Composition and method for improving medical imaging of fallopian tubes, preparation and uses thereof

Abstract

The invention pertains to a foamable, echolucent composition, wherein the composition comprises (i) a gelling agent, (ii) water, and (iii) between 0.005 and 20 vol.% oil based on total volume of the composition, wherein the composition turns echogenic when foamed, and preferably has a viscosity of at least 1500 cP. Also, the invention pertains to a foamed, echogenic, image-enhancing composition, wherein the composition comprises (i) a gelling agent, (ii) water, (iii) between 0.005 and 20 vol.% oil based on total volume of the composition, and (iv) air or gas bubbles, wherein the composition preferably has a viscosity of less than 1500 cP, most preferably 50 – 500 cP.

Description

[0001] Composition and method for improving medical imaging of fallopian tubes, preparation and uses thereof

[0002] FIELD

[0003] This invention relates to the field of echography or sonohysterography, particularly concerning the evaluation of fallopian tubal patency in infertility investigations and the confirmation of fallopian tube sterilization.

[0004] BACKGROUND

[0005] It is estimated that 30-40% of cases of female infertility are related to tube pathologies causing the tubes to be blocked. Several factors may contribute to tube blockage, for example adhesions due to surgical interventions, inflammations or endometriosis, as well as infections, previous extrauterine pregnancies, or congenital defects. Therefore, when infertility arises one of the first tests performed is a patency test. A patency test involves medical imaging of the fallopian tubes, by echography or sonohysterography. On the other end of the spectrum, fallopian tube imaging is also used to confirm tube ligation, i.e. tube sterilization.

[0006] To run a patency test or check tube sterilization, a medical professional injects a fluid into the fallopian tubes before imaging takes place. The fluid has two functions: (1) to distend the fallopian tube cavity from its “collapsed” state and (2) to enhance the image contrast. Patency tests have also been shown to increase the chances of conception after the test, because of the opening and lubrication of the fallopian tubes. Nevertheless, these (patency) tests are at the very least uncomfortable and often painful to the patient.

[0007] Given the foregoing, the choice of the contrast fluid is essential to both obtain the required image contrast, as well as to ensure patient comfort.

[0008] Conventionally, water or watery fluids are used as contrast imaging, which have the disadvantage of leaking while imaging is performed. These disadvantages have been tackled in EP1793860A1 which provides a contrast liquid which is an aqueous gel composition comprising a cellulose derivative for adding gelling behavior. A suitable commercially available aqueous gel is ExEm®. The drawback of this contrast agent was that inserting a gel into fallopian tubes may require considerable pressure, causing pain to the patient. WO201 1 / 046437 improved on EP 1793860A1 by foaming the Exem® gel with water and air. The bubbles improve image contrast compared to the non-foamed composition. The preferred volume ratio of aqueous solution to gel is in the range of 4:6 - 6:4, i.e. almost equal amounts.

[0009] WO20 19 / 004828 provides an alternative oil-based foamed image enhancing composition based on Lipiodol®. While Lipiodol® has been used as an imaging enhancing agent in hysterosalpingography (HSG) for multiple decades, it is echolucent and as such thus unsuited in sonohysterography. It was however found that foaming such water immiscible oil composition renders it echogenic when using it in sonohysterography. It is allowed to include significant amounts of 10 - 25 wt% water, allowing for ratios of water to water-immiscible hydrophobic composition in the range of 10:90 and 25:75. The disadvantage of the foamed oilbased compositions is that it takes longer for the ‘oily foams’ to leave the fallopian tubes again, as in practice viscosities are typically higher than when using foamed water-based ExEm®. While the oils advocated in WO2019 / 004828 are non-embryotoxic, it is still perceived a disadvantage that the oils are removed from the tubes and the human body at much lower pace, and in the very least it is regarded an inconvenience to the patient. Zen et al. " ipiodol visibility under ultrasound" Aust. N.Z. J. Obstetrics & Gynaecology 2020; 598-604 tests and concludes that Lipiodol is visible sonographically.

[0010] There remains a need in the art to improve on these available compositions to obtain both enhanced image contrast on one hand, and minimal patient discomfort on the other.

[0011] Outside the field of echography, CN117924793 describes the preparation of an aerogel using a diglyceride foam template, and US2018 / 000734 describes a wax foamable vehicle wherein the components are selected to provide a composition that is substantially resistant to aging and to phase separation and / or to substantially solubilize and / or stabilize active ingredients.

[0012] SUMMARY OF THE INVENTION

[0013] The inventors have surprisingly found that a foamed composition comprising a gelling agent, water and 0.005 - 20 vol.%, preferably 0.005 - 15 vol.% oil yielded better contrast in medical imaging of fallopian tubes than the corresponding foamed composition comprising a gelling agent and water (e.g. Exem® foam) without any oil as presently commercialized, a technology described in WO2011 / 046437. The relatively small amount of oil has an impact on air bubble densities which advantageously further improves the imaging. The oil should not exceed 20 vol.%, is preferably less than 15 vol.%. By making use of gelling behavior of the aqueous component, even at these higher oil concentrations between 10 and 20 vol.% a stable foam can be provided that remains stable for at least the time convenient for the intended purpose such as a patency test, typically for at least 1 minute, more preferably at least 2 minutes, most preferably at least 5 minutes, after initiating foaming. Still, lower amounts are preferred, preferably less than 10 vol%, in order to avoid emulsification and reduced contrast, and also in order to reduce the patient’s discomfort associated with these oily foams leaving the tubes again. With larger amounts of oil the handling of the emulsion interferes with the aim of achieving a stable foamable composition, which is also reflected in terms of a decrease in contrast. The foam of the present composition is stable for a time sufficient to fill the fallopian tubes and carry out a patency test without leaking, while the viscosity of the composition is ideal to minimise patient discomfort.

[0014] Hence, in a first aspect, the invention concerns a foamable, echolucent composition, wherein the composition comprises

[0015] (i) a gelling agent,

[0016] (ii) water, and

[0017] (iii) between 0.005 and 20 vol.% oil based on total volume of the composition, wherein the composition turns echogenic when foamed. The unfoamed composition preferably has a viscosity of at least 1500 cP, as measured using Brookfield rotational viscometry at 20 °C.

[0018] In a second aspect, the invention concerns a foamed, echogenic, image-enhancing composition, wherein the composition comprises

[0019] (i) a gelling agent,

[0020] (ii) water,

[0021] (iii) between 0.005 and 20 vol.% oil based on total volume of the composition, and

[0022] (iv) air or gas bubbles.

[0023] The foamed composition preferably has a viscosity of less than 1500 cP, most preferably 50 - 500 cP as measured using Brookfield rotational viscometry at 20 °C. The foamed composition is preferably obtainable by foaming the foamable, echolucent composition of the first aspect of the invention.

[0024] In view of the intended use, the composition of either of the above aspects is preferably non- embryotoxic. In a third aspect, the invention concerns a method for enhancing contrast of an image of fallopian tubes, comprising:

[0025] (a) introducing a foamed, echogenic, image-enhancing composition according to the second aspect of the invention into the fallopian tubes of a patient,

[0026] (b) scanning the patient using imaging technology, wherein said air or gas bubbles are maintained in the foamed composition for at least 1 minute after initiating foaming, sufficiently long for step (b).

