阅读说明：本技术 静脉曲张修复组合物的制备方法、装置、系统和试剂盒 (Method, device, system and kit for preparing varicosity repair composition ) 是由 恩里克·罗克·雷波洛 吉恩巴蒂斯特·盖利 吉乌·卢萨·梅伦德斯 费德里科·格瑞高梅厄 阿卡蒂 于 2019-08-20 设计创作，主要内容包括：本发明提供了用于生产泡沫硬化剂组合物的容器的示例。容器包括容器主体,该容器主体包括在容器主体的顶部和底部之间延伸的一个或多个侧壁以及底表面,在容器主体的内部限定的发泡空间。发泡空间包含无菌气体和混合元件,该混合元件被配置成与可旋转致动器可操作地联接,而致动器不进入发泡空间。该容器包括用于与注射器配合的凹形联接构件,以及用于将发泡空间内侧的压力与发泡空间外侧的压力均衡的压力均衡器。还提供了包括此类容器的系统和试剂盒。还公开了用于制备硬化剂泡沫的方法,该方法可包括在泡沫提取之前的压力释放和/或在泡沫提取的同时致动器的持续旋转。(The present invention provides an example of a container for producing a foam hardener composition. The container includes a container body including one or more sidewalls extending between a top and a bottom of the container body and a bottom surface, a foaming space defined inside the container body. The foaming space contains a sterile gas and a mixing element configured to be operably coupled with the rotatable actuator without the actuator entering the foaming space. The container comprises a female coupling member for cooperation with the syringe, and a pressure equalizer for equalizing the pressure inside the foaming space with the pressure outside the foaming space. Systems and kits comprising such containers are also provided. Also disclosed are methods for preparing a sclerosant foam, which may include pressure release prior to foam extraction and/or continued rotation of the actuator while the foam is extracted.)

1. A container for producing a foam hardener composition, the container comprising:

a sealed, sterile container body for foaming comprising one or more sidewalls extending between a top and a bottom of the container body, a foaming space defined inside the container body;

the foaming space contains a sterile gas and a disk configured to rotate on the bottom of the vessel body and comprising a magnetic portion and a shape suitable for mixing, and configured to operably couple with a magnetic stirrer without the magnetic stirrer entering the foaming space; wherein the content of the first and second substances,

the container includes a female coupling member having a luer fitting for mating with a tip of a syringe, the female coupling member located in one of the sidewalls of the container body, at or near a bottom surface of the container body, such that the syringe may be used to extract the foam sclerosant composition, and

a pressure equalizer for equalizing pressures inside the foaming space and outside the foaming space.

2. The container of claim 1, wherein the female coupling member comprises a cap for closing the coupling.

3. The container of any of claims 1-2, wherein the female coupling member for mating with a syringe further comprises a one-way valve for introducing a liquid sclerosant composition.

4. The container of any of claims 1-3, wherein the pressure equalizer is a pressure release.

5. The container of claim 4, wherein the pressure relief comprises an aperture in the container body and a releasable cover.

6. The container of claim 5, wherein the orifice is located at the top of the container body.

7. A container according to claim 5 or 6, wherein the aperture has a diameter of 1mm to 3 mm.

8. The container of any of claims 5-7, wherein the releasable cover comprises a handle for pulling out the releasable cover.

9. The container of any of claims 1-8, wherein the mixing element configured to operably couple with the rotatable actuator is a disk comprising a magnetic portion and a shape suitable for mixing;

wherein the rotatable actuator is configured to induce a rotating magnetic field, and optionally a magnetic stirrer.

10. A kit for preparing a foam sclerosant composition, comprising a container according to any of the claims 1-9, further comprising a syringe, in particular a syringe pre-filled with a liquid sclerosant composition.

11. A method for preparing and extracting a foam sclerosant composition, the method comprising:

providing a container having:

a sealed, sterile container body for foaming comprising one or more sidewalls extending between a top and a bottom of the container body, a foaming space defined inside the container body, the foaming space containing a sterile gas and a mixing element configured to be operably coupled with a rotatable actuator without the actuator entering the foaming space, wherein

The container additionally comprises: a female coupling member for cooperating with a syringe, and a pressure equalizer for equalizing pressures inside the foaming space and outside the foaming space;

and the method further comprises:

providing a syringe filled with a liquid sclerosant composition;

mating the syringe with the coupler and injecting the liquid sclerosant composition into the foaming space;

operating the actuator to rotate the mixing element and produce a foam hardener composition,

extracting the obtained foam hardener composition.

12. The method of claim 11, wherein the syringe remains mated with the coupler while foam is being generated, and optionally wherein the obtained foam sclerosant composition is extracted by aspirating the syringe.

13. The method of claim 11 or 12, wherein the actuator is operated to rotate the mixing element at a first rotational speed of 5,000RPM or less, and preferably the actuator is rotated to rotate the mixing element at a first rotational speed of between 2,000 and 4,500RPM during a first time period.

14. The method according to claim 13, wherein the first time period is between 15 and 90 seconds, in particular between 30 and 75 seconds, more in particular between 30 and 60 seconds.

15. The method of any of claims 11-14, wherein the actuator operates while extracting the obtained foam hardener composition at a second speed, wherein the second rotational speed is lower than the first rotational speed.

Technical Field

The present application relates to the technical field of vascular medicine and more particularly to the field of treatment for varicose veins and other vascular problems, such as for example spider veins and/or hemorrhoids.

