4% trisodium citrate solution for catheter locking

Abstract

The present invention relates to a 4% trisodium citrate solution for use as a catheter lock solution. Provided herein is a catheter lock solution having anti-coagulation and antimicrobial properties, the catheter lock solution comprising a citrate. The citrate may be trisodium citrate, and the catheter lock solution may additionally comprise a dilute acid to adjust the pH of the catheter lock solution.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201880069989.8 (International Application No. PCT / US2018 / 052186), whose priority date is September 22, 2017 and whose invention name is “4% trisodium citrate solution used as catheter sealing fluid”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 62 / 561,859, filed on September 22, 2017, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0004] The present invention relates to maintaining a catheter in a substantially blood and clot-free condition. More particularly, the present invention relates to the use of a citrate solution to prevent reflux and maintain patency in the lumen of a catheter. Background Art

[0005] A catheter, particularly an intravenous (IV) catheter, can be used to infuse fluids such as medications into a patient or to remove fluids such as blood from a patient. The catheter can include a lumen or reservoir containing fluids or medications to be injected into or removed from a patient. In some configurations, an injection port can be provided with a catheter.

[0006] Complications associated with catheters include thrombosis, infection, and coagulation. Catheter obstruction often occurs due to thrombotic complications related to the formation of a fibrin sheath within the lumen or at the end of the catheter. The formation of the fibrin sheath may allow bacteria to adhere to the interior of the catheter lumen and serve as a site for catheter-related infection.

[0007] In order to reduce the problems associated with coagulation and thrombosis, intravascular access catheters are often "locked" between consecutive uses. Locking typically involves first flushing the catheter with saline to remove blood and other materials from the catheter lumen. After the catheter has been flushed, an anticoagulant solution (typically heparin) is then injected to displace the saline and fill the lumen. The heparin lock solution prevents blood from entering the lumen and actively inhibits coagulation and thrombosis within the lumen.

[0008] Heparin lock solution is infused into the catheter lumen immediately after each use and remains in the catheter until the catheter is accessed again. The heparin lock solution must be removed from the catheter before the next use so that heparin is not introduced into the patient's body. In some cases, the heparin lock solution contains up to 10,000 units of heparin per catheter lumen. Infusing this amount of heparin into a patient may cause heavy bleeding.

[0009] However, even with conventional heparin lock solutions, catheters can become blocked between uses due to clotting of blood within the catheter. Blood may be present within the catheter because of insufficient volume of heparin infused into the lumen, diffusion of the heparin lock solution from the lumen, or residual blood remaining within the lumen. This can lead to thrombosis with an accompanying loss of patency and reduced flow through the catheter lumen.

[0010] There remains a need for catheter lock solutions that can provide long-lasting action, increased safety, and that do not require additional applications between catheter uses. Summary of the invention

[0011] Therefore, provided herein is a catheter lock solution comprising a citrate. In various aspects, the citrate is a sodium citrate salt. In other aspects, the citrate is trisodium citrate.

[0012] In various aspects, the catheter lock solution further comprises an acid. In various aspects, the acid is a dilute acid. In some aspects, the dilute acid is dilute hydrochloric acid (HCl).

[0013] In various aspects, the catheter lock solution comprises citrate in an amount between about 3.8% and 4.2% w / v.

[0014] In various aspects, the catheter lock solution comprises the acid in an amount between about 0% and about 0.7% v / v.

[0015] In certain aspects, the catheter lock solution comprises 4% w / v trisodium citrate, water for injection (WFI), and 0.7% v / v 10% HCl.

[0016] In certain aspects, the catheter lock solution does not contain any additional components having anti-coagulant or anti-microbial activity.

[0017] Also provided herein is a method of preparing a catheter lock solution. The method comprises the steps of dissolving a citrate, preferably trisodium citrate, in WFI, and adding dilute acid, preferably 10% HCl, until the pH of the catheter lock solution is between about 6.4 and about 7.5.

[0018] Also provided herein is a catheter lock solution comprising only trisodium citrate, water for injection (WFI), and 10% HCl.

[0019] In various aspects, the catheter lock solution. The catheter lock solution of claim 11, wherein the lock solution comprises only between about 3.8% and about 4.2% w / v trisodium citrate, WFI, and between about 0% and about 0.7% v / v 10% HCl, and has a pH between about 6.4 and about 7.5.

