL near neutral pH value (pH 6-8) at 20 ± 5℃. For example, axitinib, a compound known to be poorly soluble in water, has a solubility of about 0.2 μg/mL in aqueous media over a pH ranging between 6.0 to 7.8.

The term “aqueous vehicle” as used herein refers to a water-based carrier that is compatible with cyclodextrin (e.g., β-cyclodextrin) , allowing for the uniform dispersion or dissolution of cyclodextrin within the aqueous vehicle. According to the present disclosure, example of the aqueous vehicle includes, but is not limited to, water, biocompatible buffering solution (e.g., phosphate-buffered saline (PBS) buffer) and the like.

The term “clear solution” as used herein refers to a homogeneous mixture of a solute (for instance, an API having a poor water solubility) and a solvent with no visible particles or turbidity. It appears transparent and allows light to pass through without scattering, resulting in a clear and unclouded appearance. In the clear solution, the solute molecules or ions are evenly dispersed and do not precipitate or separate from the solvent. According to the present disclosure, the clear solutions produced by the present methods do not comprises any insoluble precipitates.

The steps comprised in the present method as disclosed herein are not subject to specific orders, unless otherwise specified. According to the present disclosure, the individual steps enumerated in the present methods can be performed separately or in combination. For example, in some alternative embodiments detailed in section 2 below, steps (a) and (b) of the present methods can be combined.

2. Description of the invention

The present disclosure is based, at least in part, on the discovery that the solubility of poorly water-soluble drugs can be enhanced via heating (e.g., a temperature higher than 100 ℃) or acid/base dissolution (e.g., in acidic or basic conditions) . Thus, the present disclosure provides methods specific for producing an ophthalmic composition of an active pharmaceutical ingredient (API) having a poor water-solubility, in which the solubility of the API in the ophthalmic composition increases about 8 to 12-folds, which is compared to that of an ophthalmic composition produced by presently known method, without using any organic solvent.

2.1 Increasing solubility of a poorly soluble API via thermal treatment

Accordingly, one objective of the present disclosure is directed to a method of increasing the solubility of a poorly soluble API in an ophthalmic composition via thermal treatment. To this purpose, the poorly soluble API is first mixed with a complexing agent (e.g., cyclodextrin) , and the mixture is then subjected to a thermal treatment. Specifically, the method comprises steps of: (a) dissolving cyclodextrin in an aqueous vehicle to produce a cyclodextrin solution; (b) mixing and stirring the API with the cyclodextrin solution of step (a) until a suspension is formed; (c) subjecting the suspension of step (b) to a heated bath at about 100-150 ℃ until a clear solution is formed; and (d) cooling the clear solution of step (c) to about 20-30 ℃ to produce the ophthalmic composition of the API.

Examples of the poorly soluble API dissolvable via the present method include, but are not limited to, loteprednol etabonate, dexamethasone, prednisolone, prednisolone acetate, fluorometholone, estradiol, ethinylestradiol, mestranol, estriol, norethindrone, norethindrone acetate, norgestrel, ethisterone, 17α-methylprogesterone, progesterone, methyltestosterone, triamcinolone, testosterone, spironolactone, alfaxalone, lanosterol, acrizanib, tivozanib, brigatinib, afatinib, erlotinib, neratinib, gefitinib, pyrotinib, icotinib, almonertinib, lapatinib, olmutinib, simotinib, osimertinib, vandetanib, dacomitinib, mobocertinib, lazertinib, sorafenib, sunitinib, pazopanib, cabozantinib, axitinib, lenvatinib, ponatinib, regorafenib, dovitinib, foretinib, apatinib, nintedainb, cediranib, catequentinib, anlotinib, pirenoxine, methotrexate, lutein, and a combination thereof. According to some embodiments, the API is axitinib. According to alternative embodiments, the API is loteprednol etabonate.

Examples of the cyclodextrin suitable for use in the present method include, but are not limited to, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and a combination thereof. In preferred embodiments of the present disclosure, the cyclodextrin is β-cyclodextrin.

