Gel forming ophthalmic compositions containing povidone iodine and steroids

Abstract

The present invention provides a gel-forming ophthalmic composition comprising povidone iodine, a steroid, a polysaccharide polymer gelling agent, water, and suitable excipients for ophthalmic preparations. This composition is not only stable, but also can effectively kill a variety of pathogens, rapidly alleviate associated signs and symptoms, and treat ocular diseases.

Description

[0001] Gel Forming Ophthalmic Compositions Containing Povidone Iodine and Steroids

[0002] Cross-Reference to Related Application

[0003]

[0001] This application claims priority to United States Application No. 63 / 733,438, filed on December 12, 2024, the contents of which are incorporated herein by reference in their entirety.

[0004] Background of the Invention

[0005]

[0002] Infectious keratoconjunctivitis is one of the most prevalent and highly contagious ophthalmic infections across the United States, Asia, and Europe. It is a major cause of eye morbidity, epidemic outbreaks, productivity loss, and significant patient discomfort. The primary causative agents include bacterial (Gram-positive and Gram-negative), fungal, and viral pathogens, with adenoviruses being the leading cause of viral conjunctivitis.

[0006]

[0003] Current treatments for ophthalmic infections face several challenges. For bacterial conjunctivitis, topical antibiotics such as moxifloxacin (Vigamox®) and levofloxacin (Quixin®) are commonly prescribed. However, antibiotic overuse has led to increasing resistance, reducing their effectiveness and prolonging disease duration. For viral conjunctivitis, there are currently no FDA-approved treatments, leaving patients without targeted therapy. Fungal keratitis, a leading cause of blindness among keratitis cases, requires precise laboratory diagnosis, which is often impractical in routine healthcare settings.

[0007]

[0004] Given these challenges, most cases are presumptively treated as bacterial conjunctivitis with antibiotics, which are ineffective against viral and fungal infections. This mismanagement underscores the urgent need for a broad-spectrum ophthalmic treatment capable of addressing multiple infectious etiologies.

[0008]

[0005] Corticosteroids are commonly used to reduce inflammation in ocular infections; however, they can increase susceptibility to bacterial, viral, and fungal pathogens. Improper use can exacerbate infections, necessitating cautious administration under medical supervision. Newer generations of steroid such as difluprednate and loteprednol, have improved efficacy while minimizing adverse effects, particularly intraocular pressure elevation.

[0009]

[0006] Prior research has explored the combination of povidone-iodine (PVP-I) with conventional steroids. For example, US 7,767,217 B2 discloses a composition including PVP-I and dexamethasone, while WO 2013 / 040347 describes a formulation with PVP-I and a steroid such as dexamethasone. Additionally, US 2012 / 0027716A1 discusses a PVP-I and dexamethasone suspension, and US 2013 / 0089510A1 presents a treatment method involving PVP-I and dexamethasone for otic applications. A 0.6% PVP-I and 0.1% dexamethasone ophthalmic suspension advanced into clinical trials, demonstrating efficacy in adenoviral conjunctivitis. However, it ultimately failed in a Phase 3 study for bacterial conjunctivitis.

[0010]

[0007] Moreover, previous formulations lacked sustained-release properties, leading to reduced bioavailability due to tear dilution and nasolacrimal drainage. Conventional liquid formulations are rapidly eliminated from the ocular surface, necessitating frequent dosing and diminishing patient compliance.

[0011]

[0008] The present invention introduces a novel gel-forming ophthalmic composition comprising povidone-iodine (PVP-I), a next-generation steroid, and an in-situ gel-forming system that unexpectedly overcomes the limitations discussed above. PVP-I is a well-established broadspectrum antiseptic with over 50 years of clinical use, demonstrating efficacy against bacteria, viruses, and fungi with no documented resistance. The next-generation steroids utilized in this invention, particularly difluprednate and / or loteprednol, exhibit potent anti-inflammatory activity, and a lower risk of intraocular pressure elevation. Their increased potency allows for lower concentrations to achieve therapeutic effects comparable to traditional steroids while minimizing glucocorticoid-associated side effects, particularly in pediatric patients. The in-situ gel-forming system, incorporating polysaccharide polymer such as deacetylated gellan gum (DGG), enables sustained drug release, enhancing ocular surface retention, bioavailability, and patient adherence.

[0012]

[0009] Key innovations of the present invention include:

[0013]

[0010] Enhanced Chemical Stability: Difluprednate and loteprednol were unexpectedly found to be chemically compatible with iodine, allowing for stable formulations, unlike steroids in general.

[0014]

[0011] Sustained Drug Release: The in-situ gel system prolongs drug retention on the ocular surface, enhancing therapeutic efficacy.

[0015]

[0012] Improved Bioavailability: PVP-I was found to significantly enhance difluprednate’ s solubility, increasing corneal penetration and therapeutic efficiency.

[0013] Optimized Release Kinetics: The formulation of the present invention is designed to provide an initial rapid release of available iodine, followed by extended release, ensuring complete eradication of infectious pathogens.

[0016]

[0014] Synergistic Effects: The combination of PVP-I and next-generation steroids (e.g., difluprednate and / or loteprednol) delivers broad-spectrum antimicrobial activity alongside rapid symptom relief for keratoconjunctivitis.

[0017]

[0015] The present invention offers a novel and effective approach to treat infectious keratoconjunctivitis by overcoming the limitations of existing therapies while improving efficacy, safety, and patient compliance.

[0018] Summary of the Invention

[0019]

[0016] The present invention provides a novel gel-forming ophthalmic composition comprising povidone iodine, a steroid (e.g., difluprednate or loteprednol), a gelling agent, water, and excipient(s). The formulation forms an in-situ gel upon ocular instillation, offering a variety of benefits including, but not limited to, broad-spectrum antimicrobial activity; sustained drug release and prolonged retention; increased solubility and bioavailability (e.g., of difluprednate); and potential applications in treating keratitis, conjunctivitis, and / or blepharitis.

[0020]

[0017] The present invention addresses the limitations of existing ophthalmic treatments by introducing a stable, broad-spectrum, and sustained-release formulation for infectious and inflammatory eye diseases.

[0021] Povidone Iodine as a Broad-Spectrum Antiseptic

[0022]

[0018] Povidone iodine (PVP-I) is a broad-spectrum antiseptic effective against bacteria, viruses, and fungi. With over 50 years of clinical use, it has demonstrated a strong safety profile and no documented drug resistance. PVP-I is widely used in preoperative and postoperative ocular surgery preparations and is an established treatment for conjunctivitis, keratitis, and endophthalmitis. See, e.g., Soleimani et al., Oman J Ophthalmol., 2023; 16:69-74.

[0023]

[0019] Dilute PVP-I solutions have been proven effective against numerous pathogens, including viruses, bacteria, fungi, and parasites. See, e.g., Berkelman et al., J Clin Microbiol. 1982; 15:635-639; and Pelletier et al., J Cataract Refract Surg., 2011; 37(4):763-766. Studies have confirmed its efficacy at a 5% concentration (see, e.g., Speaker MG et al., Ophthalmology, 1991; 98: 1769-7; Apt L. et al., Ophthamology, 1989, 96: 289-292) and at 1.25% for pre- and post-ocular surgery (see, e.g., Apt L. et al., Am J Ophthalmol, 1995; 119: 701-705; Isenberg SJ et al., Am. J. Ophthalmol., 1997; 124:31-35). Additionally, PVP-I has shown effectiveness against active infections at a 1.25% concentration. See, e.g., Isenberg SJ et al., Am J Ophthalmol, 1994; 118:701-706; Isenberg SJ \. ., NEnglJMed, 1995; 332:562-566; Isenberg SJ et al., Am. J. Ophthalmol, 2017; 176:244-253; and Isenberg SJ et al., Am J Ophthalmol., 2002; 134:681-688.

[0024]

[0020] In some embodiments of the present invention, povidone iodine is contained in the gelforming ophthalmic composition as an active antiseptic agent, e.g., at a concentration of about 0.5% (w / w) to about 2.00% (w / w).

[0025] Incorporation of New Generation Steroids

[0026]

[0021] The gel-forming ophthalmic compositions include at least one of the new generation steroids such as difluprednate, loteprednol, or their respective salts and esters, either individually or in combination. These steroids may be incorporated at concentrations ranging from 0.01% (w / w) to 1.00% (w / w).

[0027]

[0022] Compared to conventional steroids, difluprednate and loteprednol are prodrugs containing ester bonds that hydrolyze in the body to form active or inactive metabolites. These prodrugs exhibit higher anti-inflammatory activity and improved safety when applied locally, thereby enhancing drug stability, reducing side effects, and improving absorption and distribution.

[0028]

[0023] Difluprednate, a highly potent steroid of the structure shown in Fig. 1, is a difluorinated derivative of prednisolone with high biological activity (CAS# 23674-86-4, 6a, 9a di -fluoro prednisolone 17-butyrate 21 -acetate; DFB A). Difluprednate is practically insoluble in water. Durezol® [0.05% (w / w) difluprednate emulsion] was approved by the US FDA in 2018 for the treatment of postoperative inflammation and eye pain.

[0029]

[0024] The 0.05% difluprednate emulsion has demonstrated superior anti-inflammatory effects compared to a 0.1% betamethasone acetate emulsion, 0.1% prednisolone suspension, dexamethasone, and other corticosteroids. Its anti-inflammatory efficacy is four times greater than that of 0.3% prednisolone valerate and 3,200 times greater than that of 0.5% prednisolone pentanoate. Due to its increased potency, lower concentrations of difluprednate may achieve therapeutic effects comparable to those of traditional steroids, minimizing glucocorticoid- associated side effects, particularly in pediatric patients.