[0020] Also provided herein is a method of preparing a catheter lock solution. The method further comprises the steps of dissolving trisodium citrate in WFI and adding 10% HCl until the pH of the catheter lock solution is between about 6.4 and about 7.5.

[0021] Also provided herein is a catheter lock solution comprising only about 4% w / v trisodium citrate, water for injection (WFI), and about 0.7% v / v 10% HCl, the catheter lock solution having a pH of about 7.

[0022] Also provided herein are pre-filled syringes comprising a syringe containing a catheter lock solution as described herein.

[0023] Also provided herein is a catheter comprising a tube defining a lumen therethrough, at least a portion of the lumen being infused with a catheter lock solution as described herein.

[0024] Also provided herein are methods of inhibiting coagulation and microbial activity in a catheter, comprising the steps of providing a catheter comprising a tube defining a lumen therethrough, and infusing a catheter lock solution described herein into at least a portion of the lumen. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is a longitudinal cross-section of a pre-filled syringe comprising a catheter lock solution according to one aspect of the lock solutions described herein.

[0026] Figure 2 is a graphical depiction of the results of reflux of a lock solution according to one aspect of the lock solution described herein.

[0027] Figure 3 is a graphical depiction of a scatter plot of ACT results for samples according to one aspect of a catheter lock solution described herein that underwent accelerated aging.

[0028] Figure 4 is a graphical depiction of a scatter plot of ACT results for samples according to one aspect of a catheter lock solution described herein that underwent real-time aging.

[0029] Figure 5 is a graphical depiction of individual sodium citrate concentration data and 95% confidence interval data for a set of 3 mL syringes according to one aspect of a catheter lock solution described herein that underwent accelerated aging.

[0030] Figure 6 is a graphical depiction of individual sodium citrate concentration data and 95% confidence interval data for a set of 5 mL syringes according to one aspect of a catheter lock solution described herein that underwent accelerated aging.

[0031] Figure 7is a graphical depiction of individual sodium citrate concentration data and 95% confidence interval data for a set of 3 mL syringes according to one aspect of a lock solution described herein that underwent real-time aging.

[0032] Figure 8 is a graphical depiction of individual sodium citrate concentration data and 95% confidence interval data for a set of 5 mL syringes according to one aspect of a catheter lock solution described herein that underwent real-time aging.

[0033] Fig. 9 is a graphical depiction of individual pH data and 95% confidence interval data for a set of 3 mL syringes according to one aspect of a catheter lock solution described herein that underwent accelerated aging.

[0034] Fig.10 is a graphical depiction of individual pH data and 95% confidence interval data for a set of 5 mL syringes according to one aspect of a catheter lock solution described herein that underwent accelerated aging.

[0035] Fig.11 is a graphical depiction of individual pH data and 95% confidence interval data for a set of 3 mL syringes according to one aspect of a catheter lock solution described herein that underwent real-time aging.

[0036] Fig.12 is a graphical depiction of individual pH data and 95% confidence interval data for a set of 5 mL syringes according to one aspect of a catheter lock solution described herein that underwent real-time aging. DETAILED DESCRIPTION

[0037] The following description is provided to enable those skilled in the art to make and use the described aspects intended for carrying out the present invention. However, various modifications, equivalents, variations and substitutions will remain apparent to those skilled in the art. Any and all such modifications, equivalents, variations and substitutions are intended to fall within the spirit and scope of the present invention.

[0038] Provided herein are catheter lock solutions comprising citrate, a solvent, and a dilute acid. The lock solutions described herein provide patency for the catheter and exhibit anticoagulant and antibiotic activity. Without wishing to be bound by theory, it is believed that citrate chelates calcium (Ca) in the blood. 2+ ) ions act as anticoagulants. Calcium ions are necessary for the proper functioning of coagulation factors V and VII, which form the enzyme (tenase) and prothrombinase complex in the coagulation cascade. By chelating calcium ions, the cascade is blocked and coagulation is inhibited.

