«2 United States Patent McGrath US 8,367,635 B2 Feb. 5, 2013 (10) Patent No.t (4s) Date of Patent: (54) ANTIMICROBIAL SUCRALEATE PASTE, (75) Ieventor: Patrick D, MoGeath, Gurnee, I. (US) (4) Notice: Suigject to any disclaimer, the term ofthis patent is extended or adjusted under 35, U.S.C. 1540) by Odays. (21) Appl.Nos 13/049,488 (22), Filed: Mar. 16,2011 (65) Prior Publication Data US 2012100641394 Mar 15,2012 Related US. Application Data (63) Continuation of application No, PCT/US20001086374, filed on Sep. 9, 2009. (60) Provisional application No, 61/097,674, fled on Sep. 17,2008, (51) Incl. AIK 31737 (2006.01) AsIK 9700 (2006.01) (2) US.CL 514153; 530185 (58) Field of Classitication Search Susy 520185 ‘See application file for complete seach history. (56) References Cited US. PATENT DOCUMENTS. A A 1960 Nita 1668568 A SI987 Ishihara a S196405 A 1993 Packman SA2UDL3 A * 1904 Zagnol etal 5143 S5sno36 A 11904 Gordon etal 10/1999 Kashima eal sans 2002. MeGrath 102006 Burstein aubiv2s9 AL 12 72 Koma ta dougo1s77e6 Al 82004 Eni eta, 2ous01s083 AL 1/2006 Munro cal au07 036856 AI 22007 Schneider FOREIGN PATENT DOCUMENTS Wo Wosmussis 6989 (OTHER PUBLICATIONS. Rosie al, “Rheological Suly of Sucrallte Humid Gel: 2 Con- tibtion tothe Comprehension of its Suaility Propet” Eu: J ‘hay, Biopharm, ol 38, No.2, 78-8, 1992. Vai tal, “Gastric eteation of surat gland suspension in upper gasinestinal diseases Aliment Pharmacol. Ther, v0.7 31-535, 1995, IM, Gusland tal, “Et ofa Gel Fommulation of Sacalfte on Gast Micostelaton” Ta Med. Res, 21-47-80, 993 ALP. West cal, “Antibacterial activity of sucalite aint Escherichia Col Staphylococcus cures ant. Psedomones ‘aeruginosa atch a continvous cat" Bu J Cla, Micro Inf. Dis, vol. 12, No 11, 1993 (Abarat only) .Bergmns etal, “In vivo antibacterial activity of serait,” Er 1 Clin Microbiol Inject. Dis v0.13, No.7, 194 (Absit al). 8. G.L. Brgman et al, “Aetvty of sucralfate (cose octa- Sulphate, an antler agent, against opporunisic Gem-aegtive ili" Amincros Chemoter, vl. 36, Taste 4, 703-706, 1995, {Abstract onl. BL. Shomiagy ct al, *Swcralite ales the sscopibily of Heleolacier ppl!” antimicrobial ageus” Sand J Gasronteral Supp, 210, 82-84, 198 (Abstract only) IM, Mig eta, “Prevention with Sotalte Gel of NSAID-la- ced Gastduodenal Damage in Athrtie Pacts” 4m. J Garon, vo, 9, No. Ul, 2967-2371, 1996, PCT Iternsiona Search Rept andthe Written Opinion, xt 2000, * cited by examiner Primary Examiner — Michael G Hartley Assistant Examiner —Nabila Bbrain (74) torte, gent, or Firm — Haynes and Boone, LLP 6 ABSTRACT “Methods forthe prevention and treatment of infection, pret= erably antibiotic resistant wound infection, using a paste formes by the reaction of sueralfate with an aid component are provided. Methods of preparing stable sucralfate compo sitions are diselosed. Compositions of and produetscontain- ing the sucralfate paste are also described 5 Claims, No DrawingsUS 8,367,635 B2 1 ANTIMICROBIAL SUCRALFATE PASTE METHODS AND COMPOSITIONS. (CROSS REFERENCE TO RELATED "APPLICATIONS ‘This sa continuation application of Applicaton No. PCT/ {US2009/056374 filed Sep. 9, 2009, which claims priority to US. Provisional Application No. 61/097, 674 filed on Sep. 17, 2008, the contents of each which is hereby incorporated herein in its entirety by expres reference thereto ‘TECHNICAL FIELD “The present invention relates generally to methods of pre vention and treatment of infections, preferably antibiotic resistant wound infections, by applying a sucralfate paste forme by reaction of sucralfate with an acid component. The invention further relates to compositions of sucralfate paste and methods for producing the sme BACKGROUND OF THE INVENTION Sueralfate i a complex of sucrose octasulfate and alumi- ‘num hydroxide, Sncralfate is insoluble in water but dissolves, in hydrochloric acid, releasing sucrose sulfate and fre alu- ‘minum Prior to complete dissolution, serait reacted with hydrochloric acid forms an amorphous paste For therapeutic use in connection with uloets, The mechanism ef action of sucralfate is incompletely understood, but inclndes the pro- tection of uleeraed tissue by physical coverage ofthe wound base by this amomphous past, ‘The usoof sucralfate forthe treatmentofulersis knownin the art. For example, in his letter tothe editor in American Family Physician, January 1995, B. C. Demoss, M.D. con- ‘templated the use of suralfate tables (Caraate®) in eating ‘phous ulers. Suralite gel suspensions have also bee ‘employedasanantulcerativedrug. Sees. Rossietal,“Rheo- logical Stay of Surafate Humic Ge: a Contribution othe ‘Comprehension of is Stability Properties.” Eur. J. Pharm, Biopharm, 1992:38:78-81 “The use of serait gels a an ulcerheing drug has been dltciled in other journals as well. See M, Guslan etal “Effect of Gel Formulation of Sucalfate oa Gastric Micro- iculation,” J. In| Med. Res. 1993; 21: 47-50; see also M. Migloli, “Prevention with SucralfateGel of NSAID- Induced biotis, including methicillin, dcloxacllin, nafeillin, and oxacilln ‘Therefore, there isa need for improved methods and com> positions to teat such aaibioti-resistant stains of microor- anisms ‘SUMMARY OF THE INVENTION ‘The present invention relates toa method for teeatingaati- biotie resistant wound infection that includes providing an antimicrobial paste tht includes a eaction product of sueral- {ate with an acid component to form a reaction prodet, and applying the atimierobial paste topically to the wound to inhibit the growth ofthe atleast one type