WO2010067378A2 - Hydrogel composition - Google Patents
Hydrogel composition Download PDFInfo
- Publication number
- WO2010067378A2 WO2010067378A2 PCT/IN2009/000707 IN2009000707W WO2010067378A2 WO 2010067378 A2 WO2010067378 A2 WO 2010067378A2 IN 2009000707 W IN2009000707 W IN 2009000707W WO 2010067378 A2 WO2010067378 A2 WO 2010067378A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydrogel
- hydrogel composition
- peg
- pva
- composition
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0052—Mixtures of macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/008—Hydrogels or hydrocolloids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L29/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical; Compositions of hydrolysed polymers of esters of unsaturated alcohols with saturated carboxylic acids; Compositions of derivatives of such polymers
- C08L29/02—Homopolymers or copolymers of unsaturated alcohols
- C08L29/04—Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
- C08L71/02—Polyalkylene oxides
Definitions
- the present technology relates to hydrogel compositions for wound healing.
- Illustrative hydrogel compositions comprise PVA, PEG, and a viscosity enhancer, that are cross- linked by irradiation.
- the hydrogel composition does not comprise gelling agent.
- Wound dressings are available as hydrogels, hydrocolloids, films, gauzes, alginates, biologies, and foams. Amongst these, hydrogels have become more popular because of their relatively high water content, and soft and rubbery consistency. Hydrogels are three dimensional, cross-linked polymeric networks that regulate the fluid exchange from the wound surface. Because of their excellent biocompatibility, hydrogels are used in a variety of wound dressings. The three dimensional network of polymers makes them capable of imbibing water 10-1000 times its original dry weight. Due to its swelling and water retention capacity, hydrogels are used in a variety of applications in biomedical field, ranging from drug delivery system to cell delivery system to wound/burn treatment.
- Hydrogels have been prepared with various polymers such as polyvinyl alcohol (PVA). polyvinyl pyrrolidone (PVP), or polyacrylamides.
- PVA-based hydrogels are disclosed in, e.g., U.S. Patent Nos: 6,231,605; 5,346,935; 5,981 ,826; 4,663,358; and 4,988,761.
- PVA hydrogels lack desirable mechanical properties such as sufficient tensile strength and elasticity.
- Polyethylene glycol (PEG) based hydrogels provide a large degree of swelling in aqueous solutions.
- PEG based hydrogels are disclosed in U.S. Patent Nos: 5,514,379; 6,362,276; and 6,541 ,015.
- PCT application WO2006125082 provides hydrogel formulation containing pre-solidified hydrogel particles in a precursor hydrogel solution.
- Hydrogels comprising both PVA and PEG are disclosed in WO 2005/120462 ("the '462 application").
- the '462 application discloses preparing hydrogels using chemical cross- linkers, which are biodegradable groups capped to the PVA and/or PEG,. Once such cross-linker is acrylated glycine anhydride.
- cross-linker is acrylated glycine anhydride.
- residual cross-linking agents in the hydrogel may be toxic to host tissues and the usage of such chemicals requires stringent manufacturing controls, which tends to increase the cost of hydrogel manufacture.
- Chemical cross-linkers such as glutaraldehyde and boric acid are used in the preparation of hydrogels.
- Some of the disadvantages facing such hydrogels include presence of residual cross-linking agents in the hydrogel which could be toxic to the tissues. Usage of such chemicals requires stringent controls during its manufacture which tends to increase the cost of hydrogel manufacture.
- hydrogels prepared by this method are opaque and this could be a drawback in wound dressing as it prevents visualization and proper examination of the wound bed after its application without the removal of the hydrogel.
- HIZELTM which comprises PVA along with gelling agents. See, e.g., Indian Patent Numbers 0187486 and 192136, as well as WO 2001/030407.
- Hydrogels prepared using gamma-irradiation comprises PVA, PVP, PEG acrylamide/maleic acid (CAMA), HPC, etc. as described in following patents US Patent No 7235592 describes covalently cross-linked vinyl polymer hydrogel comprising the steps of: providing a physically associated vinyl polymer hydrogel having a crystalline phase; exposing the physically associated vinyl polymer hydrogel to an amount of ionizing radiation providing a radiation dose in the range of about 1-1 ,000 kGy effective to form covalent crosslinks; and removing physical associations by exposing the irradiated vinyl polymer hydrogel to a temperature above the melting point of the physically associated crystalline phase to produce a covalently cross-linked vinyl polymer hydrogel,
- US Patent No 7282165 provides a solution of polyvinyl alcohol in a solvent of DMSO/water.
- the solution is placed in a mold and is gelated by cycling the mold in a freeze-thaw cycle at a temperature at or below 4. degree. C. for a period of 2 to 24 hours.
- the hydrogel so formed is washed in a saline solution, including potassium carbonate.
- the hydrogel is then dehydrated to 20 to 70% water content and thereafter irradiated with Gamma radiation.
- the surface of the hydrogel is then cross-linked using a boric acid solution preferably between 2.5 and 5% for about 1 minute.
- the hydrogel is then rinsed and sterilized.
- European patent application No. 0107376 discloses a wound dressing which is based on a transparent layer of a water-swollen cross-linked homopolymer of N-vinyl pyrrolidone (VP).
- the homopolymer of VP is first prepared and dissolved in water, a hydrogel layer is then formed by irradiating with gamma rays while contained within a polythene bag.
- US Patent No 4871490 provides a method of manufacturing hydrogel dressings from polymers by radiation cross-linking, comprising an aqueous solution containing 2- 10 per cent by weight of polyvinylpyrrolidone, no more than 3 percent by weight of agar and 1 -3 percent by weight of poly(ethylene) glycol; pouring the solution into a mould to shape the dressing; tightly closing the mould and subjecting the mould to an ionizing radiation dose in the range of 25-40 KGy.
- US Patent No 5401508 provides a hydrogel for ocular comprising acrylamides and acrylates copolymers cross linked by ethylene glycol dimethacrylate
- US Patent No 5489437 discloses an adhesive hydrogel product comprising water and a thermoplastic, Hydroxypropyl cellulose (HPC) polymer extrudable in a dry state, then having been exposed to ionizing energy of in excess of 2.5 megarads, and then adding the water, the energy being sufficient to permit cross-linking of the polymer into a tacky hydrophilic hydrogel product having a gel breaking strength of at least 10 p.s.i., and an absorption capacity per mil of thickness in excess of 10%, by weight.
- HPC Hydroxypropyl cellulose
- US Patent No 6617372 provides polymeric hydrogel product of polyvinylpyrrolidone (PVP), poly(vinylcaprolactam) (PVCL), a copolymer of PVP and PVCL and a comonomer dimethylaminopropyl(meth)acrylamide (DMAPMA) and/or dimethylaminoethyl(meth)acrylate (DMAEMA) and a cross linking agent crosslinking agent which is a substantially water-insoluble compound selected from pentaerythritol trial IyI ether (PETE) and pentaerythritol tetraacrylate (PETA)., made by irradiating the composition with high energy electron beam or gamma-radiation.
- PVP polyvinylpyrrolidone
- PVCL poly(vinylcaprolactam)
- DMAPMA dimethylaminopropyl(meth)acrylamide
- DMAEMA dimethylaminoethyl(meth)
- the hydrogels comprise other components like natural polysaccharides (e.g. Carrageenan, agar etc.) or epichlorhydrin, etc. While some chemicals like epichlorohydrin pose health hazards, natural polysaccharides are prone to microbial contamination thus posing a limitation of its shelf life as well as duration of usage on wounds.
- Preparation of hydrogels using radiation technology is generally carried out in the vicinity of the gamma-irradiation unit due to the challenges posed in the transport of free flowing liquid contained in trays.
- hydrogel compositions generally contain gelling agents that allow the polymer solution to set at room temperature that can then be easily transported to irradiation centers for cross-linking the polymer.
- the present invention has focused on providing a hydrogel composition which can be shipped to the site of gamma- irradiation unit for crosslinking by increasing the viscosity of PVA and PEG solution without interfering with the swelling capacity of the resulting hydrogel.
- the present invention provides a unique combination of PVA and PEG polymer which can be cross-linked by gamma-irradiation.
- the resulting hydrogel aids in maintaining a moist environment thereby preventing dehydration and scab formation at the wound site and has the ability to imbibe excess wound fluid, thereby preventing maceration.
- the present invention has developed a hydrogel using calcium chloride as viscosity enhancing agent.
- the hydrogel produced by the present invention comprises PVA of low molecular weight (13000 to 23000).
- the advantage of using low molecular weight PVA versus high molecular weight PVA (available in the public domain) in the preparation of hydrogels results in hydrogels exhibiting greater swelling property and elasticity. In high molecular weight hydrogels, the swelling property and elasticity is compromised due to the greater cross-linking of the polymer.
- It is the aim of the invention to provide a hydrogel composition comprising PVA and PEG which is cross linked by gamma irradiation in the presence of calcium chloride.
- Calcium chloride increases the viscosity of the PVA and PEG solution thereby ensuring no spillage of the solution during transport of the solution for gamma irradiation.
- the resulting hydrogel has favorable physical properties such as good swelling property, sufficient tensile strength and elasticity that are required during its application on the wound bed.
- hydrogel composition having lower molecular weight of PVA in the absence of gelling agent resulting in better tensile strength
- the present invention relates to hydrogel compositions comprising polyvinyl alcohol (PVA), polyethylene glycol (PEG), and a viscosity enhancer.
- the hydrogel compositions do not comprise an additional polymer (other than PVA or PEG, where "PEG” includes mPEG), a polysaccharide, or a gelling agent.