[0030]

[0025] As a prodrug, difluprednate degrades in water and thus poses potential risks to its efficacy and safety - which is an ongoing challenge in ophthalmic formulations. The in vitro degradation pathway is illustrated in Fig. 2. (See also, Durezol® NDA#22212, Summary Basis of Approval, Pharmacology Reviews.)

[0031]

[0026] DFB is 21 -deacetylated difluoroprednisolone butyrate. Instilled difluprednate (DFB A) is rapidly metabolized through deacetylation at the 21 -position, converting into the active metabolite DFB under both acidic and basic conditions.

[0032]

[0027] Loteprednol, formulated as the ester loteprednol etabonate (structure shown in Fig. 3), is a topical corticosteroid indicated for treating ocular inflammation. It is commercially available under the brand names Lotemax® and Loterex®, marketed by Bausch and Lomb. A recently approved loteprednol-containing product is Inveltys®.

[0033]

[0028] Loteprednol etabonate (LE) is readily and extensively metabolized to two inactive metabolites, PJ-90 (Al-cortienic acid) and PJ-91 (Al-cortienic acid etabonate) after it has exerted its therapeutic effects, which helps to avoid adverse effects. See M. Coffey, Clinical Ophthalmology, 2013, 7:299-312). Loteprednol’s metabolism pathway for is shown in Fig. 4.

[0034]

[0029] Due to the acid- and base-labile nature of both difluprednate and loteprednol, these prodrug steroids contain ester bonds that are highly susceptible to hydrolysis under acidic and basic conditions. As a result, they were traditionally considered incompatible with povidone iodine solutions. The pH of a 1% povidone iodine solution ranges between 1.5 and 3.5, exhibiting strong acidity which may lead to rapid degradation of these prodrugs and compromise its shelflife stability.

[0035]

[0030] Surprisingly, the present invention has achieved unexpectedly stable formulations that combine povidone iodine with a next-generation steroid (e.g., difluprednate or loteprednol) while maintaining stability. An unexpected discovery revealed that the addition of deacetylated gellan gum (DGG), a polysaccharide polymer, significantly inhibited the degradation of difluprednate in combination with povidone iodine, thereby enhancing overall composition stability. DGG, a microbial exopolysaccharide commercially known as Gelrite®, is an anionic linear polysaccharide composed of repeating four-sugar units. The inventors conducted stability experiments to compare the 7-day stability at 25 °C of formulations containing PVP-I and difluprednate with and without DGG. The results demonstrated that a simple combination of PVP-I solution and difluprednate at pH 2.2 increased the total impurity of difluprednate from 0.08% to 2.43% within seven days. However, adding DGG to the combination significantly reduced degradation, limiting total impurity to 1.73%, a substantial improvement. This finding suggests that DGG plays a crucial role in inhibiting difluprednate degradation. Further research led to the development of stable formulations containing PVP-I, difluprednate, and DGG, achieving over 90% retention of both PVP-I and difluprednate with minimal impurity levels after one month at 2-8 °C and 25 °C.

[0036]

[0031] For instance, examples of the polysaccharide polymer described in this invention may include DGG, xanthan gum, sodium alginate, carrageenan, or any combination thereof.

[0037]

[0032] The polysaccharide polymer can form an in-situ gel, prolonging drug retention on the corneal surface and enhancing bioavailability. Ideally, an in-situ gel system remains a low- viscosity liquid during storage for easy administration as eye drops. Upon instillation into the conjunctival sac, the solution transitions into a gel, adhering to the eye surface. The in-situ gel should have sufficient viscosity to withstand ocular shear forces, prolong retention time, and facilitate sustained drug release. When a solution containing the drug API and DGG is instilled into the eye, DGG interacts with tear fluid electrolytes (such as Na+, K+, and Ca2+), thereby forming an in-situ gel.

[0038]

[0033] One aspect of the present invention provides a gel-forming ophthalmic composition, including povidone iodine (PVP-I) as an active agent, a steroid, a gelling agent, and at least one excipient, wherein the composition forms an in-situ gel at physiological temperature upon application of the composition to an eye of a subject, and wherein the steroid comprises difluprednate, loteprednol, a salt thereof, an ester thereof, or any combination thereof.

[0039]

[0034] In some embodiments, PVP-I is contained in the composition at a concentration ranging from about 0.5% (w / w) to about 2.00% (w / w). Preferably, PVP-I may be contained in the composition at a concentration ranging from about 0.5% (w / w) to about 1.50% (w / w).

[0040]

[0035] In some embodiments, the steroid is contained in the composition at a concentration ranging from about 0.01% (w / w) to about 1.00% (w / w) or from about 0.01% (w / w) to about 0.1% (w / w).

[0036] In some embodiments, the steroid includes difluprednate. In some other embodiments, the steroid includes loteprednol.

[0041]

[0037] In some embodiments, the gelling agent is contained in the composition at a concentration ranging from about 0.1% (w / w) to about 5.0% (w / w), or from about 0.1% (w / w) and 1.0% (w / w).

[0042]

[0038] In some embodiments, the gelling agent includes a polysaccharide polymer. Examples of the polysaccharide polymer include, but are not limited to, deacetylated gellan gum (DGG), xanthan gum, sodium alginate, carrageenan, and any combination thereof. For instance, the polysaccharide polymer may be deacetylated gellan gum.

[0043]

[0039] In some embodiments, the excipient includes one or more surfactants, thickening agents, osmotic pressure regulators, pH regulators, or preservatives.

[0044]

[0040] Examples of the thickening agents include, but are not limited to, HPMC, CMC-Na, sodium hyaluronate, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, anhydrous glucose, and any combination thereof.

[0045]

[0041] In some embodiments, the thickening agent is HPMC, sodium hyaluronate, CMC-Na, or any combination thereof

[0046]

[0042] In some embodiments, the concentration of the thickening agent ranges from about 0.1% (w / w) to about 5.0% (w / w), or preferably from about 0.1% (w / w) to about 1.00% (w / w).

[0047]

[0043] Examples of the osmotic pressure regulator include, but are not limited to, mannitol, glucose, sorbitol, glycerol, polyethylene glycol, propylene glycol, and any combination thereof. The concentration of the osmotic pressure regulator may range from about 0.01% (w / w) to about 10.0% (w / w).

[0048]

[0044] Examples of the pH regulator include, but are not limited to, tromethamine, sodium hydroxide, hydrochloric acid, and any combination thereof. The concentration of the pH regulator may range from about 0.01% (w / w) to about 5.0% (w / w).

[0049]

[0045] In some embodiments, the pH of the composition ranges from about 4.0 to about 7.0, or from about 4.0 to about 6.0.

[0050]

[0046] Examples of the preservatives include, but are not limited to, sorbic acid, benzalkonium chloride, benzalkonium bromide, methylparaben, ethylparaben, EDTA-2Na, and any combination thereof. The concentration of the preservatives may range from about 0.01% (w / w) to about 1.00% (w / w).

[0051]

[0047] In some embodiments, the composition is in the form of a solution, suspension, or emulsion. The composition can be with or without a sustained release carrier.

[0052]

[0048] In some embodiments, the composition is used as eye drops, or filled into rinse bottles for eye irrigation, or used with a device for ocular disease treatment.

[0053]

[0049] In some embodiment, the composition may be packaged in an eye drop bottle made from suitable material(s) such as LDPE, PP, HDPE, PET, and any combination thereof.

[0054]

[0050] In some embodiments, the gel-forming ophthalmic composition can be stored long-term at 2-8 °C or at 25 °C.

[0055]

[0051] In some embodiments, the composition is packaged in a single-dose or multi-dose formulation or container.

[0056]

[0052] In some embodiments, the composition is used for treating at least one ocular disease. For instance, the ocular disease may include infectious ocular diseases, and / or ocular inflammations. In some embodiments, the composition is used for treating acute conjunctivitis, corneal injury, ulcerative infectious keratitis, epithelial keratitis, stromal keratitis, herpes-related keratitis, fungal keratitis, and / or blepharitis.

[0057]

[0053] In some embodiments, the composition may also be used for nasal, otic, and vaginal applications.

[0058]

[0054] In some embodiments, the infectious eye diseases targeted by this invention include keratitis, conjunctivitis, and blepharitis, encompassing bacterial conjunctivitis, viral conjunctivitis, viral keratitis, fungal keratitis, acanthamoeba keratitis, and mycoplasma keratoconj uncti viti s .

[0059]

[0055] In another aspect, the present invention provides a method for treating or alleviating symptoms of an ocular disorder in a subject in need thereof, and the method includes administering to the subject a therapeutically effective amount of a gel-forming ophthalmic composition described herein.

[0060]

[0056] In some embodiment, the ocular disorder is an infectious ocular disease or ocular inflammation.

[0061]

[0057] In some embodiments, the ocular disorder is acute conjunctivitis, corneal injury, ulcerative infectious keratitis, epithelial keratitis, stromal keratitis, herpes-related keratitis, fungal keratitis, or blepharitis.