of antibiotic resis- ‘et microorganism associated with a wound. The reaction products presen in an amount sullicient toa least inbibit the {growth of he atleast one type af anbiotie resistant mniero- omganism, ‘The present invention also relates toa method for prevent= ing sntbioie resistant wound infection tat ineludes provid- ing an antimicrobial paste that includes reucting sucralfate and an acid component, and applying the antimicrobial paste ‘opieally toa wound oiahibitoravoid the presence or growth of antibiotic resistant microorganisms. The reaction product jis preferably present in an amount sufficient to prevent infec= tion of a wound by one or more types of antibiotic resistant ricroorganisns Tone embodiment, the reacting is incompletely eucting the sueralfte withthe acid component. The wounds to which the compositions are adapted and coaligured 1 eat ae typi= cally onl, topcal, nasal, alimentary: vaginal, ophthalmic, or 8 combination thereof. Inanother embodiment, the acid component is selected to ‘include hydrochloric, hydroiod, phosphoric, sulfuric, chro- nie, sulfonic, aetc citric, ascorbic, or nti acid, or 3 com bination thereof, Preferably, the reacting oceurs na more than about 28 days before applying. Te antimicrobial paste ‘optionally may be applied othe wound in association withat Teast asocondary dressing, occlusive somi-occlusivedress- ing, hydrophilic dressing, ora combination thereof. Usually, the antibiotic resistamt microorganisms include one or more typesotbacteria, one or moretypesof fag, ora combination thereof. The antibiotic resistant microorganisms are prefer- ably seleced to include bacteria comprising methicillin sistant Staphylococcus aureus of Vancomyin-esistant enterneoccus, or a combination thers. The antimicrobialUS 8,367,635 B2 3 paste is generally applied atleast once weekly. Furthermore, 'o inhibit the paste from overdrying, the method preferably ‘also includes covering the applied paste with a sacond, dif- ferent cream, oiniment, hydrogel, or paste ina amount sul ficient to maintain or inhibit loss of moisture from the paste. ° ‘The present invention also relates to an antimicrobial sucralfate composition tht includes an antimicrobial paste anda supernatant component formed froma reaction product ‘of sucralfate withan acd component. The reaction product is present inan amount suciont oat est nhibitthe growth of a least one type of antibiotic resistant microorganism. The Viscosity ofthe antimicrobial pasteistypicaly from bout SO €P 10 350,000 eP. ‘The amtimicrobial paste may advantageously further include « pharmaceutically acceptable carrie that includes ‘oncor more ofan intment-orerea-forming agent anda gel ‘component. The composition preferably further includes a local anesthetic an additional ant-infective agent, or a com bigation thereof. The local anesthtie, when present, prefer- 2 ably includes, without limitation, anesthetics of the amide type such a lidocaine, mepivicaine, piloealne, procaine, ot tetracaine, or 2 combination thereat, The additional anti- infective agent includes, for example, a source of die ion, silver, or a combination thereof. In an exemplary embodi- meat, the composition is substantially stable, The present invention farther relates to an antimicrobial sucralfate composition that ineludes an antimicrobial paste formes! from a reaction product of sucralfite with an acid ‘component, and a moisturizing component o inhibit deying. 30 ‘of the antimicrobial paste, The reaction products present in ‘anamouut sufficient oat least inhibit the growth of antibiotic resistant microorganisms, Ina prefered embodiment, the moisturizing component includes methylellulose, ptroatum, mineral oil, ceesin, lanolin alcohol, mineral wax, povidone or a combination thercof, la another embodime, the composition further includes a supemataat that is present in the reaction product «duct an excess ofthe sucralfate relative tothe acid compo- nent Ia edition, the present invention relates toa antimicr- bial wound dressing tht includes an antimicrobial paste formed from a reaction product of suerlfate incompletely reacted with an acid component, and an absorbent, exible rateial that is associated with the antimicrobial paste and provides a substrate to facilitate retention a substantial por- tion ofthe antimicrobial paste in association therewith “The antimicrobial paste is preferably packaged ia one oF ‘more oiniment jars, oF syringes or tubes associated with the absorbent, exible material. Inne embodiment, the dressing. 50 firher includes a backing layer that includes a pressure- senstiveadhesive adapted forcontact wit theskinor mucosa ‘on one surface thoreof. The backing layer is typically dis Posed adjacent the absorbent, flexible material In another embodiment, the adhesive is disposed over first side ofthe absorbent, exible material that includes the antimicrobial past adapted for application toa wound. Prof ‘erably, the acid component includes hydochlorc acid “The present invention fhe relates to 2 method of pre- Paring stable sucralfate composition that inches providing, 60 8 source of sucrallste, reacting the sucralfate with an acid ‘component to forma Stable composition that incindesa paste ‘and a supernatant, and modifying the supernatant o increase the pH of the super natant to about 3 oF higher. In one embodiment, the acid 6s ‘component reacied exceeds 8 millimoles per $ grams of sucralfate. In preferred embodiment, the acid component 4 reacted exceeds 10 millimoles per Sg of sucralfate buts