- the hydrogel compositions consist essentially of PVA, PEG, a viscosity enhancer, and water, and optionally gauze and/or a bioactive agent.
- components of the hydrogel compositions, such as PVA and PEG are cross linked by gamma irradiation.
- Example viscosity enhancers include calcium chloride (CaCI 2 ), sodium chloride (NaCI), potassium chloride (KCI), and/or magnesium chloride (MgCl 2 ).
- the hydrogel compositions comprise about 1% to about 10% (w/w), such as 1% (w/w) of the viscosity enhancer.
- the PVA has a molecular weight ranging from about 13,000 to about 23,000 g/mol, such as about 14,000 g/mol.
- hydrogel compositions comprise about 10% to about 20% (w/w), such as 20% (w/w), PVA.
- PEG has a molecular weight ranging from about 1,000 to about 4,500 g/mol, such as about 4,000 g/mol.
- the hydrogel compositions comprise about 0.3% to about 2% (w/w), such as about 0.5% (w/w), PEG, and optionally comprise about 0.1% to 0.3% (w/w) of PEG methyl ether (mPEG), for example.
- mPEG PEG methyl ether
- a hydrogel composition comprises about 1.8% (w/w) PEG and about 0.18% (w/w) mPEG.
- the hydrogel compositions comprise about 18% to about 20% (w/w) PVA, about 1.5% to about 2% (w/w) PEG, and about 1% (w/w) calcium chloride.
- the hydrogel compositions may be about 3 mm to about 5 mm thick, such as 3 mm thick, for example.
- the hydrogel compositions further comprise gauze and/or a bioactive agent, and/or are impervious to microbial contamination.
- the invention also includes methods for producing a hydrogel composition comprising: (a) combining PVA, PEG, and a viscosity enhancer with water to form a solution; and (b) cross-linking said PVA, PEG, and viscosity enhancer with gamma irradiation.
- a hydrogel composition comprising: (a) combining PVA, PEG, and a viscosity enhancer with water to form a solution; and (b) cross-linking said PVA, PEG, and viscosity enhancer with gamma irradiation.
- gamma irradiation at about 25to about 50 KGy, such as 50 KGy.
- the methods further comprise combining PVA, PEG, the viscosity enhancer, and a bioactive agent with water to form a solution, and further comprise cross-linking said PVA, PEG, viscosity enhancer and bioactive agent with gamma irradiation.
- the invention also relates to wound dressing comprising PVA, PEG, and a viscosity-enhancer.
- the wound dressings further comprise gauze and/or a bioactive agent.
- the invention further includes methods for treating a wound, comprising: (a) combining PVA, PEG, and a viscosity enhancer with water to form a solution; (b) cross-linking said solution with gamma irradiation to form a hydrogel composition; and (c) applying said hydrogel composition to said wound.
- FIGURE 1 illustrates the optimization and standardization of PVA concentration as well as thickness for hydrogel formulation.
- FIGURE 2 illustrates the optimization of calcium chloride (CaCN) concentration in hydrogel formulation to set PVA solution at room temperature
- FIGURE 3 illustrates the effect of PEG concentration on PVA hydrogels.
- FIGURE 4 illustrates the water absorption capacity of hydrogels.
- FIGURE 5 illustrates the water content of hydrogels.
- FIGURE 6 shows the percentage weight loss of hydrogels as a function of time.
- FIGURE 7 shows the effect of hydrogels on keratinocyte proliferation.
- FIGURE 8 shows the effect of hydrogels on fibroblast proliferation.
- the present disclosure relates to hydrogel compositions, and methodology for making same, wherein the hydrogels comprise PVA, PEG, and a viscosity enhancer, that are cross-linked by irradiation.
- hydrogels cross-linked using radiation technology require either (1) preparation in the vicinity of a gamma-irradiation unit due to the challenges posed in transporting free- flowing liquid contained in trays; or (2) the addition of supplemental polymers, polysaccharides, and/or gelling agents that allow the polymer solution to set at room temperature followed by transportation to irradiation centers for cross-linking.
- hydrogel compositions having a high viscosity to enable easy transport to a site for irradiation cross-linking, and yet at the same time, the hydrogels do not include harmful chemicals or gelling agents that might compromise the safety or sterility of the hydrogel.
- the present inventors developed a hydrogel composition comprising PVA and PEG with increased viscosity, which permits transporting the hydrogel to a gamma-irradiation site for cross-linking without interfering with the hydrogel's swelling capacity, and does not contain additional polymers, polysaccharides, and/or gelling agents.
- the present inventors discovered also that the instant hydrogel compositions maintain a moist environment, thereby providing a role for the hydrogel composition in wound healing directly, as the hydorgels prevent dehydration and scab formation and have the ability to imbibe excess wound fluid, thereby preventing maceration.
- the present inventors determined that the instant hydrogel compositions confer several additional features, including but not limited to (1) a transparent wound dressing for improved wound-bed visualization without disturbing the hydrogel and the healing process; (2) providing a non-adhesive wound covering that does not tightly adhere to the wound-bed; (3) providing a breathable barrier thereby preventing contamination of the underlying wound-bed; (4) removing excess liquids and keeps the wound moist, which aides healing; (5) the hydrogel is impervious to microbes; (6) by sealing in natural moisture, the hydrogel helps maintain a moist environment, thereby encouraging early epithelialization of the wound surface by preventing dehydration and scab formation at the wound site; (7) the addition of gauze impregnated inside the hydrogel aids in easy handling of the hydrogel because it increase hydrogel tensile strength beyond that of .conventional PVA-based hydrogels; (8) the absence of polysaccharides improves the shelf life of the inventive hydrogel; (9)
- Hydrogel refers to a cross-linked three dimensional network of polymers in aqueous solutions.
- a “hydrogel composition” refers to a substance formed when an organic polymer (natural or synthetic) is cross-linked via covalent, ionic, or hydrogen bonds to create a three-dimensional, open-lattice structure which entraps water molecules to form a .rel.
- PEG refers to all polymers of polyethylene glycol (PEG).
- the PEG used for the hydrogel composition are available from several commercial sources, such as Thomas Baker, India
- the molecular weight of the PEG used herein is in the range of about 1,000 to about 4,500, preferably 4,000 g/mol
- the concentration of PEG used is in the range of 0.3-2.0% w/w, preferably 0.5%.
- the term "mPEG” includes PEG methyl ether.
- mPEG is a simple derivative of PEG. It is assumed that mPEG in combination with PEG has the synergistic effect on functional properties of hydrogel.
- PEG is the precursor of mPEG
- PVA refers to all polymers of poly vinyl alcohol (PVA).
- the PVA used for the hydrogel composition are available from several commercial sources, such as Thomas Baker, India.
- the PVA is a low molecular weight PVA, ranging from about 13,000 to about 23, 000 g/mol. It is advantageous to use a lower molecular weight PVA because generally, increasing the molecular weight of PVA increases tensile strength as well as stiffness. Additionally, higher molecular weight hydrogel compositions have compromised swelling and elasticity due to greater cross-linking of the polymer.
- the concentration of PVA used is in the range of 10-20% w/w preferably 20%.
- a simple cotton gauze backing material can be impregnated inside the hydrogel to enhance its mechanical properties.
- Viscosity enhancer refers to any composition that increases or enhances viscosity of a solution.
- Exemplary but non-limiting viscosity enhancers include sodium chloride (NaCI), potassium chloride (KCl), calcium chloride (CaCI 2 ), and magnesium chloride (MgCl 2 ) and borates such as disodium tetraborate and the like.
- NaCI sodium chloride
- KCl potassium chloride
- CaCI 2 calcium chloride
- MgCl 2 magnesium chloride
- borates such as disodium tetraborate and the like.
- CaCI 2 not only facilitates cross-linking, but it also increases the viscosity of the aqueous PVA and PEG solution, thereby ensuring no spillage of the solution during transport of the solution for gamma irradiation.
- the resulting hydrogel has favorable physical properties such as good swelling, sufficient tensile strength and elasticity that are required during its application on the wound bed, and is impervious to
- Polymer, polysaccharide, or gelling agent refers to any additional polymer (excluding PVA and/or PEG), polysaccharide, or gelling agent that may be added to a hydrogel, for example to increase viscosity, tensile strength, gelling ability, and/or transportability or a hydrogel.
- Illustrative polymer, polysaccharide, and/or gelling agents include but not limited to carageenan, agar, epichlorhydrin, Sodium alginate, carboxymethyl cellulose, guar gum, gum acecia, chitosan, gelatin and the like.
- the present hydrogels comprise PEG, PVA, and a viscosity enhancing agent, but do not comprise additional polymers, polysaccharides, or gelling agents like agar, carrageenan, sodium alginate, carboxymethyl cellulose, guar gum, gum acecia, chitosan, gelatin to name a few.
- Bioactive agent means any for composition for preventing and/or treating a condition or disorder in a subject.
- exemplary and non-limiting bioactive agents include, for example, growth factors, collagen, matrix inhibitors, antibodies, cytokines, heparin, integrins, thrombins, thrombin inhibitors, proteases, anticoagulants, glycosaminoglycans, chemotherapeutic agents, antibiotic agents, cardiovascular agents, analgesics, central nervous system drugs, hormones, enzymes, proteins, insulin, and solutes such as glucose or NaCl.
- “Impervious to microbial contamination” refers to a composition's ability to prevent microbial infection because the composition either cannot support microbial growth and/or doesn't attract microbial infection because the composition does not comprise abundant polysaccharides and/or other attractants.
- the present hydrogels are impervious to microbial contamination because they do not contain additional polymers, polysaccharides, or gelling agents.
