WO2014062538A1

WO2014062538A1 - Polysaccharide-containing hydrogels, compositions, articles, and methods

Info

Publication number: WO2014062538A1
Application number: PCT/US2013/064770
Authority: WO
Inventors: HongQian BAO; Melvin Zin; Chi-Ying M. LEE; Melvina LEOLUKMAN
Original assignee: 3M Innovative Properties Company
Priority date: 2012-10-19
Filing date: 2013-10-14
Publication date: 2014-04-24

Abstract

A hydrogel comprising a polysaccharide and a gelling agent, wherein the gelling agent can be an active agent. Such hydrogels can be combined with optional secondary active agents and/or other optional additives, and used in medical compositions and articles, for example. Preferred hydrogels comprise xyloglucan as polysaccharide and gallic acid as gelling agent.

Description

POLYSACCHARIDE-CONTAINING HYDROGELS,

COMPOSITIONS, ARTICLES, AND METHODS

Cross Reference To Related Application

This application claims the benefit of U.S. Provisional Patent Application No.

61/716254, filed October 19, 2012, the disclosure of which is incorporated by reference herein in its entirety.

Background

Hydrogels are composed of hydrophilic homopolymer or copolymer networks and can swell in the presence of water or physiological fluids. "Smart" hydrogels, i.e., hydrogels that have the ability to respond to external stimuli, represent an emerging class of materials of particular interest. These polymeric materials can respond to stimuli such as pH, temperature, ionic strength, electric or magnetic field, light, chemical stimuli, and/or biological stimuli. Thus, they have a wide range of biomedical applications, including, for example, sensors, drug delivery, gene delivery and tissue engineering.

In recent years, stimuli-responsive polymers have been used in drug delivery systems (DDS). Drug delivery, as the name suggests, is the method or process of administering a pharmaceutical compound (drug) to achieve a therapeutic effect in humans or animals. Key factors are to deliver the drug to the right area, at the right time, and at the right concentration. However, there are many obstacles to achieving successful drug delivery. Such obstacles include a drug's low solubility, environmental or enzymatic degradation, fast clearance rate from the body, non-specific toxicity, and inability to cross a biological barrier. In order to overcome such obstacles, drug delivery carriers are being used, most of which are based on polymers. "Smart" polymeric carriers allow delivery of the drug at the right time and concentration by only releasing the drug in response to an external stimulus. In particular, thermo- responsive polymers are probably the most studied class of stimuli-responsive polymers in drug delivery research.

There are two main types of thermally responsive (i.e., thermo-responsive) polymers. The first presents a lower critical solution temperature (LCST) while the second presents an upper critical solution temperature (UCST). LCST and UCST are the respective critical temperature points below and above which the polymer and solvent are completely miscible.

Poly(N-isopropylacrylamide) is one of the most intensely studied polymers in biomedical applications due to its LCST being very close to body temperature. When this polymer is crosslinked into a hydrogel, the coil to globule transition causes a rapid decrease in the volume of the gel, thereby "squeezing" out any entrapped ingredients and solvent. This type of swelling behavior is known as inverse (or negative) thermo-sensitivity. Despite the wide interest in these LCST polymers, there is a problem with transdermal delivery of high molecular weight drugs or other active agents that cannot easily escape from the collapsed networks owing to entanglement.

On the other hand, certain hydrogels formed by interpenetrating networks (IPN) show positive thermo-sensitivity, i.e., swelling at high temperature and shrinking at low temperature. The polymer chains of such hydrogels expand as a result of an increase in temperature, thus enabling any incorporated drug or other active agent to diffuse out more freely. For example, it has been demonstrated that an IPN of polyacrylic acid and polyacrylamide formed hydrogels that swell above their UCST, because the interactions between two networks are disrupted at high temperatures. However, clinical applications of thermo-responsive hydrogels based on such synthetic polymers are typically formed from monomers and crosslinkers that are not generally biocompatible and biodegradable.

Additional hydrogels are desirable, particularly if they are thermally responsive and can deliver active agents.

Summary

The present disclosure provides hydrogels, compositions and articles that incorporate such hydrogels, and methods of using such hydrogels, compositions, and articles. The hydrogels include a polysaccharide and a gelling agent.

A polysaccharide includes long carbohydrate molecules of repeated monomer units (e.g., galactose, glucose, and xylose) joined together by glycosidic bonds. They range in structure from linear to highly branched. In one embodiment, the polysaccharide has no carboxylic acid groups. In one embodiment, the polysaccharide includes galactose, glucose, and xylose residues.

In the hydrogels of the present disclosure the gelling agent has the structure:

wherein each of R¹ and R² is independently H or OH, and R³ is selected from the group consisting of (^! indicating the bonding site to the phenyl ring):

As used herein, "hydrophilic gel" or "hydrogel" refers to hydrophilic polymeric material that is swollen or capable of being swollen with a polar solvent. The polymeric material typically swells but does not dissolve when contacted with the polar solvent. That is, the hydrogel is insoluble in the polar solvent. The polar solvent can be tap water, well water, deionized water, spring water, distilled water, sterile water, sea water, inorganic aqueous buffer solutions, organic aqueous buffer solutions, or physiological fluids.

The present disclosure also provides a hydrogel composition. As used herein, "composition" or "hydrogel composition" refers to a hydrogel alone, or a hydrogel with one or more secondary active agents and/or with one or more other additives incorporated in the hydrogel.

The present disclosure also provides articles (e.g., medical articles such as transdermal patches) that include hydrogel compositions of the present disclosure (e.g., hydrogel alone or hydrogel with one or more secondary active agents and/or with one or more other additives incorporated in the hydrogel). Such articles can be in the form of a substrate with a hydrogel composition disposed on at least a portion of a surface of the substrate.

