In situ gel-forming ophthalmic preparations containing difluprednate

Abstract

The present invention provides an aqueous in-situ gel ophthalmic formulation containing water, difluprednate, and a biocompatible polysaccharide, which instantly increases in viscosity upon instillation into the eye and forms a gel in situ at physiological temperatures. In the formulation, nanocarriers can be formed together with or by encapsulating difluprednate using a surfactant or solubilizer contained in the formulation, and the nanocarriers have an average particle size of 10 to 500 nm, 10 to 150 nm, or 10 to 50 nm.

Description

[Background technology]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Application No. 62 / 888,534, filed August 18, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] Difluprednate is a topical corticosteroid useful for treating inflammation and pain associated with ophthalmic surgery. It is the butyrate ester of 6α-9α-difluoroprednisolone acetate, the structure of which is shown below. [ka]

[0003] Difluprednate is practically insoluble in water. The currently available ophthalmic formulation of difluprednate, DUREZOL®, is an emulsion formulation containing 0.05% w / v difluprednate emulsified between a castor oil phase and an aqueous phase. When administered four times daily, it has been used to treat inflammation and pain associated with ocular surgery and endogenous anterior uveitis.

[0004] However, the Durezol® emulsion formulation does not provide long-lasting action, a serious drawback. It requires administration four times daily, resulting in a high rate of patient noncompliance and underdosing. Furthermore, the most common adverse reactions in patients receiving Durezol® (occurring in 5-10% of such patients) have been reported and described in the approved labeling for Durezol®, including blurred vision, eye irritation, eye pain, headache, elevated intraocular pressure (IOP), iritis, limbal and conjunctival hyperemia, and punctate keratitis. Therefore, a formulation of difluprednate with fewer or no such side effects is desirable.

[0005] Furthermore, U.S. Patent No. 10,092,514 B2 discloses a difluprednate oil-in-water emulsion for treating macular edema, and U.S. Patent No. 2012 / 0135947 discloses an oil-in-water emulsion containing difluprednate and tobramycin for topical administration. Like Durezol®, the formulations disclosed in these patents require castor oil as a hydrophobic component to form the emulsion. Castor oil is used in ophthalmic solutions such as Restasis® and Durezol®, but it can cause side effects such as itching, redness, irritation, and other unpleasant eye problems, which have also been observed with Durezol®. Furthermore, castor oil can cause allergic reactions in some patients.

[0006] In addition to oil-in-water emulsion formulations, US2018 / 0311159 discloses an eye drop solution containing difluprednate as the sole active ingredient at a concentration of 0.02% to 0.04% in an aqueous vehicle, where the solution is oil-free and administered twice daily. This eye drop solution requires a crystal growth inhibitor to prevent difluprednate from precipitating or crystallizing from the aqueous solution. The crystal growth inhibitor is polyvinyl alcohol or its derivatives. Polyvinyl alcohol is found in eye drops as a lubricant to prevent irritation or relieve dryness of the eyes. However, its use may cause temporary blurred vision, mild burning / stinging / irritation, and even rare severe allergic reactions.

[0007] In difluprednate formulations disclosed in the prior art, either emulsions (castor oil is used) or crystal growth inhibitors (polyvinyl alcohol or its derivatives) have been used to overcome the low solubility of difluprednate, but these additives result in highly undesirable side effects.

[0008] The present invention provides a solution to the above-mentioned problems associated with existing difluprednate formulations.

[0009] BRIEF DESCRIPTION OF THE INVENTION Generally, the present invention provides novel difluprednate formulations based on in situ gel technology. The novel formulations of the present invention increase the drug retention time in the eye and increase the ocular bioavailability of difluprednate (the active ingredient). Each in situ gel formulation provided by the present invention is aqueous, oil-free, and has fewer side effects. The in situ gel formulations of the present invention can prevent difluprednate from precipitating without the use of any crystal growth inhibitors. Meanwhile, the in situ gel sustained-release technology can also reduce side effects such as eye irritation, eye pain, and ocular foreign body sensation. Furthermore, the in situ gel technology can be further combined with an appropriate solubilizer / surfactant to enhance solubility and / or form nanocarriers to form smaller particles, thereby enhancing drug permeability and drug efficacy.

