BE1024110B1 - Chemical assisted dissection device, method and formulation - Google Patents

Abstract

The invention provides a device for delivering a Mesna formulation to tissues and / or organs. The device comprises a first chamber comprising Mesna in solid form, a second chamber comprising a buffer and at least one outlet for delivering the Mesna formulation, said outlet is in fluid communication with at least one of the chambers. The chambers are separated from each other by at least one breakable separating means and are in fluid communication with each other upon rupture of said separating means thereby forming the Mesna formulation. The pH of the buffer included in the second chamber is at least 8.5. The invention further provides a process for the preparation of a Mesna formulation.

Description

Chemical assisted dissection device, method and formulation

Field of the invention

The present invention relates to a device for delivering a formulation of sodium 2-mercaptoethanesulfonate (Mesna) to tissues and / or organs. The invention further provides the formulation and a process for its preparation. The formulation and / or the device and / or the process may be used for chemically assisted surgery.

Background

It is known that when applied at the cleavage plane, sodium 2-mercaptoethanesulfonate or Mesna breaks the disulfide bonds between the tissue layers, thereby facilitating tissue separation. Specifically, Mesna breaks the disulfide bonds of proteins and polypeptide chains. However, today, for tissue separation, Mesna is only commercially available as pharmaceutical dosages for other applications. A major disadvantage of mesna solutions is their instability as mentioned in US 5,728,738. The liquid form is highly prone to oxidation and is therefore highly unstable particularly in the presence of catalyst metal ions. Therefore, it is common to store mesna solutions in low iron glass containers under a nitrogen sky with stabilizers, chelating agents, ions and antioxidants. In use, the practitioner must transfer the solution from the glass containers to a delivery device or tube to bring the solution into contact with the desired tissue. This step is not convenient, increases the risk of contamination, for example by bacteria and / or glass particles, at the site of dissection and increases the time of surgery. It is in addition to the high risks of oxidation of the stored Mesna solution thus having a reduced Mesna activity when it is used to assist the surgery.

Another disadvantage of Mesna in liquid form available to date lies in the absence of the choice of concentration. In some procedures, larger amounts and / or a different concentration of Mesna, than those readily available in commercial glass containers, are required. Indeed the practitioner can only dilute Mesna which is available in liquid form and can not use higher Mesna concentrations if necessary. This makes the use of said containers boring and inadequate. As mentioned in US 5,728,738, the available Mesna solutions are stabilized using pH adjusting agents and / or additives such as antioxidants and stabilizers thereby avoiding oxidation and / or degradation. Mesna when the Mesna solution is stored. The use of such agents presents a significant risk to the health of the patient (the authorities recommend avoiding such products in injectable solutions) and increases the cost of said Mesna solutions. In addition, commercial solutions are highly hypertonating and can damage exposed cells when applied topically. The object of the invention is to overcome at least some of the previously mentioned problems. One of the objectives of the invention is to provide a Mesna formulation having a pH which is close to physiological pH and / or closer to isotonicity. Another object of the invention is to provide a process for preparing such a formulation and a device for preparing and delivering said formulation to tissues and / or organs. This and other objects are achieved according to the invention by a formulation, a process and devices as described below and in the appended claims. summary

The present invention provides a device for delivering a Mesna formulation to tissues and / or organs, comprising a first chamber comprising Mesna, a second chamber comprising a buffer and at least one outlet for delivering the Mesna formulation, said output being in fluid communication with at least one of the chambers; said chambers are separated from each other by at least one breakable separating means and are in fluid communication with each other upon rupture of said separating means thereby forming the Mesna formulation. , characterized in that the pH of the buffer included in the second chamber is at least 8.5.

In another aspect, the invention provides a process for the preparation of a Mesna formulation, comprising the steps of dissolving Mesna in a buffer thereby obtaining the Mesna formulation, wherein the process is free of steps in which stabilizers and / or antioxidants are added after the dissolution of Mesna in the buffer and is characterized in that the pH of the buffer is at least 8.5. Preferably, the Mesna solution is prepared inside a device according to one embodiment of the invention. The invention further provides a Mesna liquid formulation comprising Mesna which is dissolved in a buffer having a pH of at least 8.5. Said formulation is prepared immediately before use and has a pH ranging from 6 to 8. The mesna concentration of the formulation is at most 10%, even more preferably at most 8%, most preferably at most 5%. The liquid formulation is sterile and has a pH of from 6 to 8. The formulation is free of antioxidants and / or stabilizers. The invention further provides a process for preparing a liquid Mesna formulation. Preferably, said liquid Mesna formulation is as previously described. The process comprises the step of dissolving Mesna in a buffer having a pH of at least 8.5, preferably at least 8.7, more preferably at least 8.8, most preferably at least 9. Said pH is the pH of the buffer before reconstitution, thus before the dissolution of Mesna in the buffer. The process is characterized in that it is free of steps in which stabilizers and / or antioxidants are added after the dissolution of Mesna in the buffer.

In another aspect, the invention provides a kit comprising a device according to one embodiment of the invention, optionally a first container comprising Mesna in solid form and a second container comprising a buffer having a pH of at least 8.5 and a leaflet including instructions for the user. The kit optionally includes at least one tubing and a system allowing the surgeon to control delivery during surgery.

The device of the invention is suitable for use as or as an integral part of a chemically assisted tissue dissection system. The device is suitable for connection to any surgical spatula for tissue separation known to those skilled in the art having a fluid connector for delivery at the active edge of said surgical spatula for tissue separation. . The device allows topical and local instillation of a chemical solution to facilitate mechanical dissection and tissue separation.

The device allows the controlled instillation of mesna during dissection of tissue directly in contact with the tissue to be detached thereby reducing its diffusion. Mesna facilitates the mechanical separation of tissue by the surgical spatula for tissue separation. The chemical compound for instillation is located in the device and thus forms an integral part of the device. Mesna is stored in the solid form device prior to use to take advantage of the superior stability properties of the solid form as compared to the formulated solution.

The formulation, the process and the device of the invention have several advantages. The formulation is free of antioxidants and / or stabilizers, the use of which is unnecessary as the solution is prepared immediately before use. This reduces the risk of potential side effects due to the use of such additives, ensures high Mesna activity and reduces the costs of the solution. The invention further provides maximized sterile nature of the Mesna solution delivered and thereby surgery and / or treatment. In addition, the invention provides a controlled delivery of the Mesna solution that can be delivered at the discretion of the practitioner and at the necessary time. It avoids annoying manipulations of solutions from glass containers to achieve the desired concentration and volume. In addition, the invention provides the device manufacturer the ability to provide multiple concentrations of Mesna solution for use by practitioners through various ratios of Mesna and buffer amounts.

