Methods and compositions for removing contaminants from a PD catheter

Abstract

A method of performing peritoneal dialysis (PD), comprising delivering PD fluid through a PD catheter into a patient's peritoneal cavity; leaving the PD fluid in the peritoneal cavity; and removing biofilm from the PD catheter wall using a biofilm removal solution while leaving the PD fluid in place. The biofilm removal solution comprises sodium citrate dihydrate; citric anhydride; sodium lauryl sulfate; and water. In another aspect, a method for removing contamination and removing biofilm from a peritoneal dialysis (PD) catheter and transfer set, comprising providing a biofilm removal solution; transferring the biofilm removal solution into a syringe; connecting the syringe to the transfer set of the PD catheter; and filling the transfer set and the PD catheter with the biofilm removal solution.

Description

Background Art

[0001] Background The present disclosure generally relates to peritoneal dialysis (PD) procedures, and more specifically to indwelling PD catheters for patients. PD is a renal replacement therapy used to treat patients presenting with reduced kidney function. PD is typically performed at home by the patient under aseptic conditions. The PD procedure involves filling the patient's peritoneal cavity with PD fluid via a permanent peritoneal catheter. The PD fluid is left in the patient's body for a period of time and then removed from the patient's peritoneal cavity, removing waste products, toxins, and excess water from the patient. The patient's peritoneal cavity can typically hold from 1.5 L to 3 L of PD fluid. The length of time the PD fluid remains in the patient's peritoneal cavity is referred to as the dwell time and can be several hours or longer depending on the type of PD fluid. The patient's peritoneum covers the inside of the highly vascular abdominal organs and thus acts as a semi-permeable membrane across which diffusion (removal of toxins) and ultrafiltration (removal of excess water) occur. Waste products, toxins, and excess water are removed from the blood by passing through the peritoneum via diffusion and ultrafiltration.

[0002] For patients considering PD, several treatment options are available: automated peritoneal dialysis (APD) and continuous ambulatory peritoneal dialysis (CAPD). CAPD involves the patient or caregiver manually performing PD fluid exchanges, for example, three times a day (each lasting 4 to 6 hours), and perhaps once at night (lasting 8 to 10 hours). An APD system provides an automated cycler that performs PD fluid exchanges as either continuous cycling PD, tidal PD, or nocturnal intermittent PD. APD treatments are typically performed at night while the patient is sleeping, and the cycler performs multiple fill, dwell, and drain cycles over an 8- to 10-hour treatment.

[0003] For both CAPD and APD, the patient has a permanent PD catheter attached, which is semi - permanent and remains in the patient over multiple treatments. Before either CAPD or APD treatment, the patient aseptically connects the patient line of the treatment set to the exposed end of the permanent PD catheter. A transfer set is typically provided, which helps to assist in making a sterile connection existing between the PD catheter and the patient line. The permanent PD catheter may have a biofilm formed on its inner surface, which is difficult to remove and can create a reservoir for infectious microorganisms that cause recurrent peritonitis, potentially necessitating catheter removal. There is a need in the art for a method to prevent biofilms so that the antibiotics used in standard peritonitis treatments can more effectively kill bacteria within the catheter and prevent recurrent peritonitis. Summary of the Invention Means for Solving the Problems

[0004] Abstract Current methods for killing bacteria formed on a patient's permanent PD catheter include intraperitoneal administration of antibiotics through the catheter. In some clinics, the catheter is locked using either an antibiotic solution, heparin, or tissue plasminogen activator (TPA) solution. Heparin and TPA are each used to prevent and degrade the formation of fibrin that may be trapped within the catheter. Antibiotic catheter lock solutions are also commonly used in central venous line catheters for infection prevention. However, heparin and TPA target fibrin and not biofilms. Antibiotic lock solutions kill bacteria but cannot penetrate mature biofilms that shield the bacteria from the antibiotics and cannot assist in the physical removal or disruption of biofilms.

[0005] Methods and compositions for decontaminating a peritoneal dialysis (PD) catheter by removing biofilm from the inner wall and / or outer wall (the part present in the patient's body) of the PD catheter are disclosed herein. By disrupting the biofilm, the methods and compositions enable the administration of antibiotics intraperitoneally to reach bacteria. By disrupting and treating the biofilm, antibiotics used during or after standard peritonitis treatment can more effectively kill bacteria within the PD catheter and prevent recurrent peritonitis. One embodiment of the present disclosure provides a pre-filled syringe or similar device for delivering the biofilm removal solution of the present disclosure inside the PD catheter lumen. Thereafter, the biofilm removal solution is left in place, and at the same time, the peritoneal antibiotic is also left in place, and then drained with PD waste fluid. One embodiment of the method includes filling the patient with PD fluid in which antibiotics have been dosed, locking the catheter containing the biofilm solution, leaving the PD fluid, the biofilm solution, and the antibiotic in the patient's peritoneal cavity, then draining from the patient, and flushing each fluid containing biofilm microorganisms through the PD catheter.

[0006] In view of the disclosure shown herein, and not limiting the present disclosure in any way, in a first aspect of the present disclosure, which may be combined with any other embodiment or aspect or part thereof, a method of performing peritoneal dialysis (PD) includes delivering PD fluid through a PD catheter into the peritoneal cavity of a patient; leaving the PD fluid in the peritoneal cavity; and removing biofilm from the PD catheter wall using a biofilm removal solution while leaving the PD fluid in place.

[0007] In one embodiment, which may be combined with any other embodiment or aspect or part thereof, the biofilm removal solution includes sodium citrate dihydrate; citric anhydride; an alkyl sulfonate, such as metallauryl sulfate; and water.

[0008] In one embodiment, this may be combined with any other embodiment or aspect or a part thereof. The biofilm removal solution contains sodium citrate dihydrate in a concentration range of about 32.13 g / L to about 39.27 g / L; citric anhydride in a concentration range of about 29.25 g / L to about 35.75 g / L; an alkyl sulfonate, such as a metal lauryl sulfate, in a concentration range of about 0.95 g / L to about 1.05 g / L; and water.

[0009] In one embodiment, this may be combined with any other embodiment or aspect or a part thereof. The biofilm removal solution further contains a pH value in the range of about 3.70 to about 4.10; total citrate in a concentration range of about 57.45 g / L to about 70.21 g / L; and a specific gravity in the range of about 1.025 to about 1.042.

[0010] In one embodiment, this may be combined with any other embodiment or aspect or a part thereof. The biofilm removal solution further contains an alkyl sulfonate in a concentration range of about 0.61 g / L to about 1.10 g / L.

[0011] In one embodiment, this may be combined with any other embodiment or aspect or a part thereof. The biofilm removal solution further contains an antimicrobial component.

[0012] In one embodiment, this may be combined with any other embodiment or aspect or a part thereof. The antimicrobial component is selected from the group consisting of antibiotics, silver sulfadiazine, bleaching agents, such as sodium hypochlorite and / or bleaching agents containing hydrogen peroxide.

[0013] In one embodiment, this may be combined with any other embodiment or aspect or a part thereof. The PD solution further contains an antibiotic for treating bacteria exposed by the removed biofilm.

[0014] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The step of removing biofilm from the PD catheter wall using a biofilm removal solution includes transferring the biofilm removal solution into a syringe; establishing liquid communication between the syringe and a transfer set disposed along the PD catheter; and filling the transfer set and the PD catheter with the biofilm removal solution.

[0015] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The step of removing biofilm from the PD catheter wall using a biofilm removal solution further includes closing the transfer set valve and maintaining the biofilm removal solution in the transfer set and the PD catheter for a first duration.

[0016] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The first duration is between about 1 hour and about 12 hours.

[0017] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The first duration is between about 1 hour and about 1.8 hours.

[0018] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The first duration is about 1.5 hours.

[0019] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The step of removing biofilm from the PD catheter wall using a biofilm removal solution further includes removing the biofilm removal solution, the PD solution, and the biofilm.

[0020] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The steps of removing the biofilm removal solution, the PD solution, and the biofilm include replacing a syringe with a suitable fluid connection with a waste bag or other drain; opening a transfer set valve and draining the biofilm removal solution and the PD solution into the waste bag or other drain via gravity or a pump, wherein the biofilm removal solution and the PD solution contain the biofilm removed from the transfer set and the PD catheter.

[0021] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The biofilm is removed from the inner walls of the transfer set and the PD catheter and the outer wall of a portion of the PD catheter located within the peritoneal cavity of the patient.

[0022] In a second aspect of the present disclosure, this may be in combination with any other embodiment or aspect or a portion thereof. A method for removing contaminants from a peritoneal dialysis (PD) catheter and removing biofilm from the PD catheter and the transfer set includes providing a biofilm removal solution; transferring the biofilm removal solution into a syringe; establishing liquid communication from the syringe to a transfer set disposed along the PD catheter; and filling the transfer set and the PD catheter with the biofilm removal solution.

[0023] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The method further includes closing a transfer set valve and maintaining the biofilm removal solution in the transfer set and the PD catheter for a first duration.

[0024] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The first period is between about 1 hour and about 12 hours.

[0025] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof, and the first period is between about 1 hour and about 1.8 hours.

[0026] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof, and the first period is about 1.5 hours.

[0027] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof, and the method further includes a biofilm removal solution, a PD solution, and removing the biofilm.

[0028] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof, and the steps of removing the biofilm removal solution, the PD solution, and the biofilm include replacing a syringe with a suitable fluid connection with a waste fluid bag or other drain; opening a transfer set valve and draining the biofilm removal solution and the PD solution into the waste fluid bag via gravity or a pump, wherein the biofilm removal solution and the PD solution contain the biofilm removed from the transfer set and the PD catheter.

[0029] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof, and the biofilm is removed from the inner walls of the transfer set and the PD catheter and the outer wall of a portion of the PD catheter located within the peritoneal cavity of the patient.

[0030] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof, and the biofilm removal solution includes sodium citrate dihydrate; citric anhydride; an alkyl sulfonate, such as a metal lauryl sulfate (e.g., sodium lauryl sulfate); and water.

[0031] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The biofilm removal solution includes sodium citrate dihydrate in a concentration range of about 32.13 g / L to about 39.27 g / L; citric anhydride in a concentration range of about 29.25 g / L to about 35.75 g / L; an alkyl sulfonate, such as a metal lauryl sulfate (e.g., sodium lauryl sulfate), in a concentration range of about 0.95 g / L to about 1.05 g / L; and water.

