Patent Application: US-201113101724-A

Abstract:
an antimicrobial therapeutic hydrogel composition comprises a pharmaceutical and / or medical grade silver salt , and an aloe vera gel or extract . the composition could also include stabilizing agents , a non - ionic surfactant , polyol , and hydrophilic hygroscopic polymers . the resulting product has potent antimicrobial activity against bacteria , protozoa , fungi and viruses . the antimicrobial therapeutic composition can serve as a treatment for burns and as a wound / lesion dressing that either donates or receives moisture to provide a physiologic environment for accelerated wound healing and the relief of pain .

Description:
one aspect of the current invention comprises a composition containing a pharmaceutical or medical grade silver salt , and aloe vera gel or aloe vera extract including acemannan . it can also contain non - ionic water soluble polymer thickener , moisturizers and humectants , stabilizers , skin protectant , and allantoin for their varied wound healing properties . a silver salt serves as the primary antimicrobial agent in the composition . it is well accepted that it is the ionic form of silver that is antimicrobial . the principle mechanism of action results from ionic silver binding to microbial proteins causing structural changes in cell walls and intracellular and nuclear membranes . in addition , it has been shown that silver binds to dna and rna , denatures nucleotides and thereby inhibits replication . silver salts used in the current invention can be in the hydrous or anhydrous form . as used herein , the term “ anhydrous ” means essentially free of water , i . e . less than 10 % retained water . the term does not mean totally free of water . as used herein , the term “ hydrous ” would mean containing water greater than 10 % and would include a concentrate . examples of silver salts that could be used in the present invention include , but are not limited to , silver nitrate , silver dihydrogen citrate , silver citrate , silver chloride , silver benzoate , silver acetate , silver galacturonate , and silver glucuronate . the concentration of ionic silver as a salt formulated in the first embodiment of the present invention can range from 0 . 01 ppm to 1000 ppm , a second embodiment with a concentration of 1 - 100 ppm and a third embodiment with a concentration of 5 - 50 ppm . these concentrations of ionic silver in a topical formulation are not considered toxic . it has been demonstrated and is noteworthy that when a wound dressing containing 85 mg 100 cm − 1 of ionic silver was applied to the skin of chronic ulcer patients for four weeks , systemic blood levels of silver was not significantly different from controls . the inner clear mucilage gel of aloe vera , referred to as aloe vera gel , has been used for centuries to treat and manage wounds . aloe vera gel is separated from the rind of the aloe vera plant by filleting an aloe leaf , separating the inner gel from the outer leaf rind and separating it from the yellow sap contained within the rind . the inner gel is then homogenized and available for use or further processing either as a concentrate by removal of water or more extensive processing to create an extract . the aloe vera gel contains a variety of chemical substances with a large molecular weight complex carbohydrate , identified and given the united states adopted name , acemannan . fundamentally , acemannan the high molecular weight carbohydrate polymer of the gel can be separated either by alcohol precipitation , column purification or ultra - filtration . aloe vera gel and its principle extract including acemannan process for preparation and its uses have been described in u . s . pat . nos . 4 , 735 , 935 , 4 , 851 , 224 , 4 , 957 , 907 , 4 , 959 , 214 , 4 , 917 , 890 , 4 , 966 , 892 , 5 , 106 , 616 , 5 , 118 , 673 , 5 , 308 , 838 , 5 , 441 , 943 , 5 , 703 , 060 , 5 , 760 , 102 and 5 , 902 , 796 . the entire contents of each patent are hereby incorporated by reference . multiple properties have been attributed to this compound but the most predominant has been its immunomodulation function . included as part of the immunomodulation property is the ability to stimulate release of primary growth factors necessary for optimal and accelerated wound healing . there is also some evidence that acemannan may interfere with adherence of bacteria to epithelia cells . in addition to its immune modulation activities it has also been shown to have anti - inflammatory properties and aid in the control of pain . an aloe vera cream was compared to silver sulfadiazine in second degree burn patients and demonstrated significant improvement in re - epithelialization times as compared to silver sulfadiazine . the use of an aloe extract acemannan gel as a component of the present invention provides multiple attributes for accelerated healing , inflammation and pain control . aloe vera gel or its extract , bulk acetylated mannans from aloe vera ( acemannan ) have not been shown to be toxic or cause allergic reaction at the concentrations used in the present invention and any one of these products would be suitable for use . an anhydrous form of aloe vera gel extract was utilized in the present invention . the concentration of anhydrous aloe vera gel extract acemannan in the first embodiment of the present invention can range from 0 . 