In particular, the present application relates to devices, systems, kits and methods for obtaining foam that can be used to treat affected veins, in particular to the composition of the foam itself obtained by any of the processes described throughout the application, as well as the use of the systems, devices and kits for treating varicose veins and other vascular problems, such as for example spider veins and/or hemorrhoids.

Background

Varicose veins can occur when the venous valve (which prevents backflow of blood) fails to function properly. As a result, the vein walls weaken and they may deform and expand. Due to the fact that the valve does not work properly, blood may recirculate and may cause short circuits. Subsequently, the vein may gradually dilate. As a result, varicose veins can become more visible, and can fill with bends and become larger. The evolution of this pathology may lead to consequences beyond mere cosmetic consequences, such as skin discoloration, pain and limb swelling due to the effects of venous hypertension.

According to spanish vasculology and vascular surgery Society (SEACV) data in spain, varicose veins affect 30% to 33% of the adult population in industrialized countries.

The most commonly affected veins are those in the legs, but varicose veins can also occur internally: such as varices in the esophagus, around organs located near the pelvis (pelvic and ovarian varices), or at or near the distal-most part of the digestive tract, near the anus (hemorrhoids).

Today, there are many different treatment methods and/or strategies in order to alleviate or eliminate these problems. Among them, we can find a surgical method. These surgical methods are related to surgical extraction of affected veins using classical surgery. This technique has been used for over 100 years and is based on making different skin incisions followed by clamping, ligating and peeling of the affected vein segments. This technique is performed under spinal anesthesia (spinal cord space infiltration) in order to obtain anesthesia of both limbs, and to anesthetize more confined areas with local or nerve block anesthesia.

In the late 1990 s, significant progress was made in the treatment of varicose veins, as they were treated using minimally invasive techniques, such as intravenous techniques. Of these new approaches, it is important to highlight intravenous procedures where heat is applied through a catheter (endoscope or radio frequency system).

These systems can reduce injury due to the fact that these methods are typically performed under ultrasound guidance. The effect on the vein is produced by the release of heat or electricity from inside the vein, and thus internal damage may occur to the vein. In this way, venous thrombosis is achieved.

Another technique is sclerotherapy by injecting sclerosing foam. This technique (compared to "endo-or radio frequency therapy) is less invasive, less painful, and does not require anesthesia (R Van den Bos et al, endo therapeutics variants of lower extreme. A. meta-analysis. J. Vasc Surg 2009 Jan; 49(1): 230-9).

In summary, a trend was found to minimize the invasiveness of varicose vein therapy in the late 1990 s and early 2000 s. Among all emerging technologies, sclerotherapy appears to be less invasive and can be applied to almost any type of varicose veins.

Therefore, in recent years, the process has been developed further and the scientific community has become more and more interested in obtaining a process suitable for the manufacture of foams in a safe and convenient way.

Sclerotherapy involves the infusion of a fluid (intravenous thin layer or lining in contact with the blood stream) that has the ability to stimulate the endothelium of blood vessels.

Upon shaking, the drug or liquid drug may become a foam. Internationally recognized for this purpose is dodecanol (also known as polidocanol and as such)Commercially available) and sodium tetradecyl sulfate.

The advantage of using such products as foam is based on the enhanced effect thereof due to the larger contact surface with the endothelial wall. The larger contact surface provides the possibility of reducing the dose. The visibility of the drug as a foam can also be improved by using ultrasound through an ultrasound scanner (Schadeck M, Allaert FA, bilateral scan in sclerotherapy mechanisms: importance of spasticity Phlebology 1995; supplement: page 574 576).

The effect of foam on the endothelium involves damage to the layer of venous cells, thereby producing thrombosis of its contents. Later, the vein undergoes a fibrotic process (contraction and disposal) and may eventually disappear after several months.

The process may be faster or slower depending on the vein size or the efficacy of the varicose agent. Thus, it is sometimes necessary to apply several courses intravenously.

While there are a number of methods to eliminate or remove varicose veins, to date, such methods are less aggressive and destructive, and the method available for many pathologies is ultrasound-guided foam sclerotherapy using polidocanol or other sclerosing agents. Sclerotherapy is today known as a minimally invasive treatment of varicose veins, since it can be performed in a completely ambulatory manner in the physician's office. Accordingly, the present disclosure focuses on the use of this technology.

In 1995, doctor Juan Cabrera introduced the results of the use of foam he developed with the son pharmacist Juan Cabrera (Cabrera J. et al, "Long term results in the treatment of sclerosing varicose greater saphenous vein in the form of microbubbles", "hematology (2000) 15; 19-23). The foam is characterized by its density and high solubility due to the use of physiological gas mixtures.

Furthermore, due to his approach using a mixer, he managed to achieve a foam with very small uniform bubble sizes. By using a mixture of physiological gases, the foam has greater safety and stability. The foam is referred to as "microfoam" due to the smaller foam size, uniformity and stability.

The greatest popularity of sclerosing foams since long came from Lorenzo Tessari (Tessari L., Cavezzi A., Frullini A., preliminary experience in the treatment of varicose veins with new sclerosing foams DermatolSurg 2001 Jan; 27 (1): pages 58-60), who published his experiments with a foam that was easily manufactured by a process called the "Tessari method". The method includes stirring the sclerosant solution using two syringes connected via a three-way tap. By means of the continuous alternating movement of each injector connected to the gas/liquid mixture, a foam mixture is achieved which is located inside the injector. However, although this manufacturing technique is the most widely used, it is not the most efficient as it results in a relatively unstable and non-uniform foam.