[0062]

[0058] It should also be noted that, conventionally, the poor aqueous solubility of steroids significantly hinders their ability to penetrate the cornea effectively, resulting in reduced bioavailability in the eye. While some nanotechnologies have been developed to enhance steroid permeability, they remain complex and challenging while consistently failing to provide the desired stability. Surprisingly, it was discovered that PVP-I significantly enhances the solubility of difluprednate in water with increased solubility over a few months without altering its quality. This solubilizing effect appears to be specific, as PVP-I does not exhibit the same enhancement for other steroids such as dexamethasone, loteprednol, or fluticasone propionate. This unexpected discovery significantly improves the bioavailability and clinical efficacy of difluprednate. Franz cell release experiments demonstrated that the release rate of 0.01% difluprednate in Formulation F2 (containing 2.0% PVP-I, 0.01% difluprednate, and 0.15% DGG) was comparable to that of 0.05% Durezol® emulsion, and the release rate of 0.03% difluprednate in Formulation Fl (containing 2.0% PVP-I, 0.03% difluprednate, and 0.15% DGG) exceeded that of 0.05% Durezol®, indicating the significant solubilizing effect of PVP-I on difluprednate. This increased solubility enhances bioavailability, allowing for lower difluprednate concentrations while maintaining efficacy and improving safety.

[0063]

[0059] The inventors also unexpectedly found that incorporating difluprednate into PVP-I formulations increased the release rate of PVP-I. Example 13 (as further described hereinafter) demonstrated that Formulations Fl to F4, containing 0.05% difluprednate, 0.28% DGG, and varying concentrations of PVP-I (1.0%, 1.25%, 1.5%, and 2.0%), exhibited a faster release rate of PVP-I compared to Formulations F5 to F8, which contained PVP-I at the same concentrations and DGG, but not difluprednate.

[0064]

[0060] Another surprising discovery was that the combination of PVP-I and DGG significantly reduced the particle size distribution of loteprednol in aqueous solution. This effect, however, was not universal, as the same combination did not reduce the particle size of fluticasone propionate. Since smaller particle sizes enhance bioavailability and efficacy, this finding suggests that PVP-I and DGG specifically optimize loteprednol ’s bioavailability without altering its solubility.

[0061] In some embodiments, the gel-forming ophthalmic composition according to this invention can be formulated as a suspension. In such formulations, preventing poorly water-soluble components from aggregating or settling is crucial for maintaining long-term stability. Aggregation and sedimentation can lead to inconsistent dosing, reduced efficacy, and increased ocular irritation due to large particles. Traditional ophthalmic suspensions use stabilizers, often surfactants, which can be toxic to corneal cells and cause irritation. This invention unexpectedly demonstrated that gel-forming formulations inherently prevented aggregation and sedimentation, eliminating the need for surfactants (e.g., polyoxyl castor oil, polyoxyl hydrogenated castor oil, and polysorbate 80), while enhancing drug safety.

[0065]

[0062] As demonstrated in Example 19 (as further described in this documents), PVP-I significantly increased difluprednate concentration in corneal and conjunctival tissues, even at lower concentrations than 0.05% Durezol®. These findings indicate that the novel delivery system optimizes drug dissolution kinetics, improving bioavailability in target tissues compared to commercial preparations.

[0066]

[0063] The terminology used herein is for the purpose of describing particular cases only and is not intended to be limiting. As used herein, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, to the extent that the terms “including,” “includes,” “having,” “has,” “with,” or variants thereof are used in either the detailed description and / or the claims, such terms are intended to be inclusive in a manner similar to the term “comprising.”

[0067]

[0064] As used herein, a “dilute” PVP-I solution or formulation contains PVP-I at the concentration not greater than 5%, measured either by weight / weight (w / w) or by weight / volume (w / v).

[0068]

[0065] As used herein, the term “available iodine” or “available iodine content” refers to the free iodine that can be released from PVP-I complex to exert germicidal action.

[0069]

[0066] As used herein, the term “container” refers to any receptacle or enclosure for holding a liquid product used in storage, packaging, and shipping. It can be in the form of a bottle, a can, ajar, a box, a barrel, or a bag.

[0070]

[0067] As used herein, the term “or” may also imply “and,” unless such an interpretation results in a contradiction or infeasibility.

[0068] As used herein, the terms “bactericide” or “antiseptic” refer to therapeutic agents that eliminate or mitigate infection symptoms.

[0071]

[0069] As used herein, the term “polysaccharide” denotes polymeric sugar molecules composed of long chains of monosaccharide units linked by glycosidic bonds, which hydrolyze into constituent monosaccharides or oligosaccharides. Polysaccharides can be natural or synthetic and may have linear or highly branched structures.

[0072]

[0070] As used herein, the terms “treating,” “treatment,” “therapeutic,” or “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and / or therapy.

[0073]

[0071] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art to which this disclosure belongs. It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary. Other terms are defined herein within the description of the various aspects of the invention.

[0074] Brief Descriptions of the Drawings

[0075]

[0072] Fig. 1 illustrates the molecular structure of difluprednate.

[0076]

[0073] Fig. 2 illustrates the degradation pathway for difluprednate.

[0077]

[0074] Fig. 3 illustrates the molecular structure of loteprednol etabonate.

[0078]

[0075] Fig. 4 illustrates loteprednol’s metabolism pathway.

[0079]

[0076] Fig. 5 illustrates viscosity results of DGG formulation in Example 1.

[0080]

[0077] Fig. 6 illustrates viscosity results of xanthan gum formulation in Example 1.

[0081]

[0078] Fig. 7 illustrates viscosity results of carrageenan formulation in Example 1.

[0082]

[0079] Fig. 8 illustrates viscosity results of sodium alginate in Example 1.

[0083]

[0080] Fig. 9 illustrates change of difluprednate concentration tested in Example 3.

[0084]

[0081] Fig. 10 illustrates total impurity results of Example 5 at pH 10.

[0085]

[0082] Fig. 11 illustrates DFB results of Example 6 at pH 2.2.

[0086]

[0083] Fig. 12 illustrates the total impurity results of Example 6 at pH 2.2.

[0084] Fig. 13 illustrates the results of sedimentation ratio in top according to Example 10.

[0087]

[0085] Fig. 14 illustrates the results of sedimentation ratio in middle according to Example 10.

[0088]

[0086] Fig. 15 illustrates the results of sedimentation ratio in bottom according to Example 10.

[0089]

[0087] Fig. 16 illustrates the results of redispersion according to Example 10.

[0090]

[0088] Fig. 17 illustrates the results of in vitro release test for difluprednate in Example 12.

[0091]

[0089] Fig. 18 illustrates pictures of solutions according to Example 13, with different concentrations of povidone iodine.

[0092]

[0090] Fig. 19 illustrates the release results of Example 13 -Fl to Example 13-F4 compared with Example 13-F9.

[0093]

[0091] Fig. 20 illustrates the release results of Example 13 -Fl to Example 13-F4 compared with Example 13-F10.

[0094]

[0092] Fig. 21 illustrates the release results comparison of Example 13-F1 to Example 13-F8.

[0095]

[0093] Fig. 22 illustrates the release results comparison of Example 13-F2 to Example 13-F11 and F12.

[0096]

[0094] Fig. 23 illustrates viscosity results of 25 °C and 34 °C+AT in 10 rpm in Example 14.

[0097]

[0095] Fig. 24 illustrates viscosity results of 25 °C and 34 °C+AT in 20 rpm in Example 14.

[0098]

[0096] Fig. 25 illustrates viscosity results of 25 °C and 34 °C+AT in 50 rpm in Example 14.

[0099]

[0097] Fig. 26 illustrates the antibacterial effect of 0.6% (w / w) povidone iodine in situ gel formulation against pseudomonas aeruginosa in Example 15.

[0100]

[0098] Fig. 27 illustrates the antibacterial effect of 0.6% (w / w) povidone iodine in situ gel formulation against MRS A in Example 15.

[0101]

[0099] Fig. 28 illustrates the antifungal effect of 0.6% (w / w) povidone-iodine in situ gel formulation against Candida parapsilosis in Example 15.

[0102]

[0100] Fig. 29 illustrates the antiviral effect of 0.6% (w / w) povidone-iodine in situ gel formulation against adenovirus in Example 15.

[0103]

[0101] Fig. 30 shows PVP-I concentration in various tissues in the 30-minute tests in Example 18.

[0104]

[0102] Fig. 31 illustrates drug AUC in various Tissues / Fuild in Example 18. Detailed Description of the Invention

[0105]

[0103] Reference will now be made in detail to the preferred embodiments of the invention, examples of which are further illustrated. While the invention will be described in conjunction with the preferred embodiments, it will be understood that they are not intended to limit the invention to these embodiments. To the contrary, the invention is intended to cover alternatives, modifications and equivalents, which may be included within the spirit and scope of the invention as defined by the claims. Furthermore, in the detailed description of the present invention, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be obvious to one of ordinary skill in the art that the present invention may be practiced without these specific details. In other instances, well known methods, procedures, components, and other features have not been described in detail as not to unnecessarily obscure aspects of the present invention.

[0106]

[0104] Generally speaking, the present invention provides gel-forming ophthalmic compositions each including povidone iodine, a new-generation steroid such as difluprednate or loteprednol, a gelling agent, water, and other conventional excipient(s) used in ophthalmic preparations. The gel-forming composition transitions into an in-situ gel upon application to the eye, making it particularly suitable for treating ocular diseases.

[0107]

[0105] Povidone iodine is selected as the broad-spectrum antiseptic in this invention. Its preferred concentration range is from about 0.5% to about 2.00% (w / w).

[0108]

[0106] The new-generation steroids used in this invention may include difluprednate, loteprednol, or their salts and esters, either individually or in combination. The suitable concentration range for these steroids is from about 0.01% w / w to about 1.00% w / w, preferably from about 0.01% w / w to about 0.1% w / w.