[0010] The in situ gel delivery system of the present invention extends the retention time of the drug in front of the cornea, which helps improve the bioavailability of the drug in the eye. Ideally, the in situ gel system is a low-viscosity, free-flowing liquid during storage, allowing the eye drop to be applied repeatedly and easily to the eye. After administration to the conjunctival sac, it forms a semi-solid gel that adheres to the front of the eye. The viscosity must be sufficient to withstand the shear force of the eye and extend the retention time of the drug (difluprednate) in front of the eye. Sustained-release drugs can improve bioavailability, reduce systemic absorption, and reduce the frequency of dosing, thereby helping to improve patient compliance.

[0011] Thus, in one aspect, the present invention provides an aqueous in situ gel ophthalmic formulation comprising water, difluprednate, and a biocompatible polysaccharide, which upon instillation into the eye undergoes an instantaneous increase in viscosity and forms a gel in situ at physiological temperatures.

[0012] Examples of suitable biocompatible polysaccharides include deacetylated gellan gum (DGG), sodium alginate, carrageenan, hyaluronic acid, and any combination thereof. In some embodiments, the polysaccharide is DGG.

[0013] Difluprednate or polysaccharide may be included in the formulation at a concentration that provides the most therapeutic effect and the least side effects, for example, 0.01 to 10.0% by weight, 0.01 to 5.0% by weight, 0.01 to 2.5% by weight, or 1% or 1.5% by weight.

[0014] The aqueous in situ gel formulations of the present invention may further comprise an osmolality adjusting agent, a pH adjusting agent, a surfactant or solubilizing agent, a viscosity increasing agent, or an anti-infective agent, each of which may have a concentration of 0.01 to 10.0% by weight, 0.01 to 5.0% by weight, 0.01 to 2.5% by weight, or 1% or 1.5% by weight.

[0015] Examples of suitable osmolality adjusters include sodium chloride, mannitol, glycerol, polyethylene glycol 400 (PEG 400), boric acid, and any combination thereof. Examples of suitable pH adjusters include sodium hydroxide, trishydroxymethylaminomethan (Tris), hydrochloride, phosphoric acid, boric acid, and any combination thereof. Examples of suitable surfactants or solubilizers include polyoxyethylene surfactants, polyoxypropylene surfactants, PEG 35 castor oil, PEG 40 castor oil, ethoxylated hydrogenated castor oil, polyoxyl 40 stearate, Soluplus, and any combination thereof. Examples of suitable viscosity increasers include polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, and any combination thereof.

[0016] In some embodiments of the formulations of the present invention, the surfactant or solubilizer is Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), which has the following formula: [ka]

[0017] In some embodiments of the present invention, the anti-infective agent is an antibiotic or an antiseptic. Examples of suitable anti-infective agents include povidone-iodine (or other iodine-containing compounds), netilmicin, tobramycin, doxycycline hyclate, and ciprofloxacin.

[0018] In some embodiments of the present invention, the formulation comprises nanocarriers containing or encapsulating difluprednate formed with a surfactant or solubilizer, the nanocarriers having an average particle size of 10-500 nm (or 10-250 nm, 10-200 nm, 10-150 nm, 10-100 nm, or 10-50 nm). Such nanocarriers may be micelles formed as a result of the presence of a solubilizer or surfactant that also increases the solubility of difluprednate. When nanocarriers are formed with a surfactant or solubilizer containing difluprednate, the difluprednate and the surfactant or solubilizer together form a micellar membrane. On the other hand, when nanocarriers are formed with a surfactant or solubilizer that encapsulates difluprednate, the difluprednate is contained within the membrane formed by the hydrophilic end of the surfactant.

