WO2025030173A1 - Reducing inflammation in surgical site tissues - Google Patents

Abstract

A sterile, acidic liquid which has an effective solute concentration of from 0.3 to 0.6 Osm/L and a pH of from 3.7 to 4.2 can be used to reduce inflammation in surgical site tissue of a mammalian subject. When used during surgeries performed on mammals, the liquid composition can be introduced to a surgery site wound cavity so as to reduce inflammation in surgical site tissue at that wound cavity. Advantageously, the composition need not be diluted or removed prior to approximation of the surgical wound.

Description

REDUCING INFLAMMATION IN SURGICAL SITE TISSUES

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional patent appl. no. 63/530,523, filed on August 3, 2023, the specification and appendices of which are incorporated by reference in their entirety.

BACKGROUND INFORMATION

[0002] Advancements in perioperative surgical techniques and post-operative rehabilitation procedures have increased the number of total knee arthroplasty (TKA) procedures to relieve pain and improve joint function caused by, for example, osteoarthritis. The number of TKAs in just the U.S. is projected to reach over 1,250,000 million annually by 2030.

[0003] The invasive nature of joint replacement procedures can result in significant tissue damage, releasing molecules that trigger tissue-intrinsic and -extrinsic responses that initiate a pro-inflammatory cascade which, if unchecked, often results in a complex series of events that results in swelling in the affected joint.

[0004] On a proteomic and cellular level, the inflammatory cascade involves the active recruitment of circulating immune cells like neutrophils and monocytes from the blood into the tissue, as well as the recruitment of tissue resident macrophages that release cytokines and chemokines which contribute to joint effusion and soft tissue edema. The recruited macrophages and neutrophils act as sources for matrix metalloproteinases (MMPs).

[0005] Mitigating the deleterious inflammatory loop by decreasing the activity of early chemokines and MMPs and facilitating the beneficial proliferative and remodeling phases of wound healing could be advantageous in limiting swelling and postoperative pain resulting from surgeries including, for examplejoint replacement procedures.

[0006] Bioimpedance spectroscopy and magnetic resonance imaging, although expensive and time consuming, enable precise quantification of knee swelling that traditional volumetric and circumferential measurements lack. Quantification of swelling after joint replacement procedures such as TKA can be done in a clinician’s office with single frequency-bioelectrical impedance assessment (SF-BIA) in conjunction with the development of a reference chart to stratify patients by swelling percentiles. Lower levels of assessed bioimpedance indicate higher fluid content and therefore greater swelling.

[0007] Postoperative swelling causes pain, reduced range of motion (ROM), and delayed recovery. Reducing such postoperative swelling, by using a treatment during surgery, is highly desirable.

[0008] U.S. Patent Publ. No. 2023/0390398 describes compositions and methods useful for reducing bioburden in surgical wounds. Advantageously, the compositions described and utilized need not be rinsed after use and prior to surgical site wound approximation, permitting post-closure activity against microbes such as bacteria.

[0009] A composition effective at preventing or inhibiting bacterial infection during and after a surgical procedure that also reduces inflammation of tissues in and around the surgical site would be of significant benefit to surgeons, hospitals, and orthopedists, not to mention patients.

SUMMARY

[0010] Provided herein are compositions useful for treating wound cavities in mammalian subjects. The compositions are sterile, aqueous solutions having effective solute concentrations of from 0.3 to 0.6 Osm/L and 3.7 < pH < 4.2.

[0011] The compositions can be used during surgeries performed on mammals. Prior to approximation of a surgical wound, an inventive composition introduced to the surgery site wound cavity, simultaneously or sequentially, can reduce bioburden therein and reduce post- surgical inflammation. Advantageously, the composition need not be diluted or removed, in part or in whole, prior to the surgical wound being approximated.

[0012] In situations where a biofilm has formed or is in the process of forming in a surgical wound cavity, reduction in bioburden can involve (a) negatively impacting the integrity of the biofilm’s protective EPS/ECPS macromolecules so that the entire structure can be dissolved, washed away, or otherwise prevented from becoming permanently ensconced in or on tissue located in the surgical wound cavity and/or (b) killing previously protected bacteria. In situations where a biofilm has yet to form in a surgical wound cavity, reduction in bioburden can involve killing planktonic bacteria. (Killing of bacteria typically does not occur through interruption or modification of a cellular process but, instead, via lysing of their cellular membranes as a result of osmotic pressure, membrane integrity disruption due to the presence of a surfactant, or some combination thereof.)

[0013] Other aspects of the invention will be apparent to the ordinarily skilled artisan from the detailed description that follows. To assist in understanding that description, certain definitions are provided immediately below, and these are intended to apply throughout unless the surrounding text explicitly indicates a contrary intention:

“comprising” means including, but not limited to, the listed ingredients or steps;

“consisting of’ means including only the listed ingredients (or steps) and minor amounts of inactive additives or adjuvants;

“room temperature” means 20° to 25°C;

“body temperature” means the average temperature of a mammal ± 1.5°C, for example, -35° to ~38°C for a North American human, -37° to ~40°C for a canine, etc.;

“polyacid” means a compound having at least two carboxyl groups and specifically includes dicarboxylic acids, tricarboxylic acids, etc.;

“pH” means the negative value of the base 10 logarithm of [H⁺] as determined by an acceptably reliable measurement method such as a properly calibrated pH meter, titration curve against a known standard, or the like;

“pK_a” means the negative value of the base 10 logarithm of a particular compound’s acid dissociation constant;

“buffer” means a compound or mixture of compounds having an ability to maintain the pH of a solution to which it is added within relatively narrow limits;

“buffer precursor” means a compound that, when added to a mixture containing an acid, results in a buffer;

“electrolyte” means a compound that exhibits some dissociation when added to water; “purified water” means water having a bacterial count and a level of endotoxins below those in tap water, well water, or spring water, either as-is or after a treatment such as softening or ion exchange;