[0027] In yet another aspect, related to preparing the foamed composition according to the second aspect and carrying out the method according to the third aspect, the invention concerns a method for preparing a foamed, echogenic, image-enhancing composition by

[0028] (a) mixing a gelling agent, water, and optional further components to obtain a foamable, echolucent composition, and

[0029] (b) inserting air or gas in said foamable, echolucent composition (i.e. foaming) by mixing the foamable, echolucent composition with an aqueous and / or oil composition(s) comprising (sterile) air or gas, wherein the foamed, echogenic composition obtained in step (b) comprises 0.005 - 20 vol.% oil based on the original volume of all compositions mixed-to-be-foamed in step (b) altogether. The oil can be part of the foamable, echolucent composition prepared in step (a) and / or mixed into the foamable, echolucent composition in step (b), provided that the sum of the total amount of oil is 0.005 - 20 vol.% oil based on the volume of the foamable, echolucent composition, and wherein the foamed, echogenic, image-enhancing composition has a viscosity within acceptable levels as defined herein.

[0030] In yet another aspect, related to any of the above aspects, the invention concerns a kit of parts, comprising

[0031] (i) a first chamber or syringe with a predetermined amount of a foamable, echolucent, composition comprising a gelling agent, and water and optionally oil, the composition having a viscosity of at least 1500 cP, as measured using Brookfield rotational viscometry at 20 °C,

[0032] (ii) a second chamber or syringe with a predetermined amount of an aqueous composition comprising (sterile) air or gas, and optionally oil, and

[0033] (iii) optionally a third chamber or syringe with oil, provided that the sum of the total amount of oil comprised in (i), (ii) and optional (iii) is 0.005 - 20 vol.% oil based on the volume of the compositions of (i), (ii) and optional (iii), and wherein the kit optionally further comprises a mixing chamber suitable for mixing the content of the different chambers or syringes. In a preferred embodiment, the kit comprises (i) and (ii) and no (iii), and all oil is provided in the second chamber or syringe (i.e. no oil is present in (i)).

[0034] In the above aspects, non-limiting examples of suitable oils are safflower oil, canola oil, wheat germ, rapeseed oil, cottonseed oil, olive oil, sunflower oil, poppyseed oil, ethiodized oil or ethiodized poppyseed oil, LIPIODOL®, tetrafluorodibromoethane, and hexafluorodibrom opropane, particularly ethiodized poppyseed oil. A suitable commercially available ethiodized poppyseed oil is LIPIODOL®. A preferred oil is olive oil.

[0035] LIST OF EMBODIMENTS

[0036] 1. A foamable, echolucent composition, wherein the composition comprises

[0037] (i) a gelling agent,

[0038] (ii) water, and

[0039] (iii) between 0.005 and 20 vol.% oil based on total volume of the composition, wherein the composition turns echogenic when foamed, and preferably has a viscosity of at least 1500 cP.

[0040] 2. The foamable, echolucent composition according to embodiment 1, comprises 0.01 - 15 vol.% of oil, preferably 0.1 - 15 vol%, most preferably 0.2 - 15 vol.%, particularly 0.5 - 15 vol.%.

[0041] 3. The foamable, echolucent composition according to embodiment 2, comprising 0.01 - 10 vol.% of oil, more preferably 0.1 - 10 vol.%, and most preferably 0.2 - 10 vol.%, particularly 0.5 - 10 vol.%.

[0042] 4. A foamed, echogenic, image-enhancing composition, wherein the composition comprises

[0043] (i) a gelling agent,

[0044] (ii) water,

[0045] (iii) between 0.005 and 20 vol.% oil based on total volume of the composition, and

[0046] (iv) air or gas bubbles, wherein the composition preferably has a viscosity of less than 1500 cP, most preferably 50 - 500 cP.

[0047] 5. The foamed, echogenic composition according to embodiment 4, comprises 0.01 - 15 vol.% of oil, preferably 0.1 - 15 vol%, most preferably 0.2 - 15 vol.%, particularly 0.5 - 15 vol.%. The foamed, echogenic composition according to embodiment 5, comprising 0.01 - 10 vol.% of oil, more preferably 0.1 - 10 vol.%, and most preferably 0.2 - 10 vol.%, particularly 0.5 - 10 vol.%. The foamed, echogenic composition according to any one of embodiments 4-6, wherein the composition is obtainable by foaming the foamable, echolucent composition according to any one of embodiments 1 - 3. A method for enhancing contrast of an image of fallopian tubes, comprising:

[0048] (a) introducing a foamed, echogenic, image-enhancing composition according to any one of embodiments 4 - 7 into the fallopian tubes of a patient,

[0049] (b) scanning the patient using imaging technology, wherein said air or gas bubbles are maintained in the foamed composition for at least 1 minute after initiating foaming. A method for preparing a foamed, echogenic, image-enhancing composition, comprising:

[0050] (a) mixing a gelling agent, water, and optional further components to obtain a foamable, echolucent composition, and

[0051] (b) inserting air or gas in said foamable, echolucent composition (i.e. foaming) by mixing the foamable, echolucent composition with an aqueous and / or oil composition(s) comprising (sterile) air or gas, wherein the foamed, echogenic composition obtained in step (b) comprises 0.005 - 20 vol.% oil based on the original volume of all compositions mixed-to-be-foamed in step (b) altogether, wherein the foamed, echogenic, image-enhancing composition preferably has a viscosity of less than 1500 cP, more preferably 50 - 1000 cP, most preferably 50 - 500 cP. The method according to embodiment 9, comprising:

[0052] (a) providing a first foamable, aqueous echolucent composition comprising a gelling agent, water, and optional further components but, if any, less than 0.005 vol% oil, the composition having a viscosity of at least 1500 cP, and

[0053] (b) mixing a second aqueous composition comprising (sterile) air or gas and oil into the composition provided in (a), to obtain a foamed, echogenic composition comprising 0.005 - 20 vol.% oil based on the sum of the volume of the first and second composition, and wherein the foamed, echogenic, image-enhancing composition preferably has a viscosity of less than 1500 cP, more preferably 50 - 1000 cP, most preferably 50 - 500 cP. 11. The method according to embodiment 10, wherein the amount of oil in the second composition is 0.01 - 15 vol.%, preferably 0.1 - 15 vol%, most preferably 0.2 - 15 vol.%, particularly 0.5 - 15 vol.% based on the sum of the volume of the first and second composition.

[0054] 12. The method according to embodiment 11, wherein the amount of oil in the second composition is 0.01 - 10 vol.% of oil, more preferably 0.1 - 10 vol.%, and most preferably 0.2 - 10 vol.%, particularly 0.5 - 10 vol.%.

[0055] 13. A kit of parts, comprising

[0056] (i) a first chamber or syringe with a predetermined amount of a foamable, echolucent, composition comprising a gelling agent, and water and optionally oil, the composition having a viscosity of at least 1500 cP,

[0057] (ii) a second chamber or syringe with a predetermined amount of an aqueous composition optionally comprising (sterile) air or gas, and optionally comprising oil, and

[0058] (iii) optionally a third chamber or syringe with oil, provided that the sum of the total amount of oil comprised in (i), (ii) and optional (iii) is 0.005 - 20 vol.% oil based on the volume of the compositions of (i), (ii) and optional (iii), and wherein the kit optionally further comprises a mixing chamber suitable for mixing the content of the different chambers or syringes.

[0059] 14. The kit according to embodiment 13, comprising

[0060] (i) and (ii) and no (iii), wherein the amount of oil, if any, in (i) is less than 0.001 vol.%, and all oil is provided in (ii) the second chamber or syringe; or

[0061] (i), (ii) and (iii), wherein the amount of oil, if any, in (i) and (ii) is less than 0.001 vol.%, and all oil is provided in (iii) the third chamber or syringe; and wherein the kit optionally further comprises a mixing chamber suitable for mixing the content of the chambers or syringes.

[0062] 15. The kit according to embodiment 13 or 14, wherein the sum of the total amount of oil comprised in (i), (ii) and optional (iii) is 0.01 - 15 vol.%, preferably 0.1 - 15 vol%, most preferably 0.2 - 15 vol.%, particularly 0.5 - 15 vol.%.