01 - 1 . 0 w / w %, in the second embodiment from 0 . 05 - 0 . 3 w / w %, and a third embodiment from 0 . 075 - 0 . 2 w / w %. tetra acetic acid compounds can be used in the present invention as a stabilizer for silver salt . tetra acetic acid chelating compounds include , but are not limited to , ethylenediaminetetraacetic acid ( edta ), ethylene glycol tetraacetic acid ( egta ), and 1 , 2 - bis ( o - aminophenoxy ) ethane - n , n , n ′, n ′- tetraacetic ( bapta ). topical exposure of disodium edta for 4 hours in a human patch test showed no reactivity thus it is an excellent stabilizer for topical products . in addition , it has been shown that edta in conjunction with a silver salt , more specifically silver nitrate , significantly increased the antibacterial action of the silver . the concentration of edetate disodium in the first embodiment of the current invention can range from 0 . 01 - 5 . 0 w / w %, in a second embodiment from 0 . 1 - 2 . 5 w / w %, and in a third embodiment from 0 . 25 - 1 . 0 w / w %. a second stabilizer and dispersant that can be included in the composition is polyvinylpyrrolidone ( pvp ). pvp has been used as a dispersant for aloe vera gel , gel concentrates and gel extracts as well as for silver salt antimicrobial matrix products . the concentration of pvp in the first embodiment of the present invention can range from 0 . 1 - 5 . 0 w / w %, in a second embodiment from 0 . 5 - 2 . 5 w / w %, and in a third embodiment from 1 . 0 - 2 . 0 w / w %. polysorbates are sorbitan esters , also known as tweens , serve as non - ionic surfactants . these groups of compounds known as polyoxyethylene derivatives are fatty acid esters of sorbitol copolymerized with ethylene oxide . it has been demonstrated that polysorbate 80 increases pseudomonas aeruginosa cell permeability increasing cell leakage . however , the effect on growth rate of the bacteria was not impacted . polysorbate surfactants are currently used with multiple antimicrobial drugs to increase their pharmacologic activity . in the current invention polysorbate can be used as a surfactant and microbial membrane permeability enhancer . polysorbate compounds that can be chosen and used for the present invention include , but are not limited to , laurate ester ; palmitate ester ; mixture of stearate and palmitate esters and oleate ester . the concentration of polysorbate in the first embodiment of the present invention can range from 0 . 01 - 0 . 2 w / w %, in the second embodiment from 0 . 05 - 0 . 175 w / w %, and a third embodiment from 0 . 075 - 0 . 125 w / w %. allantoin , ( 2 , 5 - dioxo - 4 - imidazolidinyl ) urea , is the diureide of glyoxylic acid . allantoin has been used in wound healing preparations for many years and has been approved as a skin protectant by the united states food and drug administration . it currently is considered safe for use as an oral wound healing agent and in addition has a reported use in the treatment of burns as the silver salt . the concentration of allantoin in the first embodiment of the present invention can range from 0 . 0001 - 2 . 0 w / w %, a second embodiment from 0 . 1 - 1 . 5 w / w %, and a third embodiment from 0 . 5 - 1 . 0 w / w %. humectants are hygroscopic substances that have the ability to absorb or donate moisture to a wound . if a wound is dry , a humectant substance will absorb moisture from the environment and help maintain a moist wound environment for more optimal healing . if a wound is producing more serous fluid then humectant substances can aid in absorption of the extra fluid , helping maintain a more appropriate wound environment . the current invention utilizes three different humectants in the composition ; propylene glycol , panthenol and glycerin . in addition to having humectant and moisturizing properties , panthenol is a precursor to vitamin b5 , pantothenic acid , and is essential for synthesis of keratinocyte growth factor and fibroblast proliferation critical to optimal and accelerated wound healing . glycerin or glycerol is the principle humectant in the current invention . glycerin is very hygroscopic making it ideal in the absorption or donation of moisture . the humectants as part of the compositions separate the current invention from current art for hydrogel dressings . the concentration of propylene glycol in the first embodiment of the present invention can range from 0 . 