- Exemplary hydrogel compositions may be prepared by methods readily known in the art.
- a hydrogel may be prepared by mixing PVA, PEG, and a viscosity enhancer, such as CaCI 2 , with water until the components are adequately solubilized.
- Suitable solubilization processes are generally known in the art and include, for example, heating the mixture, altering the pH of the mixture, adding a solvent to the mixture, subjecting the mixture to external pressure, or any combination of these processes.
- the mixture may be autoclaved for a period of time sufficient for complete dissolution, as well as sterilization before further processing.
- the mixture can be poured into one or more pre-sterilized trays. If needed, the solution in the tray can be allowed to sit upright, or subjected to a vacuum in a vacuum chamber, to remove undesirable air bubbles.
- the shape and size of the tray may be selected to obtain a hydrogel of any desired size and/or shape.
- Sodium alginate, carboxymethyl cellulose, guar gum, gum acecia, chitosan, gelatin Trays may be made from any suitable material so long as it does not react with the mixture as well as stable upon exposure of gamma-irradiation.
- PET polyethyleneterephthalate
- LLDPE low linear density polyethylene
- HDPE high density polyethylene
- PVC polyvinyl chloride
- the hydrogel can also be processed by cutting or otherwise forming the hydrogel into the desired form after it has been produced.
- the inventive hydrogels may be made as sheets of any size, such as 6cm x 6cm or 10 x10 cm. Hydrogels can be used as single sheets on small wounds, while multiple sheets can be placed on larger wounds. Of course, hydrogel sheets can be customized in different shapes and sizes as circumstances require.
- gamma-irradiation is used to cross-link hydrogel polymers.
- gamma-irradiation also effectively sterilizes the hydrogel composition. After pouring the solution into trays, the solution is allowed to cool for 10-15 min before it is packed in the proper final boxes. The boxes are then placed in movable handing system, and almost 24 h is needed to achieve the required dose of 25 kGy.
- the instant hydrogel compositions find utility in a variety of applications, including but not limited to all biomedical applications such as wound dressings, medical coatings, skin friendly adhesives, pressure ulcer treatment, as well as wound care for diabetic foot ulcers, venous stasis ulcers, pressure ulcers, surgical wounds, ischemic ulcers, traumatic wounds, sores, 1 st and 2 nd degree burns, abrasions, and lacerations.
- the present hydrogel compositions may also comprise a bioactive agent so as to to lend the hydrogel suitable for preventing and/or treating a condition or disorder in a subject.
- bioactive agents include, for example, growth factors, collagen, matrix inhibitors, antibodies, cytokines, heparin, integrins, thrombins, thrombin inhibitors, proteases, anticoagulants, glycosaminoglycans, chemotherapeutic agents, antibiotic agents, cardiovascular agents, analgesics, central nervous system drugs, hormones, enzymes, proteins, insulin, and solutes such as glucose or NaCI.
- the hydrogel can thus act as a drug delivery vehicle.
- Other bioactive agents can be incorporated in to the hydrogel in order to support cellular growth and proliferation on the surface of a material.
- a bioactive agent is selected based upon the particular application planned and circumstances and conditions require.
- a bioactive agent may be introduced into the hydrogel solution as a sterilized powder or suspended in an aqueous solution.
- the hydrogel composition comprising a bioactive agent is then processed and cross-linked as described herein.
- the rate of release, or release kinetics, of a bioactive agent from the hydrogel compositions once administered to a patient are a determined by a variety of factors including the size of the bioactive agent, the specific backbone and cross-linking agents used to prepare the hydrogel, and the type of binding of the bioactive agent.
- Such methodologies are readily known and available to one of ordinary skill in the art.
- inventive hydrogel compositions may be impregnated with cotton gauze so as to facilitate handling of the hydrogel.
- the presence of gauze increases the inventive tensile strength of the inventive hydrogels far beyond that of conventional PVA-based hydrogels.
- the gauze may be medicated or non-medicated.
- PVA (2Og) was added to 100 ml of deionized water and then the mixture was autoclaved for I h for complete dissolution. The solution was dispensed into trays and irradiated at 25 kGy for the formation of hydrogels.
- Hydrogels of varying thicknesses were prepared with 10-20% (w/w) PVA.
- the water absorption capacity of the hydrogel as determined by Section D (b) further below, was observed over a period of 96 hours.
- 20% (w/w) PVA was the optimum concentration for all thicknesses, and 3 mm was the optimum thickness based on swelling data.
- aqueous PVA solution with polymer concentrations ranging from 10 to 20% (w/v) was made by adding PVA in CaCl 2 solution with a concentration range from 1 and 10% (w/v) and subsequently heating at 121 0 C. Additionally, 0.9 % (w/v) of NaCI was added to determine its effect on water absorption capacity. As shown in Figure 2, and summarized in Table 2 below, no significant effect was found in the presence of NaCI. As the stickiness increases with increasing CaCI 2 concentration, 1% of CaCK with 0.9 % of NaCI was optimized with respect to other parameters as essential characteristics of wound dressing material.
- PEG was used as one of the components in the hydrogel formulation. It was found that in presence of PEG, the water absorption capacity of hydrogel increases. As shown in Figure 3, as PEG concentration increases, water absorption capacity also increases to a certain extent.
- the hydrogels were dried at HO 0 C for 6h to thoroughly remove the water contained therein.
- the freshly prepared hydrogel samples were put separately into 10cm x 10cm polystyrene trays containing normal saline solution and were kept in the incubator at 37 0 C. At predetermined time point, the hydrogels were taken out and the surface water from each hydrogel was removed by cleaning with cotton cloth and the weight of each hydrogel was taken. The increase in weight was noted and its water absorption capacity was then calculated using the following formula
- % weight loss W lm ,,ai - W Fina ⁇ / W, nil ⁇ a , * 100
- Hydrogel I had the greatest percentage weight loss.
- the hydrogel was dried at 1 1O 0 C for 6h to remove the water contained therein and the dry weight (W d ) in grams was determined.
- the dried hydrogel was immersed into freshly prepared normal saline solution and was kept at 37 0 C. At defined time point, the hydrogels were taken out and their weights (W t ) were measured. This was continued until the hydrogel reached the saturation state.
- the water absorption ratio was determined as the ratio of the weight (W,) after absorption of normal saline solution to the dry weight (Wd).
- Tensile strength and Elongation- Tensile strength is determined by elongating a specimen and measuring the load carried by the specimen. From the knowledge of specific dimensions, load and deflection data can be translated into a stress-strain curve. A variety of tensile properties can be extracted from the stress-strain curve. Tensile strength as well as elongation of the hydrogel is measured using a LLOYD (Model: LRX Plus) instrument at the speed of 500 mm/min maintaining the distance 50 mm between the jaws.
- LLOYD Model: LRX Plus
- a hydrogel strip with a length of 6 cm and a width of -1.5 cm is cut from 6 cm x 6 cm x 0.3 cm hydrogel, the upper and the lower portion of the hydrogel is wrapped with rough paper and finally, placed in between two clamps.
- Table 7 shows that tensile strength of hydrogel increases by impregnating the hydrogel with gauze but percentage elongation decreases as compared to hydrogel without gauze.
- Table 7 Tensile strength and percentage elongation.
- Bacterial culture lawns (Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa) were prepared on Blood agar and MacConkey agar plates. Small pieces of hydrogel sheets were placed on the culture lawn. After overnight incubation, the upper surfaces of hydrogels were exposed to sterile media contained in petri dishes by Agar-overlay method. The exposed media in the petri dishes were incubated at 37°C for 48 hours and examined for any growth. Result: No growth was observed on the exposed media after 48 hrs.
- hydrogels were evaluated to ensure that the hydrogels do not release materials that might be detrimental to the growth of skin cells.
- the hydrogels were incubated with cell specific culture media for different time points. This contact media was added to cultures of keratinocytes and fibroblasts and its effect on cell growth was monitored for 24h, 48h, 72h, and 96h. Cell proliferation was analyzed indirectly by the MTT method. (Molinari BL, Tasat DR, Palmieri MA, O'Connor SE, Cabrini RL (2003) Cell-based quantitative evaluation of the MTT assay. Anal Quant Cytol Histol 25: 254-262).
- MTT 0.5mg/ml
- Viable cells were indirectly determined by their ability to convert soluble MTT to insoluble formazan crystals.
- the crystals were solubilized and the absorbance was determined as the difference in optical density measured at a test wavelength of 570nm and a reference wavelength of 650nm (Shimadzu UV-VIS Spectrophotometer, Japan). At each end point, the absorbance was recorded and the optical density was compared to control.
- keratinocyte proliferation was not affected by hydrogel exposure.
- fibroblast proliferation was not affected by hydrogel exposure. Thus, no toxicity was observed on skin cells incubated with the hydrogel incubated media for defined time periods.
- the hydrogel of the present invention elicited a good response in patients having skin conditions like bed sores or pressure ulcers and skin grafts
- compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents that are chemically or physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Dispersion Chemistry (AREA)
- Materials For Medical Uses (AREA)
- Processes Of Treating Macromolecular Substances (AREA)
- Compositions Of Macromolecular Compounds (AREA)
Abstract
The present disclosure relates to hydrogel compositions and methods for preparing same. Illustrative hydrogel compositions comprise PVA, PEG, and a viscosity enhancer that are cross-linked by irradiation.
Description
HYDROGEL COMPOSITION
CROSS-REFERENCE TO RELATED APPLICATION
This application claims priority to Indian Patent Application No. 2561 /MUM/2008, filed December 8, 2008.