According to embodiments of the present disclosure, the present method commences by dissolving β-cyclodextrin in an aqueous vehicle thereby producing a β-cyclodextrin solution (step (a) ) . Then, axitinib as the API, is thoroughly mixed with the β-cyclodextrin solution until a suspension is formed (step (b) ) . According to embodiments of the present disclosure, β-cyclodextrin is present in the β-cyclodextrin solution in the amount of about 20%to about 60% (w/v) , such as, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, and 60% (w/v) ; while the API (e.g., axitinib) is present in the suspension in the amount of about 0.1%to 1.6% (w/v) , such as 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 working example, the β-cyclodextrin is present in the amount of about 40% (w/v) in the β-cyclodextrin solution; and the API (e.g., axitinib) is present in the amount of about 0.8% (w/v) in the suspension.

Examples of the β-cyclodextrin suitable for use in the present method include, but are not limited to, hydroxypropyl-β-cyclodextrin (HPβCD) , methyl-β-cyclodextrin (MβCD) , sulfobutylether-β-cyclodextrin (SBE-β-CD) , randomly methylated β-cyclodextrin (RM-β-CD) , carboxymethyl-β-cyclodextrin, and a combination thereof. In one working example, the β-cyclodextrin suitable for use in the present method is HPβCD.

The aqueous vehicle suitable for use in the present disclosure is a water-based carrier that does not comprise any organic solvent. Examples of the aqueous vehicle suitable for use in the present method include, but are not limited to, water, saline, phosphate-buffered saline (PBS) , 2-Amino-2- (hydroxymethyl) propane-1, 3-diol (tris-) buffer, and borate buffered saline. In preferred embodiments, the aqueous vehicle is water, more preferably is sterile water.

Notably in some alternative embodiments, step (a) and (b) can be performed in combination. Specifically, the API and the β-cyclodextrin are mixed and dissolved in the aqueous vehicle simultaneously to form a mixture, and the mixture is stirred until the suspension is formed.

In steps (a) to (b) , several conventional preparation methods can be employed to accelerate the dissolution and suspension, such as with the aid of a magnetic stirrer, to help mixing, dissolution and/or suspension.

Alternatively or optionally, before step (b) , a thickening agent and a stabilizer can be added to the β-cyclodextrin solution. According to some embodiments of the present disclosure, the thickening agent is present in the β-cyclodextrin solution from about 0.1%to 1% (w/v) , such as 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, and 1% (w/v) . In preferred working examples, the thickening agent has a concentration of 0.5% (w/v) in the β-cyclodextrin solution. Additionally, the stabilizer is present in the β-cyclodextrin solution from about 1%to 5% (w/v) , such as 1%, 2%, 3%, 4%and 5% (w/v) . According to one working example, the stabilizer has a concentration of 2% (w/v) in the β-cyclodextrin solution.

Suitable thickening agent and stabilizer can be chosen based on general knowledge in the art and practical needs. Examples of the thickening agent suitable for use in the present method include hydroxypropyl methylcellulose (HPMC) , sodium carboxymethylcellulose, carbomer, polycarbophil, polyethylene glycol (PEG) , hyaluronic acid (HA) , and a combination thereof, but are not limited thereto. According to the present disclosure, the stabilizer of the present method can be purine, a derivative of purine, or a combination thereof. Examples of the derivative of purine that are suitable as the present stabilizers include, but are not limited to, caffeine, theobromine, isoguanine, xanthine, hypoxanthine, and uric acid. According to one preferred embodiment of the present disclosure, HPMC and caffeine are added to the β-cyclodextrin solution and thoroughly mixed before the step of mixing with the API (i.e., axitinib) .

After mixing axitinib with the β-cyclodextrin solution, a suspension is formed (step (b) ) . Note that at this point, axitinib is not completely dissolved. The thus-produced suspension is then placed in a heated bath until axitinib is completely dissolved and the suspension turns into a clear solution (step (c) ) . As the temperature increases, the suspension gradually becomes clear, and even after heating is abolished, the solution remains clear without formation of any precipitation. The duration and temperature of heating can be adjusted according to practical requirements, as long as axitinib is completely dissolved. In some embodiments, the temperature of the heated bath (e.g., an oil bath) is about 100-150 ℃, 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 ℃; preferably, about 120 ℃. In addition, the heating may be continued for about 5 minutes to several hours, such as 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, and 60 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5 hours, preferably about 120 minutes. After the thermal treatment, a clear solution containing axitinib is produced (step (c) ) . The clear solution is then cooled to 20-30 ℃, such as 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 ℃. In working examples, the clear solution is cooled to about 25 ℃, thereby producing the present ophthalmic composition containing axitinib. Note that the clear solution either in the heated or cooled state does not comprise any insoluble precipitates. In other words, the thermal treatment in the present method enables complete dissolution of axitinib in the ophthalmic composition. Even upon cooling, the axitinib remain soluble in the clear solution.