“pharmaceutical grade” means a compound which meets a chemical purity standard established by a national or regional pharmacopeia;

“medication” means a substance which provides a therapeutic benefit to a treated subject;

“benzalkonium chloride” refers to any compound defined by the following general formula

where R³ is a Cs-Cis alkyl group, or any mixture of such compounds;

“effective solute concentration” is a measurement of the colligative property resulting from the number of moles of molecules (from nonelectrolyte) or ions (from electrolytes) present in a given volume solution, often presented in units of osmoles per liter;

“sterile,” when used in connection with a liquid composition and/or a container for such a liquid, means one which has been treated so as to kill any living organisms contained therein;

“substituted” means containing a heteroatom or functionality (e.g., hydrocarbyl group) that does not interfere with the intended purpose of the group in question;

“approximate,” when used in connection with a surgical procedure, means the closing of a surgical wound;

“wound cavity” means the area of a body which, although typically covered by the dermis, is capable of being contacted by a liquid introduced from an external source;

“microbe” means any type of microorganism including, but not limited to, bacteria, viruses, fungi, viroids, and prions;

“bioburden” means microbes and/or a substance produced, excreted or resulting from the presence of microbes; and “dwell time” means the amount of time that a composition is allowed to contact a surface and/or a microbe on such a surface.

[0014] Throughout this document, unless the surrounding text explicitly indicates a contrary intention, all values given in the form of percentages are w/v, i.e., grams of solute per liter of composition and pH values are those which can be obtained from any of a variety of potentiometric techniques employing a properly calibrated electrode.

[0015] The relevant portion(s) of any specifically referenced patent and/or published patent application are incorporated herein by reference.

BRIEF DESCRIPTION OF THE FIGURES

[0016] FIG. 1A is a plot of degree of swelling measured with SF-BIA versus postoperative days (POD) for control and experimental cohorts in a TKA study involving a composition of the present invention, designated here as XP.

[0017] FIG. IB is an overlay of the FIG. I A data curves onto historical swelling reference curves for 90th, 50th, and 10th percentiles of swelling in TKA procedures.

[0018] FIG. 2A is a regression analysis plot of range of motion return versus swelling from the aforementioned TKA study.

[0019] FIG. 2B is a regression analysis plot of ambulatory assisted device (AAD) usage versus swelling from the aforementioned TKA study.

[0020] FIG. 2C is a regression analysis plot of opioid usage versus swelling from the aforementioned TKA study.

[0021] FIG. 2D is a regression analysis plot of pain versus swelling from the aforementioned TKA study.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0022] The composition is described first in terms of its properties and components, many of which are widely available and relatively inexpensive, and then in terms of certain uses.

[0023] The composition includes solvent and solute components and, in certain embodiments, includes only those two components, i.e., is a solution. [0024] The solvent component is primarily water, typically purified water. (Instances where water other than purified water might be employed are discussed below.) Relative to the total volume of the solvent component, purified water constitutes at least 95%, often at least 97%, and typically at least 99% (all w/v) thereof. On a per liter basis, a composition includes from ~925 to ~975 mL, commonly from ~937 to ~972 mL, more commonly from ~950 to ~970 mL, and typically 960 ± 5 mL purified water.

[0025] Although not preferred, the solvent component can include small volumes of one or more organic liquids listed on the U.S. Food and Drug Administration inactive ingredients list, non-limiting examples of which include ethanol and propylene glycol. Where more than one organic liquid is included, the liquids should be unreactive toward one another. The organic liquids can constitute no more than 5%, preferably no more than 3%, and most preferably no more than 1% (all w v) of the solvent component.

[0026] A preferred solvent component is 100% purified water.

[0027] Each sub-component of the solute component preferably is provided in pharmaceutical grade form, particularly where the composition is to be used in a surgical theater.

[0028] The composition is acidic, which means that at least one of the sub-components of the solute component must be an acid. Preferred acids are those which have relatively high pK_a values, i.e., are not considered to be particularly strong acids.

[0029] Examples of potentially useful weak acids include monoprotic acids such as formic acid, acetic acid and substituted variants (e.g., hydroxyacetic acid, chloroacetic acid, dichloroacetic acid, phenylacetic acid, and the like), propanoic acid and substituted variants (e.g., lactic acid, pyruvic acid, and the like), any of a variety of benzoic acids (e.g., mandelic acid, chloromandelic acid, salicylic acid, and the like), glucuronic acid, and the like; diprotic acids such as oxalic acid and substituted variants (e.g., oxamic acid), butanedioic acid and substituted variants (e.g., malic acid, aspartic acid, tartaric acid, citramalic acid, and the like), pentanedioic acid and substituted variants (e.g., glutamic acid, 2-ketoglutaric acid, and the like), hexanedioic acid and substituted variants (e.g., mucic acid), butenedioic acid (both cis and trans isomers), iminodiacetic acid, phthalic acid, and the like; triprotic acids such as citric acid, 2-methylpropane-l,2,3- tricarboxylic acid, benzenetricarboxylic acid, nitrilotri acetic acid, and the like; tetraprotic acids such as prehnitic acid, pyromellitic acid, and the like; and even higher degree acids (e.g., penta-, hexa-, heptaprotic, etc ). Where a tri-, tetra-, or higher acid is used, one or more of the carboxyl protons can be replaced by cationic atoms or groups (e.g., alkali metal ions), which can be the same or different.

[0030] Citric acid constitutes a preferred acid because mammalian bodies have such familiarity with and tolerance toward it due to its use and regeneration as part of the Krebs cycle. Those solute components which include citric acid, particularly those which have citric acid as their sole acid, are preferred.

[0031] The amount of any given acid employed can be determined from the target pH of a given composition and the pK_a value(s) of the chosen acids in view of the type and amounts of compound(s), if any, utilized to achieve the desired effective solute concentration in the composition.