[0032] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The biofilm removal solution further includes a pH value in the range of about 3.70 to about 4.10; total citrate in a concentration range of about 57.45 g / L to about 70.21 g / L; and a specific gravity in the range of about 1.025 to about 1.042.

[0033] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The biofilm removal solution further includes an alkyl sulfonate in a concentration range of about 0.61 g / L to about 1.10 g / L.

[0034] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The biofilm removal solution further includes an antimicrobial component.

[0035] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The antimicrobial component is selected from the group consisting of antibiotics, bleaching agents, and silver sulfadiazine.

[0036] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The PD solution further includes an antibiotic for treating bacteria exposed by the removed biofilm.

[0037] In a third aspect of the present disclosure, which may be combined with any other embodiment, aspect, or part thereof, a method of performing peritoneal dialysis (PD) includes pump-delivering a PD solution containing a biofilm removal solution through a PD catheter into a patient's peritoneal cavity; leaving the PD solution containing the biofilm removal solution in the peritoneal cavity; and removing biofilm from the PD catheter wall through the biofilm removal solution while leaving the PD solution containing the biofilm removal solution.

[0038] In one embodiment, which may be combined with any other embodiment or aspect or part thereof, the PD solution further contains an antibiotic for treating bacteria exposed by the removed biofilm.

[0039] In a fourth aspect of the present disclosure, which may be combined with any other embodiment or aspect or part thereof, a composition for removing contamination from a peritoneal dialysis (PD) catheter and removing biofilm from the PD catheter and transfer set includes sodium citrate dihydrate; citric anhydride; a surfactant; and water.

[0040] In one embodiment, which may be combined with any other embodiment or aspect or part thereof, the surfactant is selected from the group consisting of rhamnolipid, fengycin, glycolipid, lipopeptide, poloxamer, betaine, alkyl sulfonate, such as metal lauryl sulfate (e.g., sodium lauryl sulfate), sodium dodecyl sulfate, and cetyltrimethylammonium bromide.

[0041] In one embodiment, which may be combined with any other embodiment or aspect or part thereof, the surfactant is sodium lauryl sulfate.

[0042] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The composition includes sodium citrate dihydrate in a concentration range of from about 32.13 g / L to about 39.27 g / L; citric anhydride in a concentration range of from about 29.25 g / L to about 35.75 g / L; an alkyl sulfonate in a concentration range of from about 0.95 g / L to about 1.05 g / L, such as a metal lauryl sulfate (e.g., sodium lauryl sulfate); and water.

[0043] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The composition includes sodium citrate dihydrate at a concentration of about 35 g / L; citric anhydride at a concentration of about 33 g / L; an alkyl sulfonate at a concentration of about 1 g / L, such as a metal lauryl sulfate (e.g., sodium lauryl sulfate); and water.

[0044] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The composition further includes total citrate in a concentration range of from about 57.45 g / L to about 70.21 g / L. The biofilm removal solution containing the composition has a specific gravity in the range of from about 1.025 to about 1.042 and a pH value in the range of from about 3.70 to about 4.10.

[0045] In one embodiment, this may be in combination with any other embodiment or aspect or a portion thereof. The composition further includes an alkyl sulfonate in a concentration range of from about 0.61 g / L to about 1.10 g / L.

[0046] In one embodiment, this may be combined with any other embodiment or aspect or a part thereof. The composition includes sodium citrate dihydrate at a concentration of about 35 g / L; citric anhydride at a concentration of about 33 g / L; an alkyl sulfonate at a concentration of about 1 g / L, such as a metal lauryl sulfate (e.g., sodium lauryl sulfate); water; total citrate at a concentration of about 63.83 g / L; and an alkyl sulfonate in a concentration range of about 1.00 g / L. The solution for biofilm removal containing the composition has a specific gravity in the range of about 1.033 and a pH value of about 3.93.

[0047] In one embodiment, this may be combined with any other embodiment or aspect or a part thereof. The composition further includes an antimicrobial component.

[0048] In one embodiment, this may be combined with any other embodiment or aspect or a part thereof. The antimicrobial component is selected from the group consisting of antibiotics, bleaching agents, and silver sulfadiazine.

[0049] [[ID=1I2]]In a fifth aspect of the present disclosure, this may be combined with any other embodiment or aspect or a part thereof. A method for removing at least a part of the biofilm present in the lumen of an indwelling peritoneal catheter and simultaneously performing peritoneal dialysis therapy includes delivering dialysis fluid into the peritoneal cavity of a patient through the catheter; injecting a solution for biofilm removal into the lumen of the catheter to occupy at least a part of the lumen; leaving the dialysis fluid in the peritoneal cavity; and removing at least a part of the solution for biofilm removal from the catheter by withdrawing at least a part of the dialysis fluid from the peritoneal cavity into the catheter.

[0050] In one aspect of the present disclosure, this may be combined with any other aspect or a part thereof. Any of the features, functionalities, and alternatives described in relation to any one or more of FIGS. 1 to 11 may be combined with any of the features, functionalities, and alternatives described in relation to any other of FIGS. 1 to 11.

[0051] Additional features and advantages will be set forth in the detailed description which follows, and in part will be obvious from the description, or may be learned by practice of the herein disclosed subject matter. The features and advantages described herein are not all-inclusive and many additional features and advantages will be apparent to one of ordinary skill in the art in view of the drawings and description. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. BRIEF DESCRIPTION OF THE DRAWINGS

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[0063] Detailed Description Definitions

[0064] Hereinafter, some definitions are provided. Nevertheless, the definitions may be present in the section "Embodiments" below, and the header "Definitions" above does not mean that such disclosure is not defined in the section "Embodiments".

[0065] All percentages are by weight of the total weight of the composition, unless otherwise indicated. Similarly, all amounts and all ratios are by weight, unless otherwise indicated. When pH is referred to, the value corresponds to the pH measured at 25 °C using standard equipment. As used herein, "about", "approximately", and "substantially" refer to a number within a numerical range, e.g., from -10% to +10% of the referenced numerical value, preferably from -5% to +5% of the referenced numerical value, more preferably from -1% to +1% of the referenced numerical value, and most preferably from -0.1% to +0.1% of the referenced numerical value.

[0066] Furthermore, all numerical ranges herein are to be understood to include all integers, wholes, or fractions within the range. Additionally, these numerical ranges are to be construed as providing support for claims directed to any numerical value or subset of numerical values within that range. For example, the disclosure of 1 to 10 is to be construed as supporting ranges such as 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, and the like.

[0067] As used in this specification and the appended claims, unless the context clearly dictates otherwise, the singular forms of words include the plural. Thus, references to "a", "an", and "the" generally include the plural of the individual terms. For example, references to "an amino acid" or "the amino acid" include multiple such "amino acids". The term "and / or" as used in the context of "X and / or Y" is to be understood to mean "X", or "Y", or "X and Y". Similarly, "at least one of X or Y" is to be understood to mean "X", or "Y", or "both X and Y".

[0068] Similarly, the words "comprise", "comprises", and "comprising" should be construed as being inclusive rather than exclusive. Similarly, the terms "include", "including", and "or" should all be construed as inclusive unless such construction is clearly precluded by the context in such a phrase. However, the embodiments provided by the present disclosure may lack any element not specifically disclosed herein. Thus, the disclosure of an embodiment defined using the term "comprising" is also a disclosure of an embodiment "consisting essentially of" and "consisting of" the disclosed components.

[0069] As used herein, the term "example" is merely illustrative and exemplary, and should not be considered exclusive or inclusive, particularly when following a list of terms. Any embodiment disclosed herein may be combined with any other embodiment disclosed herein, unless specifically indicated otherwise.

[0070] As used herein, the term "patient" is understood to include animals, e.g., mammals, and preferably humans, who are undergoing or intended to undergo treatment (e.g., peritoneal dialysis (PD)) when the treatment is defined herein. Although the terms "individual" and "patient" are often used herein to refer to humans, the present disclosure is not so limited.

[0071] Thus, the terms "individual" and "patient" refer to any animal, mammal, or human who can benefit from the methods and compositions disclosed herein. In fact, PD treatment may be performed on non-human animals.

[0072] In the context of humans, the term "elderly" means those who are at least 55 years of age from birth, preferably over 63 years of age, more preferably over 65 years of age, and most preferably over 70 years of age. The terms "senior adult" or "aged individual" mean, in the context of humans, those who are at least 45 years of age from birth, preferably over 50 years of age, more preferably over 55 years of age, and include individual elderly persons.

[0073] For other animals, "aged organism" or "aged individual" exceeds 50% of the average lifespan for that particular species and / or race within the species range. An animal is considered "elderly" when it exceeds 66% of its average expected lifespan, preferably when it exceeds 75% of its average expected lifespan, and more preferably when it exceeds 80% of its average expected lifespan. The age of an aged cat or dog is at least about 5 years from birth. The age of an elderly cat or dog is at least about 7 years from birth.

[0074] The terms "treatment" and "treating" include any effect that results in an improvement in a condition or disorder, such as a reduction, decrease, modulation, or elimination of the condition or disorder. The terms do not necessarily imply treating until the subject is completely recovered. Non-limiting examples of "treating" a condition or disorder or their "treatment" include (1) inhibiting the condition or disorder, i.e., stopping the onset of the condition or disorder or their clinical symptoms, and (2) reducing the condition or disorder, i.e., resulting in a temporary or permanent regression of the condition or disorder or their clinical symptoms. Treatment may be patient-related or physician-related.

[0075] The term "peritoneal dialysis" or "PD", as used herein, refers to a type of dialysis that uses the peritoneal wall in the patient's abdomen as a membrane through which fluids and dissolved substances are exchanged with the blood. PD is used to remove excess fluid in those presenting with renal insufficiency, correct electrolyte problems, and remove toxins. Advantages of PD include high flexibility and excellent tolerance in those presenting with significant heart disease. In PD, a specific solution (e.g., PD solution) is introduced through a permanent tube in the lower abdomen and then removed. This may be done at regular intervals throughout the day, as known as continuous ambulatory peritoneal dialysis (CAPD), or at night with the aid of a machine, as known as automated peritoneal dialysis (APD). PD solution is typically made from sodium chloride, bicarbonate, and an osmotic agent, such as glucose.

[0076] The term "PD catheter", as used herein, refers to a thin tube made of a medical-grade material that functions as a medical device and can be inserted into the patient's peritoneal cavity to perform peritoneal dialysis or PD. As shown in FIG. 1, one end of the PD catheter 1 is inserted into the patient's peritoneal cavity. The other end of the PD catheter 1 is connected to a transfer set 9, which enables the PD catheter (or transfer set 9) to be connected to other devices, such as a syringe 5 or a waste fluid bag 11.