According to the present disclosure, a preservative is additionally or optionally added to the cooled clear solution. According to some embodiments of the present disclosure, the preservative is present in the ophthalmic composition in the 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%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, and 2% (w/v) . Examples of the preservative suitable for use in the present method include, but are not limited to, benzalkonium chloride (BAK) , alkyl parabens, and chlorobutanol. In one working example, the preservative benzalkonium chloride is present in the ophthalmic composition in the amount of 0.005% (w/v) .

Optionally or in addition, the cooled clear solution (i.e., the final product of step (d) ) can be further subjected to a sterilization process well-known in the art, which includes but is not limited to, autoclaving, dry-heat, filtration, ethylene oxide (ETO) , radiation, and chemical sterilization. Appropriate sterilization treatments can be chosen based on practical needs and formulation types. In some working examples, filtration sterilization is applied to the present clear solution by sequentially using filters having a pore size of 0.45 μm and 0.2 μm, respectively.

2.2 Increasing solubility of a poorly soluble API via acid dissolution

Another objective of the present disclosure is directed to a method of increasing the solubility of a poorly soluble API in an ophthalmic composition via acid dissolution. Similar to the method described above in section 2.1, this method is also characterized in not using any organic solvent. Specifically, the method comprises steps of: (a) dissolving cyclodextrin in an acidic solution having a pH value of about 0 to 2 to produce an acidified cyclodextrin solution; (b) mixing and stirring the API with the acidified cyclodextrin solution or the basified cyclodextrin solution of step (a) until a clear solution is formed; and (c) adjusting the pH of the clear solution of step (b) to a value of about 3.0 to 8.0, thereby producing the ophthalmic composition of the API.

Examples of the poorly soluble API dissolvable via the present method using acid dissolution include, but are not limited to, loteprednol etabonate, dexamethasone, prednisolone, prednisolone acetate, fluorometholone, estradiol, ethinylestradiol, mestranol, estriol, norethindrone, norethindrone acetate, norgestrel, ethisterone, 17α-methylprogesterone, progesterone, methyltestosterone, triamcinolone, testosterone, spironolactone, alfaxalone, lanosterol, acrizanib, tivozanib, brigatinib, afatinib, erlotinib, neratinib, gefitinib, pyrotinib, icotinib, almonertinib, lapatinib, olmutinib, simotinib, osimertinib, vandetanib, dacomitinib, mobocertinib, lazertinib, sorafenib, sunitinib, pazopanib, cabozantinib, axitinib, lenvatinib, ponatinib, , regorafenib, dovitinib, foretinib, apatinib, nintedainb, cediranib, catequentinib, anlotinib, pirenoxine, methotrexate, lutein, and a combination thereof. According to some embodiments, the API is axitinib. According to alternative embodiments, the API is loteprednol etabonate.

According to embodiments of the present disclosure, axitinib, which has a water-solubility of about 0.2 μg/mL is mixed with an acidified β-cyclodextrin solution having a pH value between 0 to 2, and the mixture is thoroughly mixed (e.g., via stirring with a magnetic stirrer) until a clear solution is produced (steps (a) to (b) ) . The acidified β-cyclodextrin solution may be prepared by adding acids into a β-cyclodextrin solution (e.g., the one described above in Section 2.1) until the solution reached the desired pH value (e.g., 0 to 2) . Examples of the acids suitable for use in the present disclosure include, but are not limited to, hydrochloric acid (HCl) , sulfuric acid (H₂SO₄) , nitric acid (HNO₃) , phosphoric acid (H₃PO₄) , citric acid (C₆H₈O₇) , and oxalic acid (H₂C₂O₄) solutions. According to some embodiments of the present disclosure, the acids are added to the β-cyclodextrin solution until the solution has an acid concentration above 0.01 M, preferably about 0.01 to 1 M. In one working example, HCl is added to the β-cyclodextrin solution until the solution has a pH value of 1 (i.e., the solution has a concentration of 0.1 M) . Note that in the clear solution thus formed, axitinib is completely dissolved, therefore the clear solution does not comprise any insoluble precipitates.