In recent years, many papers and articles have been published on the safety, side effects and potential complications caused by the use of these products. Thus, it seems that the optimum foam used is proven to be O with a gas of different concentrations₂/CO₂Foaming of the mixture. By this arrangement, compared to atmospheric foamSolubility and diffusion in blood are very high. In addition, the stability of the foam is related to the size of the foam. In addition, it has been found that the foam is more stable when the bubble diameters are more uniform.

As already mentioned, although there are many manufacturing systems for stiffening foams, the most common foam (and one commonly used in the world) is that obtained by the Tessari method. However, this method suffers from many problems of standardization and homogenization. The system involves the mixing of a gas stream with a selected liquid (polidocanol or sodium tetradecyl sulfate) (commercially known as sodium tetradecyl sulfate)) And (4) mixing. The foam may have medium sized bubbles, but is irregular in size and becomes unstable after several seconds of foam formation. In addition, the use of atmospheric gas as an excipient to harden the foam limits the foam that can be administered per course of treatment.

US2017144115 discloses a container for producing a foam hardener composition, kits and systems comprising such a container, and methods of preparing a foam hardener composition using such a container. In one aspect, a container includes a container body and a mixing element disposed in the container body such that a foaming space is defined between a sidewall and the mixing element inside the container body. The mixing element may be configured to be operably coupled with the rotating actuator without the actuator reaching the foaming space. In particular, the mixing element may have a magnetic core such that it can be moved when placed on the magnetic stirrer.

WO2017085209 relates to a container for producing a foam hardener composition, to a kit and a system comprising such a container, to a method of preparing a foam hardener composition using such a container, and to a foam hardener composition obtainable by such a method. In one aspect, the container includes a sealed, sterile container body having one or more sidewalls extending between a top and a bottom of the container body and defining a foaming space. The container further includes a mixing element disposed in the container body. The container contains the previously introduced gas and liquid hardener composition. The mixing element is configured to be operably coupled with the rotatable actuator without the actuator reaching the foaming space. The appropriate amount and concentration can be selected by the medical professional for each treatment.

These documents disclose methods and devices that facilitate the rapid production of high quality sclerosant foam with relatively simple tools and in a highly sterile manner.

However, there remains a need for further improved systems and methods for rigid foam production.

Disclosure of Invention

In a first aspect, the present disclosure provides a container for producing a foam sclerosant composition, the container comprising a sealed, sterile container body for foaming, the container body comprising one or more side walls extending between a top and a bottom of the container body, a foaming space being defined inside the container body. The foaming space contains a substantially sterile gas and a mixing element configured to be operably coupled with the rotatable actuator without the actuator entering the foaming space. The container comprises a female coupling member for cooperation with the syringe, and a pressure equalizer for equalizing the pressure inside the foaming space and outside the foaming space.

According to this aspect, a container is provided which is particularly suitable for the substantially aseptic preparation of a sclerosant foam, wherein a syringe may be used for introducing the liquid sclerosant composition. The introduction of the liquid hardener composition may create an overpressure inside the foaming space, i.e. the (atmospheric) pressure inside the foaming space is higher than the ambient pressure.

The syringe may also be used to aspirate or extract foam from the foaming space. It can then be injected into the patient's vein using the same syringe. An overpressure inside the foaming space may cause problems during suction, because of the presence of air or gas bubbles in the syringe. In order to avoid such problems, a pressure equalizer is provided which can reduce or avoid overpressure in the foaming space.

In another aspect, the present disclosure provides a kit for preparing a foam sclerosant composition, comprising such a container, and further comprising a syringe, optionally prefilled with a liquid sclerosant composition.

In another aspect, a system is provided that includes such a container and an actuator configured to be operably coupled to a mixing element. The actuator may in particular be a magnetic stirrer.

In another aspect, a method for preparing and extracting a foam hardener composition is provided. The method comprises providing a syringe filled with a liquid sclerosant composition and providing a container as explained above. The method additionally includes mating a syringe with the coupler and injecting the liquid sclerosant composition into the foaming space, operating the actuator to rotate the mixing element and produce the foam sclerosant composition, and extracting the obtained foam sclerosant composition.

In a method according to this aspect, a substantially sterile and relatively easy method for preparing and extracting a foam sclerosant composition is provided, which allows a syringe to be coupled with a container having a foaming space.

In another aspect, there is provided a foam hardener composition obtainable by such a process.

In some examples, the female coupling member or "socket" of the container body comprises a luer fitting. The female coupling member used throughout this disclosure may be considered to be a coupling member having a suitable receptacle or opening for receiving the male coupling member, and in the present case the male coupling member of the distal end of the syringe. The female coupling member may have the shape of a socket or sleeve.

Luer is a standardized system for small fluid fittings for leak-free connection between male tapered fittings and their mating female parts (including syringe tips) on medical and laboratory instruments.

The luer fitting of the female coupling member may be a female luer slip. Alternatively, a luer lock may be used. The luer lock fittings are securely connected together by means of a lobed hub on the female fitting which screws into a thread in a sleeve on the male fitting. The slip tip (luer slip) fitting fits only luer fitting sizes and is pressed together and secured by friction (they are not threaded).