[0032] Both to ensure that the pH of the composition is not too low and also to increase its effective solute concentration, the solute component also includes a conjugate base of at least one of the foregoing weak acids. Although not required, use of conjugate base(s) of the particular acid(s) employed is preferable.

[0033] Upon dissociation, conjugate bases, e.g., salt(s) of one or more of the acid(s), increase the effective amount of solutes in the composition without greatly impacting the molar concentration of hydronium ions while, simultaneously, act to buffer the pH of the composition. The identity of the countercation portion of the salt(s) is not believed to be particularly critical, with common examples including ammonium ions and alkali metals, with the latter being preferred countercations.

[0034] Where a conjugate base of polyacid is used, all or fewer than all of the H atoms of the carboxyl groups can be replaced with cationic atoms or groups, which can be the same or different. For example, mono-, di- and trisodium citrate all constitute potentially useful buffer precursors, whether used in conjunction with citric acid or another organic acid. However, because trisodium citrate has three available basic sites, it has a theoretical buffering capacity up to 50% greater than that of disodium citrate (which has two such sites) and up to 200% greater than that of sodium citrate (which has only one such site).

[0035] Like the acid(s) described above, the amount of conjugate base(s) can be determined based on the desired composition pH and effective solute concentration. [0036] Many organic acids and their conjugate bases can be provided in either anhydrous or hydrate forms. The particular form of these materials does not impact utility or efficacy. Because all solutes are added to a solvent component that is all or almost all purified water, any water of hydration in the solute(s) merely becomes part of the solvent component.

[0037] The amounts of acid(s) and conjugate base(s) included in the solute component are added at levels that provide two important compositional characteristics, neither one of which is dependent on the particular materials which provide them.

[0038] The first such characteristic is pH. The present composition has a pH of from 3.7 to 4.2. A composition which has an even lower pH is quite likely to be even more effective in terms of disrupting EPS/ECPS macromolecules and in killing bacteria; however, this increased efficacy comes at a cost of decreased biocompatibility. Conversely, a composition having a pH > 4.2 would have even greater biocompatibility, albeit at the cost of lower efficacy.

[0039] Within the permitted pH range, a pH of from 3.85 to 4.05 is preferred, with pH = 3.95 ± 0.1 or even 0.05 being particularly preferred.

[0040] The second important compositional characteristic is effective solute concentration, which induces sufficient osmotic pressure across a bacterium’s cortical membrane to lead to lysis. This ability to induce osmotic pressure is independent of the particular identity or nature of individual compounds of the solute component, although smaller molecules are generally more effective than larger molecules due to solvent capacity (i.e., the ability to (typically) include more small molecules in a given amount of solvent component than an equimolar amount of larger molecules) and ease of transport across cortical membranes.

[0041] The present composition has an effective solute concentration of from -300 to -700 mOsm/L. A composition which has an effective solute concentration greater than -700 mOsm/L could be even more effective in terms of lethality toward bacteria; however, this increased efficacy comes at a cost of decreased biocompatibility, specifically, tissue inflammation.

[0042] The upper limit of the effective solute concentration can be impacted by the area of the body in which it is intended for use. For example, some studies have indicated that compositions having effective solute concentrations above -600 mOsm/L can cause unacceptable results (e.g., irritation and swelling) in the human peritoneal cavity. However, other studies have indicated that compositions having effective solute concentrations of -600 mOsm/L are better tolerated than lower concentration solutions when used in and around a joint, e.g., a shoulder.

[0043] Within the aforementioned permitted effective solute concentration range, preferred ranges are (1) for peritoneal usage, from -350 to -590 mOsm/L, particularly -400 to -580 and -450 to -575 mOsm/L, and (2) for non-peritoneal usage, from -450 to -680 mOsm/L, particularly -460 to -650 and -470 to -635 mOsm/L. A preferred overall range is from 450 to 675 mOsm/L.

[0044] Effective solute concentration can be calculated at a given compositional pH, with some free calculation tools being available online. No such calculation is absolute due to an increasing potential for reassociation of previously dissociated solutes as effective solute concentration increases. Nevertheless, the effective solute concentration values and ranges set forth above are theoretical maxima based on full dissociation.

[0045] Because it is a colligative property, effective solute concentration can be determined by techniques such as vapor pressure lowering, boiling point elevation, freezing point depression, and membrane osmometry. Because of their impact on properties such as boiling point and freezing point, where a particular composition happens to include one or more organic liquids, a tested composition which includes an equivalent volume of purified water in place of the organic liquid(s) should be used when performing one of the foregoing techniques so as to determine effective solute concentration.

[0046] Using citric acid and a citrate that includes three alkali metal ions as an exemplary acid and conjugate base pair, acceptable values for the aforedescribed compositional characteristics can be achieved (or at least approached, to permit achievement via the type of minor modification described below) using from 25 to 40 g/L citric acid and from 30 to 45 g/L of a citrate. Where anhydrous citric acid and trisodium citrate dihydrate are utilized, a preferred embodiment (for peritoneal usage) can be provided from 30 to 35 g/L of the acid and 34 to 38 g/L of the citrate, while another preferred embodiment (for joint usage) can be provided from 33 to 38 g/L of the acid and 37 to 42 g/L of the citrate.

[0047] Importantly, the particular species of acid and citrate discussed in the preceding paragraph need not be utilized. An ordinarily skilled artisan desiring to use a hydrate version of the acid, an anhydrous version of the citrate, a citrate having fewer than three alkali metal atoms (i.e., mono- or disodium citrate) readily can calculate amounts of each that will provide compositions having acceptable values for the aforedescribed compositional characteristics.

[0048] The solute component also includes one or more surface active agents that bear some type of ionic charge. Of these, anionic and cationic surfactants are preferred over zwitterionic surfactants. A composition should not include surfactant types that are incompatible, i.e., anionic with cationic or zwitterionic with either anionic or cationic.