TECHNICAL FIELD
The present technology relates to hydrogel compositions for wound healing. Illustrative hydrogel compositions comprise PVA, PEG, and a viscosity enhancer, that are cross- linked by irradiation. In particular the hydrogel composition does not comprise gelling agent.
INTRODUCTION
Wound dressings are available as hydrogels, hydrocolloids, films, gauzes, alginates, biologies, and foams. Amongst these, hydrogels have become more popular because of their relatively high water content, and soft and rubbery consistency. Hydrogels are three dimensional, cross-linked polymeric networks that regulate the fluid exchange from the wound surface. Because of their excellent biocompatibility, hydrogels are used in a variety of wound dressings. The three dimensional network of polymers makes them capable of imbibing water 10-1000 times its original dry weight. Due to its swelling and water retention capacity, hydrogels are used in a variety of applications in biomedical field, ranging from drug delivery system to cell delivery system to wound/burn treatment.
Hydrogels have been prepared with various polymers such as polyvinyl alcohol (PVA). polyvinyl pyrrolidone (PVP), or polyacrylamides. Exemplary PVA-based hydrogels are disclosed in, e.g., U.S. Patent Nos: 6,231,605; 5,346,935; 5,981 ,826; 4,663,358; and 4,988,761. However PVA hydrogels lack desirable mechanical properties such as sufficient tensile strength and elasticity. Polyethylene glycol (PEG) based hydrogels provide a large degree of swelling in aqueous solutions. Various PEG based hydrogels are disclosed in U.S. Patent Nos: 5,514,379; 6,362,276; and 6,541 ,015. PCT application
WO2006125082 provides hydrogel formulation containing pre-solidified hydrogel particles in a precursor hydrogel solution.
Hydrogels comprising both PVA and PEG are disclosed in WO 2005/120462 ("the '462 application"). The '462 application discloses preparing hydrogels using chemical cross- linkers, which are biodegradable groups capped to the PVA and/or PEG,. Once such cross-linker is acrylated glycine anhydride. However, residual cross-linking agents in the hydrogel may be toxic to host tissues and the usage of such chemicals requires stringent manufacturing controls, which tends to increase the cost of hydrogel manufacture.
Chemical cross-linkers such as glutaraldehyde and boric acid are used in the preparation of hydrogels. Some of the disadvantages facing such hydrogels include presence of residual cross-linking agents in the hydrogel which could be toxic to the tissues. Usage of such chemicals requires stringent controls during its manufacture which tends to increase the cost of hydrogel manufacture.
On the other hand, preparation of hydrogels using freeze-thaw method does not require the introduction of chemical cross-linking agents. Freeze/thaw cycling of aqueous polymeric solution of PVA results in the formation of physical cross-linking (i.e. weak bonding through a non-permanent "association" of the polymer chains). It is a time- consuming and expensive method. Hydrogels prepared by this method are opaque and this could be a drawback in wound dressing as it prevents visualization and proper examination of the wound bed after its application without the removal of the hydrogel.
Recently, hydrogel wound dressings have been prepared using gamma irradiation as a cross-linker. One such product that has gained commercial importance is HIZEL™ which comprises PVA along with gelling agents. See, e.g., Indian Patent Numbers 0187486 and 192136, as well as WO 2001/030407.
Hydrogels prepared using gamma-irradiation comprises PVA, PVP, PEG acrylamide/maleic acid (CAMA), HPC, etc. as described in following patents
US Patent No 7235592 describes covalently cross-linked vinyl polymer hydrogel comprising the steps of: providing a physically associated vinyl polymer hydrogel having a crystalline phase; exposing the physically associated vinyl polymer hydrogel to an amount of ionizing radiation providing a radiation dose in the range of about 1-1 ,000 kGy effective to form covalent crosslinks; and removing physical associations by exposing the irradiated vinyl polymer hydrogel to a temperature above the melting point of the physically associated crystalline phase to produce a covalently cross-linked vinyl polymer hydrogel,
US Patent No 7282165 provides a solution of polyvinyl alcohol in a solvent of DMSO/water. The solution is placed in a mold and is gelated by cycling the mold in a freeze-thaw cycle at a temperature at or below 4. degree. C. for a period of 2 to 24 hours. The hydrogel so formed is washed in a saline solution, including potassium carbonate. The hydrogel is then dehydrated to 20 to 70% water content and thereafter irradiated with Gamma radiation. The surface of the hydrogel is then cross-linked using a boric acid solution preferably between 2.5 and 5% for about 1 minute. The hydrogel is then rinsed and sterilized.
European patent application No. 0107376 (Johnson & Johnson Products Inc.) discloses a wound dressing which is based on a transparent layer of a water-swollen cross-linked homopolymer of N-vinyl pyrrolidone (VP). The homopolymer of VP is first prepared and dissolved in water, a hydrogel layer is then formed by irradiating with gamma rays while contained within a polythene bag.
US Pat. No. 4,989,607, issued to Keusch et al., discloses highly conductive, non-stringy adhesive hydrophilic gels which include, polyvinyl pyrrolidone) cross-linked by radiation to provide the desired non-stringy property thereto.
US Patent No 4871490 provides a method of manufacturing hydrogel dressings from polymers by radiation cross-linking, comprising an aqueous solution containing 2- 10 per cent by weight of polyvinylpyrrolidone, no more than 3 percent by weight of agar and 1 -3
percent by weight of poly(ethylene) glycol; pouring the solution into a mould to shape the dressing; tightly closing the mould and subjecting the mould to an ionizing radiation dose in the range of 25-40 KGy.
US Patent No 5401508 provides a hydrogel for ocular comprising acrylamides and acrylates copolymers cross linked by ethylene glycol dimethacrylate
US Patent No 5489437 discloses an adhesive hydrogel product comprising water and a thermoplastic, Hydroxypropyl cellulose (HPC) polymer extrudable in a dry state, then having been exposed to ionizing energy of in excess of 2.5 megarads, and then adding the water, the energy being sufficient to permit cross-linking of the polymer into a tacky hydrophilic hydrogel product having a gel breaking strength of at least 10 p.s.i., and an absorption capacity per mil of thickness in excess of 10%, by weight.
US Patent No 6617372 provides polymeric hydrogel product of polyvinylpyrrolidone (PVP), poly(vinylcaprolactam) (PVCL), a copolymer of PVP and PVCL and a comonomer dimethylaminopropyl(meth)acrylamide (DMAPMA) and/or dimethylaminoethyl(meth)acrylate (DMAEMA) and a cross linking agent crosslinking agent which is a substantially water-insoluble compound selected from pentaerythritol trial IyI ether (PETE) and pentaerythritol tetraacrylate (PETA)., made by irradiating the composition with high energy electron beam or gamma-radiation.
In the above patents, besides the above specified polymers, the hydrogels comprise other components like natural polysaccharides (e.g. Carrageenan, agar etc.) or epichlorhydrin, etc. While some chemicals like epichlorohydrin pose health hazards, natural polysaccharides are prone to microbial contamination thus posing a limitation of its shelf life as well as duration of usage on wounds. Preparation of hydrogels using radiation technology is generally carried out in the vicinity of the gamma-irradiation unit due to the challenges posed in the transport of free flowing liquid contained in trays. To overcome this, hydrogel compositions generally contain gelling agents that allow the polymer
solution to set at room temperature that can then be easily transported to irradiation centers for cross-linking the polymer.
Looking into the need for a formulation that would have high viscosity to enable easy transport and at the same time does not include harmful chemicals or gelling agents that might compromise the safety or sterility of the product, the present invention has focused on providing a hydrogel composition which can be shipped to the site of gamma- irradiation unit for crosslinking by increasing the viscosity of PVA and PEG solution without interfering with the swelling capacity of the resulting hydrogel.
The present invention provides a unique combination of PVA and PEG polymer which can be cross-linked by gamma-irradiation. The resulting hydrogel aids in maintaining a moist environment thereby preventing dehydration and scab formation at the wound site and has the ability to imbibe excess wound fluid, thereby preventing maceration. Further, the present invention has developed a hydrogel using calcium chloride as viscosity enhancing agent.
The hydrogel produced by the present invention comprises PVA of low molecular weight (13000 to 23000). The advantage of using low molecular weight PVA versus high molecular weight PVA (available in the public domain) in the preparation of hydrogels results in hydrogels exhibiting greater swelling property and elasticity. In high molecular weight hydrogels, the swelling property and elasticity is compromised due to the greater cross-linking of the polymer.
OBJECTIVE OF THE INVENTION:
It is the aim of the invention to provide a hydrogel composition comprising PVA and PEG which is cross linked by gamma irradiation in the presence of calcium chloride. Calcium chloride increases the viscosity of the PVA and PEG solution thereby ensuring no spillage of the solution during transport of the solution for gamma irradiation. The resulting hydrogel has favorable physical properties such as good swelling property,
sufficient tensile strength and elasticity that are required during its application on the wound bed.
It is the aim of the present invention to provide hydrogel composition having lower molecular weight of PVA in the absence of gelling agent resulting in better tensile strength
It is the aim of the present invention to provide a hydrogel composition that aids in the transport of the solution without leakage/spillage for gamma-irradiation.
It is the aim of the present invention to provide a hydrogel composition that does not support microbial contamination.
It is the aim of the present invention to provide a hydrogel composition that has enhanced water absorption capacity and good mechanical strength.
It is the aim of the present invention to provide a process for the manufacture of the hydrogel.
It is the aim of the present invention to provide a transparent hydrogel wound dressing.
It is the further aim of the present invention to provide the hydrogel loaded with drugs or biologicals for enhancing its wound healing properties.