In some examples, the female coupling member for mating with a syringe further may include a one-way valve for introducing the liquid sclerosant composition. The one-way valve may ensure that the introduction of the liquid hardener composition can be performed without compromising the sterile environment in the foaming space. The one-way valve may be a simple sheet or foil that is cantilevered to allow pivoting and thereby provide a one-way passage to the foaming space. In some examples, the one-way valve may be disposed downstream of the injection point of the liquid composition.

In some examples, the pressure equalizer may be a pressure release. The pressure release may be configured to release pressure only after the sclerosant foam is generated.

In some examples, the pressure equalizer or release may be manually activated. In some of these examples, the pressure equalizer or releaser comprises an aperture in the container body and a lid. The lid may be removable, releasable or frangible. The user may simply remove the cover in order to reduce or avoid a pressure difference inside the foaming space, and the user may do so at the appropriate time. In some examples, instead of removing the cover, the cover may be broken. In other examples, the pressure equalizer or release may be an (automatic) release valve. "automatic" herein means that manual activation by a user or healthcare professional is not required.

In some examples, the mixing element configured to operably couple with the rotatable actuator may be a disk comprising a magnetic portion and a shape suitable for mixing. Such mixing elements may be activated and controlled by providing a varying magnetic field. In particular, the rotatable actuator may be configured to induce a rotating magnetic field, and may optionally be a magnetic stirrer.

In some examples, the gas may be a physiological gas, and optionally O₂And CO₂A mixture of (a). In other examples, the gas may be air. By physiologyGas-prepared foams may be suitable for the treatment of certain patients and/or veins which cannot be treated by foams prepared with (sterile) air.

In some examples, a syringe used to introduce the liquid sclerosant composition remains mated with the female coupling member or "socket" while the foam is being generated. If the syringe remains coupled to the container, the chance of contaminating the foam is reduced. After the foam is generated, the same syringe may be used to aspirate or extract the foam. Depending on how much foam is extracted, the pressure generated inside the foaming space may be lower than the pressure generated outside the foaming space. The pressure equalizer can also be used to equalize the pressure again so that a high quality foam is extracted.

In some examples, the actuator may be operated at a first rotational speed to produce the foam sclerosant composition and operated at a second rotational speed while extracting the foam sclerosant composition, wherein the first rotational speed is different from the second rotational speed. In particular, the first high speed rotation may be used to rapidly produce high quality foam (e.g., small bubbles), and the rotation continues as the foam is extracted. The continued rotation presses the generated foam towards the outer area of the foaming space, from where it can be sucked out.

In some examples, the foam sclerosant composition obtainable by any of the methods or systems described herein may be used to treat varicose veins, spider veins or hemorrhoids.

Drawings

Specific implementations of the present disclosure will now be described, by way of non-limiting example, with reference to the accompanying drawings, in which:

FIGS. 1A-1E schematically illustrate examples of containers for producing a foam hardener composition;

FIGS. 2A-2F schematically illustrate examples of mixing elements that may be used in a container to prepare a foam hardener composition; and is

Fig. 3 schematically shows a sequence of steps in an example of a method for producing a foam hardener composition.

Detailed Description

As used herein, the expression "therapeutically effective amount" refers to an amount of the foam composition that is sufficient to treat the disease for which it is directed when administered. The specific dosage to obtain a therapeutic benefit depending on both the volume and drug concentration of the foam sclerosant composition may vary depending on the specifics of each patient.

As previously mentioned, one aspect of the present disclosure relates to a foam hardener composition obtainable by any of the methods described herein. The expression "obtainable by … …" is used herein to define the foam hardener composition by its method of preparation. In particular, it refers to a foam composition obtainable by a preparation process comprising the aforementioned steps. For the purposes of this disclosure, the expressions "obtainable", "obtained" and similar equivalents are used interchangeably, and in any case the expression "obtainable" includes the expression "obtained". Throughout this disclosure, the terms hardener and hardening are used interchangeably. Similarly, the sclerosant foam and the foam sclerosant composition may also be used interchangeably.

For the purposes of the present disclosure, the term foam hardening composition refers to a composition capable of producing a foam of hardening action, i.e. a composition for intravenous injection of drugs capable of causing damage to the vessel wall through endothelial vacuolization of the epithelial cell membrane (the layer in contact with the blood stream). Thus, the foam sclerosant composition stimulates the inner surface of the vein and creates a thrombosis only through platelets and aggregates. Similarly, the term liquid hardening composition refers to a composition in liquid form that includes a hardening agent. The liquid hardening composition forms the ingredients to obtain a foamed hardening composition. A sclerosant composition according to examples of the present disclosure comprises a sclerosant agent and suitable excipients, which may be injected into affected veins without toxicity. In some examples, the liquid is selected from sterile water (particularly distilled water) and physiological saline. Examples of sclerosing agents that may be present in the sclerosant compositions of the present disclosure include, but are not limited to, polidocanol, sodium tetradecyl sulfate, glycerol chromate, hypertonic saline, sodium morelinate, and sclera (hypertonic saline combined with dextrose). In a particular example, the hardening composition used comprises polidocanol and water. In another embodiment, the hardening composition further comprises glycerin.