According to some embodiments of the present disclosure, the β-cyclodextrin is present in the clear solution in an amount of about 20%to about 60% (w/v) , such as, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, and 60% (w/v) , while axitinib is present in the clear solution of step (b) in an amount of about 0.1%to 1.6% (w/v) , such as 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 preferred embodiments of the present disclosure, the β-cyclodextrin has a concentration of about 40% (w/v) in the acidified β-cyclodextrin solution, and axitinib has a concentration of about 0.8%in the clear solution.

Examples of the β-cyclodextrin suitable for use in the present method include, but are not limited to hydroxypropyl-β-cyclodextrin (HPβCD) , methyl-β-cyclodextrin (MβCD) , sulfobutylether-β-cyclodextrin (SBE-β-CD) , randomly methylated β-cyclodextrin (RM-β-CD) , carboxymethyl-β-cyclodextrin, and a combination thereof. In one working example, API is mixed with an acidified HPβCD solution having a pH of about 1.0, and the mixture is thoroughly mixed to give a clear solution.

Notably in some alternative embodiments, step (a) and (b) can be performed in combination. Specifically, the API and the cyclodextrin are mixed and dissolved in the acidic solution simultaneously to form a mixture, and the mixture is stirred until the clear solution is formed.

The pH of the clear solution thus formed is then re-adjusted to about 3.0 to 8.0, for example, pH of 3.0, 4.0, 5.0, 6.0, 7.0, or 8.0; preferably about 6.0, thereby forming the ophthalmic composition of API (e.g., axitinib or other drugs) . To re-adjust the clear solution derived from the acidified cyclodextrin solution, an alkali solution is added thereto. Examples of the alkali solution suitable for use in the present method include, but are not limited to, sodium hydroxide (NaOH) , potassium hydroxide (KOH) , ammonium hydroxide (NH₄OH) solutions, and a combination thereof. In one working example, the alkali solution used in step (c) is NaOH.

According to optional embodiments of the present disclosure, a thickening agent, a stabilizer, a preservative, or a combination thereof is additionally or optionally added to the clear solution produced in step (c) . Preferably, the thickening agent, the stabilizer, and the preservative are all added to the clear solution of step (c) .

Examples of the thickening agent suitable for use in the present method include, but are not limited to, hydroxypropyl methylcellulose (HPMC) , sodium carboxymethylcellulose, carbomer, polycarbophil, polyethylene glycol (PEG) , hyaluronic acid (HA) , and a combination thereof. According to some embodiments of the present disclosure, the thickening agent is present in the clear solution of step (c) in the amount ranging from about 0.1%to 1% (w/v) , such as 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 working example, the thickening agent is HPMC, which has a concentration of 0.5% (w/v) in the clear solution.

Examples of the stabilizer suitable for use in the present method include, but are not limited to, purine, a derivative of purine, or a combination thereof. Examples of the derivative of purine suitable for use in the present method include, but are not limited to, caffeine, theobromine, isoguanine, xanthine, hypoxanthine, uric acid and etc. In some embodiments of the present disclosure, the stabilizer is present in the clear solution in the amount ranging from about 1%to 10% (w/v) , such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, and 10% (w/v) . According to one working example, the stabilizer is caffeine and present in the amount of 2.0% (w/v) in the clear solution.

Examples of the preservative suitable for use in the present method include but are not limited to, benzalkonium chloride (BAK) , alkyl parabens, and chlorobutanol. In some embodiments of the present disclosure, the preservative is present in the clear solution in the 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%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, and 2% (w/v) . In one working example, the preservative benzalkonium chloride has a concentration of 0.005% (w/v) in the clear solution.

Optionally or in addition, the product of step (c) (i.e., the clear solution or the ophthalmic composition of axitinib) can be further subjected to a sterilization process well-known in the art, which includes but is not limited to, autoclaving, dry-heat, filtration, ethylene oxide (ETO) , radiation, and chemical sterilization. Appropriate sterilization can be chosen based on practical needs and formulation types. In some working examples, filtration sterilization is applied to the present clear solution by sequentially using filters having a pore size of 0.45 μm and 0.2 μm, respectively.

