WO2016100355A1

WO2016100355A1 - Biocompatible hydrogels, systems including the hydrogels, and methods of using and forming same

Info

Publication number: WO2016100355A1
Application number: PCT/US2015/065842
Authority: WO
Inventors: Devatha P. Nair; Malik Y. Kahook; Naresh MANDAVA; Christopher Bowman; Saikripa RADHAKRISHNAN; Srinidhi RADHAKRISHNAN; Amir H. TORBATI
Original assignee: The Regents Of The University Of Colorado, A Body Corporate
Priority date: 2014-12-15
Filing date: 2015-12-15
Publication date: 2016-06-23

Abstract

Hydrogel compositions and methods of forming and using the hydrogel compositions are disclosed. Exemplary hydrogel compositions are biocompatible and can be used for various applications, including vitreous substitutes, adhesives, and drug delivery compositions. Further, exemplary hydrogel compositions have desirable properties, such as clarity, refractive index, viscosity and elastic modulus that are the same as or similar to the same properties of a healthy vitreous in an eye.

Description

BIOCOMPATIBLE HYDROGELS, SYSTEMS INCLUDING THE HYDROGELS, AND METHODS OF USING AND FORMING SAME

Inventors: Devatha P. Nair, Malik Y. Kahook, Naresh Mandava, Christopher Bowman,

Saikripa Radhakrishnan, Srinidhi Radhakrishnan and Amir Torbati Cross Reference to Related Application

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 62/092,113, entitled BIOCOMPATIBLE HYDROGELS, SYSTEMS INCLUDING THE HYDROGELS, AND METHODS OF USING AND FORMING SAME, and filed December 15, 2014, the disclosure of which is incorporated herein by reference to the extent such disclosure do not conflict with the present disclosure.

Field of Invention

[0002] The present disclosure generally relates to hydrogel compositions and to methods of forming and using the hydrogel compositions. More particularly, the disclosure relates to hydrogel compositions having a first polymer network including ionic bonds and a second polymer network having covalent bonds, to methods of forming the polymers and compositions, and to methods of using the compositions.

Background

[0003] The vitreous material in the eye resides in the space between the lens and the retina. The vitreous is a gel material, comprised primarily of water and is generally clear. The vitreous serves several functions, including as a barrier to disease, providing or maintaining desired intraocular pressure, holding the retina and/or other tissue in place, circulating metabolites, maintaining the shape of the eye, and the like.

[0004] Unfortunately, the vitreous tends to degrade with age, trauma, and/or disease, becoming less gelatinous and more liquid. If left untreated, deteriorating vitreous can lead to posterior vitreous detachment, which can lead to retinal tears or detachment and intravitreal hemorrhaging. In addition, the vitreous can form fibers, sometimes referred to as "floaters" that can interfere with vision. Accordingly, several attempts have been made to find a suitable vitreous substitute.

[0005] Some of the first attempts of vitreous substitution included transplanting healthy vitreous from animal donors, such as calves and rabbits. Such techniques were further extended to human donors. However, these methods were generally unsuccessful, because they caused immune responses within a patient's eye, causing inflammation and further complications.

[0006] Various synthetic tamponade agents that can be injected into an eye have also been developed. However, several of such agents suffer drawbacks, including short residence times, toxicity, cataract formation, increased inflammation, glaucoma, band keratopathy, scar tissue formation, and increased intraocular pressure. One of the most common shortcomings of the synthetic tamponade agents is the degradability of any tamponade.

[0007] Accordingly, improved vitreous substitutes that mimic biomechanical properties of a (e.g., human) vitreous that can maintain desired properties for an extended period of time are desirable. In addition, compositions that can be injected into a vitreous region of an eye, including those that can be used to deliver drugs and/or be used as an adhesive, are desired.

Summary

[0008] The present disclosure generally relates to hydrogels and to methods of forming and using the hydrogels. More particularly, the disclosure relates to biocompatible hydrogels that can be used for various applications, including vitreous substitutes, adhesives, and drug delivery compositions. While the ways in which the compositions and methods address various drawbacks of prior compositions and methods will be discussed in greater detail below, in general, exemplary compositions have desirable properties, such as clarity, refractive index, viscosity and elastic modulus (e.g., that are the same or similar to the same properties of a healthy vitreous in an eye), and can be injected through a relatively small needle and retain or reform as a hydrogel. The inventors surprisingly were able to develop a clear, transparent composition with a desired refractive index and other desirable properties, wherein the composition has or exhibits the desirable properties after injection.

[0009] In accordance with exemplary embodiments of the disclosure, a hydrogel composition includes a first network comprising covalently bonded first polymers and a second network comprising second polymers, wherein the hydrogel comprises a sacrificial bond (e.g., a bond between the second polymers and/or a bond between the second polymers and the first polymers) selected from the group consisting of one or more of an ionic bond, an electrostatic bond, and a hydrogen bond. The composition can also include water, such as deionized water— e.g., about 80 wt% to about 95 wt% water. In accordance with various aspects of these embodiments, the hydrogel composition can pass through a 25-gauge or smaller needle and reform as a hydrogel. In accordance with further aspects, the hydrogel composition has a refractive index between about 1.33 and about 1.35. In accordance with further aspects, the hydrogel composition has a viscosity between about 300 cp and about 2000 cp. In accordance with yet further aspects, the elastic modulus (G') of the composition is between about 1.6 pa and about 14.8 pa. In accordance with yet further aspects, the composition is clear and/or transparent. In accordance with yet further exemplary aspects, the specific gravity of the hydrogel composition is between about 1.0053 and about 1.0089. By way of examples, the first polymers include one or more polymers selected from the group consisting of methacrylate, and acrylamide. The second polymer can include, for example, alginate (e.g., derived from sodium alginate) or chitosan. Exemplary compositions can be used as a vitreous substitute, an ocular adhesive, and/or as a drug delivery system.