SUMMARY
The present invention relates to hydrogel compositions comprising polyvinyl alcohol (PVA), polyethylene glycol (PEG), and a viscosity enhancer. In certain embodiments, the hydrogel compositions do not comprise an additional polymer (other than PVA or PEG, where "PEG" includes mPEG), a polysaccharide, or a gelling agent. In certain embodiments, the hydrogel compositions consist essentially of PVA, PEG, a viscosity enhancer, and water, and optionally gauze and/or a bioactive agent. In some embodiments, components of the hydrogel compositions, such as PVA and PEG, are cross linked by gamma irradiation. Example viscosity enhancers include calcium chloride (CaCI2), sodium chloride (NaCI), potassium chloride (KCI), and/or magnesium
chloride (MgCl2). In certain embodiments, the hydrogel compositions comprise about 1% to about 10% (w/w), such as 1% (w/w) of the viscosity enhancer.
In some embodiments, the PVA has a molecular weight ranging from about 13,000 to about 23,000 g/mol, such as about 14,000 g/mol. In other embodiments, hydrogel compositions comprise about 10% to about 20% (w/w), such as 20% (w/w), PVA. In certain embodiments, PEG has a molecular weight ranging from about 1,000 to about 4,500 g/mol, such as about 4,000 g/mol. In other embodiments, the hydrogel compositions comprise about 0.3% to about 2% (w/w), such as about 0.5% (w/w), PEG, and optionally comprise about 0.1% to 0.3% (w/w) of PEG methyl ether (mPEG), for example. In one embodiment, a hydrogel composition comprises about 1.8% (w/w) PEG and about 0.18% (w/w) mPEG. In certain embodiments, the hydrogel compositions comprise about 18% to about 20% (w/w) PVA, about 1.5% to about 2% (w/w) PEG, and about 1% (w/w) calcium chloride. Additionally, the hydrogel compositions may be about 3 mm to about 5 mm thick, such as 3 mm thick, for example. In certain embodiments, the hydrogel compositions further comprise gauze and/or a bioactive agent, and/or are impervious to microbial contamination.
The invention also includes methods for producing a hydrogel composition comprising: (a) combining PVA, PEG, and a viscosity enhancer with water to form a solution; and (b) cross-linking said PVA, PEG, and viscosity enhancer with gamma irradiation. In certain embodiments, one applies gamma irradiation at about 25to about 50 KGy, such as 50 KGy. In other embodiments, the methods further comprise combining PVA, PEG, the viscosity enhancer, and a bioactive agent with water to form a solution, and further comprise cross-linking said PVA, PEG, viscosity enhancer and bioactive agent with gamma irradiation. The invention also relates to wound dressing comprising PVA, PEG, and a viscosity-enhancer. In certain embodiments, the wound dressings further comprise gauze and/or a bioactive agent. The invention further includes methods for treating a wound, comprising: (a) combining PVA, PEG, and a viscosity enhancer with water to form a solution; (b) cross-linking said solution with gamma irradiation to form a hydrogel composition; and (c) applying said hydrogel composition to said wound.
BRIEF DESCRIPTION OF DRAWINGS
The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, the inventions of which can be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.
FIGURE 1 illustrates the optimization and standardization of PVA concentration as well as thickness for hydrogel formulation.
FIGURE 2 illustrates the optimization of calcium chloride (CaCN) concentration in hydrogel formulation to set PVA solution at room temperature
FIGURE 3 illustrates the effect of PEG concentration on PVA hydrogels.
FIGURE 4 illustrates the water absorption capacity of hydrogels.
FIGURE 5 illustrates the water content of hydrogels.
FIGURE 6 shows the percentage weight loss of hydrogels as a function of time.
FIGURE 7 shows the effect of hydrogels on keratinocyte proliferation.
FIGURE 8 shows the effect of hydrogels on fibroblast proliferation.
DETAILED DESCRIPTION
The present disclosure relates to hydrogel compositions, and methodology for making same, wherein the hydrogels comprise PVA, PEG, and a viscosity enhancer, that are cross-linked by irradiation.
While numerous hydrogel compositions presently exist, the present inventors realized that hydrogels cross-linked using radiation technology require either (1) preparation in the vicinity of a gamma-irradiation unit due to the challenges posed in transporting free- flowing liquid contained in trays; or (2) the addition of supplemental polymers, polysaccharides, and/or gelling agents that allow the polymer solution to set at room temperature followed by transportation to irradiation centers for cross-linking. Because it is not practical to prepare a hydrogel composition in close proximity to a gamma- irradiation site and additional polymers, polysaccharides, and/or gelling agents compromise the safety and/or sterility of the hydrogel, the present inventors identified and fulfilled a need for producing hydrogel compositions having a high viscosity to enable easy transport to a site for irradiation cross-linking, and yet at the same time, the hydrogels do not include harmful chemicals or gelling agents that might compromise the
safety or sterility of the hydrogel. Accordingly, the present inventors developed a hydrogel composition comprising PVA and PEG with increased viscosity, which permits transporting the hydrogel to a gamma-irradiation site for cross-linking without interfering with the hydrogel's swelling capacity, and does not contain additional polymers, polysaccharides, and/or gelling agents.
In addition to improved transport properties, the present inventors discovered also that the instant hydrogel compositions maintain a moist environment, thereby providing a role for the hydrogel composition in wound healing directly, as the hydorgels prevent dehydration and scab formation and have the ability to imbibe excess wound fluid, thereby preventing maceration.
In treating a wound or providing a wound dressing, the present inventors determined that the instant hydrogel compositions confer several additional features, including but not limited to (1) a transparent wound dressing for improved wound-bed visualization without disturbing the hydrogel and the healing process; (2) providing a non-adhesive wound covering that does not tightly adhere to the wound-bed; (3) providing a breathable barrier thereby preventing contamination of the underlying wound-bed; (4) removing excess liquids and keeps the wound moist, which aides healing; (5) the hydrogel is impervious to microbes; (6) by sealing in natural moisture, the hydrogel helps maintain a moist environment, thereby encouraging early epithelialization of the wound surface by preventing dehydration and scab formation at the wound site; (7) the addition of gauze impregnated inside the hydrogel aids in easy handling of the hydrogel because it increase hydrogel tensile strength beyond that of .conventional PVA-based hydrogels; (8) the absence of polysaccharides improves the shelf life of the inventive hydrogel; (9) more cost-effective wound dressings due to fewer ingredients; and (10) PVA and PEG are nontoxic and biocompatible.
All technical terms used herein are terms commonly used in cell biology, biochemistry, molecular biology, and chemistry, and can be understood by one of ordinary skill in the art. These technical terms can be found in the current editions of Molecular Cloning: A Laboratory Manual, (Sambrook et al., Cold Spring Harbor); Gene Transfer Vectors for
Mammalian Cells (Miller & Calos eds.); and Current Protocols in Molecular Biology (F. M. Ausubel et al. eds., Wiley & Sons). Cell biology, protein chemistry, and antibody techniques can be found in Current Protocols in Protein Science (J. E. Colligan et al. eds., Wiley & Sons); Current Protocols in Cell Biology (J. S. Bonifacino et al., Wiley & Sons) and Current Protocols in Immunology (J. E. Colligan et al. eds., Wiley & Sons.). Reagents, growth media, and other materials referred to in this disclosure are available from commercial vendors such as BioRad, Stratagene, Invitrogen, ClonTech, and Sigma- Aldrich Co.
"Hydrogel" refers to a cross-linked three dimensional network of polymers in aqueous solutions. As used herein, a "hydrogel composition" refers to a substance formed when an organic polymer (natural or synthetic) is cross-linked via covalent, ionic, or hydrogen bonds to create a three-dimensional, open-lattice structure which entraps water molecules to form a .rel.
"PEG" refers to all polymers of polyethylene glycol (PEG). The PEG used for the hydrogel composition are available from several commercial sources, such as Thomas Baker, India The molecular weight of the PEG used herein is in the range of about 1,000 to about 4,500, preferably 4,000 g/mol The concentration of PEG used is in the range of 0.3-2.0% w/w, preferably 0.5%. The term "mPEG" includes PEG methyl ether. mPEG is a simple derivative of PEG. It is assumed that mPEG in combination with PEG has the synergistic effect on functional properties of hydrogel. PEG is the precursor of mPEG
"PVA" refers to all polymers of poly vinyl alcohol (PVA). The PVA used for the hydrogel composition are available from several commercial sources, such as Thomas Baker, India. In one embodiment, the PVA is a low molecular weight PVA, ranging from about 13,000 to about 23, 000 g/mol. It is advantageous to use a lower molecular weight PVA because generally, increasing the molecular weight of PVA increases tensile strength as well as stiffness. Additionally, higher molecular weight hydrogel compositions have compromised swelling and elasticity due to greater cross-linking of the polymer. The concentration of PVA used is in the range of 10-20% w/w preferably
20%. For lower molecular weight hydrogel compositions, a simple cotton gauze backing material can be impregnated inside the hydrogel to enhance its mechanical properties.
"Viscosity enhancer" refers to any composition that increases or enhances viscosity of a solution. Exemplary but non-limiting viscosity enhancers include sodium chloride (NaCI), potassium chloride (KCl), calcium chloride (CaCI2), and magnesium chloride (MgCl2) and borates such as disodium tetraborate and the like. For example, CaCI2 not only facilitates cross-linking, but it also increases the viscosity of the aqueous PVA and PEG solution, thereby ensuring no spillage of the solution during transport of the solution for gamma irradiation. Furthermore, the resulting hydrogel has favorable physical properties such as good swelling, sufficient tensile strength and elasticity that are required during its application on the wound bed, and is impervious to microbial contamination.
