Use of the liquid composition

Abstract

Biofilms present on a range of surfaces, including implanted medical devices and human skin, can be treated by applying an acidic liquid with an effective solute concentration of 0.3 to 1.4 Osm / L and a pH of 3.7 to 4.2.

Description

[Technical Field]

[0001] This application claims priority to U.S. Patent Application No. 63 / 428,165, filed November 28, 2022, which is incorporated herein by reference in its entirety. Background information

[0002] Microorganisms are present virtually everywhere, often in high concentrations, and are responsible for many diseases and infections.

[0003] Bacteria exist in a variety of forms, including planktonic, spore-like, and biofilm-like, and present particular challenges because their self-preservation mechanisms make them difficult to treat or eradicate. For example, biofilm- or spore-like bacteria are typically in a downregulated (sessile) state and are not actively dividing, making them resistant to attack by antibiotics and antimicrobial agents that attack dividing bacteria.

[0004] In biofilms, which form on any surface that is or can become wet, bacteria interact with the surface, attach, form colonies, and continue to grow. The colonies produce exopolysaccharide (EPS) and / or extracellular polysaccharide (ECPS) polymers that allow bacteria to adhere to the surface and form a protective barrier. This protection is thought to be due to the small diameter of channels within the matrix, which limits the size of molecules that can reach the underlying bacteria, and to the consumption of biocides through interactions with parts of the EPS / ECPS polymer matrix and the bacterial secretions and waste products contained therein.

[0005] Prosthetic joints and other orthopedic devices are particularly susceptible to biofilm formation due to the lack of blood flow to the infection site. Despite measures taken before, during, and after surgery to prevent bacterial growth in and around these orthopedic devices, periprosthetic joint infections (PJIs) remain frequent and represent a significant cost burden for both patients and healthcare professionals.

[0006] When treatments such as intravenous antibiotics are ineffective for PJI, patients undergo lengthy and expensive inpatient care. This treatment typically requires removal of the implant, debridement of the surrounding tissue and bone, and administration of large doses of antibiotics to the infected area, followed by a second implant surgery, known as a revision. Revision surgery is known to be associated with significant costs and increased patient morbidity and mortality.

[0007] International Patent Application Publication No. WO 2022 / 081737 discloses a method for preventing biofilm formation by introducing the composition into or around the surgical cavity prior to wound approximation after surgery. The publication does not state that the composition is used to treat existing, i.e., already formed, biofilms.

[0008] Removing microorganisms, particularly bacteria, especially biofilm-like bacteria, from surfaces is desirable for many reasons, including the treatment of infections during revision joint replacement surgery. Furthermore, biofilms are known to be important components in certain skin diseases, such as atopic dermatitis (eczema) and acne vulgaris. See, for example, M. Brandwein et al., “Microbial biofilms and the human skin microbiome,” NPJ Biofilms Microbiomes 2:3 (2016). Summary of the Invention [Problem to be solved by the invention]

[0009] Compositions that are compatible with human tissue and that can treat, reduce, remove, etc., bacteria, particularly in the form of biofilms, on inanimate surfaces, including previously implanted medical devices, and on skin, are highly desirable. In particular, compositions that do not need to be rinsed off from inanimate surfaces or surgical sites after contact with the skin or body, or before, during, or after contact with the skin or body. [Means for solving the problem]

[0010] Provided herein are methods for treating existing biofilms, regardless of where they are located, using aqueous compositions, preferably sterile aqueous compositions.

[0011] Typical compositions used have a calculated effective solute concentration of 0.3 to 1.4 Osm / L, especially 0.3 to 0.7 Osm / L. Such compositions are preferably acidic, e.g., having a pH of 3.7≦pH≦4.2.

[0012] The compositions of the present invention can be applied directly to human tissues and existing biofilms thereon, to the human body, in and around surgical cavities, and to medical devices implanted within the body. Advantageously, the compositions of the present invention do not need to be diluted or partially or completely removed after application or introduction.

[0013] In certain embodiments, the composition does not contain any substance other than the substance that makes up the composition that has active antibacterial properties, including, but not limited to, antibiotics. Alternatively, an active antibacterial substance or compound can be included in an embodiment of the composition.

[0014] PJI can be treated by applying a treatment composition to an already implanted medical device with a biofilm and, if necessary, to surrounding tissue. Application in this method is performed not only after the device is implanted, but also during its implantation or after approximation of the surgical wound cavity created for implantation. In a preferred embodiment, the treatment composition is not diluted and is not completely removed (aspirated) from the wound cavity before approximating the wound cavity to expose the already implanted medical device.

[0015] Also described are methods for treating conditions within or on the surface of human tissue, particularly of the skin, such as atopic dermatitis (eczema) and acne vulgaris, by administering a therapeutic composition by any technique that applies or introduces the composition to the dermal area where the condition is present (the "affected area"), including, but not limited to, spraying, using an applicator, bulb syringe, cotton ball, pad, etc. Also contemplated are methods for prophylactically treating these types of conditions by applying the composition to previously affected areas in a patient in need thereof and / or to areas of the body known to be susceptible to such conditions.

[0016] The composition can be applied to tissues containing a surgical wound cavity or to the area immediately surrounding such a wound cavity (e.g., skin), i.e., the area surrounding the wound cavity that may come into contact with the composition used in accordance with the method of WO 2022 / 081737. In particular, when introduced into a surgical wound cavity, the composition in this method contacts established biofilms rather than simply inhibiting biofilm formation by killing planktonic bacteria or nascent biofilms.