[00010] In accordance with further exemplary embodiments of the disclosure, a system includes a delivery device and a composition, namely a hydrogel composition, as described herein. The delivery device can include, for example, a syringe— e.g., a syringe having a 25- gauge or smaller needle. The system can be used to inject the composition directly into a vitreous cavity or other area.

[00011] In accordance with yet further exemplary embodiments of the disclosure, a method of forming a hydrogel composition includes the steps of providing a first polymer that forms a first network comprising covalent bonds, providing a second polymer having side chains that form sacrificial (e.g. ionic , electrostatic, and/or hydrogen bonds) providing a salt, providing water, providing an initiating system, mixing the first polymer, the second polymer and a first portion of the water to form a first mixture, mixing the salt, the initiating system and a second portion of the water to form a second mixture, and mixing the first mixture and the second mixture to form a hydrogel. In accordance with various aspects of these embodiments, the first polymer comprises a polymer selected from the group consisting of one or more of methacrylate and acrylamide. In accordance with further examples, the second polymer comprises one or more of alginate and chitosan. The method can further include mixing a covalent crosslinker, such as PEGDA 575, with the first mixture. The resulting composition can have one or more of the hydrogel composition properties described herein.

[00012] Additional exemplary embodiments of the disclosure relate to the use of a hydrogel, such as the hydrogel compositions described herein, in the manufacture of a medicament for treatment of an eye. For example, exemplary hydrogel compositions can be used as a vitreous substitute, a drug delivery system, and/or as an ocular adhesive. [00013] In accordance with yet additional exemplary embodiments of the disclosure, a hydrogel composition includes a first network comprising covalent bonds between side chains of a first polymer selected from the group consisting of acrylamides methacrylate, acrylates, allyl ether, norbornenes and vinyl ethers and other monomers containing vinyl group and a second network comprising sacrificial bonds (e.g., ionic, electrostatic, and/or hydrogen bonds) between the second polymers and/or the second polymers and the first polymers, the second polymers selected from the group consisting of alginate and chitosan, wherein the first network and the second network are linked to form a hydrogel composition. In accordance with various aspects of these embodiments, the hydrogel further comprises water, e.g., deionized water. The water can be present in an amount of about 80 wt% to about 95 wt% water. In accordance with further aspects of these embodiments, the hydrogel composition can pass through a 25-gauge needle and reform as a hydrogel. In accordance with further aspects, the hydrogel composition has a refractive index between about 1.33 and about 1.35. In accordance with further aspects, the hydrogel composition has a viscosity between about 300 cp and about 2000 cp. In accordance with yet further aspects, the elastic modulus (G') of the composition is between about 1.6 pa and about 14.8 pa. In accordance with yet further aspects, the composition is clear and/or transparent. In accordance with yet further exemplary aspects, the specific gravity of the hydrogel composition is between about 1.0053 and about 1.0089. Exemplary compositions can be used as a vitreous substitute, an ocular adhesive, and/or as a drug delivery system.

[00014] In accordance with yet further exemplary embodiments of the disclosure, a method of forming a hydrogel composition includes the steps of providing positively charged methacrylated alginate, providing negatively charged alginate, and mixing the positively charged methacrylated alginate with the negatively charged alginate in water to form an ionically crosslinked network. In accordance with various aspects of these embodiments, the method further includes a step of covalently crosslinking the negatively charged alginate and the positively charged methacrylated alginate to form a highly crosslinked network and an ionically crosslinked network. In accordance with some exemplary aspects, the step of covalently crosslinking includes applying UV light to the crosslinked network.

[00015] In accordance with further exemplary embodiments of the disclosure, a method of treating an eye of an animal includes the steps of providing a hydrogel composition, such as a hydrogel composition described herein, and injecting the hydrogel composition into the eye. Exemplary methods can be used for vitreous substitution, for providing a drug delivery system including the hydrogel composition and a therapeutic agent, and/or providing an ocular adhesive. A method can include injecting the hydrogel composition through a small- gauge needle, such as a 25-gauge needle or smaller.

[00016] In accordance with further exemplary embodiments, exemplary hydrogel compositions, such as those described herein provide one or more of an antioxidant capacity, a free radical trap, and biological molecule trap.

Brief Description of the Drawing Figures

[00017] A more complete understanding of exemplary embodiments of the present disclosure may be derived by referring to the detailed description and claims when considered in connection with the following illustrative figures.

[00018] FIG. 1 is an illustration of a human eye.

[00019] FIGS. 2(a), 2(b) and 2(c) illustrate ionic and covalent bonds within exemplary hydrogels in accordance with various embodiments of the disclosure.