[0063] 16. The kit according to embodiment 15, wherein the sum of the total amount of oil comprised in (i), (ii) and optional (iii) is 0.01 - 10 vol.% of oil, more preferably 0.1 - 10 vol.%, and most preferably 0.2 - 10 vol.%, particularly 0.5 - 10 vol.%.

[0064] 17. The kit according to any one of embodiments 13 - 16, wherein the oil is provided in (iii) a separate container, and the kit is accompanied by guidelines for directing the practitioner or his or her assistant to first mix (ii) and (iii), and mixing the combined content of (ii) and (iii) with (i), in order to prepare a foamed, echogenic imageenhancing composition.

[0065] 18. The composition according to any one of embodiments 1 - 7, the method according to embodiments 8 - 12 or the kit according to any one of embodiments 13-17, wherein the gelling agent comprises xanthan gum, a hyaluronic acid derivative, a cellulose derivative, or combinations thereof, more preferably the gelling agent comprises a cellulose derivative selected from methyl-cellulose (MC), ethyl-cellulose (EC), hydroxy ethyl-cellulose (EEC), hydroxypropyl-cellulose (HPC), hydroxypropyl- methyl-cellulose (HPMC), hydroxypropyl-ethyl-cellulose (HPEC), ethyl-hydroxy-ethyl-cellulose (EHEC), hydroxyethyl-m ethyl-cellulose (HEMC), most preferably EEC.

[0066] LIST OF FIGURES

[0067] Figure 1 : Ultrasound images showing (a) the baseline before adding ExEm® Foam, (b) after the addition of ExEm® Foam, (c) the baseline before adding ExEm® Foam with 500 pL of Poppyseed Oil, and (d) after the addition of ExEm® Foam with 500 pL Poppyseed Oil.

[0068] Figure 2(a) Ultrasound image showing ExEm® Foam after 20 min and (b) ExEm® Foam with 500 pL of Poppyseed oil after 20 min.

[0069] DETAILED DESCRIPTION

[0070] Definitions

[0071] The term “oil” as used herein refers to a nonpolar chemical substance which is hydrophobic and lipophilic. For the purposes of the invention, and in accordance with the skilled person’s common general knowledge, glycerine or glycerol is an alcohol which in nutritional field may be a building block of triglycerides, but glycerol on its own, i.e. unesterified with one or more fatty acids, is not part of the oil. Glycerol can be used in the gel matrix as it is for example in ExEm® and ExEm-foam® presently commercialized.

[0072] The term “air or gas bubbles” as used herein refers to pockets of air or gas; oil droplets are not, o / w emulsions are carefully avoided.

[0073] The terms “foam” as used herein refers to a mass of air or gas bubbles in or on a liquid, semiliquid (gel) or solid. The term “aqueous composition” includes water. The term “foamed composition” as used herein refers to a composition comprising trapped pockets of gas or air, i.e. air bubbles, in a liquid or semi-liquid (gel) matrix. The foamed composition is milky in appearance to the eye. Air or gas bubbles are preferably maintained within the foamed composition for at least 1 minute, more preferably at least 2 minutes, most preferably at least 5 minutes, after initiating foaming, giving sufficient time for inserting the foamed composition into the fallopian tubes and scanning these tubes using imaging technology.

[0074] The term “foamable composition” as used herein refers to a composition which is readily foamed by insertion of air or gas. Throughout the application, the terminology volume% or vol.% refers to the volume of the unfoamed composition(s).

[0075] The term “echolucenf ’ as used herein means permitting the passage of ultrasonic waves without giving rise to echoes, the representative areas appearing black on the sonogram.

[0076] The term “echogenic” as used herein means giving rise to reflections (echoes) of ultrasound waves, thus showing as a light area in an ultrasound scan.

[0077] The term “embryotoxic” as used herein means anything which can adversely affect, hamper or interfere with the implantation, growth or development of an embryo. Consequently, “non- embryotoxic” means something that does not adversely affect, hamper or interfere with embryo implantation, growth or development.

[0078] The terms “image enhancement” or “image-enhancing” as used herein refer to increasing the contrast of an image, particularly an ultrasound echography or sonohysterography image. The contrast enhancement may be either negative (black) or positive (white). Typically, enhancement also involves distension of the body cavity of which an image is made. As explained in FDA's Guidance for Industry: Developing Medical Imaging Drug and Biological Products, Part 1 : Conducting Safety Assessments (2004), a contrast agent - here imaging enhancing composition - is used to improve the visualization of tissues, organs, and physiologic processes by increasing the relative difference of imaging signal intensities in adjacent regions of the body. In the context of the invention, the imaging enhancing composition is an ultrasound contrast agent which is a type of contrast agent intended to reflect sound waves in response to ultrasound in a manner that allows the agent to stand out from the surrounding medium (e.g., surrounding blood and tissues in the body).

[0079] Composition

[0080] In a first aspect, the invention concerns a foamable, echolucent composition comprising a gelling agent, water, and between 0.005 and 20 vol.% oil based on total volume of the composition. The composition turns echogenic when foamed, and the composition is preferably non-embryotoxic.

[0081] Preferably, the gelling agent is in an amount of 0.5 - 5 wt%, more preferably 1-5 wt% of the foamable, echolucent composition.

[0082] Any non-embryotoxic gelling agent is suited to achieve the viscosity requirements set above. The gelling agent preferably comprises xanthan gum, hyaluronic acid derivatives, cellulose derivatives, or combinations thereof. More preferably the gelling agent comprises at least a cellulose derivative, even more preferably the cellulose derivatives are cellulose ethers selected from alkyl celluloses, hydroxyalkyl celluloses and hydroxyalkyl alkyl celluloses, or combinations thereof. Examples of preferred cellulose derivatives are methyl-cellulose (MC), ethyl-cellulose (EC), hydroxyethyl-cellulose (HEC), hydroxypropyl-cellulose (HPC), hydroxypropyl-methyl-cellulose (HPMC), hydroxypropyl-ethyl-cellulose (HPEC), ethyl- hydroxy-ethyl-cellulose (EHEC), hydroxyethyl-methyl-cellulose (HEMC), and the like. Hydroxyethyl-cellulose is most preferred. The above list is however non-exhaustive and preferably any other non-embryotoxic gel could be used. The gelling agent is used to increase viscosity and retain the foam created by mixing the gelled composition with water and / or oil together with air immediately prior to use, for a time sufficient to carry out ultrasound echography, preferably for at least 5 minutes, and wherein the water and / or oil that is mixed in, results in a viscosity decrease that renders the composition sufficient fluid to pass through patent tubes, preferably a viscosity of less than 1000 cP, preferably 50 - 500 cP as described above. The gelling agent and the amount used thereof are preferably selected to provide a gelled foamable, echolucent composition having a viscosity of preferably 1500 - 4000 cP as measured elsewhere herein. Without inventive skills, the skilled person is able to determine the amount of gelling agent(s) in order to arrive at the desired viscosity. Preferably the composition further comprises glycerine (also called glycerol). Preferably the composition comprises hydroxyethyl-cellulose and glycerine, the remaining part being water. Preferably hydroxyethyl-cellulose is 50 - 100 wt% of the gelling agent, more preferably 80 - 99.5 wt%, most preferably 90 - 99 wt%. Preferably glycerine is 0 - 20 wt% of the composition, more preferably 1 - 15 wt%, of the foamable (i.e. unfoamed) composition. Obviously the same weight numbers also apply to the foamed composition derived therefrom.

[0083] In a preferred embodiment, apart from the oil component according to the invention, the foamable composition essentially consists of water, hydroxyethyl cellulose and optionally glycerol, wherein the amount of hydroxy ethylcellulose is preferably 0.5 - 5 wt%, more preferably 1-5 wt%, and glycerol - if any - is present in an amount of 0 - 20 wt% of the composition, more preferably 1 - 15 wt%.