[0049] Smaller molecules generally are preferred over larger sized surfactants. The size of side-groups attached to the polar head can influence the efficacy of ionic surfactants, with larger sized groups and more side groups on the polar head potentially decreasing its efficacy.

[0050] Potentially useful anionic surfactants include, but are not limited to, ammonium lauryl sulfate, dioctyl sodium sulfosuccinate, perfluorobutanesulfonic acid, perfluorononanoic acid, perfluorooctanesulfonic acid, perfluorooctanoic acid, potassium laurylsulfate, sodium dodecylbenzenesulfonate, sodium laureth sulfate, sodium lauroyl sarcosinate, sodium myreth sulfate, sodium pareth sulfate, sodium stearate, sodium chenodeoxycholate, A-l auroyl sarcosine sodium salt, lithium dodecyl sulfate, 1 -octanesulfonic acid sodium salt, sodium cholate hydrate, sodium deoxycholate, sodium dodecyl sulfate (SDS, also called sodium lauryl sulfate (SLS)), sodium glycodeoxy cholate, and the alkyl phosphates set forth in U.S. Pat. No. 6,610,314. (Although sodium is used as the countercation in most of the foregoing exemplary anionic surfactants, other alkali metal ions can be used in its place.) SDS is a particularly preferred option. [0051] Potentially useful cationic surfactants include, but are not limited to, cetylpyridinium chloride (CPC), cetyl trimethylammonium chloride, benzethonium chloride, 5-bromo-5- nitro- 1,3 -di oxane, dimethyldioctadecylammonium chloride, cetrimonium bromide, dioctadecyldimethylammonium bromide, tetradecyltrimethyl ammonium bromide, benzalkonium chloride (BZK), hexadecylpyridinium chloride monohydrate and hexadecyltrimethyl ammonium bromide. [0052] Potentially useful zwitterionic surfactants include sulfonates (e.g. 3-[(3-cholamido- propyl)dimethylammonio]-l-propanesulfonate), sultaines (e.g. cocamidopropyl hydroxysultaine), betaines (e.g. cocamidopropyl betaine), and phosphates (e.g. lecithin).

[0053] Although not preferred, nonionic surfactant(s) can be included. [0054] For other potentially useful surface active materials, the interested reader is directed to any of a variety of other sources including, for example, U.S. Pat. Nos. 4,107,328, 6,953,772, 7,959,943, and 8,940,792.

[0055] The amount(s) of surfactant(s) included is limited to some extent by the target effective solute concentration and compatibility with other subcomponents of the solute component. The total amount of surfactant present in the composition can range from -0.07 to -0.19% (w/v), typically -0.075 to -0.15% (H’/ V), preferably 1 ± 0.25 g/L or 0.95 ± 0.2 g/L.

[0056] If the acid(s), conjugate base(s) and surfactant(s) do not provide a desired effective solute concentration, one or more electrolytes, particularly ionic compounds (salts), can be added; see, e.g., U.S. Pat. No. 7,090,882, for a list of potentially useful electrolytes.

[0057] Not preferred but permissible in the solute component is one or more inactive ingredients (additives) approved by the U.S. Food & Drug Administration, available as a zipped text fde at https://www.fda.gov/media/72482/download (link active as of filing date of this application).

[0058] A typical manner of making a composition involves adding the solute sub-components, either separately or as an admixture, to the solvent component (or to the water sub -component of the solvent component, followed by addition of the organic liquid(s)). This addition can be done with the benefit of one or both of stirring and heating of the mixing container.

[0059] If assurance of a targeted pH range is considered important, once the solute component has been added to the solvent component, very small aliquots of a concentrated acid (e.g., IM HC1) or concentrated base (e.g., IM KOH) can be used to lower or raise the composition’s pH into the targeted range.

[0060] The following table provides an ingredient list for providing exemplary compositions according to the present invention, with amounts being given in grams. The acid is shown in anhydrous form and its conjugate base in dihydrate form, but, as explained above, this is not limiting. Table 1 : Formulations for exemplary compositions

[0061] Various embodiments of the present invention have been provided by way of example and not limitation. As evident from the foregoing tables, general preferences regarding features, ranges, numerical limitations and embodiments are, to the extent feasible and as long as not interfering or incompatible, envisioned as being capable of being combined with other such generally preferred features, ranges, numerical limitations and embodiments.

[0062] Given that reducing bioburden in surgical site wound cavities is a contemplated usage of the composition, it typically will be provided to a surgical theater packaged in sterile form, i.e., its container having been subjected to sufficient heat, radiation, etc., so as to render the composition sterile (aseptic).

[0063] Typical containers include bags and bottles of a type similar to those used to deliver liquids such as saline solutions in surgical theaters.

[0064] The container has one or more access points, for example, a port covered and protected by a septum. Where a container has more than one such access point, one of the access points can be used to introduce at least one medication to the interior of the container prior to the container’s contents, i.e., the composition and medication(s), being evacuated from the container through another of the access points. Introduction of medication into the interior of the container can be accomplished by syringe injection through a septum.