[0017] Other aspects of the present invention will be apparent to those skilled in the art from the following detailed description. To aid in understanding the description, the following definitions of certain terms are provided. These definitions shall apply throughout this specification unless a contrary intention is expressly indicated by surrounding language. "Comprising" means including, but not limited to, the listed components or steps. "Consisting of" means containing only the listed ingredients (or steps) and minor amounts of inert additives or adjuvants. "Room temperature" means 20°C to 25°C. By "body temperature" is meant the mean body temperature of mammals ±1.5°C, such as about 35°C to about 38°C for North American humans and about 37°C to about 40°C for dogs. "Treat" (or variations such as "treat"), in relation to biofilms present on inanimate surfaces such as implanted medical devices, means to reduce the bioburden on that surface, and in relation to biofilms on human tissue, means to mitigate, delay, attenuate, inhibit, arrest, eliminate, and reverse one or more of the symptoms resulting from the biofilm and its associated effects, characteristics, properties, and clinical signs. "Patient in need thereof" means a mammal having one or more conditions associated with biofilms, particularly on skin tissue, such as atopic dermatitis (eczema / atopic dermatitis) or acne vulgaris, and in the case of prophylactic treatment, a person who has suffered from and / or is susceptible to one or more such conditions. "In situ" means a place or location. "In situ treatment of an implanted medical device" means treating a previously implanted medical device at the location or position where it was implanted. As used herein, "skin" does not include surgical wound cavities and the skin area immediately surrounding such cavities, i.e., the area surrounding the wound cavity that may come into contact with the compositions used in accordance with the methods of WO2022 / 081737. The term "polyacid" refers to a compound having at least two carboxyl groups, and specifically includes dicarboxylic acids, tricarboxylic acids, and the like. "pH" is determined by an acceptable and reliable method of measurement, such as a properly calibrated pH meter or a titration curve against a known standard [H + ] means the negative value of the base 10 logarithm of "pKa" refers to the negative logarithm to the base 10 of the acid dissociation constant of a particular compound. A "buffer" refers to a compound or mixture of compounds that has the ability to maintain the pH of a solution to which it is added within a relatively narrow range. "Buffer precursor" means a compound that becomes a buffer when added to a mixture containing an acid. "Electrolyte" means a compound that exhibits some degree of dissociation when added to water. "Purified water" means tap water or well or spring water with bacterial counts and endotoxin levels equal to or lower than tap water, and can be pure or treated by softening, ion exchange, or other processes. "Pharmaceutical grade" means a compound that meets standards of chemical purity established by a national or regional pharmacopoeia. "Drug" means a substance that provides a therapeutic benefit to a subject. By "thickener" is meant a compound that reduces the rate at which a liquid spreads while still allowing some flow above room temperature. "Effective solute concentration" is a measure of colligative properties resulting from the number of moles of molecules (for non-electrolytes) or ions (for electrolytes) present in a given volume of solution, usually expressed in units of osmoles per liter. "Calculated effective solute concentration" means the effective solute concentration of a composition at room temperature and a given pH, determined assuming complete dissolution of the solute, and not through or by measurement of colligative properties. "Sterile," when used in reference to a liquid composition and / or a container for such a liquid, means treated to kill all living organisms contained therein. "Substituted" means including heteroatoms or functional groups (eg, hydrocarbyl groups) that do not interfere with the intended purpose of the group in question. "Approximation," when used in reference to surgery, refers to the process by which a surgical wound is closed. By "wound cavity" is meant an area of ​​the body that is normally covered by the dermis but that may come into contact with fluids introduced from the outside. "Microorganism" means any type of microorganism, including but not limited to bacteria, viruses, fungi, viroids, and prions. "Bioburden" means microorganisms and / or substances produced, excreted, or resulting from the presence of microorganisms. "Antimicrobial agent" means a substance that has the ability to reduce the number of one or more microorganisms by 90% (1 log) or more. By "active antimicrobial agent" is meant an antimicrobial agent that is effective only or primarily during the active period of the microbial life cycle (eg, cell division). "Dwell time" means the length of time that a composition is allowed to contact a surface and / or microorganisms on such a surface. "Health care" means engaging in or relating to the maintenance or restoration of physical or mental health.

[0018] Throughout this specification, unless the surrounding text expressly indicates a contrary intention, all values ​​expressed as percentages are w / v, i.e., grams of solute per liter of composition, and pH values ​​are those obtained by any of a variety of potentiometric methods using an appropriately calibrated electrode. The terms "invention," "this invention," and the like refer only to the particular embodiment immediately referred to and should not be construed as limiting the overall contribution to the technology described herein, nor should they be construed as limiting, either generally or specifically, with respect to particular advances in the technology described.

[0019] The relevant portions of any specifically referenced patents and / or published patent applications are incorporated herein by reference.

[0020] DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS The compositions used in the methods of the present invention will be described first with reference to their properties and components, followed by a description of specific applications. Multiple compositions are described, and unless the context dictates otherwise, the term "composition" or "composition" refers to all embodiments described herein.

[0021] The composition comprises a solvent and a solute component.

[0022] The solvent component is primarily water, typically purified water. Of the total amount of the solvent component, purified water accounts for at least 95%, often at least 97%, and typically at least 99% (all w / v). Per liter, the composition contains about 925 to about 975 mL, typically about 937 to about 972 mL, more typically about 950 to about 970 mL, typically 960±5 mL of purified water. A preferred solvent component is 100% purified water.

[0023] Although not preferred, the solvent component can contain small amounts of one or more organic liquids. Examples of potentially useful organic liquids are disclosed, for example, in U.S. Patent No. 10,021,876 and include those listed on the U.S. Food and Drug Administration (FDA) Inactive Ingredients List (https: / / www.fda.gov / media / 72482 / download, a link valid as of the filing date of this application). Non-limiting examples of these include ethanol and propylene glycol. When two or more organic liquids are included, it is preferred that each does not react with the other organic liquids. The organic liquids can account for 5% or less of the solvent component, preferably 3% or less, and most preferably 1% or less (all w / v).