The device containing the Mesna formulation of the invention is easy to use and facilitates tissue dissection while preserving healthy tissue and organ functions. Observable benefits are to reduce damage to the remaining tissues or organs (including surrounding tissues and organs), reduce pre- and postoperative bleeding, reduce post-operative adhesions, reduce surgical procedure time, reduce reduction of surgical complications and increased surgeon satisfaction. In addition, the invention makes it possible to reduce the length of stay in the hospital, preventing post-operative complications and makes it possible to reduce the repetition of the disease.

The device and / or the process and / or the method according to any embodiment of the present invention, allows to mix Mesna in solid form with a buffer having a pH of at least 8.5 shortly before use. This results in a Mesna formulation having an acceptable pH for use in surgery and provides maximum Mesna activity as oxidation of said Mesna is reduced compared to Mesna formulations stored for a long period of time prior to use. The Mesna formulation of the invention is prepared and / or delivered to the target at most 24 hours, preferably at most 12 hours, more preferably at most 8 hours, even more preferably at most 4 hours, most preferably at most 30 minutes, even more preferably at most 10 minutes after dissolution of said solid Mesna in the buffer.

Brief description of the figures

FIG. 1 represents a first embodiment of the device according to the invention; Figures 2A to D show the steps of using the device shown in Figure 1; FIG. 3 represents a second embodiment of the device according to the invention; Figures 4A to D show the steps of using the device shown in Figure 3; FIG. 5A represents a perspective view of a device according to a third embodiment of the invention; Figure 5B shows a cross-sectional view of the device of Figure 5A in which the chambers are not drilled; Figure 5C shows a cross-sectional view of the device of Figure 5A in which the chambers are drilled; Figure 5 'shows a longitudinal cross section of the device shown in Figure 5A; Figure 5D shows the different uses and possible connections of an embodiment of the device of Figure 5A; FIG. 6 represents another embodiment of the device according to the invention.

detailed description

Unless otherwise stated, all terms used in the disclosure of the invention, including technical and scientific terms, have the meaning as generally understood by those skilled in the art to which this invention belongs. With additional guidance, term definitions are included to better appreciate the teaching of the present invention.

As used in this document, the following terms have the following meanings: "One", "an", and "the" or "the" as used herein refer to both singular and plural referents unless that the context clearly dictates the opposite. For example, "a compartment" refers to one or more compartments. "Approximate" as used herein with reference to a measurable value such as a parameter, a quantity, a time duration, and so on, means to encompass variations of +/- 20% or less, preferably +/- 10% or less, more preferably +/- 5% or less, even more preferably +/- 1% or less, and still more preferably +/- 0.1% or less of and from the specified value, provided that such variations are appropriate to perform in the disclosed invention. However, it will be appreciated that the value to which the "about" modifier refers is itself also specifically disclosed. "Understand", "understand", and "understand" and "consist of" as used in this document are synonymous with "include", "include", "include" or "contain", "contain", "contains" and are inclusive or open terms that specify the presence of, for example, a component and do not exclude or exclude the presence of additional components, features, elements, members, steps, not mentioned, known in the art. technical or revealed within it.

Endpoint numeric ranges include all numbers and fractions within this range, as well as the endpoints mentioned. The expression "% w / v of (Mesna)", here and throughout the description, unless otherwise indicated, refers to the relative weight of the respective solid component versus the weight of the solution, before mixing the two components, assuming that this solution has a density of 1 g / ml. "Mesna Formulation" and "Mesna solution" are used herein as synonyms and refer to the aqueous solution obtained after dissolution of Mesna in solid form in the buffer as provided by the invention. WO 2014/180902 A1 proposes a device for delivering a solution to tissues and / or organs, the solution comprising at least one solute. The device of WO 2014/180902 A1 comprises at least one chamber which comprises sodium 2-mercaptoethanesulphonate in powder form. Furthermore, WO 2014/180902 A1 describes a process comprising the steps of dissolving the solute in the solvent inside the device, thereby obtaining the solution, and immediately delivering the resulting solution to said tissues and / or organs to facilitate dissection. US2005124589A1 relates to the use of mercaptothane sulfonate-sodium to increase the solubility of ifosfamide in stable, concentrated and / or highly concentrated (supersaturated), stable storage, concentrated and / or highly concentrated (supersaturated) pharmaceutical pharmaceutical preparations of ifosfamide for parenteral administration and a process for their production.

The present invention provides a device for preparing and / or delivering a Mesna formulation to tissues and / or organs. The device comprises a first chamber and a second chamber. The first room contains Mesna. Said Mesna is preferably in solid form. The second chamber comprises a solvent. The device further comprises at least one output for delivering the formulation; said outlet is in fluid communication with at least one of the chambers. The chambers are separated from each other by at least one breakable separating means and are in fluid communication with each other upon rupture of said separating means thereby forming the Mesna formulation. . The pH of the buffer in the second chamber is at least 8.5, preferably at least 8.7, more preferably at least 8.8, most preferably at least 9.

The device comprising the chambers could be provided in a package or pouch prior to terminal sterilization by gamma, X or Beta irradiation. An oxygen scavenger is preferably placed in the bag before sealing it to increase the life of the device and / or to prevent possible oxidation of Mesna by oxygen in the presence of water vapor passing through the walls. of the liquid container. Immediately before use, the device is removed from the package. The user activates the rupture means thereby obtaining the Mesna formulation that can be used in surgery.

The inventors have surprisingly found that Mesna is in the form of pure crystalline API (Active Pharmaceutical Ingredient) or in freeze-dried form can be sterilized by irradiation with gamma, X and Beta. The irradiation is preferably carried out at least 20 kGy, preferably at least 25 kGy, more preferably at least 30 kGy and at most 50 kGy, preferably at most 45 kGy. The freeze-dried form can be sterilized by ultrafiltration in solution prior to the lyophilization step.

The buffer could be obtained by mixing a solvent with at least one buffer excipient. The solvent could consist of water of high purity (eg, water for injection according to the pharmaceutical standard) and could contain between 0 and 0.9% NaCl. The pH of the buffer could be adjusted using pH adjusting agents to achieve a desired pH of at least 8.5. The pH of the buffer results in a Mesna formulation having a pH of 6 to 8 by adding only solid Mesna in powder form or in freeze-dried form to the buffer and without the addition of pH adjusting agents. This avoids the manipulation of the Mesna formulation obtained, for example to adjust the pH, thereby providing for the immediate use of the liquid Mesna formulation obtained. This ensures maximum sterile nature of the formulation and maximum safety for the patient through the use of a solution with a pH close to physiological pH.

The buffer may further contain 0 to 0.9% NaCl as a source of chlorine ions. This reduces side effects due to the depletion of chlorine ions. In particular, the lack of sufficient chlorine ions can trigger unexpected hyperactivity of certain cells such as neurons in the brain and in the nerves.