The present disclosure also provides methods of delivering an active agent to a subject, the method comprising contacting a subject with an article or composition in a manner effective for transdermal delivery. Such delivery can be in a controlled-release manner. The terms "comprises" and variations thereof do not have a limiting meaning where these terms appear in the description and claims.

The words "preferred" and "preferably" refer to embodiments of the disclosure that may afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the disclosure.

In this application, terms such as "a," "an," and "the" are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terms "a," "an," and "the" are used interchangeably with the term "at least one."

The phrases "at least one of and "comprises at least one of followed by a list refers to any one of the items in the list and any combination of two or more items in the list.

As used herein, the term "or" is generally employed in its usual sense including "and/or" unless the content clearly dictates otherwise. The term "and/or" means one or all of the listed elements or a combination of any two or more of the listed elements.

Also herein, all numbers are assumed to be modified by the term "about" and preferably by the term "exactly." As used herein in connection with a measured quantity, the term "about" refers to that variation in the measured quantity as would be expected by the skilled artisan making the measurement and exercising a level of care commensurate with the objective of the measurement and the precision of the measuring equipment used.

Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range as well as the endpoints (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

The above summary of the present disclosure is not intended to describe each disclosed embodiment or every implementation of the present disclosure. The description that follows more particularly exemplifies illustrative embodiments. In several places throughout the application, guidance is provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.

Drawings

The disclosure may be more completely understood in connection with the following drawings. Figure 1. Turbidity behavior of Example E3 tested by UV-vis during heating and cooling process.

Figure 2. Calorimetric thermograms of all examples during (a) heating and (b) cooling processes.

Figure 3. In vitro release profile of gallic acid (GA) from Example E3 in PBS buffer (pH 7.4) at 22°C and 37°C. Detailed Description of Illustrative Embodiments

The present disclosure provides hydrogels, compositions and articles that incorporate such hydrogels, and methods of using such hydrogels, compositions, and articles. The hydrogels include a polysaccharide and a gelling agent that are selected such that they form crosslinked networks through physical interactions (e.g., hydrogen bonding, electrostatic force, or hydrophobic association).

The hydrogels of the present disclosure can be used to deliver an active agent. In certain embodiments, the gelling agent is an active agent. In certain embodiments, the hydrogel has incorporated therein one or more secondary active agents (i.e., active agent other than the gelling agent). Accordingly, hydrogels of the present disclosure can be considered a smart hydrogel system, thereby having potential in biomedical applications for drug delivery as well as in other fields, e.g., in the cosmetic and personal care industries, by changing the delivered ingredients.

Preferably, hydrogels of the present disclosure possess temperature-dependent gel-forming reversibility, and more preferably positive thermo-sensitivity, i.e., swelling at high temperature and shrinking at low temperature. The polymer chains of such hydrogels expand and/or the physical interactions such as hydrogen bonding between polymer chains weaken as a result of an increase in temperature, thus enabling any incorporated drug or other active agent to diffuse out more freely. Upon cooling, if sufficient gelling agent is still present a hydrogel can reform.

Accordingly, hydrogels of the present disclosure can be used for controlled release of an active agent, whether it be the gelling agent or a secondary active agent. By this it is meant that the release of an active agent (e.g., with respect to timing and amount) can be predetermined and designed into the formulation. For example, when a composition is applied to the skin of a subject, the release of the active agent can be predetermined to depend on the subject's body temperature (e.g., a subject with a fever).

Polysaccharides

A polysaccharide includes long carbohydrate molecules of repeated monomer units joined together by glycosidic bonds. They range in structure from linear to highly branched.

In certain embodiments, suitable polysaccharides are ones that do not include carboxylic acid groups. In certain embodiments, suitable polysaccharides include at least galactose, glucose, and xylose residues (i.e., monomer units, moieties, or segments). Optionally, suitable polysaccharides can include other residues, typically as side-chain residues, such as fucose residues, and arabinose residues. Preferred such polysaccharides are pristine, i.e., not degraded (e.g., by enzymatic digestion), in contrast to previous reports that have used partially degraded polysaccharides such as xyloglucan in drug release.

A preferred polysaccharide is a xyloglucan. A xyloglucan is a hemicellulose that occurs in the primary cell wall of all vascular plants. It is mainly extracted from tamarind seeds. Xyloglucan has a backbone of i→4-linked glucose residues, most of which are substituted with 1-6 linked xylose sidechains. The xylose residues are often capped with a galactose residue sometimes followed by a fucose or arabinose residue. The specific structure of xyloglucan varies among plant families, but they are typically soluble in cold water.

The unit structures of xyloglucans are typically classified into three types of structures, heptasaccharide (Glu₄Xyl₃), octasaccharide (Glu₄Xyl₃Gal), and nonasaccharide (Glu₄Xyl₃Gal₂). Typical xyloglucan contains all of these three types of unit structures, with an overall molar ratio of Glu:Xyl:Gal segments of 3 :2: 1. Molecular weights of xylolucan typically range from 5 KDa to 10 MDa.

Commercially available xyloglucans are typically supplied as refined tamarind seed xyloglucan. Examples include those available under the trade designations: GLYLOID (molecular weight of 470 KDa) from DSP GOKYO Food & Chemical Co., Ltd., Osaka, Japan; P-XYGLN (molecular weight of 202 KDa; sugar weight ratio of xylose:glucose:galactose:arabinose = 36:45: 16:3) from Megazyme International Ireland Ltd., Wicklow, Ireland; and XGa (molecular weight of 2.5 MDa; sugar weight ratio of xylose:glucose:galactose:arabinose = 35:45: 16:4) from Innovassynth Technologies Ltd., Khopoli, India.