[00020] FIG. 3 illustrates modulus data for hydrogel compositions in accordance with exemplary embodiments of the disclosure.

[00021] FIG. 4 illustrates exemplary refractive index values of exemplary hydrogels in accordance with various embodiments of the disclosure.

[00022] FIG. 5 illustrates an exemplary method of forming methacrylated alginate in accordance with exemplary embodiments of the disclosure.

[00023] FIG. 6 illustrates an exemplary method of forming an exemplary hydrogel in accordance with further exemplary embodiments of the disclosure.

[00024] FIG. 7(a) illustrates a hydrogel after injection of an uncured sample through a 27- gauge needle in accordance with exemplary embodiments of the disclosure.

[00025] FIGS. 7(b) and 7(c) illustrate the hydrogel illustrated in FIG. 7(a) after UV curing.

[00026] It will be appreciated that the figures are not necessarily drawn to scale. For example, the dimensions of some of the elements in the figures may be exaggerated relative to other elements to help to improve understanding of illustrated embodiments of the present disclosure. Detailed Description of Embodiments of the Disclosure

[00027] The description of exemplary embodiments of the present disclosure provided below is merely exemplary and is intended for purposes of illustration only; the following description is not intended to limit the scope of the invention disclosed herein. Moreover, recitation of multiple embodiments having stated features is not intended to exclude other embodiments having additional features or other embodiments incorporating different combinations of the stated features.

[00028] Various exemplary embodiments of the disclosure provide a hydrogel suitable for use in a variety of applications. For example, exemplary hydrogels can be used as a vitreous substitute, an adhesive (e.g., an ocular adhesive), and/or as part of a drug delivery system that further includes one or more therapeutic agents. Exemplary therapeutic agents include: anti- fibrotic agent, anti-inflammatory agent, immunosuppressant agent, anti-neoplastic agent, migration inhibitors, anti-proliferative agent, rapamycin, triamcinolone acetonide, everolimus, tacrolimus, paclitaxel, actinomycin, azathioprine, dexamethasone, cyclosporine, bevacizumab, an anti-VEGF agent, an anti-IL-1 agent, canakinumab, an anti-IL-2 agent, viral vectors, beta blockers, alpha agonists, muscarinic agents, steroids, antibiotics, non-steroidal anti-inflammatory agents, prostaglandin analogues, ROCK inhibitors, nitric oxide, endothelin, matrixmetalloproteinase inhibitors, CNPA, corticosteroids, an antibody-based immunosuppressants, apatmers, medications that decrease eye pressure, medications that decrease edema in and around the eye, medications that treat neovascular diseases of the eye, and any combination thereof.

[00029] As set forth in more detail below, exemplary hydrogel compositions are transparent, optically clear, and when used as a vitreous substitute are thought to not cause inflammation, cataracts, glaucoma or scar tissue. Furthermore, exemplary hydrogels do not degrade or emulsify, and can therefor maintain an ocular volume over a sustained period of time (e.g., in in- vitro experiments, they have been observed to stay cohesive for up to 6 months), while providing desired clarity. Further, hydrogel compositions as described herein can exhibit globe stability, and are suitable for visual function. The physical properties of various exemplary hydrogel compositions exhibit a refractive index, transparency, specific gravity, and/or viscosity that match or substantially match (e.g., within about 5% or 10%) such properties of a healthy vitreous; this allows use of such compositions for long-term optical applications, such as vitreous substitution, ocular adhesive, and/or long-term (e.g., 6 weeks) drug delivery systems. Further, in accordance with some exemplary embodiments, the hydrogel compositions allow for in situ polymerization using various modes of polymerization to allow for low rates of free monomers in an aqueous and oxygen rich environment. The in-situ polymerization also allows for in-situ varying the physical properties of the hydrogel composition— e.g., polymerization or crosslinking of the composition after the composition has been injected into the vitreous cavity allows for additional tuning of physical properties of the hydrogel.

[00030] As set forth in more detail below, exemplary hydrogel compositions can be injected through a relatively small needle, such as 25-gauge, or smaller (e.g., 26- to 34- gauge) and form and/or reform a hydrogel after injection into a site. In accordance with various aspects of these embodiments, a composition can be a hydrogel, and pass through a needle or other high shear-force delivery device, where sacrificial bonds within the composition may break. The sacrificial bonds can then reform after injection, whereby the composition can reform as a hydrogel. Additional crosslinking of the composition after injection can also occur. The additional crosslinking can be used to fine-tune desired properties, such as viscosity and elastic modulus of the composition after injection.

[00031] Turning now to the figures, FIG. 1 illustrates an eye 100, including a lens 102, a retina 104, and a vitreous humor 106 (also referred to herein as a vitreous or vitreous material) that resides within a vitreous cavity 108. As noted above, vitreous humor 106 can degrade with time, disease, or trauma. In such circumstances, it may be desirable to remove and replace vitreous humor 106. As discussed in more detail below, exemplary hydrogel compositions exhibit clarity, transparency, a refractive index, a viscosity, and/or an elastic modulus value that is the same as or similar to the respective values for a healthy vitreous.