less than about $5 millimoles per Sg of suerllte. Inne embodiment, the molar rato ofthe sucralfate tothe cid component is about 1:2 0 1:10, Preferably. the molar rat ofthe sueralfate to the acid eompanet i about 1:5 0 1:10, In another embodiment, tae modifying includes llow= ing the paste 1 remain in contat with the supernatant foe at Jeast about Sours, adding a base othe supematat, adding supernatant with a pH of greater than about 3, ora combina tion thereof Lastly, the present invention relates toa stable sueralfite composition that includes a reaction product of sucralfate with an acid component. The molar ratio ofthe sucralfate to the acid component reacted is atleast about 1:5 to ensure a sulficent amount of the acid component, but contains an insufficient amount ofthe acid component to completely dis- solve the sucralfate therein, Preferably the molar ato of the sucralfate to the acid component is about 1610 1:10, DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS ‘he presnt invention relates tothe use o sucrallat paste for preventing or treating infection by antibiotic resistant bacteria or fungi, particularly in topical wounds, and pocifi- cally Pseudomonas auruginoso, Escherichia coll mbit linsesistant Staphylococcus aureus (MRSA) and vancomy- cin-esistantenterococeus. The reaction of sorte with an acid component under controled conditions before dosing limits thereaction to preferably an acomplete stage o yield paste thats biologically activated and advantageous forthe treatment of wounds Preferably. the reaction limited bythe amovat of aid with an exces of sucralate “The satimirobial action of surat paste as advantae sgeously been found 1 have uty forthe treatment o p= ‘eation of wound inition from a are of pathogenic organisms, which ae preferably anit resistant, inelud- ing MRSA. Thesueralate pst prepared and used acconing tothe invention has boon validated and tested, as desriod hea, through routine microbial preserve eectveness research, The esting ecaled a suprising and an unexpected dntinicrobial effet of the srallate paste. Without being bound by thor itis believed tat nreacted suralitemate= fal, when present, euresses, inhibits, or even prevents the now of antbioe-esistant-microoganims, but the Potency js believed to be greater withthe sucralfate paste prepared by reaction of sucralfate with an acid componct preferably othat the reactions incomplete and the serallte $8 not completly dissolved, Tis suprising ad unexpected finding suggests forthe irs ime the advantage fr teatment orpeventionof wound infections from variety of organisms including the antibiotic resistant organi MRSA, to be achieved by administration of surat paste formed bythe reaction of sucralfate with an acid component, preferably the incomplete ection thereof. Moreover the inventive suecal- fate paste proce substantial rection sting af greater than about 4 Tog reduction in the orignal inoculums of Pseudomonas auriginosa, Escherichia col, nd Stphyo occas aureus, and. meibcilin-resistant Saphyfococeus aureus (MRSA) asdeseribodherinand about? lg redction in the origina inoculum of Candida albicans. The present ‘invention provides sneraliate composition forthe eatment of wounds and a method for preparation of serait paste not ony o proiace protective and healing bones, bao teat orprevent wound infection and to otherwise prevent or ‘eat inectionpanicularl by antbiveresistntmicroorean-US 8,367,635 B2 5 “The sucralfate paste ofthe present invention i preferably ‘an amorphous hydrogel paste preferably formed by the trolled reaction of sralfate witha limited quantity ofan acid ‘component. Although any suitable acid component may be used as desribed herein, preferably hydrochloric acid (FICD) is sed. This compounding process i preferably executed by pharmacist, dentist, physician, podiatrist, veterinarian, ‘other licensed prescriber or others trained to handle parma ‘ceutical acids, ‘The formation ofa past, preferably by the controlled and limited reaction of sucralfate with acid, poe to dosing creates the opportunity to use sucralfate asa physical wound dressing in conditions other than doodenal uleer. Preferably, the sucralfate and an acid component are reacted no more than about 28 days before application. The suerafite paste is typically compounded shorly before dispensing 10 the Patent by reacting sucralfate tablets witha volume of acid ‘component, for example, 1,0N HCI, sullicient oiniiate paste formation but, none embodiment, insufficient to cause com plete sucralfate dissolution. The tables can be whole, But are preferably crushed, cut, ground up, milled o otherwise pul- ‘rized to facilitate the reaction, Although a wide variety of pHranges may be suitable, typically th paste pl is about 210 5, more preferably about 3 to 3.8. in an exemplary emibodi- ‘meat, the paste fod in this manner is self-butfered toa pH of about 35. The acd component used to react with the seralfate can include any suitable acid or acid mixture that reacts with sucralfate to form a paste, For example, the acid component may include hydrochloric, ydroiodie, phosphoric, sufi, chromic, sulfonic, acetic, cite, ascorbic, nitric acid, or a ‘combination thereof. Hydrochloric aid is prefered, because ‘of certain drug development coaveniences, but alternatives also should provide equivalent therapeutic activity THC has a greater density of roton donation per acid mass than most alternatives for ether acids. The paste formed by reaction of sueralfate with IClisalso the most closely elated to