The amount of polysaccharide is selected such that sufficient physical interactions are established with the gelling agent and a hydrogel is formed. Typically, a polysaccharide is present in a hydrogel is an amount of at least 0.5 weight percent (wt-%), at least 1 wt-%, or at least 2 wt-%, based on the total weight of the hydrogel composition of the disclosure (i.e., composition including hydrogel, secondary active agent, and optional additives). Typically, a polysaccharide is present in a hydrogel in an amount of no more than 20 wt-%, no more than 10 wt-%, or no more than 5 wt-%, based on the total weight of the hydrogel composition of the disclosure.

Gelling Agents

Suitable gelling agents include those that form crosslinked networks with a polysaccharide through physical interactions (e.g., hydrogen bonding, electrostatic force, or hydrophobic association). Preferred gelling agents are derivatives of phenol, are typically naturally occurring, and have the following structure:

In certain preferred embodiments of the gelling agent, R¹ and R² are each OH.

In certain embodiments of the gelling agent, R³ is -COOH or

Exemplary gelling agents include gallic acid, flavanols (e.g., (epi)afzelechin (wherein the "(epi)" designation means the term includes epiafzelechin and afzelechin, trans/cis isomers), (epi)catechin, (epi)gallocatechin, (epi)catechin gallate, (epi)gallocatechin gallate, mesquitol, guibourtinidol, fisetinidol, robinetinidol, kaempferol, quercetin, and myricetin), flavones (e.g., apigenin, luteolin, and genistein), and anthocyanidines (e.g., pelargonidin, cyanidin, and delphinidin), heperidin, isoquercetin, resveratrol, naringin, columnidin, chlorogenic acid, rosmarinic acid, casuarictin, vitamin C, and combinations thereof. Such gelling agents are commercially available from a variety of sources. Various combinations of gelling agents can be used as desired.

Structures of preferred flavanols, flavones, and anthocyanidines are as follows:

Guibourtinidol Fisetinidol

Robinetinidol Kaempferol

Quercetin Myricetin

Apigenin

Genistein Pelargonidin

Cyanidin Delphinidin A particularly preferred gelling agent is gallic acid, which has the following structure:

Gallic acid acts as an antioxidant and helps to protect human cells against oxidative damage. Gallic acid also seems to have antifungal and antiviral properties. It has been reported to show cytotoxicity against cancer cells, without harming healthy cells. It is used as a remote astringent in cases of internal haemorrhage. Gallic acid is also used to treat albuminuria and diabetes. And, some ointments that treat psoriasis and external haemorrhoids contain gallic acid.

Thus, in certain embodiments, suitable gelling agents are active agents and provide some desirable affect. In certain embodiments, the gelling agent has one or more of the following activities: antioxidant, antimicrobial, antiviral, antifungal, anti-inflammatory, antitumor, anti-carcinogenic, anti- mutagenic, anti-hyperglycemic, anti-aging, skin soothing and tightening, skin repair, anti-acne, corn and callus removing, anti-dandruff, anti-itch, monoamine oxidase (MAO) inhibiting, muscle fatigue resistance, cardio-protective, and scavenger of one or more volatile organic compounds.

The amount of gelling agent is selected such that sufficient physical interactions are established with the polysaccharide and a hydrogel is formed. Typically, a gelling agent is used in a hydrogel in an amount of at least 0.1 wt-%, at least 0.2 wt%, or at least 0.4 wt-%, based on the total weight of the hydrogel composition of the disclosure (i.e., composition including hydrogel, secondary active agent, and optional additives). Typically, a gelling agent is used in a hydrogel in an amount of no more than 20 wt-%, no more than 10 wt-%, or no more than 5 wt-%, based on the total weight of the hydrogel composition of the disclosure.

Optional Secondary Active Agents

Whether the gelling agent is capable of acting as an active agent or not, a hydrogel of the present disclosure can have one or more optional secondary active agents (i.e., ones that are not the gelling agent) incorporated therein. The active agent provides some added functionality to the hydrophilic gel material (i.e., hydrogel). The hydrophilic gel material functions as a carrier for the active agent.

Such incorporated components can be a wide variety of substances such as water-soluble small and large molecules, vaccines, and extracts from organisms, etc. Some active agents are biologically active agents. As used herein, the terms "biologically active agent," "biological active," and "bioactive agent" are used interchangeably and refer to a compound or mixture of compounds that has some known effect on living systems such as, for example, a bacteria or other microorganisms, plant, fish, insect, or mammal. The bioactive agent is added for the purpose of affecting the living system such as affecting the metabolism of the living system.

Desirably, such components do not interfere with the physical interactions (e.g., hydrogen bonding, electrostatic force, or hydrophobic association) between the gelling agent and polysaccharide.

Examples of bioactive agents include, but are not limited to, medicaments, herbicides, insecticides, antimicrobial agents, disinfectants and antiseptic agents, local anesthetics, astringents, antifungal agents, antibacterial agents, growth factors, vitamins, herbal extracts, antioxidants, steroids or other anti- inflammatory agents, compounds that promote wound healing, vasodilators, exfoliants such as alphahydroxy acids or beta-hydroxy acids, enzymes, nutrients, proteins, and carbohydrates. Still other bioactive agents include artificial tanning agents, tanning accelerants, skin soothing agents, skin tightening agents, anti-wrinkle agents, skin repair agents, sebum inhibiting agents, sebum stimulators, protease inhibitors, anti- itch ingredients, agents for inhibiting hair growth, agents for accelerating hair growth, skin sensates, anti-acne treatments, depilating agents, hair removers, com removers, callus removers, wart removers, sunscreen agents, insect repellants, deodorants and antiperspirants, hair colorants, bleaching agents, and anti-dandruff agents. A wide variety of other suitable bioactive agents known in the art can be used.

Preferred secondary active agents include a bioactive peptide, a metal compound, an antimicrobial agent, an antibiotic, and combinations thereof.

Exemplary bioactive peptides include, but are not limited to: fibronectin; active and adhesion- promoting peptides, such as RGD (arginine-glycine-aspartate) peptides; and cosmeceutical peptides, such as copper peptide GHK-Cu, epidermal growth factor, and palmitoyl hexapeptide.