[0039] The sealing solution described herein and the pre-filled syringe also minimize the backflow of syringe-induced blood to the implanted catheter. The sealing solution described herein provides obvious advantages compared with typical heparin-based sealing, because the adverse events associated with the use of heparin, such as heparin-induced thrombocytopenia, systemic bleeding complications and determination interference can be avoided. In addition, the sealing solution based on citrate provides obvious cost and time savings compared with heparin-based solutions. The sealing solution as described herein also provides advantages about stable shelf life, such as at least two years from the time of manufacture. In addition, the use of pre-filled syringes saves time, improves the sterility and safety of the product and its delivery, and eliminates the possibility of contamination that may occur during manual filling.

[0040] As used herein, the term "catheter lock solution" or "catheter lock solution" refers to a solution injected or otherwise infused into the lumen of a catheter, with the purpose of allowing most of the solution to remain in the lumen until it is desired or required to enter or re-enter the lumen, typically for additional treatment or maintenance. Additional treatment may include, for example, infusing a fluid into the lumen of a catheter or removing a fluid from the lumen of a catheter. The catheter lock solution may be placed in the catheter to provide short-term or long-term protection. Preferably, the catheter lock solution may be retained in the lumen for a desired time of about a week, and in various aspects, up to about a month. However, the catheter lock solution may be replaced every day, such as during regular care or aseptic maintenance of the catheter. The catheter may be replaced or refreshed by extracting the catheter lock solution from the catheter lumen and sealing the catheter for the desired time with a new catheter lock solution in the catheter. The use of the catheter lock solution described herein may extend the life of the catheter, extend the interval between the need to replace the catheter lock solution, and / or inhibit infection in the patient.

[0041] The term "catheter" as used herein refers to a tube defining a lumen therethrough that can be inserted into a part of the body or provided to communicate with the body or other biological culture to deliver fluids thereto or remove fluids therefrom. In various aspects, the catheter lock solutions described herein can be used to provide anticoagulant activity (inhibit clotting) and antimicrobial activity in catheters such as soft or hard catheters.

[0042] As used herein, the term "anticoagulant activity" refers to the inhibition or prevention of blood clotting.

[0043] As used herein, the term "antimicrobial activity" refers to the destruction, inhibition or prevention of the proliferation, growth or reproduction of undesirable microorganisms, such as aerobic and anaerobic Gram-positive and Gram-negative bacteria, undulating bacteria, spirochetes, spores, spore-forming microorganisms, yeasts, fungi, molds, viruses, aerobic organisms, anaerobic organisms and mycobacteria.

[0044] Catheter lock solutions as described herein can be used to inhibit microbial activity and coagulation of catheters placed in specific parts of the body to allow, for example, drainage of urine from the bladder during catheterization; drainage of fluid collections; injection of intravenous fluids, medications or prenatal nutrients; angioplasty; angiography; balloon puncture; and direct measurement of blood pressure in an artery or vein. Although catheter lock solutions as described herein can be used to inhibit microbial activity and coagulation of any catheter, catheter lock solutions can also be used to inhibit microbial activity and coagulation of such catheters, such as those used for hemodialysis and hemofiltration that rely on separate withdrawal and return catheters implanted in a vein to allow extracorporeal processing of blood or for peritoneal dialysis, which relies on a single catheter implanted in the peritoneum to allow introduction and withdrawal of dialysate to allow in situ dialysis.

[0045] By preventing clotting within the lumen of the catheter, a citrate lock solution such as described herein maintains patency within the catheter. As used herein, the term "patency" means that the catheter is open or not blocked by, for example, a clot or fibrin sheath within the lumen of the catheter.

[0046] As described above, the catheter lock solution includes a citrate. As used herein, the term "citrate" refers to a salt of citric acid. Citric acid is a tricarboxylic acid having the formula C6H8O7 and is considered a weak acid. Examples of suitable citrates for use in the catheter lock solution described herein are sodium and potassium salts. In various aspects, the citrate is monosodium citrate, disodium citrate, or trisodium citrate. In particular aspects, the citrate is trisodium citrate. In some aspects, trisodium citrate is trisodium citrate dihydrate, which is a powder form of trisodium citrate that can be dissolved in a solvent.