that formed by eacton with sucralfate and stomach aed, and this most closely characterizes the bulk of wound healing dlata for sucralfate as used inthe teatment of ulcers, The ‘documentation of poteaialexwironmental impact of coat ‘mercial intmxdction of the anion into commercial distibu- tion or this paste is most ready established with HCI versus ‘other acids. Among acids, TCI offers freedom from taste, ‘smell tissue strining, and potential toxicity concerns ass0¢ sted witha variety of other acids, For these reasons, HCLis a preferred acid inthe ac component Other acids may provide additonal funetions. For ‘example, hydreiodic acid may provide other antimicrobial ‘effect by the donation ofthe iodide ion. Phosphoric acid, hydoiodic acid, and the weak acids in general can offer the ‘advantages ofan integrated acid donor such that paste forma tion can be executed by simply adding water A suficent amount of the acid component should be reacted with the suralfate to produce sueralite polymeriza- tion, while, in one embodiment, preferably esrcting the total acid availabilty so as to inhibit or prevent compete dissoluionof the sucralfate. The molar rato of sucralfate and ‘cid component reacted can typically be about 0.5 vo 1:10, preferably about 1:0:75 to 1:8, and in a more prefered ‘embodiment, about 1:1 to 1:5. A typical rato used is about 1:15. These pastes provide aa optimal viscosity and supee- natant pH immediately aler mixing, but stiffen over the ‘course of 24 hours. In an exemplary embodiment, about $ trams of strate tablet matex is reaeted with about 2108 nillimoles of HCl at conceatration of greater than or equal ‘to O.1N. Smaller volumes of more concentrated aid may be 6 used. A preferred embodiment uses small volumes of ON HCL. Further, greater quantities of sucralfite and HCI can be employed to produce larger quantitesof paste. Theamountof the acid component used is based on te feedstock concen tration used and the desired thickness ofthe paste. A lager amount ofthe acid component tends to procuce a thinner pase, while smaller amount produce thicker paste Stabilization of the paste for periods of greater than 24 hours has unexpectedly boon found o be associated with the use of about 150 percent to 350 percent, ofthe amount of the cid component previously recognized asthe upper init for the preparation of suitable pastes. Use of more than 8 mi LON HClperS gram sucraliteresulted intoothina pasteand. ‘noticeable drop of supemmatant pH below 2. Increasing the molar rato of suoralfateracid component toa least about |, preferably about 1:60 1:10, produces a paste hat is thinner, but suitable (with about 10 percent additional moisture retained within the matrix). Surprisingly and unexpectedly. this paste demoustates a prolonged stability exceeding 7 days, and preferably excveding 8 days, As sed herein, “sub- stantially stable” or “stable” is defined fo mean suitable for useinthe present methods fora east24 hours, preferably for atleast 7 days, and more preferably, exceeding 28 days Inone aspect ofthe invention, the antimicrobial paste can be applied to the wound with at least a secondary dressing, The secondary dressing can keep the paste over and essoci= sted with the wound and help prevent the paste fom drying cout. The sovondary dressing may also act to absorb exudates fom the wound, and can be changed pecidically typically without disturbing the wound, A suitable secondary dressing nay include gauze or cotton, Inanotheraspeet ofthe invention, second, different paste, ream, ointment, or hydrogel canbe used in combination with thepasteortocover the applied paste to help preventthepaste fiom drying out. The second, different paste, cream, oint- reat, or hydrogel is ypially spread over tae applied paste in ‘amount sullicient to cover the applied paste partially or completely to inhibitor prevent desiccation of the applied paste. For example, the second, dierent paste cream, cint- ‘meat, or hydrogel can he applied to a wound dressing, which can help retain the sueraste paste in association with ‘wound, Suitableagents can include one or more of petolatum ormineraloilalone, petrolatum andor mineral vilmixed with lipophilic compounds such at mineral wax, wool wax aleo- hal, or povidone, or any variety of other pasts or creams or hydrogels. Any suitable amount of such a second, diferent paste, cream, ointment, or hydrogel may be used in associa- tion with the sucralfate paste of the invention, preferably an amount sufiient to minimize or prevent substantially all, ot all, moisture loss trom the sucralfate compositions of the ianention. For example, the second, diffeent paste, eream, ointment, or hydrogel ean be applied to create a substantially surrounding harmer, or preferably a complete baer, becwoen the ambient atmosphere and the suealfate compo sition. ‘The present invention also relates to an antimicrobial sucralfate composition that includes an antimicrobial paste orm from 2 reation product of sucralfate with an acid component, and a supematant formed by the reaction ofthe sworlfate and the acid component. The resctono the sueral= fate and acid component forms a supemataat that may be decanted or preferably may be retained ia whole or in part in association with the paste. Without being bound by theory keeping the supernatant or other humectant component (e distilled water) associated with the paste ean help prevent desiccation and ca help increases life.US 8,367,635 B2 7 ‘The viscosity ofthe sural paste can be adjusted by the ‘amount of