Compositions and Methods for Treatment of Ocular Conditions

Abstract

The present disclosure relates to compositions and methods for treating ocular conditions or diseases with low or poorly water-soluble therapeutics incorporated into a hydrogel. In particular, the disclosure relates to non-blurring, therapeutic-containing hydrogel compositions that have an extended contact time on the eye and do not interfere with wound healing.

Claims

1. An ocular composition, comprising: a shear-thinning hydrogel comprising hyaluronic acid, wherein the hyaluronic acid is at a concentration of about 3 to about 10 mg/ml and is covalently crosslinked; and a therapeutic agent, wherein the therapeutic agent has a solubility in water of less than about 1.5 mg/ml.

2. The ocular composition of claim 1, wherein the hyaluronic acid is modified or unmodified hyaluronic acid.

3. The ocular composition of claim 1, wherein the therapeutic agent has a concentration in the composition at least about 10 times greater than the solubility in water.

4. The ocular composition of claim 1, wherein the therapeutic agent has a concentration in the composition at least about 100 times greater than the solubility in water.

5. The ocular composition of claim 4, wherein the therapeutic agent comprises one or more of: an antimicrobial agent, an antibacterial agent, an antiviral agent, an immunosuppressant, an anti-inflammatory agent, and an antihistamine.

6. The ocular composition of claim 5, wherein the therapeutic is cyclosporin.

7. The ocular composition of claim 5, wherein the therapeutic is a corticosteroid.

8. The ocular composition of claim 7, wherein the therapeutic is prednisolone or a salt of prednisolone.

9. The ocular composition of claim 5, wherein the therapeutic is loteprednol or a salt of loteprednol.

10. The ocular composition of claim 2, wherein the modified hyaluronic acid is thiolated hyaluronic acid or thiolated carboxymethyl hyaluronic acid.

11. The composition of claim 10 wherein the hydrogel is disulfide crosslinked.

12. An ocular composition comprising: a shear-thinning hydrogel comprising thiolated hyaluronic acid, wherein the thiolated hyaluronic acid is at a concentration of about 3 to about 10 mg/ml and is disulfide crosslinked; and a therapeutic agent, wherein the therapeutic agent has a solubility in water of less than about 1.0 mg/ml, and the therapeutic agent is at a concentration in the composition of at least 10 times the solubility in water.

13. The composition of claim 12, wherein the thiolated hyaluronic acid has a thiol modification of about 0.05 μmol to about 1.0 μmol thiol/mg.

14. The composition of claim 13, wherein the thiol modification is about 0.05 μmol to about 0.2 μmol thiol/mg, and wherein the thiolated hyaluronic acid is at a concentration of about 6.5 mg/ml to about 8.5 mg/ml.

15. The composition of claim 12, wherein the therapeutic is a corticosteroid, optionally wherein the corticosteroid is prednisolone or a salt of prednisolone.

16. A method of treating ocular disease in a subject, comprising applying the composition of claim 1 to an eye of the subject.

17. The method of claim 16, wherein the ocular disease is selected from the group consisting of conjunctivitis, diabetic retinopathy, dry eye, eye infections, glaucoma, macular degeneration, ocular allergies, presbyopia, retinal detachment, and uveitis.

18. A method of treating ocular disease in a subject, comprising applying the composition of claim 12 to an eye of the subject.

19. The method of claim 18, wherein the ocular disease is selected from the group consisting of conjunctivitis, diabetic retinopathy, dry eye, eye infections, glaucoma, macular degeneration, ocular allergies, presbyopia, retinal detachment, and uveitis.

20. The ocular composition of claim 1, wherein the therapeutic agent has a solubility in water of less than about 1.0 mg/ml, 0.9 mg/ml, 0.8 mg/ml, 0.7 mg/ml, 0.6 mg/ml, 0.5 mg/ml, 0.4 mg/ml, 0.3 mg/ml, 0.2 mg/ml, 0.1 mg/ml, 0.01 mg/ml, or 0.001 mg/ml.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0044] The following detailed description, given by way of example, but not intended to limit the disclosure solely to the specific embodiments described, may best be understood in conjunction with the accompanying drawings, in which:

[0045] FIGS. 1A and 1B are graphs showing viscosity as a function of shear rate for hydrogel (“OBG”) alone (black squares) or with therapeutic incorporated. FIG. 1A shows the viscosity for prednisolone acetate (PredA) incorporated at a concentration of 1 (red circles), 5 (green circles), or 10 (blue circles) mg/ml. FIG. 1B shows the viscosity for loteprednol etabonate (LE) incorporated at a concentration of 1 (red circles), 2.5 (green circles), or 5 (blue circles) mg/ml.