[0019] The combination of an in situ gel system (based on specific biocompatible polysaccharides) and a nanocarrier / micelle delivery system may not only improve membrane transport of difluprednate via nanocarriers, but also enhance the permeability of difluprednate into biofilms, improve the stability, drug solubility, and provide targeted delivery of difluprednate in a sustained manner.

[0020] Another aspect of the present invention provides a method for treating or alleviating the symptoms of an ocular disorder in a patient (subject) in need thereof. The method comprises administering to the patient or subject a therapeutically effective amount of an aqueous in situ gel ophthalmic formulation, as described above. Upon instillation into the eye, the formulation forms a gel in situ and continuously releases difluprednate to the eye.

[0021] Examples of such eye disorders include ocular inflammatory disorders or pain, particularly inflammation or pain associated with (during or after) eye surgery. [Brief explanation of the drawings]

[0022] [Figure 1] Viscosity data for Formulation 1 is shown.

[0023] [Figure 2] Viscosity data for Formulation 2 is shown.

[0024] [Figure 3] Viscosity data for Formulation 3 is shown.

[0025] [Figure 4] 1 shows viscosity data for formulation 4.

[0026] [Figure 5] 1 shows viscosity data for formulation 5.

[0027] [Figure 6] 1 shows the release profile (percentage) over time for Formulation 3 (in situ gel micelle solution) and Formulation 6 (emulsion solution).

[0028] [Figure 7] FIG. 1 is a diagram of a micelle. DETAILED DESCRIPTION OF THE INVENTION

[0029] (Detailed Description of the Invention) The formulations of the present invention are aqueous compositions containing difluprednate and a water-soluble, biocompatible polysaccharide that form a gel in situ upon instillation into the eye, and are useful for treating ocular inflammatory disorders, such as inflammation and pain associated with ocular surgery.

[0030] Specifically, the formulation of the present invention is an aqueous composition containing difluprednate as an active ingredient and a biocompatible polysaccharide as an in situ gelling material or matrix.

[0031] As used herein, the term "in situ gel" refers to a system that can be applied as a solution or suspension and undergo a rapid sol-to-gel transformation triggered by an external stimulus (temperature, pH, etc.) upon injection.

[0032] The polysaccharides included in the formulations of the present invention may include deacetylated gellan gum (DGG), carrageenan, and sodium alginate, or mixtures of these materials. Deacetylated gellan gum may be preferred, at concentrations ranging from 0.05% to 1% (w / w).

[0033] The formulations of the present invention may further include osmolality adjusters, pH adjusters, surfactants, viscosity increasing agents, and other pharmaceutically acceptable ingredients.

[0034] Suitable osmolality adjusters for inclusion in the formulations of the present invention may include sodium chloride, mannitol, glycerol, polyethylene glycol 400 (PEG 400), or boric acid. The concentration of the osmolality adjuster may range from 0.1 to 5.0% (w / w).

[0035] Suitable pH adjusters in the formulations of the present invention include sodium hydroxide, tris(hydroxymethyl)aminomethanone (Tris), hydrochloride (HCl), phosphoric acid, or boric acid. The final pH of the formulation may range from 3.5 to 8.0, preferably from 4.0 to 6.0.

[0036] Suitable surfactants for inclusion in the formulations of the present invention include polyoxyethylene surfactants, polyoxypropylene surfactants, PEG 35 castor oil, PEG 40 castor oil, polyoxyethylene hydrogenated castor oil, polyoxyl 40 stearate, Soluplus, or any combination thereof. The surfactant in the pharmaceutical composition may have a concentration ranging from 0.01% to 5%.

[0037] As used herein, the term "nanocarrier" is interchangeable with "micelle" or "nanomicelle" and refers to an aggregate (or supramolecular assembly) of surfactant molecules dispersed in a liquid colloid.