[0024] Each subcomponent of the solute component is preferably provided in pharmaceutical grade form, especially when the composition is used to treat a mammalian, typically human, patient.

[0025] The composition is acidic, meaning that at least one subcomponent of the solute component is an acid. Preferred acids are those that have a relatively high pKa value, i.e., are not considered strong acids. Examples of potentially useful weak acids include monobasic acids such as formic acid, acetic acid and substituted versions (e.g., hydroxyacetic acid, chloroacetic acid, dichloroacetic acid, phenylacetic acid, etc.), propanoic acid and substituted versions (e.g., lactic acid, pyruvic acid, etc.), various benzoic acids (e.g., mandelic acid, chloromandelic acid, salicylic acid, etc.), glucuronic acid; dibasic acids such as oxalic acid and substituted versions (e.g., oxamic acid), butanedioic acid and substituted versions (e.g., malic acid, aspartic acid, tartaric acid, cytosine acid, etc.). Examples of suitable acids include hydroxycarboxylic acids, such as hydroxycarboxylic acids (e.g., hydroxycarboxylic acids), ...

[0026] Citric acid is the preferred acid because it is familiar and well tolerated in mammals, as it is utilized and recycled as part of the Krebs cycle. Solute components containing citric acid, especially those containing citric acid as the only acid, are preferred.

[0027] The amount of any acid used can be determined from the target pH of a given composition and the pKa value of the selected acid, taking into account the type and amount (if any) of compound utilized to achieve the desired effective solute concentration.

[0028] To prevent the pH of the composition from becoming too low and to increase the effective solute concentration, the solute component also includes at least one conjugate base of the aforementioned weak acid. Although not required, it is preferred to use the conjugate base of the particular acid used.

[0029] Upon dissociation, the conjugate base, e.g., salt, of one or more acids acts to increase the effective amount of solute in the composition while buffering the pH of the composition without significantly affecting the molar concentration of the hydronium ion. The type of countercation of the salt is not believed to be particularly important; common examples include ammonium ion and alkali metals, the latter being the preferred countercation.

[0030] When using the conjugate base of a polyacid, all or some of the H atoms of the carboxyl groups can be replaced with the same or different cationic atoms or groups. For example, monosodium, disodium, and trisodium citrates are all potentially useful buffer precursors when used in combination with citric acid or other organic acids. However, because trisodium citrate has three available basic sites, its theoretical buffering capacity is up to 50% higher than that of disodium citrate (which has two basic sites) and up to 200% higher than that of sodium citrate (which has only one basic site).

[0031] As with the acids discussed above, the amount of conjugate base can be determined based on the pH and effective solute concentration of the desired composition.

[0032] Many organic acids and their conjugate bases can be provided in anhydrous or hydrated forms. The particular form of these substances does not affect their usefulness or efficacy. The water of hydration in the solute simply becomes part of the solvent component.

[0033] The amounts of acid and conjugate base contained in the solute component are added in amounts that provide two important compositional properties, neither of which is dependent on the particular material providing them.

[0034] The first property is pH. The pH of the present compositions is between 3.7 and 4.2. Lowering the pH will most likely be more effective at degrading and sterilizing EPS / ECPS polymers. However, this increased effectiveness comes at the expense of reduced biocompatibility. Conversely, compositions with a pH above 4.2 are less effective but still highly biocompatible.

[0035] Within the acceptable pH range, a pH of 3.85 to 4.05 is preferred, with a pH of 3.95±0.1 and even more preferred ±0.05. Preferred pH values ​​include 3.7, 3.8, 3.9, 4, 4.1, and 4.2.

[0036] The second important compositional property is the effective solute concentration, which induces a sufficient osmotic pressure difference across the bacterial surface membrane to induce lysis. This ability to induce an osmotic pressure difference is independent of the specific properties or characteristics of the individual compounds (or their dissociation products) that make up the solute component, but is generally more effective for small molecules and ions than for larger molecules due to the ease of transport across the surface membrane and the solvent capacity (i.e., the ability to contain (typically) more small molecules than equimolar amounts of larger molecules in a given volume of solvent component).

[0037] The compositions have a calculated effective solute concentration of about 300 to about 1400 mOsm / L, with a preferred range of about 300 to about 1000 mOsm / L, and more preferably about 300 to about 700 mOsm / L. (Compositions with effective solute concentrations greater than about 1400 mOsm / L may be more effective in terms of bacterial lethality, albeit at the expense of reduced biocompatibility, particularly tissue inflammation.) Within the aforementioned general ranges, preferred ranges include about 325 to about 1325, about 350 to about 1275, about 375 to about 1200, about 400 to about 1150, about 450 to about 1100, about 325 to about 975, about 350 to about 900, and about 375 to about 800, about 400 to about 750, about 450 to about 700, about 325 to about 675, about 350 to about 650, about 375 to about 600, about 400 to about 590, about 450 to about 700, about 300 to about 590, about 350 to about 450, about 350 to about 500, about 350 to about 590, about 400 to about 580, about 450 to about 575, about 450 to about 680, about 460 to about 650, and about 470 to about 635 mOsm / L. The recommended overall range is 450 to 675 mOsm / L, and the recommended calculated effective solute concentration targets are 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, and 700 mOsm / L.

[0038] (The calculated effective solute concentration values ​​are the theoretical maximum if all solutes were completely dissociated. However, in the aforementioned concentration ranges, the likelihood of dissociated solutes reassociating is high, so these maximum values ​​are theoretical. Nevertheless, due to the ease of calculation and the availability of free online calculation tools, calculated effective solute concentrations are the preferred method for discussing and exploring this concept. For example, the calculated effective solute concentration value for 0.1 M NaCl is 200 mOsm / L (i.e., the theoretical maximum value for fully dissociated NaCl). + ions and Cl ? ions are 0.1 moles each).