[0084] Additional components may be dissolved in the water. In one embodiment, a buffering agent and / or a salt are dissolved in the water. Preferably the pH value of the foamable, echolucent composition is buffered and / or adjusted in the range between about 5.5 and about 7.5, more preferably between about pH 6.0 and about 7.5. It is preferred that the foamable and foamed compositions has a physiologically accepted pH.

[0085] Advantageously, the foamable, echolucent composition comprises a small amount of oil to enhance medical image contrast, which is readily removed from the fallopian tubes and also low enough to avoid the formation of an emulsion, i.e. small droplets of oil in water. Since the foamed echogenic composition of the invention comprises much lower amounts of oil than those in echogenic compositions known in the art (for example known from WO2019 / 004828), a quicker emptying of the fallopian tubes after medical imaging can be established, which adds to safety and convenience of the patient. Also, by limiting the amount of oil in the foamable composition, emulsification before or during the foaming process is carefully avoided. The formation of emulsions adversely affects medical image contrast, and importantly, also makes processing more difficult. Hence, for reasons outlined here above, the foamable composition is not an emulsion. Particularly starting at 10 vol% oil, next to air pockets significant amounts of oil droplets form, and with further increase in oil content, emulsification increases and processibility becomes more challenging. Still, significant amounts of bubbles are formed. By making use of gelling behavior of the aqueous component, even at these higher oil concentrations between 10 and 20 vol.% a stable foam can be provided that remains stable for at least the time convenient for the intended purpose.

[0086] The foamable, echolucent composition preferably comprises 0.005 - 15 vol.%, more preferably 0.01 - 15 vol.%, even more preferably 0.1 - 15 vol.%, and most preferably 0.2 - 15 vol.%, particularly 0.5 - 15 vol.% of oil based on the total volume of the composition. With reference to the experiments herein, at these (more) preferred ranges the number of bubbles increases significantly compared to the foamed, aqueous counterpart without the corresponding oil component; the number increase in bubbles and air pockets corresponds to improved imaging contrast. This link between the number of bubbles and air pockets and imaging strength is in line with the skilled person’s expectations; in the past the FDA also assessed the strength of an cardiac imaging agent like Lumason (sulfur hexafluoride lipid-type A microspheres) in terms of the number of microspheres per ml.

[0087] Still, in order to avoid the disadvantages with emulsification, the amount of oil is preferably less than 15 vol%. That is, the foamable, echolucent composition preferably comprises 0.01 - 15 vol.%, more preferably 0.1 - 15 vol.%, and most preferably 0.2 - 15 vol.%, particularly 0.5 - 15 vol.% of oil based on the total volume of the composition. Further improvements are achieved when the oil component is further reduced; it is preferred that the foamable, echolucent composition comprises 0.01 - 10 vol.%, more preferably 0.1 - 10 vol.%, and most preferably 0.2 - 10 vol.%, particularly 0.5 - 10 vol.% of oil based on the total volume of the composition. It is most preferred that the foamable, echolucent composition comprises 0.01 - 5 vol.%, more preferably 0.1 - 5 vol.%, and most preferably 0.2 - 5 vol.%, particularly 0.5 - 5 vol.% of oil based on the total volume of the composition.

[0088] Preferably, the density of air or gas bubbles in the foamed echogenic composition according to the invention is more than 150*10A3 bubbles / ml, more preferably between 200*10A3 and 10,000* 10A3 bubbles / ml, even more preferably between 1000* 10A3 and 10,000* 10A3 bubbles / ml, most preferably between 2,000* 10A3 and 10,000* 10A3 bubbles / ml. The bubble density may be measured by any means known in the art, for example by optical microscopy. Reference is made to the examples. The bubbles are the active ingredient because the bubble in their entirety provide a direct effect in the diagnosis of fallopian tube patency. That said, the interface between the air and the composition is important; air alone would not be useful for fallopian tube imaging due to interference from image artifacts. When air alone is imaged on ultrasound, image artifacts, such as ring-down artifact, comet-tail artifact, and dirty shadowing.

[0089] The oil can be pharmaceutical oil or a naturally occurring oil, such as aricinoleic acid (12- hydroxy-9-cis-octadecenoic acid ), lesquerolic acid, esters derived from aricinoleic acid and / or lesquerolic acid with glycerol: monoglycerides, di glycerides triglycerides (oil) or ethanol (ethyl esters), poppy seed oil, glycerol esters of poppy seed oil, ethyl esters of poppy seed oil, oils containing tocopherol, tocopheryl esters, tocotrienols, phytosterols, campesterol, stigmasterol, sitosterol, poppy seed oil, ethiodized oil, ethiodized poppyseed oil, palm oil, rice bran oil, wheat germ, olive oil, sunflower oil or almond oil, or mixtures thereof. A preferred example is olive oil.

[0090] The foamable, echolucent composition may comprise further components, preferably selected from disinfectants and / or local anaesthetic. Preferably the further components selected from disinfectants and / or local anaesthetic are present in the foamable, echolucent composition. It is preferred that further components are non-embryotoxic. In one preferred embodiment, the composition comprises local anaesthetic, for example lidocaine and / or chlorohexidine. In an alternative preferred embodiment, the use of local anaesthetic is avoided, and the composition is free of local anaesthetic.

[0091] To ensure that the foambale composition is echolucent, the foamable composition is preferably clear and does not contain particles, protein, or (solid) particulate material, such as starch. In other words, the foamable echolucent composition does not contain any detectable amount of (solid) particulate materials, protein or starch.

[0092] The echolucent composition turns echogenic when foamed, i.e. when air or gas bubbles are inserted in the echolucent composition, for example mechanically. Without wishing to be bound to a theory, it is believed that air or gas bubbles improve image contrast. Additionally, it was surprisingly found a small amount as characterized here above enhanced image contrast compared to the same composition devoid of oil. Another advantage of the foamed echogenic composition of the invention is that the viscosity is ideal to minimise patient discomfort, while at the same time avoid any leakage during the medical exam. In order to optimize the stable formation of gas bubbles or pockets it is preferred to refrain from adding surfactants to the foamable composition before creating bubbles, or to the foamed composition after mixing water and / or oil together with air or gas into the foamable, echolucent composition.

[0093] Therefore in a second aspect, the invention pertains to a foamed, echogenic, image-enhancing composition comprising a gelling agent, water, and a small amount of oil and with air or gas bubbles entrapped therein, which foamed composition is obtained from foaming the foamable, echolucent composition as described here above. The foamed, echogenic, image-enhancing composition comprises the foamable, echolucent composition described above and air or gas bubbles. The foamed, echogenic, image-enhancing composition is directly obtainable by (mechanically) mixing water and / or oil together with air or gas into the foamable, echolucent composition described above. Therefore, the skilled person will understand that the preferred features describes above concerning the foamable, echolucent composition apply to the foamed, echogenic, image-enhancing composition as well. The foamed, echogenic, imageenhancing composition preferably does not contain particles, protein, or (solid) particulate material, such as starch. The foamed, echogenic, image-enhancing composition is distinct from those prior art medical imaging compositions comprising non-settling powdered agents suspended therein.

[0094] In the context of the invention, the gas bubbles are dispersed in the aqueous continuous phase. The structure of the foam is described by the density of the foam combined with the bubble diameter distribution. Foams are highly compressible media wherein the flow characteristic is not adequately described by the viscosity, like in liquids. In such context, the term apparent viscosity is used and is a function of foam density and bubble diameter distribution.