The buffer comprises phosphate so that the ratio of phosphate to Mesna of the Mesna formulation is at least 1/500, preferably at least 1/400, more preferably at least 1/300, even more preferably at least 1/250, most preferably at least 1/150, even more preferably at least 1/100. Said ratio is at most 1/1, preferably at most 1 / 1.5, more preferably at most 1/2, most preferably 1/3. Preferably, the buffer comprises or consists of Na2HPC> 4 and NaCl. More preferably, the buffer comprises or consists of 10 mM Na2HPC> 4 and 75 mM NaCl. The buffer may also comprise or consist of Na 2 HPO 4, more preferably 10 mM Na 2 HPO 4. The buffer excipient is selected from the group consisting of sodium acetate, acetic acid, glacial acetic acid, ammonium acetate, arginine, aspartic acid, sodium benzoate, acid benzoate, sodium carbonate, sodium bicarbonate, acid citrate, and the like. , sodium citrate, disodium citrate, trisodium citrate, glucono-delta-lactone, glycine, glycine HCl, histidine, histidine HCl, hydrobromic acid, meglumine, acid phosphate, potassium phosphate monobasic, dibasic potassium phosphate, sodium phosphate monobasic, dibasic sodium phosphate, sodium tartrate, acid tartrate, tromethamine (tris) or any combination thereof. The concentration of the buffer excipient is from 2 mM to 60 mM, preferably from 2.5 mM to 50 mM, more preferably from 5 to 40 mM, more preferably from 7.5 mM to 35 mM, most preferably preferably from 10 mM to 30 mM.

The solid Mesna could be Mesna in powder form, also referred to herein as crystalline form or pure crystalline Mesna from API production. Solid Mesna could also be in lyophilized form. Mesna from API production preferably meets pharmacopoeia criteria. The lyophilized form is preferably obtained by freeze-drying a Mesna solution resulting from the dissolution of Mesna powder in pure water for injection. The freeze-dried form is preferably as described in WO 2015/101 665, the contents of which are included in this document. Said solution of Mesna could be sterilized, preferably by microfiltration before lyophilization. Solid Mesna is stable under normal conditions and eliminates the need for special precautions to prevent the oxidation of Mesna solutions during storage. Normal conditions refer to the ambient temperature and a normal humidity level.

The final Mesna concentration in the resulting formulation is at most 10%, even more preferably at most 8%, most preferably at most 5%. Said concentration of Mesna is at least 1%, preferably at least 2%, more preferably at least 3% and most preferably at least 4% or any value between the previously mentioned values. These concentrations are advantageous for topical applications, such as in surgery, to limit the cytotoxicity of Mesna while maintaining sufficient Mesna activity. The hypertonizing characteristic of formulations having Mesna concentrations of 10% or more is a concern in topical applications. Experiments show that toxicity to cells and organs is a consequence of the hypertonicity of Mesna formulations with concentrations of 10% or more. Formulations with Mesna concentrations of 5% or less have reduced and almost absent toxicity. The said toxicity is not a consequence of the use of Mesna as such. In addition, preclinical and clinical studies in surgery show the efficacy of all Mesna concentrations on disulfide bond cleavage.

Preferably, the pH of the resulting formulation is from 6 to 8, preferably from 6.8 to 7.8, more preferably about 7.3. The pH of said formulation is obtained without pH adjustments, i.e. without the use of pH adjusting agents or molecules. It will be understood that the pH of the buffer itself - thus before the dissolution of the solid Mesna in said buffer - can be adjusted using pH adjusting agents to have a buffer with a pH of at least 8.5, preferably at least 8.7, more preferably at least 8.8, most preferably at least 9. The pH of the Mesna formulation - thus after mixing Mesna with the buffer - is not adjusted with agents of pH adjustment and is from 6 to 8. High pH values of the buffer, i.e. at least 8.5, preferably at least 8.7, more preferably at least 8.8, the more preferably at least 9, reduce the risk of bacterial growth and avoid the use of stabilizers.

The buffer is preferably free of carbon atoms. Lack of carbon inhibits and / or inhibits bacterial growth thereby improving the microbiological quality of the buffer and the Mesna formulation. In particular, the lack of carbon ensures a low level of bioburden inside the buffer and mesna formulation. The lack of carbon also ensures endotoxin contamination limited or absent from the buffer and therefore Mesna solution. In addition, the absence of carbon atoms does not provide additional tone to the buffer and / or Mesna formulation.

The separation means could comprise a spatial separation between the first chamber and the second chamber. This means that when the device is not in use, the chambers do not share any common elements, such as membranes and / or walls. In this embodiment, before using the device, a fluid connection is established between the two chambers to reconstitute the Mesna solution in the second chamber. The second chamber is then connected to user applications, such as surgery. Preferably, when the device is used, at least one of the first or second chambers is movable towards the other chamber and / or the two chambers are movable towards each other. One of the advantages of this design is that it offers the possibility of filling the rooms separately from one another in a sterile / clean environment. The assembly of the device can then be performed later in a non-sterile environment. After assembly of the device, a terminal sterilization step can be performed.

The separation means could be free of spatial separation between the first chamber and the second chamber. For example, the first chamber and the second chamber may be attached to each other by said separating means which separates the chambers from one another. After removal of the separating means immediately prior to use, the chambers are in fluid communication with each other and the reconstituted solution can be delivered to the user.

Preferably, the separating means comprises at least one breaking means for breaking said separating means. Preferably, the device further comprises a breakable sealing membrane positioned between the outlet and the chamber which is suitable for being in fluid communication with said outlet.

Preferably, the device comprises at least one control means that allows the control of the volume of solution flowing out of the device. Said control means could be any means known to those skilled in the art.

The device could include at least one sterilization microfilter positioned between the device outlet and the chamber that is suitable for fluid communication with said outlet. Preferably said microfilter is a membrane made of polyethylene terephthalate, polyamide, polyethersulfone, nylon or any other suitable material. In a preferred embodiment, the pore size is from 0.1 to 3 μm, preferably from 0.15 to 2 μm, more preferably from 0.2 to 1 μm, most preferably about 0.22 μm. . The presence of said microfilter further enhances the sterile nature of the solution and / or instills the sterile solution of the device, i.e. Mesna solution, during dissection. In a preferred embodiment, said microfilter has an additional venting membrane for removing air bubbles during delivery. In a preferred embodiment, the pore size of the vent membrane is 0.01 to 0.05 μm, preferably about 0.02 μm. The ventilation membrane is preferably made of polytetrafluoroethylene or any other suitable material.