[0038] Micelles are approximately spherical. Other phases are possible, including ellipsoids, cylinders, and bilayers. The shape and size of a micelle are a function of the molecular structure of its surfactant molecules and solution conditions such as surfactant concentration, temperature, pH, and ionic strength. The process of forming micelles is known as micellization and forms part of the phase behavior of many lipids, depending on their polymorphism. Figure 7 shows a spherical micelle.

[0039] Suitable viscosity-increasing agents of the present invention include polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, or any combination thereof. The concentration of the viscosity-increasing agent can range from 0.01% to 2% (w / w).

[0040] The formulations of the present invention may further comprise an anti-infective agent as a second active ingredient. The anti-infective agent in the present invention may be an antibiotic, an iodine-containing compound, or other anti-infective agent suitable for ophthalmic formulations. The antibiotic may be netilmicin, tobramycin, doxycycline hyclate, ciprofloxacin, or other suitable antibiotic. The iodine-containing compound may be an iodophor containing iodine complexed with a solubilizing agent such as povidone-iodine.

[0041] The formulations of the present invention may optionally contain an antimicrobial preservative. While any antibiotic agent may function as a self-preservative, a suitable antimicrobial preservative may be added to prevent contamination of multi-dose packages. Such agents may include benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, EDTA, sorbic acid, Onamer M, other agents known to those skilled in the art, or combinations thereof. Typically, such preservatives are used at levels of 0.001% to 1.0% (w / w).

[0042] The present invention will be further elucidated using specific examples. It is understood that these examples are used only to illustrate the present invention and are not intended to limit the scope of the present invention. Experimental methods without specific conditions in the following examples are usually prepared under conventional conditions in the literature or according to the conditions suggested by the excipient manufacturer. Unless otherwise specified, all percentages, ratios, proportions or fractions in the present invention are calculated by weight. Unless otherwise defined in the present invention, all technical and scientific terms used herein have the same meaning as that of a well-trained person. Furthermore, any methods and materials similar or equivalent to those described in the present invention may be applied to the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0043] Example 1: Formulation of an in situ gel suspension of Fluprednate Various polysaccharides, including deacetylated gellan gum (DGG), xanthan gum, kappa-carrageenan, sodium alginate, and sodium hyaluronate, were screened to select the optimal ocular gel-forming matrix. Formulations containing xanthan gum or sodium hyaluronate failed to demonstrate in situ gelation. The viscosity of formulations containing xanthan gum or sodium hyaluronate did not increase after mixing with artificial tears. Formulations containing carrageenan or sodium alginate showed an increase in viscosity after mixing with artificial tears, which demonstrated some in situ gelation properties. However, their viscosity after mixing with artificial tears was too low (<50 cp), and therefore, their in situ gelation properties were suboptimal. When carrageenan or sodium alginate is used as a gel-forming agent, additional ingredients, such as an appropriate viscosity-increasing agent, are required to optimize the formulation. Formulations containing DGG generally demonstrated in situ gelation under physiological conditions when the DGG concentration was optimized. Therefore, DGG was selected as the gel-forming matrix in the formulation.

[0044] Formulation preparation process: Sodium chloride and mannitol were dissolved in water for injection. Next, gellan gum was slowly added to the solution and heated to 60-70°C until completely dissolved. The solution was then cooled to room temperature to provide Solution 1. Difluprednate was dispersed in glycerin to provide Suspension 2. Suspension 2 was added to Solution 1 and mixed well. The pH of the final suspension was adjusted to pH 5.5 with tromethamine. A typical formulation (Formulation 1) is shown in Table 1. The suspension was stable, with no solids settling out of the suspension for at least two months at room temperature. [Table 1]

[0045] The viscosity of the samples was tested at 33°C with and without mixing with artificial tears (0.678% NaCl, 0.218% NaHCO3, 0.0084% CaCl2·2H2O, and 0.138% KCl in water). The mixing ratio of sample to artificial tears was 3:7. Table 2 and Figure 1 show the viscosity at various shear rates. The viscosity decreased with increasing shear rate in both conditions. After mixing with artificial tears, the viscosity was found to increase significantly, indicating in situ gel properties. [Table 2]

[0046] The in-situ gel suspension of the example can prevent aggregation and precipitation of difluprednate. However, it does not increase the solubility and therefore the permeability of the drug. To provide better solubility and bioavailability, micronized difluprednate may be required, as reducing the particle size can improve solubility and permeability.