By the virtue of the above features set forth in sections 2.1 and 2.2, the present disclosure provides improved methods for enhancing the solubility of poorly water-soluble APIs, thereby increasing their yields in aqueous ophthalmic composition.

EXAMPLE

Example 1 Preparation and characterization of ophthalmic composition of axitinib

1.1 Preparation of ophthalmic composition

1.1.1 Thermal treatment

Formulation for limited production

Hydroxypropyl-β-cyclodextrin (HPβCD) (2 g) , caffeine (100 mg) , and hydroxypropyl methylcellulose (HPMC, 25 mg) were sequentially dissolved in 3.5 mL of distilled water with the aid of stirring (i.e., via using a magnetic stirrer at a stirring speed of 250 rpm) , thereby producing a HPβCD solution. Axitinib (60 mg) was added to the HPβCD solution with continuously stirring until a suspension was formed. The suspension was placed in a heated oil bath at about 120 ℃ for about 10 minutes. Subsequently, it was transferred to a water bath to cool to the ambient temperature, thereby producing a clear, transparent or light-yellow solution. 0.25 mg of benzalkonium chloride (BAK) was added to and completely mixed with the clear solution, which was diluted to about a total volume of 5 mL with distilled water, then filtered through 0.45 μm and 0.2 μm filters, to produce the liquid form of ophthalmic composition of axitinib (herein after, Formulation I-1) .

Formulations for mass production in various batches

To further verify the versatility of the present thermal treatment, various batches of ophthalmic compositions (i.e., Formulation I-2 to I-7) were prepared using different proportions and heating conditions as listed in Table 1 by following the same procedure as set forth above.

Table 1 Different conditions for preparing formulations I-1 to I-7

1.1.2 Acidic dissolution

Hydroxypropyl-β-cyclodextrin (HPβCD) (2 g) and axitinib (60 mg) were mixed in 3 mL of HCl solution (0.1 N) with continuous stirring (at a stirring speed of 200 rpm) until a clear transparent or light-yellow solution was formed. The pH value of the clear solution was then re-adjusted to pH 6 by adding NaOH (1.0 N) . Caffeine (100 mg) , HPMC (25 mg) and 0.25 mg of BAK were subsequently added to the clear solution and stirred until they were completely dissolved. The solution was diluted to about 5 mL with distilled water and then filtered through 0.45 μm and 0.2 μm filters, to produce the liquid form of ophthalmic composition of axitinib.

To further verify the versatility of the present acidic dissolution, various batches of ophthalmic compositions were prepared using different proportions and acidic concentrations as listed in Table 2 by following the same procedure as set forth above.

Table 2 Different conditions for preparing formulations II-1 to II-14

1.2 Characterization of the ophthalmic composition of Example 1.1

Whether the present method may enhance the solubility of axitinib in the ophthalmic composition of Example 1 was evaluated by measuring the amount of axitinib present in the final composition of Example 1.1 via high-performance liquid chromatography (HPLC) . Specifically, if the solubility of axitinib in liquid increased, then higher amount of axitinib would be present in the final composition.

The results confirmed that axitinib was about 8 mg/mL to 12 mg/mL in the ophthalmic compositions of Example 1.1.1 and 1.1.2; which was much higher than that of an axitinib composition prepared by existing method (i.e., about 1.8 mg/mL) .

Further, the stability of the ophthalmic compositions of Example 1.1.1 and 1.1.2 were verified by individually storing at 25 ℃ and 40 ℃ for one month. Results are summarized in Table 3 and Table 4, respectively.

Table 3 Stability results of the ophthalmic composition of Example 1.1.1, in which formulation I-3 was depicted as the representative example.

Table 4 Stability results of the ophthalmic composition of Example 1.1.2, in which formulation II-4 was depicted as the representative example.

The data in Table 3 and Table 4 collectively indicates that the ophthalmic compositions prepared by the present method possess higher stability.

Example 2 Comparison between the characteristic parameters of axitinib compositions prepared by the present and known methods

To the purpose of comparison, a comparative composition was prepared by 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 resulted solution was then spray-and oven-dried to produce the comparative composition. Characteristic parameters including yields, impurity contents, organic solvent residue, and the like are compared between the ophthalmic compositions of Example 1.1 and the comparative composition. Results are summarized in Table 5.