[0077] As used herein, the term "biofilm" refers to any synergistic consortium of microorganisms that often adhere to one another and also to a surface (e.g., the inner or outer wall surface of a PD catheter). These attached cells become embedded within a mucinous extracellular matrix composed of extracellular polymeric substances (EPS). The cells within a biofilm typically produce EPS components that are polymeric aggregates of extracellular polysaccharides, proteins, lipids, and DNA. These cells have a three-dimensional structure and represent a community lifestyle for the microorganisms, and thus have been metaphorically referred to as a "microbial city." In one embodiment, the biofilm is present on the surface of the inner or outer wall of a PD catheter (a part within the peritoneal cavity of a patient).

[0078] As used herein, the term "peritoneal dialysis solution" or "PD solution" refers to a specific solution used in peritoneal dialysis. The PD solution is typically introduced through a permanent tube in the lower abdomen and then removed. This process may be performed at regular intervals throughout the day, as known as continuous ambulatory peritoneal dialysis (CAPD), or may be performed with the assistance of a machine at night, as known as automated peritoneal dialysis (APD). The PD solution is typically made from sodium chloride, bicarbonate, and an osmotic agent, such as glucose. The PD solution used in peritoneal dialysis is listed in the World Health Organization's list of essential medicines.

[0079] As used herein, the term "biofilm removal solution" refers to a solution containing the compositions of the present disclosure that are unexpectedly effective in removing biofilms from a surface. In one embodiment, the biofilm removal solution contains sodium citrate (e.g., sodium citrate dihydrate); citric acid (e.g., citric anhydride); a surfactant (e.g., sodium lauryl sulfate); and water. In one embodiment, the biofilm is present on the surface of the inner or outer wall of a PD catheter (a part within the peritoneal cavity of a patient).

[0080] The citric acid of the present disclosure has been surprisingly found to bind to the metal binding of extracellular polymeric substances secreted by microorganisms, remove them, remove the extracellular polymeric substances of biofilms, and thus remove biofilms (e.g., FIGS. 9A and 9B). It has further surprisingly been found that the citric acid of the present disclosure can prevent further cross-linking of the extracellular polymeric substances of biofilms (e.g., FIG. 9C).

[0081] The terms "surfactant", "detergent", or "surface active agent", as used herein, refer to any organic compound that is amphiphilic, i.e., contains both a hydrophobic group ("tail") and a hydrophilic group ("head"), thereby rendering the surfactant soluble in both organic solvents and water. Surfactants can be classified by the presence of a formal charged group in their head. Nonionic surfactants do not have a charged group in their head, while ionic surfactants carry a net charge in their head. Zwitterionic surfactants contain a head with two oppositely charged groups. Some examples of common surfactants include anionic (based on sulfate, sulfonate, or carboxylate anions): alkyl sulfonates such as metal lauryl sulfates (e.g., sodium lauryl sulfate; SLS), perfluorooctanoate (PFOA or PFO), perfluorooctane sulfonate (PFOS), sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, and other alkyl sulfates, sodium laureth sulfate (also known as sodium lauryl ether sulfate, or SLES), alkyl benzene sulfonates; cationic (based on quaternary ammonium cations): cetyltrimethylammonium bromide (CTAB) also known as hexadecyltrimethylammonium bromide, and other alkyltrimethylammonium salts, cetylpyridinium chloride (CPC), polyethoxylated tallow amine (POEA), benzalkonium chloride (BAC), benzethonium chloride (BZT); zwitterionic (amphoteric): dodecyl betaine; cocamidopropyl betaine; cocoamphoglycinate; nonionic: alkyl poly(ethylene oxide), alkylphenol poly(ethylene oxide), copolymers of poly(ethylene oxide) and poly(propylene oxide) (commercially known as poloxamers or poloxamines), alkyl polyglucosides including octyl glucoside, decyl maltoside, fatty alcohols (e.g., cetyl alcohol and oleyl alcohol), cocamide MEA, cocamide DEA, polysorbates (Tween® 20®, Tween® 80®, etc.), Triton detergents, and dodecyldimethylamine oxide.

[0082] In one embodiment, the surfactant may include biosurfactants (such as rhamnolipid, fengycin, glycolipid, lipopeptide, etc.), synthetic ones (such as poloxamer and betaine), and natural ones (such as sodium lauryl / dodecyl sulfate, cetyltrimethylammonium bromide, etc.). In one embodiment, the surfactant is selected from the group consisting of rhamnolipid, fengycin, glycolipid, lipopeptide, poloxamer, betaine, sodium lauryl sulfate, sodium dodecyl sulfate, and cetyltrimethylammonium bromide. In an exemplary embodiment, the surfactant includes sodium lauryl sulfate. More preferably, the surfactant is sodium lauryl sulfate.

[0083] As used herein, the term "alkyl sulfonate" refers to an ester of an alkane sulfonic acid having the general formula R-SO2-O-R' (where R and R' are alkanes). Alkyl sulfonates act as alkylating agents, and some of them are used in the treatment of cancer as alkylating antineoplastic agents, such as busulfan.

[0084] As used herein, the term "antimicrobial component" refers to any agent or component that kills microorganisms or stops their growth. Antimicrobial components can be grouped mainly according to the microorganisms they act on. For example, antibiotics are used against bacteria, and antifungal agents are used against fungi. These can also be classified according to their functions. Agents that kill microorganisms are called microbicides, and those that only inhibit their growth are called bacteriostatic agents.

[0085] The main classes of antimicrobial agents or antimicrobial components are bactericides (non-selective agents, such as bleaches including sodium hypochlorite), which kill a wide range of microorganisms on inanimate surfaces to prevent the spread of disease, disinfectants (which are applied to living tissue and help reduce infection during surgery), and antibiotics (which destroy microorganisms within the body). In various embodiments, any other chemical that provides "free chlorine" (which is the active agent in bleaches) may also be provided.

[0086] As used herein, the term "antibiotic" refers to agents derived from living microorganisms and synthetic agents, such as sulfonamides or fluoroquinolones. Antimicrobial agents or antimicrobial components include antibacterial agents and all antimicrobials. Antibacterial agents can be further subdivided into bactericidal agents that kill bacteria and bacteriostatic agents that slow or stall the growth of bacteria.

[0087] In one embodiment, the antimicrobial component is selected from the group consisting of antibiotics, bleaches, and silver sulfadiazine.

[0088] As used herein, the term "antibacterial agent" refers to any agent or chemical substance for treating bacterial infections. Antibacterial agents may generally be classified as beta-lactams, macrolides, quinolones, tetracyclines, or aminoglycosides.

[0089] Embodiments

[0090] Compositions

[0091] In an aspect, the present disclosure relates to a composition or solution (e.g., a biofilm removal solution) for removing contaminants from a peritoneal dialysis (PD) catheter and removing biofilm from the PD catheter. In one embodiment, the composition comprises a metal citrate (e.g., sodium citrate); an acid (e.g., citric acid); a surfactant (e.g., an anionic surfactant); and water.

[0092] For example, the metal citrate may contain sodium citrate. The acid may contain citric acid. The surfactant may include biosurfactants (such as rhamnolipid, fengycin, glycolipid, lipopeptide, etc.), synthetic ones (such as poloxamer and betaine), and natural ones (such as sodium lauryl / dodecyl sulfate, cetyltrimethylammonium bromide, etc.). In one embodiment, the surfactant is selected from the group consisting of rhamnolipid, fengycin, glycolipid, lipopeptide, poloxamer, betaine, sodium lauryl sulfate, sodium dodecyl sulfate, and cetyltrimethylammonium bromide. In an exemplary embodiment, the surfactant contains sodium lauryl sulfate. More preferably, the surfactant is sodium lauryl sulfate.

[0093] In one embodiment, the composition contains sodium citrate (such as sodium citrate dihydrate); citric acid (such as citric anhydride); a surfactant (such as sodium lauryl sulfate); and water.

[0094] In an exemplary embodiment, the composition contains sodium citrate dihydrate; citric anhydride; sodium lauryl sulfate; and water.

[0095] It has unexpectedly been found that a biofilm removal solution containing sodium citrate dihydrate, citric anhydride, sodium lauryl sulfate, and water can be used to remove biofilms from the inner and outer wall surfaces of a device, such as a PD catheter.

[0096] Furthermore, the citric acid of the present disclosure was surprisingly found to bind to the metal binding of extracellular polymeric substances secreted by microorganisms and remove them, thereby removing the extracellular polymeric substances of biofilms, and thus the biofilms are removed (e.g., FIGS. 9A and 9B). It was further surprisingly found that the citric acid of the present disclosure can prevent further cross-linking of the extracellular polymeric substances of biofilms (e.g., FIG. 9C). In various embodiments, other chelating agents may be provided and used to bind to the metal binding of extracellular polymeric substances secreted by microorganisms and remove them, thereby removing the extracellular polymeric substances of biofilms and thus removing the biofilms. Examples of other chelating agents can include, for example, ethylenediaminetetraacetic acid (EDTA) and nitrilotriacetic acid (NTA).

[0097] FIGS. 9A, 9B, and 9C show a potential mechanism for removing biofilms by deconstructing the extracellular polymeric substances (EPS) of biofilms according to certain embodiments of the present disclosure. For example, FIG. 9A shows that the citric acid of the present disclosure attaches to the metal binding that holds the EPS structure together and removes it. FIG. 9B shows that the polymer is released and the EPS is degraded. FIG. 9C shows that sodium is detached from the sodium citrate of the present disclosure. Thus, the presence of citric acid prevents the reformation of cross-links. The EPS polymer may take on a random amorphous arrangement and may be absorbed into solution. Surfactants may also be provided where solubilization of EPS by surfactants is an important part of biofilm removal.

[0098] In an exemplary embodiment, the composition of the present disclosure comprises sodium citrate dihydrate, citric anhydride, sodium lauryl sulfate, and water.