[0047] Example 2: Selection of an appropriate surfactant / solubilizer To improve the solubility of difluprednate, various surfactants / solubilizers were investigated to identify a suitable solubilizer. Various surfactants / solubilizers, including poloxamer 188, poloxamer 407, polysorbate 80, PEG 40 castor oil, PEG 60 castor oil, PEG 40 hydrogenated castor oil, polyoxyl 40 stearate, and Soluplus, were dissolved in water at various concentrations. Difluprednate was added to the surfactant solution to a final difluprednate concentration of 0.05%. The solubility of difluprednate was measured. Table 3 shows the solubility of difluprednate with different surfactants / solubilizers. It was found that common solubilizers, such as poloxamer 188 and polysorbate 80, were unable to effectively increase the solubility of difluprednate. Surprisingly, Soluplus was found to be the optimal solubilizer for difluprednate, as the solubility of difluprednate in the formulation exceeded 99% with only 0.6% Soluplus. Soluplus is a polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam graft copolymer (PVAc-PVCap-PEG). It forms nanomicelles in water or other aqueous solutions, which can solubilize the poorly soluble difluprednate.

[0048] In addition to Soluplus, polyoxyethylene castor oil surfactants can also improve the solubility of difluprednate. Difluprednate solubility is 99.5% in 5% polyoxyethylene castor oil (EL-40) and >98% in 5% polyoxyethylene castor oil (RL-40). Polyoxyethylene (60) castor oil and polyoxyethylene castor oil (EL-35) can also increase the solubility of difluprednate to greater than 95%, but it was found that at least 4 or 5% of such solubilizers were required to achieve greater than 95% solubility of difluprednate. Therefore, Soluplus was the preferred solubilizer. [Table 3]

[0049] Example 3: Formulation of a difluprednate in situ gel solution using Soluplus as a solubilizer In situ gel nanomicelle solutions of difluprednate were prepared using Soluplus as a solubilizer. The formulations were prepared in a manner similar to that described in Example 1. Two solutions using Soluplus were obtained with the formulations shown in Table 4. [Table 4]

[0050] Particle size measurements revealed that the mean particle size was 74.5 nm for Formulation 2 and 67.0 nm for Formulation 3, indicating that nanomicelles were formed by the addition of Soluplus. The viscosity of the two formulations was also tested. Table 5, Figures 2, and 3 show the viscosities of the two formulations tested with and without artificial tears. Formulation 2 had a much lower viscosity than Formulation 1, resulting in a very weak in-situ gel. Therefore, the addition of Soluplus as a solubilizer to the in-situ gelling formulation was found to actually weaken the gel-forming properties of gellan gum, resulting in a lower viscosity. Formulation 3, in which the sodium chloride concentration was increased from 0.20% to 0.25%, formed a significant in-situ gel after mixing with artificial tears. Therefore, we suggest optimizing the ionic strength of the formulation to achieve a better in-situ gelling nanomicelle formulation. [Table 5]

[0051] Example 4: Formulation of a difluprednate in situ gel formulation using RH-40 as a solubilizer Difluprednate in situ gel formulations were prepared using polyoxyethylene hydrogenated castor oil (RH-40) as a solubilizer in a manner similar to that described in Example 1. Two solutions were obtained with the formulations shown in Table 6. Because the FDA IIG safety requirement for RH-40 is 1% or less, 1% RH-40 and 0.8% RH-40 were used in these formulations. [Table 6]

[0052] The particle size of formulations 4 and 5 was measured, and it was found that no micelles were formed for these two formulations. A slight white suspension was observed during storage at room temperature, but no solid precipitated from the formulation. Surprisingly, it was found that micelles were not formed even when 5% RH-40 containing difluprednate was added. Since a small amount of suspension was observed after storage for more than 3 days, the stability of the solution was not as good as that of the in situ gel micelle solution.