[0109]

[0107] Examples of the gelling agent used in this invention may include polysaccharide polymers, thickeners, or a combination thereof. Examples of polysaccharide polymers include, but are not limited to, deacetylated gellan gum, xanthan gum, sodium alginate, and carrageenan, while thickeners include HPMC, CMC -Na, sodium hyaluronate, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, anhydrous glucose, and any combination thereof. The suitable concentration range for the gelling agent is from about 0.1% w / w to about 5.0% w / w, preferably from about 0.1% w / w to about 1% w / w. Deacetylated gellan gum (DGG) is particularly preferred due to its ability to form an in-situ gel in the eye at a concentration ranging from about 0.1% w / w to about 1% w / w.

[0110]

[0108] The in-situ gel delivery system extends the retention time of the drug on the ocular surface, thereby enhancing drug bioavailability. Ideally, the system remains a low-viscosity liquid during storage for ease of administration as eye drops. Upon instillation into the conjunctival sac, the solution transitions into an in-situ gel that adheres to the eye surface. The viscosity of the in-situ gel must be sufficient to resist ocular shear forces, prolong retention time, and support sustained drug release. This prolonged absorption improves bioavailability, reduces systemic absorption, decreases dosing frequency, and enhances patient compliance.

[0111]

[0109] DGG, a microbial exopolysaccharide commercially known as Gelrite®, is a key in-situ gel-forming polymer with proven safety in humans. DGG is an anionic linear polysaccharide composed of repeating tetrasaccharide units. When a DGG solution containing the drug is instilled into the eye, DGG interacts with tear fluid electrolytes (e.g., Na+, K+, Ca2+, etc.) to form an in-situ gel, enabling a sol-to-gel phase transition.

[0112] [HO] The gel-forming ophthalmic compositions may also contain at least an osmotic pressure regulator, examples of which may include but are not limited to mannitol, glucose, sorbitol, glycerin, polyethylene glycol, propylene glycol, and any combination thereof, e.g., at a concentration ranging from about 0.01% w / w to about 10.0% w / w. The resulting osmotic pressure may be between 270 and 320 mOsmol / kg.

[0113] [Hl] The gel-forming ophthalmic compositions may also include at least a pH adjuster, such as tromethamine, sodium hydroxide, hydrochloric acid, or any combination thereof, e.g., at a concentration ranging from about 0.01% w / w to about 5.0% w / w. The resulting pH may range from about 4.0 to about 7.0, preferably from 4.0 to about 6.0.

[0114]

[0112] The gel-forming ophthalmic compositions may further include at least a preservative such as sorbic acid, benzalkonium chloride, benzalkonium bromide, methylparaben, ethylparaben, EDTA-2Na, or any combination thereof, e.g., at a concentration ranging from about 0.01% w / w to about 5.0% w / w.

[0115]

[0113] The compositions may be formulated as a solution, suspension, or emulsion, with or without a sustained-release carrier.

[0114] The gel-forming ophthalmic compositions may be used as an eye drop, for ocular surface irrigation in rinsing bottles, or in combination with devices for ocular disease treatment.

[0116]

[0115] These compositions form an in-situ gel upon application to the eye and are intended for the treatment of infectious and inflammatory ocular diseases. The compositions may also be used for nasal and vaginal applications.

[0117]

[0116] The gel-forming ophthalmic compositions may be packaged as single-dose or multi -dose formulations. For instance, the compositions may be packaged in an eye drop bottle made from LDPE, PP, HDPE, PET, combination thereof, or similar materials.

[0118]

[0117] The gel-forming ophthalmic compositions can be stored long-term at 2-8°C or 25°C.

[0119]

[0118] Examples of the infectious eye diseases treatable with this invention may include, but are not limited to, keratitis, conjunctivitis, and blepharitis, encompassing bacterial conjunctivitis, viral conjunctivitis, viral keratitis, fungal keratitis, acanthamoeba keratitis, and mycoplasma keratoconj uncti viti s .

[0120]

[0119] The present invention is further exemplified through specific examples, which serve to illustrate the invention but should not be construed as limiting its scope. Unless otherwise specified, all percentages, ratios, proportions, or fractions are expressed by weight. Additionally, all professional and scientific terms used herein are intended to be understood as defined by those skilled in the art, unless explicitly stated otherwise. Methods and materials that are similar or equivalent to those described in this invention may also be utilized. The preferred embodiments and materials provided are exemplary and not restrictive.

[0121] Example 1: Screening In-Situ Gelling Agents

[0122]

[0120] In this example, various polysaccharide polymers were screened by evaluating their gel phase transition ability. The base formulation and viscosity measurement results are presented in Tables 1-4 below and Figs. 5-8. More specifically, Figs. 5 illustrates viscosity results of DGG formulation. Fig. 6 illustrates viscosity results of xanthan gum formulation. Fig. 7 illustrates viscosity results of carrageenan formulation. Fig. 8 illustrates viscosity results of sodium alginate.

[0123]

[0121] Preparation of Gel Solution: To prepare the gel solution, a precise amount of sodium chloride was weighed and slowly added to 85g of purified water. The mixture was stirred until the sodium chloride was fully dissolved; then, the corresponding gel matrix was gradually incorporated while continuously stirring. The solution was placed in a 90°C water bath and stirred for one hour. Afterwards, the mixture was cooled to room temperature and purified water was added to reach a final volume of 100g.

[0124]

[0122] Viscosity Testing Method: (1) 20 mL of the sample solution was added to a sample bottle and allowed to stand for 5 minutes. The initial viscosity was measured at 25°C using a rotational viscometer. (2) At 34°C (with the addition of 40:7 artificial tear solution), 20 mL of the sample solution was added to the sample bottle and allowed to stand for 5 minutes. The viscosity value was then measured.

[0125] Table 1 : DGG formulations and viscosity results

[0126] Table 2: Xanthan gum formulations and viscosity results

[0127] Table 3: Carrageenan formulations and viscosity results

[0128] Table 4: Sodium alginate formulations and viscosity results

[0129]

[0123] Based on the data presented in Tables 1-4, a comparison of the viscosity values at 25°C and 34°C, both before and after the addition of artificial tear fluid, has indicated that deacetylated gellan gum exhibited the best in-situ gel-forming properties, with the greatest change in viscosity. Following the addition of artificial tear fluid, the viscosity of the deacetylated gellan gum formulations increased significantly. Even a small amount of deacetylated gellan gum produced a substantial increase in viscosity. In contrast, xanthan gum, carrageenan, and sodium alginate also displayed in-situ gel-forming properties, with viscosity values increasing after the addition of artificial tear fluid. However, the viscosity change was not as pronounced as that of deacetylated gellan gum. Therefore, deacetylated gellan gum is preferred as the in-situ gel-forming matrix.

[0130] Example 2: Study on the Chemical Compatibility of Povidone-Iodine, Difluprednate, and Deacetylated Gellan Gum (DGG)

[0131]

[0124] Sample Preparation: The corresponding amounts of povidone-iodine and DGG were accurately weighed for Formulations Fl to F3, as described in this example. Each of the mixtures was slowly and evenly added to 85 g of purified water and stirred until fully dissolved. Next, the corresponding amount of difluprednate was added while continuously stirring. The pH was adjusted to 5.0-6.0 using a 10% tromethamine solution. Then water was added to bring the final volume to 100g. Formulations Fl to F3 and test results are detailed in Tables 5-7.

[0132] Table 5: Formulation Compositions of Example 2-F1-F3

[0133]

[0125] After completing the sample preparation, the samples were stored at 2-8°C and 25°C. The assay of povidone-iodine and difluprednate were measured on day 0 and after 1 month.

[0134] Table 6: Results and changes of povidone iodine assay in Example 2-F1-F3

[0135] Table 7: Results and changes of difluprednate assay in Example 2-F3

[0136]

[0126] Based on the data above, the combination of povidone-iodine, difluprednate, and deacetylated gellan gum (DGG) exhibited good chemical compatibility. It was observed that the combination formulation of PVP-I, difluprednate, and DGG reduced the degradation of PVP-I after one month of storage at both 2-8°C and 25°C.

[0137] Example 3: Investigation of the Solubilization and Sustained Solubilization Effects of Povidone-iodine on Difluprednate

[0138]

[0127] Sample Preparation: The corresponding amounts of povidone-iodine for Formulations Fl to F12 were accurately weighed, as described in this example. Each of the mixtures was slowly and evenly added to 85g of purified water and stirred until completely dissolved. Next, the corresponding amount of difluprednate was added while continuously stirring. The pH was adjusted to 5.0-6.0 using a 10% tromethamine solution. Then water was added to bring the final volume to 100g. Formulations are detailed in Table 8 below.

[0139] Table 8: Formulation Compositions of Example 3-F1-F12

[0140]

[0128] After completing the sample preparation, the samples were stored at 2-8°C. The assay of difluprednate was measured on day 0, 1 -month, 2-month, and 3 -month. For the measurement, a certain amount of the top level of each sample was taken and filtered with 0.22 pm membrane filter. Then the difluprednate content in the filtrate was measured using HPLC. The test results are shown in Table 9 and Fig. 9. Fig. 9 illustrates change of difluprednate concentration.

[0141] Table 9: Changes of difluprednate concentration in the top level samples over time

[0142]

[0143]

[0129] Based on the results shown in Table 9 and Fig. 9, it was found: 1) Povidone iodine had a significant solubilizing effect on difluprednate. 2) As the concentration of povidone iodine increased, its solubilizing ability for difluprednate also increased. 3) The solubilizing ability of povidone iodine for difluprednate was sustained and the solubility of difluprednate in povidone iodine gradually increased until 6-month.

[0144] Example 4: Investigation of the solubilization and sustained solubilization effects of povidone iodine on other steroids

[0145]

[0130] To investigate whether povidone iodine has a solubilizing effect on other steroids, the inventors selected several poorly water-soluble steroids, namely loteprednol, fluticasone propionate, and dexamethasone, to examine whether the solubility of these steroids in povidone iodine also increases over time.