[0099] In one embodiment, the composition comprises sodium citrate dihydrate at a concentration of from about 1 g / L to about 100 g / L, from about 2 g / L to about 95 g / L, from about 3 g / L to about 90 g / L, from about 4 g / L to about 85 g / L, from about 5 g / L to about 80 g / L, from about 6 g / L to about 75 g / L, from about 7 g / L to about 70 g / L, from about 8 g / L to about 65 g / L, from about 9 g / L to about 60 g / L, from about 10 g / L to about 55 g / L, from about 15 g / L to about 50 g / L, from about 20 g / L to about 45 g / L, from about 25 g / L to about 43 g / L, from about 30 g / L to about 42 g / L, from about 31 g / L to about 41 g / L, from about 32 g / L to about 40 g / L, or from about 32.13 g / L to about 39.27 g / L; citric anhydride in a concentration range of from about 1 g / L to about 90 g / L, from about 2 g / L to about 80 g / L, from about 3 g / L to about 85 g / L, from about 4 g / L to about 80 g / L, from about 5 g / L to about 75 g / L, from about 6 g / L to about 70 g / L, from about 7 g / L to about 65 g / L, from about 8 g / L to about 60 g / L, from about 9 g / L to about 55 g / L, from about 10 g / L to about 50 g / L, from about 15 g / L to about 45 g / L, from about 20 g / L to about 40 g / L, from about 25 g / L to about 39 g / L, from about 26 g / L to about 38 g / L, from about 27 g / L to about 37 g / L, from about 28 g / L to about 36 g / L, from about 29 g / L to about 35.9 g / L, or from about 29.25 g / L to about 35.75 g / L; sodium lauryl sulfate in a concentration range of from about 0.01 g / L to about 100 g / L, from about 0.02 g / L to about 90 g / L, from about 0.03 g / L to about 80 g / L, from about 0.04 g / L to about 70 g / L, from about 0.05 g / L to about 60 g / L, from about 0.06 g / L to about 50 g / L, from about 0.07 g / L to about 40 g / L, from about 0.08 g / L to about 30 g / L, from about 0.09 g / L to about 20 g / L, from about 0.10 g / L to about 10 g / L, from about 0.2 g / L to about 9 g / L, from about 0.3 g / L to about 8 g / L, from about 0.4 g / L to about 7 g / L, from about 0.5 g / L to about 6 g / L, from about 0.6 g / L to about 5 g / L, from about 0.7 g / L to about 4 g / L, from about 0.8 g / L to about 3 g / L, from about 0.85 g / L to about 2 g / L, from about 0.9 g / L to about 1.5 g / L, or from about 0.95 g / L to about 1.05 g / L; and water.

[0100] In one embodiment, the composition comprises sodium citrate dihydrate at a concentration of from about 32.13 g / L to about 39.27 g / L; citric anhydride in a concentration range of from about 29.25 g / L to about 35.75 g / L; sodium lauryl sulfate in a concentration range of from about 0.95 g / L to about 1.05 g / L; and water.

[0101] In an exemplary embodiment, the composition comprises sodium citrate dihydrate at a concentration of about 35 g / L; citric anhydride at a concentration of about 33 g / L; sodium lauryl sulfate at a concentration of about 1 g / L; and water.

[0102] In one embodiment, the biofilm removal solution comprising the composition has a pH value in the range of from about 1 to about 10, from about 1.1 to about 9.5, from about 1.2 to about 9, from about 1.3 to about 8.5, from about 1.4 to about 8, from about 1.5 to about 7.5, from about 1.6 to about 7, from about 1.7 to about 6.5, from about 1.8 to about 6, from about 1.9 to about 5.5, from about 2.0 to about 5, from about 2.2 to about 4.9, from about 2.4 to about 4.8, from about 2.6 to about 4.7, from about 2.8 to about 4.6, from about 3.0 to about 4.5, from about 3.2 to about 4.4, from about 3.4 to about 4.3, from about 3.5 to about 4.25, from about 3.6 to about 4.2, or from about 3.70 to about 4.10.

[0103] In an exemplary embodiment, the biofilm removal solution comprising the composition has a pH value of about 3.93.

[0104] In one embodiment, the composition further comprises total citrate in a concentration range of from about 1 g / L to about 200 g / L, from about 5 g / L to about 160 g / L, from about 10 g / L to about 140 g / L, from about 15 g / L to about 120 g / L, from about 20 g / L to about 100 g / L, from about 25 g / L to about 95 g / L, from about 30 g / L to about 90 g / L, from about 35 g / L to about 85 g / L, from about 40 g / L to about 80 g / L, from about 45 g / L to about 75 g / L, from about 50 g / L to about 74 g / L, from about 51 g / L to about 73 g / L, from about 52 g / L to about 72 g / L, from about 53 g / L to about 71.5 g / L, from about 54 g / L to about 71 g / L, from about 55 g / L to about 70.9 g / L, from about 56 g / L to about 70.8 g / L, from about 56.5 g / L to about 70.7 g / L, from about 57 g / L to about 70.6 g / L, from about 57.2 g / L to about 70.4 g / L, or from about 57.45 g / L to about 70.21 g / L.

[0105] In an exemplary embodiment, the composition further comprises total citrate at a concentration of about 63.83 g / L.

[0106] In one embodiment, the biofilm removal solution comprising the composition has a specific gravity in the range of from about 1.0 to about 1.2, from about 1.005 to about 1.1, from about 1.006 to about 1.085, from about 1.007 to about 1.080, from about 1.008 to about 1.075, from about 1.010 to about 1.070, from about 1.015 to about 1.065, from about 1.020 to about 1.060, from about 1.021 to about 1.055, from about 1.022 to about 1.050, from about 1.023 to about 1.045, from about 1.022 to about 1.043, or from about 1.025 to about 1.042.

[0107] In an exemplary embodiment, the biofilm removal solution comprising the composition has a specific gravity of about 1.033.

[0108] In one embodiment, the composition further comprises total citrate in a concentration range of from about 57.45 g / L to about 70.21 g / L, the biofilm removal solution comprising the composition has a specific gravity in the range of from about 1.025 to about 1.042, and has a pH value in the range of from about 3.70 to about 4.10.

[0109] In one embodiment, the composition further comprises an alkyl sulfonate in a concentration range of from about 0.1 g / L to about 10 g / L, from about 0.15 g / L to about 9 g / L, from about 0.2 g / L to about 8 g / L, from about 0.25 g / L to about 7 g / L, from about 0.3 g / L to about 6 g / L, from about 0.35 g / L to about 5 g / L, from about 0.4 g / L to about 4 g / L, from about 0.45 g / L to about 3 g / L, from about 0.5 g / L to about 2 g / L, from about 0.51 g / L to about 1.9 g / L, from about 0.52 g / L to about 1.8 g / L, from about 0.53 g / L to about 1.7 g / L, from about 0.54 g / L to about 1.6 g / L, from about 0.55 g / L to about 1.5 g / L, from about 0.57 g / L to about 1.4 g / L, from about 0.59 g / L to about 1.3 g / L, from about 0.60 g / L to about 1.2 g / L or from about 0.61 g / L to about 1.10 g / L.

[0110] In an exemplary embodiment, the composition further comprises an alkyl sulfonate in a concentration range of about 1.00 g / L.

[0111] In an exemplary embodiment, the composition comprises sodium citrate dihydrate at a concentration of about 35 g / L; citric anhydride at a concentration of about 33 g / L; sodium lauryl sulfate at a concentration of about 1 g / L; water; total citrate at a concentration of about 63.83 g / L; and an alkyl sulfonate in a concentration range of about 1.00 g / L, and the biofilm removal solution containing the composition has a specific gravity in the range of about 1.033 and a pH value of about 3.93.

[0112] In one embodiment, the composition further comprises an antimicrobial component. In one embodiment, the antimicrobial component includes antibiotics, bleaching agents, and silver sulfadiazine. In one embodiment, the antimicrobial component is selected from the group consisting of antibiotics, bleaching agents, and silver sulfadiazine.

[0113] In one embodiment, the composition specifically targets the biofilm structure to disrupt and remove it, or to allow antibiotics to penetrate deeper. By doing this in conjunction with the co - use of IP antibiotics, a significant improvement in killing bacteria is obtained. This may also reduce toxicity with respect to any microorganisms that survive antibiotic treatment and enable the immune system to more easily eliminate the infection.

[0114] Figures 3A, 3B, 4, and 5 demonstrate the effectiveness of a biofilm - removing solution containing the composition of the present disclosure in removing biofilms on PD catheters. For example, Figure 3 shows a micrograph of a P. aeruginosa biofilm on catheter material (silicone), and the biofilm on the catheter material after using a biofilm - removing solution containing the composition of the present disclosure (Figure 3B; see Product X) was completely removed compared to the control (Figure 3A; see untreated).

[0115] Figure 4 shows the viable bacteria recovered from the catheter material after treatment with a biofilm - removing solution containing the composition of the present disclosure for 6 hours. The log reduction value (LRV) indicates the removal of viable organisms. As shown in Figure 4, viable organisms were significantly removed after treatment with a biofilm - removing solution containing the composition of the present disclosure (Product X) for 6 hours compared to the untreated control.

[0116] Figure 5 shows the percentage of biomass removal of P. aeruginosa recovered from the catheter material after 6 - hour treatment relative to the untreated control. As shown in Figure 5, the biomass was significantly removed after treatment with a biofilm - removing solution containing the composition of the present disclosure (Product X) for 6 hours compared to the untreated control.

[0117] Method

[0118] In one aspect, the present disclosure relates to a method of performing peritoneal dialysis (PD). Biofilms may form on the surface of PD catheters, which are difficult to remove and may create a reservoir for infectious microorganisms that cause recurrent peritonitis, potentially necessitating catheter removal. The present disclosure provides a method for treating the interior of the catheter lumen to disrupt and remove biofilms on the catheter wall by using a biofilm removal solution (BRS) as the biofilm removal solution. Disrupting and treating the biofilm may enable antibiotics used in standard peritonitis treatment to more effectively kill bacteria within the catheter, preventing recurrent peritonitis or helping to prevent the occurrence of peritonitis. In one embodiment, the present disclosure uses a pre-filled syringe or similar device for delivering the biofilm removal solution (i.e., the biofilm removal solution) into the interior of the PD catheter lumen. The biofilm removal solution is then left in place while at the same time the PD fluid in the peritoneum is left in place and drained out with the drainage of the PD waste fluid. In one embodiment, a method of performing peritoneal dialysis (PD) includes filling a patient with PD fluid with or without antibiotics being dosed, locking a PD catheter containing a biofilm removal solution (biofilm solution), leaving it in the patient and then draining it therefrom, and flushing all from the PD catheter containing biofilm microorganisms and biofilm matrix material.