[00032] In accordance with some exemplary embodiments of the disclosure, a hydrogel composition includes a first polymer and a second polymer crosslinked with the fist polymer. In accordance with various aspects of these embodiments, a hydrogel composition includes a first network comprising covalently bonded first polymers and a second network comprising second polymers, wherein the hydrogel comprises a sacrificial bond, selected from the group consisting of one or more of an ionic bond, an electrostatic bond, and a hydrogen bond, between one or more of the polymers of the second network and the polymers of the second network and the polymers of the first network. The composition can also include water, such as deionized water, salt, such as calcium sulfate, polymerization initiators, such as APS and TEMED, described below, and/or covalent crosslinker(s), such as PEGDA 575.

[00033] The sacrificial bonds (e.g., ionic bonds, electrostatic bonds, and/or hydrogen bonds) can be reversible, such that as the composition passes through a high shear-force delivery device (e.g., a needle having a 25-gauge or smaller needle), the sacrificial bonds break, while the covalent bonds of the hydrogel composition remain substantially intact. The sacrificial bonds can then reform after injection into a site, thereby forming or reforming the hydrogel.

[00034] In accordance with exemplary embodiments of the disclosure, the first polymers comprise one or more polymers selected from the group consisting of acrylamides methacrylates, acrylates, allyl ether, norbornenes and vinyl ethers and other monomers containing vinyl group. FIG. 2(a) illustrates ionic bonds 202 formed between first polymers (e.g., acrylamide polymers) 204. The ionic bonds can include a cation 203, such as Ca²⁺ from a salt. The ionic bonds can be reversibly broken and illustrate one form of sacrificial bond.

[00035] The second polymers can include, for example, one or more of alginate (e.g., alginate derived from sodium alginate, available from Sigma-Aldrich) and chitosan. FIG. 2(b) illustrates covalent bonds 206 that form between second polymers (e.g., alginate polymers) 208. In the illustrated example, the covalent bonds form between side chains of the second polymer, thereby facilitating gel formation. In accordance with illustrative examples, bonds 210 between the first and second polymers do cleave and therefore, the hydrogel does not undergo phase separation; thus, the hydrogel remains as an intact system. The multiple bonds fortify the hydrogel and minimize degradation of the hydrogel over time.

[00036] In accordance with additional exemplary embodiments of the disclosure, a hydrogel includes a first network comprising covalent bonds between side chains of a first polymer selected from the group consisting of acrylamides methacrylate, acrylates, allyl ether, norbornenes and vinyl ethers and other monomers containing vinyl group and second network comprising sacrificial bonds (e.g., ionic bonds) between the second polymers— e.g., selected from the group consisting of alginate and chitosan, wherein the first network and the second network form a hydrogel— e.g., are linked to form a hydrogel composition. The hydrogel composition can also suitably include about 80-95 or 90-95 wt% (e.g., deionized) water, one or more salts, and/or one or more crosslinking and/or initiating system agents as noted herein.

[00037] Methods of Forming a Hydrogel

[00038] In accordance with additional exemplary embodiments of the disclosure, methods of forming a hydrogel composition include the steps of: providing a first polymer that forms a first network comprising covalent bonds, providing a second polymer having side chains that form sacrificial bonds (e.g., ionic, electrostatic, and/or hydrogen bonds) providing a salt, providing water, providing an initiating system, mixing the first polymer, the second polymer and a first portion of the water to form a first mixture, mixing the salt, the initiating system and a second portion of the water to form a second mixture, and mixing the first mixture and the second mixture to form a hydrogel. The first and second polymers can be the same as the first and second polymers noted herein. Exemplary methods can additionally include a step of adding a crosslinker (e.g., PEGDA 575), such as a first polymer crosslinker to the first mixture.

[00039] In accordance with additional exemplary embodiments of the disclosure, the hydrogel includes methacrylated alginate. In these cases, a robust hydrogel composition can be formed by additional covalent crosslinks between the methacrylated alginate and the vinyl groups present within the hydrogel network. FIGS. 5 and 6 illustrate exemplary methods of forming methacrylated alginate and a hydrogel including the methacrylated alginate.

[00040] With reference to FIG. 5, the methacrylated alginate can be prepared accordingly by reacting sodium alginate with 2-aminoethyl methacrylate in the presence of N- hydroxy succinimide (NHS) and l -ethyl-3-(3-dimethylaminopropyl carbodiimide hydrochloride (EDC). An exemplary method of forming methacrylated alginate is disclosed in Jeon, O.; Bouhadir, K. H. ; Mansour, J. M. ; Alsberg, E. Biomaterials 2009, 30, 2724-2734, the contents of which are hereby incorporated herein by reference to the extent such contents do not conflict with the present disclosure.

[00041] A hydrogel composition including the methacrylated alginate can be prepared by mixing the positively charged methacrylated alginate with the negatively charged calcium sulfate alginate in water. Initially, the calcium sulfate and methacrylated alginate can form an ionically crosslinked network. During the injection of vitreous substitute by, for example, a 27-gauge needle, the ionic bonds break down to ease the injection procedure. Once the vitreous substitute is set in the eye, the ionic bonds are reformed and the methacrylated alginate can also be further crosslinked covalently by a UV light to form a highly crosslinked network, as illustrated in FIG. 6. Other chemicals, such as 2-hydroxyethyl acrylate (HEA) and Poly(ethylene glycol) diacrylate (Mn=575 g/mol) (PEGDA 575), can be used in conjunction with methacrylated alginate and sodium alginate to change the overall properties of the vitreous substitute.