[0146]

[0131] Sample preparation: For each of Formulations Fl to F3 in this example, 1.00g of povidone-iodine was accurately weighed, and was slowly and evenly added to 85g of purified water. The solution was stirred until completely dissolved. Then the corresponding weight of the respective type of steroid was slowly and evenly added while continuously stirring. The pH was adjusted to 5.0-6.0 with a 10% tromethamine solution, and water was added to a final volume of 100g. Formulations Fl to F3 are shown in Table 10.

[0147] Table 10: Formulati on Compositions of Example 4-F1-F3

[0132] After completing the sample preparation, the samples were stored at 2~8°C. For each sample, a certain amount of the top level was taken, and filtered with 0.22 pm membrane filter. Then, different steroid contents in the filtrate were measured using HPLC. The assay contents of different steroids in the povidone iodine solutions were measured on day 0, 1 -month, and 2- month, as shown in Table 11.

[0148] Table 11 : Solubility of different steroids in povidone-iodine

[0149]

[0133] From the results in Table 12, it was evident that: 1) Povidone iodine had no solubilizing or sustained solubilizing effect on fluticasone propionate. 2) Povidone iodine had some solubilizing effects on dexamethasone and loteprednol but did not show sustained solubilizing capacity.

[0150]

[0134] In summary, compared to these three steroids, povidone iodine exhibited a unique solubilizing effect on difluprednate, with significant and sustained solubilization, which was not observed with other steroids.

[0151] Example 5: Investigation of the inhibitory effect of deacetylated gellan gum on the degradation of difluprednate under basic condition

[0152]

[0135] Surprisingly, it was discovered that deacetylated gellan gum may prevent the degradation of difluprednate, which was confirmed by experiments in Examples 5 and 6.

[0136] Sample preparation: For each of Formulation Example 5-F1, 0.03g of difluprednate was accurately weighted, and slowly and evenly added to 85g of purified water. The solution was stirred until evenly dispersed; then the pH was adjusted to 10 with 0.1 mol / L sodium hydroxide solution, and water was added to a final volume of 100g. For Formulation Example 5-F2, 0.6g of deacetylated gellan gum was also accurately weighed, and slowly and evenly added to 85g of purified water. For each sample, the solution was stirred until completely dissolved, and then 0.03g of difluprednate was slowly and evenly added while continuously stirring. The pH was adjusted to 10 with 0.1 mol / L sodium hydroxide solution, and water was added to a final volume of 100g. Formulations Example 5-F1 to Example 5-F2 are shown in Table 12.

[0153] Table 12: Formulation Compositions of Example 5-FT-F2

[0154]

[0137] After the preparation of the aforementioned samples, under continuous stirring, samples were taken from the middle layer of each solution at Oh, 20min, 40min, 60min, 1.5h, and 2h, and the impurity assay of difluprednate was determined, including known impurities (DF21A, DFB, and DF21B) and total impurities. The results are shown in Table 13. Further, Fig. 10 shows total impurity results of Example 5 at pH 10.

[0155] Table 13: Impurity results of Example 5 in pH 10

[0156]

[0138] From the results in Table 13 and Fig. 10 it could be seen very clearly that difluprednate degraded rapidly in aqueous solution (pH 10), with total impurities rising to 14.4% within 120min. However, under the same pH conditions, deacetylated gellan gum could reduce the degradation rate of difluprednate by about 50%. It was evident that deacetylated gellan gum significantly reduced the degradation rate of difluprednate in basic aqueous systems and could remarkably improve its stability.

[0157] Example 6: Investigation of the inhibitory effect of deacetylated gellan gum, povidone iodine on the degradation of difluprednate under acidic condition

[0158]

[0139] It was also surprisingly found that combinations of povidone iodine and deacetylated gellan gum could also prevent the degradation of difluprednate under acidic conditions.

[0159]

[0140] Sample preparation: For Formulation Example 6-F1, 0.025g difluprednate was accurately weighed, and slowly and evenly added to 50g purified water. For Formulation Example 6-F2, 0.025g difluprednate and 0.75g povidone-iodine were accurately weighed, and slowly and evenly added to 45g of purified water. The solution was stirred until evenly dispersed, and then the pH was adjusted to 2.2 with 0.1 mol / L hydrochloric acid. Next, water was added to a final volume of 50g. For Formulation Example 6-F3, 0.025g difluprednate and 0.3g deacetylated were accurately weighted, and slowly and evenly added to 45g of purified water. The solution was stirred until evenly dispersed; then the pH was adjusted to 2.2 with 0.1 mol / L hydrochloric acid, and water was added to a final volume of 50g. For Formulation Example 6-F4, 0.025g difluprednate, 0.3g deacetylated and 0.75g povidone-iodine were weighed, and slowly and evenly added to 45g of purified water. The solution was stirred until evenly dispersed, the pH was adjusted to 2.2 with 0.1 mol / L hydrochloric acid, and then water was added to a final volume of 50g. Formulations of Example 6 are detailed in Table 14. The impurity test results are shown in Table 15. Further, Fig. 11 illustrates DFB results of Example 6 at pH 2.2. Fig. 12 illustrates the total impurity results of Example 6 at pH 2.2.

[0160] Table 14: Formulation Compositions of Example 6-F1-F5

[0161] Note:* As pH of 1.50% PVP-I solution was 2.2, inventors adjusted sample pH to 2.2.

[0162] Table 15: Impurity results of Example 6 in pH 2.2 for 7 days at 25 °C

[0163]

[0141] It was accordingly found that povidone iodine increased difluprednate’s degradation under acidic conditions, which potentially would destroy the compatibility of PVP-I combination with difluprednate. However, it was surprisingly discovered that the further addition of deacetylated gellan gum prevented the degradation of difluprednate in PVP-I solution under strong acidic conditions. This has solved the biggest challenge of improving stability of difluprednate in PVP-I solutions under acidic conditions.

[0164] Example 7: Composition and preparation of gel forming ophthalmic compositions containing povidone iodine, difluprednate, and deacetylated gellan gum

[0165]

[0142] Samples containing different concentrations of povidone iodine, difluprednate, and deacetylated gellan gum were prepared. Formulations are detailed in Table 16.

[0166] Table 16: Formulation Compositions of Example 7-F l~F15

[0167]

[0143] Sample preparation: For each sample in Table 16, the prescribed amount of deacetylated gellan gum was added to water at a certain ratio; then, the mixture was stirred until evenly dispersed and was heated in a water bath until fully swollen. The mixture was cooled to room temperature and was sterilized by filtration to obtain Solution 1. The prescribed amount of povidone iodine was dissolved in water at a certain ratio, stirred until fully dissolved, and sterile filtered to obtain Solution 2. Sterile Solutions 1 and 2 were mixed at a certain ratio and stirred evenly to obtain sterile Solution 3. The prescribed amount of sterile difluprednate powder was slowly added into Solution 3 while stirring until evenly dispersed, in order to obtain sterile Solution 4. The pH was adjusted to 5~6, and purified water was added to 100% (w / w). As such, the final formulation samples were obtained.

[0168] Example 8: Composition and preparation of gel forming ophthalmic compositions containing povidone iodine, loteprednol, and deacetylated gellan gum

[0169]

[0144] Samples containing different concentrations of povidone iodine, difluprednate, and deacetylated gellan gum were prepared. Formulations are detailed in Table 17.

[0170] Table 17: Formulation Compositions of Example 8-F1-F15

[0171]

[0145] Sample preparation: For each sample in Table 17, the prescribed amount of deacetylated gellan gum was added to water at a certain ratio, stirred until evenly dispersed, and heated in a water bath until fully swollen. The mixture was cooled to room temperature and was sterilized by filtration to obtain Solution 1. The prescribed amount of povidone-iodine was dissolved in water at a certain ratio, stirred until fully dissolved, and sterile filtered to obtain Solution 2. Sterile Solutions 1 and 2 were mixed at a certain ratio and stirred evenly to obtain sterile Solution 3. The prescribed amount of loteprednol or loteprednol butyrate powder was slowly added into Solution 3 while stirring until evenly dispersed, in order to obtain Solution 4. The pH was adjusted, making up the volume to 100% (w / w). As such the final formulation samples were obtained.

[0172] Example 9: Effect of povidone iodine on the particle size distribution of loteprednol and fluticasone propionate

[0173]

[0146] For suspensions, the particle size distribution or particle size of the active ingredient in aqueous systems has a significant impact on bioavailability. This example investigated the effect of povidone iodine and deacetylated gellan gum on particle size distribution or particle size in aqueous systems.

[0174] Table 18: Formulation Compositions of Example 9-F1-F8

[0175] Table 19 Results of particle size

[0176]

[0147] As shown by the results in Table 19, it was observed that: 1) Povidone iodine significantly reduced the particle size of loteprednol. 2) Deacetylated gellan gum also significantly reduced the particle size of loteprednol. 3) Combination of povidone iodine and deacetylated gellan gum also significantly reduced the particle size of loteprednol. 4) Povidone iodine and deacetylated gellan gum had no effect on the particle size of fluticasone propionate. 5) The ability of povidone iodine and deacetylated gellan gum to reduce the particle size of loteprednol was a surprising discovery, which had never been reported before, while povidone iodine and deacetylated gellan gum did not reduce the particle size of all steroids. 6) The combination of povidone iodine and deacetylated gellan gum reduced the particle size of loteprednol, which could significantly increase the bioavailability of the drug and thereby enhanced its efficacy. This was an exciting finding.