[0095] In order to achieve easier handling of the imaging composition in the fallopian tubes, it is preferred that the size of the bubbles is smaller than the passage diameter, whereby the fluidity is increased as the bubbles are able to deform in order to pass each other. If the ratio between the passage diameter and the bubble diameters is large, the slip velocity is not only dependent on shear stress at the wall of the passage but also on the passage diameter, which causes the fluidity to increase. The inventors thus realized that rheological properties in particular the high deformability and high fluidity of a foam make it particularly suitable for establish filling of the fallopian tubes at low applied pressure. It is preferred that the air or gas bubbles in the foamed echogenic composition of the invention have an average diameter between 5 and 40 pm, more preferably between 5 and 20 pm, as determined for instance by using optical microscopy.

[0096] The closed cell structure of a foam is produced from bubbles, after which a stable foam is obtained as a highly flexible, compressible and fluid body, which does not release bubbles as result of the viscoelastic forces. After use the foam will dissolve in a defoaming process, leaving only a small amount of liquid.

[0097] One of the advantages of the composition according to the invention is that the foam is maintained for a time sufficiently long to perform imaging without loss of echogenicity, and without the need for replenishment. The bubbles maintained in the foamed echogenic composition render it ‘milky’ or ‘white’ appearance. The air or gas bubbles inserted into the foamed echogenic composition are maintained within the composition for at least 1 minute, more preferably at least 2 minutes, most preferably at least 5 minutes, preferably 5 - 60 minutes, after initiating foaming. Over the above time periods, the foam is stable, meaning that the composition retains its excellent echogenic properties over that time.

[0098] Foaming increases dynamic fluidity and improves the ease with which the fallopian tubes can be filled with the composition. Advantageously, the composition is sufficiently viscous to provide a stable distribution of air or gas bubbles during examination, while at the same time its viscosity is low enough to be inserted into the fallopian tubes without excessive force and associated pain for the patient. Hence, the composition does not interfere with the diagnosis whether the fallopian tubes are open or closed.

[0099] The viscosity of the foamed, echogenic, image-enhancing composition is important to ensure minimal patient discomfort and minimal leaking during medical imaging. The viscosity of the foamable, echolucent composition of the invention is preferably less than 4000 cP, more preferably between 1500 and 4000 cP as measured as described above, at 20 °C. The viscosity of the foamed, echogenic, image-enhancing composition may be readily set by the medical examiner (gynaecologist) when preparing the foam, depending on the application. The increased fluid dynamics are particularly preferred when examining the fallopian tubes after fallopian tube sterilization surgery. At lower viscosities, the risk of pressure build-up, pain and potential damage to the tubes is avoided. The lower viscosities may however necessitate catheters. The viscosity of the foamed, echogenic, image-enhancing composition is preferably less than 1500 mPa.s, more preferably less than 1000 mPa.s, even more preferably less than 750 mPa.s, even more preferably less than 500 mPa.s. It is preferred that the viscosity of the foamed, echogenic, image-enhancing composition is more than 10 mPas, even more preferably more than 50 mPas. At this viscosity, leakage of image enhancing composition is minimized, and foam stability is guaranteed. The viscosity is measured by standard viscosity determination methods (such as Brookfield rotational viscometry), and it is measured at room temperature (20 °C) and under atmospheric pressure.

[0100] The composition may be used in connection with catheters known in the art. Excellent results are obtained with the sealing stopper and assembly disclosed in W02007 / 030002, its contents herein incorporated by reference.

[0101] Fertility enhancing effects have been ascribed to the gel composition according to EP1793860, which - without wishing to be bound to any theory - are associated with the lubricating effect of the composition. The same fertility enhancing effects are expected for the present composition. For this reason, both the foamable, echolucent composition and the foamed, echogenic, image-enhancing composition are preferably non-embryotoxic. In other words, the foamable, echolucent composition and the foamed, echogenic, image-enhancing composition of the invention do not contain any ingredients that may hamper, interfere or adversely affect embryo implantation, growth and / or development.

[0102] Method of performing patency test

[0103] Related to the above, the invention also concerns a method for enhancing contrast of an image of fallopian tubes, comprising:

[0104] (a) introducing a foamed, echogenic, image-enhancing composition as described herein into the fallopian tubes of a patient,

[0105] (b) scanning the patient using imaging technology, wherein said air or gas bubbles are maintained in the foamed composition for at least 1 minute after initiating foaming, preferably for at least 2 minutes, more preferably for at least 5 minutes.

[0106] The method is preferably for imaging the shape and / or size and / or for diagnosing abnormalities of fallopian tubes in a patient. The foamed, echogenic, image-enhancing composition of the invention may be used for all types of medical imaging, including echography, and ultrasound imaging. Preferably the imaging is ultrasound imaging, more preferably 3 -dimensional ultrasound imaging. In one embodiment, the compositions of the invention are used in 2D, 3D or 4D sonohysterography.

[0107] A medium comprising the foamed, echogenic, image-enhancing composition of the invention may be administered or introduced in the patient’s fallopian tubes by methods known in the art. The composition is typically administered via an instillation device, such as a catheter. The method comprises introducing the foamed, echogenic, image-enhancing composition in small aliquots in the patient’s fallopian tubes. The skilled person is able to set the amount to be administered. Typically, 1 - 10 ml of foamed, echogenic, image-enhancing composition is sufficient. Constant infusion is not necessary, as the composition of the invention is viscous enough not to leak.

[0108] In a preferred embodiment, the invention pertains to the use of the foamed, echogenic, imageenhancing composition in a patency test, i.e. to determine whether the fallopian tubes are open or closed. A patency test may be performed in case of infertility. The composition of the invention can also be applied in a control of anti -conception methods known in the art, particularly in combination with Adiana®, Essure® and OvabLoc® intratubal devices, and devices developed by Femasys (FemBloc) and Altrascience. Typically such a test is performed within 3 to 6 months after fallopian tube sterilization surgery or intratubal placement.

[0109] Method o f preparing the foamed, echogenic, image-enhancing composition

[0110] The present invention also pertains to a method for preparing the foamed, echogenic, imageenhancing composition by

[0111] (a) mixing a gelling agent, water, and optional further components to obtain a foamable, echolucent composition, and

[0112] (b) inserting air or gas in said foamable, echolucent composition (i.e. foaming) by mixing the foamable, echolucent composition with an aqueous and / or oil composition(s) comprising (sterile) air or gas, wherein the foamed, echogenic composition obtained in step (b) comprises 0.005 - 15 vol.% oil based on the original volume of all compositions mixed-to-be-foamed in step (b) altogether. The oil can be part of the foamable, echolucent composition prepared in step (a) and / or mixed into the foamable, echolucent composition in step (b), provided that the sum of the total amount of oil is 0.005 - 15 vol.% oil based on the volume of the foamable, echolucent composition, and wherein the foamed, echogenic, image-enhancing composition has a viscosity within acceptable levels as defined herein.

[0113] The “insertion” of air or gas can be realized by all means that result in foaming. Preferably air or gas is inserted mechanically, for example by pumping air into a syringe filled with the aqueous and / or oil composition.

[0114] In a most preferred embodiment, the invention concerns a method for preparing a foamed, echogenic, image-enhancing composition according to the first aspect of the invention, comprising:

[0115] (a) providing a first foamable, aqueous echolucent composition comprising a gelling agent, water, and optional further components but, if any, less than 0.005 vol% oil, the composition having a viscosity of at least 1500 cP, as measured using Brookfield rotational viscometry at 20 °C, and

[0116] (b) mixing a second aqueous composition comprising (sterile) air or gas and oil into the composition provided in (a), thus obtaining a foamed, echogenic composition comprising 0.005 - 20 vol.% oil based on the sum of the volume of the first and second composition, and wherein the foamed, echogenic, image-enhancing composition has a viscosity within acceptable levels as defined herein.