Fig. 1A-1E schematically illustrate examples of containers for producing a foam hardener composition. The container 10 according to this example may comprise a dome-shaped container body 12 with a separately manufactured bottom 11. The dome-shaped container body 12 may have a top 18 with an aperture 19. In this example, the aperture is closed by a removable cap 20.

The dome shape is formed by curved side walls 14. Inside the container 10, a foaming space is defined. The container 10 of both the dome-shaped body 12 and the base 11 may be made of a suitable polymer, such as polyethylene terephthalate (PET) or other suitable material, such as plastics that are commonly accepted in the manufacture of medical devices.

In some examples, the material from which the container is made is transparent to allow visual inspection of the formation of foam. The dome-shaped container body 12 and the bottom 11 may be manufactured by injection molding in the same mold or by separate molds. Other manufacturing processes may also be used.

If manufactured separately, the base 11 and the dome-shaped body 12 may be joined by ultrasonic welding or other suitable means for joining plastic parts.

The container 10 according to this example can be sterilized and packaged. For example, a plastic foil or wrapper may be disposed around the container for delivery to a medical professional.

During manufacture and assembly, sterile gas may be introduced into the foaming space. The gas may be air, but may also be a mixture of physiological gases, for example carbon dioxide (CO)₂) And oxygen (O)₂) A mixture of (a). As provided, the foaming space further comprises a mixing element 30 (see fig. 1 c). The sterile container with the previously introduced gas and mixing element can thus be provided to a medical professional.

In the illustrated example, the device of the present disclosure is sealed and closed, with access to the interior of the container only through the access port, spigot and access aperture, which are positioned for optimal performance and reproducible production of improved foam. Limiting access to the interior of the device may reduce the risk of misuse and mishandling.

As shown in fig. 1b, the container 10 according to this example further comprises a female coupling member in the form of a socket 15 with a plug or cap 16. The socket 15 may include external threads 15a and the plug 16 may include mating threads 16a to facilitate installation and removal of the plug. However, alternative fittings for the socket and plug are also foreseen, such as a press fit or snap fit.

In this example, the coupling socket 15 comprises a luer fitting, and in particular a luer slip. As shown in fig. 1c, the luer 17 may be sized such that it can mate with the tip of a syringe, in particular a hypodermic syringe. The tip of the syringe may be pressed into the luer to provide a leak free fitting. In some examples, the syringe may be rotated to lock the syringe in the socket by means of a luer lock.

In this example, the socket 15 is formed integrally with the container 10 and is in particular provided on the side wall 14, close to the bottom 11. In some examples, the socket 15 is centered on the sidewall 14, 20mm furthest from the bottom 11 of the container 10. In particular, the center of the socket 15 may be on the side wall 14, 10mm furthest from the bottom 11 of the container 10. However, other suitable locations for coupling the sockets 15 are contemplated. The plug 16 may be made of polyethylene or other suitable material.

Although not shown in this particular example, the socket 15 or its connection to the foaming space may comprise a one-way valve, or any other element that facilitates the passage of liquid from the inside of the syringe and substantially prevents the passage of gas from the inside to the outside.

In this example, the coupling socket 15 has an inclination with respect to the horizontal plane to facilitate insertion and extraction from the syringe.

Filling of the foaming space with a suitable sterile gas can be carried out through the same socket 15 for injecting the sclerosant liquid composition and possibly for extracting the foam. An example of an assembly process is as follows: after injection moulding of the container 10 and before attachment of the bottom 11, the mixing element 30 is introduced into the foaming space of the container and the housing is then closed. Sterile gas may be introduced through a suitable valve coupling that allows introduction of sterile gas (e.g., a mixture of air and/or physiological gases) and evacuation of pre-existing gases.

The container 10 may include a pressure equalizer and, in this particular example, a pressure release. In this particular example, an orifice 19 with a releasable cover 20 is provided as a pressure relief. In other examples, the pressure relief device may be a safety valve, or an orifice with a frangible cap or tab. The function of the pressure release is to equalize the pressure inside the container 10 with the pressure outside the container. The balance of pressure may avoid the potential formation of undesirably large bubbles in the sclerosant foam.

The orifice 19 may have a relatively small diameter sufficient for gas exchange. Without limitation, the orifice 19 may be 0.5mm to 5mm in diameter. In particular, the orifice 19 may be between 1mm and 3mm in diameter.

The orifice 19 may be particularly positioned where it is not exposed to the foam generated, such as at a high point of the container 10. In this example, the aperture 19 is covered by a releasable cover 20 (such as aluminium foil sealed over the aperture 19). As seen, for example, in fig. 1B and 1C, the lid 20 may have a shape suitable for easy pulling of the lid down, and may include a grip or handle 22 that a user may grasp for manipulation. The handle may be provided at one end of the cap 20 and the other end may seal the aperture 19. The orifice 19 may also include a filter element or microbial barrier to reduce the potential exposure of the foam to airborne particles and microbes upon pressure equalization and foam withdrawal.

The opening of the orifice 19 may be performed at different times of operation of the device. In the particular examples disclosed herein, the orifice 19 remains closed in operation during the initial formation of foam, and is only exposed shortly before withdrawal of the foam contained in the container 10. The orifice 19 or, in general, the pressure equalizer or releaser may be configured such that it only begins operation immediately before or while the foam is withdrawn.