[0046] FIGS. 2A and 2B are graphs showing viscosity as a function of shear rate for hydrogel (“OBG”) alone (black squares) or with therapeutic incorporated at a concentration of 1 mg/ml. FIG. 1A shows the viscosity for olopatadine (Olo) incorporated into the hydrogel (green triangles). FIG. 1B shows the viscosity for dexamethasone (Dex) incorporated into the hydrogel (red circles).

[0047] FIGS. 3A, 3B, 3C, and 3D show the release of therapeutic from hydrogel (“OBG”; blue circles on the graphs) or PBS (green circles on the graphs) into PBS in a medi-dialysis chamber (MWCO, 50 kDa) over time. FIG. 3A shows the release of PredA incorporated at 2 mg/ml. FIG. 3B shows the release of LE incorporated at 1 mg/ml. FIG. 3C shows the release of Olo incorporated at 1 mg/ml. FIG. 3D shows the release of Dex incorporated at 1 mg/ml.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0048] The present disclosure is based, at least in part, on the discovery that a hydrogel may be formulated to contain low or poorly water-soluble therapeutics (e.g., a water solubility of less than about 1.5 mg/ml) to provide enhanced prevention/treatment of ocular diseases, while simultaneously having increased contact time with the surface of the eye in a way that allows the subject to have clear vision (e.g., does not blur a subject's vision). The present disclosure provides therapeutic-containing hydrogels formulated in an exemplary embodiment as an eye drop. Advantageously, the therapeutic-containing hydrogel is formulated to be non-blurring while having extended contact time with the surface of the eye, which provides beneficial effects in terms of preventing or treating an ocular disease. Moreover, the therapeutic-containing hydrogel disclosed herein also has the ability to aid in the wound healing process. The hydrogel is shear-thinning and comprises modified or unmodified hyaluronic acid that is covalently crosslinked. In one aspect, the therapeutic has a solubility in water of less than about 1.5 mg/ml and is at a concentration of at least about 10 times the water solubility. It is contemplated within the scope of the disclosure that the therapeutic may have a solubility in water that is between about 0.001 mg/ml and 0.05 mg/ml, or between about 0.05 mg/ml and about 0.5 mg/ml, or between about 0.5 mg/ml and about 1.0 mg/ml, or between about 1.0 mg/ml and about 1.5 mg/ml. In some embodiments, the therapeutic may have a solubility in water that is less than about 1.0 mg/ml, 0.9 mg/ml, 0.8 mg/ml, 0.7 mg/ml, 0.6 mg/ml, 0.5 mg/ml, 0.4 mg/ml, 0.3 mg/ml, 0.2 mg/ml, 0.1 mg/ml, 0.01 mg/ml, or 0.001 mg/ml. In another aspect, the therapeutic is a corticosteroid. The compositions herein provide a number of advantages over the prior art, including: enhanced residence time on the surface of the eye, a non-blurring ophthalmic formulation, and the ability to deliver a poorly water-soluble therapeutic from a hydrogel.

Compounds of the Disclosure

[0049] An ocular composition in the form of a hydrogel is provided that incorporates a low or poorly water-soluble therapeutic. The hydrogel is a covalently crosslinked hyaluronic acid (HA), and the hyaluronic acid may be modified or unmodified. Unmodified hyaluronic acid may be covalently crosslinked by a variety of methods, including crosslinking using 1,4-butanediol diglycidyl ether (BDDE), divinylsulfone, and dihydrazide. The hyaluronic acid may be modified to change the charge of the molecule, change its biological activity, or to include groups that may be used for crosslinking purposes. Particularly useful are thiolated hyaluronic acid or thiolated carboxymethyl hyaluronic acid (CMHA). Modified hyaluronic acid may be crosslinked with an external molecule for crosslinking, or without an external crosslinker molecule. For crosslinking thiolated HA or CMHA, a molecule with thiol-reactive sites, such as acrylates, methacrylates, haloacetates, haloacetamides, or maleimides, may be used as an external crosslinker molecule, examples of which include poly(ethylene glycol) diacrylate and poly(ethylene glycol) bisbromoacetate. For crosslinking without an external crosslinker molecule, in particular, thiolated HA or CMHA may be disulfide crosslinked via an oxidation process. Such disulfide crosslinking may be aided by use of an oxidant such as sodium hypochlorite or peroxide.