Exemplary metal compounds (typically in the form of metal oxides) include, but are not limited to, silver compounds, copper compounds, zinc compounds, and titanium compounds.

Exemplary antimicrobial agents include, but are not limited to, parachlorometaxylenol, chlorhexidine and salts thereof, iodophores, triclosan, propylene glycol, and fatty acid monoesters of glycerol (glycerol monolaurate, glycerol monocaprylate, glycerol monocaprate, propylene glycol monolaurate, propylene glycol monocaprylate, and propylene glycol monocaproate).

Exemplary antibiotics include, but are not limited to, neomycin, bacitracin, polymyxin B, mupirocin, gramicidins, benzoyl peroxide, and clindamycin.

Various combinations of secondary active agents can be used if desired.

If used, the amount of secondary active agent is selected such that it can achieve a desired active effect while not seriously deteriorating the hydrogel, particularly the hydrogel thermal- sensitivity. Typically, this is an amount of at least 0.1 wt-%, at least 0.2 wt-%, or at least 1 wt-%, based on the total weight of a hydrogel composition of the present disclosure (i.e., composition including hydrogel, secondary active agent, and optional additives). Typically, this is an amount of no more than 40 wt-%, no more than 20 wt-%, or no more than 10 wt-%, based on the total weight of a hydrogel composition of the present disclosure. Other Optional Additives

Hydrogel compositions of the present disclosure can include a wide variety of optional additives in addition to the optional secondary active agents. Examples include, but are not limited to, absorbent particles (e.g., such as those described in U.S. Pat. No. 5,369,155), foaming agents, swelling agents (e.g., polyols, monosaccharides, ether alcohols, and those disclosed in U.S. Pat. No. 5,270,358), fillers, pigments, dyes, plasticizers (for example, mineral oil and petrolatum), tackifiers, crosslinking agents (other than the gelling agents), stabilizers, compatibilizers, extruding aids, chain transfer agents, and combinations thereof.

The fillers can be inorganic or organic. Examples of inorganic fillers include, but are not limited to, barytes, chalk, gypsum, kieserite, sodium carbonate, titanium dioxide, cerium oxide, silica dioxide, kaolin, carbon black, and hollow glass microbe ads. Examples of organic fillers include, but are not limited to, powders based on polystyrene, polyvinyl chloride, ureaformaldehyde, and polyethylene. The fillers may be in the form of fibers, such as chopped fibers. Examples of suitable chopped fibers include glass fibers (typically 0.1 millimeter (mm) to 1 mm long) or fibers of organic origin such as, for example, polyester or polyamide fibers.

In order to confer color to the hydrogel compositions it is possible to use dyes or colored pigments of an organic or inorganic basis such as, for example, iron oxide or chromium oxide pigments or phthalocyanine- or monoazo-based pigments.

Hydrogel compositions in the form of creams or lotions can include optional additives such as lipids, surfactants, moisturizers/humectants, and excipients (e.g., chemical enhancers for skin penetration).

Suitable lipids in the oil phase of creams can be chosen from the group of branched and unbranched hydrocarbons and hydrocarbon waxes, silicone oils, dialkyl ethers, as well as saturated or unsaturated, branched or unbranched alcohols, fatty acid triglycerides (e.g., triglycerol esters), and/or unsaturated, branched or unbranched alkanecarboxylic acids having a chain length of from 8 to 24 (in particular, 12 to 18) carbon atoms. The fatty acid triglycerides can, for example, advantageously be chosen from the group of synthetic, semisynthetic, and natural oils, e.g., olive oil, sunflower oil, soybean oil, groundnut oil, rapeseed oil, almond oil, palm oil, coconut oil, palm kernel oil, and the like.

A cream can also contain ionic, zwitter-ionic, non-ionic surfactants, or a combination thereof.

Examples of moisturizers include a material that allows the hydrogel compositions to maintain the proper mechanical strength, elasticity, and skin-adhesion properties. Examples moisturizers may preferably include 1,3-butylene glycol, ethylene glycol, propylene glycol, hexylene glycol, sorbitol, mannitol, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hyaluronic acid, xanthan gum, acacia powder, etc. These may be used alone or in a combination thereof.

Hydrogel compositions may also include a skin penetration enhancer that enhances the delivery and/or penetration of the active agents to and/or into the skin. Nonlimiting examples of penetration enhancers can include sulphoxides, dimethylsulphoxide (DMSO), laurocapram, pyrrolidones such as 2- pyrrolidone, alcohols, ethanol, alkanols, decanol, glycols, propylene glycol, terpenes, and the like.

Combinations of various additives may be selected such that they can achieve a desired active effect while not seriously deteriorating the hydrogel, particularly the hydrogel thermal- sensitivity.

Typically, an additive is used in an amount of at least 0.1 wt-%, at least 0.5 wt-%, or at least 1 wt-%, based on the total weight of a hydrogel composition of the present disclosure (i.e., composition including hydrogel, secondary active agent, and optional additives). Typically, an additive is used in an amount of no more than 20 wt-%, no more than 10 wt-%, or no more than 5 wt-%, based on the total weight of a hydrogel composition of the present disclosure.

Uses, Compositions, and Articles

Hydrogels and compositions of the present disclosure can be in a variety of forms. For example, a hydrogel can be a coating on a substrate, or in the form of a gel, cream or lotion. Hydrogels of the present disclosure can be used in various articles, e.g., medical articles. Medical articles can be any of a wide variety of products, such as, for example, wound dressings, wound fillers, wound packing materials, or transdermal patches.