[00042] Examples

[00043] Examples 1 -3 [00044] To create the hydrogel, the appropriate masses of alginate and acrylamide are added to half of the amount of DI water and vortexed this system. In a separate tube, we added the appropriate masses of calcium disulfate dihydrate (CaSO4*2H20), ammonium persulfate (APS), N,N-methylenebisacrylamide (MBAA), and Ν,Ν,Ν',Ν'- tetramethylethylenediamine (TEMED) in the remaining amount of DI water. After mixing both of these samples, we let it sit for 24 hours in a sealed tube. Various gels formed using this techniques are presented in the table below.

[00045] *The weight percent indicates a weight percent of water in the composition.

[00046] The hydrogels noted above were transparent, clear, and colorless. The samples with 95% water appear to maintain an appearance most similar to a natural, healthy human vitreous for the longest period of time.

[00047] A rheometer was used to measure the elastic modulus of the samples. To operate the rheometer once the sample is loaded, a strain sweep curve gives the relative strain range that yields a constant modulus value (G') for a constant frequency. The frequency was kept constant for all tests at 5 Hz. The general range of the strain for the strain sweep was between 1 and 300. Then, a time sweep analyzed the G' values over 300 seconds. These values were then averaged. FIG. 3 illustrates elastic modulus values for the hydrogel compositions formed according to examples 1-3.

[00048] In the illustrative examples 1-3, modifying the mass of alginate and its crosslinker affected the swelling of the hydrogel created, thus affecting the degradability of the hydrogel. Altering the mass of acrylamide and its activator affected the stiffness and transparency of the hydrogel. Halving the mass of alginate (1/2 alginate) and quartering the mass of CaSO4*2H20 (1/4 CaSO4*2H20) helped the hydrogel maintain its shape and its heterogeneity. As well, reducing the acrylamide to two thirds of the normal amount (2/3 acrylamide) and its activator most closely mimicked the vitreous of a human.

[00049] Refractive index values for Gel 1 and Gel 2, as measured using a refractometer, are illustrated in FIG. 4.

[00050] Example 4

[00051] A hydrogel composition including 95 wt% DI water, with 1/2 algin, 1/4 CaSO4*2H20, and 1/2 acrylamide was formed according to the above method. The hydrogel withstood transportation and injection through a 32 G syringe without altering its structure immediately after formation and at different time points.

[00052] Example 5

[00053] A hydrogel was formed according to the following procedure: in a vial, add in 4ml of water via syringe; add the appropriate measurements of alginate, then mix via vortex and add HEA and vortex. Care was taken to not move the vial after HEA was added so bubbles would not form.

[00054] In a centrifuge tube, add the appropriate measurements of Ca2S04 followed by APS.

[00055] In a separate new vial, add lml of water along with PEGDA-575 and vortex.

[00056] Mix the new vial contents in the centrifuge tube then vortex, add the TEMED quickly via pipette and mix. Rapidly add the centrifuge tube contents to the vial with alginate and mix gently.

[00057] Label vial and let cure for a day or so, then add 2.5-5 ml water until desired consistency is met.

[00058] Mixing order

1)

Vial 1

4 ml water

Alginate

HEA/Acrylamide

2)

Centrifuge tube

Ca2SQ4

APS 3)

Vial 2

1 ml water

PEGDA-575

TEM ED

[00059] Pour vial 2 into centrifuge tube after TEMED is added, then adding the tube contents to vial 1 *must be done quickly.

[00060] When making the gels with MBAA:PEGDA, add the MBAA with Vial 1 and it is added as the last component.

[00061] Example 6

[00062] The composition of Example 6 was formed using the method described above connection with Example 5.

S2. 90 wt% Alginate, HEA, PEGDA

[00063] Example 7

[00064] The composition of Example 7 was formed using the method described above in connection with Example 5.

HEA 12.4 0.23 g

Ca2S04 0.028 0.002

APS 0.1 0.0056

MBAA 0.002 .0002

PEGDA-575 0.002 3 ul

TEMED 0.004 0.0003

[00065] Example 8

[00066] The composition of Example 8 was formed using the method described above in connection with Example 5.

S4: 95 wt% Al inate, Acr larnide, MBAA

[00067] Examples 9-12, corresponding to formulation nos. 1-4.

[00068] The tables below illustrate properties of hydrogels formed by mixing positively charged methacrylated alginate with the negatively charged calcium sulfate alginate in water, as described above. The polymer wt% in the table below indicated the wt/v% of the hydrogel polymer in water.

Chemical components of formulations designed for vitreous substitute study.

[00069] FIGS. 7(a)-7(c) illustrate formulation no. 4 after inj ection of uncured sample through a 27-gauge needle. The sample is then cured under UV, between glass slides, for 5 minutes using the Omnicure 2000 series UV light source at the intensity of 320 mW/cm2. FIG. 7(b) illustrates the optical clarity of cured sample while FIG. 7(c) illustrates the durability and flexibility of cured sample.