"Polymer, polysaccharide, or gelling agent" refers to any additional polymer (excluding PVA and/or PEG), polysaccharide, or gelling agent that may be added to a hydrogel, for example to increase viscosity, tensile strength, gelling ability, and/or transportability or a hydrogel. Illustrative polymer, polysaccharide, and/or gelling agents include but not limited to carageenan, agar, epichlorhydrin, Sodium alginate, carboxymethyl cellulose, guar gum, gum acecia, chitosan, gelatin and the like. In certain embodiments, the present hydrogels comprise PEG, PVA, and a viscosity enhancing agent, but do not comprise additional polymers, polysaccharides, or gelling agents like agar, carrageenan, sodium alginate, carboxymethyl cellulose, guar gum, gum acecia, chitosan, gelatin to name a few.
"Bioactive agent" means any for composition for preventing and/or treating a condition or disorder in a subject. Exemplary and non-limiting bioactive agents include, for example, growth factors, collagen, matrix inhibitors, antibodies, cytokines, heparin, integrins, thrombins, thrombin inhibitors, proteases, anticoagulants, glycosaminoglycans, chemotherapeutic agents, antibiotic agents, cardiovascular agents, analgesics, central nervous system drugs, hormones, enzymes, proteins, insulin, and solutes such as glucose or NaCl.
"Impervious to microbial contamination" refers to a composition's ability to prevent microbial infection because the composition either cannot support microbial growth and/or doesn't attract microbial infection because the composition does not comprise abundant polysaccharides and/or other attractants. The present hydrogels are impervious to microbial contamination because they do not contain additional polymers, polysaccharides, or gelling agents.
A. Hydrogel Preparation.
Exemplary hydrogel compositions may be prepared by methods readily known in the art. For example, and in no way limiting, a hydrogel may be prepared by mixing PVA, PEG, and a viscosity enhancer, such as CaCI2, with water until the components are adequately solubilized. Suitable solubilization processes are generally known in the art and include, for example, heating the mixture, altering the pH of the mixture, adding a solvent to the mixture, subjecting the mixture to external pressure, or any combination of these processes. In one embodiment, the mixture may be autoclaved for a period of time sufficient for complete dissolution, as well as sterilization before further processing. First, calcium chloride is dissolved into de-ionized water followed by addition of sodium chloride ensuring that both are homogeneously distributed throughout the solution. Then PVA followed by PEG is added into the solution. After that the entire mixture is subjected to autoclave for a period of time sufficient for complete dissolution before further processing. It is advised to use closed vessel with lightly loosen lid for autoclaving.
Once prepared, the mixture can be poured into one or more pre-sterilized trays. If needed, the solution in the tray can be allowed to sit upright, or subjected to a vacuum in a vacuum chamber, to remove undesirable air bubbles. The shape and size of the tray may be selected to obtain a hydrogel of any desired size and/or shape. Sodium alginate, carboxymethyl cellulose, guar gum, gum acecia, chitosan, gelatin Trays may be made from any suitable material so long as it does not react with the mixture as well as stable upon exposure of gamma-irradiation. PET (polyethyleneterephthalate), LLDPE (low linear density polyethylene), HDPE (high density polyethylene) and PVC (polyvinyl
chloride) of medical or food grade quality can be used. In ours case, LLDPE is used in fabricating disposable tray.
The hydrogel can also be processed by cutting or otherwise forming the hydrogel into the desired form after it has been produced. For example, and in one embodiment, the inventive hydrogels may be made as sheets of any size, such as 6cm x 6cm or 10 x10 cm. Hydrogels can be used as single sheets on small wounds, while multiple sheets can be placed on larger wounds. Of course, hydrogel sheets can be customized in different shapes and sizes as circumstances require.
B. Cross-linking
As explained above, the present inventors discovered that the present of a viscosity enhancer in a PVA/PEG hydrogel solution provides a better means for transporting a hydrogel composition to a site for irradiation. In one embodiment, gamma-irradiation is used to cross-link hydrogel polymers. In addition to cross-linking, gamma-irradiation also effectively sterilizes the hydrogel composition. After pouring the solution into trays, the solution is allowed to cool for 10-15 min before it is packed in the proper final boxes. The boxes are then placed in movable handing system, and almost 24 h is needed to achieve the required dose of 25 kGy.
C. Hydrogel Applications
The instant hydrogel compositions find utility in a variety of applications, including but not limited to all biomedical applications such as wound dressings, medical coatings, skin friendly adhesives, pressure ulcer treatment, as well as wound care for diabetic foot ulcers, venous stasis ulcers, pressure ulcers, surgical wounds, ischemic ulcers, traumatic wounds, sores, 1st and 2nd degree burns, abrasions, and lacerations. The present hydrogel compositions may also comprise a bioactive agent so as to to lend the hydrogel suitable for preventing and/or treating a condition or disorder in a subject. Exemplary and non-limiting bioactive agents include, for example, growth factors, collagen, matrix inhibitors, antibodies, cytokines, heparin, integrins, thrombins, thrombin inhibitors, proteases, anticoagulants, glycosaminoglycans, chemotherapeutic agents, antibiotic agents, cardiovascular agents, analgesics, central nervous system drugs,
hormones, enzymes, proteins, insulin, and solutes such as glucose or NaCI. The hydrogel can thus act as a drug delivery vehicle. Other bioactive agents can be incorporated in to the hydrogel in order to support cellular growth and proliferation on the surface of a material. Of course, a bioactive agent is selected based upon the particular application planned and circumstances and conditions require.
In order to embed a bioactive agent into an instant hydrogel composition, a bioactive agent may be introduced into the hydrogel solution as a sterilized powder or suspended in an aqueous solution. The hydrogel composition comprising a bioactive agent is then processed and cross-linked as described herein. The rate of release, or release kinetics, of a bioactive agent from the hydrogel compositions once administered to a patient are a determined by a variety of factors including the size of the bioactive agent, the specific backbone and cross-linking agents used to prepare the hydrogel, and the type of binding of the bioactive agent. Such methodologies are readily known and available to one of ordinary skill in the art.
In other embodiments, the inventive hydrogel compositions may be impregnated with cotton gauze so as to facilitate handling of the hydrogel. The presence of gauze increases the inventive tensile strength of the inventive hydrogels far beyond that of conventional PVA-based hydrogels. The gauze may be medicated or non-medicated.
The following examples are illustrative and non-limiting. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
EXAMPLE 1: General Preparation of Hydrogel
PVA (2Og) was added to 100 ml of deionized water and then the mixture was autoclaved for I h for complete dissolution. The solution was dispensed into trays and irradiated at 25 kGy for the formation of hydrogels.
A) Effect of PVA concentration:
Hydrogels of varying thicknesses (3, 4, and 5 mm) were prepared with 10-20% (w/w) PVA. The water absorption capacity of the hydrogel, as determined by Section D (b) further below, was observed over a period of 96 hours. As shown in Figure 1 , and summarized in Table 1 below, 20% (w/w) PVA was the optimum concentration for all thicknesses, and 3 mm was the optimum thickness based on swelling data.
Table 1: Water absorption capacity (%) after 96 hours
B) Effect of Calcium Chloride (CaCI2)
An aqueous PVA solution with polymer concentrations ranging from 10 to 20% (w/v) was made by adding PVA in CaCl2 solution with a concentration range from 1 and 10% (w/v) and subsequently heating at 1210C. Additionally, 0.9 % (w/v) of NaCI was added to determine its effect on water absorption capacity. As shown in Figure 2, and summarized in Table 2 below, no significant effect was found in the presence of NaCI. As the stickiness increases with increasing CaCI2 concentration, 1% of CaCK with 0.9 % of NaCI was optimized with respect to other parameters as essential characteristics of wound dressing material.
Table 2: Optimization of CaCI2 concentration by water absorption capacity (%).
C) Effect of PEG
PEG was used as one of the components in the hydrogel formulation. It was found that in presence of PEG, the water absorption capacity of hydrogel increases. As shown in Figure 3, as PEG concentration increases, water absorption capacity also increases to a certain extent.
D) Results The results of hydrogels with different compositions are enumerated as follows:
a) Study on the water content
The hydrogels were dried at HO0C for 6h to thoroughly remove the water contained therein. The water content of PVA hydrogels were determined from the gel weight W0 and W i, in gram prior to and after drying respectively, by the following formula: Water content of hydrogel = W0- W1/ W0 * 100
Table 3: Determination of water content of hydrogels
The freshly prepared hydrogel samples were put separately into 10cm x 10cm polystyrene trays containing normal saline solution and were kept in the incubator at 370C. At predetermined time point, the hydrogels were taken out and the surface water from each hydrogel was removed by cleaning with cotton cloth and the weight of each hydrogel was taken. The increase in weight was noted and its water absorption capacity was then calculated using the following formula
Water absorption capacity = WF,nai - W|nitιa|/ Winι,,aι * 100
Table 4: Determination of water absorption capacity of hydrogels (Figure 4)
The freshly prepared hydrogel samples were weighed individually and were put separately on each 10 cm x 10 cm glass plate. The hydrogel samples were kept in the oven at 370C. At each predetermined time point, the hydrogels were taken out and were weighed. Percentage weight loss was calculated by the following formula:
% weight loss = Wlm,,ai - WFinaι/ W,nilιa, * 100
As shown in Figure 6, and summarized in Table 5 below, Hydrogel I had the greatest percentage weight loss.
The hydrogel was dried at 1 1O0C for 6h to remove the water contained therein and the dry weight (Wd) in grams was determined. The dried hydrogel was immersed into freshly prepared normal saline solution and was kept at 370C. At defined time point, the hydrogels were taken out and their weights (Wt) were measured. This was continued until the hydrogel reached the saturation state. The water absorption ratio was determined as the ratio of the weight (W,) after absorption of normal saline solution to the dry weight (Wd).