In certain embodiments, an article that includes a substrate can have a hydrogel composition disposed on at least a portion of a surface of the substrate. Suitable substrate materials include, for example, fabric, nonwoven fibrous webs, woven fibrous webs, knits, polymer films, foams, and the like. Such substrates can be porous or nonporous. Suitable substrates can be made of natural or synthetic fibers, including, for example, cotton, rayon, wool, hemp, jute, alginates, fiberglass, ceramic fibers, natural rubber, elastomeric polymers, thermoplastic polymers, other familiar backing materials, and combinations thereof. Such materials are typically used as backing substrates in a variety of conventional medical products.

A hydrogel composition of the present disclosure can be in the form of a transdermal patch.

Suitable transdermal patches include single-layered or multi-layered patches, matrix-based patches, reservoir-based patches, as well as combinations thereof. Preferably, a hydrogel composition of the present disclosure can be stored in a single- or multi-compartment reservoir-type transdermal patch (e.g., such as those described in U.S. Pat. Pub. No. 2007/0248657).

In some embodiments, a hydrogel composition of the present disclosure carried by a transdermal patch can be used with a solid microneedle device (e.g., such as described in U.S. Pat. Pub. No.

2005/0261631). This combined "Press & Patch" system is expected to further improve the transdermal delivery efficacy of active agents by using the generated microchannel across the skin.

In some embodiments, a hydrogel composition of the present disclosure can be used with a hollow microneedle device (e.g., such as described in U.S. Pat. Pub. No. 2012/0123387) and stored in the device's reservoir. Typically, suitable hollow microneedles may have a length of at least 100 micrometers (μηι), at least 250 μηι, or at least 500 μηι. Typically, suitable hollow microneedles may have a length of no greater than 3 millimeters (mm), no greater than 1500 μηι, or no greater than 1000 μηι.

In some embodiments, the hydrogel can be configured into an oil-in-water (O/W) emulsion (e.g., gel cream, or lotion, such as a light-weight product with low emulsifier and lipid content). The oil phase can include one or more active agents, and can serve as a depot or reservoir. In some instances, a depot can be formed similarly to a capsule, and the one or more active agents included within the hydrogel matrix. Such depots can be formed during preparation of the hydrogel composition or can be provided into the hydrogel after being prepared. Oil-in-water emulsions can be achieved via the processes described, for example, in U.S. Pat. Nos. 7,030,203 and 6,620,420.

Methods of Preparation of Hydrogels, Compositions, and Articles

Hydrogels of the present disclosure are typically formed by combining separate solutions of a polysaccharide and a gelling agent, each dissolved in water with vigorous stirring. Optional secondary active agents and additives can be added during preparation of the hydrogel or can be added to the hydrogel after it is prepared. Mixing methods can be any of a wide variety of techniques well known to those of skill in the art.

To apply hydrogel compositions onto a surface of a substrate, suitable coating methods can be used, including, for example, spray coating, dip coating, spin coating, inkjet printing, screen printing, and other methods used in roll-to-roll processes such as slot die coating, doctor knife coating, curtain coating, gravure coating, knife-over-roll coating, and roll coating. As for articles like transdermal patches, microneedle devices, gel creams or lotions, that include hydrogel compositions of the present disclosure, suitable fabrication methods are well known to those of skill in the art.

Exemplary Embodiments

Embodiment 1 is a hydrogel comprising: a polysaccharide having no carboxylic acid groups; and a gelling agent having the following structure:

Embodiment 2 is a hydrogel comprising: a polysaccharide comprising galactose, glucose, and xylose residues; and a gelling agent having the following structure:

wherein each of R¹ and R² is independently H or OH, and R³ is selected from the group consisting of (^: indicating the bonding site to the phenyl ring):

Embodiment 3 is the hydrogel of embodiment 1 or 2 wherein R¹ and R² are each OH.

Embodiment 4 is the hydrogel of any one of embodiments 1 through 3 wherein R³ is

-COOH or

Embodiment 5 is the hydrogel of any one of embodiments 1 through 4 wherein the gelling agent is selected from the group consisting of gallic acid, (epi)afzelechin, (epi)catechin, (epi)gallocatechin, (epi)catechin gallate, (epi)gallocatechin gallate, mesquitol, guibourtinidol, fisetinidol, robinetinidol, kaempferol, quercetin, myricetin, apigenin, luteolin, genistein, pelargonidin, cyanidin, delphinidin, heperidin, isoquercetin, resveratrol, naringin, columnidin, chlorogenic acid, rosmarinic acid, casuarictin, vitamin C, and combinations thereof. Embodiment 6 is the hydrogel of any one of embodiments 1 through 4 wherein the polysaccharide comprises galactose, glucose, xylose residues, and optionally fucose and/or arabinose residues.

Embodiment 7 is the hydrogel of any one of embodiments 1 through 6 wherein the

polysaccharide is a xyloglucan.

Embodiment 8 is the hydrogel of any one of embodiments 1 through 7 wherein the

polysaccharide is present in an amount of 0.5 wt-% to 20 wt-%, based on the total weight of the hydrogel composition.

Embodiment 9 is the hydrogel of any one of embodiments 1 through 8 wherein the gelling agent is present in an amount of 0.1 wt-% to 20 wt-%, based on the total weight of the hydrogel composition.

Embodiment 10 is the hydrogel of any one of embodiments 1 through 9 wherein the gelling agent is an active agent.

Embodiment 1 1 is the hydrogel of embodiment 10 wherein the gelling agent has one or more of the following activities: antioxidant, antimicrobial, antiviral, antifungal, anti-inflammatory, antitumor, anti-carcinogenic, anti-mutagenic, anti-hyperglycemic, anti-aging, skin soothing and tightening, skin repair, anti-acne, corn and callus removing, anti- dandruff, anti-itch, monoamine oxidase (MAO) inhibiting, muscle fatigue resistance, cardio-protective, and scavenger of one or more volatile organic compounds.

Embodiment 12 is the hydrogel of any one of embodiments 1 through 1 1 which possesses temperature-dependent gel-forming reversibility.