[0119] Figure 1 shows exemplary PD catheter contamination removal and biofilm removal according to some embodiments of the present disclosure. As shown in Figure 1, one end of the permanent PD catheter 1 is inserted into the peritoneal cavity 2 of the patient 3. The other end of the permanent PD catheter 1 is connected to the transfer set 9. Through the PD catheter 1, the antibiotic-containing PD solution 4 is delivered into the peritoneal cavity 2 of the patient 3. A biofilm removal solution (i.e., biofilm-removing solution) containing the composition of the present invention is injected through the transfer set 9 and the PD catheter 1 by a syringe 5 and left in the transfer set 9 and the PD catheter 1 for a sufficient length of time (e.g., 6 hours), and the biofilm attached to the inner wall (and outer wall) of the PD catheter 1 is removed. Reference numeral 6 shows an example of the inner wall of the PD catheter 1 having the biofilm 8, and reference numeral 7 shows an example of the inner wall PD catheter 1 without the biofilm after the biofilm removal solution containing the composition of the present invention is injected into the PD catheter 1.

[0120] Figure 1 shows exemplary PD catheter contamination removal and biofilm removal, and the biofilm removal solution (i.e., biofilm-removing solution) is injected through the transfer set 9 and the PD catheter 1 and left therein after the antibiotic-containing PD solution 4 has been delivered (by gravity or by pump) into the peritoneal cavity 2 of the patient 3.

[0121] In one embodiment, the biofilm removal solution of the present disclosure may be injected through the transfer set and the PD catheter and left therein before, after, or simultaneously with the filling of the peritoneal cavity of the patient with the antibiotic-containing PD solution. In an exemplary embodiment, the biofilm removal solution of the present disclosure may be injected through the transfer set and the PD catheter and left therein after the peritoneal cavity of the patient has been filled with the antibiotic-containing PD solution.

[0122] In one embodiment, a method of performing peritoneal dialysis (PD) includes delivering PD fluid through a PD catheter into a patient's peritoneal cavity; leaving the PD fluid in the peritoneal cavity; and removing biofilm from the PD catheter wall using a biofilm removal solution while leaving the PD fluid in place.

[0123] As shown in FIG. 1, the PD fluid 4 may be delivered through the transfer set 9 and the PD catheter 1. The transfer set 9 is connected to one end of the PD catheter 1, and the other end of the PD catheter 1 is inserted into the peritoneal cavity 2 of the patient 3. Thus, the PD fluid 4 may be delivered through the transfer set 9 and the PD catheter 1 into the peritoneal cavity 2 of the patient 3.

[0124] As shown in FIG. 1, when the PD fluid is delivered through the PD catheter into the patient's peritoneal cavity, a pharmaceutically sufficient amount of the PD fluid 4 is left in the peritoneal cavity 2 of the patient 3 for a first period. The pharmaceutically sufficient amount of the PD fluid 4 and the first period may be determined independently based on the age, weight, gender, disease severity, and other factors of the patient 3.

[0125] As shown in FIG. 1, while the PD fluid 4 is left in the peritoneal cavity 2 of the patient 3, the biofilm derived from the PD catheter wall is removed by using a biofilm removal solution.

[0126] In one embodiment, the biofilm removal solution may be injected through the transfer set 9 and the PD catheter 1 by using a syringe. As shown in FIG. 1, the biofilm removal solution was injected through the transfer set 9 and the PD catheter 1 by using the syringe 5.

[0127] In one embodiment, the biofilm removal solution may be provided as a syringe pre-filled for immediate use. In another embodiment, the biofilm removal solution may be provided as a sterile ampoule, vial, or bag that can be later transferred to a syringe.

[0128] In one embodiment, the syringe has an adjustable setting so that the volume to be delivered can be preset. The reason for the variability in delivery is that commercially available catheter volumes vary significantly (e.g., 3 - 15 mL) and it is not possible to provide a set volume. Catheters of suspect volume can be identified and then the syringe preset, thus minimizing overfill. For example, there is an adjustable stop that limits the amount that can be transferred to the syringe.

[0129] In one embodiment, as shown in FIG. 2, the adjustable clamp or stop 5s may be a clamped or threaded ring on the shaft of the plunger 5p of the syringe 5. As shown in FIG. 2, the shaft of the plunger 5p of the syringe 5 may be graduated so that the amount of solution delivered can be set to a stop state after the fluid has been withdrawn into the syringe 5 or upon receiving a pre - filled syringe 5. In one embodiment, the solution may be delivered via a pump or via connection to a bag with gravity drip.

[0130] The syringe 5 may be a "smart" syringe that can detect when the solution reaches the end of the catheter. For example, a "smart" syringe can be achieved by acoustic, electrical, optical, or pressure transmission. In one embodiment, when the biofilm removal solution reaches the peritoneal implant, this may initiate a change in signal. A threshold value indicating that the user should stop the injection of the biofilm removal solution can be used to send a notification via an audible or visual display, or simply prevent further pushing of the biofilm removal solution within the PD catheter.

[0131] In one embodiment, the biofilm removal solution discussed above contains sodium citrate (e.g., sodium citrate dihydrate); citric acid (e.g., citric anhydride); a surfactant (e.g., sodium lauryl sulfate); and water. In an exemplary embodiment, the biofilm removal solution discussed above contains sodium citrate dihydrate; citric anhydride; sodium lauryl sulfate; and water.

[0132] In one embodiment, the biofilm removal solution discussed above contains sodium citrate dihydrate in a concentration range of about 32.13 g / L to about 39.27 g / L; citric anhydride in a concentration range of about 29.25 g / L to about 35.75 g / L; sodium lauryl sulfate in a concentration range of about 0.95 g / L to about 1.05 g / L; and water.

[0133] In one embodiment, the biofilm removal solution further has a pH value in the range of about 3.70 to about 4.10 (preferably, about 3.93); a total citrate in a concentration range of about 57.45 g / L to about 70.21 g / L (preferably, about 63.83 g / L); and a specific gravity in the range of about 1.025 to about 1.042 (preferably, about 1.033). In one embodiment, the biofilm removal solution further contains an alkyl sulfonate in a concentration range of about 0.61 g / L to about 1.10 g / L (preferably, about 1.00 g / L). In another embodiment, the biofilm removal solution further contains an antimicrobial component selected from the group consisting of an antibiotic, a bleach, and silver sulfadiazine.

[0134] In one embodiment, the transfer set 9 may include a transfer set valve that can stop the flow of the biofilm removal solution, so that the biofilm removal solution can be retained within the transfer set 9 and the PD catheter 1. In one embodiment, the biofilm removal solution can be retained within the transfer set 9 and the PD catheter 1 for a second period sufficient to remove biofilm on the inner wall and / or outer wall of the transfer set and the PD catheter.

[0135] In one embodiment, the second period ranges from about 0.1 hour to about 100 hours, from about 0.5 hour to about 50 hours, from about 1 hour to about 25 hours, from about 1 hour to about 20 hours, from about 1.5 hours to about 15 hours, from about 2 hours to about 10 hours, from about 3 hours to about 9 hours, from about 4 hours to about 8 hours, from about 5 hours to about 7 hours, or from about 5.5 hours to about 6.5 hours.

[0136] In one embodiment, the third period ranges from about 0.1 hour to about 20 hours, from about 0.2 hour to about 15 hours, from about 0.3 hour to about 10 hours, from about 0.4 hour to about 5 hours, from about 0.5 hour to about 4 hours, from about 0.6 hour to about 3 hours, from about 0.7 hour to about 2 hours, from about 0.8 hour to about 1.9 hours, from about 0.9 hour to about 1.9 hours, from about 1.0 hour to about 1.8 hours, from about 1.1 hour to about 1.7 hours, from about 1.2 hour to about 1.6 hours, from about 1.3 hour to about 1.55 hours, from about 1.4 hour to about 1.54 hours, from about 1.45 hour to about 1.53 hours, from about 1.47 hour to about 1.52 hours, from about 1.48 hour to about 1.51 hours, or about 1.5 hours.

[0137] In one embodiment, the second period is about 1 hour and about 12 hours, or between about 1 hour and about 12 hours.

[0138] A method of performing peritoneal dialysis (PD) including removal of biofilm on the inner wall and / or outer wall of the transfer set and PD catheter may be performed in any order understood by those skilled in the art. For example, the biofilm removal solution of the present disclosure is injected through and left in the transfer set and PD catheter before, after, or simultaneously with filling the patient's peritoneal cavity with the antibiotic-containing PD solution. In an exemplary embodiment, the biofilm removal solution of the present disclosure may be injected through and left in the transfer set and PD catheter after filling the patient's peritoneal cavity with the antibiotic-containing PD solution.

[0139] In one embodiment, the biofilm removal solution containing the composition of the present disclosure may be applied to a patient presenting with an active (reactive) infection or to a patient to reduce the likelihood of infection.

[0140] In one embodiment, the biofilm removal solution containing the composition of the present disclosure may be locked into the PD catheter after dropping a PD solution with or without antibiotics. The duration of dropping the biofilm removal solution may correspond to a typical intraperitoneal (IP) antibiotic treatment, typically about 6 hours, but depends on the facility protocol. The biofilm removal solution may also be applied after treating a normal PD fluid implant (e.g., Dianeal™ PD fluid) with an antibiotic.

[0141] In another embodiment, the biofilm removal solution containing the composition of the present disclosure may be locked into the PD catheter after dropping the PD solution at various frequencies. For example, once a month, once each time visiting the clinic, once each time replacing the transfer set (typically every 6 months). This treatment can be particularly beneficial for patients prone to peritonitis. The treatment time may be more appropriately adjusted according to the typical indwelling duration; for example, it may be adjusted from 1 hour to 6 hours (e.g., 1.5 hours). However, the effectiveness may decrease as the duration shortens.

[0142] In one embodiment, the step of removing the biofilm from the PD catheter wall using the biofilm removal solution includes transferring the biofilm removal solution to a syringe; connecting the syringe to the transfer set of the PD catheter; and filling the transfer set and the PD catheter with the biofilm removal solution.

[0143] Figures 6A, 6B, 6C, 7A, 7B, 7C, 8A, 8B and 8C show exemplary treatment sequences according to some embodiments of the present disclosure. For example, Figures 6A, 6B, 6C, 7A, 7B, 7C, 8A, 8B and 8C show an example where the biofilm removal solution of the present disclosure may be injected through the transfer set 9 and the PD catheter 1 after an antibiotic-containing PD solution has been delivered (by gravity or pump) into the peritoneal cavity 2 of the patient and left to dwell therein.

[0144] In particular, FIGS. 6A, 6B, and 6C show preparations of a patient's peritoneal cavity 2 and the solution of the present disclosure before treatment. As shown in FIGS. 6A and 6B, to prepare the patient's peritoneal cavity, the patient's peritoneal cavity 2 is filled with PD fluid through a transfer set 9 and a PD catheter 1. As shown in FIG. 6B, several treatment options are available for patients considering PD: automated peritoneal dialysis (APD) and continuous ambulatory peritoneal dialysis (CAPD).