[0050] When modified HA is crosslinked via the modification (e.g., disulfide crosslinking of thiolated HA), the level of modification may be adjusted to control the amount of crosslinking of the hydrogel, such that a higher level of modification leads to more crosslinking. Particularly useful for formulating hydrogels of the present disclosure is thiolated HA or thiolated CMHA, where the thiol modification is about 0.05 to about 1.0 μmol thiol per mg of HA or CMHA. Modification levels within this range are particularly suitable for forming crosslinked hydrogels with a desired shear-thinning profile and viscosity.

[0051] When placed on the surface of the eye, shear-thinning hydrogels made using thiolated CMHA and having a concentration range of about 3 to about 10 mg/ml remain in contact with the eye surface for at least 30 minutes and up to about 2 hours.

Combination Treatments

[0052] The therapeutic-containing hydrogel compositions and methods described herein may be used to direct the administration of combination therapies to treat particular ocular diseases. In order to increase the effectiveness of a treatment with the compositions of the present disclosure, e.g., an antibiotic selected and/or administered as a single agent, or to augment the protection of another therapy (second therapy), it may be desirable to combine these compositions (e.g., include more than one therapeutic in the therapeutic-containing hydrogel compositions) and methods with one another, or with other agents and methods effective in the treatment, amelioration, or prevention of diseases and pathologic conditions.

[0053] Administration of a composition of the present disclosure to a subject will follow general protocols for the administration described herein, and the general protocols for the administration of a particular secondary therapy will also be followed, taking into account the toxicity, if any, of the treatment. It is expected that the treatment cycles would be repeated as necessary.

Pharmaceutical Compositions

[0054] Therapeutics that may be incorporated in the therapeutic-containing hydrogel compositions disclosed herein are those that are clinically relevant for ocular conditions and may include antimicrobials, antibiotics, antiviral agents, immunosuppressants, anti-inflammatory agents, antihistamines, and combinations thereof. Particularly useful in the present disclosure are therapeutics that have a solubility in water of less than about 1.5 mg/ml. It is contemplated within the scope of the disclosure that the therapeutic may have a solubility in water that is between about 0.001 mg/ml and 0.05 mg/ml, or between about 0.05 mg/ml and about 0.5 mg/ml, or between about 0.5 mg/ml and about 1.0 mg/ml, or between about 1.0 mg/ml and about 1.5 mg/ml. In some embodiments, the therapeutic may have a solubility in water that is less than about 1.0 mg/ml, 0.9 mg/ml, 0.8 mg/ml, 0.7 mg/ml, 0.6 mg/ml, 0.5 mg/ml, 0.4 mg/ml, 0.3 mg/ml, 0.2 mg/ml, 0.1 mg/ml, 0.01 mg/ml, or 0.001 mg/ml. An exemplary immunosuppressant that may be used in cyclosporin (water solubility <0.05 mg/ml). An exemplary anti-inflammatory agent that may be used is a corticosteroid, e.g., prednisolone acetate (water solubility <0.05 mg/ml). An exemplary antiviral agent that may be used is acyclovir (water solubility of 1.4 mg/ml). The therapeutic may be incorporated at a concentration of at least about 10 to 100 times the water solubility of the therapeutic, and may be incorporated prior to, during, or after crosslinking of the hydrogel.

Method of Treatment

[0055] The topical application of a therapeutic can be used to treat or prevent a variety of ocular conditions or diseases including bacterial or viral infections, post-surgical pain, inflammation, correctable congenital defects, and allergic reactions. Ocular conditions or diseases which may benefit from therapeutic application of the present invention include but are not limited to: conjunctivitis, diabetic retinopathy, dry eye, eye infections, glaucoma, macular degeneration, ocular allergies, presbyopia, retinal detachment, and uveitis.

[0056] The agents contained in the disclosed drug delivery systems will be released from the therapeutic-containing hydrogel compositions at rates that depend on such factors as the therapeutic itself and its physical form and the concentration of therapeutic in the hydrogel.

[0057] The therapeutics used in the present invention are commercially available or readily obtained by a worker skilled in the art through known reactions techniques. The therapeutic can be combined with the other ingredients in the chosen dosage form by conventional methods known in the art.

[0058] The therapeutic-containing hydrogel composition is topically applied to an eye of a human or non-human animal, the latter including cows, sheep, horses, pigs, goats, rabbits, dogs, cats, and other mammals. The composition can be topically applied, without limitation, to the front of the eye, under the upper eyelid, on the lower eyelid and in the cul-de-sac. The application can be as a treatment of a condition or disease of the eye or as a preventive such as prior to surgery.