[0065] Non-limiting categories of medications which can be added to the composition include steroids such as hydrocortisone, clobetasol propionate, betamethasone dipropionate, halobetasol propionate, diflorasone diacetate, fluocinonide, halcinonide, amcinonide, desoximetasone, triamcinolone acetonide, mometasone furoate, fluticasone propionate, betamethasone dipropionate, halometasone, fluocinolone acetonide, hydrocortisone valerate, hydrocortisone butyrate, flurandrenolide, triamcinolone acetonide, mometasone furoate, fluticasone propionate, desonide, fluocinolone acetonide, hydrocortisone valerate, alclo- metasone dipropionate, triamcinolone acetonide, fluocinolone acetonide, and desonide; antibiotics such as Amikacin, Amoxicillin, Ampicillin, Arsphenamine, Azithromycin, Azlocillin, Aztreonam, Bacitracin, Capreomycin, Cefaclor, Cefadroxil, Cefalexin, Cefamandole, Cefazolin, Cefdinir, Cefditoren, Cefepime, Cefixime, Cefmetazole, Cefonicid, Cefoperazone, Cefotaxime, Cefotetan, Cefoxitin, Cefpodoxime, Cefprozil, Ceftaroline, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftobiprole, Ceftriaxone, Cefuroxime, Cephalosporins, Cephalothin, Cephapirin, Cephradine, Chloramphenicol, Ciprofloxacin, Clarithromycin, Clindamycin, Clofazimine, Colistin, Cycloserine, Dalbavancin, Dapsone, Daptomycin, Dicloxacillin, Doripenem, Doxycycline, Enoxacin, Ertapenem, Erythromycin, Ethambutol, Ethionamide, Fidaxomicin, Flucioxacillin, Fosfomycin, Furazolidone, Fusidic acid, gatifloxacin, Geldanamycin, gemifloxacin, Gentamicin, grepafloxacin, Halicin, Herbimycin, Imipenem/Cilastatin, Isoniazid, Kanamycin, levofloxacin, Lincomycin, Line- zolid, lomefloxacin, Loracarbef, Mafenide, Malacidins, Meropenem, Metacycline, methicillin, Metronidazole, Mezlocillin, Minocycline, Moxalactam, moxifloxacin, Mupirocin, nadifloxacin, Nafcillin, Nalidixic acid, Neomycin, Netilmicin, Nitrofurantoin, norfloxacin, ofloxacin, Omadacycline, Oritavancin, Oxacillin, Oxazolidinones, Oxytetracycline, Paromomycin, Penicillin G, Penicillin V, Piperacillin, Piperacillin/tazobactam, Platensimycin, Polymyxin B, polypeptides, Posizolid, pyrazinamide, Quinupristin/Dalfopristin, Radezolid, Rifabutin, Rifampicin, Rifapentine, Rifaximin, Roxithromycin, Serotonin Syndrome, silver sulfadiazine, sparfloxacin, Spectinomycin, Spiramycin, Streptomycin, Sulfacetamide, Sulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Sulfonamidochrysoidine, Tedizolid, Teicoplanin, Teixobactin, Telavancin, Telithromycin, temafloxacin, Temocillin, tetracycline, Thiamphenicol, Thrombocytopenia, Ticarcillin, Ticarcillin/clavulanate, Tigecycline, Tinidazole, Tobramycin, Torezolid, Trimethoprim, Trimethoprim/sulfamethoxazole, trovafloxacin, and Vancomycin; anticoagulants such as heparin, Apixaban, Dabigatran, Edoxaban, Enoxaparin, Rivaroxaban, and warfarin; clotting promoters such as aprotinin, epsilon-aminocaproic acid, aminomethylbenzoic acid, and tranexamic acid; antifungals such as Amphotericin B, Candicidin, Filipin, Hamycin, Natamycin, Nystatin, Rimocidin, Bifonazole, Butoconazole, Clotrimazole, Econazole, Fenticonazole, Isoconazole, Ketoconazole, Luliconazole, miconazole, Omoconazole, Oxiconazole, Sertaconazole, Sulconazole, Tioconazole, Albaconazole, Efinaconazole, Epoxiconazole, fluconazole, Isavuconazole, Itraconazole, Posaconazole, Propiconazole, Ravuconazole, Terconazole, Voriconazole, Abafungin, amorolfin, butenafme, naftifine, terbinafme, Anidulafungin, Caspofungin, Micafungin, Aurones, benzoic acid, Ciclopirox, Flucytosine or 5-fluoro. cytosine, Griseofulvin, Haloprogin, Tolnaftate, undecylenic acid, Triacetin, Crystal violet, Orotomide, Miltefosine, potassium iodide, Nikkomycin, copper(II) sulfate, selenium disulfide, sodium thiosulfate, Piroctone olamine, lodoquinol (diiodohydroxyquin), Acrisorcin, zinc pyrithione, and sulfur; anesthetics such as lidocaine, benzocaine, butamben, dibucaine, oxybuprocaine, pramoxine, proxymetacaine and tetracaine; and analgesics such as 2-(4-(2-methylpropyl)phenyl)propanoic acid (i.e., ibuprofen), capsaicin, diclofenac, lidocaine, methyl salicylate, and trolamine.

[0066] Such medications preferably are delivered in purified water. Because some of the aforementioned classes of medications, or certain species within a given class, can have limited solubility in water, delivery in an organic liquid (or a solution which includes an organic liquid) might be necessary or desirable. In such cases, the considerations regarding type and amount of such organic liquid(s) set forth above should be taken into account.

[0067] When adding one or more of such medications to the composition container, the solubility limits of the medications at the composition’s temperature necessarily must be taken into account.

[0068] Prior to evacuation of the container contents, the container and those contents can be warmed. While such warming can assist in assuring that all solute components are fully dissolved, it also provides the side benefit of bringing the temperature of the composition closer to that of the surgical patient’s internal temperature. In view of the latter, the temperature of the composition preferably is within 5°C of the body temperature of the particular type of mammal on which the surgery is being performed. (In extremely hot climates, bringing the temperature of the composition to within the desired range might require cooling rather than warming.) [0069] Where a medication is to be introduced into the container prior to the container contents being evacuated, the aforementioned temperature adjustment can occur before or after introduction of the medication to the composition.

[0070] Transferring the composition from the interior of the container to the surgical wound cavity of the patient can be accomplished in numerous ways.

[0071] One option involves decanting the contents of the container into a sterile basin by means of a tube with a spiked end. Evacuation of container contents typically occurs solely through the force of gravity. Once decanted, a medical professional, e.g., surgeon, can pour the decanted composition from the basin over and into the wound cavity.