[0145] As shown in FIG. 6C, to fill the patient's peritoneal cavity 2 with PD fluid through a transfer set 9 and a PD catheter 1, and when the patient is treated, a biofilm removal solution is prepared. For example, as shown in FIG. 6C, the biofilm removal solution is transferred from a sterile ampule to a 10 - 20 mL syringe using a Luer connector.

[0146] In one embodiment, the biofilm removal solution may be provided as a pre - filled syringe that is ready for use. In another embodiment, the biofilm removal solution may be provided as a vial or bag that can be transferred to a syringe later.

[0147] In one embodiment, the step of removing biofilm from the PD catheter wall using the biofilm removal solution further includes closing the transfer set valve and maintaining the biofilm removal solution in the transfer set and the PD catheter for a first duration. In one embodiment, the first duration is about 6 hours.

[0148] Referring to FIGS. 7A, 7B, and 7C, when the biofilm removal solution is prepared in a syringe 5, the biofilm removal solution is delivered into and retained within a transfer set 9 and a PD catheter 1.

[0149] As shown in FIG. 7A, the lure connection solution-containing syringe 5 is connected to the transfer set 9, and the biofilm removal solution is delivered to and retained within the transfer set 9 and the PD catheter 1. FIG. 7B shows that the transfer set 9 and the PD catheter 1 are filled with a sufficient amount (e.g., 5-10 mL) of the biofilm removal solution.

[0150] In one embodiment, the transfer set valve includes a twist-operated valve that, when closed, stops the flow of the biofilm removal solution and can maintain the biofilm removal solution within the transfer set and the PD catheter.

[0151] FIG. 7C shows closing the valve of the transfer set 9 to maintain the biofilm removal solution within the transfer set and the PD catheter over a third retention period.

[0152] In one embodiment, the third period ranges from about 0.1 hour to about 100 hours, about 0.5 hour to about 50 hours, about 1 hour to about 25 hours, about 1 hour to about 20 hours, about 1.5 hours to about 15 hours, about 2 hours to about 10 hours, about 3 hours to about 9 hours, about 4 hours to about 8 hours, about 5 hours to about 7 hours, or about 5.5 hours to about 6.5 hours.

[0153] In one embodiment, the third period ranges from about 0.1 hour to about 20 hours, about 0.2 hour to about 15 hours, about 0.3 hour to about 10 hours, about 0.4 hour to about 5 hours, about 0.5 hour to about 4 hours, about 0.6 hour to about 3 hours, about 0.7 hour to about 2 hours, about 0.8 hour to about 1.9 hours, about 0.9 hour to about 1.9 hours, about 1.0 hour to about 1.8 hours, about 1.1 hour to about 1.7 hours, about 1.2 hour to about 1.6 hours, about 1.3 hour to about 1.55 hours, about 1.4 hour to about 1.54 hours, about 1.45 hour to about 1.53 hours, about 1.47 hour to about 1.52 hours, about 1.48 hour to about 1.51 hours, or about 1.5 hours.

[0154] In one embodiment, the third period is about six hours. In one embodiment, the third period is sufficient to remove biofilm located on the inner wall of the transfer set and the PD catheter, and a portion of the outer wall of the PD catheter located within the peritoneal cavity of the patient.

[0155] Once the biofilm on the inner wall of the transfer set and PD catheter and (a portion of the outer wall) is removed, the biofilm removal solution, biofilm, and antibiotic-containing implant can be removed by any method understood by those skilled in the art.

[0156] For example, in one embodiment, the biofilm removal solution, biofilm, and antibiotic-containing implant may be manually removed by a syringe. In one embodiment, a manual syringe pull allows for higher shear stress than via gravity or a cycler, which will lead to better washing. In one embodiment, the clinician may drain the catheter using a syringe and then complete the drainage of the implant using CAPD / APD.

[0157] In one embodiment, the step of removing biofilm from the PD catheter wall using the biofilm removal solution further comprises removing the biofilm removal solution, PD solution, and biofilm.

[0158] In one embodiment, the steps of removing the biofilm removal solution, PD solution, and biofilm include replacing a syringe with a suitable fluid connection with a waste bag; opening the transfer set valve and draining the biofilm removal solution and PD solution into the waste bag via gravity or a pump, wherein the biofilm removal solution and PD solution contain biofilm removed from the transfer set and the PD catheter.

[0159] In one embodiment, the biofilm is removed from the inner wall of the transfer set and the PD catheter, and a portion of the outer wall of the PD catheter located within the peritoneal cavity of the patient.

[0160] Referring to FIGS. 8A, 8B and 8C, when the biofilm on the inner and outer walls of the transfer set and the PD catheter is removed, the biofilm removal solution, the biofilm and the antibiotic-containing indwelling device can be removed, for example, by the waste liquid bag 11.

[0161] For example, FIG. 8A shows that the syringe 5 has been replaced with a proper fluid connection to the waste liquid bag (CAPD or APD). As shown in FIG. 8B, the valve of the transfer set 9 is open, and the drainage from the PD catheter 1 and the patient's peritoneal cavity 2 is initiated via gravity or a pump.

[0162] In one embodiment, a CAPD twin bag containing a biofilm solution and / or an APD solution bag may be provided within the bag. For example, the biofilm removal solution may be injected into the patient's body through a normal CAPD workflow or delivered by an APD cycler. The CAPD and APD bags may be pre-made or prepared by a healthcare practitioner at the clinic.

[0163] In one embodiment, the drainage of the patient after indwelling may remove the biofilm via shear stress. In one embodiment, normal drip and drainage settings may be used, but may potentially be increased to increase the shear stress on the surface of the catheter lumen where biofilms are typically present. The higher the shear stress, the better or faster the solubilized biofilm is presumably removed, but there may be a trade-off with patient discomfort.

[0164] In one embodiment, pulsatile flow (in the most extreme case: start / stop) may be used to aid in the disruption of the biofilm, and the pulsatile flow may be enabled using a syringe, gravity, or a pump (e.g., via a PD cycler). For example, pulsatile shear of the fluid may be applied, and the shear force may be increased and decreased over different pulses to provide shear, mixing, and potential disruption to the biofilm. For example, cycler software may be used to generate a pulsation of the flow of the fluid that is more apparent during drainage.

[0165] Figure 8C shows that fluid has been drained from the peritoneal cavity 2 of the patient and that the biofilm has been removed from the catheter and transfer set 9. The treatment / therapy may continue according to the facility protocol.

[0166] In one embodiment, the peritoneal cavity may first be filled with PD fluid, and then a biofilm removal solution within the catheter may be locked in. The purpose is to dilute any biofilm removal solution with several liters of PD fluid to minimize the safety risk to the patient. The biofilm removal solution may include those containing antibiotics intended to simultaneously treat the catheter with the biofilm removal solution and simultaneously treat peritonitis, and may be administered with various indwelling devices. Alternatively, a basic PD fluid (e.g., Dianeal™ PD fluid) that may optionally be used after the antibiotic treatment may be left in place. The biofilm removal solution and the indwelling device may be drained at the clinic or at the patient's home.

[0167] In one embodiment, the biofilm may be removed by using a biofilm removal solution within the catheter prior to antibiotic treatment.

[0168] In another embodiment, the biofilm may be removed by using a biofilm removal solution within the catheter after antibiotic treatment.

[0169] In one embodiment, the transfer set may remain attached, be removed, or be replaced with a new transfer set during biofilm removal solution treatment. Locking of the valve / closure may be performed using the transfer set itself or may be locked using a valved line connected to a syringe or other delivery system. This additional valve or valved tube may be provided as part of a catheter contamination removal product.

[0170] In some embodiments, the PD catheter may be flushed more than once with a biofilm removal solution to assist in the physical removal of biofilm and microorganisms. Flushing may be done manually or assisted with an automated pump. In other embodiments, an antibiotic may be mixed into the biofilm removal solution to provide both biofilm removal and killing of microorganisms, which may be either infectious or non-infectious microorganisms. Another embodiment of the present invention involves mixing a biofilm solution into the PD fluid that is to be infused into the peritoneum to remove biofilm on the outer wall of the catheter. Such embodiments may be particularly useful for APD, which may be more difficult to perform with a syringe.

[0171] In one embodiment, the following additional options may improve the efficiency of biofilm removal: 1. Raising the temperature during or prior to dripping into the PD catheter (e.g., pre-warming the solution) may improve effectiveness. A means of doing this is to use a heating wrap or cover (such as a heating blanket) to warm the catheter. Even body temperature of 37 °C may assist effectiveness. In one embodiment, the solution may be pre-warmed. 2. Vibration may be applied during dripping into the PD catheter, which may improve effectiveness. This is similar to the function of sonicating a sample to remove it from the surface, but it will probably be necessary to apply it in a gentler manner. The trade-off is that it may cause discomfort to the patient and there is a risk of inadvertent leakage of the solution into the peritoneum. For example, sonic or ultrasonic energy may be used to improve biofilm removal. Ultrasonic energy is normally applied to the human body without causing discomfort. Ultrasonic energy is also suitable for assisting in biofilm disruption. 3. The rinse drip / drain cycle may be included after a workflow similar to or the same as that shown in FIG. 2. For example, the peritoneum and catheter may be rinsed three times with PD solution after use and drainage of the biofilm removal solution. This may help remove residual BRS or biofilm components that may remain in the peritoneum / catheter. 4. Mechanical forces exceeding the shear stress applied to the biofilm may help in biofilm removal. For example, a manual or electric brush may be used with the biofilm removal solution to brush wash the lumen of the PD catheter.

[0172] Aspects of the present disclosure are methods for removing contaminants from a peritoneal dialysis (PD) catheter and removing biofilm from the PD catheter and transfer set. The method includes providing a biofilm removal solution; transferring the biofilm removal solution to a syringe; connecting the syringe to the transfer set of the PD catheter; and filling the transfer set and the PD catheter with the biofilm removal solution.

[0173] In one embodiment, the method further includes closing the transfer set valve and maintaining the biofilm removal solution in the transfer set and the PD catheter for a first duration.

[0174] In one embodiment, the first period is about 6 hours.

[0175] In one embodiment, the first period is between about 0.5 hours and about 12 hours.

[0176] In one embodiment, the first period is between about 0.5 hours and about 6 hours.

[0177] In one embodiment, the first period is between about 1 hour and about 2 hours.