The device could comprise at least one particle filter positioned between the chambers of the device. The particulate filter removes accidental particles that could be released during dissolution of Mesna in solid form in the buffer. The pore size of the particulate filter is 0.1 to 10 μm, preferably 0.22 to 8 μm, more preferably 0.5 to 6 μm, most preferably 1 to 5 μm.

The output of the device may be connected to at least one second device selected from the group consisting of surgical devices, high pressure pumps, delivery tubes, applicators, imperceptibly invasive surgical systems, robot-assisted device and low pressure pump. The output of the device can be connected to high pressure pumps for use in hydrosurgery. Said output could be connected via a Luer-Lok mechanism to said second device. The surgical device may be a spatula instrument for tissue separation known to those skilled in the art whose primary function is tissue separation in mechanical surgery. The spatula for tissue separation is a general manual surgical instrument used in gynecology, ENT surgery, orthopedics, neurosurgery and all other surgical procedures where tissues must be separated. Said spatulas for the separation of fabrics are stainless steel or titanium instruments with different hooks and curves, such as a long, intermediate, short bevelled hook, hook with ball, straight and curved, small and large versions. The spatulas for tissue separation may be provided with an internal capillary tube for delivering the fluid at their active edge. The shape of the spatula for separating the tissues to be used in surgery depends on the application and the surface. Many spatulas for tissue separation are reusable or disposable, made of plastic, stainless steel, titanium or other metals. The spatula for tissue separation may also be provided with a cavity and a second capillary tube for the aspiration of excess fluids and Mesna solution, as generally used to remove excess fluids from the operative field during the procedure that would otherwise prevent complete vision of the field. In a preferred embodiment, said surgical device or delivery tube may be combined with suction and / or aspiration / irrigation devices used in open and imperceptibly invasive surgery. For imperceptibly invasive surgery, said surgical device or delivery tube may be inserted into the suction / irrigation device instrument channel.

The device, according to any embodiment of the invention, can be connected to and / or controlled by an electrically driven mechanical system for delivering the Mesna solution to the target location. The system may be a syringe driver, syringe pump, or other system known to those skilled in the art.

Said system is preferably controlled by the practitioner using a pedal connected to the electrically driven mechanical system. This is advantageous as it provides the practitioner with a high level of freedom of the hands required for example for laparoscopic surgery also called minimally invasive surgery. Indeed, said practitioner will be able to use both hands for operations other than manipulating the device to deliver a Mesna solution to the target location.

The device, according to any embodiment of the invention, can also be held by hand and manipulated manually by the operator. When necessary, the device is further provided with a plunger which is used by the operator to deliver said Mesna solution. The plunger is slidably engaged in a particular chamber of the device.

The device is a disposable device. Preferably, it is a spatula for single-use chemically assisted tissue separation indicated for cleavage and separation of tissue layers to facilitate various surgical procedures, including abdominal surgery, thoracic surgery, urology, gynecology, orthopedics and otoneurological surgery.

The device and / or the process according to any embodiment of the present invention makes it possible to mix Mesna in solid form with a buffer having a pH of at least 8.5 very shortly before use. The resulting Mesna solution does not require any pH adjustment and can be used immediately. The use of the resulting solution allows maximum Mesna activity as the Mesna oxidation is greatly reduced compared to mesna solutions stored for a long period of time before use. The Mesna solution is prepared and / or delivered to the target at most 24 hours, preferably at most 12 hours, more preferably at most 6 hours, even more preferably at most 4 hours, most preferably at most 30 minutes even most preferably at most 10 minutes after dissolution of the solute in the solvent. In a preferred embodiment, the device is adapted to contain 5 to 200 ml, preferably 10 to 150 ml, more preferably 15 to 100 ml, most preferably 20 to 50 ml of buffer or any volume included in the mentioned beaches. Preferably, the device is designed to hold about 30 ml of buffer.

The different embodiments of the device will now be described with reference to the accompanying drawings.

Referring to Figure 1, a first embodiment of the device is shown. The device comprises a first chamber 8 housing Mesna in solid form and a second chamber 6 housing a buffer having a pH of at least 8.5. The chambers are separated from each other by separable means of separation. In this embodiment, the chambers are also attached to each other by the same breakable separating means which is in this case a breakable membrane 7. The first chamber 8 is sealed by a sealing membrane The proximal end X of the device is provided with an outlet 1 and an outlet tube 1 'for guiding the mixture out of the device. The outlet tube 1 'is movable and its distal end Y is suitable for breaking the sealing membrane 2 of the first chamber 8. Said distal end of the outlet tube 1' could be a pointed shape as shown in FIG. be of any other type and / or form suitable for breaking the sealing membrane 2. The device further comprises a microfilter 9 positioned between the outlet 1 of the device and the first chamber 8 which is suitable for being in fluid communication with said outlet 1. Preferably, the microfilter is integrated with and / or in the outlet tube 1 '. Said microfilter improves the sterile nature and prevents contamination of the device and the solution and / or the powder contained therein. In a preferred embodiment, said microfilter is made of a polyethylene terephthalate, nylon, polyethersulfone or polyamide membrane.

The device shown in Figure 1 is further provided with a breaking means for breaking the separating means, that is to say the membrane can be broken 7. Said breaking means comprises a lever 4, a trigger 3 and a ratchet gear 5, preferably a gear with a locking ratchet. The trigger 3 is movable from a position in which its proximal end X is in contact with the device, called the low position, to a position in which the proximal end X of the trigger 3 is not in contact with the device. the device, called high position. The lever 4 is in contact with the ratchet gear 5 and also in contact with one of the chambers, preferably with the second chamber 6 which is at the distal end Y of the device, more preferably with the device containing the liquid solvent. With this design, the movement of the trigger 3 leads to the rotation of the ratchet gear 5 which in turn moves the lever 4, thereby applying pressure to the second chamber 6. The steps showing the use of the Figure 1 are shown in Figures IA to 1D.

The device is simple to use and offers a fast system for dissolving the solute in the solvent. The device is also practical as it is suitable for being manually held by the user so that said holding is comparable to a pen hold in which the index moves the trigger 3 of the device.

The device is provided with a control means for controlling the volume of fluid flowing out of the device. Said control means comprises the trigger 3, the ratchet gear 5 and the lever 4 which are designed and / or positioned so that a predetermined volume of solution flows out of the device with each movement of the trigger 3 from its position high in its low position. In this way, the user can have control over the amount of fluid flowing out of the device, thereby avoiding any excess volume of delivered solution. In addition, the user will be provided with a command during the time the fluid flows out of the device. These possibilities are not offered by the devices of the prior art.

In a preferred embodiment, the trigger and / or the lever and / or gear with the locking ratchet and / or the outer walls of the device are made of injectable plastic material. In a preferred embodiment, the separating means and / or the sealing membrane are made of aluminum laminate.