[0053] Table 7, Figures 4, and 5 show the viscosities of the two formulations before and after mixing with artificial tears. Formulation 4 was found to form a gel even before mixing with artificial tears. Comparing Formulations 1 and 2, which used the same concentrations of gellan gum and sodium chloride, it was found that the use of RH-40 as a solubilizer increased gel formation, thus forming a gel even before mixing with artificial tears. Lowering the concentrations of gellan gum, sodium chloride, and RH-40 (Formulation 5) prevented initial gel formation, and an in-situ gel formed only after mixing with artificial tears. It was also found that a formulation containing 5% RH-40 and 0.2% gellan gum and sodium chloride was not necessary to form a suitable in-situ gel formulation. The viscosity was 100 cp at 6 RPM, but after mixing with artificial tears, the viscosity increased to 160 cp. [Table 7]

[0054] Example 5: In-vitro dissolution studies To evaluate the in-vitro release of the in-situ gel micelle formulations, Formulation 3 in Example 3 was selected for dissolution studies because it was capable of forming a suitable in-situ gel based on viscosity testing and had optimal solution stability due to the formation of micelles.

[0055] A difluprednate emulsion formulation (Formulation 6) was prepared as a control using the same commercially available Durezol® formulation as shown in Table 8. Briefly, difluprednate was dissolved in castor oil as the oil phase. Glycerin, polysorbate 80, boric acid, sodium acetate, sodium EDTA, and sorbic acid were dissolved in water for injection. The pH of the aqueous solution was adjusted to pH 5.5 as the aqueous phase. The oil phase was added to the aqueous phase, and the mixture was homogenized using a homogenizer. The particle size of the resulting solution was measured, and the average diameter was 123.7 nm, indicating that the emulsion was successfully formed. Formulation 6 was used as a control to study the sustained-release performance of the in situ gel solution (Formulation 3).

[0056] In vitro release studies were conducted using the dissolution method. First, 1 g of sample (in situ gel solution or emulsion solution) and 4 g of artificial tears were placed in a 50 ml plastic tube and allowed to stand for 5 minutes to form an in situ gel for the in situ gel solution. Next, 35 g of PBS buffer (pH 7.4 containing 0.05% SDS) was slowly added down the wall of the tube, avoiding agitation of the solution at the bottom. 1 g of solution samples were collected from the top at 10, 20, 30, and 1 hour. After each solution sample, 1 g of PBS buffer was added to maintain a total dissolution medium of 40 g. The difluprednate concentration was measured using HPLC. The total difluprednate concentration in each formulation was obtained by shaking the dissolution solution and taking a 1 g sample for HPLC analysis. [Table 8]

[0057] When mixed with artificial tears, a gel was observed to form for the in situ gel micelle solution of Formulation 3. Upon addition of PBS solution, the gel slowly swelled, with the gel matrix gradually expanding from the bottom to the top of the tube. The in vitro dissolution study was conducted for 60 minutes, and the gel remained intact at the end of the study and was not completely eroded. For Formulation 6, no gel was found to form, and the entire solution in the tube quickly became homogenous.