[0178] In one embodiment, the first period is at least about 6 hours.

[0179] In one embodiment, the first period is at most about 6 hours.

[0180] In one embodiment, the method further comprises removing the biofilm removal solution, the PD solution, and the biofilm.

[0181] In one embodiment, the steps of removing the biofilm removal solution, the PD solution, and the biofilm include replacing a syringe with a suitable fluid connection with a waste liquid bag; opening a transfer set valve and draining the biofilm removal solution and the PD solution into the waste liquid bag via gravity or a pump, wherein the biofilm removal solution and the PD solution contain the biofilm removed from the transfer set and the PD catheter.

[0182] In one embodiment, the biofilm is removed from both the inner walls of the transfer set and the PD catheter and the outer wall of the PD catheter in the patient's peritoneal cavity.

[0183] In one embodiment, the biofilm removal solution discussed above contains sodium citrate dihydrate; citric anhydride; sodium lauryl sulfate; and water.

[0184] In one embodiment, citric acid binds to the metal binding of extracellular polymeric substances secreted by microorganisms and removes them, resulting in the removal of the extracellular polymeric substances of the biofilm.

[0185] In one embodiment, citric acid prevents further crosslinking formation.

[0186] In one embodiment, the biofilm removal solution comprises sodium citrate dihydrate in a concentration range of about 32.13 g / L to about 39.27 g / L; citric anhydride in a concentration range of about 29.25 g / L to about 35.75 g / L; sodium lauryl sulfate in a concentration range of about 0.95 g / L to about 1.05 g / L; and water.

[0187] In one embodiment, the biofilm removal solution further comprises a pH value in the range of about 3.70 to about 4.10; total citrate in a concentration range of about 57.45 g / L to about 70.21 g / L; and a specific gravity in the range of about 1.025 to about 1.042.

[0188] In one embodiment, the biofilm removal solution further comprises alkyl sulfonate in a concentration range of about 0.61 g / L to about 1.10 g / L.

[0189] In one embodiment, the biofilm removal solution further comprises an antimicrobial component.

[0190] In one embodiment, the antimicrobial component is selected from the group consisting of antibiotics, bleaching agents, and silver sulfadiazine.

[0191] Figures 10A and 10B show the effectiveness of a biofilm removal solution containing sodium citrate (35 g / L), citric acid (33 g / L), and sodium lauryl sulfate (1 g / L) in water at pH = 4. For example, Figures 10A and 10B show the removal of biofilm and viable bacteria by using the biofilm removal solution. As shown in Figure 10B, the biofilm was removed or substantially removed after washing with the biofilm removal solution (i.e., Product X) for 6 hours compared to the untreated control (Figure 10A) that was not washed with the solution.

[0192] Figure 11 shows that the biofilm removal solution of the present disclosure is superior to antibiotics in removing bacteria. In particular, Figure 11 shows the removal of biofilm from silicone. As shown in Figure 11, viable bacteria (e.g., P. aeruginosa ATCC15442 and S. aureus ATCC6538) were not recovered after treatment with the biofilm removal solution (i.e., the solution of Product X).

[0193] Aspects of the present disclosure include a method of removing at least a portion of a biofilm present in the lumen of an indwelling peritoneal catheter and simultaneously performing peritoneal dialysis therapy, the method comprising delivering a dialysis fluid into a patient's peritoneal cavity via the catheter; injecting a biofilm removal solution into the lumen of the catheter to occupy at least a portion of the lumen; leaving the dialysis fluid in the peritoneal cavity; and removing at least a portion of the biofilm removal solution from the catheter by withdrawing at least a portion of the dialysis fluid from the peritoneal cavity into the catheter.

Example

[0194] Example

[0195] The following non-limiting examples present scientific data that develop and support the concept of performing peritoneal dialysis (PD), removing contamination from a peritoneal dialysis (PD) catheter, and removing biofilm from a PD catheter and transfer set by using a biofilm removal solution comprising sodium citrate dihydrate; citric anhydride; a surfactant, such as sodium lauryl sulfate; and water.

[0196] (Example 1)

[0197] PD Biofilm Removal Solution

[0198] The solution for removing PD biofilm is a colorless and transparent aqueous solution containing water, citric acid, sodium citrate, and sodium lauryl sulfate (Table 1). Sodium lauryl sulfate, a surfactant contained in the solution, helps solubilize the organic debris coating the catheter lumen and makes it easier to further remove the debris by hydrodynamic shear generated as part of the normal dialysate drainage process.

[0199] The solution for removing PD biofilm may be provided as a sterile vial / pre-filled syringe. The solution for removing PD biofilm may be delivered to the catheter by a healthcare provider after the patient fills it with fresh PD solution as part of their normal PD therapy. The total filling volume of the solution for removing PD biofilm can be approximately 3 - 6 mL, which typically matches the filling volume of the most commonly used PD catheter. After dripping, the distal end of the catheter may be sealed to generate a pressure gradient that inhibits the solution for removing PD biofilm from exiting the catheter. The solution for removing PD biofilm remains in the catheter for up to 6 hours and may then be drained from the catheter when the patient drains the dialysate as part of the normal PD therapy process.

[0200] A portion of the solution for removing PD biofilm may penetrate the peritoneum through the fenestration and tip of the catheter. However, any solution that penetrates the peritoneum is significantly diluted by leaving a fresh PD solution (typically 1.5 L - 3 L), and thus the concentration of the solution for removing PD biofilm in the peritoneal cavity is low and is not expected to have an impact on the peritoneum or other patient tissues. Animal biocompatibility studies can be conducted to demonstrate patient safety at the worst-case concentration expected in the peritoneum. [Table 1] [Table 2]

[0201] Chemical, physical, or biological composition

[0202] Tables 3 and 4 provide the composition and properties of the solutions for biofilm removal. [Table 3] [Table 4]

[0203] Table 5 provides information on the feasibility tests conducted on the PD biofilm removal solution device. The feasibility study shows that 1) the PD biofilm removal solution can solubilize the components of EPS as demonstrated in the alginate-based model; 2) the PD biofilm removal solution can remove organic debris from the catheter material (silicone); and 3) together with the organic debris, the PD biofilm removal solution can promote the removal of microorganisms. [Table 5-1] [Table 5-2]

[0204] (Example 2)

[0205] Presentation of the solution: The Biofilm Removal Solution (BRS) may be provided as a pre-filled syringe ready for immediate use. Alternatively, the BRS may be provided as a sterile ampoule, vial, or bag that is transferred to a syringe. The syringe itself may have adjustable settings so that the clinician can pre-set the volume to be delivered. The reason for the variability in delivery is that commercially available catheter volumes vary significantly (e.g., 3 - 15 mL), making it impossible to provide a set volume. The clinician can determine the catheter of a suspect volume and then pre-set the syringe, thus minimizing overfilling. For example, there is an adjustable stop that limits the amount that can be transferred to the syringe. The adjustable stop may be a clamp or threaded ring on the plunger shaft, as shown in Figure 2. The plunger shaft may be graduated so that the clinician can set the amount of solution to be delivered in a stopped state after withdrawing fluid into the syringe or upon receiving a pre-filled syringe. Additionally, the BRS may be delivered via connection to a bag through a pump or gravity drip.

[0206] Furthermore, a "smart" syringe may be used to detect when the solution reaches the end of the catheter. This can be achieved by the transmission of sound, electricity, light, or pressure. For example, when the biofilm removal solution reaches a peritoneal implant, this may initiate a change in the signal. A threshold value indicating that the user should stop the injection can be used to send a notification via an audible or visual display or simply prevent further pushing of the fluid within the catheter.

[0207] Solution composition: Some classes of surfactants may be used to reduce the formation or presence of bacterial biofilms. These include biosurfactants (such as rhamnolipids, fengycin, glycolipids, lipopeptides, etc.), synthetic ones (poloxamers and betaines), and natural ones (such as sodium lauryl / dodecyl sulfate, cetyltrimethylammonium bromide, etc.). Additionally, citrates such as sodium citrate and citric acid may help chelate key metal ions to assist in the destruction of the biofilm matrix. The solution may also contain antimicrobial components such as antibiotics, bleaching agents, silver sulfadiazine, etc.

[0208] When BRS is going to result in a high or low pH, the PD fluid implant may contain a buffer to once reduce the impact on the peritoneum.

[0209] Note that BRS uses a combination of sodium lauryl sulfate, sodium citrate, and citric acid in an aqueous solution. Data demonstrating the effectiveness of this stock solution is illustrated in Figure 3.

[0210] Treatment frequency: BRS may be applied to patients presenting with active infectious diseases or to patients to reduce the likelihood of infectious diseases:

[0211] For example, the solution may be locked into the PD catheter after filling with PD fluid with or without antibiotics. The duration of dripping BRS may correspond to typical intraperitoneal (IP) antibiotic treatment, typically about 6 hours, but depends on the facility protocol. The BRS solution may also be applied after treating with antibiotics using a normal PD fluid implant (e.g., Dianeal™ PD fluid).

[0212] In another example, the solution may be locked within the PD catheter after instilling the PD solution at several frequencies. For example, once a month, once each time the clinic is visited, or once each time the transfer set is changed (typically every six months). This procedure may be particularly beneficial for patients prone to peritonitis. The treatment time may be more appropriately adjusted according to the typical indwelling duration; for example, it may be adjusted to 1.5 hours. However, the effectiveness may decrease as the duration shortens.

[0213] Workflow: There are several workflows that can be performed. Regarding safety, these will probably involve first filling the peritoneum with the PD solution and then locking the BRS within the catheter. The purpose is to dilute any BRS with several liters of PD solution to minimize the safety risk to the patient. The biofilm removal solution may be administered with various indwelling devices, including those containing antibiotics intended to simultaneously treat the catheter with the biofilm removal solution and treat peritonitis simultaneously. Alternatively, the indwelling device may be a basic PD solution (e.g., Dianeal™ PD solution) that may be used optionally after the antibiotic treatment is completed. The post-indwelling biofilm removal solution may be drained at the clinic or at the patient's home.

[0214] Examples of "responsive" workflows are illustrated in FIGS. 6A, 6B, 6C, 7A, 7B, 7C, 8A, 8B, and 8C. The workflow may not contain antibiotics to avoid complications in non-infected patients.

[0215] Fluid circuit: The components present during the procedure offer several options. For example, the transfer set may remain attached, be removed, or be replaced with a new transfer set during the BRS procedure. The transfer set itself may be used to perform the lock valve / closure during locking, or a valved line connected to a syringe or other delivery system may be used for locking. This additional valve or valve with additional tubing may be provided as part of a catheter contamination removal product.