[00070] Properties of Exemplary Hydrogels

[00071] Exemplary hydrogels formed according to the techniques described above can pass through a 25-gauge to 32-gauge needle and form a hydrogel after injection. Exemplary hydrogels have a refractive index between about 1.33 and about 1.35 or between 1.33 and 1.34. Further, exemplary hydrogels have a viscosity between about 300 cp and about 2000 cp or between 400 cp and 1800 cp. The elastic modulus of the hydrogel composition can be between about 1.6 Pa and about 14.8 Pa or between 1.5 Pa and 15 Pa. The specific gravity of the composition can be between about 1.0053 and about 1.0089 or between 1.006 and 1.009. Further, the hydrogels of the above examples were clear and transparent. Further, the pH of the composition can be between about 7.0 and about 7.4 or between 7 and 7.5.

[00072] Uses

[00073] Reduce cataract formation- The increase in oxygen tension in the vitreous cavity after vitrectomy has been implicated in cataract formation. Oxidative stress to the lens increases nuclear sclerosis and cataract formation. Exemplary hydrogel composition as described herein when used as a vitreous substitute will decrease the rate of cataract formation seen with current vitrectomy and vitreous substitutes by leveraging anti-oxidant capabilities within the vitreous scaffold. Methods for imparting anti-oxidant capabilities include both long-term and short-term solutions. Short-term solutions include addition of anti-oxidants such as ethyl pyruvate to the scaffold. Long-term solutions include the addition of oxygen radical scavengers to the backbone of the vitreous scaffold.

[00074] Reduce glaucoma- Others have reported an increase in glaucoma development after vitrectomy. The increase in oxygen tension in the vitreous cavity after vitrectomy has been implicated in glaucoma development. Oxidative stress to the trabecular meshwork causes irreversible damage to this delicate structure. The anti-oxidant capabilities described above will be leveraged to decrease the rate of glaucoma formation.

[00075] Drug delivery- Exemplary hydrogel compositions have chemical properties, which allow for slow release of drug to the retina, choroid, ciliary body, trabecular meshwork, lens, and cornea. The drug delivery can be, for example, via molecular donating or molecular trapping.

[00076] Long-term tamponade agent-exemplary hydrogel compositions have the appropriate physical properties to allow for long-term tamponade of retinal breaks and retina and use of such compositions have fewer complications. This will prevent re-detachment of the retina. Current vitreous substitutes are fraught with complications, as they do not match the physical characteristics of natural human vitreous. Inflammation, scar tissue formation, emulsification, and damage to retina secondary to compressive effects of the tamponade agents are common with long-term instillation of agents such as silicone oil and liquid perfluorocarbons. Exemplary vitreous substitutes as described herein result in less of all of these complications due to matching of the physical properties measured in natural, healthy human vitreous.

[00077] Further exemplary embodiments of the disclosure include the use of a composition as described herein in the manufacture of a medicament. The medicament can be used for, for example, a vitreous substitute, an ocular adhesive, and/or a drug delivery system that includes a therapeutic agent.

[00078] Systems

[00079] In accordance with yet additional exemplary embodiments of the disclosure, a system (e.g., a drug delivery system) includes a hydrogel composition as described herein and a delivery device. Exemplary delivery devices include syringes, such as syringes having a 25-, 26- 26s-, or 27- to 34-gauge needle.

[00080] Specific Examples:

1. A hydrogel composition comprising:

a first network comprising covalently bonded first polymers; and

a second network comprising second polymers,

wherein the hydrogel comprises a sacrificial bond, selected from the group consisting of one or more of an ionic bond, an electrostatic bond, and a hydrogen bond, between one or more of the polymers of the second network and the polymers of the second network and the polymers of the first network.

2. The hydrogel composition of example 1 , further comprising water. 3. The hydrogel composition of any of examples 1 and 2, wherein the hydrogel composition can pass through a 25-gauge needle and reform as a hydrogel.

4. The hydrogel composition of any of examples 1-3, wherein the hydrogel composition has a refractive index between about 1.33 and about 1.35.

5. The hydrogel composition of any of examples 1-4, wherein the hydrogel composition has a refractive index between 1.33 and 1.34.

6. The hydrogel composition of any of examples 1-5, wherein the hydrogel composition has a viscosity between about 300 cp and about 2000 cp.

7. The hydrogel composition of any of examples 1-6, wherein the hydrogel composition has a viscosity between 400 cp and 1800 cp.

8. The hydrogel composition of any of examples 1-7, wherein the elastic modulus (G ) of the composition is between about 1.6 Pa and about 14.8 Pa.

9. The hydrogel composition of any of examples 1-8, wherein the elastic modulus (G ) of the_composition is between 1.5 Pa and 15 Pa.

10. The hydrogel composition of any of examples 1-9, wherein the hydrogel composition is clear.

11. The hydrogel composition of any of examples 1-10, wherein the hydrogel composition is transparent.

12. The hydrogel composition of any of examples 1-11, wherein a specific gravity of the composition is between about 1.0053 and about 1.0089.

13. The hydrogel composition of any of examples 1-12, wherein a specific gravity of the composition is between 1.006 and 1.009. 14. The hydrogel composition of any of examples 1-13, wherein the hydrogel composition comprises about 80 wt% to about 95 wt% water.