[0039] Effective solute concentration is itself a colligative property and can be determined by any of a variety of colligative property measurement techniques, such as vapor pressure depression, boiling point elevation, freezing point depression, membrane osmometry, etc. (If a particular composition contains one or more organic liquids because of their impact on properties such as boiling point or freezing point, a test composition containing an equal volume of purified water in place of the organic liquids is used when performing one of the aforementioned techniques to determine effective solute concentration.)

[0040] Preferred ranges of effective solute concentration as measured by freezing point depression are about 250 to about 1300, about 275 to about 1250, about 300 to about 1200, about 325 to about 800, about 350 to about 725, about 250 to about 600, about 275 to about 575, about 300 to about 550, about 325 to about 500, about 350 to about 425, about 450 to about 600, about 300 to about 500, about 250 to about 450, about 350 to about 500, and about 450 to about 535 mOsm / L. The preferred measurement range is 350 to 550 mOsm / L.

[0041] Using citric acid and a citrate salt containing three alkali metal ions as examples of acid and conjugate base, the acceptable compositional properties described above can be achieved (or at least come close with minor modifications, as described below) by using 25 to 40 g / L of citric acid and 30 to 45 g / L of citrate. Using anhydrous citric acid and trisodium citrate dihydrate, a preferred embodiment (for intraperitoneal administration) can be provided with 30 to 35 g / L of acid and 34 to 38 g / L of citrate. Another preferred embodiment (for combined use) uses 33 to 38 g / L of acid and 37 to 42 g / L of citrate.

[0042] Importantly, the specific acids and citrates mentioned in the previous paragraphs need not be used: Those skilled in the art who wish to use acid hydrates, anhydrous citrates, or citrates with fewer than three alkali metal atoms (i.e., monosodium or disodium citrate) can readily calculate the amounts of each to provide a composition with acceptable values ​​for the aforementioned compositional properties.

[0043] The upper limit of effective solute concentration may be influenced by the body site for intended use. For example, some studies have shown that compositions with effective solute concentrations of approximately 600 mOsm / L are better tolerated than lower concentration solutions when used in and around joints such as the shoulder. However, other studies have shown that compositions with effective solute concentrations above approximately 600 mOsm / L can cause inflammation and swelling in the abdominal cavity in humans.

[0044] In a preferred embodiment, the solute component also includes one or more surfactants having a certain ionic charge. Of these, anionic surfactants and cationic surfactants are preferred over zwitterionic surfactants. The composition preferably does not contain incompatible surfactants, i.e., anionic surfactants and cationic surfactants, or zwitterionic surfactants and either anionic or cationic surfactants. Cationic surfactants are preferred in methods where no part of the composition remains in the body, such as in the treatment of removed devices, hardware, etc. For in vivo treatments, anionic surfactants are preferred, and cationic surfactants and / or zwitterionic surfactants are preferably excluded.

[0045] In general, surfactants with small molecules are preferred over those with large molecules. The size of the side chain attached to the polar group can affect the efficacy of ionic surfactants; the larger the size of the polar group and the greater the number of side chains, the lower the efficacy may be.

[0046] Potentially useful anionic surfactants include, but are not limited to, ammonium lauryl sulfate, sodium dioctyl sulfosuccinate, perfluorobutanesulfonic acid, perfluorononanoic acid, perfluorooctanesulfonic acid, perfluorooctanoic acid, potassium lauryl sulfate, sodium dodecylbenzenesulfonate, sodium laureth sulfate, sodium lauroyl sarcosinate, sodium myreth sulfate, sodium pareth sulfate, sodium stearate, sodium chenodeoxycholate, sodium N-lauroyl sarcosinate, lithium dodecyl sulfate, sodium 1-octanesulfonate, sodium cholate hydrate, sodium deoxycholate, sodium dodecyl sulfate (SDS, also known as sodium lauryl sulfate (SLS)), sodium glycodeoxycholate, and the alkyl phosphate esters described in U.S. Patent No. 6,610,314. (Most of the aforementioned representative anionic surfactants use sodium as the counter cation, but other alkali metal ions can be used instead.) SDS is a particularly preferred option.

[0047] Potentially useful cationic surfactants include, but are not limited to, cetylpyridinium chloride (CPC), cetyltrimethylammonium chloride, benzethonium chloride, 5-bromo-5-nitro-1,3-dioxane, dimethyldioctadecylammonium chloride, cetrimonium bromide, dioctadecyldimethylammonium bromide, tetradecyltrimethylammonium bromide, benzalkonium chloride (BZK), hexadecylpyridinium chloride monohydrate, and hexadecyltrimethylammonium bromide.

[0048] Potentially useful zwitterionic surfactants include sulfonates (e.g., 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate), sultaines (e.g., cocamidopropyl hydroxysultaine), betaines (e.g., cocamidopropyl betaine), and phosphates (e.g., lecithin).

[0049] Although not preferred as the sole surfactant, nonionic surfactants can also be used in combination with any of the other types of surfactants.

[0050] For other potentially useful surface-active materials, the interested reader is referred to a variety of other sources including, for example, U.S. Patent Nos. 4,107,328, 6,953,772, 7,959,943, and 8,940,792.

[0051] The amount of surfactant included is limited in part by the target effective solute concentration and compatibility with other subcomponents of the solute component. The total amount of surfactant present in the composition ranges from about 0.07 to about 0.19% (w / v), typically from about 0.075 to about 0.15% (w / v), and preferably 1±0.25 g / L or 0.95±0.2 g / L.

[0052] If the acid, conjugate base, and surfactant do not provide the desired effective solute concentration, one or more electrolytes, particularly ionic compounds (salts), can be added. See, for example, U.S. Patent No. 7,090,882 for a list of potentially useful electrolytes.

[0053] The solute component is preferably, but not necessarily, permissible to, one or more inert ingredients (excipients) approved by the US Food and Drug Administration (see above).