01 - 1 . 0 w / w %, a second embodiment from 0 . 05 - 0 . 5 w / w %, and a third embodiment from 0 . 15 - 0 . 3 w / w %. the concentration of panthenol in the first embodiment of the present invention can range from 0 . 1 - 3 . 0 w / w %, a second embodiment from 0 . 5 - 2 . 0 w / w %, and a third embodiment from 0 . 75 - 1 . 5 w / w %. the concentration of glycerin in the first embodiment of the present invention can range from 1 - 25 w / w %, a second embodiment from 5 - 20 w / w %, and a third embodiment from 10 - 15 w / w %. nonionic water soluble polymers have been used for many years as components of therapeutic products as binders , stabilizers , suspending agents and thickeners . these polymers are generally non - irritating and non - allergenic . examples of these polymers that are acceptable for use in the present invention include , but are not limited to , hydroxyethylcellulose , carboxymethylcellulose , hydroxypropylcellulose , hypromellose , ethylcellulose , or their derivatives . the concentration in the first embodiment of the current invention can range from 0 . 01 - 5 . 0 w / w %, a second embodiment from 0 . 25 - 2 . 5 w / w %, and a third embodiment from 0 . 5 - 1 . 5 w / w %. a buffering agent is utilized in the present invention to achieve a ph appropriate for optimal wound healing . buffers suitable for use include , but are not limited to , sodium hydroxide ( naoh ), triethanolamine and tromethamine . the desired ph in the first embodiment for the present invention can range from 4 - 7 . 4 . the examples of compositions that follow were compounded by adding ingredients except glycerin to pharmaceutical grade water ( usp purified water ) at a temperature of 35 to 50 ° c . and mixing using a rotary mixer at speeds from 400 to 1500 rpm to allow for sufficient agitation to solubilize and disperse the ingredients . dependent on the volume and mixer used , mixer speeds can vary . total time for appropriate mixing varied dependent on materials selected to allow for ingredient solubilization and dispersion but in general , mixing was carried out for up to 4 hours . the last step in the formulation process was the addition of glycerin while cooling , mixing for 30 minutes to arrive at the final antimicrobial therapeutic hydrogel composition . ingredients are commercially available . an embodiment of the present invention was compounded as described to determine materials compatibility and range of material usage . silver citrate salt 1 . 5 ppm , aloe vera acemannan 0 . 15 w / w %, hydroxyethylcellulose 1 w / w %, polyvinylpyrrolidone 1 . 5 w / w %, disodium edta 0 . 5 w / w %, dl - panthenol 1 w / w %, propylene glycol 0 . 2 w / w %, glycerin 15 w / w %, purified water 79 . 6 %, buffered with 0 . 1 m sodium hydroxide to ph 6 . 5 . an embodiment of the present invention was compounded as described to determine materials compatibility and range of material usage . silver citrate salt 15 ppm , aloe vera acemannan 0 . 15 w / w %, hydroxyethylcellulose 1 . 0 w / w %, polyvinylpyrrolidone 1 . 5 w / w %, disodium edta 0 . 5 w / w %, allantoin 0 . 6 w / w %, dl - panthenol 1 . 0 w / w %, propylene glycol 0 . 2 w / w %, polysorbate 0 . 1 w / w %, glycerin 12 w / w %, purified water 69 . 9 w / w %, buffered with 0 . 1 m triethanolamine to ph 6 . 15 . an embodiment of the present invention was compounded as described to determine materials compatibility and range of material usage . silver citrate salt 36 ppm , aloe vera acemannan 0 . 15 w / w %, carboxymethylcellulose 1 . 75 w / w %, polyvinylpyrrolidone 1 . 5 w / w %, disodium edta 0 . 5 w / w %, allantoin 0 . 6 w / w %, dl - panthenol 1 w / w %, propylene glycol 0 . 2 w / w %, glycerin 15 w / w %, purified water 53 . 3 %, buffered with 0 . 1m triethanolamine to ph 5 . 7 . an embodiment of the present invention was compounded as described to determine materials compatibility and range of material usage . silver citrate salt 50 ppm , aloe vera acemannan 0 . 15 w / w %, hydroxyethylcellulose 1 . 0 w / w %, polyvinylpyrrolidone 3 . 0 w / w %, disodium edta 0 . 6 w / w %, allantoin 1 . 5 w / w %, dl - panthenol 1 . 0 w / w %, propylene glycol 0 . 2 w / w %, glycerin 15 w / w %, purified water 35 . 4 w / w %, buffered with 0 . 1 m triethanolamine to ph 5 . 8 . an embodiment of the present invention was compounded as described to determine materials compatibility and range of material usage . silver citrate salt 75 ppm , aloe vera acemannan 0 . 