[0047] As described above, it is believed that trisodium citrate acts by chelating calcium (Ca 2+ ) ions, interrupting the coagulation cascade and acting as an anticoagulant. As a catheter sealing fluid, trisodium citrate works in two ways to maintain catheter patency. First, the physical presence of the catheter sealing fluid prevents blood from flowing back into the catheter lumen from the patient, reducing the risk of coagulation or blockage of the lumen. Second, to the extent any blood does flow back into the catheter lumen, trisodium citrate prevents coagulation in the catheter lumen and at the catheter tip by interrupting the coagulation cascade.

[0048] The catheter lock solution includes a solvent in which citrate is dissolved. The solvent can be any biocompatible solvent. In various aspects, the solvent is water for injection (WFI). In various aspects, citrate is included in the solvent at a mass / volume concentration between about 3.8% and about 4.2% weight / volume (w / v), including all subranges and values ​​therebetween. As used herein, the term "about" refers to a difference of ±10% of the value. In various aspects, the catheter lock solution is made by dissolving trisodium citrate dihydrate at a mass / volume in WFI of about 4% (w / v).

[0049] The sealing solution also includes a dilute acid to adjust the pH of the solution. The dilute acid can be any biocompatible organic or inorganic acid. In various aspects, the dilute acid is 10% hydrochloric acid (HCl). In various aspects, the sealing solution includes a dilute acid between about 0 and about 0.7% v / v, including all subranges and values ​​therebetween. In various aspects, the sealing solution includes 10% HCl between about 0 and about 0.7% v / v. However, it will be appreciated by those skilled in the art that the amount of the dilute acid can be adjusted to reach a preferred pH of the sealing solution between about 6.4 and about 7.5.

[0050] In the particular aspects of the lock solution described herein, the solution includes trisodium citrate in WFI between about 3.8% and about 4.2% w / v, and the lock solution has a pH between about 6.4 and about 7.5, and in some aspects between about 6.54 and about 7.25, including all subranges therebetween. In some aspects, the pH of the lock solution is between about 6.57 and about 7.16 when delivered to the syringe during the preparation of a pre-filled syringe, including all subranges therebetween. In some aspects, the pH of the lock solution is about 6.87 when delivered to the syringe during the preparation of a pre-filled syringe.

[0051] In various aspects, 10% HCl between about 0 and about 0.7% v / v is included in the catheter lock solution. In some aspects, the catheter lock solution includes about 4% w / v of trisodium citrate dihydrate in WFI, and sufficiently diluted (e.g., 10%) HCl to provide a catheter lock solution with a pH of about 6.9. In other aspects, the catheter lock solution includes trisodium citrate, WFI, and optional HCl to provide the required pH, and does not include additional anti-coagulation or antimicrobial additives. In various aspects, the catheter lock solution does not contain excipients. In the following aspects, the catheter lock solution does not contain alcohol, glycerol, polyethylene glycol, citric acid, and / or polysorbate. In various aspects, the catheter lock solution does not contain any components other than citrate, WFI, and optional HCl.

[0052] Also provided herein is an infusion device containing a catheter locking solution as described above. In various aspects, the infusion device is a prefilled syringe including a catheter locking solution as described above. In various aspects, the prefilled syringe includes a distal end, a proximal end, and a barrel therebetween that defines a storage period. The prefilled syringe includes a plunger at the proximal end and a connector at the distal end that is configured to connect to a catheter, other needleless connectors, a Y-shaped location, etc. In various aspects, the connector at the distal end of the prefilled syringe is a male Luer connector or a female Luer connector. Reference Figure 1 , a pre-filled syringe 10 containing a catheter lock solution 20 as described above is shown. The pre-filled syringe includes a barrel 12, a plunger rod 14, a stopper 16, and a Luer connector 18. In some aspects, the pre-filled syringe is formed of polypropylene. In a specific aspect, one or more of the barrel 12, the plunger rod 14, and the top end cap (not shown) are formed of polypropylene. In various aspects, the stopper 16 of the pre-filled syringe is an elastic stopper.

[0053] In various aspects, the prefilled syringe 10 is designed or constructed to reduce or prevent blood backflow into the catheter when flushing with a lock solution as described herein is completed. In various aspects, the prefilled syringe is configured so that the plunger rod 14 is shorter than a typical plunger rod, thereby substantially or completely preventing compression of the plug 16 after infusion of the lock solution 20. In other aspects, the plug 16 is designed or constructed so that the nose of the plug contacts the distal end of the barrel adjacent to the Luer connector 18 and blocks the opening, preventing vacuum and thus backflow of blood into the catheter.