[0054] A typical method for preparing the composition involves adding the solute subcomponents, either separately or as a mixture, to the solvent component (or to the water subcomponent of the solvent component, followed by the organic liquid), which can be accomplished with either or both of agitation and heating of the mixing vessel.

[0055] If achieving a target pH range is deemed important, after the solute component has been added to the solvent component, very small aliquots of concentrated acid (e.g., 1 M HCl) or concentrated base (e.g., 1 M KOH) can be used to lower or raise the pH of the composition to the target range.

[0056] The following table lists ingredients, amounts in grams, to provide an exemplary composition according to the present invention.

[0057] [Table 1]

[0058] The various embodiments of the present invention are provided by way of example, not limitation. As is apparent from the foregoing table, it is contemplated that the generally preferred features, ranges, numerical limits, and embodiments may be combined with other generally preferred features, ranges, numerical limits, and embodiments to the extent feasible and as long as they do not interfere with or contradict each other.

[0059] The compositions can be packaged in a sterile condition, i.e., the container can be sufficiently heated, irradiated, etc. to render the composition sterile (aseptic). Typical containers include bags or bottles of the type used in operating rooms to administer fluids such as saline.

[0060] When treating human tissue, particularly conditions associated with biofilms on human skin, such as atopic dermatitis (eczema) and acne vulgaris, it may be advantageous to include in the composition an agent or other component that aids in such treatment, i.e., an agent or other component that can provide benefit by, for example, disrupting, removing, etc., biofilms with solvent and solute components.

[0061] Non-limiting categories of drugs that can be added to the compositions include steroids, such as hydrocortisone, clobetasol propionate, betamethasone dipropionate, halobetasol propionate, diflorasone diacetate, fluocinonide, halcinonide, amcinonide, desoximetasone, triamcinolone acetonide, mometasone furoate, fluticasone propionate, halometasone, fluocinolone acetonide, betamethasone dipropionate, hydrocortisone valerate, hydrocortisone butyrate, flurandrenolide ... methasone furoate, fluticasone propionate, desonide, fluocinolone acetonide, hydrocortisone valerate, alclometasone dipropionate, triamcinolone acetonide, fluocinolone acetonide, and desonide; antibiotics such as amikacin, amoxicillin, ampicillin, arsphenamine, azithromycin, azlocillin, aztreonam, bacitracin, capreomycin, cefaclor, cefadroxil, cephalexin, cefamandole, cefazolin, cefdinir, cefditoren, cefepime, cefiromycin, Cefoxitin, cefmetazole, cefonicid, cefoperazone, cefotaxime, cefotetan, cefoxitin, cefpodoxime, cefprozil, ceftaroline, ceftazidime, ceftibuten, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cephalosporin, cephalothin, cephapirin, cephradine, chloramphenicol, ciprofloxacin, clarithromycin, clondamycin, clofazimine, colistin, cycloserine, dalbavancin, dapsone, daptomycin, dicloxacillin, doripenem, doxycycline Cyclin, enoxacin, ertapenem, erythromycin, ethambutol, ethionamide, fidaxomicin, flucloxacillin, fosfomycin, furazolidone, fusidic acid, gatifloxacin, geldanamycin, gemifloxacin, gentamicin, grepafloxacin, halicin, herbimycin, imipenem / cilastatin, isoniazid, kanamycin, levofloxacin, lincomycin, linezolid, lomefloxacin, loracarbef, mafenide, malacidine, meropenem, methacycline, methicillin, metronidazole,Mezlocillin, minocycline, moxalactam, moxifloxacin, mupirocin, nadifloxacin, nafcillin, nalidixic acid, neomycin, netilmicin, nitrofurantoin, norfloxacin, ofloxacin, omadacycline, oritavancin, oxacillin, oxazolidinone, oxytetracycline, paromomycin, penicillin G, penicillin V, piperacillin, piperacillin / tazobactam, platensimycin, polymyxin B, polypeptide, pocizolid, pyrazinamide, quinupristin / dalfopristin, radezolid Ridromycin, rifabutin, rifampicin, rifapentine, rifaximin, roxithromycin, serotonin syndrome, silver sulfadiazine, sparfloxacin, spectinomycin, spiramycin, streptomycin, sulfacetamide, sulfadiazine, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole, sulfonamide chrysoidine, tedizolid, teicoplanin, teixobactin, telavancin, telithromycin, temafloxacin, temocillin, Tetracycline, thiamphenicol, thrombusitopenia, ticarcillin, ticarcillin / clavulanic acid, tigecycline, tinidazole, tobramycin, torezolid, trimethoprim, trimethoprim / sulfamethoxazole, trovafloxacin, and vancomycin; anticoagulants, such as heparin, apixaban, dabigatran, edoxaban, enoxaparin, rivaroxaban, warfarin; procoagulants, such as aprotinin, epsilon aminocaproic acid, aminomethylbenzoic acid, tranexamic acid; antifungals, such as amphotericin, benzocaine, benzophenone, benzocaine ... Tericin 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, amorolfine, butenafine, naftifine, terbinafine, anidulafungin, caspofungin, micafungin, aurone, benzoic acid, ciclopirox, flucytosine or 5-fluorocytosine, griseofulvin, haloprogin, tolnaftate, undecylenic acid, triacetin, crystal violet, orotomide, miltefosine, potassium iodide, nikkomycin, copper(II) sulfate, selenium disulfide, thiosulfate sodium, piroctone olamine, iodoquinol (diiodohydroxyquin), acrisorcin, zinc pyrithione, and sulfur; anesthetics such as lidocaine, benzocaine, butamben, dibucaine, oxybuprocaine, pramoxine, proxymetacaine, and tetracaine; analgesics such as 2-(4-(2-methylpropyl)phenyl)propanoic acid (ibuprofen), capsaicin, diclofenac, lidocaine, methyl salicylate, and trolamine.