Figure 3 shows a second embodiment of the device. The device comprises a first chamber 8 housing Mesna in solid form and a second chamber 6 housing a buffer having a pH of at least 8.5. At least one of the walls of each chamber is at least partially made of a rupturable membrane. The chambers are separated from each other by a separating means which comprises a spatial separation between the first chamber and the second chamber. This means that the rooms are separated from each other in the space. The separation means further comprises the rupturable membranes 26, 27 of said chambers. In this embodiment, at least one of said chambers is movable to the other chamber which can be mobile or non-movable. Preferably said movement is a sliding movement. The first chamber 8 is sealed by a breakable sealing membrane 2 which does not form part of the separating means. The proximal end X of the device is provided with an outlet 1 and an outlet tube 1 'for guiding the mixture out of the device. The outlet tube 1 'is movable and its distal end Y is suitable for breaking the sealing membrane 2 of the first chamber 8. Said distal end of the outlet tube 1' could have a pointed shape as shown in FIG. be of any other type and / or take a form suitable for breaking the sealing membrane 2. The device further comprises a microfilter 9 positioned between the outlet 1 of the device and the first chamber 8 which is suitable for being in fluid communication with said outlet 1. Preferably, the microfilter is integrated with and / or inside the outlet tube 1 '. Said microfilter improves the sterile nature and prevents contamination of the device and the solution and / or the powder contained therein. In a preferred embodiment, said microfilter is made of a membrane of polyethylene terephthalate, polyethersulfone, nylon or polyamide. The device is also provided with a handle 24 through which the device is maintained in a manner similar to maintaining a gun.

The device shown in Figure 3 is further provided with a breaking means for breaking the separating means. Said breaking means comprises a piercing means 20, a trigger 3 ', a linear ratchet 22 and a piston 21. The piercing means is positioned between the first chamber 8 and the second chamber 6; preferably said piercing means 20 is positioned between the rupturable membranes 26, 27 of the chambers which form part of the separating means of the device. Said piercing means 20 is provided with at least two opposite piercing elements 30, 31 for piercing and breaking the rupturable membranes 26, 27 of the first and second chambers. The piercing means 20 could be attached to the first chamber 8 as shown in Figure 3. Alternatively, said piercing means 20 could be attached to the second chamber 6 or the walls of both chambers. The trigger 3 'is suitable for being tightened or pushed towards the handle 24 of the device. Said trigger 3 'is connected to a sliding block 28 having a drive tooth 29 suitable for engaging a tooth of the linear ratchet 22 (Fig. 3). When the device is not in use, the trigger 3 'is in its "off position" in which it is not pushed into the handle 24 and the drive tooth 29 engages the most proximal tooth of the linear ratchet 22, as shown in FIG. 3. Preferably, the shape of the proximal end X of the linear ratchet 22 is a shape fitting to the distal end Y of the piston 21. Said piston 21 is positioned between the linear ratchet 22 and one of the chambers of the device, preferably the second chamber 6 containing the solvent as shown in Figure 3. The distal end Y of the piston 21 could be provided with a breakable sealing membrane 23 (Figure 3). The steps showing the use of the device of FIG. 3 are shown in FIGS. 4A to 4D.

The device is simple to use and offers a fast system for dissolving the solute in the solvent. The device is also convenient as it is suitable for being manually maintained by the user as said holding is comparable to a gun hold in which the index moves the trigger 3 'of the device.

The device is provided with a control means for controlling the volume of fluid flowing out of the device. Said control means comprises the trigger 3 ', the sliding block 28 and the linear ratchet 22 which are designed and / or positioned as a predetermined volume of solution flows out of the device with each movement of the driving tooth 29. By the movement of the drive tooth, refers to the sliding of said drive tooth by which the drive tooth 29 will engage the neighboring teeth of the linear ratchet 22. In this way, the user can have a controlling the amount of fluid flowing out of the device, thereby avoiding any excess volume of delivered solution. In addition, the user will be provided with a control of the time during which the fluid leaves the device. Devices of the prior art do not offer these possibilities.

Referring to Figure 5A, another embodiment of the device is shown. The device comprises a first chamber 50 for housing Mesna in solid form; a second chamber 51 for housing a buffer having a pH of at least 8.5 and at least one output 55 for delivering the solution. Said output is suitable for being in fluid communication with at least one of the chambers. In Fig. 5A, the output 55 is suitable for being in fluid communication with the second chamber 51. Said output 55 is covered by a removable cap (not shown) when the device is not in use.

The chambers are separated from each other by at least one separation means comprising at least one breakable separating means (52, 53 in Fig. 5B) and are in fluid communication with each other upon rupture of said severable separating means. At least one of the walls of each chamber is at least partially made of a rupturable membrane thereby forming the rupturable separating means. Said separable separating means could consist of two laminated aluminum sheets.

Figure 5B shows the details of the separation means. The chambers are separated from each other by a means of separation which comprises a spatial separation between the first chamber 50 and the second chamber 51. This means that the chambers are separated from each other in space and when the device is not in operation, the chambers do not share any common elements, such as membranes and / or walls. The separation means further comprises the aforementioned rupturable membranes 52, 53 of said chambers. At least one of said chambers is movable to the other chamber which may be mobile or non-movable. Said movement can be a sliding and / or rotating movement. Preferably, the first chamber 50 is movable to the second chamber 51 which is non-movable. The first chamber 50 is sealed by a non-breakable sealing membrane 60 which does not form part of the separating means.

The device is further provided with a breaking means 56 for breaking the breakable separating means, more particularly for breaking the rupturable membranes 52 and 53. Said breaking means comprises at least one piercing means 56. The piercing means is positioned between the first chamber 50 and the second chamber 51. Preferably, said piercing means 56 is included in the separating means and is positioned between the rupturable membranes 52, 53 of the chambers which are part of the means. separation of the device. Said piercing means 56 is provided with at least two opposed piercing elements for piercing and breaking the rupturable membranes 52, 53 of the first and second chambers (Fig. 5B). In a preferred embodiment, the rupturable membranes 52, 53 are made of aluminum laminate.

In a preferred embodiment, the device is provided with at least one air duct 57 for evacuating and / or inserting air from the device. Said air duct is covered by a sealing membrane that can not be broken when the device is not used (FIG. 5B). Said air duct 57 is preferably disposed at the distal end W of the device outer wall. FIG. 5C represents a cross-sectional view of the device in which the chambers are pierced by the piercing means 56.

The chambers of the device could be filled separately in a clean production environment. After filling, the device is assembled with a breaking means 56 inserted between the two chambers. The assembled device is placed in a sealed pouch and sterilized in the last place by irradiation. The device is stored until use.