acid used to form the pase. Increasing the amount ‘of acid tends to produce a thinner paste. The viscosity ofthe paste typically can range from about SO cPr0350,000eP The Viscosity should be sullciently low wallow easy spreading of the paste onto the wound but suflciently high to allow sepa- ration of past fom superstant. Exemplary viseosities might be that of toothpaste, fresh caulk, or rubber cement before ‘curing, but would preferably be that of syrup. ‘The sucralfate paste preferably is applied directly to a ‘wound with as litle dilution as possible by incorporation of| ‘other pharmaceutically acceptable carries. However, itis not beyond the spirit and scope ofthe invention to formate the paste to include a pharmaceutically acceptable carrier that includes oae oF moge of anointmeat-or ream forming ageat, ‘2 gel component, a stabilizing agent, and a humectantcom- ponent. The pase, with or without associated supernatant is preferably applied diretly tothe wound with less than 60 percent dilution by other cariers such as ointment, eream or tel forming agents. Placing the pastes into other agents like 2 Petrlatum, Aquaphor™, or carboxymethylcellulose pro- Vides two (0 three days of usability, but often reduces the -ceptability foe use.on oral lesions or wet mos like vagi- nal lesions. A suitable ointment or cream forming agent can inelude petrolatum, lanolin, polyethylene glycol mineral el, mineral Wax ora combination thereof: When included i the compo sikon ofthe invention, the ointment or eream-forming agent is preferably present in an amouat sufficient to help retain moisture inthe paste to fecilitate application, Preferably the ‘ointment or ereaforming agent also aets to moisturize the ‘wounded membrane, e, skin Typical amounts of the oint- reat or cream-forming agent, when resent, are about 1010 60 weight percent of the otal composition, preferably about 15 « 30 weight perent ofthe total composition, and more preferably, about 25 to 40 weight percent ofthe total eompo- Sion. A suitable gel component to help provide a semisolid matrix can include acacia, alginic aid, bentonite, carbomer, carboxymethyeellulose sodium, cetosteary aleal,eolloi- dl silicon dioxide, ethylcellulose, gelatin, guar gum, hydeoxyethyleelulose, ydroxypropyleeliulse, hydeox- -ypropykellulose, hydroxylpropylmetiyleliuose, magne- ‘ium aluninum silicate, maltodextia, methylcellulose, poly- Viayl aleahol, povidone, propylene carbonate, propylene elyeol alginate, sodium alginate, sodium starch glycolat; starch, tragacanth, xanthan gum, ora combination thereof When included inthe composition ofthe invention, the ge ‘component is preferably present in an amount suficien 10 bina the resulting composition together ofiiltteapplica- tion the composition tothe wound, Typical amount of the ‘gel component, when present, ae about 0.5 19 40 weight Peteent of the total composition, preferably about 3 to 30 ‘weight percent of the total composition and more preferably, bout 20 0 25 weight percent ofthe total composition. Laan ‘exemplary embodiment, 2010 25 weight pereea of povidone isincloded inthe composition Inanother embodiea, the composition can also include a local anesthe, a additional ant-infective agent, or com bination thoreo The anesthetic, whon present, cts to mum pain from the wound, while the additional antiinfetve can ‘id in the inhibition oF Kling ofthe bacterial or fungal organ- isms, Any suitable topical anesthetic may be used, including ‘without Timtation benzoesine, lidocaine, chlonoprocaine, rovocaine,mepvicsne,prilocale, procaine, tetracaine, oF ‘combination thereof, Use of an anesthetic of the ester Iype such as benzocaine is less preferable due to acid catalyzed s 8 hydroysisofesterstrutures. The anesthetic, when preset is included in an amount sufcieat eieve pain when adie istored tothe wound, Suitable amounts of the anesthetic, wen present, ate ypcally about to about 25 weight percent of the tal camposion, preferably about 10 wo about 25 ‘sight erent ofthe total composition, and more preferably shout 20 weight percent ofthe ttl composition. ‘Any suitable atonal ant-nfstive agent can be wed. anu when present may incudea source fede on, iver. oF a combination thereof. In parila, a source of iodide on is hydric acid, which may be used o form te scralate poste self. The acid could alsa provide a secondary beni through release of the joie ion. The ant-infective agent, ‘when present, stypcll inelode nan amount suet a ressthespeadof infection inthe wound Suitable smountof the antinori, when preset are about 005 to 3 percent available iodine, and preferably, about 05 101.5 perent available iodine The preferred way to inhibit dying of the antimicrobial svcrlite pst sto apply an oclsive or semioccusve dressing over the suorlite paste afer application. The soerafate pase generally dies out aftr application. The ccs sem-nosisive dressing, when present, can p> erably include metylelaose, petrol, miner il t= esi, lanolin alcool, mineral wax, povidone or any combi- nation toro, which is applied ae fest applying undid ‘vera paste othe wound sit Another way to inhibit the drying of the antimirobil sucralfate paste sto incorporate the speratnt into a hydo- philic dressing, which can preferably include metivlel- Jose petuatun, mineral cei, lanfinleokel, mineral ‘ax, povidone, or any combination thee, whichs applied air fist applying undiluted sucralite paste to the wound sie ‘Yt another way to use the supernatant with potential there peat efet sw apply supernatant witout fuer mdifi- Cation