[0054] Also provided herein is a method for locking a catheter, comprising the step of infusing the locking solution described above into the catheter lumen. In various aspects, the method further comprises the step of flushing the catheter lumen before infusing the locking solution.

[0055] In various aspects, the method comprises the following steps: providing a catheter with an inner surface and an outer surface and infusing a catheter lock solution into at least a portion of the inner surface. Preferably, the lock solution is infused into the inner surface, thereby substantially filling the inner surface. Non-limiting examples of the inner surface of the catheter filled with the catheter lock solution described herein include a lumen, related pipelines, plungers, caps, and expansion kits. Other devices that can be coated or filled with the catheter lock solution described herein include the inner lumen of a vascular access device and a needleless access device. The lock solution can be infused by any conventional method well known to those skilled in the art such as dipping, spraying, or injection, for example and without limitation, using a pre-filled syringe as described herein.

[0056] When the sealing solution described above is infused into the inner surface of the catheter, a sufficient amount of sealing solution can be injected to fill or substantially fill the inner volume / space of the catheter, and any adjacent surface or lumen of the access device connected arbitrarily. Alternatively, the volume less than the amount of fluid required for filling the catheter can be infused into the inner surface. For example, a sufficient amount of sealing solution can be infused into the catheter to fill, for example, 80% to 250% of the inner volume of the catheter, including all sub-ranges and percentages therebetween. In another aspect, the amount greater than the inner volume of the catheter can be infused. For example, the sealing solution greater than the amount of the inner volume of the catheter can be infused into the lumen. Different from the sealing solution based on heparin, this overflow can be utilized without negatively affecting the coagulation system of the patient. The sealing solution can be infused or flushed into the catheter between 1 and 1000 times, including all sub-ranges and values ​​therebetween.

[0057] As described above, the method of locking the catheter effectively prevents blood from flowing back from the patient into the lumen of the catheter into which the locking solution is infused or introduced. In addition, the locking solution reduces the occurrence of clot formation or prevents clot formation, maintaining catheter patency.

[0058] Also provided herein are methods for preparing the catheter lock solutions described above. The catheter lock solutions can be prepared by simply mixing the above components at room temperature to provide anti-coagulation and antimicrobial activity. In other aspects, the solutions are prepared in batches and loaded into syringes to prepare pre-filled syringes that can be distributed and stored until needed.

[0059] Also provided herein is a catheter comprising a tube defining a lumen therethrough, the lumen being pre-filled with the catheter lock solution described above prior to insertion into a patient.

[0060] Example

[0061] Example 1

[0062] Samples of the catheter lock solutions described herein were tested in vitro. Briefly, 5 mL syringes prefilled with sterile 4% sodium citrate compounded at a pH of 6.9 were prepared. 635 samples were tested for reflux using a 4FR single lumen catheter (Bard, Covington GA), and the results are presented in Figure 2 It can be seen that the average reflux is 0.0±1.4446cm.

[0063] In addition to the above reflux test, additional samples of sterile 4% sodium citrate compounded at a pH of 6.9 were prepared and subjected to accelerated aging at 40°C ± 2°C / 75% RH ± 5% RH and real-time aging at 25°C ± 2°C / 60% RH ± 5% RH. Accelerated aging results were collected and analyzed at 0, 4, and 6.5 months, while real-time aging results were collected and analyzed at 6 months. The results are presented below in Tables 1 and 2 (average reflux in cm).

[0064] Table 1 – Accelerated Aging

[0065]

[0066] Table 2 – Real-time aging

[0067]

[0068] As can be seen from the table above, the aged samples demonstrated an average regurgitation of 0 ± 0.6 cm.