Embodiment 13 is the hydrogel of any one of embodiments 1 through 12 in the form of a cream or lotion.

Embodiment 14 is a hydrogel composition comprising the hydrogel of any one of embodiments 1 through 13.

Embodiment 15 is the hydrogel composition of embodiment 14 further comprising a secondary active agent incorporated in the hydrogel.

Embodiment 16 is the hydrogel composition of embodiment 15 wherein the secondary active agent is selected from the group consisting of a bioactive peptide, a metal compound, an antimicrobial agent, an antibiotic, and combinations thereof.

Embodiment 17 is an article comprising a substrate and a hydrogel composition of any one of embodiments 14 through 16 disposed on at least a portion of a surface of the substrate.

Embodiment 18 is an article in the form of a transdermal patch comprising a hydrogel composition of any one of embodiments 14 through 16.

Embodiment 19 is a method of delivering an active agent to a subject, the method comprising contacting a subject with an article of embodiment 17 or 18 in a manner effective for transdermal delivery. Embodiment 20 is the method of embodiment 19 wherein the active agent is delivered in a controlled-release manner.

Embodiment 21 is a method of delivering an active agent to a subject, the method comprising contacting a subject with a hydrogel composition of any one of embodiments 14 through 16 in a manner effective for transdermal delivery.

Embodiment 22 is the method of embodiment 21 wherein the active agent is delivered in a controlled-release manner.

Examples

The present disclosure is more particularly described in the following examples that are intended as illustrations only, since numerous modifications and variations within the scope of the present disclosure will be apparent to those skilled in the art. Unless otherwise noted, all parts, percentages, and ratios reported in the following examples are on a weight basis, and all reagents used in the examples were obtained, or are available, from the chemical suppliers described below, or may be synthesized by conventional techniques. The polysaccharide (XG, xyloglucan, molecular weight of 202 kDa, viscosity of 6.5 dL/g, and sugar composition of xylose:glucose:galactose:arabinose = 36:45: 16:3) was obtained from Megazyme International Ireland Ltd. (Wicklow, Ireland). Gallic acid (GA, 3,4,5-trihydroxybenzoic acid) was purchased from Fluka, and employed as gelling agent and the model active ingredient, because it exhibits broad biological and pharmaceutical activities such as antioxidant, anti-carcinogenic, anti- hyperglycaemic, anti-mutagenic, and cardio-protective properties.

XG-GA Hydrogel Preparation and Characterization

A stock solution of XG was prepared by dispersing a desired amount of XG in deionized (DI) water via a slow homogenizing process at 50°C for 4 hours (h). GA solutions were prepared by dissolving various amounts of GA in DI water at 40°C. Under vigorous stirring at 50°C, different amounts of GA solutions were added into the XG solution to obtain 0.199%, 0.398%, 0.596%, 0.794%, and 0.99% by weight (wt-%) of GA in 0.99 wt-% XG, respectively.

Table 1 : Composition of XG-GA samples

Various characterization techniques were employed to evaluate the sol-gel transition and the physical properties of the hydrogels. A UV-vis spectrometer (CARY 50 Bio) equipped with a single cell peltier thermo-controller was used to measure the transmittance (%) of solutions at a wavelength of 500 nanometers (nm). The rheological properties were measured using a dynamic rheometer (ARES 100FRTN1, Rheometric Scientific, Piscataway, NJ) equipped with parallel plates with a diameter of 25 millimeters (mm) or 50 mm. Samples in liquid state were loaded onto the bottom plate at 50°C, then the initial temperature was adjusted as required. For temperature sweap, the mechanical spectra at the angular frequency of 2 picorad per second (prad/sec, 1 Hz) were recorded with a heating and cooling rate of 0.5° Centigrade per minute (°C/min). All rheological measurements were performed within the range of linear viscoelasticity by choosing suitable shear amplitude. Calorimetric measurements were carried out on a micro-differential scanning calorimeter (VP-DSC, Microcal LLC, Northampton, MA). The thermograms were measured at a heating and cooling rate of 0.5°C/min, which was the same rate used in the rheological tests. Standard Hastelloy vessels were used with a calibrated volume of 0.516 milliliters (mL), and DI water was used as the reference. Before each test, the sample cell was thoroughly cleaned with a water baseline session to ensure a noncontamination condition. ^lH NMR spectra of selected examples dissolved in D₂0 were recorded at 30°C using a Bruker DMX-400 spectrometer. The micrograph of the hydrogel was taken using a scanning electron microscope (SEM, JEOL JSM 5600LV) operating at an accelerating voltage of 5 kilovolts (kV). The SEM sample was prepared by casting sol onto the glass substrate and equilibrating it at room temperature before the lyophilization.

The in vitro release of GA from hydrogel was performed using modified Franz Cell method (as disclosed in U.S. Pat. Pub. No. 2007/0225357) at different temperatures. In brief, a dialysis membrane was first put onto a wire mesh which covered the top of a donor cell. Approximately 200 milligrams (mg) of hydrogel (taken from a 4°C fridge before testing) was uniformly dispersed onto a 1 cm² backing film, and the film was placed onto the dialysis membrane with gel inside. After charging 4.8 mL of phosphate buffered saline (PBS) buffer solution into the receiving cell, the whole unit was placed in a chamber equipped with thermo-controller. At selected time intervals, the solution was taken out from the receiving cell and an equal volume of fresh buffer was replenished. The released GA was evaluated by measuring the UV-vis absorbance at 265 nm.