Prior to use, the sterile device is removed from the bag and the Mesna solution is reconstituted by pushing the first chamber 50 against the second chamber 51. This causes the separation means to rupture and dissolve Mesna powder in the buffer. After mixing and dissolving, which takes from 1 to 60 seconds, the device is ready to be connected to an irrigated surgical instrument such as cannula elevators. The volume of the Mesna formulation is at most 200 ml, preferably at most 150 ml, more preferably at most 100 ml, even more preferably at most 50 ml, most preferably at most 30 ml, making it makes the device more ergonomic.

In use, the user moves the first chamber 50 to the second chamber 51. The movement leads to rupture of the rupturable membranes 52, 53 by the piercing means 56 (Figure 5C). The contents of the first and second chambers will mingle to get Mesna's solution. The device may further be shaken or shaken to ensure complete dissolution of Mesna in the buffer. Then, the removable cap is removed thereby uncovering the outlet 55. The sheet tab 60 is then removed to allow air to replace the volume of the dispensed solution. The output of the device can then be used to direct delivery of the Mesna solution to the target or can be connected to any other suitable device such as a spatula for tissue separation 61. It will be understood that the air duct 57 and the tongue 60 can be replaced by a permeable membrane.

In a preferred embodiment, the device could be provided with pressure means 58 for manually applying pressure to the first chamber walls and / or second chamber walls thereby delivering the solution to said tissues and / or organs. . The pressure means 58 is preferably visible to the user. The pressure means 58 may be a soft button. Preferably, the second chamber is provided with pressure means 58. Said pressure means 58 is suitable for applying a manual pressure thereby delivering the solution to said tissues and / or organs. The open air duct 57 admits air when the flexible wall of the chamber returns to its stable position.

In a preferred embodiment, the mesna solution is delivered in the form of droplets by applying manual pressure to the pressure medium 58. The control means of the device comprises the pressure means 58. The droplets have a predetermined volume which will from 50 to 300 μΙ, preferably from 60 to 200 μΙ, more preferably from 70 to 150 μΙ, most preferably from 80 to 100 μΙ. In this way the user is able to manually manipulate the device to directly deliver the Mesna solution from the device to the desired location and in desired volumes. The design, manufacture and use of the device are simple thus saving money and time. In addition, the device provides a possibility of controlling the amount of fluid flowing out of the device, thereby avoiding any excess volume of delivered solution. In addition, the user will be provided with a control of the time during which the fluid flows out of the device. Devices of the prior art do not offer these possibilities.

Figure 5 'shows a longitudinal cross-section of a device that can be used to prepare a Mesna solution based on similar principles, except that the surgical instruments are now separated from the cartridge and the fluid lines shown in FIG. Figure 5D are not used. The device comprises a first chamber 50 and a second chamber 51 separated by at least one breakable separating means 52, 53. A breaking means 56 is positioned between the first and second chambers. The device is provided with a suspension device 160 whose presence is optional. The device comprises at least one air duct 57 and a cap 163 which closes the outlet of the device and which must be removed before connecting the device to a second device. To connect to a second device, an activated luer valve 162 is positioned between the second chamber 51 and the device output.

As shown in FIG. 5D, the device 11 can be provided with a suspension device 160 for hanging it on a pole in an operating room. The output 55 of the device can be connected to a surgical instrument by a sterile piping 12. Three types of output connections 55 are shown in FIG. 5E: connection to an open surgical tool with a manual dispenser 13, connection to a tool for open surgery with a remote pump 14 to control the distribution of the Mesna solution and connection to a laparoscopic or endoscopic instrument implemented manually or by surgical robots 15. In a preferred embodiment, a filter could be inserted into the piping 12 to avoid contamination with microparticles and bacteria larger than a defined size (usually 0.2 to 10 microns).

Figure 6 shows another embodiment of the device. Said device comprises a first chamber 101 comprising Mesna in solid form and a second chamber 102 comprising a buffer. The first and second chambers are separated from each other by at least one breakable separating means which is represented by the cap 112 of the first chamber and the orifice 106 on the chamber 102.

The contents of the first chamber 101 are dissolved in the second chamber 102 after rupture of the separating means and fluid connection of the two chambers using a sterile fluid line 107 by pumping the liquid into and out of the first chamber 101. embodiment, the second chamber is provided with at least one orifice 106 for fluidly connecting the second chamber to the first chamber. Preferably the second chamber is provided with at least one outlet 108 for delivering the Mesna formulation. Said exit 108 may be connected to a surgical device such as manual instruments or imperceptibly invasive irrigated instruments inserted in trocars or robots. As shown in FIG. 6, a peristaltic pump 104, a foot switch 105 and at least one connecting tube 110, 103 could be used depending on the surgical device 109 to be connected to the second chamber 102.

The present invention further provides a process for the preparation of a Mesna formulation. The process comprises the steps of dissolving Mesna in a buffer thereby obtaining the Mesna formulation, wherein the process is free of steps in which stabilizers and / or antioxidants are added after dissolving Mesna in the buffer and is characterized in that the buffer pH is at least 8.5. Mesna is preferably in solid form which is a crystalline form or a lyophilized form. The buffer is preferably free of carbon atoms.

In a preferred embodiment, the dissolution step is performed in a device as provided by any embodiment of the present invention. The process further comprises the steps of providing a device comprising two chambers as previously described, breaking the separation means of the device thereby obtaining the Mesna solution, and delivering the Mesna solution obtained through the output from the device to a target location, particularly to tissues and / or organs.

In a preferred embodiment, the process comprises the steps of filling Mesna in solid form in a first container and filling the pad having a pH of at least 8.5 in a second container. Said containers are suitable for insertion into the device. Each filling step could be performed under aseptic or non-aseptic conditions followed by a sterilization step. The Mesna container and / or the buffer container could be stored and subsequently inserted into the device. This avoids the aseptic filling of the device chambers which facilitates the production process.

The process according to any embodiment of the invention provides controlled delivery of the Mesna solution. Said controlled delivery could be carried out using control means of the device and / or using an electrically driven mechanical system. The system may be a syringe driver, a syringe pump, or any other system known to those skilled in the art. Said system is preferably controlled by the practitioner using a pedal connected to the electrically driven mechanical system. This is advantageous as it provides the practitioner with a high level of freedom of the hands required for example for laparoscopic surgery also called minimally invasive surgery. Indeed, said practitioner will be able to use both hands for operations other than manipulating the device to deliver the Mesna solution to the target location. The invention further provides a method for weakening adhesion between tissues and / or organs by delivering a Mesna formulation to tissues and / or organs. The formulation is as previously described. The formulation may be delivered to said tissues and / or organs by a device according to any embodiment of the present invention.