[0069] Example 2

[0070] Three different batches of trisodium citrate were used to compound the experimental samples at a pH of 6.9. These samples were subjected to accelerated aging at 40°C ± 2°C / 25% RH ± 5% RH and real-time aging at 25°C ± 2°C / 40% RH ± 5% RH. The anticoagulation efficacy of 4% sodium citrate sealing solution on whole blood was tested using Coagulation & Platelet Function Analyzer (Sienco Inc., Boulder CO) is used to perform the assay, which can calculate the onset of clot formation by monitoring the mechanical changes that occur in a blood sample during hemostasis. The mechanism is a tubular probe that moves up and down within a blood sample. As the sample progresses through the various stages of coagulation, an electronic circuit (transducer) detects the increase in resistance. This generates a series of electronic signals that are processed by a microcomputer. The output is the total time of clot formation, in which the blood is more viscous than when it was initially introduced.

[0071] The results of the above tests indicate that, by forming a clot during the lock and flush, a lock solution as described herein is able to maintain the patency of a vascular access device such as a catheter by preventing / reducing catheter occlusion that may result from a blood clot. Specifically, accelerated aging results were collected and analyzed at 0, 2, 3, 4, 6, and 6.5 months, while real-time aging results were collected and analyzed at 3 and 6 months (Tables 3 and 4 below) and compared to heparin, saline, or blood alone (control).

[0072] Table 3 – Accelerated Aging

[0073]

[0074] * = Equivalent to two years of real-time aging

[0075] Table 4 – Real-time aging

[0076]

[0077] Figure 3 and 4 Shows accelerated aging ( Figure 3 ) and real-time aging ( Figure 4 ) conditions. It can be understood that the results show that the tube lock solution described herein exhibits a consistent delayed coagulation start-activated coagulation time (ACT) ( Figure 3 and 4 On average, the ACT results were no less than 204.50 seconds (3.41 minutes) and no more than 320.58 seconds (5.34 minutes) (Tables 1 and 2 above). Within this range were 10 U / mL heparin sealing solutions ( Figure 3 and 4 ). It can therefore be concluded that, as described herein, sodium citrate catheter lock solution can maintain its anticoagulant efficacy throughout the shelf life of the product. The results also showed that, compared with heparin catheter lock solution, the solution demonstrated comparable anticoagulant effects and maintained catheter patency without the negative effects of using heparin, such as heparin-induced thrombocytopenia, bleeding risk, and systemic anticoagulation. This was further confirmed by performing a general linear model analysis on the ACT results of sodium citrate catheter lock solution and 10U / mL heparin catheter lock solution. The analysis presented in Table 5 below shows that the anticoagulant efficacy of 4% sodium citrate solution is comparable to the anticoagulant effect of 10U / mL pre-filled heparin product (p value is 0.752, no significant difference).

[0078] Table 5 – General linear model for ACT of citrate compared to heparin

[0079] source DF Adj Sum of Squares Adj mean square F-number P-value Blood Group 17 348440 20496.4 0.86 0.618 Solution type 1 2230 2230.0 0.10 0.752 Blood Group* Solution Type 17 404073 23769.0 25.82 0.000 error 540 497142 920.6 sum 575 1263984

[0080] Finally, the results demonstrated that sodium citrate lock delayed the onset of clotting longer than saline ( Figure 3 and 4 On average, the ACT results for saline were no greater than 135.42 seconds (2.26 minutes), compared to no less than 204.50 seconds (3.41 minutes) and up to 320.58 seconds (5.34 minutes) for the 4% sodium citrate lock solution (Tables 3 and 4 above).

[0081] Example 3

[0082] As described herein, sodium citrate tube-locking liquid has proved excellent stability, and it is believed that there is a guaranteed shelf life of 2 years from the date of manufacture. In order to test this point, 3 different salt batches are used to compound 5 batches of 3mL and 5mL experimental samples in the pH range of 6.8 to 7.0, to evaluate the concentration and pH of 4% sodium citrate tube-locking liquid. As mentioned above, these samples are experienced in the accelerated aging of 40 ℃ ± 2 ℃ / 25% RH ± 5% RH and the real-time aging of 25 ℃ ± 2 ℃ / 40% RH ± 5% RH. At 0, 2, 3, 4, 6 and 6.5 months, the accelerated aging results are collected and analyzed, and at 3 and 6 months, the real-time aging results are collected and analyzed. Table 6 and Table 7 (hereinafter) present the results of sodium citrate concentration, and Table 8 and 9 (also hereinafter) provide the results of pH.