15 w / w %, hydroxyethylcellulose 1 . 0 w / w %, polyvinylpyrrolidone 1 . 5 w / w %, disodium edta 0 . 5 w / w %, dl - panthenol 1 . 0 w / w %, propylene glycol 0 . 2 w / w %, glycerin 15 w / w %, purified water 53 . 3 w / w %, buffered with 0 . 1 m sodium hydroxide to ph 6 . 2 . an embodiment of the present invention was compounded as described to determine materials compatibility and range of material usage . silver benzoate salt 100 ppm , aloe vera acemannan 0 . 15 w / w %, hydroxyethylcellulose 1 . 0 w / w %, polyvinylpyrrolidone 1 . 5 w / w %, disodium edta 0 . 5 w / w %, allantoin 0 . 6 w / w %, dl - panthenol 1 . 0 w / w %, propylene glycol 0 . 2 w / w %, polysorbate 0 . 1 w / w %, glycerin 12 w / w %, purified water 70 . 0 w / w %, buffered with 0 . 1 m triethanolamine to ph 6 . 35 . an embodiment of the present invention was compounded as described to determine materials compatibility and range of material usage . silver nitrate salt 1000 ppm , aloe vera acemannan 0 . 15 w / w %, hydroxyethylcellulose 1 . 0 w / w %, polyvinylpyrrolidone 1 . 5 w / w %, disodium edta 0 . 5 w / w %, allantoin 0 . 6 w / w %, dl - panthenol 1 . 0 w / w %, propylene glycol 0 . 2 w / w %, polysorbate 0 . 1 w / w %, glycerin 12 w / w %, purified water 70 . 0 w / w %, buffered with 0 . 1 m triethanolamine to ph 5 . 99 . the antimicrobial activity of silver citrate ( sc ) in usp purified water and silver antimicrobial hydrogel ( sc - gel ), described herein in example 2 , was tested using the microtube dilution method for determining minimal inhibitory concentrations ( mic ) listed in the chart below . in brief , a standard inoculum ( 100 μl of a 1 : 200 dilution of a 0 . 5 macfarland turbidity standard ) of each microorganism was prepared in standard growth media and added to equal volumes of two - fold serial dilutions of sc and sc - gel . mics were determined visually as the highest dilution of sc , or sc - gel , that inhibited growth after incubating the mixtures overnight at 35 ° c ., except for candida albicans , which required 48 hrs incubation . mixtures demonstrating no growth remained clear while mixtures exhibiting growth turned cloudy . the mic dilution was converted to μg / ml by multiplying the neat drug ( ag + ) concentration by the dilution appropriate dilution factor . this example demonstrates that the composition of the sc - gel outperform sc alone in the diverse selection of microorganisms tested . the antimicrobial activity of silver antimicrobial hydrogel ( sc - gel ), described herein in example 2 , was compared against two currently marketed drugs ( miconazole / mic and silver sulfadiazine / ssd ) in a small group of diverse microorganisms : candida albicans ( yeast ); pseudomonas aeruginosa ( gram negative bacterium ), staphylococcus aureus ( gram positive bacterium ), and trichomonas vaginalis ( protozoan ). trichomonas vaginalis was tested as described in the next paragraph , and the bacteria and yeast were tested using the microtube dilution method for mic determination . in brief , a standard inoculum ( 100 μl of a 1 : 200 dilution of a 0 . 5 macfarland turbidity standard ) of each microorganism was prepared in standard growth media and added to equal volumes of two - fold serial dilutions of sc and sc - gel . mics were determined visually as the highest dilution of sc , or sc - gel , that inhibited growth after incubating the mixtures overnight at 35 ° c ., except for c . albicans , which required 48 hrs incubation . mixtures demonstrating no growth remained clear while mixtures exhibiting growth turned cloudy . the mic dilution was converted to μg / ml by multiplying the neat drug ( ag + ) concentration by the dilution appropriate dilution factor . trichomonas vaginalis was purchased from biomed diagnostics inc , white city , oreg . and subcultured per the manufacturer instructions in inpouch ™ tvc subculture medium . on the day of subculturing , 50 μl of t . vaginalis live culture was added to 250 μl of a 50 : 50 mixture of sc - gel and inpouch ™ tvc subculture medium ( test ), as well as a 50 : 50 mixture of sterile deionized water and inpouch ™ tvc subculture medium ( control ). after 4 days incubation at 30 ° c ., 50 μl of test and control solution were viewed under 400 × microscopically . sc - gel test mixture revealed 0 - 1 non - motile t . vaginalis organisms / microscopic field , and the control mixture revealed 3 - 4 motile t . vaginalis organisms / microscopic field . these data suggest sc - gel inhibits or kills t . vaginalis at the concentration tested ( 7 . 