del tothe wound prior a covering the wound with ‘vera pte “Anotheraspect ofthe imvention san antnierbil wound dressing thatinludes asuficient amount ofthe antimicrobial pole associated with nabsorbeat, exible material hat pro ides substrate to retain atleast substantial portion, and preferably substantial all or ll ofthe antimicrobial pase ‘The desig ca faite the rapid application of he peste to a woud can exp te past in poston over the wound, and also can hep inhibit moisture loss rom the paste. The dres- ing eanalsofcltate simple reappiaton of aiional pate orfeshly prepared pasteto the woud by providing in onoor over the desing and then replying the dressing to the wound Prelerably, the dressing cn also include backing layer that ncdes a presure-sesitveadsve including one of more achsive materials adapted for conte! with he wound, suchas the skin or macosa on one srface. The hacking ayer js preferably disposed adjaceat the absorbent, Nexble mate- Fal to hep resin the desing sociation wih the wound ‘which can include region adjacent the wound. The adhesive ‘stypcallycisposed onto the absorbent, exile material an a side ofthe material hat includes the antimicrobial pate adapted for application to wound. The adhesive can allow thedressing the easily attache tothe skinor mucosa of the wound around he wound or both, while keeping the pstein ‘sociation withthe wound to provide proplaetic o thea peat eet according tothe invention. “A variety of amounts and compositions canbe prepared sccordingto the invention. Purely by way of example Without limitation, ait with 2o 4 prams of suralfateina mixtoreofUS 8,367,635 B2 9 5 parts sucralfate wih 1 part povidone, about Sm purified Water and about 2 to 8 millimles of HCI in concentration jreater than or qual to 0.1N can be provided. The sucralfate ‘can then be reacted with the HCI, preferably ina contolled manner whereby the sucralfate is polymerized, but the com- plete dissolution of the sucralfate is prevented. Next, the mixture canbe titurated into a smooth mass of paste andthe resulting paste can be distinguished from and separate from, the supertaiat to facilitate dosing. The amorphous hydrogel paste can be used to provide complete or patil physical ‘coverage of wouncls whete gastric aid o focal wound bed ‘city is not avilable, ois iacoasistently presen. portion ‘of the paste ean also be applied to an open oral or topical ‘wound, proferably atleast onee a week. In other embod meats, the paste canbe applied once a day (or moze often if rede depending on patient wound dressing roquiremeats), ‘every other day, or twice a week, ‘One suitable way of preparing the paste is adding about 4 jgramsof sucralfate oa jaras four | gram tables, About 4m, ‘of purified water can then be pipeted 10 wet the sueralfite tables resulting in tablet pulverization. An amount suicien to barely cover the tablet could be used. About 5.0 ml. 1.0N, Han subsequently be added to cause paste formation. The paste can be sired and triturated using 2 pipette tip. Aer paste fonnation, the supernatant can be decanted and retained 'o allow a small portion to cover te paste after rinsing. The paste can then be washed with distilled water, which ean be decanted or allowed to remain over the paste. Finally the paste can be covered with a small portion of retained super- natant or distilled water. Covering the paste with supernatant ‘or water is not believed to cause significant changes in the Paste’s characteristics. Yer another method of peeparation involves adding 4 grams ‘of suerafate toa jar as powder. About 5.5 t 6.0m of LON HCI ean then be petted into the open jar to cause paste formation, preferably after firs weting the powder with puri fied water in an amouat equal or greater than the mass of powder. The reaction takes about half minute to five mine utes. The pastecanbe sired and triturated using pipet tip, Aer paste formation, the supematant can be decanted and supernatant cam be retained 0 allow a smal portion to cover the pase aller rising. The paste cin then be rinsed ith purified water, and the rinse discarded, The past can finally be covered with a small portion of retained supernatant or isle water ‘The soralfate pase is packaged in any suitable container, ‘eg, | Sgof sucralfate paste canbe placed ina S mi syringe, 44 go sucrallate paste can be placed ina 15 ml ointaent jar, 4 grams of suealfte paste can be placed in a § to 10 gram ‘ointment tube, In @ preferred embodiment, the sucralfate paste is retained in container that inhibits or even prevents ‘moisture from escaping the paste. Without being bound by theory, it is boloved that reducing loss of moisture in the paste, which occurs through water migration out ofthe paste and the package, can aid in preserving the shel-ife and stability ofthe paste Tn support of preparation ofa kit or other product contain- ing the paste compositions ofthe invention, sucrallate can be repackaged from commercially available 1 gram sucralfate tables labeled to identify the drug name, the manufecturer ‘contact information and fot numberof the sverafate batch, ‘and anexpiation date. Funheemore, .ON HClean be repack ‘aged in 11030 ml. quantities in unbreakable plastic ight seal ‘containers, such a vals or dispensing pipttes. These pack: ‘ages canbe labeled to reflect the name, stength, and volume ‘of the conten, the manufacturer contact information, lot number, and an expiration date, Packaging and labeling ean 10 be construct to address the eguirements for exception to hazardous material