EP-4736897-A2 - HYDROGEL-BASED BIOLOGICAL DELIVERY VEHICLE

Abstract

A hydrogel-based biological delivery vehicle used to effectively deliver drug and biological material to tissue or organ sites. More specifically, a hydrogel binding matrix having a biopolymer backbone containing carboxyl groups. Tyramine may be substituted for at least a portion of the carboxyl groups, so that, when hydrogen peroxide is added, it causes creation of covalent bonds between tyramine molecules and cross-links the hydrogel binding matrix, thereby enabling the hydrogel binding matrix to transition from liquid to gel state. The hydrogel binding matrix, in its liquid form, is capable of encapsulating drug reservoirs to create a homogenous liquid with evenly distributed particles containing drugs or target molecules. As the hydrogel binding matrix solidifies into a gel state, the newly created cross-links do not disrupt or react with the drugs or target molecules contained within the drug reservoirs. This hydrogel-based biological delivery vehicle can be used in several medical applications.

Inventors

• TAYLOR, WILLIAM
• SIPPLE, Daniel
• SEGERMARK, JAMES

Assignees

• Insitu Biologics, Inc.

Dates

Publication Date

20260506

Application Date

20170512

Claims (14)

1. A hydrogel-based biological delivery vehicle for delivering target molecules into a biological organism, comprising: a binding matrix having water, a hydrogel matrix, an enzyme, a cross-linking agent, and a plurality of drug reservoirs, wherein: the hydrogel matrix is comprised of tyramine substituted sodium hyaluronate with tyramine substitution at 1.0%-5.0%; the enzyme is horseradish peroxidase; the cross-linking agent is hydrogen peroxide; the plurality of drug reservoirs are selected from the group consisting of liposomes, dense hydrogel particles, porous particles, cellulosic particles, concentrated aggregations of a plurality of target molecules, and combinations thereof; and at least one of the plurality of target molecules is associated with the at least one drug reservoir; the hydrogel matrix is capable of encapsulating the drug reservoir and creating a homogenous liquid with the at least one drug reservoir evenly distributed throughout; and the hydrogel matrix is capable of solidifying from a liquid state into a solid state by creating covalent bonds between the tyramine molecules that do not disrupt or react with the drug reservoirs or the target molecules.
2. The hydrogel-based biological delivery vehicle of claim 1, wherein no more than five and one half percent of the carboxyl groups on the biopolymer hydrogel matrix of the biding matrix are substituted with tyramine molecules.
3. The hydrogel-based biological delivery vehicle of claim 2, wherein between one and five percent of the binding matrix is comprised of the biopolymer hydrogel matrix of the binding matrix.
4. The hydrogel-based biological delivery vehicle of claim 3, wherein the plurality of drug reservoirs include dense hydrogel particles comprised of: water; a hydrogel matrix having a biopolymer containing carboxyl groups, wherein each of at least some of the carboxyl groups are substituted with a tyramine molecule; horseradish peroxidase; target molecules solubilized in the hydrogel matrix; and a cross-linking agent; wherein, the combination of the hydrogel matrix, horseradish peroxidase, target molecules, and the cross-linking agent create a solid hydrogel matrix with bound target molecules configured to be ground and sized to uniform diameter drug reservoirs
5. The hydrogel-based biological delivery vehicle of claim 4, wherein at least five percent of the carboxyl groups on the biopolymer hydrogel matrix of the dense hydrogel particles are substituted with tyramine molecules.
6. The hydrogel-based biological delivery vehicle of claim 4, wherein between fifteen and twenty percent of the dense hydrogel particles are comprised of the biopolymer.
7. A dense, hydrogel-based drug reservoir comprising: water; a hydrogel matrix having a biopolymer containing carboxyl groups, wherein each of at least some of the carboxyl groups are substituted with a tyramine molecule; horseradish peroxidase; target molecules solubilized in the hydrogel matrix; and a cross-linking agent; wherein, the combination of the hydrogel matrix, horseradish peroxidase, target molecules, and the cross-linking agent create a solid hydrogel matrix with bound target molecules configured to be ground and sized to uniform diameter drug reservoirs.
8. The dense, hydrogel-based drug reservoir of claim 7, wherein at least five percent of the carboxyl groups on the biopolymer hydrogel matrix are substituted with tyramine molecules.
9. The dense, hydrogel-based drug reservoir of claim 8, wherein the biopolymer includes sodium hyaluronate.
10. The dense, hydrogel-based drug reservoir of claim 8, wherein between fifteen and twenty percent of the dense, hydrogel-based drug reservoir is comprised of the biopolymer.
11. The dense, hydrogel-based drug reservoir of claim 8, wherein the biopolymer includes proteins.
12. The dense, hydrogel-based drug reservoir of claim 7, wherein the uniform diameter drug reservoirs are added to a binding matrix, the binding matrix comprised of: a hydrogel matrix having a biopolymer containing carboxyl groups, wherein less than five percent of the carboxyl groups are substituted with a tyramine molecule; horseradish peroxidase; and a cross-linking agent; wherein, the combination of the hydrogel matrix, horseradish peroxidase, and the cross-linking agent create the binding matrix with bound uniform diameter drug reservoirs.
13. The dense, hydrogel-based drug reservoir of claim 12, wherein no more than five and one half percent of the carboxyl groups on the biopolymer hydrogel matrix of the biding matrix are substituted with tyramine molecules.
14. The dense, hydrogel-based drug reservoir of claim 13, wherein between one and five percent of the binding matrix is comprised of the biopolymer hydrogel matrix of the binding matrix.