[0058] Figure 6 shows the cumulative release percentage of difluprednate for Formulations 3 and 6. Surprisingly, Formulation 3 released only 40% of the difluprednate after 1 hour, whereas Formulation 6 achieved 100% release within 10 minutes. An in situ gel was formed in Formulation 3, and although the gel swelled, it maintained a gel matrix throughout the study. 60% of the difluprednate was still contained within the gel and was not released after 1 hour in the current in vitro study. The gel did not degrade in the current in vitro study. In vivo conditions are expected to differ from current in vitro conditions. The gel is expected to degrade slowly in vivo and be washed away by tears; therefore, the drug loaded in the gel is expected to be released slowly into the eye. The in vitro release study demonstrated that the formed in situ gel was able to release a portion of the difluprednate (40% for Formulation 3) and prolong the release of the remaining difluprednate (60%). The in situ gel is expected to slowly disintegrate in vivo, releasing difluprednate in a prolonged manner.

Claims

1. 1. An aqueous in-situ gel ophthalmic formulation comprising water, difluprednate, and a biocompatible polysaccharide comprising deacetylated gellan gum (DGG), wherein the formulation undergoes an instantaneous increase in viscosity upon instillation into the eye and forms a gel in situ at physiological temperatures, and the aqueous in-situ gel ophthalmic formulation is free of crystal growth inhibitors and castor oil.

2. 10. The aqueous in-situ gel formulation of claim 1, wherein difluprednate is included in the formulation at a concentration of 0.01 to 5.0% by weight.

3. 3. The aqueous in situ gel ophthalmic formulation of claim 1, wherein the biocompatible polysaccharide is present in the formulation at a concentration of 0.01 to 5% by weight.

4. 4. The aqueous in situ gel formulation of claim 1, further comprising an osmolality adjusting agent, a pH adjusting agent, a surfactant or solubilizing agent, a viscosity increasing agent, or an anti-infective agent.

5. 5. The aqueous in situ gel formulation of claim 4, wherein each of the osmolality adjusting agent, the pH adjusting agent, the surfactant or solubilizing agent, the viscosity increasing agent, or the anti-infective agent is included in the formulation at a concentration of 0.01 to 5% by weight.

6. 6. The aqueous in situ gel formulation of claim 4 or 5, wherein the osmolality adjusting agent comprises sodium chloride, mannitol, glycerol, polyethylene glycol 400 (PEG 400), boric acid, or any combination thereof.

7. 6. The aqueous in situ gel formulation of claim 4 or 5, wherein the pH adjuster comprises sodium hydroxide, trishydroxymethylaminomethan (Tris), hydrochloride, phosphoric acid, boric acid, or any combination thereof.

8. 6. The aqueous in situ gel formulation of claim 4 or 5, wherein the surfactant or solubilizer comprises a polyoxyethylene surfactant, a polyoxypropylene surfactant, PEG 35 castor oil, PEG 40 castor oil, polyoxyethylene hydrogenated castor oil, polyoxyl 40 stearate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or a combination thereof.

9. 9. The aqueous in situ gel formulation of claim 4, 5, or 8, wherein the surfactant or solubilizer comprises a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

10. 6. The aqueous in situ gel formulation of claim 4 or 5, wherein the viscosity increasing agent comprises polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, or any combination thereof.

11. 6. The aqueous in situ gel formulation of claim 4 or 5, wherein the anti-infective agent is an antibiotic or an antiseptic.

12. 6. The aqueous in situ gel formulation of claim 4 or 5, wherein the anti-infective agent comprises povidone iodine, netilmicin, tobramycin, doxycycline hyclate, or ciprofloxacin.

13. 11. The aqueous in situ gel ophthalmic formulation of any one of claims 4 to 5 and 9 to 10, wherein nanocarriers are formed by the surfactant or the solubilizing agent together with or encapsulating difluprednate, wherein difluprednate is part of a micelle membrane or is encapsulated within the nanocarriers, and the nanocarriers have an average particle size of 10 to 500 nm.

14. 14. The aqueous in situ gel ophthalmic formulation of claim 13, wherein the nanocarriers have an average particle size of 10 to 150 nm or 10 to 50 nm.

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