shipping eglatons as describe ia 49 CER $193.4. Distilled water canbe repackage in suitable monogrph forant- nikrobil fforvones testing (L10° CFU). Other inocunes were prepared wth 2), 4fld and Sold greater ongnism concentrations compared the USP ino ine concentration, Inoculates were intoduced int the sucralfate pasts afer preparation ofthe paste with mdi tons ofthe process esblish te contoleotons fr Test Groups 2ant 3 "Tat Group i was prepared scoring to the following procedure container olding 4 grams of crate tbls Srasepene, About 4m of watervae add, athe bets allowedtadisinegrate by adsorption of water About 60m, {of LON HCL was tnsfeed nthe open ro nie pose formation, Tenn was allowed o et forD SoS ints. ‘Theater paste wos sted and wate sing pete tp. Aer pst formation, the sopermatant was ean and nt dled fate “Test Group 2 was prepared aecoring 1 the following procedure, Aconsiner oldng 4 grams of ucrafie tblas ‘ras opened Abo mL of water ws ade, and the ables Mlowedto disinerate by adsorption of water. Aout 60m fpr water wos aed 0 prea hiner my with no paste formation Themix wa alowed to stand for Sto $ tims. The sacral sro ied an tut sng 2 pipet tp. With ao paste Formation the sperstant was ‘ned ant cistt foroe “Tet Group 3 was pepued aconting to the following proved Teen smpyvintnent jess add 148 grams of ‘ate I as ot furtr dit or combined with anything che er all samples of paste formed by HL tection, each cosine was nul witha sspesiono the MRSA test ‘npn fo given inoculum insomplane withthe stated {sof preparation, The count of able enon perl an thvolimeof each inpeulum was sored acc fate The cetualsyte weight for 4 gram active deg was 48 grams total tablet weight, plus 10 grams added fluid weight (4 mL, water and 6 mL, HC! or 6 mL, water). or sntnicrbileffctvenes testing, the poste was inoeloted by inediing he inoculum in he paste beneath the superaatant and then siting th pst and supertant together odvtabute the inoultn, The cote was left uit and ver ime the supernatant seperate, estring ts veri poition above the past For con rps of Test Grp 3nd Test Groop the nels we inraed below te suri ofthe suspension or water omic the tcchnigie wed for Group "The animirbilefesy in terns of abso inhibin of recovery or log redocton ‘sane oti notation concentration as este Revs TABLE] sme Pte Comme CH Imccuuioe___‘T 2 nes pot aun) logeiion Lee! Gap cmp? Gp3 Multiple” CRs SCRHCHPase SCRSopeaion Wale Tod xu 20x ax oak Aiod —62510% 12010? 2010" 630x108 ok TTF HbR Spe 950.107 ‘Table 1 demonstrates an immediate xuction in viable microbial recovery with both forms of suorallate as early 2 s 18 us rin, Th etn priya Uhexpesely more pronouced with sure paste an wih serlittabe suspend ater ‘TABLE? anole se Tusaaion Gp Gap? Imation "Loe SCRHC! SCR” Group Tel Wixi ad dW Ow Dhl S0a10° “Io G43) 100 G3) BW S210? Io GaAs) 150 G7) Sex AD) Soll Roo DOH LoL ‘Table 2 demonstrates a slight reduction (1.0 10 1.3 log reduction) in Group 3 (water contrl) which was thought Without being bound by theory, to represent the effect of ‘nutrient limitation. Both sucralfate groups demoastated an antimicrobial effect witha higher level of potency demon strated bythe sucrallate paste compared to sucralfate tablets suspend ia wate. With 2-fold, fold and Ssfold increase in ‘inoculate concentration, residtal omganisms are recovered fiom the Group 2 systems (sucralfate tablets suspended in water), Sueralfate paste continues to demonstrate complete suppression of microbial growth at 2-fold and 4-foldintease in inoculate concentration. Only upon 8-fold increase in noculate concentration does sucralfate paste demoastate any recoverable growthof MRSA organism. Evenatthis evel of inoculation, sucralfate paste continues to surprisingly and unexpectedly demonstrate at east 4 log kllof MRSA. ‘Of the three tatment groups, all demonstrated 2-day reduction in organism recovery, The reduction in the water system (negative contol) was fess than 1.5 Tog and, without being bound by theory, may represent the effect of limited nutrient concentration, Both sucralfate systems surprisingly and unexpectedly demonstrated in vitw bactericidal eflect With the more potent effect demonstrated by sucralfate paste comparedo seralfate alone suspended in water Both seral= fate paste and sucralfate alone suspended in water surris- ingly and unexpectedly demonstrated at least 3 log kill gains al levels of inoculate. Sueralfate suspended in water, however, filed to tolerate sucoessive increases in inoculate concentrations; recoverable ‘onganisms were demonsizated With igoculate concentrations slow as 2 times tat typically used in antimicrobial elfec- tiveness tests, Sueralfate paste continued to demonstrate recoveries of <10 CFU at2 and times the inoculate concen tration, AtS-foldiaerease inthe inoculate concentration (1-1 10°), suerafite paste demonstrated the first measurable onanism covery at 120 efi. “The test results support a concTusion that both sucralfate paste and sucralfate particulate suspension suprisingly and "unexpectedly demonstrated an antimicrobial effec, but with greater potency demonstrated by sucralfate past, The ativ- ity demonstrated by sucralfate pariculate suspension climi- nates the possibility that the meckanism of antimicrobial eft the smpleresult of ow pl. contribution of low pH «cannot be ruled out asthe explanation forthe relative increase jn potency demonstrated by the paste compared othe ga= Jar form, although further testing can clr this Example 4 Stability Testing Stability of sucralfate