Table 6: Weights of the hydrogels at different time intervals
e) Mechanical properties
Tensile strength and Elongation- Tensile strength is determined by elongating a specimen and measuring the load carried by the specimen. From the knowledge of specific dimensions, load and deflection data can be translated into a stress-strain curve. A variety of tensile properties can be extracted from the stress-strain curve. Tensile strength as well as elongation of the hydrogel is measured using a LLOYD (Model: LRX Plus) instrument at the speed of 500 mm/min maintaining the distance 50 mm between the jaws. In this case, a hydrogel strip with a length of 6 cm and a width of -1.5 cm is cut from 6 cm x 6 cm x 0.3 cm hydrogel, the upper and the lower portion of the hydrogel is wrapped with rough paper and finally,
placed in between two clamps. Table 7 shows that tensile strength of hydrogel increases by impregnating the hydrogel with gauze but percentage elongation decreases as compared to hydrogel without gauze. Table 7: Tensile strength and percentage elongation.
1. Microbe penetration test
Method: Bacterial culture lawns (Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa) were prepared on Blood agar and MacConkey agar plates. Small pieces of hydrogel sheets were placed on the culture lawn. After overnight incubation, the upper surfaces of hydrogels were exposed to sterile media contained in petri dishes by Agar-overlay method. The exposed media in the petri dishes were incubated at 37°C for 48 hours and examined for any growth. Result: No growth was observed on the exposed media after 48 hrs.
2. Cellular Toxicity
The effect of hydrogel on skin cells were evaluated to ensure that the hydrogels do not release materials that might be detrimental to the growth of skin cells. For this, the hydrogels were incubated with cell specific culture media for different time points. This contact media was added to cultures of keratinocytes and fibroblasts and its effect on cell growth was monitored for 24h, 48h, 72h, and 96h. Cell proliferation was analyzed indirectly by the MTT method. (Molinari BL, Tasat DR, Palmieri MA, O'Connor SE, Cabrini RL (2003) Cell-based quantitative evaluation of the MTT assay. Anal Quant Cytol Histol 25: 254-262). Briefly, MTT (0.5mg/ml) was added to the cells in triplicate dishes after 24, 48, 72 and 96h exposure to the contact media. Viable cells were indirectly determined by their ability to convert soluble MTT to insoluble formazan crystals. The crystals were solubilized and the absorbance was determined as the
difference in optical density measured at a test wavelength of 570nm and a reference wavelength of 650nm (Shimadzu UV-VIS Spectrophotometer, Japan). At each end point, the absorbance was recorded and the optical density was compared to control. As shown in Figure 7, keratinocyte proliferation was not affected by hydrogel exposure. Similarly, and as shown in Figure 8, fibroblast proliferation was not affected by hydrogel exposure. Thus, no toxicity was observed on skin cells incubated with the hydrogel incubated media for defined time periods.
Table 8: Summary of Hydrogel Characteristics
The hydrogel of the present invention elicited a good response in patients having skin conditions like bed sores or pressure ulcers and skin grafts
All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents that are chemically or physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
Claims
1. A hydrogel composition comprising polyvinyl alcohol (PVA), polyethylene glycol (PEG), and a viscosity enhancer.
2. The hydrogel composition of claim 1, wherein the composition does not comprise an additional polymer, a polysaccharide, or a gelling agent.
3. A hydrogen composition consisting essentially of PVA, PEG, a viscosity enhancer and water.
4. The hydrogel composition of claim 1, wherein said PVA and PEG are cross linked by gamma irradiation.
5. The hydrogel composition of claim 1 , wherein said viscosity enhancer is one or more of sodium chloride (NaCI), potassium chloride (KCI), calcium chloride (CaCI2), and magnesium chloride (MgCI2).
6. The hydrogel composition of claim 1 , wherein said viscosity enhancer is calcium chloride.
7. The hydrogel composition of claim 1, wherein the composition comprises about 1 % to about 10% (w/w) of the viscosity enhancer.
8. The hydrogel composition of claim 7, wherein the composition comprises about 1 % (w/w) of the viscosity enhancer.
9. The hydrogel composition of claim 1 , wherein said PVA has a molecular weight ranging from about 13,000 to about 23,000 g/mol.
- 22 -
10.- The hydrogel composition of claim 9, wherein said PVA has a molecular weight of about 14,000 g/mol
1 1. The hydrogel composition of claim 1, wherein the composition comprises about 10% to about 20% (w/w) of said PVA
12. The hydrogel composition of claim 11, wherein the composition comprises about 20% (w/w) of said PVA.
13. The hydrogel composition of claim 1, wherein said PEG has a molecular weight ranging from about 1,000 to about 4,500 g/mol.
14. The hydrogel composition of claim 13, wherein said PEG has a molecular weight of about 4,000 g/mol.
15. The hydrogel composition of claim 1, wherein the hydrogel composition comprises about 0.3% to about 2% (w/w) of said PEG.
16. The hydrogel composition of claim 15, wherein the hydrogel composition comprises about 0.5% (w/w) of said PEG.
17. The hydrogel composition of claim 15, wherein the composition further comprises about 0.1% to 0.3% (w/v) of PEG methyl ether (mPEG).
18. The hydrogel composition of claim 17, wherein the composition comprises about 1.8% (w/w) of said PEG and about 0.18% (w/w) of said mPEG.
19. The hydrogel composition of claim 1, wherein the composition comprises about 18% to about 20% (w/w) of said PVA, about 1.5% to about 2% (w/w) of said PEG, about 1% (w/w) of calcium chloride and about 0.15% to about 0.2% mPEG.
- 23 -
20. The hydrogel composition of claim 1 , wherein the composition is about 3 mm to about 5 mm thick.
21. The hydrogel composition of claim 20, wherein the composition is about 3 mm thick.
22. The hydrogel composition of claim 1 , further comprising gauze.
23. The hydrogel composition of claim 1, further comprising a bioactive agent.
24. The hydrogel composition of claim 1, wherein said composition is impervious to microbial contamination.
25. A method for producing a hydrogel composition, comprising:
(a) combining PVA, PEG, and a viscosity enhancer with water to form a solution; and
(b) cross-linking said PVA, PEG, and viscosity enhancer with gamma irradiation.
26. The method of claim 25, wherein said gamma irradiation is applied at a range of about 25 to about 50 KGy.
27. The method of claim 26, wherein said irradiation is applied at about 50 kGy.
28. The method of claim 25, wherein said viscosity enhancer is calcium chloride.
29. The method of claim 25, wherein step (a) further comprises combining PVA, PEG, the viscosity enhancer, and a bioactive agent with water to form a solution, and wherein step (b) further comprises cross-linking said PVA, PEG, viscosity enhancer and bioactive agent with gamma irradiation.
30. A wound dressing comprising PVA, PEG, and a viscosity-enhancer.
31. The wound dressing of claim 30, further comprising gauze.
- 24 -
32. The wound dressing of claim 30, further comprising a bioactive agent.
33. A method for treating a wound, comprising:
(a) combining PVA, PEG, and a viscosity enhancer with water to form a solution;
(b) cross-linking said solution with gamma irradiation to form a hydrogel composition; and
(c) applying said hydrogel composition to said wound.
34. The method of claim 33, wherein the hydrogel composition further comprises gauze.
35. The method of claim 33, wherein the hydrogel composition further comprises a bioactive agent.
36. The hydrogel composition, its method of preparation and uses as claimed above exemplified herein substantially in the examples and figures.