The present invention further provides a kit comprising a device as previously described and / or a second device selected from the group consisting of surgical devices, high pressure pumps, delivery tubes and applicators and / or at least a first device. container filled with Mesna as previously described and / or at least a second container filled with a buffer as previously described. The kit further comprises a leaflet with user instructions and / or information concerning the Mesna and / or the buffer and / or the device of said kit. The kit optionally includes at least one piping and at least one dispenser or tubing compatible with a peristaltic pump.

The present invention further provides the use of a device and / or a process according to any embodiment of the invention for delivering a formulation comprising Mesna dissolved in a buffer having a pH of at least 8.5, preferably at least 8.7, more preferably at least 8.8, most preferably at least 9 to target tissues and / or organs. The present invention further provides the use of a Mesna formulation to weaken adhesion between tissues and / or organs.

It will be understood that for all embodiments of the device and / or method and / or process of the present invention, the amount of Mesna and the volume of buffer are selected so that the Mesna concentration of the formulation is at most 10%, even more preferably at most 8%, most preferably at most 5%. Said concentration of Mesna is at least 1%, preferably at least 2%, more preferably at least 3% and most preferably at least 4% or any value between the previously mentioned values.

It will be understood that for all embodiments of the device and / or the method and / or the process of the present invention, the powdered Mesna contained in the device and / or the buffer is sterilized, preferably by gamma or radiation irradiation. X. The irradiation is preferably carried out at least 20 kGy, preferably at least 25 kGy, more preferably at least 30 kGy and at most 50 kGy, preferably at most 45 kGy.

In embodiments where the powder chamber is physically separated from the liquid chamber, sterilization of the powder can be achieved by ultrafiltration of an aqueous solution followed by aseptic filling and lyophilization in the powder container or vial. Similarly, the buffer solution can be sterilized by conventional means prior to aseptic filling of the container or liquid bag.

Examples - Buffers

Different buffers were mixed with 5% w / v Mesna. The pH of the buffers used was at least 8.5, preferably at least 8.7, more preferably at least 8.8, most preferably at least 9. The buffers had different concentrations. The pH of the Mesna formulation obtained was measured. The results obtained are shown in Table 1.

Table 1: Mesna formulation pH after mixing 5% by weight / volume Mesna with different buffers

The results obtained show that the buffers evaluated after mixing with 5% w / v Mesna provide a Mesna formulation having a pH of 6 to 8 provided that said buffers have a pH of at least 8.5, preferably minus 8.7, more preferably at least 8.8, most preferably at least 9. - Sterilization of Mesna by irradiation

The purity of Mesna was evaluated before and after sterilization using X-rays and gamma radiation. The purity results are shown in Table la below.

Table la: purity of Mesna before and after sterilization using X-rays and gamma radiation

The results show that the irradiations used have a very limited effect on the purity of Mesna. Indeed, the maximum loss of purity observed was about 1%. Therefore, the Mesna powder or lyophilized Mesna can be sterilized by irradiation. - Toxicity of Mesna formulations with different Mesna concentrations

In vitro cytotoxicity of Mesna in human MRC-5 fibroblasts was evaluated. Two experiments were carried out. The first was performed with two doses of Mesna (5% and 10%) and NaCl (7.06 and 3.53%) and the second was performed with three doses of Mesna (5, 10 and 20%) and the three corresponding doses of NaCl (7.06, 3.53 and 1.76%). All samples were tested in triplicate. The evaluation of the cytotoxicity was carried out after the following times: T15 min, T30 min, Tlh, T2h, T4h, T8h and T24h.

The cells were thawed according to Standard Operating Procedure No. TEC-005 and subcultivated according to Standard Operating Procedure No. TEC-001. The cell line was cultured in flasks of 75 cm 2 in a suitable culture medium. Qualitative evaluation of cytotoxicity: At observation time T15 min, T30 min, Tlh, T2h, T4h, T8h and T24h, cells were examined under a microscope and changes in general morphology, formation of a vacuole, detachment, cell lysis and membrane integrity were observed and evaluated in comparison to untreated cells. A score was assigned based on observations. The score criteria are specified in Table 2 and the results are provided in Table 3.

Table 2: Criteria for Qualitative Evaluation of Cytotoxicity by Microscopic Examination

No cytotoxicity was observed by microscopic examination of cells incubated in cell culture medium only. Significant cell damage with up to 70% of round or lysed cells and more than 50% growth inhibition was observed (score 3) from 15 minutes of exposure to a 0.5% positive control phenol (Table 3). In general, there was a clear tendency for cytotoxicity, concentration-dependent, observed over time exposure for both Mesna and NaCl solutions (Table 3). There was no or very little difference between the cytotoxicity of each assessed Mesna concentration and the corresponding osmolarity-like NaCl solution (Table 3). The increase in cytotoxicity severity was slightly slower in Mesna at 20% and 10% and faster in 5% Mesna compared to their NaCl counterparts. At 30 minutes, the effects of Mesna at 5% appeared to be greater than Mesna at 10 or 20%.

Table 3: Qualitative Evaluation of Cytotoxicity by Microscopic Examination of the MRC-5 Cell Line Treated with 20%, 10% or 5% Mesna, 0.5% Phenol, 7.06% NaCl Control, 3, 53% or 1.76% or culture medium for 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours or 24 hours. The scores shown are the average of the two scores. The values are given as mean ± SD (standard deviation).

Quantitative Cytotoxicity Evaluation by MTT Assay: The quantitative cytotoxicity was evaluated after treatment at T15 min, T30 min, Tlh, T2h, T4h, T8h and T24h by viability assay using an MTT reagent. Cytotoxicity is defined as viability of a test substance below 70% in comparison to the culture medium. Percentages of cell viability are shown in Table 4 and Table 5.

Table 4: Quantitative Evaluation of the Cytotoxicity of the MRC-5 Cell Line Treated with 20%, 10% or 5% Mesna, 0.5% Phenol, 7.06% NaCl Control, 3.53% or 1.76% or culture medium for 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours or 24 hours. The results are expressed as a percentage of cell viability in comparison with the culture medium (100% viability).

° Value excluded (not in line with qualitative observations); * significant difference between Mesna and corresponding NaCl (p <0.05).

According to ISO 10993-5: 2009 guidelines, the lower the viability value (in percentage), the higher the cytotoxicity of the test substance. The results of the quantitative evaluation of the cytotoxicity confirm the results of the qualitative analysis: in the positive control group a cytotoxicity of phenol at 0.5% (percentage of viability below 70% in comparison with the culture medium) has been observed at all points in time.

In general, there was a clear tendency for cytotoxicity, concentration-dependent, observed over time exposure for both Mesna and NaCl solutions. Generally the cytotoxicity of Mesna at 5% is less than the cytotoxicity of Mesna at 10% and 20%, justifying the preference for low concentrations of Mesna, ie 5% and less, compared to high concentrations. Mesna, ie 10% or 20%, for clinical indications. This is particularly evident for exposure times between 1 and 4 hours (Table 5).