[0177] Example 10: Investigation of the redispersion and sedimentation ratio properties of different gelling agents in gel forming ophthalmic compositions

[0178]

[0148] Sedimentation ratio: A stoppered measuring cylinder was used to take 50ml of the sample, which was stoppered, and shaken vigorously for 1 minute. (2) After letting it stand, samples were taken from the top, middle, and bottom layers at specific time points (Ih, 3h, 7h, and 12h), and the assay of difluprednate was measured. (The top layer was about 2cm from the liquid surface, and the bottom layer was about 2cm from the bottom.)

[0179]

[0149] Redispersion: After 12 hours, the mixture was shaken vigorously again for 1 minute. After letting it stand for 3 hours, it was then shaken vigorously again before sampling from the top, middle, and bottom layers to measure the difluprednate assay.

[0180] Table 20: Formulation Compositions of Example 10-F1-F7

[0181]

[0150] Sample preparation: For each sample, the prescribed amount of the gelling agent was added to 50g of purified water, stirred until evenly dispersed, and transferred to a 70 °C water bath. The mixture was stirred for 1 hour until the solution was completely clear and then cooled to the room temperature. The prescribed amounts of mannitol and glycerin were added, and the mixture was stirred until clear, in order to obtain Solution 1. The prescribed amounts of povidone-iodine and sodium chloride were dissolved in 45g of water, and the mixture was stirred until fully dissolved. The prescribed amount of difluprednate was slowly added to the solution while stirring until evenly dispersed, to obtain Solution 2. Solution 2 was slowly poured into Solution 1 while stirring. The pH was adjusted with 10% tromethamine solution to 5.0-6.0, and the weight was adjusted with purified water to 100g, thereby obtaining the final product.

[0182]

[0151] The sedimentation results of upper, middle and lower levels are shown Fig. 13~ Fig. 15, and the redispersion results are shown Fig. 16. More specifically, Fig. 13 illustrates the results of sedimentation ratio in top. Fig. 14 illustrates the results of sedimentation ratio in middle. Fig. 15 illustrates the results of sedimentation ratio in bottom. Table 21 : Results of redispersion and sedimentation

[0183]

[0152] The results shown in Figs. 13-15 revealed the following observations. First, glycerin had no effect on the sedimentation rate. Second, in the different gelling agent systems described in this invention, the sedimentation rates of difluprednate particles varied, but all systems exhibited strong sedimentation prevention within the first 3 hours, meeting the suspension quality standards outlined in the US Pharmacopoeia. Third, over the entire 12-hour test period, deacetylated gellan gum demonstrated a superior anti-sedimentation effect compared to HPMC and CMC-Na.

[0184]

[0153] The data in Fig. 16 also showed that after shaking the sample again following 3 hours of standing, the assays of the top, middle, and bottom layers in the 7 prescription samples showed no significant difference from the 0-hour assay. This has indicated that the gelling agents described in this invention satisfy the quality requirements for the redispersion of suspension formulations.

[0185]

[0154] In summary, while there were no significant differences observed in the test results of the various gel matrices within the first 3 hours, deacetylated gellan gum exhibited the best antisettling effect over the full 12-hour period.

[0186] Example 11: Formulation and sample preparation of gel forming ophthalmic compositions containing povidone iodine, difluprednate, gelling agents and other excipients

[0187]

[0155] Formulations were prepared, each containing povidone iodine and difluprednate as active ingredients, with various gelling agents, including deacetylated gellan gum, HPMC, CMC-Na, sodium hyaluronate(NaHA), sodium chloride, mannitol, pH adjusters, and other components. The formulations are detailed in Table 22.

[0188] Table 22: Formulation Compositions of Example 11-F1-F4

[0189]

[0156] Sample preparation: For each sample, the prescribed amounts of deacetylated gellan gum, HPMC, and / or sodium hyaluronate were added to a certain ratio of purified water. The mixture was stirred until evenly dispersed, heated in a water bath until fully swollen, and cooled to the room temperature. The solution was sterilized by filtration to obtain Solution 1. The prescribed amount of povidone-iodine was dissolved in a certain ratio of purified water. The mixture was stirred until fully dissolved, and sterile filtered to obtain Solution 2. Sterile Solutions 1 and 2 were mixed at a certain ratio, stirred evenly to obtain sterile Solution 3. The prescribed amount of sterile difluprednate solid powder was slowly added into Solution 3 under sterile conditions, and the mixture was stirred until evenly dispersed to obtain sterile Solution 4. Then the pH was adjusted using tromethamine and the final weight was adjusted with purified water to 100% (w / w), thereby obtaining the final gel forming ophthalmic compositions.

[0190] Example 12: In vitro Release Test (Franz Cell)

[0191]

[0157] Several formulations were prepared to investigate the release rates of these formulations compared to the 0.05% Durezol®. The formulations are detailed in Table 23.

[0192] Table 23: Formulation Compositions of Example 12-F1-F3

[0193]

[0158] Durezol® was used as the control for Example 12-F3, and a Franz Cell release test was conducted. The release profiles of different samples were compared, with difluprednate being the release target. Table 24 below shows results of in vitro release test for difluprednate. The results of in vitro release test for difluprednate are also shown in Fig. 17.

[0194] Table 24: Results of in vitro release test for difluprednate

[0195]

[0159] First, for Example 12-F2, the concentration of difluprednate was 0.01%, which was only 20% of 0.05% Durezol® drug concentration. However, the release amount within 6 hours is similar to that of the 0.05% Durezol®. Second, for Example 12-F1, the concentration of difluprednate was 0.03%, and the release amount was much greater than that of the 0.05% Durezol®. This was due to the significant solubilizing effect of povidone iodine for difluprednate.

[0196] Example 13: Comparation of the release of povidone-iodine in different formulations using Franz cell release experiments

[0197]

[0160] To investigate the release of povidone iodine in different formulations, including the effect of difluprednate on the release of povidone-iodine and the comparison of release rates at different concentrations of povidone-iodine, a series of formulations were prepared and Franz cell was used to study the release of povidone iodine.

[0198]

[0161] A semi -quantitative method was employed to assess the amount of povidone iodine. Specifically, a series of povidone iodine standard solutions with different concentrations were prepared, such as lOpg / ml, 20pg / ml, 30pg / ml, 50pg / ml, 80pg / ml, lOOpg / ml, 120pg / ml, 150 .g / ml, and 200 .g / ml (calculated as povidone iodine), and 1ml starch indicator solution was added. During the experiment, artificial tear and 0.5ml starch indicator were added to the Franz cell receptor chamber. The color of the receptor chamber at different time points was compared with the povidone iodine standard solutions to estimate the amount of povidone iodine released into the receptor chamber.

[0199]

[0162] Fig. 18 shows different concentration of povidone-iodine standard solution. From left to right, the concentrations are 10, 20, 30, 50, 80, 100, 120, 150, and 200pg / ml. Table 25 below shows specific formulations of Example 13-F1-F10.

[0200] Table 25: Formulation Compositions of Example 13-F1-F10

[0201]

[0163] The inventor previously invented SHP640 (FST - 100), which is shown in Example 13 - F10 and Fll. SHP640 (FST - 100) in these examples respectively contained 1.50% and 1.00% povidone iodine, 0.1% dexamethasone, 0.35% sodium chloride, EDTA, anhydrous sodium sulfate, hydroxyethyl cellulose and tyloxapol. See US Pat. No. 7,767,217 B2. It completed successful Phase II clinical trials to treat acute virus conjunctivitis.

[0164] Example 13-F12, which contained 1.00% povidone iodine , 0.20% sodium chloride, mannitol, deacetylated gellan gum and tromethamine, was disclosed in US Pat. No. 11,576,973 B2.

[0202]

[0165] Example 13-F9 and F13 are formulations that respectively contained 1.50% and 1.00% povidone iodine aqueous solution.

[0203]

[0166] Sample preparation: For each sample, the prescribed amount of gelling agent was added to 50g of purified water. The mixture was stirred until evenly dispersed and transferred to a 70°C water bath. The mixture was further stirred for 1 hour until the solution was completely clear, then cooled to the room temperature. The prescribed amount of mannitol was added, and the mixture was stirred until clear, to obtain Solution 1. The prescribed amounts of povidone- iodine and sodium chloride were dissolved in 45g of water, and the mixture was stirred until fully dissolved. The prescribed amount of difluprednate was slowly added to the solution while stirring until evenly dispersed, in order to obtain Solution 2. Solution 2 was slowly poured into Solution 1 while stirring. The pH was adjusted with 10% tromethamine solution to 5.0-6.0, and the weight was adjusted with purified water to 100g, thereby obtaining the final product. Table 26 below shows results of in vitro release test.

[0204] Table 26: Results of in vitro release test.

[0205]

[0167] Fig. 19 illustrates the release results of Example 13-F1 to Example 13-F4 as compared with Example 13-F9. As shown in Fig. 19, a comparison with Example 13-F9 (povidone-iodine aqueous solution) revealed that the composition of the present invention, containing deacetylated gellan gum, demonstrated a remarkable sustained release effect. This formulation allowed for the gradual release of the drug, extending its retention time on the ocular surface and enhancing drug efficacy.

[0206]

[0168] Fig. 20 illustrates the release results of Example 13-F1 to Example 13-F4 compared with Example 13-F10. From the data in Fig. 20, it was observed that the formulations in Example 13-F1 to Example 13-F4 exhibited faster and higher release rates compared to Example 13-F10. Surprisingly, despite the lower povidone-iodine concentrations in Examples 13-F1 (1.0%) and 13-F2 (1.25%) as compared to Example 13-F10 (1.50% PVP-I with SHP640 formulation), the release of PVP-I was faster and more pronounced in the former. It was believed that the concentrations of povidone-iodine at 1.00%, 1.25%, 1.50%, and 2.00% offered good therapeutic effects when compared to Example 13-F10.