Positive thermo-sensitivity of hydrogels

A facile demonstration of the thermo-responsive properties of the XG-GA hydrogels could be achieved by monitoring their physical state and turbidity. Example E3 behaved as a solid gel at low temperature and could not flow freely. When it was heated to human body temperature (approximately 37°C), it became sol-like and flowable. A more quantitative test of the sol-gel transition of Example E3 was achieved using a UV-vis equipped with a thermo-control unit. The sample temperature could be manually changed from 15°C to 50°C, and the upper critical solution temperature (UCST) of Example E3 was determined from the plot showing 50% of the transmittance versus temperature. During the heating process, the derived UCST from Fig. 1 is 37.7°C, which is about 16°C higher than that obtained from the cooling process. Subsequently, systematic evaluations of the XG-GA hydrogels were carried out using a rheometer and on a micro-differential scanning calorimeter ("micro DSC") because their testing temperature could be automatically adjusted. Temperature sweep measurements were performed to evaluate the changes in the viscoelasticity and microstructure of XG-GA mixtures during heating and cooling processes. -The G' and G" as a function of temperature for Examples E1-E6 are studied respectively (spectra are not shown). The G' and G" of Example El gradually decrease with the increasing temperature. G' is below G" over the entire range of temperature, indicating that the XG along displayed a typical sol behavior of a polymer. For Example E2, the similar rheometry curves as Example El demonstrate that it was also in a solution state in the whole temperature range. For Examples E3-E6, in the region of low temperature, their G' values are all higher than those of G", revealing a viscoelastic behavior of gels. Thereafter, G' decrease abruptly with the elevating temperature and cross with G" at one point, accompanying with the phenomenon of gel's "melting." The crossover temperatures (i.e., UCST's) are observed at 39.6°C, 45.0°C, 50.5°C, and 54.7°C for Examples E3-E6, respectively (shown in table 2). In the subsequent cooling process, both moduli of sols increase with decreasing temperature, and G' show a sharp increase and the crossover point of G' and G", which indicates a transition from a viscous sol to an elastic gellike as well, are observed at 23.2°C, 29.6°C, 35.6°C, and 41.2°C, respectively.

Table 2: The sol-gel transition temperature (°C) of XG-GA samplesdetermined by dynamic rheometer

Based on micro DSC results, the endothermic and exothermic peaks (Fig. 2a and 2b) for XG-GA hydrogels (Examples E3-E6) could be identified as their respective UCSTs during heating and cooling processes. Herein, the endothermic peak represents the gel-to-sol transition, whereas the exothermic peak is the sol-to-gel transition. The endothermic and exothermic peaks of the samples shifted to the higher temperature with the increasing GA concentration. As shown in Fig. 3 a, the endothermic peaks for hydrogels with 0.4, 0.6, 0.8 and 1% GA appear at 33.0°C, 40.2°C, 46.6°C, and 49.7°C, respectively. At the same time, the corresponding exothermic peaks are observed at 17.1°C, 24.1°C, 30.7°C, and 34.1°C upon cooling (Fig. 2b). It is interesting to note that the temperatures of the endothermic peaks in the DSC heating curves were all about 16°C higher than those of exothermic peaks in cooling curves. This significant thermal hysteresis phenomenon during a heating and cooling cycle could be observed from both micro DSC and rheological measurements. For physically crosslmked thermo-reversible gel, the thermal hysteresis is usually caused by the stabilization of the system through further aggregation of polymer chains. On the other hand, the gelling and melting temperatures obtained by the measurements using rheometer, micro DSC, and even UV-vis spectrometer are not exactly the same. The differences between them should be attributed to the variations in the measurement principle of each method. For instance, micro DSC detects the amount of heat absorbed or released by a sample during a thermo- induced sol-gel transition, while rheological measurement reflects the change in sample's viscoelasticity. During the heating process, heat absorption occur first to break the hydrogen bonds in the junction zones of a XG-GA hydrogel, then the gradual disassociation of the networks would affect the rheological property. Thus, the gel melting temperatures obtained by the rheometer should appear later (or higher) than those obtained by the micro DSC.

In order to verify the formation of hydrogels is affected by the hydrogen bonding, ^lH NMR was applied to investigate the interaction between GA and XG using Examples E2 and E4 for comparison (spectra are not shown). Example E2 (containing 0.2% GA) cannot form a hydrogel at any temperature, but Example E4 (containing 0.6% GA) becomes a gel at a low temperature. For Example E2, the chemical shift (δ) of the aromatic protons of GA can be observed around 7.1 ppm at 30°C, and the peak is very sharp. A similar peak can be found in the Example E2 spectrum, as well as the sharp

characteristic peaks of XG polymer near 3.2-4.0 ppm, showing it was in sol state. For Example E4, the significant broadening of GA peaks clearly demonstrates that the mixture was in the gel state. In addition, as a consequence of the inductive effect from the hydrogen bonding between XG and GA, a small downfield shift (Δδ = 0.03 ppm) of the proton signals also appears in the Example E4 spectrum.

The morphology of freeze-dried samples was evaluated by scanning electron microscopy (SEM) (images are not shown). Large porous microstructures are observed for Examples El and E2. However, the SEM pictures of hydrogel samples (Examples E3 and E5) reveal that both porous and fibrillar microstructures were obtained after lyophilization. The strong hydrogen bonding between XG and GA is considered as the driving force to rearrange the polymer chains into a fibrillar network-structure. Furthermore, it seems that the higher concentration of GA inputted the gels, the more condensed network will be achieved.