There was no or very little difference between the cytotoxicity of each assessed Mesna concentration at 20% or 10% and the corresponding NaCl solutions with similar osmolarity (respectively 7.06% and 3.53%). The time to reach cytotoxicity (70% cell viability compared to culture medium) is shorter in Mesna at 20% compared to its NaCl counterpart (Table 5).

After 15 minutes, the Mesna at 5 and 10% are very close to the limit of 70% (respectively 66 and 62.3% viability). The 1.76% NaCl is not cytotoxic after 2 hours.

Table 5: Comparison between the various concentrations of Mesna

* significantly different (p <0.05); ° excluded value

The results of these experiments show that the effects of Mesna are more deleterious to cells than similar osmolarity NaCl. This is more pronounced when a low dose of both products (5% Mesna and 1.76% NaCl) is used. This is explained by the fact that the impact on mesna disulfide bonds is clearly perceptible, whereas at a higher dose the impact of hypertonicity is largely dominant.

By comparing concentrations of Mesna at 5% and 10%, ie the concentrations used in most clinical trials, 5% Mesna appears clearly less cytotoxic than 10% Mesna, particularly after a long period of time. time period of exposure. - Effect of buffer on bacterial viability and growth

A buffer consisting of a solution of 10 mM Na2HPC> 4 + 75 mM NaCl and having a pH of 9 was evaluated for its ability to remain contaminated over time. The buffer was contaminated with 100 bacteria / ml. The bacteria were selected for their resistance to basic pH and their ability to produce a significant endotoxin concentration. The contamination was carried out in triplicate using a mixture of 3 bacteria: Escherichia coli, Pseudomonas aeruginosa and Vibrio parahaemolyticus.

Contaminated buffers were incubated for 3 weeks. A negative control, being an uncontaminated buffer, was also incubated for 3 weeks. The number of viable bacteria was determined immediately after inoculation (T0), 1 week after inoculation (Tl) and 2 weeks after inoculation (T2). The viability of the bacteria was determined by inoculating 100 μl of the contaminated buffer onto nutrient agar which was incubated at 35 ° C for up to 72 hours. The results are shown in Table 6 below.

Table 6: Number of viable bacteria in the buffer of 10 mM Na2HPO4 + 75 mM NaCl

The results show that the buffer of the Mesna formulation inhibits bacterial viability and growth. - Effect of buffer on bacterial endotoxin production

In parallel with the tests carried out to determine the bacterial viability in the buffer of the invention, tests to evaluate the level of production of bacterial endotoxin were carried out. The tests were according to the criteria of process D of the European Pharmacopoeia (edition 8.6), namely the chromogenic kinetic process. 750 ml of 10 mM phosphate buffer containing 75 mM NaCl were introduced into a sterile sealed flask. Six flasks were prepared of which 3 flasks were inoculated with the previously described bacterial mixture and 3 flasks were not inoculated with bacteria (used as a negative control).

The cap of the sealed flask was disinfected using ethanol, then 150 μl of the sample was taken using a 1 ml syringe and a 25G needle and inserted into an "Endosafe" tube.

The inoculated buffer was then diluted 40 times. A 10-fold diluted solution was first prepared. To do this, 900 μΙ of water for a bacterial endotoxin test (BET) and 100 μΙ of the inoculated buffer were introduced into an Endosafe® tube. The tube was then a parafilm, vortexed for 30 seconds and left for 5 minutes. The solution diluted 10 times is ready. For the preparation of the 40-fold dilution, 750 μΙ of water for BET and 250 μΙ of buffer diluted 10-fold were introduced into an Endosafe® tube. The tube was then covered with a parafilm, vortexed for 30 seconds and left out for 5 minutes. The parafilm was removed and 25 μΙ of the solution was introduced into each channel of the cartridge. The cartridge was analyzed using the Endosafe® nexgen-PTSTM. For replicate samples (three replicates), the entire procedure was performed (independent replicas).

The B ET tests were performed at the following time points: day 0, day 4, day 11 and day 21 after inoculation. The results are shown in Table 7 below.

Table 7: BET test results for 10 mM Na2HPC> 4 + 75 mM NaCl buffer

The level of endotoxin was always <0.025 EU / ml which is the acceptable endotoxin limit for injectables, the evaluated buffer does not promote the production of bacterial endotoxin and prevents bacterial growth, Similar results were obtained for phosphate buffer (10 mM Na2HPO4) only (i.e., without the 75 mM NaCl).

Claims (13)

A device for delivering a Mesna formulation to tissues and / or organs, comprising a first chamber comprising Mesna in solid form, a second chamber comprising a buffer and at least one outlet for delivering the Mesna formulation, said exit is in fluid communication with at least one of the chambers; said chambers are separated from each other by at least one breakable separating means and are in fluid communication with each other upon rupture of said separating means thereby forming the Mesna formulation. , characterized in that the pH of the buffer included in the second chamber is at least 8.5. 2. Device according to claim 1, wherein the buffer is free of carbon atoms. 3. Device according to any one of claims 1 or 2, wherein the buffer comprises phosphate so that the ratio of phosphate on Mesna is at least 1/500 and at most 1/2. 4. Device according to any one of claims 1 to 3, wherein the concentration of the Mesna formulation is at most 10%, preferably at most 5%, 5. Device according to any one of claims 1 to 4, wherein the buffer comprises between 0% and 0.9% NaCl, preferably between 0.2% and 0.6% NaCl. 6. Device according to any one of claims 1 to 5, comprising at least one control means which allows the control of the volume of solution flowing out of the device. 7. Device according to any one of claims 1 to 6, wherein the outlet can be connected to a second device selected from the group comprising surgical devices, high pressure pumps, delivery tubes, applicators, systems. imperceptibly invasive surgery and a low pressure pump. 8. Device according to any one of claims 1 to 7, wherein the mesna included in the first chamber is in crystalline form or in freeze-dried form. 9. Process for the preparation of a Mesna formulation, comprising the steps of dissolving Mesna in solid form in a buffer thereby obtaining the Mesna formulation, wherein the process is free of steps in which stabilizers and / or or antioxidants are added after dissolving Mesna in the buffer and characterized in that the pH of the buffer is at least 8.5. The process of claim 9 wherein the Mesna is in crystalline form or in freeze-dried form. The process of any of claims 9 and 10, wherein the buffer is free of carbon atoms. The process of any one of claims 9 to 11, wherein the steps of dissolving Mesna in a buffer are conducted in a device as described in any one of claims 1 to 8. The process of any one of claims 9 to 12, wherein the concentration of the prepared Mesna formulation is at most 10%, preferably at most 5%.