Kits

[0059] In general, therapeutic-containing hydrogel compositions of the invention may be provided as a kit that contains the therapeutic or compositions of the invention packaged to facilitate dispensing and/or applying the composition to affected or susceptible regions of the eye. The packaging or dispenser may include a dropper, bottle, tube, spray bottle, or other dispenser and instructions for use.

[0060] The kits are manufactured using medically acceptable conditions and contain components that have sterility, purity and preparation that is pharmaceutically acceptable.

[0061] The instructions generally include information as to dosage, dosing schedule, and route of administration for the intended treatment. The containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses. Instructions supplied in the kits of the instant disclosure are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.

[0062] The label or package insert indicates that the composition is used for treating or preventing an ocular condition or disease in a subject. Instructions may be provided for practicing any of the methods described herein.

[0063] The kits of this disclosure are in suitable packaging. Suitable packaging includes, but is not limited to, droppers, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. The container may further comprise a second pharmaceutically active agent.

[0064] Kits may optionally provide additional components such as buffers and interpretive information. Normally, the kit comprises a container and a label or package insert(s) on or associated with the container.

[0065] Reference will now be made in detail to exemplary embodiments of the disclosure. While the disclosure will be described in conjunction with the exemplary embodiments, it will be understood that it is not intended to limit the disclosure to those embodiments. To the contrary, it is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the disclosure as defined by the appended claims.

Examples

[0066] The present disclosure is further illustrated by the following examples, which should not be construed as limiting. The contents of all references, published patents and patent applications cited throughout the application are hereby incorporated by reference. Those skilled in the art will recognize that the disclosure may be practiced with variations on the disclosed structures, materials, compositions and methods, and such variations are regarded as within the scope of the disclosure.

Example 1: Hydrogel Formation

[0067] Thiol-modified carboxymethyl HA (CMHA-S) was synthesized as described in Lawyer et al. [1] and Wendling et al. [2], with a thiol modification of 0.1, 0.2, 0.4, or 0.7 μmol thiol/mg. Hydrogels were created by dissolving CMHA-S in phosphate-buffered saline (PBS; pH 7.4). The CMHA-S was disulfide crosslinked under continuous mixing with the addition of sodium hypochlorite. Rheological testing was performed using a parallel plate format rheometer with a 25 mm-diameter stainless steel geometry. Samples (5-6 ml) of hydrogel were placed in a 35 mm Petri dish, and the geometry was lowered to a gap of 5 mm. To determine viscosity and shear-thinning, the shear rate was varied from 0.1 to 10 Hz. A decreasing viscosity as shear rate increases indicates shear-thinning behavior. Table 1 provides the thiol modification of the CMHA-S, concentration of CMHA-S, and resultant viscosity of the hydrogel (at 2.5 Hz) for 4 hydrogel formulations. All 4 formulations displayed shear-thinning behavior.

TABLE-US-00001 TABLE 1 Examples of hydrogel formulations and viscosity. Thiol CMHA-S modification concentration Viscosity at Hydrogel # (μmol thiol/mg) (mg/ml) 2.5 Hz (Pa .Math. s) 1 0.12 8.3 2.6 2 0.15 7.8 3.6 3 0.13 7.3 2.4 4 0.39 4.0 0.9

Example 2: Therapeutic-Containing Hydrogels

[0068] Therapeutics were mixed into a hydrogel made as in Example 1, with a thiol modification about 0.1 μmol thiol/mg and CMHA-S concentration about 7.5 mg/ml. Therapeutics used were: prednisolone acetate (predA) at a concentration of 1, 5, or 10 mg/ml; loteprednol etabonate (LE) at a concentration of 1, 2.5, or 5 mg/ml; and olopatadine (Olo) and dexamethasone (Dex), each at a concentration of 1 mg/ml. PredA is considered poorly soluble to practically insoluble in water. LE has a water solubility of less than 0.001 mg/ml. Olo has a water solubility of about 0.03 mg/ml. Dex has a water solubility of less than 0.09 mg/ml. All of these therapeutics are therefore considered to have very low to poor solubility in water. Therapeutics were added as a finely ground powder to the crosslinked hydrogel and the mixture stirred or shaken vigorously to incorporate the therapeutic throughout. The therapeutic was dispersed throughout the hydrogel but was not fully dissolved.