[0062] Such drugs are preferably administered in purified water. Some of the aforementioned drug classes, or even certain species within particular classes, have low solubility in water and may therefore require or be desirable to administer in an organic liquid (or a solution containing an organic liquid). In such cases, the considerations regarding the type and amount of organic liquid mentioned above should be taken into account.

[0063] When adding one or more such agents to the composition container, the solubility limits of the agent at the temperature of the composition must be taken into consideration.

[0064] Before dispensing the contents of the container, the container and contents can be warmed. Such warming helps ensure that all solute components are completely dissolved, while also providing the secondary benefit of bringing the temperature of the composition closer to the patient's body temperature. With this latter consideration in mind, it is preferred that the temperature of the composition be within 5°C of the body temperature of certain types of mammalian patients. (In extremely hot climates, cooling rather than heating may be necessary to bring the composition's temperature into the desired range.)

[0065] If the agent is introduced into the container before the contents of the container are emptied, the temperature adjustment can be carried out either before or after the agent is introduced into the composition.

[0066] When the composition is applied to and / or around an already implanted medical device, for example, to treat an implanted medical device having a biofilm (e.g., as seen in patients exhibiting signs of PJI), application occurs after the initial implantation of the medical device or approximation of the original surgical wound cavity formed at the time of implantation. There is no time period after the initial implantation of the medical device or approximation of the surgical wound cavity formed for implantation before the composition becomes unusable.

[0067] After reopening the patient and exposing the implanted device to allow the composition to contact the implanted hardware in situ, the composition can be introduced by any method, including all of the methods described in WO 2022 / 081737. Transfer of the composition from within the container to the patient's surgical wound cavity can be accomplished in a variety of ways.

[0068] One option is to transfer the contents of the container into a sterile container using a spiked tube. The contents of the container typically drain by gravity alone. After transfer, a healthcare professional (e.g., a surgeon) can pour the composition from the container onto and into the wound cavity.

[0069] A variation of the foregoing is that the medical practitioner may use a bulb syringe (or similar) to better direct the flow of the composition into and around the wound cavity.

[0070] If the container is a bottle (usually housed in a thermoformed polymer tray with a removable polymer lid), the contents can be dispensed in the same manner as described above. If the bottle is sealed, the seal is removed and a cap with a nozzle is attached. (If the bottle has an integrated nozzle, this step can be omitted.) The nozzle allows the healthcare professional to direct the flow of the composition into and around the wound cavity, similar to a bulb syringe.

[0071] Another option is to use a device capable of delivering the composition under pressure, such as a pulsed or jet-type irrigation delivery system, such as the Interpulse® Pulsed Lavage System (Stryker, Kalamazoo, Michigan) or the Pulsavac® Plus Irrigation System (Zimmer Biomet, Warsaw, Indiana). Similar to the gravity-feed option described above, the composition can be accessed using a spiked tube, the other end of which is connected to a delivery device to deliver the composition. The medical professional uses the wand or gun portion of the delivery device to direct the flow of the composition to irrigate the surgical wound cavity.

[0072] Regardless of the method of introduction, the amount of composition delivered into the surgical wound cavity can vary from just a few milliliters for small surgical sites to up to 0.5, 1, 1.5, or 2 liters (optionally delivered in multiple aliquots).

[0073] The residence time can vary over a wide range, from a few seconds to several hours. Exemplary residence times are 30 seconds, 60 seconds, 120 seconds, 180 seconds, 240 seconds, 300 seconds, 360 seconds, 420 seconds, 480 seconds, 540 seconds, 600 seconds, 900 seconds, 1200 seconds, 1500 seconds, 1800 seconds, 3600 seconds, 4800 seconds, etc. The residence time can be adjusted as needed, for example, if the surface to be treated is inanimate, by measuring colony forming units (CFUs) during application of the composition to the surface.

[0074] There is no limit to the amount of composition used in the described methods. For example, a given surface may be covered / coated / contacted entirely or partially with the composition, followed by a predetermined dwell time. In other embodiments, the composition may be continuously or intermittently reapplied to the surface to provide fresh composition to the treated surface. After application of the composition, the treated surface may be left exposed to air, or may be covered with a cover or other material that inhibits evaporation of the composition, as needed. If desired, the treated surface may be scraped, abraded, or scrubbed during the dwell time to promote, enhance, and / or accelerate bioburden reduction.

[0075] In all examples herein, regardless of whether the composition is applied to a surface, applied to a biofilm on a surface, or whether the application is described as a biofilm on a surface contacting the composition, typically both the surface and the biofilm are in intimate physical contact with the composition, since surface coating by a biofilm is not complete.

[0076] Regardless of when and how it is used, in preferred embodiments, the composition does not require rinsing or aspirating and can remain partially or completely at the site of the medical device, whether or not the treatment includes a surgical procedure.

[0077] In processes for in situ treatment of biofilms on and / or around already implanted medical devices, at least a portion of the introduced composition typically remains after approximation of the surgical wound, similar to that described in the aforementioned WO 2022 / 081737, but here remains after treatment of the existing biofilm. The amount of remaining composition can range from the amount needed to coat the exposed (internal) tissue (0.5 to 10 mL) to a significant fraction of the volume of the composition introduced during treatment. The fact that some of the composition remains means that it can act to reduce bioburden after biofilm disruption, during the approximation process, and until such portion is bioabsorbed.

[0078] If a substantial amount of composition (e.g., about 100 mL or more) is introduced into a surgical wound cavity during a therapeutic procedure, partial removal by suction may be preferred. If a substantial amount of composition (e.g., about 250 mL or more) is introduced during a procedure, partial removal by suction is also preferred. (Some composition may be expelled by normal flow during or after introduction.)