[0207]

[0169] Fig. 21 illustrates the release results comparison of Example 13-F1 to Example 13-F8. In Fig. 21, it was observed that the formulations F1-F4 in Example 13 displayed faster release rates compared to formulations F5-F8, even at the same concentration of povidone-iodine and other excipients. Interestingly, it was found that difluprednate also enhanced the release of povidone-iodine.

[0208]

[0170] Fig. 22 illustrates the release results comparison of Example 13-F2 to Example 13-F11 and F12.

[0209]

[0171] From the data in Fig. 22, under the same povidone iodine concentration (1.0%), the release rate of Example 13-F13 (aqueous solution) was the fastest, which quickly released the available iodine and reach to its maximum release, while that of F 12 (black line) was the slowest and the initial release of available was the lowest. Fll with the previous SHP640 formulation also showed a low initial release of available iodine but with a slightly extended release comparing to F13 formulation, which was an aqueous solution formulation with rapid release of available iodine. However, Fl formulation still exhibited a sustained-release property comparing to F12, the aqueous formulation, but with a higher initial release of available iodine comparing to Fll. It potentially would have sufficient initial killing power of all pathogens while with a longer acting efficacy.

[0210]

[0172] While previous clinical trials of PVP-I formulations with different concentrations failed to achieve both clinical cure and microbial eradication in the treatment of viral and / or bacterial conjunctivitis, it was believed that the sufficient initial release of free iodine and the sustained release of available iodine over time were key to achieving the clinical goals necessary for approval. The inventors had surprisingly discovered that formulations with 1.00%, 1.25%, 1.50%, and 2.00% PVP-I, as shown in Examples 13, had significant potential for therapeutic efficacy.

[0211] Example 14: Investigation of the in-situ gel forming characteristics of formulations Example 14-F1 to F8

[0212]

[0173] Deacetylated gellan gum is an ion-sensitive in situ gel that can transition from a liquid to a semi-solid gel under appropriate ionic strength. The viscosity changes of Formulations Example 14-F1 to F8 were investigated, simulating the formation of gels on the surface of the eye. The formulations are detailed in Table 27.

[0213] Table 27: Formulation Compositions of Example 14-F1-F8

[0214]

[0174] Sample preparation was the same as described in Example 13.

[0175] Viscosity testing: 1) 20 mL of the sample solution was added to a beaker and sit for 5 minutes. Then a rotational viscometer was used to measure the initial viscosity at 25°C, the rotation speed being 10 rpm, 20 rpm and 50 rpm. 2) 20 mL of the sample solution and 3.5ml artificial tear were added to a beaker (sample solution: artificial tear solution = 40:7). After letting it sit at 34 °C for 5 minutes, the initial viscosity was measured with a rotational viscometer at the same speed.

[0215] Table 28: Viscosity results of Example 14-F1-F8

[0216] Note: *means artificial tear.

[0217]

[0176] The viscosity results are shown in Figs. 23-25. Specifically, Fig. 23 illustrates viscosity results of 25 °C and 34 °C+AT in 10 rpm. Fig. 24 illustrates viscosity results of 25 °C and 34 °C+AT in 20 rpm. Fig. 25 illustrates viscosity results of 25 °C and 34 °C+AT in 50 rpm.

[0218]

[0177] Based on the viscosity results, it was observed that at different rotational speeds, the viscosity of these formulations increased after adding artificial tears. This showed that the compositions containing DGG exhibited in-situ gel properties. The increase in viscosity would be beneficial for the adhesion of the formulations on the surface of the eye.

[0219] Example 15: In vitro efficacy of povidone iodine in killing bacteria, fungi, and viruses

[0220]

[0178] According to the method described in Journal of Clinical Microbiology , p635-639 (1982), the bactericidal activity of a 0.6% (w / w) povidone iodine in-situ gel formulation against Pseudomonas aeruginosa, MRSA, and Candida parapsilosis was tested at 15 s, 30 s, and 1 min. The results showed that the 0.6% (w / w) povidone-iodine in-situ gel formulation killed all tested pathogens within 15 s, 30 s, and 1 min. As shown in Fig. 26, Fig. 27, Fig. 28 and Fig. 29. Povidone iodine in-situ gel 0.6% (w / w) formulation exhibited antibacterial activity when in contact with ocular isolates of Pseudomonas aeruginosa, MRS A, and Candida parapsilosis.

[0221]

[0179] The objective of this study was to evaluate whether contact with povidone-iodine can inactivate (or “kill”) the virus. Povidone-iodine was mixed directly with the virus and allowed to stand for 30 ± 5 minutes, then neutralized. The surviving virus was quantified. Neutralization controls confirmed that the virus was effectively detected in the titer assay. Toxicity controls indicated that the titer plates were valid, with no toxicity observed at a 1 / 10 dilution of povidone-iodine. 70% ethanol proved fully effective, and untreated virus controls behaved as expected. The undiluted compound was found to be an effective virucidal agent, while the 1 / 3.2 dilution (28% after the virus was added) exhibited only slight virucidal activity. The povidone- iodine gel-forming composition demonstrated complete inactivation of the virus. This study assumes that the undiluted compound contains 0.6% povidone-iodine, with 10 pL of the virus added to 90 pL of the test solution. The limit of detection was 0.67 CCID50 per 100 pL, and the 0.54% compound inactivated all detectable viruses. In vitro antiviral studies confirmed that povidone-iodine exhibited complete inactivation of the virus.

[0222]

[0180] The in vitro efficacy results are shown in Figs. 26-29. Specifically, Fig. 26 illustrates the antibacterial effect of 0.6% (w / w) povidone iodine in situ gel formulation against Pseudomonas aeruginosa. Fig. 27 illustrates the antibacterial effect of 0.6% (w / w) povidone iodine in situ gel formulation against MRSA. Fig. 28 illustrates the antifungal effect of 0.6% (w / w) povidone- iodine in situ gel formulation against Candida parapsilosis. Fig. 29 illustrates the antiviral effect of 0.6% (w / w) povidone-iodine in situ gel formulation against adenovirus.

[0223]

[0181] According to the in vitro efficacy studies results, PVP-I gel forming compositions demonstrated high-efficiency killing effect on bacteria, fungi and viruses.

[0224] Example 16: Stability test

[0225]

[0182] Table 29 below shows the formulations of Example 16.

[0226] Table 29: Formulation Compositions of Example 16.

[0227]

[0183] Sample preparation: For each sample, the prescribed amounts of gellan gum (DGG) , mannitol, and sodium chloride were taken, placed into a solution of a certain proportion of purified water, stirred until evenly dispersed, heated in a water bath until fully swollen, and cooled to the room temperature. The solution was sterilized by filtration to obtain Solution 1. The prescribed amount of povidone-iodine was taken, placed in a solution of purified water, stirred until completely dissolved. After the pH was adjusted, the solution was sterilized by filtration to obtain Solution 2. Sterile Solution 1 was mixed with Solution 2 in a certain proportion, and the solution was stirred to mix evenly, thereby obtaining sterile Solution 3. Under sterile conditions, the prescribed amount of sterile difluprednate solid powder was slowly added to Solution 3 while stirring until evenly dispersed. As such, the final product was obtained and filled into 5 mL PP bottles.

[0228]

[0184] Stability Testing: Evaluations were conducted for stability under 2-8 °C and 25 °C, testing appearance, related substances, assay of povidone-iodine, assay of difluprednate , pH, osmolarity, and particle size. The results are shown in Table 30 below.

[0229] Table 30: Results of the stability test

[0230] Note: NA means not detected.

[0231] ND means results lower than LOD(0.1%).

[0232]

[0185] The results indicated that all samples showed no significant changes within 2 months under both 2~8 °C and 25 °C conditions.

[0233] Example 17: Ocular Irritation Study in Rabbits

[0234]

[0186] The samples from Example 16 were taken for the irritation test. The sample information is shown in Table 31 below.

[0235] Table 31

[0236]

[0187] Study Protocol: New Zealand White (NZW) rabbits (2 rabbits per formulation) were used to evaluate ocular tolerability of Ophthalmic Suspension formulations shown above (test article). Ocular placebo and test article formulations were administered topically via eye drop, using a calibrated positive displacement pipette to administer 35 pL total onto the globe of each eye (OU), 4 times daily (QID) for three days. Animals were observed daily for mortality, clinical health, body weight change, and gross ocular observations assessed using Draize Scoring System after instillation. Ophthalmic examinations, including slit lamp, were measured using the Modified McDonald Shaddock Scoring system. Based on clinical observation and scoring assessment, the most well-tolerated and least irritating formulations were selected for advancement to the next stage of development.

[0237]

[0188] The details of the group settings in this study are shown in Table 32 below.

[0238] Table 32

[0239]

[0189] Table 33 below shows the irritation results.

[0240] Table 33

[0241]

[0190] Conclusion: Under the conditions of this study, test articles I (Example 16-F2), II (Example 16-F3), III (Example 16-F6), and IV (Example 16-F8) were administered as eye drops to New Zealand White rabbits for three consecutive days. All four test articles caused transient conjunctival hyperemia, secretion production, and frequent blinking or eye closure within 1 minute post-dose. However, the ocular irritation scores remained within the non-irritation range. Similar effects were observed in both the left and right eyes of each animal. A comparison of the degree of blinking and eye closure post-dose showed the following order of effect: test article I (Example 16-F2) ~ test article III (Example 16-F6) < test article II (Example 16-F3) ~ test article IV (Example 16-F8).