Table 5 Characteristic parameters of the ophthalmic compositions of Example 1.1 and the comparative composition

*The yield was obtained by dividing the volume after filtration by the total batch size.

The data in Table 5 collectively indicates that not only did the ophthalmic compositions prepared by the present method possess higher amount of poorly soluble API, but they were also produced in shorter duration (i.e., < 24 hrs) in single reaction tank with less amounts of impurities and higher production yields without using any organic solvent, as compared with those of the comparative composition prepared by existing method.

Example 3 Preparation of ophthalmic composition of loteprednol etabonate

To examine whether the present method is applicable for other poorly soluble compounds, another ophthalmic composition was prepared by using loteprednol etabonate as the API via thermal treatment.

3.1 Thermal treatment

2 g of HPβCD, caffeine (100 mg) , and HPMC (25 mg) were sequentially dissolved in 3 mL of distilled water with the aid of stirring (i.e., via using a magnetic stirrer at a stirring speed of 500 rpm) , thereby producing a HPβCD solution. Loteprednol etabonate (40 mg) was added to the HPβCD solution with continuously stirring until a suspension was formed. The suspension was placed in a heated oil bath at 120 ℃ for about 5 minutes. Subsequently, it was transferred to a water bath to cool to the ambient temperature, thereby producing a clear, transparent or light-yellow solution. 0.25 mg of BAK was added to and completely mixed with the clear solution, which was diluted to about a total volume of 5 mL with distilled water, then filtered through 0.45 μm and 0.2 μm filters, to produce the liquid form of ophthalmic composition of loteprednol etabonate (5 mL) .

3.2 Characterization of the ophthalmic composition of Example 3.1

The concentration of loteprednol etabonate in the ophthalmic compositions of Example 3.1 was measured to be 8 mg/mL, which was much higher than that of a loteprednol etabonate composition prepared by existing methods (data not shown) .

It will be understood that the above description of embodiments is given by way of example only and that various modifications may be made by those with ordinary skill in the art. The above specification, examples, and data provide a complete description of the structure and use of exemplary embodiments of the invention. Although various embodiments of the invention have been described above with a certain degree of particularity, or with reference to one or more individual embodiments, those with ordinary skill in the art could make numerous alterations to the disclosed embodiments without departing from the spirit or scope of this invention.

Claims

A method for producing an ophthalmic composition of an active pharmaceutical ingredient (API) having a poor water-solubility, the method comprises steps of:

(a) dissolving cyclodextrin in an aqueous vehicle to produce a cyclodextrin solution;

(b) mixing and stirring the API with the cyclodextrin solution of step (a) until a suspension is formed;

(c) subjecting the suspension of step (b) to a heated bath at about 100-150 ℃ until a clear solution is formed; and

(d) cooling the clear solution of step (c) to about 20-30 ℃ to produce the ophthalmic composition of the API,

wherein,

the clear solution in steps (c) or (d) does not comprise any insoluble precipitates; and

the method is characterized in not using any organic solvent.
The method of claim 1, wherein the API is selected from the group consisting of loteprednol etabonate, dexamethasone, prednisolone, prednisolone acetate, fluorometholone, estradiol, ethinylestradiol, mestranol, estriol, norethindrone, norethindrone acetate, norgestrel, ethisterone, 17α-methylprogesterone, progesterone, methyltestosterone, triamcinolone, testosterone, spironolactone, alfaxalone, lanosterol, acrizanib, tivozanib, brigatinib, afatinib, erlotinib, neratinib, gefitinib, pyrotinib, icotinib, almonertinib, lapatinib, olmutinib, simotinib, osimertinib, vandetanib, dacomitinib, mobocertinib, lazertinib, sorafenib, sunitinib, pazopanib, cabozantinib, axitinib, lenvatinib, ponatinib, regorafenib, dovitinib, foretinib, apatinib, nintedainb, cediranib, catequentinib, anlotinib, pirenoxine, methotrexate, lutein, and a combination thereof.
The method of claim 1, wherein the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and a combination thereof.
The method of claim 3, wherein the β-cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin (HPβCD) , methyl-β-cyclodextrin (MβCD) , sulfobutylether-β-cyclodextrin (SBE-β-CD) , randomly methylated β-cyclodextrin (RM-β-CD) , carboxymethyl-β-cyclodextrin, and a combination thereof.
The method of claim 1, wherein the aqueous vehicle is selected from the group consisting of water, saline, phosphate-buffered saline, 2-Amino-2- (hydroxymethyl) propane-1, 3-diol (tris-) buffer, and borate buffered saline.
The method of claim 5, wherein the aqueous vehicle is water.
The method of claim 1, further comprising adding a thickening agent and a stabilizer to the cyclodextrin solution of step (a) prior to step (b) .
The method of claim 7, wherein the thickening agent is selected from the group consisting of hydroxypropyl methylcellulose (HPMC) , sodium carboxymethylcellulose, carbomer, polycarbophil, polyethylene glycol (PEG) , and hyaluronic acid (HA) .
The method of claim 7, wherein the stabilizer is purine, a derivative of purine, or a combination thereof.
The method of claim 9, wherein the derivative of purine is selected from the group consisting of caffeine, theobromine, isoguanine, xanthine, hypoxanthine, and uric acid.
The method of claim 1, further comprising adding a preservative to the clear solution of step (d) .
The method of claim 11, wherein the preservative is selected from the group consisting of benzalkonium chloride (BAK) , alkyl parabens, and chlorobutanol.
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) .
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) .
A method for producing an ophthalmic composition of an active pharmaceutical ingredient (API) having a poor water-solubility, the method comprises steps of:

(a) dissolving cyclodextrin in an acidic solution having a pH value of about 0 to 2.0, to produce an acidified cyclodextrin solution;

(b) mixing and stirring the API with the acidified cyclodextrin solution of step (a) until a clear solution is formed; and

(c) adjusting the pH of the clear solution of step (b) to a value of about 3.0 to 8.0, thereby producing the ophthalmic composition of the API,

wherein,

the clear solution does not comprise any insoluble precipitates, and

the method is characterized in not using any organic solvent.
The method of claim 15, wherein the API is selected from the group consisting of loteprednol etabonate, dexamethasone, prednisolone, prednisolone acetate, fluorometholone, estradiol, ethinylestradiol, mestranol, estriol, norethindrone, norethindrone acetate, norgestrel, ethisterone, 17α-methylprogesterone, progesterone, methyltestosterone, triamcinolone, testosterone, spironolactone, alfaxalone, lanosterol, acrizanib, tivozanib, brigatinib, afatinib, erlotinib, neratinib, gefitinib, pyrotinib, icotinib, almonertinib, lapatinib, olmutinib, simotinib, osimertinib, vandetanib, dacomitinib, mobocertinib, lazertinib, sorafenib, sunitinib, pazopanib, cabozantinib, axitinib, lenvatinib, ponatinib, regorafenib, dovitinib, foretinib, apatinib, nintedainb, cediranib, catequentinib, anlotinib, pirenoxine, methotrexate, lutein, and a combination thereof.
The method of claim 15, wherein the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and a combination thereof.
The method of claim 17, wherein the β-cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin (HPβCD) , methyl-β-cyclodextrin (MβCD) , sulfobutylether-β-cyclodextrin (SBE-β-CD) , randomly methylated β-cyclodextrin (RM-β-CD) , , carboxymethyl-β-cyclodextrin, and a combination thereof.
The method of claim 15, wherein the acidic solution is an HCl solution about 0.01 to 0.1 M.
The method of claim 15, further comprising adding a thickening agent, a stabilizer, a preservative, or a combination thereof to the clear solution of step (c) .
The method of claim 20, wherein the thickening agent is selected from the group consisting of hydroxypropyl methylcellulose (HPMC) , sodium carboxymethylcellulose, carbomer, polycarbophil, polyethylene glycol (PEG) , and hyaluronic acid (HA) .
The method of claim 20, wherein the stabilizer is purine, a derivative of purine, or a combination thereof.
The method of claim 22, wherein the derivative of purine is selected from the group consisting of caffeine, theobromine, isoguanine, xanthine, hypoxanthine, and uric acid.
The method of claim 20, wherein the preservative selected from the group consisting of benzalkonium chloride (BAK) , alkyl parabens, and chlorobutanol.
The method of claim 15, wherein the cyclodextrin is present in the clear solution of step (b) in an amount of about 20%to about 60% (w/v) .
The method of claim 15, wherein the API is present in the clear solution of step (b) in an amount of about 0.1%to about 1.6%(w/v) .