[0072] A variation of the foregoing involves use of a bulb syringe (or similar) by the medical professional to better direct flow of the composition into and around the wound cavity. [0073] Where the container is a bottle (typically packaged in a thermoformed polymeric tray with a removable, polymeric lid), its contents can be evacuated similarly to the option just described. If the bottle is sealed, the seal is removed and a cap with nozzle applied. (If the bottle includes an integrated nozzle, this step can be avoided.) The medical professional can use the nozzle to direct composition flow into and around the wound cavity similarly to the manner employed with a bulb syringe.

[0074] Another option involves use of a device that can deliver the composition under pressure, e.g., a pulsed or jet lavage delivery system such as Interpulse™ pulsed lavage system (Stryker; Kalamazoo, Michigan) or Pulsavac™ Plus lavage system (Zimmer Biomet; Warsaw, Indiana). Similar to the gravity feed option described above, the composition can be accessed using a tube with a spiked end, with the other end of that tube being attached to and feeding the delivery instrument. A medical professional using the wand or gun portion of the delivery instrument directs flow of the composition into and rinses the surgical wound cavity.

[0075] Regardless of how introduced, the amount of composition delivered into the surgical wound cavity can vary from as little as a few milliliters for small surgical sites up to 0.5, 1, 1.5 or 2 L (optionally delivered in more than one aliquot).

[0076] Although the composition is designed for use prior to a surgical wound being approximated at the end of a surgery, this is not limiting. The composition can be used at any point during a surgical procedure, for example, in the washing away of debris of one step prior to moving on to the next step of the procedure.

[0077] Regardless of when used during a surgical procedure, the composition does not require rinsing or suctioning; some or all can remain in the surgical wound cavity during and after surgical wound approximation.

[0078] At least a portion of the introduced composition remains behind after approximation of the surgical wound. The amount of composition remaining in the former surgical wound cavity can be as little as necessary to provide a coating on exposed (internal) tissues (0.5 to 10 mL) to as much composition as was introduced during the surgery. The fact that some composition remains behind means that it can work to reduce bioburden during the process of approximation and until such portion is biosorbed.

[0079] In situations where a not insubstantial amount of composition is introduced to the surgical wound cavity during the surgical procedure (e.g., -100 mL or more), partial removal via suction can be preferred. In situations where a substantial amount of composition is introduced to the surgical wound cavity during the surgical procedure (e.g., -250 mL or more), partial removal via suction is preferred. (Some composition might exit the surgical wound cavity via normal outflow during or after introduction.) Many pressure delivery (e.g., pulsed lavage) systems have integrated suctioning, i.e., the same device that introduces the composition is designed to also remove it with suction.

[0080] Importantly, removal by suction need not be preceded and/or followed by a saline solution rinse, i.e., the composition is sufficiently gentle and biocompatible that its continued presence in a wound cavity does not result in significant deleterious effects.

[0081] The amount of composition that remains in the surgical wound cavity during and after wound approximation typically ranges from a few milliliters up to -250 mL, with the amount largely depending on whether partial removal via suction has been employed.

[0082] When wounds are closed, edges of the wound are approximated by standard techniques including sutures, staples, adhesive(s) and the like. Approximation can be complete or partial, e.g., incorporation of a wound drain.

[0083] After a surgical wound is approximated, it and the surrounding area can be rinsed with a disinfecting solution and/or covered with a sterile protecting layer (optionally with an antimicrobial gel or cream such as BLASTX™ wound gel or SURGX™ sterilized gel, both available from Next Science (Jacksonville, Florida)).

[0084] The foregoing has focused on a common usage of the inventive compositions, i.e., use in surgical theaters. The compositions have additional utilities and methods of use, however, including specifically emergency medical care for open wounds, regardless of whether in hospital emergency departments, during patient transport (e.g., ambulance, life flight, etc.), or on the battlefield. In each of these situations, wound closure soon after introduction of the composition to a wound cavity is unlikely; instead, the composition can be introduced as soon as possible to the wound cavity, where it will remain for bioburden reduction purposes until more thorough wound treatment can be undertaken.

[0085] In situations such as emergency departments and patient transport, the composition often will be packaged similarly to that described above with respect to surgical theater usage. This might also be true for battlefield usage, but not necessarily so. For example, a medic or corpsman might prefer to carry the subcomponents of the solute component of the composition in a packet, sachet, or other container, then add them to an appropriate amount of water (which need not, and often will not, be purified) or vice versa. Once constituted, the composition then can be introduced directly into a wound cavity. Additional composition can be added during patient transport.

[0086] As discussed above, compositions described herein advantageously reduce bioburden in wound cavities.

[0087] The reduction in bioburden can be quantified, for example by assaying a change in bacterial colony forming units (CFU) before and after treatment with the composition. When bacteria are killed upon exposure to the composition, the change in CFU reflects the change in the number of living bacteria.

[0088] Alternatively or additionally, a biofilm might lose integrity due to exposure of the protective EPS/ECPS to the composition, such that the some or all of the structure can be dissolved, washed away, or otherwise prevented from becoming permanently ensconced in or on tissue located in the surgical wound cavity. In such a situation, the change in CFU reflects the loss of such bacteria (even though not killed by the composition) due to the dissolving, washing away, or otherwise being prevented from becoming permanently ensconced. [0089] When quantified by a change in CFU, the reduction in bioburden may be a reduction of at least 90% (1 log) in CFU, preferably a reduction of at least 99% (2 log) in CFU, more preferably a reduction of at least 99.9% (3 log) in CFU, or even more preferably a reduction of at least 99.99% (4 log) in CFU. This reduction in bioburden typically is measured over a time representative of the method for treating the wound. For example, the change in CFU may be measured starting from the time the composition is introduced to the wound cavity until the time the wound is approximated. Alternatively, the time may be specified as a specific value, such as 60 seconds, 120 seconds, 240 seconds, or 300 seconds.