[0117] The second composition which is mixed into the foamable composition in step (b) is preferably an aqueous composition with the limited amount of oil according to the invention, which means that the oil is added to the first, oil-free composition immediately prior to foaming, that is in mixing step (b). The term ‘oil-free’ is preferably understood that there is less than 0.005 vol% oil, more preferably less than 0.001% oil, based on the sum of the volume of the first and second composition.

[0118] Although there are no limitations regarding the ways to insert air or bubbles into the foamable, echolucent composition, this is preferably achieved by pumping the composition (b) comprising (sterile) air or gas using a syringe. Preferably the composition that is mixed into the foamable composition is an aqueous composition which comprises or consists of demineralised or purified water or a saline salt solution. The aqueous composition may however comprise a buffering agent. Conveniently, foam may be realized by the practitioner or assistant in the presence of the patient immediately prior to (medical) imaging of the fallopian tubes, preferably by

[0119] (a) connecting a first syringe (cylinder / piston), containing a predetermined amount of the foamable, echolucent composition, with a second syringe filled with the predetermined amount of the second composition comprising (sterile) air or gas and oil; and

[0120] (b) pumping the contents of the second syringe and the first syringe back and forth, thus mixing until a suitable foam in is formed, and a foamed, echogenic, image-enhancing composition is thus obtained.

[0121] The syringes may be connected using any connecting means, such as simple (medical) tubing, optionally with a mixing chamber in-between. The mixing chamber has an outlet for dispensing the foamed composition. The device may be used in combination with standard intrauterine catheters. When the additional oil is provided by the second syringe comprising a predetermined amount of an aqueous composition comprising (sterile) air or gas, and oil, the second syringe may first have been prepared by the practitioner or his or her assistant by mixing a syringe filled with a predetermined amount of an aqueous composition comprising (sterile) air or gas, with a predetermined amount of oil, for instance provided in a separate syringe or sterile container.

[0122] In a preferred embodiment, the oil provided by mixing the foamable, echolucent composition of step (a) and the composition mixed into the foamable, echolucent composition in step (b) is 0.01 - 15 vol.% oil based on the total volume of the foamable, echolucent composition and the composition added thereto, preferably 0.1 - 15 vol%, most preferably 0.2 - 15 vol.%, particularly 0.5 - 15 vol.%. Even more preferred, there is 0.01 - 10 vol.% oil based on the total volume of the foamable, echolucent composition and the composition added thereto, preferably 0.1 - 10 vol%, most preferably 0.2 - 10 vol.%, particularly 0.5 - 10 vol.%. As evidenced in the experimental parts, while an improvement was indeed observed already at 0.005 vol.% oil compared to the oil-free counterpart, bubble densities and associated imaging contrast increased when the amount of oil was at least 0.01 vol.%, more preferably at least 0.1 vol.%, even more preferably at least 0.2 vol.%, even more preferably at least 0.5 vol.%. In order to avoid the disadvantages with emulsification, the amount of oil is preferably less than 10 vol%, even more preferred less than 5 vol%. That is, the foamable, echolucent composition preferably comprises 0.01 - 10 vol.%, more preferably 0.1 - 10 vol.%, and most preferably 0.2 - 10 vol.%, particularly 0.5 - 10 vol.% of oil, particularly 0.01 - 10 vol.% of oil, based on the total volume of the foamable, echolucent composition and the composition added thereto. Preferably, the composition comprises 0.1 - 5 vol.%, and most preferably 0.2 - 5 vol.%, particularly 0.5 - 5 vol.% of oil, based on the total volume of the foamable, echolucent composition and the composition added thereto.

[0123] The relative amounts of the foamable, echolucent composition and the composition comprising (sterile) air or gas (all or partly comprised in the composition) are selected such that the end viscosity is within the desired range and sufficiently foaming is established. This may conveniently be assessed by the medical practitioner, and he / she may adjust the amount of air / gas and aqueous composition mixed with the foamable, echolucent composition according to his / her needs.

[0124] Kit of parts

[0125] The invention also pertains to a kit of parts, comprising a first chamber or syringe with a predetermined amount of a foamable, echolucent, composition comprising

[0126] (i) a first chamber or syringe with a predetermined amount of a foamable, echolucent, composition comprising a gelling agent, and water and optionally oil, the composition having a viscosity of at least 1500 cP, as measured using Brookfield rotational viscometry at 20 °C,

[0127] (ii) a second chamber or syringe with a predetermined amount of an aqueous composition, the composition optionally comprising (sterile) air or gas (in an amount sufficient for foaming the composition (i)), and optionally comprising oil, and

[0128] (iii) optionally a third chamber or syringe with oil, provided that the sum of the total amount of oil comprised in (i), (ii) and optional (iii) is 0.005 - 20 vol.% oil based on the volume of the compositions of (i), (ii) and optional (iii), and wherein the kit optionally further comprises a mixing chamber suitable for mixing the content of the different chambers or syringes. The gas or air in (ii) is optional since the necessary gas or air for foaming purposes is preferably provided for using the mixing chamber including tubing for connecting the syringes. The total amount of oil provided by (i), (ii) and (iii) is preferably between 0.01 - 15 vol.% oil based on the sum of the volume of (i), (ii) and (iii), preferably 0.1 - 15 vol%, most preferably 0.2 - 15 vol.%, particularly 0.5 - 15 vol.%. In order to avoid the disadvantages with emulsification, the amount of oil is preferably less than 10 vol%, even more preferred less than 5 vol%. That is, the total amount of oil provided by (i), (ii) and (iii) is preferably 0.01 - 10 vol.%, more preferably 0.1 - 10 vol.%, and most preferably 0.2 - 10 vol.%, particularly 0.5 - 10 vol.% of oil. Preferably, the total amount of oil provided bv (i), (ii) and (iii) is 0.1 - 5 vol.%, and most preferably 0.2 - 5 vol.%, particularly 0.5 - 5 vol.%.

[0129] In the context of the invention, the mixing chamber may be a means for connecting two syringes. An example of mixing chamber is a piece of medical tubing.

[0130] In one embodiment, the kit comprises (i) and (ii) and no (iii), and all oil is provided in the second chamber or syringe (i.e. no oil is present in (i)), and the kit optionally further comprises a mixing chamber suitable for mixing the content of the first and second chambers or syringes. In a preferred embodiment, the kit comprises (i), (ii) and (iii), and all oil is provided in the third chamber or syringe (i.e. no oil is present in (i) and (ii)), and the kit optionally further comprises a mixing chamber suitable for mixing the content of the chambers or syringes. In both embodiments described in this paragraph, it is preferred that the composition (i) essentially consists of water, hydroxyethyl cellulose and optionally glycerol, wherein the amount of hydroxyethylcellose is preferably 0.5 - 5 wt%, more preferably 1-5 wt% of the composition (i), and glycerol - if any - is present in an amount of 0 - 20 wt%, more preferably 1 - 15 wt% of the composition (i). The viscosity of composition (i) is preferably less than 4000 cP, more preferably at least 1500 cP (between 1500 and 4000 cP).

[0131] The oil according to the invention may be present in the first and / or the second chamber. However, for reason of shelf stability, it is preferred that the oil is provided in (iii) a separate container which is first added to (ii) and mixed into (i) together immediately prior to use. The composition (i) may be described as in the paragraph here above.

[0132] The mixing chamber may be as defined here above. It is preferred to use the same mixing chamber for all mixing steps. The kit may be accompanied by guidelines for directing the practitioner or assistant to first mix the second and third chambers or syringes, and then mix the combined content of the second and third chambers or syringes with the first chamber or syringe, in order to prepare a foamed, echogenic image-enhancing composition.