Details of the mixing element 30 can be seen in particular in fig. 2A-2F. In this example, the mixing element 30 may be a disc and, as can be seen for example in fig. 2b, it may comprise a magnetic element 33, in particular a magnetic core. As shown for example in fig. 2a, the magnetic element may be provided in a receptacle 34, for example a centrally arranged receptacle 34. The magnetic element 33 may be a permanent magnet or may be made of a (soft) ferromagnetic material. When a (soft) ferromagnetic material is used instead of a permanent magnet, the element 33 acquires its magnetic properties due to its arrangement in the presence of a magnet, for example of a magnetic stirrer. Then, when the magnet is removed, the magnetism disappears. The magnetic element 33 may for example be made of neodymium or other material with good magnetic properties. In another example, the magnetic element may be made of stainless steel.

Around the periphery of the disc, a number of appropriately shaped features for mixing may be provided. Such features may include, for example, vanes, rings, or teeth to ensure mixing of the liquid and gas by creating sufficient turbulence and mixing of the various components as the disk rotates. Mixing can be increased by forcing through openings or spaces in the disc.

The tray may be freely arranged, i.e. not supported or suspended by any element on the side walls or the top of the container. The mixing element 30 may include a central protrusion 36, the central protrusion 36 configured to reduce contact and friction between the bottom of the mixing element and the bottom of the container. The protrusion 36 may be tapered and pointed. When the mixing element starts to rotate, the protrusion 36 remains in contact with the bottom of the container body.

In this particular example, an annular mixing feature 35 is shown, but it should be clear that many other shapes may be suitable.

In this particular example, as shown, for example, in fig. 2c, a disc may be manufactured by assembling an upper half 30A and a lower half 30B. Each of halves 30A, 30B may include half-rings 35A, 35B, half-compartments 34A, 34B, and suitable coupling features. Once coupled with half-compartment 34B, half-compartment 34A forms a housing for magnetic element 33.

Each half may be made of a suitable polymer, such as polyethylene, and may be made, for example, by injection molding. As can be seen for example in fig. 2d, the halves may comprise suitable connecting features, for example fingers 37 with protruding tips 38 which can be snap-fitted on corresponding protrusions 39A on the side walls 39 of the other half.

One example of preparing a sclerosant foam with a container 10 and a mixing element 30 may be illustrated with reference to fig. 3.

A container according to the previously shown example or similar examples may be provided. A syringe filled with the sclerosant liquid composition may also be provided. In an example, such a syringe may be provided as a pre-filled syringe, possibly as part of a kit that also includes the container 10. Alternatively, the syringe may be filled with the sclerosant liquid immediately prior to preparing the foam.

In one particular example, the sclerosant composition may comprise a solution of a sclerosant (such as e.g. polidocanol) in a liquid (such as water or physiological saline) at a concentration of 2mg to 30mg (equivalent to 0.20-3.0%) (w/v) in 1mL of liquid. In another example, the sclerosant composition may comprise a solution of sclerosant (such as e.g. polidocanol) in a liquid (such as water or physiological saline) at a concentration of 2mg to 5mg (equivalent to 0.20-0.50%) (w/v) in 1mL of liquid. Using the apparatus and methods described herein, it has been found that stable foams can be obtained even at very low concentrations, e.g. 0.2% or 0.3% (w/v), compared to, e.g., the Tessari method.

In another particular example, the sclerosant composition may comprise a solution of polidocanol in water or physiological saline at a concentration of 5 mg/mL.

In another particular example, the sclerosant composition may comprise a solution of polidocanol in water or physiological saline at a concentration of 20 mg/mL.

In another particular example, the liquid composition may include Sodium Tetradecyl Sulfate (STS) at a concentration of 0.2-3%.

The volume of the syringe may be, for example, 5cc, 10cc, or 20 cc. The syringe may contain, for example, 2ml or more of the liquid sclerosant composition.

At block 102, the syringe may be mated to the socket 15 by inserting the syringe. Before this, the plug 16 is removed from the socket 15. Immediately after removal of the stopper 16, the syringe may be introduced to avoid any contamination. In further examples, the coupling socket or the container body may comprise a one-way valve or a selectively displaceable element to avoid any contamination. In further examples, the container may be provided with a slight overpressure (i.e. above ambient pressure) to avoid potential contamination once the plug 16 is removed. Combinations of these are also possible. In an example, the plug 16 may be configured for single use only. That is, the plug 16 may be in the form of a cap or seal that is broken, damaged or otherwise rendered unusable when removed.

Once a leak free fitting is established between the syringe and the socket 15, the liquid composition inside the syringe may be injected and may enter the foaming space at block 104. Because the liquid is introduced into the closed system, a slight overpressure can be generated inside the foaming space, that is to say the pressure inside the foaming space is higher than the external atmospheric pressure. Any air or gas inside the injector may also be injected into the foaming space, but this may be done at any time before the foam is extracted.

The foregoing actions may be performed particularly after placing vessel 10 on a magnetic stirrer. This may be a standard magnetic stirrer, which is commonly found in many laboratories. In some other examples, the magnetic stirrer may be particularly adapted to the vessel and comprise a receptacle for receiving the vessel. A slight press fit may be provided between the container and the receptacle.

Then, at block 106, the magnetic stirrer may be activated. The mixing element may thus be arranged to rotate. A mixing element, such as the disk with magnetic elements described previously, may rotate at the bottom of the container. Depending on the type of foam to be produced, depending on the liquid hardener composition, and depending on the gas in the foaming space, different rotation speeds and times may be used. In some examples, the magnetic stirrer may include a memory having a plurality of predetermined programs adapted for different foams, such that a user need only select an appropriate program.