[0090] A reduction in inflammation, including a reduction in post-surgical inflammation, can be quantified, for example by comparing a degree of swelling of a patient after treatment to a predicted degree of swelling based on control experiments including untreated patients. The degree of swelling can be measured using techniques such as SF-BIA in conjunction with developing a reference chart to stratify patients by swelling percentiles. This approach has been validated for the measurement of swelling in patients following TKA.

[0091] The following embodiments are specifically contemplated. An embodiment relating to a method of use involving a composition is intended to be read as also relating to the composition for use in that method.

[0092] Embodiment [1] relates to a method for reducing inflammation in surgical site tissue in a mammalian subject, the method comprising: a) providing a sterile, acidic liquid composition, the composition consisting of solvent and solute components and having an effective solute concentration of from 0.3 to 0.7 Osm/L and a pH of from 3.7 to 4.2; b) introducing the composition to a wound cavity of the mammalian subject prior to approximation of the wound; and c) permitting at least a portion of the composition to remain in the wound cavity during and after approximation of the wound.

[0093] Embodiment [2] relates to the method of Embodiment [1] wherein the composition has an effective solute concentration of from 350 to 590 mOsm/L.

[0094] Embodiment [3] relates to the method of Embodiment [1] wherein the composition has an effective solute concentration of from 450 to 680 mOsm/L. [0095] Embodiment [4] relates to any one of the methods of Embodiments [1] to [3] wherein the composition has a pH of from 3.85 to 4.05.

[0096] Embodiment [5] relates to the any one of the methods of Embodiments [1] to [4] wherein the composition is undiluted prior to the wound approximation.

[0097] Embodiment [6] relates to any one of the methods of Embodiments [1] to [4] wherein a portion of the composition is removed or diluted prior to the wound approximation. [0098] Embodiment [7] relates to any one of the methods of Embodiments [1] to [6] wherein the solvent component consists of purified water.

[0099] Embodiment [8] relates to any one of the methods of Embodiments [1] to [7] wherein all solutes in the solute component are pharmaceutical grade.

[0100] Embodiment [9] relates to any one of the methods of Embodiments [1] to [7] wherein the solute component comprises a buffer system and an ionic surfactant.

[0101] Embodiment [10] relates to any one of the methods of Embodiments [1] to [7] wherein the solute component consists of a buffer system and an ionic surfactant.

[0102] Embodiment [11] relates to any one of the methods of Embodiments [9] to [10] wherein the buffer system comprises dissociation products of a carboxylic acid and a conjugate base of a carboxylic acid.

[0103] Embodiment [12] relates to any one of the methods of Embodiments [9] to [10] wherein the buffer system consists of dissociation products of at least one carboxylic acid and at least one conjugate base of at least one carboxylic acid.

[0104] Embodiment [13] relates to any one of the methods of Embodiments [11] to [12] wherein the carboxylic acid is citric acid and wherein the conjugate base is a citrate.

[0105] Embodiment [14] relates to the method of Embodiment [13] wherein the buffer system comprises dissociation products of from 25 to 40 g/L citric acid and from 30 to 45 g/L of a citrate that comprises three alkali metal ions.

[0106] Embodiment [15] relates to any one of the methods of Embodiments [9] to [10] wherein the composition comprises from 0.7 to 1.9 g/L ionic surfactant.

[0107] Embodiment [16] relates to any one of the methods of Embodiments [9] to [10] and [15] wherein the ionic surfactant is an anionic surfactant. [0108] Embodiment [17] relates to the method of Embodiment [16] wherein the anionic surfactant is SLS.

[0109] Embodiment [18] relates to any one of the methods of Embodiments [1] to [17] wherein the surgical site tissue is joint tissue in the mammalian subject.

[0110] Embodiment [19] relates to any one of the methods of Embodiments [1] to [18] wherein the method is performed during an orthopedic surgery in the mammalian subject.

[0111] Embodiment [20] relates to the method of Embodiment [19] wherein the orthopedic surgery involves replacing a joint in the mammalian subject.

[0112] The following non-limiting, illustrative examples provide detailed conditions and materials that can be useful in the practice of the present invention. Unless specifically indicated to the contrary, any preparation and testing was done at room temperature, i.e., an ambient temperature of from 20° to 25°C.

EXAMPLES

[0113] The examples from U.S. Patent Publ. No. 2023/0390398, which focused on compositions capable of preventing infections that otherwise might result from post-surgical microbial activity. Of those compositions, the one deemed most worthy of safety and efficacy testing (pH ~ 4.0, calculated osmolarity ~ 670 mOsm/L) was made from 32.5 g anhydrous citric acid, 35.7 g trisodium citrate dihydrate, 1.0 g SLS, and 962.0 g water.

[0114] The safety testing included evaluation of different types of mammalian tissue: articular cartilage, cranial dura mater, mesentery, and pericardium. The animals underwent surgery to expose the required tissue for exposure to either the tested composition or the control composition. The tissues were evaluated histologically approximately 30 minutes, 24 hours, and 7 days after exposure, with the tested composition being found to be a non-irritant at these time points for all tissue types tested.

[0115] Here, an almost identical composition (abbreviated below as “XP”) was tested for safety and efficacy in human subjects undergoing TKA. The control group, which received the standard of care treatment (povidone iodine solution applied intraoperatively) included 30 patients, and the experimental group, which was treated with undiluted XP, included 31 patients. [0116] All TKA procedures were conducted by a single surgeon using identical cemented prostheses with the same surgical approach and no tourniquet utilization. For the patients in the control cohort, 0.45% (w/v) aqueous povidone iodine solution was applied prior to closure of the deep layer and allowed to sit in the surgical wound space for three minutes before being rinsed from the wound with normal saline using pulsatile lavage, followed by closure of the deep layer. After closure of the deep layer, the surrounding superficial layer was rinsed with saline using pulsatile lavage prior to closure of the superficial layer.