[0133] The entire kit can be disposed of after preparing the foam and the treatment / examination has taken place. The skilled person will understand that the above-described features pertaining to the foamable, echolucent composition according to the invention are applicable to the foamable echolucent composition in the method for performing a patency test, in method for making a foamed, echogenic, image-enhancing composition, and in the kit of parts according to the invention.

[0134] EXAMPLE 1

[0135] This example aimed to assess and compare the echogenicity of ExEm® compositions to which small amounts of poppy seed oil was added, generating approximately 10 ml compositions. Foam with oil compositions were generated by removing the plunger of the syringe containing the oil with water and adding the oil. After this, foam (based on ExEm®gel, water and oil) was generated by mixing 10 times, ensuring uniform distribution of foam. Foamed ExEm® (i.e. based on ExEm®gel, and water without oil) served as a control. The size and density of air pockets was studied using a microscope. The results are reported in table 1. Table 1. ExEm® compositionsAto which poppyseed oil was added sterile clear viscous gel containing hydroxyethylcellulose, glycerine, buffered with acetic acid [Exem® (GISKIT MD B.V. and GISKIT PHARMA B.V.)]

[0136] It was noticed that the compositions with 16.67% and 25% oil were more difficult to handle, more oily, and a substantive amount of oil droplets next to air pockets were obtained. Microscopic analysis showed that after adding oily substances, the foam bubbles appeared as stable black rings with white centres indicating clean air bubbles. Smaller grey bubbles were also visible and corresponded to the added oils. As the volume of poppyseed oil increased, emulsification was observed causing the bubbles to separate, with oil bubbles settling at a lower level than the ExEm® Foam bubbles. At these higher oil concentrations, separation may lead to dilution effects; bubble diameter increased while bubble count decreased. This effect was attributed to the presence of larger water / oil bubbles, which contributed to a higher average diameter. Furthermore, as these larger bubbles are unable to pass through the aperture, they reduced the overall bubble count.

[0137] Still, in all events the bubble densities remained stable for a period of at least 5 minutes. Imaging still resulted in acceptable results. ExEm® foam without any oil had an average air pocket diameter of 45 pm, and 140*10A3 bubbles / ml. Small amounts of oil increased the number of air pockets (bubbles / ml), improvements already visible at 0.005 vol% oil.

[0138] In Table 2 below the time stability of the ExEm®foam (0% oil) and 4.76 vol% oil was compared in terms of the number of bubbles per ml (and mean diameter between brackets):

[0139] Table 2 - time stability of ExEm®foam (0% oil) and 4.76 vol% oil poppy seed oi

[0140] Using small amounts of oil, droplet size was stabilized. EXAMPLE 2

[0141] Subsequently, the samples prepared in example 1 were injected into a custom made PVCP ultrasound phantom. PVCP Ultrasound Phantom A self-made PVCP ultrasound phantom was utilized for injecting and visually inspecting the echogenicity of the samples. The PVCP material mimicked the acoustic properties of human tissue, enabling accurate representation of ultrasound interactions with the injected substances. The phantoms are constructed with an of- the-shelf PVCP (BrightBaits, Belgium;. A 60%wt Liquid Plastic - Strong (BrightBaits, Belgium) with 40 %w / w Liquid Plastic - Softener (BrightBaits, Belgium) were mixed together until a homogenous milky white substance was obtained. After this the mixture was heated in the microwave to at least 180 °C rendering the material transparent. A ceramic cup was used for a mould in which a 3 mm iron rod was fixated in to create a cavity that mimics the fallopian tube.

[0142] With all of the compositions acceptable contrast was obtained. The ultrasound image after combining ExEm® Foam with 500 pL of Poppy seed Oil revealed a significant increase in bubble formation as evident from figure 1; it showed a larger and more prominent bright white area below the uterine lining compared to ExEm® Foam alone, suggesting improved visibility. ExEm® Foam with poppyseed oil retained bubbles even after 20 minutes, whereas ExEm® Foam alone appeared completely dark, indicating bubble dissipation. This suggests that the addition of poppyseed oil enhanced bubble stability and prolonged bubble presence, thus improving ultrasound contrast. Furthermore, the dead zone, where ultrasound signals are lost due to wave reflections, appeared reduced. This may have resulted from the formation of smaller, more numerous bubbles, which increased echogenicity and enhanced signal scattering. As illustrated in Figure 2, after 20 minutes, ExEm® foam combined with 500 pl of Poppyseed oil maintained higher contrast than ExEm® Foam, further supporting its improved ultrasound performance.

[0143] It was visually observed that over the range of 0.005 vol.% to 9.09 vol.% the viscosity behavior of the foamed oil-containing compositions was similar if not identical, i.e. below 500 mPas.

[0144] EXAMPLE 3

[0145] This study explored enhancing ExEm® Foam by incorporating oily substances to improve bubble formation, stability, and ultrasound visibility (HyFoSy). Materials and methods

[0146] Five samples of ExEm® Foam (based on ExEm®gel and water) were analyzed using a Multisizer 4e. Foam was prepared by repeatedly passing the solution through the kit coupling part. A 1 mL sample was then transferred to the Multisizer beaker within 5 minutes to ensure accuracy. All equipment was cleaned with ISOTON after each test to avoid contamination.

[0147] Oily substances tested:

[0148] • Lipiodol Ultra Fluid (Guerbet)

[0149] • 100% Poppy Seed Oil (Cemil Efendi)

[0150] • White Oil (SILICONES and more)

[0151] • Olive Oil (Albert Heijn NL)

[0152] • Sunflower Oil (Albert Heijn NL)

[0153] Samples were prepared by mixing oily substances into the foam using a syringe, then analyzed with the Multisizer. Each oily substance had a fresh setup and accuvette. Cleaning was done thoroughly between tests. A time-dependent test with poppyseed oil was also performed at 0, 2, 5, and 10 minutes to measure bubble stability over time.

[0154] From each lipid-modified ExEm® Foam sample, 200 pL was collected during Multisizer analysis and placed on glass slides. Covered with coverslips, the samples were examined under a microscope (4x magnification) to observe bubble structure and distribution.

[0155] Results and Discussion

[0156] By measuring bubble count and average bubble size, the study assessed foam stability and structure. Microscopy showed an increase in bubble formation after adding oils, while ultrasound imaging confirmed improved performance in a simulated setting. There was no significant difference between the microscopy results obtained with 200 pl Lipiodol, poppy seed oil, white oil, olive oil and sunflower oil. Together, these results demonstrated how oily substances influence the formation, stability, and imaging quality of the foam.

[0157] For bubble count and mean bubble size, reference is made to Table 3. For all oils, the minimum mean diameter of the droplets was about 10 pm, compared to the minimum mean diameter of 45 pm for ExEm®Foam. Table 3 presents the effect of various oily substances on bubble count, mean diameter, and stability of ExEm® Foam. Among the tested substances, poppyseed oil demonstrated the highest bubble count and the most stable performance over 10 minutes, while baseline ExEm® Foam showed rapid degradation and large initial bubbles.

[0158] Table 3 - Bubble Formation and Stability with Oily Substances in ExEm® Foam

[0159] The results indicated that ExEm® Foam alone generates a substantial number of bubbles, but the addition of various oily substances enhances bubble formation while reducing their diameter.

[0160] EXAMPLE 4

[0161] The study of example 3 was repeated with the following 2 oil samples:

[0162] • Super Refined Soybean Oil-LQ-(MH)

[0163] • Super Refined Castor Oil-LQ-(MH) (CRODA)

[0164] Samples were prepared by mixing oily substances into ExEm® Foam (based on ExEm®gel and water) using a syringe, then analyzed with the Multi sizer. Each oily substance had a fresh setup and accuvette. Cleaning was done thoroughly between tests.