GA in vitro release from thermo-responsive hydrogel

It has been recognized that GA has many therapeutic applications, such as protecting human cells against oxidative damage, being cytotoxic against cancer cells without harming healthy cells, being used as a remote astringent for internal haemorrhage, and being used to treat albuminuria and diabetes. Therefore, GA itself also can act as a model drug that exemplifies the controlled-release capability of XG-GA hydrogel system. Fig. 3 shows the release profiles of GA from Example E3 at different temperatures. At 37°C, the release curve is plateaued after 2.5 hours (h), indicating relative quick release of GA from the hydrogel matrix. The final accumulative value of approximately 96% of GA release was reached upon 12 h. But when the environment temperature was set to 22°C, the velocity of drug release was remarkably retarded and less than 50% of GA was released from the gel after 12 h. For the same hydrogel, the big difference in GA release could be explained by the status of Example E3 at two conditions. Example E3 is in the gel and sol states at 22°C and 37°C, respectively. It is easy to comprehend that the small molecular drug has more chance to diffuse through the membrane in liquid status, thus resulting in a fast and high release profile. XG-EG Hydrogel Preparation and Characterization

Another positive thermo-sensitive hydrogel example comprising xyloglucan (XG) and epigallocatechin gallate (EG, obtained from Sigma-Aldrich, Singapore) was prepared and characterized as follows. A stock solution of XG was prepared by dispersing a desired amount of XG in deionized (DI) water via a slow homogenizing process at 50°C for 4 hours. EG solutions were prepared by dissolving various amounts of EG in DI water at 25 °C. Under vigorous stirring at 50°C, different amount of GA solutions were added into the XG solution to obtain 0.1%, 0.2%, 0.3%, 0.4%, and 0.6% by weight (wt- %) of EG in 1.0 wt-% XG, respectively.

According to micro DSC testing, the endothermic and exothermic peaks for XG-EG hydrogels could be identified as their respective UCSTs during heating and cooling processes. The endothermic peak represents the gel-to-sol transition, whereas the exothermic peak is the sol-to-gel transition. As shown in Table 3, the gel-to-sol transition temperatures for hydrogels with 0.1 wt-%, 0.2 wt-%, 0.3 wt- %, 0.4 wt-%, and 0.6 wt-% EG are at 28.3°C, 31.8°C, 36.0°C, 38.8°C, and 41.1°C, respectively. The corresponding sol-to-gel transition temperatures are observed at 12.8°C, 19.3°C, 24.1°C, 26.9°C, and 31.0°C upon cooling (Table 3).

Table 3: The sol-gel transition temperature (°C) of XG-EG samples determined by micro DSC

The complete disclosures of the patents, patent documents, and publications cited herein are incorporated by reference in their entirety as if each were individually incorporated. While the disclosure is susceptible to various modifications and alternative forms, specifics thereof have been shown by way of example and drawings, and will be described in detail. It should be understood, however, that the disclosure is not limited to the particular embodiments described. On the contrary, the intention is to cover modifications, equivalents, and alternatives falling within the spirit and scope of the disclosure.

Claims

WHAT IS CLAIMED IS:

A hydrogel comprising:

a polysaccharide having no carboxylic acid groups; and

a gelling agent having the following structure:

wherein each of R¹ and R² is independently H or OH, and R³ is selected from the group consisting of (* indicating the bonding site to the phenyl ring):

. A hydrogel comprising:

a polysaccharide comprising galactose, glucose, and xylose residues; and

a gelling agent having the following structure:

3. The hydrogel of claim 2 wherein R¹ and R² are each OH. The hydrogel of claim 2 wherein R is -COOH or

5. The hydrogel of claim 2 wherein the gelling agent is selected from the group consisting of gallic acid, (epi)afzelechin, (epi)catechin, (epi)gallocatechin, (epi)catechin gallate, (epi)gallocatechin gallate, mesquitol, guibourtinidol, fisetinidol, robinetinidol, kaempferol, quercetin, myricetin, apigenin, luteolin, genistein, pelargonidin, cyanidin, delphinidin, heperidin, isoquercetin, resveratrol, naringin, columnidin, chlorogenic acid, rosmarinic acid, casuarictin, vitamin C, and combinations thereof.

The hydrogel of claim 2 wherein the polysaccharide comprises galactose, glucose, xylose residues, and optionally fucose and/or arabinose residues. 7. The hydrogel of claim 6 wherein the polysaccharide is a xyloglucan.

The hydrogel of claim 2 wherein the polysaccharide is present in an amount of 0.5 wt-% to 20 wt-%, based on the total weight of the hydrogel composition. 9. The hydrogel of claim 2 wherein the gelling agent is present in an amount of 0.1 wt-% to 20 wt- %, based on the total weight of the hydrogel composition.

10. The hydrogel of claim 2 wherein the gelling agent is an active agent. 1 1. The hydrogel of claim 10 wherein the gelling agent has one or more of the following activities: antioxidant, antimicrobial, antiviral, antifungal, anti-inflammatory, antitumor, anti-carcinogenic, anti-mutagenic, anti-hyperglycemic, anti-aging, skin soothing and tightening, skin repair, antiacne, corn and callus removing, anti-dandruff, anti-itch, monoamine oxidase (MAO) inhibiting, muscle fatigue resistance, cardio-protective, and scavenger of one or more volatile organic compounds.

12. The hydrogel of claim 2 which possesses temperature-dependent gel-forming reversibility.

13. The hydrogel of claim 2 in the form of a cream or lotion.

14. A hydrogel composition comprising the hydrogel of claim 2.

15. The hydrogel composition of claim 14 further comprising a secondary active agent incorporated in the hydrogel.

16. The hydrogel composition of claim 15 wherein the secondary active agent is selected from the group consisting of a bioactive peptide, a metal compound, an antimicrobial agent, an antibiotic, and combinations thereof.

17. An article comprising a substrate and a hydrogel composition of claim 14 disposed on at least a portion of a surface of the substrate.

18. An article in the form of a transdermal patch comprising a hydrogel composition of claim 14.

19. A method of delivering an active agent to a subject, the method comprising contacting a subject with an article of claim 17 in a manner effective for transdermal delivery.

20. The method of claim 18 wherein the active agent is delivered in a controlled-release manner.

21. A method of delivering an active agent to a subject, the method comprising contacting a subject with a hydrogel composition of claim 14 in a manner effective for transdermal delivery.

22. The method of claim 21 wherein the active agent is delivered in a controlled-release manner.