[0117] In the experimental cohort, a total volume of 500 mL XP was used during the entirety of the surgery: 250 mL using pulsatile lavage at the beginning of implantation, 200 mL at the end of implantation after final saline pulsatile lavage, and 50 mL to wash the deep layer and superficial layer during deep layer closure and prior to superficial layer closure. Excess XP was suctioned from the surgical cavity, but the product was not rinsed out after the 200 mL addition at the end of implantation. The final 50 mL was not suctioned.

[0118] Swelling as an indication of inflammation in the lower extremity post-surgery was measured using SF-BIA. Measurements were obtained using a Quantum™ II body composition analyzer (RJL Systems; Clinton Township, Michigan). Subjects were made to lie flat for 10 minutes before surface electrodes were placed on the non-surgical limb at four locations. Once appropriately placed, the electrodes were attached to the analyzer. The device was turned on and, after a lag of at least 5 seconds, values were recorded. This same process was repeated for the planned surgical limb.

[0119] Normalizing swelling in the surgical limb against the non-surgical limb of the same patient enabled accurate measurements of changes in fluid status in the surgical limb over time and allowed for valid swelling curve comparisons between patients and cohorts despite variability in body compositions.

[0120] In FIG. 1 A, error bars indicate 95% confidence intervals, with results of pairwise statistical results per day via Wilcoxon signed rank tests; * indicates p < 0.05; ** indicates p < 0.01; and “ns” indicates not significant. A statistically significant improvement in swelling in the experimental cohort occurring at days 7 and 14 can be seen relative to the control cohort. [0121] FIG. IB shows that both cohorts trended towards the 10th percentile of the reference curves, indicating much reduced swelling (better inflammation management) compared to historical reference standards. Comparing the control cohort to the experimental cohort shows a notable improvement in swelling at days 7 and 14. As seen in this figure, these days correspond to the peak of swelling, so an improvement (reduction) in swelling is particularly beneficial. These time points show that substituting XP for povidone iodine at the time of surgical closure reduced post-operative swelling up to two weeks after surgery.

[0122] To evaluate limb functionality, subjects were assessed for their ability to regain baseline or better ROM. As shown in the following table, subjects in the experimental cohort exhibited significantly greater return to baseline ROM at day 7 compared to the control cohort.

Table 2: Range of Motion

[0123] Dependence on AADs over the post-surgical 6-week period also was evaluated, with the results being shown below.

Table 3: Ambulatory Assistive Device Usage

[0124] The experimental cohort exhibited at least a 10% lower AAD usage compared to the control cohort at 7 days and all days following, with statistical significance at day 21 (p = 0.049).

[0125] Tables 2 and 3 strongly suggest that the XP cohort on the whole exhibited a quicker return of limb functionality compared to the control.

[0126] Opioid use was summarized as a binary response regardless of drug identity and/or dosage, with the results shown below.

Table 4: Opioid Usage

[0127] Opioid use decreased over time for both the control and experimental cohorts.

Although the results did not reach statistical significance, opioid usage was between 4 and 14 absolute percentage points lower in the experimental cohort compared to the control cohort at each time point. (Evaluation of pain using a numerical rating scale determined that there were no significant differences in perceived levels of pain between the cohorts, although the XP cohort patients who used an opioid did wean off those opioids more quickly than did control cohort patients.)

[0128] Correlations were used to evaluate the relationship between the key parameter of swelling associated with inflammation and the other parameters evaluated.

[0129] As seen in FIGS. 2A to 2D, reduced swelling was significantly associated with increased return of ROM (0/1 scale, R-sq 64%) and decreased reliance on AAD usage (R-sq 45%). Decreased opioid usage and pain were considered as surrogate indicators of improved quality of life. The increase in swelling correlated with an increase in the percentage of patients using opioids (0/1 scale, R-sq 63%), but swelling was not significantly associated with patients’ reported perception of pain (R-sq 1.2%).

[0130] Use of XP, relative to aqueous povidone iodine solution as standard of care control, resulted in a statistically significant improvement in post operative knee swelling. Meaningful improvement in ROM and a statistically significant reduction in dependence on AADs were noted.

Claims

CLAIMS That which is claimed is:

1. A method for reducing post-operative inflammation of tissue involved in a joint replacement surgery in a mammalian subject, said method comprising: a) providing a sterile, acidic liquid composition, said composition consisting of solvent and solute components and having an effective solute concentration of from 0.3 to 0.7 Osm/L and a pH of from 3.7 to 4.2; b) introducing said composition to a wound cavity of the mammalian subject during joint replacement surgery and prior to approximation of said wound; and c) permitting at least a portion of said composition to remain in said wound cavity during and after approximation of said wound, thereby reducing post-operative inflammation of tissue involved in said joint replacement surgery.

2. The method of claim 1 wherein said composition has an effective solute concentration of from 350 to 590 mOsm/L.

3. The method of claim 1 wherein said composition has an effective solute concentration of from 450 to 680 mOsm/L.

4. The method of claim 1 wherein said composition has a pH of from 3.85 to 4.05.

5. The method of any of claims 1 to 4 wherein said solvent component consists of purified water.

6. The method of any of claims 1 to 4 wherein all solutes in said solute component are pharmaceutical grade.

7. The method of claim 4 wherein said solute component comprises or consists of a buffer system and an ionic surfactant.

8. The method of claim 7 wherein said buffer system comprises dissociation products of a carboxylic acid and a conjugate base of a carboxylic acid.

9. The method of claim 8 wherein said buffer system consists of dissociation products of at least one carboxylic acid and at least one conjugate base of at least one carboxylic acid.

10. The method of claim 9 wherein said at least one carboxylic acid is citric acid and wherein said at least one conjugate base is a citrate.

11. The method of claim 10 wherein said buffer system comprises dissociation products of from 25 to 40 g/L citric acid and from 30 to 45 g/L of a citrate that comprises three alkali metal ions.

12. The method of claim 10 wherein said composition comprises from 0.7 to 1.9 g/L ionic surfactant.