[0165] The results are plotted in Table 4. For both oils, the minimum mean diameter of the droplets was about 12-15 pm, compared to the minimum mean diameter of 45 pm for ExEm®Foam. Table 4 - Bubble Count and Mean Diameter with EU-compliant oils in ExEm® Foam

[0166] The findings of this study demonstrated that the integration of Super Refined Soybean Oil and Super Refined Castor Oil into ExEm® Foam significantly improved bubble formation, with a notable increase in bubble count and a reduction in mean diameter.

Claims

CLAIMS1. A foamable, echolucent composition, wherein the composition comprises(i) a gelling agent comprising xanthan gum, a hyaluronic acid, a cellulose derivative, or a combination thereof, wherein the cellulose derivative is selected from methyl-cellulose (MC), ethyl-cellulose (EC), hydroxyethyl-cellulose (HEC), hydroxypropyl-cellulose (HPC), hydroxypropyl- methyl-cellulose (HPMC), hydroxypropyl-ethyl-cellulose (HPEC), ethyl-hydroxy-ethyl-cellulose (EHEC), hydroxyethyl-methyl-cellulose (HEMC), most preferably HEC,(ii) water, and(iii) between 0.005 and 20 vol.% oil based on total volume of the composition, wherein the composition turns echogenic when foamed, wherein the composition has a viscosity of at least 1500 cP, and wherein the composition turns echogenic when foamed.

2. The foamable, echolucent composition according to claim 1, comprises 0.01 - 15 vol.% of oil, preferably 0.1 - 15 vol%, most preferably 0.2 - 15 vol.%, particularly 0.5 - 15 vol.%.

3. The foamable, echolucent composition according to claim 2, comprising 0.01 - 10 vol.% of oil, more preferably 0.1 - 10 vol.%, and most preferably 0.2 - 10 vol.%, particularly 0.5 - 10 vol.%.

4. A foamed, echogenic, image-enhancing composition, wherein the composition comprises(i) a gelling agent comprising xanthan gum, a hyaluronic acid, a cellulose derivative, or a combination thereof, wherein the cellulose derivative is selected from MC, EC, HEC, HPC, HPMC, HPEC, EHEC, HEMC, most preferably HEC,(ii) water,(iii)between 0.005 and 20 vol.% oil based on total volume of the composition, and(iv) air or gas bubbles, wherein the composition has a viscosity of less than 1500 cP, most preferably 50 - 500 cP.

285. The foamed, echogenic composition according to claim 4, comprises 0.01 - 15 vol.% of oil, preferably 0.1 - 15 vol%, most preferably 0.2 - 15 vol.%, particularly 0.5 - 15 vol.%, and more preferably the foamed, echogenic composition comprises 0.01 - 10 vol.% of oil, more preferably 0.1 - 10 vol.%, and most preferably 0.2 - 10 vol.%, particularly 0.5 - 10 vol.%.

6. The foamed, echogenic composition according to any one of claims 4-5, wherein the composition is obtainable by foaming the foamable, echolucent composition according to any one of claims 1 - 3.

7. The foamed, echogenic composition according to any one of claims 4 - 6, wherein the composition is non-embryotoxic.

8. A method for enhancing contrast of an image of fallopian tubes, comprising:(a) introducing a foamed, echogenic, image-enhancing composition according to any one of claims 4 - 7 into the fallopian tubes of a patient,(b) scanning the patient using imaging technology, wherein said air or gas bubbles are maintained in the foamed composition for at least 1 minute after initiating foaming.

9. A method for preparing a foamed, echogenic, image-enhancing composition, comprising:(a) mixing a gelling agent, water, and optional further components to obtain a foamable, echolucent composition, wherein the gelling agent comprises xanthan gum, a hyaluronic acid, a cellulose derivative, or a combination thereof, wherein the cellulose derivative is selected from MC, EC, HEC, HPC, HPMC, HPEC, EHEC, HEMC, most preferably HEC; and(b) inserting air or gas in said foamable, echolucent composition (i.e. foaming) by mixing the foamable, echolucent composition with an aqueous and / or oil composition(s) comprising (sterile) air or gas, wherein the foamed, echogenic composition obtained in step (b) comprises 0.005 - 20 vol.% oil based on the original volume of all compositions mixed-to-be-foamed in step (b) altogether, wherein the foamed, echogenic, image-enhancing composition preferably has a viscosity of less than 1500 cP, more preferably 50 - 1000 cP, most preferably 50 - 500 cP.

10. The method according to claim 9, comprising:(a) providing a first foamable, aqueous echolucent composition comprising a gelling agent, water, and optional further components but, if any, less than 0.005 vol% oil, the composition having a viscosity of at least 1500 cP, and(b) mixing a second aqueous composition comprising (sterile) air or gas and oil into the composition provided in (a), to obtain a foamed, echogenic composition comprising 0.005 - 20 vol.% oil based on the sum of the volume of the first and second composition, and wherein the foamed, echogenic, image-enhancing composition preferably has a viscosity of less than 1500 cP, more preferably 50 - 1000 cP, most preferably 50 - 500 cP.

11. The method according to claim 10, wherein the amount of oil in the second composition is 0.01 - 15 vol.%, preferably 0.1 - 15 vol%, most preferably 0.2 - 15 vol.%, particularly 0.5 - 15 vol.% based on the sum of the volume of the first and second composition, and more preferably the amount of oil in the second composition is 0.01 - 10 vol.% of oil, more preferably 0.1 - 10 vol.%, and most preferably 0.2 - 10 vol.%, particularly 0.5 - 10 vol.%.

12. A kit of parts, comprising(i) a first chamber or syringe with a predetermined amount of a foamable, echolucent, composition comprising a gelling agent, and water and optionally oil, wherein the gelling agent comprises xanthan gum, a hyaluronic acid, a cellulose derivative, or a combination thereof, wherein the cellulose derivative is selected from MC, EC, HEC, HPC, HPMC, HPEC, EHEC, HEMC, most preferably HEC, the composition having a viscosity of at least 1500 cP,(ii) a second chamber or syringe with a predetermined amount of an aqueous composition optionally comprising (sterile) air or gas, and optionally comprising oil, and(iii) optionally a third chamber or syringe with oil, provided that the sum of the total amount of oil comprised in (i), (ii) and optional (iii) is 0.005 - 20 vol.% oil based on the volume of the compositions of (i), (ii) and optional (iii), and wherein the kit optionally further comprises a mixing chamber suitable for mixing the content of the different chambers or syringes.

13. The kit according to claim 12, comprising(i) and (ii) and no (iii), wherein the amount of oil, if any, in (i) is less than 0.001 vol.%, and all oil is provided in (ii) the second chamber or syringe; or(i), (ii) and (iii), wherein the amount of oil, if any, in (i) and (ii) is less than 0.001 vol.%, and all oil is provided in (iii) the third chamber or syringe; and wherein the kit optionally further comprises a mixing chamber suitable for mixing the content of the chambers or syringes.

14. The kit according to claim 12 or 13, wherein the sum of the total amount of oil comprised in (i), (ii) and optional (iii) is 0.01 - 15 vol.%, preferably 0.1 - 15 vol%, most preferably 0.2 - 15 vol.%, particularly 0.5 - 15 vol.%, and more preferably the sum of the total amount of oil comprised in (i), (ii) and optional (iii) is 0.01 - 10 vol.% of oil, more preferably 0.1 - 10 vol.%, and most preferably 0.2 - 10 vol.%, particularly 0.5 - 10 vol.%.

15. The kit according to any one of claims 12 - 14, wherein the oil is provided in (iii) a separate container, and the kit is accompanied by guidelines for directing the practitioner or his or her assistant to first mix (ii) and (iii), and mixing the combined content of (ii) and (iii) with (i), in order to prepare a foamed, echogenic imageenhancing composition.

Images