15. The hydrogel composition of any of examples 1-14, wherein the hydrogel composition comprises 90 wt% to 95 wt% water.

16. The hydrogel composition of any of examples 2-15, wherein the water is deionized water. 17. The hydrogel composition of any of examples 1-16, wherein the second polymers comprise alginate.

18. The hydrogel composition of example 17, wherein alginate is derived from sodium alginate.

19. The hydrogel composition of any of examples 1-16, wherein the second polymer comprises chitosan.

20. The hydrogel composition of any of examples 1-19, wherein the first polymers comprise one or more polymers selected from the group consisting of acrylamides methacrylate, acrylates, allyl ether, norbomenes and vinyl ethers and other monomers containing vinyl group.

21. The hydrogel composition of any of examples 1-20, wherein extruding the composition through a needle having a size of 25 -gauge or smaller causes the ionic bonds of the composition to break while the covalent bonds remain substantially (>90, 95, 99, or 99.9%) unbroken.

22. An ocular adhesive comprising the composition of any of examples 1-21.

23. A vitreous substitute comprising the composition of any of examples 1-21.

24. A drug delivery system comprising the composition of any of examples 1-21 and a therapeutic agent. 25. The drug delivery system of example 24, wherein the therapeutic agent is selected from the group consisting of anti-fibrotic agent, anti-inflammatory agent, immunosuppressant agent, anti-neoplastic agent, migration inhibitors, anti-proliferative agent, rapamycin, triamcinolone acetonide, everolimus, tacrolimus, paclitaxel, actinomycin, azathioprine, dexamethasone, cyclosporine, bevacizumab, an anti-VEGF agent, an anti-IL-1 agent, canakinumab, an anti-IL-2 agent, viral vectors, beta blockers, alpha agonists, muscarinic agents, steroids, antibiotics, non-steroidal anti-inflammatory agents, prostaglandin analogues, ROCK inhibitors, nitric oxide, endothelin, matrixmetalloproteinase inhibitors, CNPA, corticosteroids, an antibody-based immunosuppressants, apatmers, medications that decrease eye pressure, medications that decrease edema in and around the eye, medications that treat neovascular diseases of the eye, and any combination thereof.

26. A system comprising:

a delivery device; and

a composition according to any of examples 1 -21.

27. The system of example 26, wherein the delivery device comprises a syringe.

28. The system of example 27, wherein the syringe is 25-gauge or smaller.

29. A method of forming a hydrogel composition, the method comprising the steps of: providing a first polymer that forms a first network comprising covalent bonds;

providing a second polymer having side chains that form sacrificial bonds;

providing a salt;

providing water;

providing an initiating system;

mixing the first polymer, the second polymer and a first portion of the water to form a first mixture;

mixing the salt, the initiating system and a second portion of the water to form a second mixture; and

mixing the first mixture and the second mixture to form a hydrogel. 30. The method of example 29, wherein the first polymer comprises a polymer selected from the group consisting of one or more of acrylamides methacrylate, acrylates, allyl ether, norbornenes and vinyl ethers and other monomers containing vinyl group. 31. The method of any of examples 29 and 30, wherein the second polymer comprises one or more of alginate and chitosan.

32. The method of any of examples 29-31 , further comprising a step of mixing a covalent crosslinker with the first mixture.

33. The method of example 32, wherein the crosslinker comprises PEGDA 575.

34. The use of a hydrogel of any of examples 1 -21 in the manufacture of a medicament for treatment of an eye.

35. The use of a hydrogel of any of examples 1 -21 in the manufacture of a medicament for a vitreous substitute.

36. The use of a hydrogel of any of examples 1 -21 in the manufacture of a medicament for an ocular adhesive.

37. A hydrogel composition comprising:

a first network comprising covalent bonds between side chains of a first polymer selected from the group consisting of acrylamides methacrylate, acrylates, allyl ether, norbornenes and vinyl ethers and other monomers containing vinyl group; and

a second network comprising sacrificial bonds between the second polymers selected from the group consisting of alginate and chitosan, wherein the first network and the second network are linked to form a hydrogel composition. 38. The hydrogel composition of example 37, further comprising water.

39. The hydrogel composition of any of examples 37 and 38, wherein the hydrogel composition can pass through a 25-gauge needle and reform as a hydrogel. 40. The hydrogel composition of any of examples 37-39, wherein the hydrogel composition has a refractive index between about 1.33 and about 1.35.

41. The hydrogel composition of any of examples 37-40, wherein the hydrogel composition has a refractive index between 1.33 and 1.34.

42. The hydrogel composition of any of examples 37-41, wherein the hydrogel composition has a viscosity between about 300 cp and about 2000 cp. 43. The hydrogel composition of any of examples 37-42, wherein the hydrogel composition has a viscosity between 400 cp and 1800 cp.

44. The hydrogel composition of any of examples 37-43, wherein the elastic modulus (G ) of the composition is between about 1.6 pa and about 14.8 pa.

45. The hydrogel composition of any of examples 37-44, wherein the elastic modulus (G ) of the composition is between 1.5 Pa and 15 Pa.