It should be noted that it may be advantageous not to remove the syringe and keep it coupled to the container during foam formation.

In a particular example, the magnetic stirrer is first set to a high first speed at block 108, which is reached in a short time, e.g., a few seconds. Such high first speeds may be between 2,000 to 5,000RPM, and particularly between 2,500 to 4,000 RPM. As little as 15 seconds later, foam may be generated.

To improve the stability and quality of the foam, the high speed rotation may be maintained. After a first period of time, which may be 30 to 90 seconds, in particular about 60 seconds, the speed of the magnetic stirrer is reduced to a second speed at block 110.

The second speed may be chosen such that the already generated foam is pushed to the outer periphery of the foaming space due to centrifugal forces. The second speed may be below 1,500 RPM. In an example, the second speed may be between 200 and 1200RPM, in particular between about 1000 RPM.

Prior to extracting the foam at block 112, the releasable cover 20 may be removed from the pressure release orifice 19 to equalize the overpressure on the inside with the atmospheric pressure on the outside. Preferably, the orifice 19 remains open during the extraction of the sclerosant foam from the container, to avoid the creation of negative pressure inside the foaming space and the syringe during extraction. The equalization of pressure is intended to avoid the potential formation of undesirably large air bubbles in the sclerosant foam within the collecting syringe.

After extracting the sclerosant foam, the foam may be used to treat the patient at block 114.

The volume of the container 10 as disclosed herein may be, for example, 30 ml. Such containers are used in various experiments. With the method according to embodiments disclosed herein, when 2ml of the liquid sclerosant composition (having any of the above concentrations) is introduced, about 10ml of stable foam is obtained and easily extracted.

When 4ml of the liquid hardener composition was introduced, about 20ml of stable foam was obtained and easily extracted.

For completeness, various aspects of the disclosure are set forth in the following numbered clauses:

clause 1. a container for producing a foam hardener composition, the container comprising:

a sealed, sterile container body for foaming comprising one or more side walls extending between a top and a bottom of the container body, a foaming space defined inside the container body,

the foaming space contains a sterile gas and a mixing element configured to be operably coupled with the rotatable actuator without the actuator entering the foaming space, wherein,

the container comprises a female coupling member for cooperation with a syringe, an

And the pressure equalizer is used for equalizing the pressure inside the foaming space and the pressure outside the foaming space.

Clause 2. the container of clause 1, wherein the female coupling member comprises a luer fitting.

Clause 3. the container of clause 2, wherein the luer fitting is a female luer slip.

Clause 4. the container of any of clauses 1-3, wherein the female coupling member comprises a cap for closing the coupler.

Clause 5. the container of clause 4, wherein the cap optionally has threads for mating with threads on the coupler.

Clause 6. the container of any of clauses 1-5, wherein the female coupling member for mating with a syringe further comprises a one-way valve for introducing the liquid hardener composition.

Clause 7. the container of any of clauses 1-6, wherein the female coupling member is located in a sidewall of the container body.

Clause 8. the container of clause 7, wherein the female coupling member is disposed at or near an edge of the bottom surface of the container body, and optionally has an inclination with respect to a horizontal plane.

Clause 9. the container of any one of clauses 1 to 8, wherein the pressure equalizer is a pressure relief for relieving excess pressure within the foaming space, and optionally wherein the pressure relief is configured to release pressure only after the sclerosant foam is formed.

Clause 10. the container of any of clauses 1-9, wherein the pressure relief comprises an aperture in the container body and a releasable cover.

Clause 11. the container of clause 10, wherein the aperture is located at the top of the container body.

Clause 12. the container of clause 10 or 11, wherein the releasable cover comprises a handle for pulling out the releasable cover.

Clause 13. the container of any of clauses 10-12, wherein the releasable cover is heat sealed over the aperture.

Clause 14. the container of any of clauses 1-13, wherein the mixing element configured to operably couple with the rotatable actuator is a disk comprising a magnetic portion and a shape suitable for mixing, and

wherein the rotatable actuator is configured to induce a rotating magnetic field, and optionally a magnetic stirrer.

Clause 15. the container of clause 14, wherein the mixing element is a disk comprising a magnetic portion having a plurality of blades around its circumference.

Clause 16. the container of clause 15, wherein the blade comprises one or more of: a ring, vertical teeth and horizontal teeth.

Clause 17. the container of any of clauses 15-16, wherein the tray comprises an upper tray and a lower tray configured to be coupled to each other, the upper and lower trays defining a compartment for containing the magnetic portion.

Clause 18. the container of clause 17, wherein the upper disc and the lower disc are configured to snap fit together.

Clause 19. the container of any of clauses 15-18, wherein the disk comprises a central protrusion configured to contact the bottom of the container body.

Clause 20. the container of any of clauses 1-19, wherein the gas is a physiological gas, and optionally O₂And CO₂A mixture of (a).

Clause 21. the method of clause 20A container of wherein O₂Is between 70% and 50%, and the remainder is CO₂。

Clause 22. the container of any one of clauses 1-21, enclosed in sterile packaging.

Clause 23. a kit for preparing a foam sclerosant composition, comprising a container according to any of clauses 1-22, further comprising a syringe, optionally prefilled with a liquid sclerosant composition.