pastes formed by reaetion of sueral- fate wit an aid component have remained limited to dura-US 8,367,635 B2 19 tions of about 24 hours primarily because ofan increase in Viscosity and reduction in paste tackiness that develops with the passage of 24 hour or more time, Opportunities to resist, these changes in physical characteristics of the sucralfate paste have been explored with incomplete success by the Incorporation of sucralfate pastes into humoctant systems suchas that afforded by petolatum, mineral ol, mineral wax, ‘and woo! wax aleobol, povidone, carboxymetiylcellulse or ‘combinations thereof. Although trials of various systems ‘demonsrate the possibility of a modest increase inthe period ‘of physical and chemical stability of sucralfate past, all of these techniques iavolve significantly changing the paste from that known wo accelerate healing of duodenal uleer by ‘covering ofthe uler base wth a hydrogel formed by reaction ‘of seralfate with minor content of other formulation exc ‘ents with stomach acid to one in which the active drug is ‘gnifeanly incorporated into another external matrix. Adi ferent method for extending stability while voiding embed «ing the activated sucralfate molecule into a matrix that could ‘change the interaction of the paste withthe wound bod was pursued without succes through multiple tals. fer much testing, preparation of pastes using ratios of sucralfate to acid ‘component that were previously observed to proce unsal- isfactory characteristics immediately ater compounding were surprisingly and unpredictably found to provide satis factory characteristic ifallowed to ageat least I8hours prior owe, Paste were prepared to increase the relative excess of acid per sucralfate beyond the limits previously taught while stil avoiding complete sucralfate dissolution. In the series of pastes prepared below (Series 08.0723), pases with 4 sueral- fate I gram tablets with Sm. waterand 6 ml. acid component represent the high end of the practical limit ofthe sucralfate: sci ratio previously tht (7.5 millimoles acid component per 5 gram sucrallse). In this example, pastes prepared with tice that amount of acid demonstrated the phenomenon previously reported, These pastes appeared to demonstrate too low a viscosity and to acidic a pH ofthe supematant Direct application ofthese systems to tissue would not be recommended. For reasons that are not understood, neutal- ization of acid within the supernatant continued such that afer 18 hours, the pH was not different fom the pastes prepared with the typical formula of4 tablets with Sm. water ‘and 6 ml aci, With the passage of time extending through 8 ‘lays, the paste specimens prepared with the typical ratio thickened and became unsuitable fr use while pastes which ‘were initially unsuitable developed an optimal vseosity eine rte testy Serle gam —_Pate Forlatios Pporon flags Peis Wer Sat Fat Sm BCILON. ft a om. Ac SCR io us 1s iss mili HCI per Steam scale pi Sipenatt saws 23 ur Initiate ‘pouting i Siperst jams amas Baas Tsou 20 continued xan Lisi ofits Say Seite gsm fuse Folios Psoorons Fess ies 4 2 2 Sipe Dos swis Sawi5 Bans Vaconty ‘Tpicd —Adequie, Tota Inmedinely afer Missy ir Leveapact Noahs conpausiig = othicksyap. ptemase ppetestie rick Viosty pink Adee Adee Isitows The hime vise Ione, NetOp Adee Nevtky system ou Da 1 Examples teaches forthe fisttime that prolonged stability ofsuoralat pases formed by reaction of sucralfate with acid can be achieved by extending the relative excess of acid per sveralfae beyond those which ye opima pases immedi- ately upon completion othe ection. By agig the paste this formed, stabilization of the system is achieved and opti pH and stability are achieved foe prolonged periods The foregoing olnes ears of several enbadiments so thatthoseo ordinary sili th art may better understand the ‘ious aspects ofthe present disclosure deserting heaven tin. Those of ordinary skill inthe at shoud appreciate that they may readily use the present disclosure 3 bass for designing oF modiving other chemical or phamaceutcal deals for carying out the same purposes andor achieving tho same advantages of the embodiments introduced herein ‘Those of oninary kil ia the ar should also elie that sch, equivalent details donot dear fom the spit and scope of the present disclosure, a that they muy make various changes, substitutions and alterations herein without dpa dng ro the pit and scope a the present dnlosve ‘What is elaimed is 1.A metho of preparing a stable surallatecompesition comprising: providing a source of suerte Facing the seralfte with an eid component to form ‘able composition comprising a paste and a superna- tat wherein he av componcat ected excods ail limols per 5 arams of sural; and losing te pesto resin in contact withthe sypenstant forat leas abou I8hourssoas to ineease the pH of the supernatant to about 3 or highe 2. The method of claim, wherein the molar aio ofthe suerte tothe aid component is aout 1:2 10 1:10. 53. The method of claim 1, furber comprising aking a nuilicent amount of «basic componeat to the supemati, adding supematan with pl of greater than about 3, ora combination hero “4 The method of claim 1 wherein the reacting is incom pletely reacting the surallate with the acid componet ‘wherein ectng occurs no mor than about 28 days before the applying, or bth '. The method of claim 1, wherein the aid component is seleta to comprise hydrochloric, hydriedc, phosphoric, sulfur, ehromie, sulfonic esi ii, acute, or nile acid, combination thereof