Example 3: Physical Properties of Therapeutic-Containing Hydrogels

[0069] Viscosity, pH, and refractive index (RI) were measured for hydrogels described in Example 2 with and without therapeutic incorporated. Viscosity was determined as described in Example 1. RI was measured with a refractometer and pH was measured with a pH meter.

[0070] For predA, increasing concentration of the therapeutic in the hydrogel led to a slight increase in the viscosity (Table 2), although not significantly different than hydrogel without the predA, and the hydrogel maintained its shear thinning property (FIG. 1A). Further, the addition of the therapeutic did not substantially change the refractive index or pH of the hydrogel. The hydrogel did become slightly more opaque with increasing concentration of the predA; however, because only a small drop would be used and would spread across the surface of the eye, it would not be considered to be blur the vision.

TABLE-US-00002 TABLE 2 Viscosity, refractive index (RI), and pH of hydrogels with and without prednisolone acetate (predA) incorporated. PredA Concentration Viscosity at (mg/ml) 2.5 Hz (Pa .Math. s) RI pH 0 1.9 1.3354 7.05 1 2.0 1.3354 7.09 5 2.7 1.3355 7.13 10 3.0 1.3354 7.17

[0071] Similar results were seen for LE incorporated into the hydrogels (FIG. 1B and Table 3). The pH increased a little more with increasing amounts of LE compared to predA, although the pH remained well within the acceptable range for topical ophthalmics (generally, a pH of about 6-8), and the pH could be adjusted either before or after incorporation of the drug if desired.

TABLE-US-00003 TABLE 3 Viscosity, refractive index (RI), and pH of hydrogels with and without loteprednol etabonate (LE) incorporated. LE Concentration Viscosity at (mg/ml) 2.5 Hz (Pa .Math. s) RI pH 0 1.9 1.3357 7.04 1 2.3 1.3355 7.11 2.5 2.7 1.3354 7.24 5 3.3 1.3353 7.55

[0072] For olopatadine and dexamethasone, the physical appearance (transparency), pH, and refractive index of the hydrogel were the same with and without the therapeutic incorporated (Table 4), although the appearance was slightly more opaque with dexamethasone incorporated. The viscosity decreased compared to hydrogel without the therapeutic (Table 4), although the hydrogel with therapeutic still demonstrated shear-thinning properties (FIGS. 2A and 2B), and the viscosity was still within the desired specifications for the hydrogel. Further, a hydrogel with a slightly higher viscosity could be used for incorporating these therapeutics to ensure a final viscosity in a desired range.

TABLE-US-00004 TABLE 4 Viscosity, refractive index (RI), and pH of hydrogels with and without olopatadine or dexamethasone incorporated at a concentration of 1 mg/ml. Viscosity at Drug incorporated 2.5 Hz (Pa .Math. s) RI pH None 1.6 1.3353 7.3 Olopatadine 1.1 1.3353 7.3 Dexamethasone 1.0 1.3354 7.2

Example 4: Release of Low/Poorly Soluble Therapeutics from Hydrogels

[0073] Hydrogels described in Example 2 containing PredA at 2 mg/ml, or LE, Olo, or Dex at 1 mg/ml, were used to assess the release of the therapeutic from the hydrogel. The release was monitored over 24 hours and compared to release of the therapeutic from solution in PBS. For this assessment, a 0.5 ml sample of hydrogel plus therapeutic or PBS plus therapeutic was placed into a medi-dialysis chamber, and the chamber was placed in a beaker containing 100 ml of PBS. The remaining amount of therapeutic in the dialysis chamber was monitored using UV spectroscopy at various time points. The release of PredA, olopatadine, and Dex from the hydrogel was similar to their release from PBS (FIGS. 3A, 3C, and 3D, respectively). Release of LE from the hydrogel was reduced compared to its release from PBS (FIG. 3B); however, release of the therapeutic still occurred, and such a reduction in the rate may lead to a more controlled delivery.

INCORPORATION BY REFERENCE

[0074] All documents cited or referenced herein and all documents cited or referenced in the herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated by reference, and may be employed in the practice of the disclosure.

EQUIVALENTS

[0075] It is understood that the detailed examples and embodiments described herein are given by way of example for illustrative purposes only, and are in no way considered to be limiting to the disclosure. Various modifications or changes in light thereof will be suggested to persons skilled in the art and are included within the spirit and purview of this application and are considered within the scope of the appended claims. Additional advantageous features and functionalities associated with the systems, methods, and processes of the present disclosure will be apparent from the appended claims. Moreover, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein. Such equivalents are intended to be encompassed by the following claims.