46. The hydrogel composition of any of examples 37-45, wherein the hydrogel composition is clear.

47. The hydrogel composition of any of examples 37-46, wherein the hydrogel composition is transparent. 48. The hydrogel composition of any of examples 37-47, wherein a specific gravity of the composition is between about 1.0053 and about 1.0089.

49. The hydrogel composition of any of examples 37-48, wherein a specific gravity of the composition is between 1.0053 and 1.0089.

50. The hydrogel composition of any of examples 37-49, wherein the hydrogel composition comprises about 90 wt% to about 95 wt% water. 51. The hydrogel composition of any of examples 37-50, wherein the hydrogel composition comprises 80 wt% to 95 wt% water.

52. The hydrogel composition of any of examples 38-51 , wherein the water is deionized water.

53. A method of forming a hydrogel composition, the method comprising the steps of: providing positively charged methacrylated alginate;

providing negatively charged alginate; and

mixing the positively charged methacrylated alginate with the negatively charged alginate in water to form an ionically crosslinked network.

54. The method of example 53, further comprising a step of covalently crosslinking the negatively charged alginate and the positively charged methacrylated alginate to form a highly crosslinked network and an ionically crosslinked network.

55. The method of example 54, wherein the step of covalently crosslinking comprises applying UV light to the crosslinked network. 56. The method of any of examples 53-55, further comprising the steps of providing HEA and mixing the HEA with the positively charged methacrylated alginate and the negatively charged alginate.

57. The method of any of examples 53-56, wherein negatively charged alginate comprises calcium sulfate alginate.

58. The method of any of examples 53-57, further comprising the step of providing PEGDA

575.

59. A method of treating an eye of an animal, the method comprising the steps of:

providing a hydrogel composition according to any of examples 1-21 and 37-52; and injecting the hydrogel composition into the eye. 60. The method of example 59, wherein the method includes vitreous substitution.

61. The method of example 60, wherein the method includes applying an ocular adhesive.

62. The method of any of examples 59-61, wherein the step of injecting comprises passing the hydrogel through a 25-gauge or smaller needle.

63. The method of any of examples 59-62, further comprising providing a sustained release of a therapeutic agent using the hydrogel.

64. The method of example 63, wherein the sustained release is obtained using one or more of molecular donating and molecular trapping.

65. A vitreous tamponade agent comprising a hydrogel composition of any of examples 1-21, 37-51 that carries surface tension and other physical properties that allow the retina to remain attached and prevent fluid from traveling through a retinal break.

[00081] The present disclosure has been described above with reference to a number of exemplary embodiments and examples. It should be appreciated that the particular embodiments shown and described herein are illustrative of the exemplary embodiments of the disclosure, and are not intended to limit the scope of the invention. It will be recognized that changes and modifications may be made to the embodiments described herein without departing from the scope of the present disclosure. These and other changes or modifications are intended to be included within the scope of the present disclosure.

Claims

We Claim:

1. A hydrogel composition comprising:

a first network comprising covalently bonded first polymers; and

a second network comprising second polymers,

2. The hydrogel composition of claim 1 , further comprising water.

3. The hydrogel composition of any of claims 1-2, wherein the hydrogel composition can pass through a 25-gauge needle and reform as a hydrogel.

4. The hydrogel composition of any of claims 1-2, wherein the hydrogel composition has a refractive index between about 1.33 and about 1.35.

5. The hydrogel composition of any of claims 1-2, wherein the hydrogel composition has a viscosity between 300 cp and 2000 cp.

6. The hydrogel composition of any of claims 1-2, wherein the elastic modulus (G ) of the composition is between about 1.6 Pa and about 14.8 Pa.

7. The hydrogel composition of any of claims 1-2, wherein the second polymers comprise alginate.

8. The hydrogel composition of any of claims 1 -2, wherein the second polymer comprises chitosan.

9. The hydrogel composition of any of claims 1 -2, wherein the first polymers comprise one or more polymers selected from the group consisting of acrylamides methacrylate, acrylates, allyl ether, norbomenes and vinyl ethers and other monomers containing vinyl group.

10. An ocular adhesive comprising the composition of any of claims 1 -2.

11. A vitreous substitute comprising the composition of any of claims 1 -2.

12. A drug delivery system comprising the composition of any of claims 1-2 and a therapeutic agent.

13. A system comprising:

a delivery device; and

a composition according to any of claims 1 -2.

14. The system of claim 13, wherein the delivery device comprises a syringe.

15. The system of claim 14, wherein the syringe is 25-gauge or smaller.

16. A method of forming a hydrogel composition, the method comprising the steps of: providing a first polymer that forms a first network comprising covalent bonds;

providing a second polymer having side chains that form sacrificial bonds;

providing a salt;

providing water;

providing an initiating system;

mixing the first mixture and the second mixture to form a hydrogel.

17. The method of claim 16, wherein the first polymer comprises a polymer selected from the group consisting of one or more of acrylamides methacrylate, acrylates, allyl ether, norbornenes and vinyl ethers and other monomers containing vinyl group.

18. The method of any of claims 16-17, wherein the second polymer comprises one or more of alginate and chitosan.

19. The method of any of claims 16-17, further comprising a step of mixing a covalent crosslinker with the first mixture.

20. The use of a hydrogel of any of claims 1 -2 in the manufacture of a medicament for treatment of an eye.