[0242] Example 18: In Vivo Pharmacokinetic (PK) Study in Rabbit

[0243]

[0191] The formulations were prepared according to Table 34 below.

[0244] Table 34

[0245] Note: Durezol was purchased commercially.

[0246]

[0192] Study Protocol: A single-dose ocular pharmacokinetics study was conducted using 30 New Zealand White (NZW) rabbits. The study involved three groups of test articles formulated as eye drops, as previously described. A calibrated positive displacement pipette was used to administer 35 pL of the test article onto the globe of each eye. Ocular tissues, including the bulbar conjunctiva, cornea, aqueous humor (AH), iris ciliary body (ICB), and plasma, were collected post-dose at 0.5, 1, 2, 4, and 8 hours (n=2 / timepoint / group) following topical ocular administration. At the specified time points (approximately 0.5, 1, 2, 4, and 8 hours post-dose), two animals per group and time point were euthanized by intravenous barbiturate overdose. After euthanasia and prior to enucleation, aqueous humor was collected via paracentesis of the anterior chamber of each eye. The bulbar conjunctiva was then removed, rinsed, and collected from each eye. Both eyes of each rabbit were harvested, rinsed to remove residual compound, and dissected for the collection of ocular tissues (cornea and ICB). Following dissection, all fluids and tissues were placed in pre-tared tubes, weighed, stored on dry ice, and subsequently frozen at -80°C or lower until analysis. The active metabolite 21 -desacetyl difluprednate concentrations in the collected tissues and fluids were analyzed using LC-MS / MS. Pharmacokinetic (PK) parameters were derived using the sparse sampling noncompartmental analysis method in Phoenix WinNonlin®.

[0247]

[0193] Table 35 below shows the PK Study of 30-minute and AUC results.

[0248] Table 35

[0194] Additionally, Fig. 30 illustrates drug concentration in various Tissues in the 30-minute tests. Fig. 31 illustrates drug AUC in various Tissues / Fuild.

[0249]

[0195] Results: The observations below are indicated by the findings.

[0250]

[0196] First, the exposure concentrations in ocular tissues were ranked as follows: AH > Cornea > ICB > Conjunctiva.

[0251]

[0197] Second, the area under the curve (AUC) for the cornea and conjunctiva in these two samples was greater than that of Durezol, showing a dose-dependent relationship, and in the ICB, the values were comparable.

[0252]

[0198] Third, at the 30-minute time point, the concentrations of Example 16-F6 and F7 in the cornea and conjunctiva were higher than those of 0.05% Durezol. It was surprisingly discovered that the combination formulations of PVP-I and difluprednate, such as Formulations Example 16-F6 and F7, exhibited superior distribution in ocular tissues compared to Durezol.

[0253]

[0199] Conclusion: In developing topical therapeutics for acute conjunctivitis, the conjunctiva and cornea are key target tissues. The pharmacokinetic study results showed that Examples 16- F6 and F7 achieved significantly higher drug concentrations in these tissues compared to 0.05% Durezol. This superiority was primarily attributed to the unique solubilizing effects of povidone-iodine on difluprednate. By forming a stable drug-excipient complex, povidone- iodine not only enhanced the solubility of the active pharmaceutical ingredient but also significantly improved drug permeability across the corneal and conjunctival tissues, thereby increasing bioavailability at the target sites. This suggested that these formulations could potentially achieve a similar anti-inflammatory effect with much lower concentrations of the steroid in the combination composition.

[0254]

[0200] Although specific embodiments and examples of this invention have been illustrated herein, it will be appreciated by those skilled in the art that any modifications and variations can be made without departing from the spirit of the invention. The examples and illustrations above are not intended to limit the scope of this invention. Any combination of embodiments of this invention, along with any obvious extensions or analogs, are within the scope of this invention. Further, it is intended that this invention encompass any arrangement, which is calculated to achieve that same purpose, and all such variations and modifications fall within the scope of the appended claims.

[0201] All the features disclosed in this specification (including any accompanying claims, abstract and drawings) may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example of a generic series of equivalent or similar features.

Claims

WHAT IS CLAIMED IS:

1. A gel-forming ophthalmic composition, comprising povidone iodine (PVP-I) as an active agent, a steroid, a gelling agent, and at least one excipient, wherein the composition forms an in-situ gel at the physiological temperature upon application of the composition to an eye of a subject, wherein the steroid comprises difluprednate or loteprednol, or a salt, an ester, or any combination thereof.

2. The gel-forming ophthalmic composition of claim 1, wherein povidone iodine is contained in the composition at a concentration ranging from about 0.5% (w / w) to about 2.00% (w / w).

3. The gel-forming ophthalmic composition of claim 2, wherein povidone iodine is contained in the composition at a concentration ranging from about 0.5% (w / w) to about 1.50% (w / w).

4. The gel-forming ophthalmic composition of any one of claims 1 to 3, wherein the steroid is contained in the composition at a concentration ranging from about 0.01% (w / w) to about 1.00% (w / w).

5. The gel-forming ophthalmic composition of any one of claims 1 to 4, wherein the steroid is contained in the composition at a concentration ranging from about 0.01% (w / w) to about 0.1% (w / w).

6. The gel-forming ophthalmic composition of any one of claims 1 to 5, wherein the steroid comprises difluprednate.

7. The gel-forming ophthalmic composition of any one of claims 1 to 5, wherein the steroid comprises loteprednol.

8. The gel-forming ophthalmic composition of any one of claims 1 to 7, wherein the gelling agent is contained in the composition at a concentration ranging from about 0.1% (w / w) to about 5.0% (w / w).

9. The gel-forming ophthalmic composition of claim 8, wherein the gelling agent is contained in the composition at a concentration ranging from about 0.1% (w / w) and 1.0% (w / w).

10. The gel-forming ophthalmic composition of any one of claims 1 to 9, wherein the gelling agent comprises a polysaccharide polymer.

11. The gel-forming ophthalmic composition of claim 10, wherein the polysaccharide polymer comprises deacetylated gellan gum, xanthan gum, sodium alginate, carrageenan, or any combination thereof.

12. The gel-forming ophthalmic composition of claim 11, wherein the polysaccharide polymer is deacetylated gellan gum.

13. The gel-forming ophthalmic composition of any one of claims 1 to 12, wherein the excipient comprises a surfactant, a thickening agent, an osmotic pressure regulator, a pH regulator, or a preservative.

14. The gel-forming ophthalmic composition of claim 13, wherein the thickening agent comprises HPMC, CMC-Na, sodium hyaluronate, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, anhydrous glucose, or any combination thereof.

15. The gel-forming ophthalmic composition of claim 14, wherein the thickening agent comprises consisting of HPMC, sodium hyaluronate, CMC-Na, or any combination thereof16. The gel-forming ophthalmic composition of any one of claims 14 to 15, wherein the thickening agent is contained in the composition at a concentration ranging from about 0.1% (w / w) to about 5.0% (w / w), or from about 0.1% (w / w) to about 1.00% (w / w).

17. The gel-forming ophthalmic composition of any one of claims 13 to 16, wherein the composition comprises the osmotic pressure regulator selected from the group consisting of mannitol, glucose, sorbitol, glycerol, polyethylene glycol, propylene glycol, and any combination thereof, at a concentration ranging from about 0.01% (w / w) to about 10.0% (w / w).

18. The gel-forming ophthalmic composition of claim 13, wherein the pH regulator comprises tromethamine, sodium hydroxide, hydrochloric acid, or any combination thereof.

19. The gel -forming ophthalmic composition of claim 18, wherein the pH regulator is contained in the composition at a concentration ranging from about 0.01% (w / w) to about 5.0% (w / w).

20. The gel -forming ophthalmic composition of any one of claim 1 to 19, wherein the pH of the composition ranges from about 4.0 to about 7.0, or from about 4.0 to about 6.0.

21. The gel-forming ophthalmic composition of claim 13, wherein the preservative comprises sorbic acid, benzalkonium chloride, benzalkonium bromide, methylparaben, ethylparaben, EDTA-2Na, or any combination thereof.

22. The gel-forming ophthalmic composition of claim 21, wherein the preservative is containedin the composition at a concentration ranging from about 0.01% (w / w) to about 1.00% (w / w).

23. The gel-forming ophthalmic composition of any one of claims 1 to 22, wherein the composition is in the form of a solution, suspension, or emulsion, optionally with a sustained release carrier.

24. The gel-forming ophthalmic composition of any one of claims 1 to 23, wherein the composition is used as eye drops, or filled into a rinse bottle for eye irrigation, or used with a device for ocular disease treatment.

25. The gel-forming ophthalmic composition of any one of claims 1 to 24, wherein the composition is packaged in single-dose or multi -dose containers.

26. The gel-forming ophthalmic composition of any one of claims 1 to 25, wherein the composition is used for treating at least one ocular disease.

27. The gel-forming ophthalmic composition of claim 26, wherein the ocular disease is an infectious ocular disease or ocular inflammation.

28. The gel-forming ophthalmic composition of claim 26, wherein the composition is used for treating acute conjunctivitis, corneal injury, ulcerative infectious keratitis, epithelial keratitis, stromal keratitis, herpes-related keratitis, fungal keratitis, or blepharitis.

29. A method for treating or alleviating symptoms of an ocular disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a gel- forming ophthalmic composition of any one of claims 1 to 28.

30. The method of claim 29, wherein the ocular disorder is an infectious ocular disease or ocular inflammation.

31. The method of claim 30, wherein the ocular disorder is acute conjunctivitis, corneal injury, ulcerative infectious keratitis, epithelial keratitis, stromal keratitis, herpes-related keratitis, fungal keratitis, or blepharitis.

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