[0079] Where treatment and composition introduction involves surgical incision and traction, the use of pressure delivery (e.g., pulsatile lavage) systems is common, and many of these devices incorporate suction, i.e., the same device that introduces the composition is also designed to remove the composition by suction.

[0080] The amount of composition remaining in the surgical wound cavity during and after wound approximation typically ranges from a few milliliters to about 250 ml, depending largely on whether partial removal by suction is employed.

[0081] Importantly, saline rinses before and / or after removal by suction are not necessary; i.e., the composition is sufficiently gentle and biocompatible that its continued presence does not result in significant adverse effects.

[0082] Wound closure involves approximation of the wound edges using standard techniques such as sutures, staples, adhesives, etc. Approximation can be complete or partial, such as by inserting wound drains.

[0083] After treatment, the area where the composition was applied and the surrounding area can be rinsed with an antiseptic solution and / or covered with a sterile protective layer (optionally using an antibacterial gel or cream such as SURGX® Sterilizing Gel (Next Science, Jacksonville, Fla.)).

[0084] In preferred embodiments, the composition is not partially or totally diluted or removed from the area surrounding and adjacent to the medical device, allowing treatment of the biofilm thereon after treatment has ceased.

[0085] The types of implantable medical devices that can be treated with the compositions according to the methods disclosed herein are not limited and include screws, pins, wires, rods, plates, or prosthetic joint components.

[0086] As discussed above, the compositions described herein effectively reduce bioburden wherever an existing biofilm is present. Alternatively, or in addition, when the integrity of the protective EPS / ECPS is compromised by exposure to the composition, some or all of the biofilm can be dissolved, washed away, or otherwise removed.

[0087] Analysis of the change in bacterial CFU before and after treatment with the composition can quantify the change in viable count (if bacteria are killed by exposure to the composition) and / or reflect the reduction in bacteria (whether killed or not) due to a reduction in biofilm size. When quantified by change in CFU, the reduction in bioburden is preferably at least 90% (1 log), more preferably at least 99% (2 logs), even more preferably at least 99.9% (3 logs), and even more preferably at least 99.99% (4 logs).

[0088] The following embodiments are specifically contemplated: Embodiments relating to methods of use employing a composition shall be construed as also relating to the composition used in that method.

[0089] Embodiment [1] relates to a method of treating a wound cavity in a mammalian subject, the method comprising: a) preparing a sterile liquid composition having an effective solute concentration of 0.3 to 0.7 Osm / L and a pH of 3.7 to 4.2, wherein the composition consists of a solvent and a solute component; b) introducing the composition into the wound cavity prior to approximating the wound; and c) allowing at least a portion of said composition to reduce bioburden within the wound cavity during and after wound approximation.

[0090] Embodiment [2] relates to the method of embodiment [1], wherein the solvent component is purified water.

[0091] Embodiment [3] relates to the method of any of the previous embodiments, wherein the solute component comprises 0.7 to 1.9 g / L of an ionic surfactant.

[0092] Embodiment [4] relates to the method of any of the preceding embodiments, wherein the preparing step comprises delivering the composition in a container comprising at least one access point.

[0093] Embodiment [5] relates to the method of any of the preceding embodiments, wherein the solute component comprises a buffer system and an ionic surfactant.

[0094] Embodiment [6] relates to a process for treating a wound cavity in a mammalian subject, the process comprising: a) providing a container with at least one access point holding a sterile liquid composition having an effective solute concentration of 0.3 to 0.7 Osm / L and a pH of 3.7 to 4.2, the composition comprising: 1) a solvent component consisting of purified water; 2) A buffer system and a solute component containing 0.7 to 1.9 g / L of an ionic surfactant; b) introducing the composition into the wound cavity prior to approximating the wound; and c) allowing at least a portion of said composition to reduce bioburden within the wound cavity during and after approximation of the wound.

[0095] Embodiment [7] relates to the method of any of embodiments [4] to [6], wherein the container comprises multiple access points, and further comprising adding at least one agent to the composition prior to the introducing step.

[0096] Embodiment [8] relates to the method of any of embodiments [5] to [7], wherein the buffer system comprises a dissociation product of a carboxylic acid and a conjugate base of the carboxylic acid.

[0097] Embodiment [9] relates to the method of embodiment [8], wherein the buffer system comprises a dissociation product of at least one carboxylic acid and at least one conjugate base of the at least one carboxylic acid.

[0098] Embodiment

[10] relates to the method of any of embodiments [8] to [9], wherein the carboxylic acid is citric acid and the conjugate base is citrate.

[0099] Embodiment

[11] relates to the method of any of the preceding embodiments, wherein the composition has an effective solute concentration of 450 to 680 mOsm / L.

[0100] Embodiment

[12] relates to the method of any of the preceding embodiments, wherein the pH of the composition is 3.85 to 4.05.

[0101] Embodiment

[13] relates to the method of any one of embodiments [5] to

[12] , wherein the ionic surfactant is an anionic surfactant.

[0102] Embodiment

[14] relates to the method of any of the preceding embodiments, wherein the composition has an effective solute concentration of 350 to 590 mOsm / L.

[0103] Embodiment

[15] relates to a method of treating a surgical site in a mammalian subject, the method comprising the steps of: a) providing a container with at least one access point holding a sterile liquid composition having an effective solute concentration of 450 to 675 mOsm / L and a pH of 3.85 to 4.05, wherein the composition comprises: 1) a solvent component consisting of purified water, and 2) a solute component consisting of: (A) a buffer system comprising citric acid and at least one citrate dissociation product; (B) 0.75 to 1.25 g / L of an anionic surfactant, and (C) optionally, one or more adjuvants selected from dyes, preservatives, and thickeners; b) optionally adding at least one agent to the composition if the container includes multiple access points; c) introducing the composition into the opening at the surgical site prior to approximating the opening; and d) allowing at least a portion of the composition to reduce the bioburden of the surgical site during and after approximation.