[0216] Filling and Drainage: Normal patient filling and drainage settings may be used, but may potentially be increased to increase the shear stress on the surface of the catheter lumen where biofilm is typically present. In one embodiment, sonication may be used during drainage to improve biofilm removal. The higher the shear stress, the better the solubilized biofilm is presumably removed, but there may be a trade-off with patient discomfort. Pulsatile flow (in the most extreme case: start / stop) can help break down the biofilm and may be enabled by the use of a syringe, gravity, or a pump (e.g., a PD cycler). For example, cycler software may be used to generate a more pronounced pulsation of the fluid flow during drainage. The APD pump may be run to pump fresh and / or used PD fluid back and forth or slosh it through the PD catheter and transfer set at certain times to increase the contact time and turbulence of the fluid.

[0217] It should be understood that various changes and modifications to the preferred embodiments of the invention described herein will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the spirit and scope of the subject matter of the invention and without sacrificing its intended advantages. Accordingly, such changes and modifications are intended to be covered by the appended claims.

Claims

1. A method of performing peritoneal dialysis (PD), comprising: delivering a PD solution through a PD catheter into a peritoneal cavity of a patient; leaving the PD solution in the peritoneal cavity; removing biofilm from the PD catheter wall using a biofilm removal solution while leaving the PD solution in place and a method comprising the steps.

2. The method according to claim 1, wherein the biofilm removal solution comprises: sodium citrate dihydrate; citric anhydride; alkyl sulfonate; and water .

3. The method according to claim 1, wherein the alkyl sulfonate is a metal sulfonate.

4. The method according to claim 1, wherein the metal sulfonate is sodium lauryl sulfate.

5. The method according to claim 1, wherein the biofilm removal solution comprises: sodium citrate dihydrate; citric anhydride; sodium lauryl sulfate; and water .

6. The method according to claim 1, wherein the biofilm removal solution comprises: sodium citrate dihydrate in a concentration range of about 32.13 g / L to about 39.27 g / L; citric anhydride in a concentration range of about 29.25 g / L to about 35.75 g / L; sodium lauryl sulfate in a concentration range of about 0.95 g / L to about 1.05 g / L; and water .

7. The method according to claim 1, wherein the biofilm removal solution further comprises: a pH value in the range of about 3.70 to about 4.10; total citrate in a concentration range of about 57.45 g / L to about 70.21 g / L; and a specific gravity in the range of about 1.025 to about 1.042 .

8. The method according to claim 2, wherein the biofilm removal solution comprises: the alkyl sulfonate in a concentration range of about 0.61 g / L to about 1.10 g / L .

9. The method according to claim 8, wherein the biofilm removal solution further comprises an antimicrobial component.

10. The method according to claim 9, wherein the antimicrobial component is selected from the group consisting of antibiotics, bleaching agents, and silver sulfadiazine.

11. The method according to claim 1, wherein the PD solution further comprises an antibiotic for treating bacteria exposed by the removed biofilm.

12. The step of removing the biofilm from the PD catheter wall using the biofilm removal solution comprises: transferring the biofilm removal solution to a syringe; Liquidly communicating the syringe with a transfer set disposed along the PD catheter; Filling the transfer set and the PD catheter with the biofilm removal solution The method according to claim 1, comprising:

13. The step of removing the biofilm from the PD catheter wall using the biofilm removal solution, Closing the transfer set valve to maintain the biofilm removal solution in the transfer set and the PD catheter for a first duration The method according to claim 12, further comprising:

14. The method according to claim 13, wherein the first period is between about 1 hour and about 12 hours.

15. The method according to claim 13, wherein the first period is between about 1 hour and about 1.8 hours.

16. The method according to claim 13, wherein the first period is about 1.5 hours.

17. The step of removing the biofilm from the PD catheter wall using the biofilm removal solution further comprises removing the biofilm removal solution, the PD solution, and the biofilm,

18. The step of removing the biofilm removal solution, the PD solution, and the biofilm, Replacing the syringe with a waste bag or other drain having a suitable fluid connection; Opening the transfer set valve and draining the biofilm removal solution and the PD solution into the waste bag or other drain via gravity or a pump Including, The biofilm removal solution and the PD solution include the biofilm removed from the transfer set and the PD catheter, The method according to claim 17.

19. The method according to claim 17, wherein the biofilm is removed from the inner walls of the transfer set and the PD catheter and a portion of the outer wall of the PD catheter located in the peritoneal cavity of the patient.

20. A method for removing contamination from a peritoneal dialysis (PD) catheter and removing biofilm from the PD catheter and a transfer set, comprising: Providing a biofilm removal solution; Transferring the biofilm removal solution to a syringe; Liquidly communicating the syringe with a transfer set disposed along the PD catheter; Filling the transfer set and the PD catheter with the biofilm removal solution A method comprising.

21. Closing the transfer set valve and maintaining the biofilm removal solution in the transfer set and the PD catheter for a first duration The method according to claim 20, further comprising.

22. The method according to claim 21, wherein the first period is between about 1 hour and about 12 hours.

23. The method according to claim 21, wherein the first period is between about 1 hour and about 1.8 hours.

24. The method according to claim 21, wherein the first period is about 1.5 hours.

25. The method according to claim 20, further comprising removing the biofilm removal solution, the PD solution and the biofilm.

26. The step of removing the biofilm removal solution, the PD solution and the biofilm comprises Replacing the syringe with the appropriate fluid connection with a waste bag or other drain; Opening the transfer set valve and draining the biofilm removal solution and the PD solution into the waste bag via gravity or a pump Including, The biofilm removal solution and the PD solution contain the biofilm removed from the transfer set and the PD catheter, The method according to claim 25.

27. The method according to claim 20, wherein the biofilm is removed from the inner walls of the transfer set and the PD catheter and a part of the outer wall of the PD catheter located in the peritoneal cavity of the patient.

28. The biofilm removal solution is Sodium citrate dihydrate; Citric anhydride; Alkyl sulfonate; and Water The method according to claim 20, comprising.

29. The method according to claim 20, wherein the alkyl sulfonate is metal lauryl sulfate.

30. The method according to claim 20, wherein the metal lauryl sulfate is sodium lauryl sulfate.

31. The biofilm removal solution is Sodium citrate dihydrate in a concentration range of about 32.13 g / L to about 39.27 g / L; Citric anhydride in a concentration range of about 29.25 g / L to about 35.75 g / L; Sodium lauryl sulfate in a concentration range of about 0.95 g / L to about 1.05 g / L; and Water The method according to claim 20, comprising.

32. The biofilm removal solution is A pH value in the range of from about 3.70 to about 4.10; Total citrate in a concentration range of from about 57.45 g / L to about 70.21 g / L; and A specific gravity in the range of from about 1.025 to about 1.042 The method according to claim 31, further comprising.

33. The biofilm removal solution is An alkyl sulfonate in a concentration range of from about 0.61 g / L to about 1.10 g / L The method according to claim 32, further comprising.

34. The biofilm removal solution further comprises an antimicrobial component, the method according to claim 32.

35. The method according to claim 34, wherein the antimicrobial component is selected from the group consisting of antibiotics, bleaching agents, and silver sulfadiazine.

36. The method according to claim 20, wherein the PD solution further comprises an antibiotic for treating bacteria exposed by the removed biofilm.

37. A method of performing peritoneal dialysis (PD), comprising: Pump-delivering a PD solution containing a biofilm removal solution through a PD catheter into a patient's peritoneal cavity; Leaving the PD solution containing the biofilm removal solution in the peritoneal cavity; Removing biofilm from the PD catheter wall through the biofilm removal solution while leaving the PD solution containing the biofilm removal solution A method comprising.

38. The method according to claim 37, wherein the PD solution further comprises an antibiotic for treating bacteria exposed by the removed biofilm.

39. A composition for removing contamination from a peritoneal dialysis (PD) catheter and removing biofilm from the PD catheter and transfer set, comprising: Sodium citrate dihydrate; Citric anhydride; A surfactant; and Water A composition comprising.

40. The composition according to claim 39, wherein the surfactant is selected from the group consisting of rhamnolipid, fengycin, glycolipid, lipopeptide, poloxamer, betaine, sodium lauryl sulfate, sodium dodecyl sulfate, and cetyltrimethylammonium bromide.

41. The composition according to claim 40, wherein the surfactant is sodium lauryl sulfate.

42. Sodium citrate dihydrate in a concentration range of from about 32.13 g / L to about 39.27 g / L; Citric anhydride in a concentration range of from about 29.25 g / L to about 35.75 g / L; Sodium lauryl sulfate in a concentration range of from about 0.95 g / L to about 1.05 g / L; and Water The composition according to claim 39, comprising

43. Sodium citrate dihydrate at a concentration of about 35 g / L; Citric anhydride at a concentration of about 33 g / L; Sodium lauryl sulfate at a concentration of about 1 g / L; and Water The composition according to claim 39, comprising

44. Total citrate in a concentration range of about 57.45 g / L to about 70.21 g / L further comprising, the biofilm removal solution comprising the composition has a specific gravity in the range of about 1.025 to about 1.042 and a pH value in the range of about 3.70 to about 4.10 The composition according to claim 39.

45. Alkyl sulfonate in a concentration range of about 0.61 g / L to about 1.10 g / L The composition according to claim 39, further comprising.

46. Sodium citrate dihydrate at a concentration of about 35 g / L; Citric anhydride at a concentration of about 33 g / L; Sodium lauryl sulfate at a concentration of about 1 g / L; Water; Total citrate at a concentration of about 63.83 g / L; and Alkyl sulfonate in a concentration range of about 1.00 g / L comprising, the biofilm removal solution comprising the composition has a specific gravity in the range of about 1.033 and a pH value of about 3.93 The composition according to claim 39.

47. The composition according to claim 39, further comprising an antimicrobial component.

48. The composition according to claim 47, wherein the antimicrobial component is selected from the group consisting of antibiotics, bleaching agents, and silver sulfadiazine.

49. A method for removing at least a part of the biofilm present in the lumen of an indwelling peritoneal catheter and simultaneously performing peritoneal dialysis therapy, comprising delivering dialysis fluid to the peritoneal cavity of a patient through the catheter; injecting a biofilm removal solution into the lumen of the catheter to occupy at least a part of the lumen; leaving the dialysis fluid in the peritoneal cavity; removing at least a part of the biofilm removal solution from the catheter by withdrawing at least a part of the dialysis fluid from the peritoneal cavity into the catheter A method comprising.

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