Clause 24. the kit of preparing a foam sclerosant composition according to clause 23, wherein the syringe is a luer lock syringe comprising one of the following volumes: 2.5cm³、5cm³、10cm³Or 20cm³。

Clause 25. the kit for preparing a foam sclerosant composition according to any of the clauses 23-24, wherein the syringe comprises 2-4ml of the liquid sclerosant composition.

Clause 26. the kit of any one of clauses 23-25, wherein, once the liquid hardener composition is introduced into the container body, the volume ratio of gas to liquid in the foaming space is 7.5: 1 to 20: 1.

clause 27. the kit for preparing a foam sclerosant composition according to any of the clauses 23-26, wherein the liquid sclerosant composition is a solution of the drug in distilled water or saline.

Clause 28. a system for producing a foam sclerosant composition comprising the sterile container according to any of clauses 1-22 and an actuator configured to be operably coupled to the mixing element.

Clause 29. the system for producing a foam hardener composition of clause 28, wherein the actuator is a magnetic stirrer.

Clause 30. a method for preparing and extracting a foam sclerosant composition, comprising:

providing a syringe filled with a liquid sclerosant composition;

providing a container, and optionally providing a container according to any of clauses 1-22;

mating the syringe with the coupler and injecting the liquid hardener composition into the foaming space;

the actuator is operated to rotate the mixing element and produce the foam hardener composition,

the obtained foam hardener composition is extracted.

Clause 31. the method of clause 30, wherein the syringe remains mated with the coupler while the foam is generated.

Clause 32. the method of clause 30, wherein the obtained foam sclerosant composition is extracted by aspirating the syringe.

Clause 33. the method of any of clauses 30-32, wherein the actuator is operated to rotate the mixing element at a first rotational speed of 5,000RPM or less, and preferably, the actuator is rotated to rotate the mixing element at the first rotational speed of between 2,000 and 4,500RPM during the first time period.

Clause 34. the method of clause 33, including rotating the mixing element at a variable speed at a first rotational speed for a first period of time.

Clause 35. the method of clause 33 or 34, wherein the first time period is between 15 seconds and 90 seconds, specifically between 30 seconds and 75 seconds, more specifically between 30 seconds and 60 seconds.

Clause 36. the method of any one of clauses 30-35, wherein the actuator is operated while extracting the obtained foam hardener composition.

Clause 37. the method of any of clauses 30-36, wherein the actuator is operated at a first rotational speed to produce the foam sclerosant composition and while the foam sclerosant composition is extracted, the actuator is operated at a second rotational speed, wherein

The first rotational speed is different from the second rotational speed.

Clause 38. the method of clause 37, wherein the second rotational speed is lower than the first rotational speed.

Clause 39. the method of clause 37 or 38, including rotating the actuator to rotate the mixing element at a second rotational speed of 1,500RPM or less, specifically between 500 and 1,200RPM, more specifically around 1,000 RPM.

Clause 40. the method of any one of clauses 30-39, further comprising releasing the overpressure within the foaming space prior to extracting the obtained foam sclerosant composition.

Clause 41. the method of any one of clauses 30-40, wherein the liquid sclerosant composition is a solution of the sclerosant drug in water, optionally distilled water or saline.

Clause 42. the method of clause 41, wherein the concentration of the drug is 0.20-3.0% (w/v).

Clause 43. the method of clause 42, wherein the concentration of the drug is 0.20-0.50% (w/v).

Clause 44. a foam hardener composition obtainable by the method according to any one of clauses 30-43.

Clause 45. the foam sclerosant foam according to clause 44, wherein the ratio of liquid to gas in the sclerosant foam is between 1: 4 to 1: 7, respectively.

Clause 46. the foam sclerosant composition according to clause 44 or 45, for use in the treatment of varicose veins.

Clause 47. the foam sclerosant composition according to clause 44 or 45, for use in the treatment of spider veins.

Clause 48. the foam sclerosant composition according to clause 44 or 45, for use in the treatment of hemorrhoids.

Clause 49. a magnetic stirrer having one or more magnets for generating a rotating magnetic field, wherein the magnetic stirrer has a control comprising a processor and a memory

Wherein the memory includes instructions corresponding to one or more predetermined rotation programs such that, when the instructions are executed by the processor, the magnet generates a rotating magnetic field according to the predetermined rotation program,

the predetermined rotation program corresponds to the rotation defined in any of clauses 33-39.

Clause 50. the magnetic stirrer of clause 49, wherein the one or more magnets are rotating magnets.

Clause 51. the magnetic stirrer of clause 49, wherein the one or more magnets are static electromagnets.

Clause 52. the magnetic stirrer according to any one of clauses 49-51, further comprising a user interface, wherein the user interface enables a user to select a predetermined rotation program.

Clause 53. the magnetic stirrer of clause 52, wherein the user interface comprises a touch screen display.

Clause 54. the magnetic stirrer according to clause 52 or 53, wherein the predetermined rotation program is determined by one or more of: the gas in the foaming space and the liquid hardener composition, in particular the concentration of the drug in the liquid hardener composition.

Although only a few examples are disclosed herein, other alternatives, modifications, uses, and/or equivalents are possible. Furthermore, all possible combinations of examples are also described. Accordingly, the scope of the present disclosure should not be limited by particular examples, but should be determined only by a fair reading of the claims that follow.