[0083] Table 6 - Accelerated Aging, Sodium Citrate Concentration (w / v%)

[0084]

[0085] Table 7 - Real-time aging, sodium citrate concentration (w / v%)

[0086]

[0087] Table 8 – Accelerated aging, pH

[0088]

[0089]

[0090] Table 9 – Real-time aging, pH

[0091]

[0092] Figure 5-12 A scatter plot of selected data from the table above is shown. Figure 5 , 6 , 9 and 10 show data under accelerated aging conditions ( Figure 5 and Figure 6 The sodium citrate concentration is shown. Fig. 9 and Fig.10 pH is shown), and Figure 7 , 8 , 11 and 12 show the data of real-time aging conditions ( Figure 7 and 8 The sodium citrate concentration is shown. Fig.11 and 12 pH is shown).

[0093] As shown in the data, throughout the two-year equivalent time point (6.01 months for 3 mL syringes and 5.04 months for 5 mL syringes) and beyond (6.5 months), the results for these five batches demonstrated that the solution concentrations and pH values ​​for the anticoagulant 4% sodium citrate, 3.8-4.2% w / v ( Figure 5-8 ) and pH 6.4-7.5 ( Figure 9-12 ) within the corresponding USP38-NF33 specification interval.

[0094] Although the present invention has been described according to the above detailed description, those skilled in the art will appreciate that changes can be made within the spirit of the present invention. Therefore, the above should not be considered limiting, and the scope of the present invention is defined by the appended claims.

Claims

1. A catheter sealing solution, comprising: 3.8% w / v to 4.2% w / v trisodium citrate, based on the total volume of the locking solution; Water for injection; and 0.1% to 0.7% v / v HCl, based on the total volume of the sealing solution, wherein the pH of the catheter lock solution is between 6.4 and 7.5, and The catheter lock solution does not include additional anti-coagulation or anti-microbial additives.

2. The catheter lock solution of claim 1, wherein the HCl is dilute HCl.

3. The catheter lock solution of claim 1, wherein the catheter lock solution comprises 4% w / v trisodium citrate, water for injection, and 0.7% v / v 10% HCl. The catheter lock solution of claim 1 , wherein the catheter lock solution does not contain an excipient.

5. The catheter lock solution of claim 1, wherein the catheter lock solution does not contain parabens, alcohol, citric acid and / or polysorbate. The catheter locking solution according to claim 1 , wherein the catheter locking solution does not contain glycerol and / or polyethylene glycol.

7. A prefilled syringe comprising a syringe containing the catheter locking solution of claim 1.

8. A catheter sealing solution, comprising: 3.8% w / v to 4.2% w / v trisodium citrate, based on the total volume of the locking solution; Water for injection; and Amount of HCl sufficient to maintain the pH of the catheter lock solution between 6.4 and 7.5, The catheter lock solution does not include additional anti-coagulation or anti-microbial additives.

9. The catheter lock solution of claim 8, wherein the HCl is dilute HCl.

10. The catheter lock solution of claim 8, wherein the catheter lock solution comprises HCl in an amount between 0.1% to 0.7% v / v.

11. The catheter lock solution of claim 8, wherein the catheter lock solution comprises 4% w / v trisodium citrate, water for injection, and 0.7% v / v 10% HCl.

12. The catheter lock solution of claim 8, wherein the catheter lock solution does not contain an excipient.

13. The catheter lock solution of claim 8, wherein the catheter lock solution does not contain parabens, alcohol, citric acid and / or polysorbate.

14. The catheter lock solution of claim 8, wherein the catheter lock solution does not contain glycerol and / or polyethylene glycol.

15. A prefilled syringe comprising a syringe containing the catheter locking solution of claim 8.

16. A catheter sealing solution, comprising: 3.8% w / v to 4.2% w / v trisodium citrate; Water for injection; and An amount of HCl sufficient to maintain the pH of the catheter lock solution between 6.4 and 7.

5.

17. The catheter lock solution of claim 16, wherein the HCl is dilute HCl.

18. The catheter lock solution of claim 16, wherein the catheter lock solution comprises HCl in an amount between 0.1% to 0.7% v / v.

19. The catheter lock solution of claim 16, wherein the catheter lock solution comprises 4% w / v trisodium citrate, water for injection, and 0.7% v / v 10% HCl.

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