5 μg / ml ). this example demonstrates that the constituents of the sc - gel appear to have equal too or greater potency than silver sulfadiazine in inhibiting the growth of tested strains of pseudomonas aeruginosa and staphylococcus aureus , and demonstrates that it has greater inhibitory properties against candida albicans than miconazole as well as having inhibitory properties against trichomonas vaginalis . in - toto , these data suggest sc - gel exhibits a very broad antimicrobial range , covering bacteria ( gram positive and gram negative ), yeast , and protozoans . an eight - year old equine gelding suffered a severe substantial laceration to the right rear hock . the wound extended from right below the joint and was approximately 22 . 5 cm by 14 cm extending from the medial to the lateral side of the canon bone with the depth visually exposing the joint capsule . the horse was placed on systemic antibiotics for one week and a topical antimicrobial . the wound wasn &# 39 ; t progressing in healing and the animal &# 39 ; s topical primary dressing was changed to the silver antimicrobial hydrogel dressing described in example 2 . the wound was treated every other day and bandaged . wound color rapidly improved with enhanced granulation formation and wound shrinkage was observed within 7 days of initiation of therapy . treatments have progressed with wound improvement over an eight - week period . the animal exhibited no pain from the administration of the dressing . a 42 year old female caucasian presented with a first - degree burn to the forearm . the patient was treated with the silver antimicrobial hydrogel described in example 2 . the patient applied the composition without a secondary dressing three to four times per day for two days . prior to application of the hydrogel pain was assessed using the pain quality assessment scale ( pqas ); results are as follows : hot scored 1 , cold scored 4 , sensitivity to touch scored 2 , and surface pain scored 2 . after application of the hydrogel , pain was reassessed using the pqas , results are as follows : hot scored 0 , cold scored 0 , sensitivity to touch scored 0 , and surface pain scored 0 . upon application of the composition pain subsided within less than one minute . after two days the signs and symptoms had abated . a 57 year old male caucasian presented with herpes labialis , commonly known as a fever blister . the patient reported a history of recurrent episodes of herpes labialis outbreaks . the silver antimicrobial hydrogel described in example 2 was applied to the patient &# 39 ; s lesion approximately four times a day as needed based on onset of a painful muco - cutaneous sensation . complete loss of pain sensation was experienced within less than one minute after application of the antimicrobial hydrogel . no signs and symptoms of the herpes labialis infection were observed after three days of treatment with the composition . atiyeh b s , costagliola m , hayek s n , dibo s a . effect of silver on burn wound infection control and healing : review of the literature , burns 33 ; 2007 : 139 - 148 azghani a o , williams i , holiday d b , johnson a r . a beta - linked mannan inhibits adherence of pseudomonas aeruginosa to human lung epithelial cells . glycobiology . 1995 february ; 5 ( 1 ): 39 - 44 becker l c , bergfeld w f , belsito d v , klaassen c d , marks j g , shank r c , slaga t j , snyder p w , and andersen f a . final report of the safety assessment of allantoin and its related complexes . international journal of toxicology : 29 ( supplement 2 ); 2010 : 845 - 975 bouwstra j a , groenink w w , kempenaar j a , romeijn s g , and ponec m . water distribution and natural moisturizer factor content in human skin equivalents are regulated by environmental relative humidity . journal of investigative dermatology : vol 128 ; 2008 : 378 - 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83 remington , the science and practice of pharmacy . 21 st edition , part 5 ; 2006 : 1080 remington , the science and practice of pharmacy . 21 st edition , part 7 ; 2006 : 1290 report of data from 1999 - 2008 . american burn association , national burn repository , version 5 , 2009 reynolds t , aloes , the genus aloe . medicinal and aromatic plants - industrial profiles . crc press , 2004 . chapt 9 - 11 roberts d b , travis el . acemannan - containing wound dressing gel reduces radiation - induced skin reactions in c3h mice . int j radiat oncol biol phys : 32 ( 4 ); 1995 jul . 15 : 1047 - 1052 robson m c . wound infection a failure of wound healing caused by an imbalance of bacteria . surgical clinics of north america : vol 77 , isse 3 ; jun . 4 , 1997 : 637 - 650 shimizu f ., et al . specific inactivation of herpes simplex virus by silver nitrate at low concentrations and biological activities of the inactivated virus . antimicrobial agents and chemotherapy ; july 1976 : 57 - 63