Description

CROSS-REFERENCE TO RELATED APPLICATION This application claims the benefit of U.S. Provisional Application No. 62/335,457, filed May 12, 2016 titled HYDROGEL-BASED BIOLOGICAL DELIVERY VEHICLE. FIELD OF THE INVENTION This disclosure relates to a hydrogel binding matrix used to effectively deliver drug and biological material formulations. More specifically, it relates to a hydrogel binding matrix that creates cross-links when it transitions from liquid to gel state. The hydrogel binding matrix, in its liquid form, is capable of encapsulating drug reservoirs to create a homogenous liquid with evenly distributed particles containing one or more target molecules. As the hydrogel binding matrix solidifies into a gel state, it creates cross-links that do not disrupt or react with the one or more target molecules contained within the drug reservoirs. This hydrogel-based biological delivery vehicle can be used in a variety of medical applications. BACKGROUND OF THE INVENTION Hydrogels have become popular in medical application for several reasons. To form them, frequently they need to be cross-linked using free-radical generating compounds or other radiation. However, this results in residual material that needs to be removed due to its potentially dangerous effects to the receiving subject. Additionally, drugs or medications are usually added to a hydrogel through passive diffusion or by using thermal treatment or irradiation. These are not ideal ways to load hydrogels, though, because passive diffusion results in low concentrations of the drugs or medications, and thermal treatment or irradiation often cause drug agents to react with the hydrogel or damage or inactivate biological agents. Liposome formulations are often dilute and have a viscosity relatively close to water. When used as a drug delivery vehicle, the liposome formulations can easily extrude back out of the injection site or drain away from targeted tissues through the interstitial spaces and carry the drug or target molecule away from the targeted site. Liposomes sometimes have unpredictable stability. For example, they may release the target molecule too quickly if they coalesce and quickly break apart or, if they are sufficiently dilute, they may remain stable and prevent the target molecule from being delivered to the target tissue in a timely fashion. Other forms of alternative drug delivery vehicles or drug reservoirs also exist, such as dense hydrogel particles or porous particles. However, particles also migrate after injection or placement and are prone to aggregating in one spot. Therefore, a solution is needed that enables a hydrogel to cross-link without creating residual material, that promotes higher level of drug/medication concentration loading, that does not react with or deactivate drugs/medications loaded into the hydrogel, and that enables drug delivery vehicles, also referred to as drug reservoirs, to have more stability and to release at a predictable rate in a desired location. SUMMARY OF THE INVENTION The hydrogel binding matrix disclosed herein acts as a support to keep drug reservoirs dispersed evenly throughout the hydrogel binding matrix when it is implanted in or on a subject. The hydrogel binding matrix does not significantly hinder diffusion and elution of the active target molecule from the drug reservoir. According to one embodiment, the desired hydrogel formulation can be adjusted to impact diffusion of the target molecule and increase or decrease the elution rate. More specifically, the hydrogel binding matrix disclosed herein addresses problems with liposome formulation stability and release by allowing the liposome formulation to be encapsulated within a liquid formation of a hydrogel before cross-linking occurs. This creates a homogenous liquid with liposomes thoroughly mixed throughout. Once mixed, the relatively gentle reaction conditions that create cross-links within the hydrogel do not disrupt the liposomes or react with the liposome components or the drugs or target molecules that are contained within the liposomes. The hydrogel binding matrix disclosed herein also addresses problems with entrained particle formulation release by suspending and evenly dispersing the particles throughout the hydrogel and retaining them in place relative to each other. This allows for even and predictable elution of the drug from the particles after injection or placement into a specific delivery site. Whereas the liposome elution depends on a physical separation of the target molecule from its surroundings with a lipid bilayer, the particles elute target molecules depending on diffusion from the particle. Diffusion is dependent upon the target molecule's affinity for the particle material, the path tortuosity, osmotic changes within and at the particle boundary, and chemical potential and the resulting chemical gradient. Sometimes a phase change can be a limiting step if the target molecule has to first dissolve into the su