- 25 -
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN2561/MUM/2008 | 2008-12-08 | ||
IN2561MU2008 | 2008-12-08 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2010067378A2 true WO2010067378A2 (en) | 2010-06-17 |
WO2010067378A3 WO2010067378A3 (en) | 2010-12-16 |
Family
ID=42232748
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2009/000707 WO2010067378A2 (en) | 2008-12-08 | 2009-12-08 | Hydrogel composition |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2010067378A2 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018200372A1 (en) | 2017-04-24 | 2018-11-01 | Cell Constructs I, Llc | Skin-protective hydrogel wound dressing |
KR20190048150A (en) * | 2017-10-30 | 2019-05-09 | 주식회사 애니 테이프 | A hydro colloid based hotmelt dressing tape protecting uv light |
KR102004212B1 (en) * | 2018-02-28 | 2019-07-29 | 주식회사 애니테이프 | Manufacturing method for a better absorbing hydro colloid based hotmelt dressing tape |
WO2023012208A1 (en) | 2021-08-04 | 2023-02-09 | Piezomedic | Device and system for exchanging energy and/or data, in particular for localisation purposes, with at least one implant and/or at least one organ in a human or animal body and/or an apparatus external to the body via piezoelectric and/or capacitive transducers |
Citations (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0107376A1 (en) | 1982-09-28 | 1984-05-02 | Johnson & Johnson Products Inc. | Polyvinylpyrrolidone gel dressings |
US4663358A (en) | 1985-05-01 | 1987-05-05 | Biomaterials Universe, Inc. | Porous and transparent poly(vinyl alcohol) gel and method of manufacturing the same |
US4871490A (en) | 1986-12-30 | 1989-10-03 | Politechnika Lodzka, Lodz, Ul. Zwirki | Method of manufacturing hydrogel dressings |
US4988761A (en) | 1988-09-22 | 1991-01-29 | Dow Corning K.K. | Process for producing a low water content PVA hydrogel |
US4989607A (en) | 1989-03-30 | 1991-02-05 | Preston Keusch | Highly conductive non-stringy adhesive hydrophilic gels and medical electrode assemblies manufactured therefrom |
US5346935A (en) | 1991-05-28 | 1994-09-13 | Takeda Chemical Industries, Ltd. | Hydrogel |
US5401508A (en) | 1992-01-15 | 1995-03-28 | Allergan, Inc. | Hydrogel compositions and structures made from same |
US5489437A (en) | 1993-08-17 | 1996-02-06 | Applied Extrusion Technologies, Inc. | Hydrogel products and methods of producing same |
US5514379A (en) | 1992-08-07 | 1996-05-07 | The General Hospital Corporation | Hydrogel compositions and methods of use |
US5981826A (en) | 1997-05-05 | 1999-11-09 | Georgia Tech Research Corporation | Poly(vinyl alcohol) cryogel |
WO2001030407A1 (en) | 1999-10-27 | 2001-05-03 | Department Of Atomic Energy | A process for manufacture of hydrogels for burn and injury treatment |
US6362276B1 (en) | 1998-01-07 | 2002-03-26 | Debio Recherche Pharmaceutique S.A. | Degradable heterobifunctional poly(ethylene glycol) acrylates and gels and conjugates derived therefrom |
US6541015B2 (en) | 1999-12-23 | 2003-04-01 | Shearwater Corporation | Hydrolytically degradable carbamate derivatives of poly(ethylene glycol) |
US6617372B2 (en) | 2001-10-23 | 2003-09-09 | Isp Investments Inc. | Process of making polymeric hydrogel products |
WO2005120462A2 (en) | 2004-06-07 | 2005-12-22 | Callisyn Pharmaceuticals, Inc. | Biodegradable and biocompatible crosslinked polymer hydrogel prepared from pva and/or peg macromer mixtures |
WO2006125082A2 (en) | 2005-05-18 | 2006-11-23 | The General Hospital Corporation Dba Massachusetts General Hospital | Hydrogels and hydrogel particles |
US7235592B2 (en) | 2004-10-12 | 2007-06-26 | Zimmer Gmbh | PVA hydrogel |
US7282165B2 (en) | 2004-04-27 | 2007-10-16 | Howmedica Osteonics Corp. | Wear resistant hydrogel for bearing applications |
-
2009
- 2009-12-08 WO PCT/IN2009/000707 patent/WO2010067378A2/en active Application Filing
Patent Citations (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0107376A1 (en) | 1982-09-28 | 1984-05-02 | Johnson & Johnson Products Inc. | Polyvinylpyrrolidone gel dressings |
US4663358A (en) | 1985-05-01 | 1987-05-05 | Biomaterials Universe, Inc. | Porous and transparent poly(vinyl alcohol) gel and method of manufacturing the same |
US4871490A (en) | 1986-12-30 | 1989-10-03 | Politechnika Lodzka, Lodz, Ul. Zwirki | Method of manufacturing hydrogel dressings |
US4988761A (en) | 1988-09-22 | 1991-01-29 | Dow Corning K.K. | Process for producing a low water content PVA hydrogel |
US4989607A (en) | 1989-03-30 | 1991-02-05 | Preston Keusch | Highly conductive non-stringy adhesive hydrophilic gels and medical electrode assemblies manufactured therefrom |
US5346935A (en) | 1991-05-28 | 1994-09-13 | Takeda Chemical Industries, Ltd. | Hydrogel |
US5401508A (en) | 1992-01-15 | 1995-03-28 | Allergan, Inc. | Hydrogel compositions and structures made from same |
US5514379A (en) | 1992-08-07 | 1996-05-07 | The General Hospital Corporation | Hydrogel compositions and methods of use |
US5489437A (en) | 1993-08-17 | 1996-02-06 | Applied Extrusion Technologies, Inc. | Hydrogel products and methods of producing same |
US5981826A (en) | 1997-05-05 | 1999-11-09 | Georgia Tech Research Corporation | Poly(vinyl alcohol) cryogel |
US6231605B1 (en) | 1997-05-05 | 2001-05-15 | Restore Therapeutics | Poly(vinyl alcohol) hydrogel |
US6362276B1 (en) | 1998-01-07 | 2002-03-26 | Debio Recherche Pharmaceutique S.A. | Degradable heterobifunctional poly(ethylene glycol) acrylates and gels and conjugates derived therefrom |
WO2001030407A1 (en) | 1999-10-27 | 2001-05-03 | Department Of Atomic Energy | A process for manufacture of hydrogels for burn and injury treatment |
US6541015B2 (en) | 1999-12-23 | 2003-04-01 | Shearwater Corporation | Hydrolytically degradable carbamate derivatives of poly(ethylene glycol) |
US6617372B2 (en) | 2001-10-23 | 2003-09-09 | Isp Investments Inc. | Process of making polymeric hydrogel products |
US7282165B2 (en) | 2004-04-27 | 2007-10-16 | Howmedica Osteonics Corp. | Wear resistant hydrogel for bearing applications |
WO2005120462A2 (en) | 2004-06-07 | 2005-12-22 | Callisyn Pharmaceuticals, Inc. | Biodegradable and biocompatible crosslinked polymer hydrogel prepared from pva and/or peg macromer mixtures |
US7235592B2 (en) | 2004-10-12 | 2007-06-26 | Zimmer Gmbh | PVA hydrogel |
WO2006125082A2 (en) | 2005-05-18 | 2006-11-23 | The General Hospital Corporation Dba Massachusetts General Hospital | Hydrogels and hydrogel particles |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018200372A1 (en) | 2017-04-24 | 2018-11-01 | Cell Constructs I, Llc | Skin-protective hydrogel wound dressing |
KR20190048150A (en) * | 2017-10-30 | 2019-05-09 | 주식회사 애니 테이프 | A hydro colloid based hotmelt dressing tape protecting uv light |
KR102004208B1 (en) * | 2017-10-30 | 2019-07-29 | 주식회사 애니테이프 | Manufacturing method for a hydro colloid based hotmelt dressing tape protecting uv light |
KR102004212B1 (en) * | 2018-02-28 | 2019-07-29 | 주식회사 애니테이프 | Manufacturing method for a better absorbing hydro colloid based hotmelt dressing tape |
WO2023012208A1 (en) | 2021-08-04 | 2023-02-09 | Piezomedic | Device and system for exchanging energy and/or data, in particular for localisation purposes, with at least one implant and/or at least one organ in a human or animal body and/or an apparatus external to the body via piezoelectric and/or capacitive transducers |
FR3125957A1 (en) | 2021-08-04 | 2023-02-10 | Piezomedic | Device and system for locating an implant or an organ in a human or animal body, by emission-reception of ultrasound signals via piezoelectric and/or capacitive transducers |
Also Published As
Publication number | Publication date |
---|---|
WO2010067378A3 (en) | 2010-12-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Tavakoli et al. | Honey/PVA hybrid wound dressings with controlled release of antibiotics: Structural, physico-mechanical and in-vitro biomedical studies | |
Pan et al. | Non-stick hemostasis hydrogels as dressings with bacterial barrier activity for cutaneous wound healing | |
Singh et al. | Radiation synthesis of PVP/alginate hydrogel containing nanosilver as wound dressing | |
Lu et al. | Healing of skin wounds with a chitosan–gelatin sponge loaded with tannins and platelet-rich plasma | |
Tomić et al. | Smart poly (2-hydroxyethyl methacrylate/itaconic acid) hydrogels for biomedical application | |
Li et al. | An antibacterial bilayer hydrogel modified by tannic acid with oxidation resistance and adhesiveness to accelerate wound repair | |
Wu et al. | Preparation and characterization on mechanical and antibacterial properties of chitsoan/cellulose blends | |
CN112300420B (en) | Injectable antibacterial interpenetrating double-network hydrogel and preparation method and application thereof | |
US20070009580A1 (en) | Non-adhesive hydrogels | |
JP3947391B2 (en) | Method for producing chitin derivative and / or chitosan derivative having bridge structure | |
Gupta et al. | Hydrogels for wound healing applications | |
US20050287193A1 (en) | Wound dressing made of chitin and alginate and method for forming the same | |
CN111228565A (en) | PLGA microsphere-loaded hyaluronic acid-gelatin composite hydrogel and preparation method thereof | |
Xing et al. | Alginate membrane dressing toughened by chitosan floccule to load antibacterial drugs for wound healing | |
Escobar-Sierra et al. | Manufacturing and evaluation of Chitosan, PVA and Aloe Vera hydrogels for skin applications | |
Bidault et al. | Self-supported fibrin-polyvinyl alcohol interpenetrating polymer networks: an easily handled and rehydratable biomaterial | |
KR100440239B1 (en) | Method for the preparation of hydrogels for wound dressings | |
CN105228658A (en) | A kind of medical dressing hydrogel compound fabric and its preparation method and application | |
WO2018167623A1 (en) | Process for the preparation of antimicrobial hydrogel | |
WO2023198126A1 (en) | Medical tissue adhesive used for sealing pancreas, preparation method therefor, and use thereof | |
KR20120035032A (en) | Hydrogels for wound dressing comprising nano-silver particle and preparation method thereof | |
WO2010067378A2 (en) | Hydrogel composition | |
Khadem et al. | Colorimetric pH-responsive and hemostatic hydrogel-based bioadhesives containing functionalized silver nanoparticles | |
Wang et al. | Chitosan-based composites reinforced with antibacterial flexible wood membrane for rapid hemostasis | |
Chen et al. | Mussel‐Inspired Adhesive, Antibacterial, and Stretchable Composite Hydrogel for Wound Dressing |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09828419 Country of ref document: EP Kind code of ref document: A2 |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 09828419 Country of ref document: EP Kind code of ref document: A2 |