[0104] Embodiment

[16] relates to the method of embodiment

[15] , wherein the at least one citrate salt comprises trisodium citrate.

[0105] Embodiment

[17] relates to the method of any of the preceding embodiments, wherein the pH of the composition is 3.95±0.05.

[0106] Embodiment

[18] relates to the method of any of the preceding embodiments, wherein the composition is not diluted prior to approximation of the wound.

[0107] Embodiment

[19] relates to the method of any of the preceding embodiments, wherein a portion of the composition is removed or diluted prior to approximation of the wound.

[0108] Embodiment

[20] relates to the method of any of embodiments [6] and [8] through

[19] , wherein the buffer system comprises 25 to 40 g / L citric acid and 30 to 45 g / L of the dissociation product of a citrate salt containing three alkali metal ions.

[0109] Embodiment

[21] relates to the method of embodiment

[20] , wherein the buffer system comprises 30 to 38 g / L of citric acid and 34 to 42 g / L of the dissociation product of trisodium citrate.

[0110] Embodiment

[22] relates to the method of any of the preceding embodiments, wherein all solutes in the solute component are pharmaceutical grade.

[0111]

[0033] Embodiment

[23] relates to the method of any of the preceding embodiments, further comprising, prior to the introducing step, providing the container at a temperature within 5°C of the body temperature of the mammalian subject, or adjusting the temperature of the composition to within 5°C of the body temperature of the mammalian subject.

[0112]

[0033] Embodiment

[24] relates to the method of any of the preceding embodiments, wherein the composition is introduced by an emergency medical services provider and at least a portion of the bioburden reduction occurs before or during transport of the mammalian subject.

[0113]

[0023] Embodiment

[25] relates to the method of any of the preceding embodiments, wherein the composition is introduced during surgery in an operating room, and bioburden reduction occurs before, during, and after wound approximation.

[0114] Embodiment

[26] relates to the method of any of embodiments

[13] to

[25] , wherein the anionic surfactant is sodium lauryl sulfate.

[0115] Embodiment

[27] relates to the method of any of the preceding embodiments, wherein the composition has an effective solute concentration of 525±50 mOsm / L.

[0116] Embodiment

[28] relates to the method of embodiment

[27] , wherein the effective solute concentration is 525±25 mOsm / L.

[0117] Each aspect, embodiment, feature, etc. of the invention described herein, whether preferred or not, can be used or combined with one or more other aspects, embodiments, features, etc. of the invention described herein.

[0118] When an amount, concentration, or other value or parameter is given as a range or list of values, this is understood to include the endpoints, specifically disclosing all ranges formed from any combination of any upper and lower values, and specifically disclosing all integers and fractions within the range. This applies whether or not the range, all integers, and fractions are individually disclosed. For example, when an amount, concentration, or other value or parameter is given as a range of 3 to 10, or as a list of values ​​of 3, 6, 7, 9, and 10, both specifically disclose and include ranges of 5 to 7 and 6 to 9, as well as the value 4.7.

Claims

1. A method for the in situ treatment of an implantable medical device having a biofilm on its surface or a method for treating human skin having a biofilm, comprising contacting the biofilm with a liquid composition comprising a solvent and a solute component, the liquid composition having a calculated effective solute concentration of 0.3 to 1.4 Osm / L and a pH of 3.7 to 4.2, for a time sufficient to reduce the bioburden on the surface or skin resulting from the biofilm.

2. 10. The method of claim 1, wherein the composition has a calculated effective solute concentration of 350 to 590 mOsm / L.

3. 4. The method of claim 3, wherein the composition has a calculated effective solute concentration of 525±50 mOsm / L.

4. 10. The method of claim 1, wherein the composition has a calculated effective solute concentration of 450 to 680 mOsm / L.

5. 10. The method of claim 1, wherein the pH of the composition is from 3.85 to 4.

05.

6. 6. The method of claim 5, wherein the pH is 3.95±0.

05.

7. 7. The method of any one of claims 1 to 6, wherein the solvent component comprises purified water.

8. 7. The method of any one of claims 1 to 6, wherein the solute component comprises or consists of a buffer system and an ionic surfactant.

9. 9. The method of claim 8, wherein the buffer system comprises at least one carboxylic acid and a dissociation product of at least one conjugate base of the at least one carboxylic acid.

10. 10. The method of claim 9, wherein the buffer system comprises 25 to 40 g / L of citric acid and 30 to 45 g / L of a dissociation product of citrate salt containing three alkali metal ions.

11. 9. The method of claim 8, wherein the composition comprises 0.7 to 1.9 g / L of an ionic surfactant.

12. 12. The method of claim 11, wherein the ionic surfactant is an anionic surfactant, optionally sodium lauryl sulfate.

13. 7. The method according to any one of claims 1 to 6, wherein the liquid composition is sterile.

14. 7. The method of claim 1, wherein the solute component comprises a buffer system comprising citric acid and at least one dissociation product of citrate.

15. 15. The method of claim 14, wherein the buffer system comprises 30 to 38 g / L of citric acid and 34 to 42 g / L of the dissociation product of trisodium citrate.

16. 16. The method of claim 15, wherein the pH is 3.95±0.

1.

17. 15. The method of claim 14, wherein the solute component further comprises 0.75 to 1.25 g / L of an anionic surfactant, optionally sodium lauryl sulfate.

18. 7. The method according to any one of claims 1 to 6, wherein the liquid composition remaining in the body after treatment is not completely removed.

19. 7. The method of claim 1, wherein an implanted medical device having a biofilm is the subject of in-situ treatment, and the solute component of the composition comprises an anionic surfactant.

20. 7. The method of any one of claims 1 to 6, wherein the composition is applied to the skin of a patient suffering from atopic dermatitis or acne vulgaris.

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